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YALE UNIVERSITY

MRS. HEPSA ELY SILLIMAN MEMORIAL LECTURES


IRRITABILITY




SILLIMAN MEMORIAL LECTURES

PUBLISHED BY YALE UNIVERSITY PRESS


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IRRITABILITY, A PHYSIOLOGICAL ANALYSIS OF THE GENERAL EFFECT OF STIMULI
IN LIVING SUBSTANCE. _By_ MAX VERWORN, M.D., PH.D., _Professor at Bonn
Physiological Institute_.

_Price $3.50 net; postage 20 cents extra._




                             IRRITABILITY

                A PHYSIOLOGICAL ANALYSIS OF THE GENERAL
                 EFFECT OF STIMULI IN LIVING SUBSTANCE

                                  BY

                       MAX VERWORN, M.D., PH.D.

              _Professor at Bonn Physiological Institute_

                    WITH DIAGRAMS AND ILLUSTRATIONS

                            [Illustration]

                   NEW HAVEN: YALE UNIVERSITY PRESS
                         LONDON: HENRY FROWDE
                        OXFORD UNIVERSITY PRESS
                                MCMXIII




                            COPYRIGHT, 1913
                       BY YALE UNIVERSITY PRESS

                  First Printed May, 1913, 600 Copies




THE SILLIMAN FOUNDATION.


In the year 1883 a legacy of eighty thousand dollars was left to the
President and Fellows of Yale College in the city of New Haven, to be
held in trust, as a gift from her children, in memory of their beloved
and honored mother, Mrs. Hepsa Ely Silliman.

On this foundation Yale College was requested and directed to establish
an annual course of lectures designed to illustrate the presence and
providence, the wisdom and goodness of God, as manifested in the
natural and moral world. These were to be designated as the Mrs. Hepsa
Ely Silliman Lectures. It is the belief of the testator that any
orderly presentation of the facts of nature or history contributed
to the end of this foundation more effectively than any attempt to
emphasize the elements of doctrine or creed; and he therefore provided
that lectures on dogmatic or polemical theology should be excluded from
the scope of this foundation, and that the subjects should be selected
rather from the domains of natural science and history, giving special
prominence to astronomy, chemistry, geology, and anatomy.

It was further directed that each annual course should be made the
basis of a volume to form part of a series constituting a memorial
to Mrs. Silliman. The memorial fund came into the possession of the
corporation of Yale University in the year 1901; and the present volume
constitutes the ninth of the series of memorial lectures.




PREFACE


The lectures on irritability here published were held at the University
of Yale in October, 1911. When the authorities of that University
honored me by an invitation to give a course of Silliman memorial
lectures, I accepted with the more pleasure as it furnished me with
the opportunity of summarizing the results of numerous experimental
researches carried out with the assistance of my co-workers during
the course of more than two decades in the physiological laboratories
of Jena, Göttingen and Bonn, to unite therewith the results obtained
by other investigators and thus present a uniform exposition of the
general effects and laws of stimulation in the living substance. I have
long entertained this plan and this for the following reason:

The physiologist, the zoölogist, the botanist, the psychologist,
the pathologist, have to deal, day in, day out, with the effects of
stimulation on the living substance. No living substance exists without
stimulation. In the vital manifestations of all organisms the interplay
of the most varied stimuli produces an enormous and manifold variety of
effects. Experimental biological science employs artificial stimulation
as the most important aid in the methodic production of certain effects
of stimulation. The number of researches in which special effects
of stimulation are treated is endless. Nevertheless the systematic
investigation of the effects of stimulation have, curiously enough,
been strangely neglected. Although countless results of individual
effects of stimulation have been studied, the attempt has never been
made to establish a general physiology of the laws of stimulation
and consider it as an independent problem. This circumstance induced
me to systematically investigate the general laws of the effect of
stimulation. In the fifth and sixth chapters of my book on general
physiology the results of these studies are recorded for the first
time. Since then, especially during our own researches on the general
physiology of the nervous system, a great number of new facts of
importance for the general physiology of the effects of stimulation
have been obtained. All these results I have endeavored to combine and
elucidate in the following lectures.

The text of the lectures in its present form was written in German in
1911. The English translation was made by my wife, with the help of
our friend, Dr. Lodholz of the University of Pennsylvania, who also
undertook the reading of the proofs. We wish here to thank him once
again and express our deep appreciation of the great sacrifice of
time and labor involved in this task. I am likewise much indebted to
Dr. Julius Vészi for his assistance unstintingly given, especially in
obtaining a number of curves. Finally, I wish to take this opportunity
to render warmest thanks to the authorities of Yale University, and
especially to President Hadley and Professor Chittenden, as well as
to my special colleagues, for the hospitality and cordial reception
extended to me in New Haven and for the pleasant hours I was privileged
to spend in their midst.

  MAX VERWORN.

  Bonn.

  Physiological Laboratory of the University.




CONTENTS


  I

  _Contents_: Introductory. Earliest period. _Francis Glisson_ as
  founder of the doctrine of irritability. _Albrecht von Haller._ The
  vitalists. _Bordeu_ and _Barthez_. _John Brown’s_ system. _Johannes
  Müller_ and the specific energy of living substance. _Rudolf
  Virchow’s_ doctrine of the irritability of the cell. Discovery of
  the inhibitory effects of stimulation. _Weber_, _Schiff_, _Goltz_,
  _Setschenow_, _Sherrington_. _Claude Bernard_ studies on narcosis.
  Tropisms. _Ehrenberg_, _Engelmann_, _Pfeffer_, _Strassburger_,
  _Stahl_. _Semon’s_ speculations on mneme.                            1


  II

  _Contents_: Principles of scientific knowledge and research. Origin
  and meaning of the conception of cause. Cause and condition.
  Criticism of the conception of cause. The conditional point of view.
  Conception of cause. The conditional point of view applied to the
  investigation of life. Conception of vital conditions. Definition of
  the conception of stimulation.                                      18


  III

  _Contents_: The quality of the stimulus. Positive and negative
  alterations of the factors which act as vital conditions. Extent of
  the alteration in vital conditions or intensity of the stimulus.
  Threshold stimuli, sub-threshold, submaximal, maximal and
  supermaximal intensities of stimulus. Relations between the intensity
  of stimulus and the amount of response. The _Weber_ and _Fechner_
  law. All or none law. Time relations of the course of the stimulus.
  Form of individual stimulus. Absolute and relative rapidity in the
  course of the stimulus. Duration of the stimulus after reaching its
  highest point. Adaptation to persistent stimuli. Series of individual
  stimuli. Rhythmical stimuli. The _Nernst_ law.                      39


  IV

  _Contents_: Various examples of the effects of stimulation.
  Metabolism of rest and metabolism of stimulation. Metabolic
  equilibrium, Disturbances of equilibrium by stimuli. Quantitative and
  qualitative alterations of the metabolism of rest under the influence
  of stimuli. Excitation and depression. Specific energy of living
  substance. Qualitative alterations of the specific metabolism and
  their relations to pathology. Functional and cytoplastic stimuli.
  Relations of the cytoplastic effects of stimuli to the functional.
  Hypertrophy of activity and atrophy of inactivity. Metabolic
  alterations during growth of the cell. Primary and secondary effects
  of stimulation. Scheme of effects of stimulation.                   65


  V

  _Contents_: Indicators for the investigation of the process of
  excitation. Latent period. The question of the existence of
  assimilatory excitations. Dissimilatory excitations. Excitations of
  the partial components of functional metabolism. Production of energy
  in the chemical splitting up processes. Oxydative and anoxydative
  disintegration. Theory of oxydative disintegration. Dependence
  of irritability on oxygen. Experiments on unicellular organisms,
  nerve centers and nerve fibers. Restitution after disintegration by
  metabolic self-regulation. Organic reserve supplies of the cell.
  The question of a reserve supply of oxygen of the cell. Metabolic
  self-regulation as a form of the law of mass effect, and metabolic
  equilibrium as a condition of chemical equilibrium. Functional
  hypertrophy.                                                        87


  VI

  _Contents_: Only processes of excitation are conducted, not
  processes of depression. Conduction of excitation in its two extreme
  instances. Conduction in undifferentiated pseudopod protoplasm of
  rhizopoda. Conduction of excitation with decrement of intensity
  and rapidity. Conduction of excitation in the nerve. Rapidity of
  conduction. Conduction of excitation without decrement. Relation
  between irritability and conductivity. Conduction of excitation with
  decrement of the nerve after artificial depression of irritability by
  narcosis. Theory of the decrementless conduction of the normal nerve.
  Proof of the validity of the “all or none law” in the medullated
  nerve. Theory of the process of the conductivity of excitation.
  Theory of core model (Kernleiter). Electrochemical theory of
  conduction based on the properties of semi-permeable surfaces.     118


  VII

  _Contents_: Conception of specific irritability. Alteration of
  specific irritability during and after excitation. Refractory
  period in various forms of living substance. Absolute and relative
  refractory period. Curve of irritability during refractory period.
  Dependence of the duration of the refractory period on the rapidity
  of the course of the metabolic processes in the living substance.
  Dependence on temperature. Dependence on supply of oxygen. Theory of
  refractory period. Refractory period as basis of fatigue. Fatigue as
  a form of asphyxiation. Alterations of irritability and the course
  of excitation in fatigue. Recovery from fatigue. The rôle played by
  oxygen in recovery. Fatigue as an expression of the prolongation of
  the refractory period conditioned by the relative want of oxygen.
  Fatigue of the nerve.                                              154


  VIII

  _Contents_: Examples of effects of interference of stimuli in
  unicellular organisms. Interference of galvanic and thermic
  stimuli in Paramecia. Interference of galvanic and thermic stimuli
  and narcotics. Interference of galvanic and mechanical stimuli.
  Interference of galvanotaxis and thigmotaxis in Paramecia and hypotin
  infusoria. Real or homotop interference, apparent or heterotop
  interference. The two effects of homotop interference of excitations:
  Summation and inhibition of excitations. Theory of the processes of
  inhibition. _Hering-Gaskell_ Theory. Inhibition as an expression
  of the refractory period. Individual possibilities of interference
  of two stimuli. Interference of an excitating and a depressing
  stimulus. Interference of two depressing stimuli. Interference of two
  excitating stimuli. Analysis of the interference of two excitations.
  Interference of two single stimuli. Conditions upon which the
  result of interference is dependent. Heterobole and isobole living
  systems. Intensity of the two stimuli. Interval between the stimuli.
  Specific irritability and rapidity of reaction of the living system.
  Latent period. Interference of single stimuli in a series. General
  scheme of the development of the effect of interference. Summation
  and inhibition. Apparent increase of irritability. Conditions of
  summation. Tonic excitations. Conditions of inhibitions. Various
  types of inhibition. Interference of two series of stimuli. Relations
  in the nervous system. Peculiarities of the nerve fibers. Conversion
  of the nerve by relative fatigue from an isobolic into a heterobolic
  system.                                                            189


  IX

  _Contents_: Necessity of cellular physiological analysis of toxic
  depressions by pharmacology. Apparent variety of processes of
  depression. Depression of oxydative disintegration as the most
  extended principle in the processes of depression. Asphyxiation,
  fatigue, heat depression, as a consequence of restriction of
  oxydative disintegration. Narcosis. Theories of narcosis. The
  alteration of specific irritability and conductivity in narcosis.
  Depression of oxydative processes in narcosis. Asphyxiation of
  living substance when oxygen is present during narcosis. Persistence
  of anoxydative disintegration in narcosis. Increase of the same by
  stimuli. Depression by narcosis as a form of acute asphyxiation.
  Hypothesis on the mechanism of depression of oxygen exchange by
  narcotics. Possibility of combining the facts with the observations
  of _Meyer_ and _Overton_.                                          235




IRRITABILITY




CHAPTER I

THE HISTORY OF THE SUBJECT

 _Contents_: Introductory. Earliest period. _Francis Glisson_ as
 founder of the doctrine of irritability. _Albrecht von Haller._ The
 vitalists. _Bordeu_ and _Barthez_. _John Brown’s_ system. _Johannes
 Müller_ and the specific energy of living substance. _Rudolf
 Virchow’s_ doctrine of the irritability of the cell. Discovery of
 the inhibitory effects of stimulation. _Weber_, _Schiff_, _Goltz_,
 _Setschenow_, _Sherrington_. _Claude Bernard_ studies on narcosis.
 Tropisms. _Ehrenberg_, _Engelmann_, _Pfeffer_, _Strassburger_,
 _Stahl_. _Semon’s_ speculations on mneme.


Irritability is a _general_ property of living substance but not
exclusively so. Irritable systems also exist in inanimate nature. What
characterizes living substances is not irritability as _such_, but
an irritability of a specific type. The irritability of the living
system can, therefore, not be studied alone, but as the properties of
a living system are dependent upon each other, so this property must
be considered with the others possessed by a living substance. In this
sense irritability presents a problem of fundamental physiological
importance. For if we could analyze the irritability of living
substance to its essence, then the nature of life itself would be
fathomed. The analysis of irritability of living substance offers us,
therefore, a path to the investigation of life and herein lies the
importance of the study of irritability.

I wish to follow this path toward the knowledge of the vital processes
and to endeavor to show in these lectures what information the analysis
of irritability and that of the effect of stimuli can give us of the
mechanism of the processes in living substance. Before doing so,
however, I wish to consider somewhat more in detail the question as to
how we have arrived at the conception of the nature of irritability.

To the thinkers both in the field of physiology and medicine of
ancient and mediæval times the conception of irritability was quite
foreign. Even a comprehension of the nature of stimuli had not yet
begun to crystallize from vague impressions of the various influences
of different agents on the human being. Nevertheless they knew of
such influences of the most varying kinds upon the human body. The
ancients already possessed a materia medica, founded on the real or
supposed influence of various mineral, vegetable and animal substances
upon the organism. It was also known that heat and cold, light and
darkness had an effect upon disease. They likewise believed in the
influence of certain factors upon the health of man, which in reality
have no effect whatsoever, as the stars and the magnet. But neither
in ancient nor in mediæval times was the state of knowledge reached
wherein generalizations were made from these agents, which had a real
or supposed action upon the organism, and to combine these to a general
conception of stimulation.

The conception of stimulation and irritability cannot however be
separated.

The founder of the doctrine of the irritability of living substance
is _Francis Glisson_ (1597–1677), member of the _Collegium Medicum_
in London and at the same time Professor in Cambridge. It is a fact
also not altogether without interest, that _Glisson_ at the same time
was in a certain sense a forerunner of those who interpreted nature
from a physical standpoint. _Glisson_ as an anatomist and physiologist
was an excellent observer and experimenter, but the most prominent
trait of his character was his inclination to philosophic observation
and analysis of nature. His “_Tractatus de natura substantiæ
energetica_”[1] must, therefore, be considered as the chief work of
his life. In this voluminous book _Glisson_ develops an entire system
of natural philosophy, which in accord with the character of the
philosophy of that time is unfortunately of an absolutely speculative
nature and which had hardly emancipated itself from the scholasticism
of the preceding period of thought. When the ideas of _Glisson_ are
isolated from the wilderness of scholastic phraseology, the system
is somewhat as follows. The basis of all existence, “_substance_,”
has according to him two general properties, its “_fundamental
subsistence_,” that is, the essence of its being, and its “_energetic
subsistence_,” that is, the essence of its activity. To these are added
the properties possessed in specific cases, that is, its “_additional
subsistence_.” The energetic subsistence forms the basis of all life.
Life is therefore present not only in organic nature, but in all
nature which is characterized by the union of the general energetic
subsistence with the special additional subsistence of an animal and
vegetable nature. In other forms of life in nature the energetic
subsistence is combined with other special forms of the additional
subsistence. The universal essence of all life, that is the energetic
subsistence, has only three fundamental faculties: the “_appetitiva_,”
the “_perceptiva_” and the “_motiva_.” The _modus_ is the result
of a “_perceptio_,” but the “_perceptio_” is not thinkable unless
the object has the “_appetitus_” to receive the external influence.
_Glisson’s_ doctrine of irritability is based on this conception, which
he develops in a second work already begun before the “_Tractatus de
natura substantiæ_,” but not finished until later and only published
after his death. In this “_Tractatus de ventriculo et intestinis_,”[2]
_Glisson_ dwells in detail on the physiological properties of
animal structures and develops for the first time his conception
of irritability in the chapter “_De irritabilitate fibrarum_.” The
“irritability” manifests itself in the appearance of the alteration of
movement, which is brought about by external influences on the animal
structure, for: “_Motiva fibrarum facultas nisi irritabilis foret,
vel, perpetuo quiesceret, vel perpetuo idem ageret._” The fundamental
factor of this irritability _Glisson_ attributes to the “_perceptio_,”
which he distinguishes as a “_perceptio naturalis_, _sensitiva_ and
_animalis_.” The want of clearness produced here by _Glisson’s_
artificial distinctions and mode of expression is in part removed
if we endeavor to transfer his meaning into our present methods of
thought. This distinction would then simply point out the different
means by which the stimuli can reach the irritable structures. The
“_Perceptio naturalis_” is that which today we should call “direct
response” to stimulation, that is, the excitation of the fiber by
artificial stimuli applied directly to the tissue. _Glisson_ shows
here, that the intestines and muscles in the body immediately after
death and even when removed from the body can be stimulated to movement
by means of corrosive fluids or cold. The “_Perceptio sensitiva_”
is, according to _Glisson_, the excitation of the fibers by external
stimuli which act on the intact body as a whole by way of the sensory
nerves. The “_Perceptio ab appetitu animali regulata_” finally is the
excitation by inner stimuli proceeding from the brain. The _Perceptio
naturalis_ is possessed by all parts of the body, even the fluids,
the bones and the fat. All of them are irritable. But a “vitale” and
a special “animal” irritability they do not possess to a perceptible
degree. These forms of irritability belong only to the special parts
of the body. Here, however, the distinctions made by _Glisson_, are
quite vague and contradictory. In his “_Tractatus de ventriculo et
intestinis_” _Glisson_ sharply distinguishes the “_sensatio_” from the
“_perceptio_.” The perceptio in itself is not a sensation, for although
individual organs of the body are irritable, as they all possess a
“perceptio,” they are not in themselves sensitive. The “_sensatio_,”
the sensation, only arises when the external “_perceptio_” of the
individual organs combine through the nerves with the internal
“perceptio” of the brain. “_Nisi enim percepto externa ab interna simul
percipiatur, non est cognitio sensitiva completa._” Sensitivity is,
therefore, a special faculty, that is only based upon irritability.

  [1] _Franciscus Glissonius_: “Tractatus de natura substantiæ
  energetica seu de vita natura ejusque tribus primis facultatibus
  perceptiva, appetitiva, motiva,” etc. Londini M D C L XXII.

  [2] _Franciscus Glissonius_: “Tractatus de ventriculo et intestinis
  cui præmittitur alius de partibus continentibus in genere et in
  specie de iis abdominis.” Amstelodami M D C L XXVII.

I have treated the views of _Glisson_ somewhat in detail for on the one
hand this seemed to me to be only due to the founder of the doctrine
of irritability, and on the other we have here for the first time,
although in somewhat vague and little worked out form, the discovery
of a general property of all living substance, and its fundamental
importance for the life of the organisms. One might, therefore, in
a _certain_ sense, date from _Glisson_ the beginning of general
physiology, and all the more so, because _Glisson_ from the very
first connected the irritability of the living substance through its
possessing universal energy with the phenomena in nature generally,
just as we do today two hundred years after, on the basis of the modern
teachings of energy.

It might appear strange that a teaching of such fundamental importance
as that of _Glisson’s_ theory of irritability was not at once accepted
on all sides and further developed. There were two reasons, however,
which prevented this. Firstly, _Glisson_ did not devote himself to his
post of teacher at the University of Cambridge with any particular
zeal and so consequently did not establish a school of his own, to
further work out and develop his ideas. Secondly, his doctrines were
so speculative and difficult to understand, his differentiations and
definitions so artificial and labored, that it required the greatest
effort to penetrate to his fundamental conceptions and so it happened
that _Glisson’s_ theory of irritability received attention only at a
comparatively late date. Even then, of his speculative theories hardly
more than the name “doctrine of irritability” was adopted. Since the
middle of the eighteenth century this name, however, was destined to
lead to excited controversies.

The first attempt to give _Glisson’s_ expression “irritability” a more
concrete meaning was made by _Haller_ (1708–1777)[3]. Unfortunately,
though, he confined this conception solely to muscles, in that he
understood by the term irritability “the capability of the muscles to
contract, when stimulated, as the result of vital force (_vi viva_).”
He, therefore, applied the term “irritability” to that which we today
refer to as “contractility.” On the other hand he applied the term
contractility solely to a property possessed by other living and
dead animal as well as vegetable matter, elasticity, that is, the
capability to resume its original form after distortion. He makes a
sharp distinction between “irritability,” which manifests itself by a
contraction of the muscles after stimulation by its own vital force
(_vi viva_), and the “sensitivity,” which is possessed only by the
nervous system. “_Sola fibra muscularis contrahitur vi viva; sentit
solus nervus et quæ nervos acciperunt animales partes._” By confining
the conception of irritability to a single living substance, the
muscle, _Haller’s_ theory represents a great regression in comparison
to the correct fundamental thoughts of _Glisson_. This unfortunate
use of the term of “irritability,” “contractility” and “sensitivity”
has opened wide the gates to confusion and misunderstanding. This
confusion was still further augmented by the fact that the vitalistic
school of Montpelier confused the idea of vital force with that
of irritability. In the works of _Bordeu_ (1722–1776) these views
are comparatively clear, if one bears in mind that he substitutes
_Glisson’s_ term of “_irritability_” with that of “_sensitivity_.” He
assumes a “_sensibilité générale_” or a common property of all living
structures, both solid and fluid. Besides this, each different part
has according to him its “_sensibilité propre_.” Here in place of the
clear conception of irritability we find one of more or less mythical
nature possessing traces of _Stahl’s_ “anima.” Nevertheless we observe
here the idea that all living organisms possess in common a capability
to respond to stimuli. Even though _Bordeu’s_ differentiation of the
“sensibilité propre” and the “sensibilité générale” is too artificial
and the coexistence of both not justifiable, his discussion of the
“sensibilité propre” shows that he is already on the track of the
characteristics of the effect of stimuli which only later under the
name of “specific energy” was clearly recognized as a fundamental
property of all living substance. On the other hand the celebrated
pupil of _Bordeu_, _Barthez_ (1734–1806), accepted the existence of
a meaningless vital principle, the “_principe vitale_,” governing
all vital manifestations. The two forms of vital force of all living
substances, the “_forces sensitives_” and the “_forces motrices_,”
were according to his views manifestations of this vital principle.
He differentiates the “_force sensitive_” into a “_sensibilité avec
perception_” and “_sensibilité sans perception_,” using the term
sensibility in the sense adopted by _Bordeu_ and which today we, with
_Glisson_, call irritability.

  [3] _Albrecht v. Haller_: “Elementa Physiologiæ corporis humani.”
  Tomus IV. Lausannæ M D C L XVI.

In this way serious thinkers of that time trifled with the words
irritability, sensitivity, contractility, perception. This led to
futile conceptions, which equalled the phantasies of the worst period
of speculative philosophy and which in no way led to progress. Hence it
is easy to understand that numerous attempts were made in those days
to reconcile in some way these different conceptions. An explanation,
which was the beginning of further development, came from England in
the works of _John Brown_ (1735–1788),[4] a man who was as talented
as he was dissolute. _Brown_ was an independent thinker, not without
genius, whose knowledge in practice and theory, however, was limited.
This combination in his mentality enabled him to observe the problems
somewhat differently than through the glasses of the usual conceptions
of that time. In direct opposition to his teacher _Cullen_ (1712–1790),
one of the leading minds in the medical school of Edinburgh, who
considered irritability only as an effect of sensibility and pronounced
the latter a specific property of the nervous system, _Brown_ took the
standpoint that all living substance, vegetable as well as animal, in
contrast to lifeless matter, possessed a fundamental property which he
designated as excitability, that is to say, the capability of being
stimulated to specific vital manifestations through external factors
or “stimuli,” in which sensitivity and indeed all mental processes
as well as movement are interpreted as specific effects, which the
“stimuli” produce on the irritable organs. This was an important
advance and from a wilderness of trifling conceptions his observations
led to a clearer knowledge of this subject. But _Brown_ went even
further. In his so-called “theory of irritation,” he has presented
a whole system of responsivity to stimulation, which in the first
chapters of his chief work he expounds with wonderful clearness. The
fundamental principles here established must be accepted even today.
The essential basis of this “theory of irritability” which he worked
out especially for his doctrine of disease, and which has also played
an important part in pathology, is the following: Every living, that
is, excitable system, is continually influenced by stimuli. The stimuli
consist of either external factors, such as heat, food, foreign matter,
poisons, etc., or inner factors which result from the influence of
the activity of one organ upon another. Only as a result of the
continual action of stimuli is life maintained, in that the stimuli
produce continual “excitement” in the irritable substance. The degree
of irritability differs in various plants, animals, in different
structures of the body, and even in the same individual at different
times under different circumstances. The strength of the “excitement”
depends on the one hand upon the degree of irritability, and on the
other upon the strength of the stimulus. The irritability itself is
influenced and changed by the action of the stimuli. If the stimuli are
too strong and are of prolonged duration, the irritability diminishes
as a result of exhaustion; if weak stimuli act during a prolonged
time, the irritability increases. The healthy organism has a mean
degree of irritability. Disease occurs when this state is altered by
_strong_ stimuli or by an _absence_ of stimulation. Disease and health,
therefore, differ not qualitatively but only quantitatively. It is here
seen that we have the first attempt at a systematic interpretation
of the effects of stimulation, and it is astonishing how sharply and
successfully _Brown_ has pointed out the foundations of this important
field. He has in this way not only amply compensated for the great
setback in the history of the teaching of irritability produced by
the confusions of conceptions created by _Haller_ and the vitalists,
but also placed the whole of the physiology of stimulation on a firm
foundation upon which it is possible to build further. Though it is
true that many of his special theories, in particular those on nature
and the origin of disease, are quite erroneous, still a just critic
must judge work in relation to the period in which it was written, and
I question if at the present day the science of medicine does _not_
contain teachings which in a hundred years will also prove untenable.

  [4] _John Brown_: “Elementa medicinæ.” 1778. English translation.
  London 1778.

_Johannes Müller_ (1801–1858) then added an important stone to the
building up of our knowledge of irritability. This was the clear
recognition of the _specific energy_ of living substances. We have
already found the germ in _Bordeu’s_ term “_sensibilité propre_” or
“_sensibilité particulière_.” _Brown_ was also of the opinion that
different living objects possessed different types of irritability and
that excitation of their special functions was not dependent upon
the _kind_ of stimulus acting upon them. _Johannes Müller_, grasping
the idea hidden in this presentation, transformed it into a clear
and fundamental conception. Already in the work written in his early
years treating of optical illusions he says:[5] “It is immaterial by
which means the muscle is stimulated, whether by galvanism, chemical
agents, mechanical irritation, inner organic stimuli or sympathetic
response from quite different organs; to every means by which it is
stimulated and an effect produced, it responds by movement. Movement
is, therefore, the _effect_ and the _energy_ of the muscle at the same
time.” “Thus it is throughout with all reactions in the organisms.”
“The sensory nerve, responding to any stimulus of whatever kind, has
its specific energy; pressure, friction, galvanism and inner organic
stimuli produce in nerves of sight that which is peculiar to them,
light sensation; in the nerves of hearing, that which is peculiar to
them, sound sensation; and in the nerves of touch, touch sensations.
On the other hand, everything which affects a secretory organ produces
change of the secretion; that which affects the muscle, movement.
Galvanism is not superior to any other methods, of whatever kind,
which can bring about stimulation.” And in his handbook of physiology
_Johannes Müller_[6] formulates the law of specific energy for the
sensory structures briefly in the following words: “The same external
factor produces different sensations in the different senses according
to the nature of each sense, namely, the sensation of the particular
sensory nerves; and the reverse: the characteristic sensations peculiar
to every sensory nerve can be produced by several internal and external
influences.” This doctrine of the specific energy of the sense
substance possesses an importance which extends far beyond the domain
of the physiology of stimulation, for it forms the basis on which the
whole theory of human knowledge must be built up, no matter how it may
be constructed in detail.

  [5] _Johannes Müller_: “Über die phantastischen
  Gesichtserscheinungen. Eine physiologische Untersuchung mit
  einer physiologischen Urkunde des Aristotles über den Traum, den
  Physiologen und den Arzten gewidmet.” Coblenz 1826.

  [6] _Johannes Müller_: “Handbuch der Physiologie des Menschen für
  Vorlesungen.” Coblenz 1837.

As _Johannes Müller_ already clearly emphasizes, it is here not
the question of a law confined to the sense substance, but one that
applies to all living substances. Every living substance has its
“specific energy,” that is, its characteristic vital phenomena and
this is produced by stimuli of the most varied kind. This doctrine
received an extension of inestimable value for its future development
by the great discovery of _Schleiden_, that the cell is the elementary
building stone of the plant organism. Subsequently _Schwann_ at the
instigation of _Schleiden_ made further investigations and found that
this discovery applied also to the animal organism. Irritability
having been recognized as a general property of living substance,
it followed that, after the foundation of the cell doctrine, every
cell must possess irritability and have its own specific energy. It
now became necessary to study the manifestations of irritability of
the cells in their specific form. Strange to say, this was done at
an earlier date in pathology than in physiology. Indeed, since the
time of _Brown_ the study of irritability was furthered far more by
pathology than by physiology. The chief reason for this is probably the
great practical interest that the investigation of disease possesses,
_Brown_ having already quite correctly ascribed the existence of
disease to the relations of the organism or its parts to stimuli.
_Rudolph Virchow_ then, after the establishment of the cell doctrine,
arrived at the momentous conclusion, that disease must be considered as
reactions of the body cells to stimuli. In his epoch-making “Cellular
pathologie,”[7] he has carried out this idea in a classical manner.
By irritability _Virchow_ understands “a property of the cells, by
virtue of which they are set into activity, when affected by external
influences.” There are, however, _various_ kinds of actions which
can be brought about by external influences. But essentially there
are three kinds. The effects produced are functional, nutritive,
formative. The result of excitation, or if one will, of stimulation of
a living part, can, therefore, according to circumstances, be either
merely a functional process, or there can be a more or less intense
nutritive activity produced without the function being necessarily at
the same time activated, or finally, it is possible that a process of
formative change may occur which produces new elements in greater or
less numbers. _Virchow_ touches here for the first time upon a question
of extraordinary moment, the important bearings of which have only
now begun to be recognized and seriously considered. We now know, for
example, that the functional excitation can be separated to a certain
degree from the cytoplastic excitation of the muscle. If the muscle is
acted upon by functional stimuli, the excitation takes place mainly in
the form of functional metabolism, nitrogen-free substances are broken
down in increased quantities, whereas cytoplastic metabolism, which
produces more profound alteration in the living substance, and which
goes so far as to bring about a breaking down and building up of the
nitrogen containing atom groups, is hardly at all increased. It would
be an error, however, to look upon these different kinds of metabolism
as quite independent. Considering the close correlation which all the
phases of metabolism bear to each other, this idea cannot well be
entertained. If, however, we question in what manner, for instance,
the functional and the cytoplastic metabolism are linked together, we
have a problem before us which does not belong to the past, but to the
present and future. Indeed, _Virchow_ seems already to have felt that
a sharp division between the different phases and parts of functional
metabolism in the cell does not exist, for he says: “It is true
that it cannot be denied that, especially between the nutritive and
formative processes and likewise between the functional and nutritive,
intermediate gradations occur.” Still they differ essentially in
their characteristic action and in the internal alterations which
the stimulated part undergoes, depending on whether it functionates,
nourishes itself, or is the seat of special growth. Disease consists of
the influence of stimuli upon these physiological processes. The law
of the specific energy of living substance is as clearly expressed in
functional disease as it is in the physiological effects of stimuli.
The pathological disturbance of function is purely quantitative,
“nowhere is there a qualitative divergence.” The function exists or
it does _not_ exist. If it is present, it is either strengthened or
weakened. This gives the three fundamental forms of disturbance:
absence, weakening and strengthening of the function. No function
other than the physiological, even under the greatest pathological
alterations, exists in any _structure_ of the body. “The muscle does
_not_ perceive, the nerve moves no bone, the cartilage does not think.”
In this way _Virchow_ rediscovered in the domain of pathology the
law that his great teacher, _Johannes Müller_, had already clearly
established in the field of physiology. But this law can no longer be
applied to all pathological disturbances of the nutritive and formative
activities of the cell. Here processes occur which do not consist of
a quantitative change of the normal phenomena, but in the appearance
of wholly foreign states, as in the case of amyloid degeneration or
heteroplastic tumors. The question today and for the future arises,
therefore, as to where the limits of the validity of the law of the
specific energy of living substances are to be placed, a question
closely connected with the other before mentioned, of the relations
between functional and cytoplastic metabolism.

  [7] _Rudolph Virchow_: Die Zellularpathologie in ihrer Begründung auf
  physiologische und pathologische Gewebelehre. 1 Aufl. Berlin 1858–4
  Aufl. 1871.

By means of cell pathology _Virchow_ has laid the foundations upon
which our modern medical attitude is built and which must remain
essentially forever the basis of all future medical thought. Certain
critics, lacking in appreciation of the interrelations between things
and ignoring the safer and established knowledge, have considered,
in view of the unfoldings of the researches on immunity and of serum
therapy, that the time of cell-pathology was _passed_ and must be
replaced by the humoral-pathological teaching. These ultramodern
critics, however, have here completely ignored the fact that, on the
one hand, the life of our body is built up from the life of all of the
contained cells, for life in our body exists only in the cells; and on
the other, a fact not considered by them is that the components of the
body fluids originate from vital activity of the cells either directly
or indirectly. No result, indeed, of present serology can alter in the
least degree the fact that every disease represents only a disturbance
of the physiological processes of cell life of the organism and the
harmony in their combined workings. Indeed the more recent observations
of serology and chemotherapy are so little opposed to cell-pathology
that they are in fact only possible when based on the latter. They are
only comprehensible then from the unfoldings of cellular pathology.

Until quite recently all those effects of external factors on the
living substance which consist in excitation, that is, in an increase
of their specific vital processes, have always stood in the foreground
of all researches and observations on irritability. It was gradually,
however, more and more recognized that the depressing influence of
stimuli played a great rôle in the vital process of the organism.
_Brown_ was acquainted with exhaustion produced by stimuli, and the
discussion of “asthenic” diseases, in which the irritability was
reduced, occupied an important place in his pathology. That, however,
in the normal activities of the organism such depression or lessening
of vital manifestation could result from the influence of stimulation,
first became clear after the brothers _Weber_[8] in 1846 discovered the
inhibitory effects of the galvanic stimulation of the vagus upon the
heart.

  [8] _Eduard Weber_: “Muskelbewegung.” Article in Wagner’s
  Handwörterbuch der Physiologie, Bd. 3. Braunschweig 1846.

Since then the inhibitory processes in nerves have been frequently
investigated by _Schiff_ (1823–1896), _Goltz_ (1834–1901) and others,
who gave us a theory concerning the same. Only a small number of
inhibitory processes were known at that time, as for instance the
inhibition of the croak reflex of the frog, or the inhibition of
the grasp reflex during copulation of these animals through skin
stimuli, and a few other cases. They regarded the inhibitory nervous
processes as a special state, of which the inhibition of the heart
through the vagus was the best illustration. Further, the Russian
physiologist _Setschenow_ succeeded by directly stimulating certain
parts of the central nervous system, especially the optic lobes of
the frog, in producing inhibition. It was, therefore, frequently
assumed, as _Setschenow_ did, that in the brain there exist special
inhibitory centers, just as there are motor centers. This view was
later shown to be untenable. It is only quite recently, and especially
since _Sherrington_ has shown that inhibition plays a part in all
antagonistic muscle movements, that we have obtained a broad and more
thorough understanding of the inhibitory processes in the life of the
organism, and a physiological explanation of this important group of
activities of the central nervous system. This inhibitory effect of
stimulation, brought about by the involvement of the central nervous
system in the normal organism, was studied side by side with the
depressing effects of stimulation. _Claude Bernard_ (1813–1878)[9]
first discovered that the excitation of all living substance could
be depressed or totally suspended through the influence of certain
anæsthetics, such as ether or chloroform. By a series of experiments,
as simple as they were convincing, the French scientist showed that
irritability could be depressed in mimosa leaves, the growth of
germinating plant seeds and the ferment action of yeast cells stopped,
likewise the disintegration of the carbon dioxide in the cells of the
green leaf, as well as the development of the egg cells, and also the
movements of the animal organism and the sensations of man. By this
means he recognized that not only does all living protoplasm possess
irritability, but that it can also by means of certain substances
be put into the condition of “anæsthesia,” a state dependent upon
a change of the protoplasm, which he termed “semi-coagulation.”
Finally, besides the more apparent processes of excitation and those
less so, belonging to the group of inhibition and depression, in
the last century the knowledge of the subject was greatly increased
by the addition of another group, which recently in consequence of
various reasons has met with particular interest. These being effects
of stimuli on the direction of movements of motile organisms, it
became more and more recognized that these curious manifestations of
irritability, which appeared to have such a surprising likeness to
the mysterious attraction and repulsion in the sphere of electricity
and magnetism, occur universally in the vegetable as well as in
the animal world. These movements are of the greatest biological
importance for the obtaining of food, propagation, protection against
disease, etc. Botanists have long known of the geotaxis of the roots
and stems of plants, the heliotaxis of their leaves and flowers
and of the thigmotaxis of their tendrils. Likewise the phototaxis
of freely moving protistæ had been often observed, especially by
_Ehrenberg_[10] of Berlin, well known for his researches on infusoria.
Then _Engelmann_, _Pfeffer_, _Strassburger_, _Stahl_, and many others
discovered and studied more carefully the facts concerning chemotaxis,
thigmotaxis, rheotaxis, geotaxis, phototaxis, etc., of bacteria, motile
spores, rhizopoda, and so on. The question arose if one should regard
this singular behavior of the unicellular organisms as an expression
of conscious sensations, discrimination or will. This view was as
determinedly denied on the one hand as it was accepted on the other.
Whilst even today certain scientists still consider the reactions of
the unicellular organisms as a manifestation of conscious sensation,
discrimination or will, others look upon them as unconscious reflex
reactions of cell organism, taking place as purely mechanically as
the spinal cord reflexes of vertebrates. This divergence of opinion
would have practically no value for the development of our knowledge
of irritability had not here, as in the case of the relations between
the mental and physical processes in man, the view been entertained
with more or less fervor, that at some stage or other in the chain
of the purely physiological processes of responsivity, an intangible
factor had been introduced which was considered as the essential
“cause” of the peculiar reactions to stimuli. It is not here the
place to enter into the question if, and in what degree, animal
psychology may be a field of scientific research. Even if one looks
upon conscious processes as effects of stimulation, in both lower
animals and in man, in no case should one assume them to be factors
of an essentially different nature, interrupting the chain of the
mechanical reactions; neither should one consider the particular
characteristic responses observed in unicellular organisms as effects
of non-mechanical “causes.” As a result, a mysticism, in reality quite
foreign to it, would be introduced into physiology. As a matter of fact
the physiological investigations for the tropic reactions of stimuli,
which have been carried out in great number since the end of the
eighties, have shown more and more clearly that this peculiar behavior
of unicellular organisms towards unilateral stimuli is produced by a
comparatively simple mechanism. The analysis of this shows a difference
in the intensity of the exciting or depressing effect produced by the
stimulus. The stimulus exerts its influence unequally upon the specific
activity of the motor elements of different parts of the surface of the
cell body. This difference in response causes the axis of the freely
moving organism to assume a different direction in which to move. It
is _compelled_ to move in a definite direction and so, in this field,
the apparently mysterious attraction and repulsion of living organisms
toward stimuli has, by means of the most simple analysis, been robbed
of its mystical character.

  [9] _Claude Bernard_: “Lecons sur les phénomènes de la vie communs
  aux animaux et aux végétaux.” Paris 1878.

  [10] _Ehrenberg_: “Die Infusionstiere als vollkommene Organismen.”
  Leipzig 1838.

Finally, I should like to touch briefly upon a view of the irritability
of living substance which has recently been brought forward by
_Semon_.[11] It assumes the proportions of a whole system and is
proclaimed as a basis for the comprehension of organic phenomena. It
originated with an idea which _Hering_[12] developed many years ago
and which later was accepted by _Haeckel_,[13] namely that heredity
is a species of memory of the living substance. _Semon_ attributes to
living substance, in contrast to non-living, a “_Mneme_.” By “_Mneme_”
he understands the capability of living substance to assume, through
the influence of a stimulus, a permanently altered condition. The
latent alteration resulting from the stimulus he terms “_Engramm_.”
These “_Engramms_” can later, however, not only be activated by the
reapplication of the original stimulus, but also by other stimuli,
so that the state of excitation once brought about by the original
stimulus reappears. _Semon_ calls the reproduction of the state of
primary excitation by a later stimulus “_Ekphorie_.” A great number of
other new word formations, such as “_chronogene Engramme_,” “_phasogene
Ekphorie_,” “_mnemische Homophonie_,” “_mnemisches Protomer_” and
countless others are supposed to serve for the better understanding
of a series of special facts, chiefly in the domain of the processes
of heredity. That which is termed “_Mneme_” and “_Engramm_” is not
further analyzed. _Semon_ expressly declines to discuss the kind of
alterations in which the physical or chemical nature of an “_Engramm_”
consists. Hence physiological analysis has not been advanced in any way
by _Semon’s_ new formation of words applied to long-known facts. With
a series of new expressions the originator of the “_Mneme doctrine_”
deceives himself, as well as a number of his readers not endowed with
the critical faculty, into supposing that he has achieved a serious
analysis. Of such, however, there is not a trace. As can be conceived,
this way of treating the manifestations of life has met with no further
attention from the physiological side. For indeed, what physiologist
would consider that the fact of muscle responding by a contraction
to an induction shock, or to any other stimulus, is sufficiently
analyzed by the explanation that we have the “_Ekphorie_” of a state of
excitation that was once previously produced by an original stimulus
of some unknown kind, and of which the living substance of the muscle,
in consequence of its “_Mneme_,” has retained a latent “_Engramm_”?
Here the deep gulf is apparent which exists between the demands of
a physiological analysis and the futile explanation of the mneme
doctrine. Physiological investigation must reject such a manner of
treating its problems.

  [11] _Semon_: “Die Mneme als erhaltendes Princip im Wechsel des
  organischen Geschehens.” Zweite verbesserte Auflage, Leipzig.

  [12] _Ewald Hering_: “Uber das Gedächtniss als allgemeine Function
  der organischen Materie.” Wein 1876.

  [13] _Ernst Haeckel_: “Die Perigenesis der Plastidule oder die
  Wellenzeugung der Lebenstheilchen.” Berlin 1876.

With this the history of the doctrine of irritability enters into its
present phase of development. To future research remains then the
problem of further analyzing irritability, this common property of
living substance, and finally rendering it into its simplest chemical
and physical components. This last goal can only be approached very
gradually, step by step. With the analysis of irritability we shall
investigate life itself. In the following lectures it will be my
endeavor to show how far, with our present knowledge, we can penetrate
by this path into the great secret.




CHAPTER II

THE NATURE OF STIMULATION

 _Contents_: Principles of scientific knowledge and research. Origin
 and meaning of the conception of cause. Cause and condition. Criticism
 of the conception of cause. The conditional point of view. Conception
 of cause. The conditional point of view applied to the investigation
 of life. Conception of vital conditions. Definition of the conception
 of stimulation.


The common problem of all scientific research is the investigation
and formulation of natural laws. The assumption of a unity in the
happenings and of existence in the world, in accordance with definite
laws, forms the indispensable foundation of all scientific study and
is fully justified by experience. Experience has taught us, as a
result of innumerable individual observations, the existence of such
an accordance, whereas in not a single instance has it been shown
that this is not the case. We are thus justified in assuming without
further discussion that every scientific research, every new problem
which we approach, is likewise founded on this unity of occurrences in
accordance with natural laws. Only on the firm basis of this assumption
has scientific investigation a purpose, and every success is a new
proof of this. There is an unanimity of opinion concerning this among
scientific investigators in all fields.

Not such complete agreement, however, exists in regard to the question
by what symbols of human thought and speech these laws can be described
in part as well as _in toto_, so that existing laws can not only be
_fully_ and conclusively defined, but at the same time without the
use of _superfluous_ terms. According to _Ernst Mach_, thought is an
adaptation to facts. Our speech is simply a method of expression of
our thoughts and indeed the most satisfactory form we have. We must,
therefore, use those symbols which are most closely adapted to facts
as the most precise expression of these existing laws. What forms of
expression have we?

It might appear that a discussion of this fundamental question
has not a close connection with our special subject of physiology
of stimulation. This, however, is not the case. Indeed, it is an
irremissibly previous requirement not only for the elucidation, but
also for the understanding itself in this particular field. We _could
not_ come to a clear understanding in this field without such analysis.
The interpretation of the unity of being and happenings in accordance
with natural laws, which today is widely accepted in the scientific
world as the only exact one, implies the assumption of a “_causation_”
according to which things are explained by the law of “_cause_”
and “_effect_.” I[14] have already on various occasions taken the
opportunity to criticise this view and to show the error and confusion
to which it leads. I should like here to enter somewhat more in detail
into the reason for this criticism. It is particularly directed against
the scientific use of the term “_cause_” on the basis of our best-known
theoretical principles. It is clear that all scientific observations
and explanations are founded on experience. Can it be said that the
conception of “cause” originates from experience?

  [14] Compare with this _Max Verworn_: “Die Entwickelung des
  menschlichen Geistes.” Jena, Gustav Fischer, 1910.

  _Max Verworn_: “Die Erforschung des Lebens.” II Auflage. Jena,
  _Gustav Fischer_, 1911.

  The same: “Die Fragen nach den Grenzen der Erkenntniss.” Jena,
  _Gustav Fischer_, 1908.

  The same: “Allgemeine Physiologie.” V Auflage. _Gustav Fischer_, 1909.

We can say with absolute certainty that the conception of cause dates
from prehistoric times. Its beginning reaches back to the stone age,
at least to neolithic, possibly to palæolithic culture. This is
demonstrated by the careful reconstruction of these prehistoric races
based on a critical comparison of the remains of their culture with
that of primitive races living today. The ideas of these primitive
races show an inclination to an extraordinary degree to explain
all happenings in the world anthropomorphously. All happenings in
surrounding nature are given the same origin as the activities of man
himself. To man, on this plane of phantastic religious speculation, all
events in nature appear as acts of the will of invisible powers, which,
having originally proceeded from the souls of dead human beings, think,
feel and act exactly as _he does_. This anthropomorphic conception of
the occurrences in the surrounding world is one of the many conclusions
which ensue from the supposition of an invisible soul, which can be
separated from the body. It was this conception which gave the impetus
for the transition of human thought from the era of the naïvely
practical to the era of the theoretical spirit in that far removed
age. In this anthropomorphic transference of personal subjective
impulses of will to the objectively observed events of the surrounding
world, lies the origin of causal conception, which since then has been
generally used as the explanation of the happenings in the world. One
cannot assert that the formation of the conception of cause is purely
a product of _experience_, but rather a result of _naïve speculation_.
Even if a later evolution of human thought shows a continued endeavor
to dismantle the conception of cause of its primitive trappings and
to modernize, as it were, its outer appearance, we still find today
many inner components clinging to it, which do not agree with the
strict demands of critical scientific exactness, demands which must
particularly be made concerning a conception which has been given such
fundamental importance in theoretical knowledge.

I wish to observe here, however, that the conception of cause, even
though more or less unconsciously so, is still the remains of a part of
the old anthropomorphic mysticism carried over into our own times. This
shows itself especially in the conception of _force_, which is nothing
more than a form of the conception of cause. Force is the cause of
movement. One has here in anthropomorphic manner transferred the action
of the _will_ of man, which produces movement of the muscles, into
lifeless nature. The force of the sun attracts the earth, that of the
magnet attracts iron, etc. In short, one has introduced a mysterious
unknown factor instead of being content with the simple description of
facts, such as _Kirchhoff_[15] has advanced in the field of mechanics.
Although of late natural science has also dispensed more and more with
conception of force as a means of explanation, it is still today not
wholly done away with. That which applies to the conception of force is
likewise true of the conception of cause.

  [15] _Gustav Kirchhoff_: “Vorlesungen über mathematische Physik.
  Mechanik.” Leipzig 1876.

Another point concerning the application of the conception of cause
seems to me, however, to be of much more importance, namely that a
single cause is held responsible for the taking place of a process. One
endeavors to explain a process in general by seeking for its “cause.”
The cause being found, the process is considered as fully accounted
for. This idea is not only widely spread in everyday life, but is even
found frequently in natural science, especially in biology, although
here, it should be known, the processes are decidedly more complicated.
The search for the “cause” of development, for the “cause” of heredity,
for the “cause” of death, for the “cause” of the respiration, for the
“cause” of the heart beat, for the “cause” of sleep, for the “cause”
of disease, etc., was for a long time and frequently even today a
characteristic of biological investigation. As if such a complicated
process as development, death or disease could be explained by a single
factor! In reality, one has obtained very little as a result of the
analysis of a process by discovering its cause; and in addition the
false impression arises that through the finding of this one factor the
process has been definitely explained. It has been generally recognized
in the natural sciences in recent times that no process in the world is
dependent upon one single factor and attempts have been made to give
this fact more consideration.

It is the custom at the present time to hold the view that every
process or state is brought about by its _cause_, but that a series
of _conditions_ are also necessary to the production of the process.
Such a view, however, which considers that two different factors
existing at the same time are necessary to the accomplishment of every
happening or state, namely, the cause and the conditions, leads to new
difficulties, for then, upon a more exact analysis arises the question:
Which is the cause and what are the conditions? It is very soon found,
however, that this does not permit of any strict differentiation, as
the two conceptions can not be sharply separated. This difficulty
was brought to my notice with particular force during an animated
discussion with a friend and colleague about twenty years ago, which I
have always remembered. I had observed at that time the dependence of
pseudopod formation of amœboid cells on the oxygen of the medium, and
had found that the expansion phase of protoplasmic movement, that is,
the extension of pseudopods, the centrifugal flowing of the protoplasm
into the surrounding medium and with this the enlargement of the
surface of the cell body, only takes place when oxygen is contained
in the surrounding medium and never occurs in its absence. Being at
that time wholly under the influence of the conception of cause, I
believed that oxygen was the cause of the formation of the pseudopods.
To this my friend made the objection: “Yes, I quite acknowledge the
fact of the dependence of the formation of pseudopods on oxygen, but
what informs me that the oxygen is really the _cause_? It might be
simply a necessary _condition_.” This objection led to a long debate,
which ended, however, without our being able to agree. We were not in
a position to distinguish between the conception of cause and that
of condition, and at that time the idea _did not occur_ to us to
emancipate ourselves from the conception of cause deeply implanted in
us as a result of our training. In fact, one is greatly embarrassed if
one attempts to sharply distinguish by a definition the conception of
cause and that of condition. A condition is a factor on which a state
or a process is dependent for its existence or its taking place. To the
conception of condition belongs, besides the factor of _relation_, that
of _necessity_. Every condition is necessary to the existence or taking
place of this state or process. Without the condition in question the
state or process does not occur. The same must be demanded for the
conception of cause. No state exists, no process takes place, without
its cause. The cause then has itself the specific character of a
condition, it is itself a condition. Has it perhaps then some specific
peculiarity in contrast to the other conditions, which would give it a
prominent place? Experience teaches us that nothing, that is to say,
no state or process in the world, is dependent upon a single factor
alone. There are always numerous factors which bring about the state or
process. Would it be possible to distinguish which of these particular
conditions is of the greatest importance?

First of all, it must here be taken into consideration that the
importance of a condition is not one which is capable of increase
or decrease, for the simple reason that necessity, which forms an
essential component of the conception of cause cannot be varied. A
factor cannot be _more_ than necessary for the existence of a state or
the taking place of a process. If, however, it is less than necessary,
then it is not necessary at all, and the state or process exists also
without it, that is to say, the factor is not a condition. In other
words: _all conditions for a state or process are of equal value for
its existence, as they are all necessary_.

If one attempts to prove by means of concrete examples this statement
obtained by purely logical deduction--a control which, considering the
experimental nature of modern thought, never should be neglected even
in the simplest of reasoning--it might appear that an objection could
still be made against its general validity. From various instances it
might be concluded that there are conditions, which as such are not
absolutely necessary for a state or process, but can be replaced by
other factors. An example may serve to make this clear. I pour diluted
hydrochloric acid on powdered carbonate of sodium, and carbon dioxide
is set free. The addition of hydrochloric acid is here a condition
for the liberation of the carbon dioxide. Without the presence of
the hydrochloric acid the process does not occur. Nevertheless I can
substitute diluted sulphuric acid for the hydrochloric acid. Here it
would appear that one condition can be replaced by another. But one
must not be deceived. A closer observation soon shows that the process
has not been sufficiently analyzed if we look upon the addition of
hydrochloric acid as a condition for the liberation of carbon dioxide.
It is not the presence of hydrochloric acid or sulphuric acid, as such,
which is a condition for the process, but rather the separation of the
sodium atoms from their combinations with the oxygen in the molecule of
the carbonate. This reaction can occur as a partial component in very
different complexes of processes. Or to quote another example, taken
from the subject with which we are especially here concerned. I allow
an induction shock to act on the nerve of a nerve muscle preparation of
the frog. The muscle contracts. The electric stimulus is the condition
for the muscle contraction. But I can substitute for the induction
shock a mechanical stimulus by sudden pressure of the nerve. The
muscle again contracts. The analysis again shows that the induction
shock as such was not the condition for the muscle contraction, but
the excitation of the nerve which it produced and which is conducted
as a specific impulse to the muscle. This excitation of the nerve can,
however, be induced by very different kinds of processes, namely,
by all processes which possess in common the condition that they
suddenly increase certain disintegration processes in the living
nerve substance. Indeed, the further analysis of the whole process
shows in addition that the nerve impulse as such likewise does not
form a condition for the contraction of the muscle, but it first of
all produces the necessary condition for the muscle contraction by
suddenly greatly increasing certain chemical processes, which take
place in the living substance of the resting muscle. The nerve impulse
can, therefore, also be replaced by other processes, if only these
contain the condition for an increase of disintegration of the muscle
substance, as in the case of the direct stimulation of the curarized
muscle, where the influence of nervous impulses is totally eliminated.
In a further analysis of this process we should penetrate even more
deeply into the differentiation of the individual constituent processes
and the isolating of the special conditions on which each link in the
chain is dependent.

Such an analysis then shows us the following: Every thing, every state
or process, is a complex of numerous components, of which _one_ always
conditions the other in the manner that the individual conditioning
components are themselves in their turn contained as constituents of
other complexes and are conditioned here again by other factors. These
factors in themselves as such are not directly necessary to the taking
place or existing of the special component and can, therefore, be
replaced by others. Closer observation shows that there is a constant
interdependence between all things in the world. _Every_ thing in the
world is _indirectly_ dependent upon _every other_, although often so
remotely that we are not able to trace the connection. Absolute things,
completely isolated and independent of others, _do not_ exist in the
world. In observing and studying complexes individually, we must not
forget that we only _think_ of them as isolated from the great eternal
coherence, from which they are in reality not separated. The conception
of condition, however, only then has meaning, if we refer to it in
connection with the direct dependence of one factor upon another.
Nevertheless if we understand by conditions those which are connected
by multitudinous intermediate components, then we would render the
conception of conditions useless. For if every thing in the world were
the condition for every other, the conception of relation would lose
its value in special states or processes. Should the conception of
condition have a meaning in regard to a _certain_ state or process,
then we should only look upon _that_ part of a complex upon which the
other is _directly_ dependent as a condition. When, however, we meet
with a factor for a process or state, which can apparently be replaced
by another factor, we have not carried the analysis far enough. Upon
deeper penetration into the subject, it is found that the essential
condition for the process, which exists, is a component common to both
factors, one of which in consequence can replace the other.

It is the task of all scientific research to penetrate deeper and
deeper into these relations, these connections and the order of
succession of states and processes and to separate them into their
individual components, and in this way gain a more thorough knowledge
of the constancy of existence and happenings in the world.

This analytical process, it is true, only advances very gradually, and
we must accept for the present, especially in the complex biological
processes, that a whole complexity of members appear conditioned,
and that a complex aggregate is a condition of the whole process.
We are not yet in the position to define the special components of
the constituent processes. It is only step by step that we are able
to differentiate the necessary from the accessory parts in these
complexes. However, we are here only concerned for the present with
a purely theoretical question and we may be permitted to say: If we
maintain that the conception of condition has as an integral part the
element of necessity and of relation to a special thing, then there
are no substituting conditions. For then every condition for a state
or process is of equal value. There is no justification to give more
prominence to one condition and place it in the position of being the
“_cause_.”

If the cause is elevated, then it is done from some superficial motive.
This is confirmed by a glance at the practical use of the term cause.
The cases in which the cause is always at once clearly recognized and
named without doubt or hesitation are those where a new factor is
added to an already existing system of conditions, which bring about
a process. When such a process is produced, the last added condition
is considered as “cause.” A shock acts on an explosive body, the body
explodes: the shock is considered the cause. An induction shock acts
on a muscle, the muscle contracts; the induction shock is looked upon
as the cause of the muscle contraction. To regard only the last added
condition as being of especial importance to the taking place and the
explanation for a process is, however, a standpoint which could satisfy
only the most superficial of observers.

In a scientific investigation such methods should play no rôle. For to
every careful observer it must appear quite clear from the beginning,
that the previously existing conditions have as great a value for the
taking place of the process and its explanation as that last added.

The induction shock would not have produced the characteristic effect
had not the other conditions been already previously combined, had not
certain special atoms in the molecule of the explosive combination
in consequence of former processes assumed quite a peculiar labile
position, had not in the evolution of the muscle in the growth and
metabolism certain combinations been formed, and certain chemical
processes taken place.

Therefore if I do not analyze these previously existing processes and
the conditions brought about by them in the system of the explosive
substances or the muscle, and simply know the condition added last,
then I have learned nothing of the process itself, have _explained_
nothing. The time of application of a new condition does not justify
in any degree the assignment of a dominant position to a factor. But
more: in many cases there is not a question at all of the _addition_
of a process to an existing state, but rather of the _simultaneous_
interference of two or more processes. Several conditions can appear
at the _same_ time. In other cases the sequence of the combination can
be reversed. Which then is the cause? Has the process several causes,
or has it no cause? Here one sees plainly to what absurd results it
leads if time alone is used as a basis of the conception of cause.
To illustrate this I return to the case of the liberation of carbon
dioxide from carbonate of sodium. I place anhydrous carbonate of sodium
in a beaker and add hydrochloric acid. The carbon dioxide escapes. Here
the addition of hydrochloric acid would be assumed to be the cause of
the freeing of the gas. Then I put hydrochloric acid in a beaker and
add carbonate of sodium. The same process takes place, but now the
addition of _carbonate of sodium_ would be considered the cause for the
formation of gas. Now I put both simultaneously into a beaker. Again
the same process. Which was now the cause? Has the process now _two_ or
has it _no_ cause at all? Finally I put anhydrous carbonate of sodium
and hydrochloric acid in ether solution into the beaker. The formation
of gas does not take place, and _yet_ both causes for this formation
of gas are present, the carbonate of sodium and the hydrochloric acid.
Only when I add water to the mixture does the formation of carbon
dioxide take place. Here water would be considered the cause. Hence
every condition would be in succession the cause for one and the same
process. Under some circumstances the same process would have _several_
and in others _no_ cause at all. It is scarcely necessary for further
comments upon the value of the conception of cause for the scientific
explanation of a state or process. If we do not seek to introduce
into exact science the antiquated symbols which have become useless
and belong to a primitive phase of development of human thought,
there cannot be a moment’s doubt that a strict scientific analysis in
whatever field of investigation it may be carried on can consist only
in the study of all the conditions concerned in a state or process. If
this is done, then the work of exact research is accomplished. Further
problems do not exist. The use of superfluous terms or symbols for
the definition of things would be in opposition to the fundamental
principle, already brought forward by _Kirchhoff_, especially for
mechanics, namely, that of formulating comprehensively and in the
simplest manner the processes which take place in nature.

At first glance one might be tempted to find an incompleteness in the
observation and description, when a conditional standpoint is adopted.
It might be thought that conditionalism were a purely _formal_ method
of observation, and only considered the _interdependence_ of things,
but not the _properties_, the _nature_ of the objects themselves.
Regarded more closely, however, it is seen that this objection does not
hold good. For what is a condition?

A condition is in itself a _thing_ of quite distinct _properties_.
The properties of a thing are, however, determined by the specific
combination of conditions which characterize the thing. The conditions
by which a thing, that is to say, a state or process, is determined,
are _identical_ with its being and nature; in other words, they are
the thing itself. Purely formal relations without essence would be
altogether an absurd fiction _not_ in accord with reality, and which
even the science of mathematics does not acknowledge, for we cannot
have a conception without concrete content, just as in nature we do
not find a form existing independently of a thing. Every thing is
equal to the sum of all its conditions and depending upon the uniform
constancy in accordance with natural laws is solely determined by its
conditions. The problem of all scientific research consists wholly in
the ascertaining of the conditional interdependency.

_A state or process is solely determined by the sum total of its
conditions. A state or process is identical with all of its conditions
in totality._ From this it follows that equal states or processes
are always the expression of equal conditions and wherever unequal
conditions exist, unequal states or processes will result; and further,
a state or process is completely investigated when the entire number of
its conditions is ascertained.

This fundamental statement of conditionism should be engraved over the
portals to the entrance of every scientific investigation.

That there is not the least difficulty in presenting scientific
observations strictly according to these principles of conditionism,
and that one can perfectly well do without the causal conception in a
scientific description, I have shown by a concrete example, namely,
in the fifth edition of my “General Physiology.” In the whole volume
the conception of cause is only mentioned in one place, where its
theoretical value is criticised, elsewhere not at all, and yet I do
not think that any one will miss this conception, and indeed, if
their attention is not especially called to the fact, even notice the
omission.

These principles of an exact conditional investigation must also guide
us in the analysis of the processes of stimulation. The process of
stimulation is especially apt to tempt one to employ the old conception
of cause, for it belongs to that group of processes which originate
from an already existing system by the addition of a new factor.
An electric stimulus acts on the muscle. The muscle contracts. The
stimulus is considered the cause of the contraction. But what would I
explain if I were to prove that the stimulation is the cause of the
contraction?

The history of physiology shows us that this subject has advanced long
since far beyond the stage of being satisfied with such an explanation.
Today the process would only then be fully investigated if we knew
the entire number of its conditions and had traced the dependency of
the individual partial constituents of the whole complex process upon
one another. For this, however, it is essential that we study the
conditions already existent in the entire system previous to the action
of the stimulus.

That which we describe with the word life is an exceedingly complex
process. If we analyze life, it is found to be composed of an immense
number of separate constituent processes, each one being conditioned
by the others. These constituent processes are the vital conditions. A
vital process occurs, and must occur, where and when the whole sum of
vital conditions is realized. It is identical with the sum total of the
vital conditions. If only one condition is absent, then life does not
exist. It is then expedient to reserve the expression “life” for the
_entire sum_ of the vital conditions. When we speak of the individual
constituent processes as “_vital processes_” in the plural, we must
bear in mind that in reality each is not in itself life. Only the whole
complex “lives,” not an individual constituent of the same. Living
substance is rather the _whole_ system, and not a constituent part of
the same, not a piece of protoplasm, not a nucleus and not a specific
protein combination in the cell.

A property of this system should receive our consideration at this
point. It is a characteristic of every system in the world, namely,
the fact that a system _is not isolated_ from its surroundings. It
is a deception resulting from the selective action of our sensory
organs, if we consider the bodies as separated and isolated from their
environment. This deception disappears upon further analysis and when
we assist our organs of sense, which only respond to certain parts
of the whole process, by experimental methods of investigation. Our
experience then shows us that an isolated system does not exist, but
that there are instead everywhere connections which extend further and
further into the infinity of the world. An organism is consequently
no delimitated system and the vital process cannot, therefore, be
sharply separated from the processes in the medium. We cannot draw
a sharp line between vital processes and say: on the right we have
factors which are necessary for the maintenance of life, and on the
left factors which are not necessary. The conditional connection
between individual processes extends to the entire world, and likewise
a great series of constituents, each influencing the others, extend
from the medium into the organism. The nature of our sense perception,
and consequently the knowledge derived therefrom, is such that we are
obliged to arbitrarily take into consideration merely _fragments_ from
the endless interdependence of all things in the world, and so we
separate the vital conditions of the organisms from their surrounding
factors, as though they were independent. A conscientious theoretical
analysis requires that we should never forget that in reality such an
isolation does not exist. Only with the recognition of this can we
distinguish for practical purposes between _internal_ and _external_
vital conditions. In such a differentiation the _internal vital
conditions_ which compose the living system conceived to be isolated,
are the organs, the tissues, the cells, the protoplasm and the cell
nucleus, and within the protoplasm and the nucleus the arrangement and
quantitative relations of certain substances, such as proteins, salts,
water and the thousands of special components with their interactions
and continued alterations. On the other hand, the _external vital
conditions_, which act on the periphery, are the conditions of the
surrounding medium, as foodstuffs, water, oxygen, static and osmotic
pressure, temperature, light, etc. But this distinction has only a
_practical_ value for the study of the organism as an _independent_
system. Theoretically it is as impossible to make a sharp distinction
between internal and external vital conditions, as to distinguish
between the vital conditions generally and the more remote conditions
of the environment. All these conditions form a widely branching
system of factors of which one is conditioned by the other reaching
continually from the interior of the vital system into the surrounding
medium, so that on the periphery of the system it cannot always be said
whether or not a component still belongs to life. Considering these
circumstances we can roughly for the present define the conception of
stimulus as follows:

_A stimulus is every change in the vital conditions._

The most essential point in this definition is the relation of the
conception of stimulus to that of vital conditions. These relations,
however, call for a brief explanation. Here again the conditional
method of observation saves us from error, for it would be wrong to
place the conception of stimulus and vital conditions in contrast to
one another, one excluding the other. On the other hand, this method of
observation shows that the stimuli are likewise only conditions, but
conditions producing certain changes in the vital system. If a stimulus
acts, that is, if there is any change whatever in the vital conditions,
the whole complex of life in consequence of the dependency of the
constituent parts upon each other is also changed, and a new state
of living substance occurs. Stimuli are, therefore, also only vital
conditions, but vital conditions for new vital manifestations. The
_relation_ of _one_ given state to _another_, forms an indispensable
point in the understanding of vital conditions as well as that of the
stimulus. The stimulus becomes a vital condition for the new state
which it produces. It is only a stimulus _relatively_ to the original
state, which _previously_ existed. The essential point, therefore,
in the conception of the stimulus is that of alteration. An example
will serve to make this clearer. If _Amœba limax_ are bred in a hay
infusion they appear in countless masses. Observed in water in a
watch glass they show at first the well-known form of _Amœba proteus_
with short, broad, lobate pseudopods. (Figure 1, A.) After a period
of rest, however, they gradually assume the characteristic elongated
_limax_ form. (Figure 1, B.) In this shape they constantly move about.
But if I add to the water only a faint trace of diluted solution of
caustic potash, the amœbæ first assume the shape of a ball (Figure
1, C), and then after a time, stretch out long, pointed pseudopods,
which give them the characteristic form of _Amœba radiosa_. (Figure 1,
D and E.) They remain permanently[16] in this form. I have observed
them for several hours at a time. They move in the same manner as
_Amœba radiosa_. They draw in one pseudopod, stretch out another and
float freely in the water in contrast to their _limax_ state, in which
they are always attached to some support. The long, pointed, often
threadlike pseudopods, yield to every movement of the water, bending
in consequence like whipcords. In this example the amœbæ under the
vital conditions existing in tap water have _limax_ form. The vital
conditions undergo a change by the addition of a solution of caustic
potash, which acts as a stimulus. The consequence is a reaction, in
which the animal assumes _radiosa_ form. By the action of the stimulus
a new state of the living substance is produced, and remains as long
as the solution of caustic potash is contained in the medium. The
solution of caustic potash is, therefore, a stimulus for the state of
the vital system, which is manifested in the _limax_ form, whilst for
the state of the system which shows itself in the _radiosa_ form, it
is a vital condition. If I place the amœbæ of the _radiosa_ form once
again in tap water, they assume the _proteus_ and then the _limax_
form. The withdrawal of the solution of caustic potash, the presence of
which is a vital condition for the _radiosa_ state, acts as a stimulus,
which results in a transition of the vital system to another state. By
altering the medium I can at will bring about this change of form in
the same individuals. In this way one and the same factor can figure
as stimulus and vital condition, according to the state of the vital
system on which it acts. Whilst its addition acts as stimulus in the
one state, its withdrawal acts as a stimulus in the other state, which
it has produced. The same fact is shown by the well-known example of
_Artemia salina_, which on being placed in fresh water changes into
_Branchipus stagnalis_ and, when again introduced into sea water,
becomes once more _Artemia salina_.

  [16] _Max Verworn_: “Die polare Erregung der lebendigen Substanz
  durch den galvanischen Strom.” In Pflügers Archiv. f. d. ges.
  Physiologie Bd. 65, 1896.

[Illustration: _A_

_B_

_C_

_D_

_E_

Fig. 1.]

These facts show clearly that some stimuli can also be considered
as vital conditions. In the absence of certain stimuli, life could
not exist for any length of time. In the highly differentiated cell
community of the animal organism, for instance, as a result of the
coexistence of the cells and the tissues, many parts have forfeited
in a measure their independence. An example of this is the skeletal
muscle, which, in the absence of impulses from the nervous system,
reaches a low level of chemical change and energy transformation. Here
the nervous impulses which act as momentary stimuli, are also in the
course of time indispensable vital conditions. Without them the muscle
would gradually become atrophied from inactivity. The same applies
to all other tissues of our bodies. The functional stimuli are for
them at the same time vital conditions. These vital conditions undergo
fluctuations and interruptions but at each alteration from a given
state they act as stimuli.

_Stimulus is every change in the vital conditions._ But is this
definition complete? Are we really justified in regarding _every_
alteration in the vital conditions as a stimulus?

In considering this question, one point must not be omitted. This is
the fact that one of the chief characteristics of the vital process
is, that it undergoes continuous change. A vital process involves not
simply an alteration in metabolism or transformation of energy in the
sense that the same chemical processes continuously reoccur in the same
manner. Such a view could only be admissible for the observation of
living substance during a limited period. An investigation over a long
period of time shows rather that every living system alters as long as
it exists, although this alteration is very gradual. The constituent
processes, in short, continuously undergo metabolic change both
quantitative and qualitative in nature.

If we observe the occurrences in a living system at various moments
of the cycle of life, we will find that the condition differs
qualitatively at each period. The progressive alteration of the system
is such that every state of living substance conditions another, by
which it is followed. No state can permanently exist as such. Every
state is the product of the preceding, as it in turn conditions
its successor. Consequently the relations of the system to the
surrounding medium also undergo alteration, even when the external
factors themselves in no way alter. That which today is still a vital
condition, is not in consequence necessarily one tomorrow. These
progressive changes exist continuously until the death of the system
takes place. They characterize life. It is development, and life cannot
exist without development. Death is only the last phase of development.
The individual constituent processes of metabolism gradually change
to such a degree that they can no longer work harmoniously together.
Then the chain of processes is interrupted at one point or another.
The system develops into death or, on the other hand--and this,
as _Weissman_ especially emphasizes, is realized in the case of
unicellular organisms--a corrective process takes place, a process of
cell division by which the original state of the cell is restored and
development begins anew and in a similar manner.

Ought we to designate these constant alterations in the inner vital
conditions as “stimuli”? Usage in this connection has already answered
in the negative, by applying to them the word “_development_.” And
this use is in a certain sense justified. Let us imagine an organism
or any other object for the purpose of investigation as isolated from
its surroundings. This conception, which we have already stated, proves
untenable on closer analysis, but it, however, is based on the nature
of the methods of human observation and is indispensable for practical
use within certain limits. Then the inner vital conditions belong to
the organism, the external to the medium. They differ in so far that
the external vital conditions can exist permanently without alteration,
that is, independently of the development of living systems, whilst
the inner vital conditions of every living organism continuously and
progressively undergo alteration. In this sense, but only in this,
there is evidently a difference between the inner and outer vital
conditions, which permits a separation of the two groups. But we should
always bear in mind that this separation cannot be sharply defined. On
the same basis we assume that the organism for purposes of study is
separated from its surroundings as an independent system, which leads
us in consequence to contrast the alterations in the internal with
those in the external vital conditions, in which we designate the first
as processes of _development_, the latter as stimuli. This distinction,
as all differentiations and separations in nature, gives us only a
practical working basis.

In this way we confine the conception of the stimulus to all
alterations in the external vital conditions of a living system,
considered as isolated. This view does not exclude the fact that
stimuli can also occur and act within an organism. If a nervous impulse
is conducted from the cerebral cortex through the pyramidal tract
to a skeletal muscle, this impulse acts upon the muscle cells as a
stimulus. Although the explosion of the impulse is an alteration within
the body, nevertheless, as far as the muscle is concerned, it may be
looked upon as an external vital condition, therefore as a stimulus.
As the conception of stimulus involves the relation to a given state,
it likewise involves at the same time the relation to a given living
system, upon which it acts from the exterior.

What is the value then of all this theoretical discussion?

In presenting the conception of stimulation from a conditional
standpoint, I desired to show what difficulties stand in the way of
a theoretical isolation of a fundamental conception in the field of
physiology, which indeed is used in our practical research work at
every step. “_Natura non facit saltus._” I wished to demonstrate
that the sharp separation of the conception of stimulation, like all
artificial divisions which we make in nature, must always contain
an arbitrary note, as in reality isolated systems do not exist in
the world. I wished to show that, for this reason, the conception
of vital system, the conception of life, the conception of vital
conditions are not sharply defined. I wished likewise to show that
as a necessary consequence of this fact a sharp separation of the
conception of stimulation, which can only be made in relation to that
of vital conditions, cannot be maintained theoretically. I wished to
show further that there is no sharp line of division between inner and
outer vital conditions, and that we cannot, therefore, make a strictly
theoretical distinction between the conception of stimulation and that
of the processes of development. I wished to show that, for these
reasons, we must not expect from the conception of stimulation, as we
understand it, anything beyond its possibilities. But finally I wished
also to show that, whilst fully conscious of and with due consideration
of all these difficulties, it is possible to work out a definition of
stimulation which is of great _practical_ working value. The definition
in short is: “_Stimulus is every alteration in the external vital
conditions._”

This definition gives to the conception of stimulation its most
complete, that is to say, its generally applicable and simplest form.
The great importance from a methodical standpoint of this definition
of stimulation for the research of life is evident. Our whole
experimental natural science always employs for investigation of any
state or process the same method: the state or process to be observed
is studied under systematically altered conditions. By stimulating the
living substance it is brought under changed external conditions. A
systematic employment of stimulus is, therefore, the experimental means
for the research of life.




CHAPTER III

THE CHARACTERISTICS OF STIMULI

 _Contents_: The quality of the stimulus. Positive and negative
 alterations of the factors which act as vital conditions. Extent of
 the alteration in vital conditions or intensity of the stimulus.
 Threshold stimuli, sub-threshold, submaximal, maximal and supermaximal
 intensities of stimulus. Relations between the intensity of stimulus
 and the amount of response. The _Weber_ and _Fechner_ law. All or
 none law. Time relations of the course of the stimulus. Form of
 individual stimulus. Absolute and relative rapidity in the course of
 the stimulus. Duration of the stimulus after reaching its highest
 point. Adaptation to persistent stimuli. Series of individual stimuli.
 Rhythmical stimuli. The _Nernst_ law.


We have found that stimuli are alterations in the external vital
conditions and that the irritability of living substance consists in
the capability to respond to stimuli by changes of the vital processes.
It now behooves us in the interest of experimental research to
investigate the relations between the nature of the alterations in the
external vital conditions on the one hand, and that of the alterations
of the vital process on the other; that is to say, to systematically
study the effects of stimulation on the living organism. For this
purpose it is above all necessary to become acquainted with the almost
countless numbers of alterations which take place in the external
vital conditions of an organism, and to create a systematic scheme of
stimulation which differentiates and presents in comprehensive order
those various elementary factors which, among the innumerable varieties
of stimuli, would prove effectual. For this purpose it is necessary to
select the various factors which are involved in an alteration of the
external vital conditions.

The first of these factors is the _quality of the stimulus_. The
external vital conditions are, in short, a series of chemical factors,
such as foodstuffs, water and oxygen; the presence of a certain
temperature; the existence of a certain light intensity; the existence
of a definite static pressure; and finally the presence of an equal
osmotic pressure. The stimulus according to its quality can be
differentiated into chemical, thermal, photic, mechanical and osmotic
varieties. To these must be added other forms of stimuli not ordinarily
operative, for instance, many uncommon chemicals, and certain kinds of
rays. The form of stimulation, par excellence, which has acquired the
greatest importance for the _experimental_ investigation of life, is
electricity. In its manifold forms it permits, as no other, of such
fine gradations of intensity and duration that it has become in the
hand of the physiologist an invaluable means of research.

Alterations in those factors which act as vital conditions compose the
great mass of physiological stimuli which act continuously on every
living organism. The first point to be considered in every alteration
is its _direction_. The alterations produced by stimuli may be of
two different kinds, either positive or negative. The quantity of
foodstuffs, water or oxygen, in the surrounding medium, can undergo an
increase or diminution; as may the temperature, intensity of light, the
atmospheric and osmotic pressure. The strength of the electric current,
which may be applied, can also be regulated. In accordance with the
definition of stimulation already referred to, we must consider these
alterations, whether negative or positive, as forms of _stimulation_.
Now the question arises: Is this point of view justifiable? Should one
also consider, for example, the lessening or total removal of a vital
condition as a stimulus? Should one consider the removal of water or
oxygen, cooling or darkening, as a stimulus? It has, in point of fact,
been occasionally attempted _not_ to regard these negative deviations
as forms of stimuli. These observers permitted themselves to be led by
the dogma, that only that which produces an excitation, that is, an
increase of the processes in the living substance, should be regarded
as a stimulus. Such a limitation of the conception of stimuli would
only result from the one-sided consideration of an all too limited
circle of facts. Considered from the point of view which results from a
broader range of experience, this narrow view becomes untenable.

In the first place it does not follow that only _positive_ fluctuations
of a factor, acting as a vital condition, result in _excitation_ in
the existing vital processes. The _withdrawal_ of water produces a
diametrically opposite effect. A muscle, from which water has been
removed, if exposed to dry air or placed in a hypertonic salt solution,
shows violent _excitation_, which manifests itself in great increase of
irritability and development of fibrillary contractions. The breaking
of a constant current which has for a long time flowed through a
nerve or muscle also elicits a momentary excitation. Further, the
abrupt removal of light may also bring about stimulation. To cite an
example from the physiology of the single cell, I should like to call
to your attention the interesting observations of _Engelmann_[17] on
the _Bacterium photometricum_, of which he was the discoverer. When
the field containing these organisms is suddenly darkened, all the
individuals contained in the drop immediately dart forward for some
distance, at the same time, as is usually the case, quickly rotating
around their own axis, and then after a moment of immobility, swim
on quickly in another direction. An analogous responsivity has also
been shown by other single cell organisms, as has been pointed out by
several observers and especially by _Jennings_.[18] In all these cases
the excitation was produced by a lessening or total withdrawal of the
factors which act as vital conditions; and even those who take the
standpoint that only such factors are to be considered as stimuli which
produce an _exciting_ effect, are compelled to regard these alterations
as stimuli, in spite of the fact that they are _negative_ variations of
external vital conditions.

  [17] _Th. W. Engelmann_: “Bacterium photometricum ein Beitrag zur
  vergleichenden Physiologie des Licht-und Farbensinns.” In Pflügers
  Archiv. Bd. 30. 1883.

  [18] _Jennings_: “Behavior of the lower organisms.” New York 1906.

But further, the restriction of the term stimulation to those
alterations which increase the course of the changes in the living
substance involves the observer in still greater contradictions. It
can easily be shown that one and the same factor in one and the same
form of living substance has now an exciting, now a depressing effect
on the vital processes. This fact can be readily demonstrated[19]
by means of the infusoria _Colpidium colpoda_, which can be grown
without difficulty in a hay infusion. A number of individuals in a
drop of fluid may be placed in a warm stage and observed under the
microscope; one then sees that at room temperature they swim about
by moving their ciliary processes at a definite rate. Now if the
temperature is raised to about 35° C., the ciliary movement becomes
enormously increased. The infusoria swim madly through the field of
vision. They are in a state of violent excitement. The increase has,
therefore, acted as a strong, exciting stimulus. But if one allows
the temperature to further increase only a few degrees the ciliary
movements are suddenly greatly retarded. The infusoria now swim
sluggishly through the field of vision and finally remain stationary.
In this case the increase in the temperature has had a depressing
effect. If the infusoria are not quickly removed, the depression is
followed by death. Should the increase in temperature be regarded in
the _first_ instance as a stimulus, and _not as such_ in the _second_,
in which the temperature rises only a few degrees higher? Here the
change in the vital conditions concerned is in both instances positive.
In all cases of overstimulation we are confronted by the same question.
Nevertheless it is not at all necessary to refer to such strong or even
life-endangering stimuli for the observation of these conditions. In
this connection I would like to cite an even more striking instance and
which is of special interest for the understanding of the phenomena
in nerve centers. If the posterior spinal roots of a _Rana temporara_
are severed, and the eighth root stimulated with a faradic current,
whilst the _musculus Gastrocnemius_ of the same side is connected
with a writing lever, one obtains, as _Vészi_[20] has found, at the
moment of the beginning of stimulation a contraction of the muscle.
The faradic stimulus has, therefore, produced an excitation reflexly.
If instead of the _eighth_ the _ninth_ posterior root is stimulated,
the result obtained is also an excitation of the muscle. In this case,
however, the excitation in the form of a tetanic contraction lasts
for some time, provided that the stimulation is not at once stopped.
If now during tetanic stimulation of the ninth root the eighth is at
the same time stimulated, with a strength of current equal to that
which previously brought about contraction of the muscle, instead of
an _increase_ and a _strengthening_ of contraction there is, on the
contrary, an _inhibition_ which continues throughout the time during
the stimulation of the eighth root. If the stimulation of the eighth
root is discontinued, the tetanic response of the ninth root reappears.
If, on the other hand, the faradic stimulation of the ninth root is
interrupted and the eighth root now again stimulated, one obtains once
more, as in the beginning, with each stimulation a contraction of the
muscle. This fact is illustrated by the accompanying tracings. (Figure
2.) In this investigation undertaken in the Göttingen laboratory it
was further shown that a faradic current of the same strength and the
same frequency had at one time an augmenting, at another an inhibitory
effect, and these effects could be produced alternately at will. Should
the faradic current at one time be called a stimulus, at another not?
It is here clearly shown to what absurd consequences it leads if the
conception of stimulation is limited solely to the cases in which an
external factor has an exciting effect; and yet an immense number of
instances of a like nature could be cited to show the untenability of
this view.

  [19] _Max Verworn_: “Physiologisches Prakticum für Medizinen.” Jena
  1907.

  [20] _Julius Vészi_: “Der einfachste Reflexbogen im Rückenmark.” In
  Zeitschrift f. allgemeine Physiologie Bd. XI, 1910.

[Illustration: Fig. 2.

Lower thick line shows duration of stimulation of 9th root; upper thick
line that of 8th root.]

It follows from this, that it is altogether impracticable to define
the stimulus itself in relation to the nature of the effects which
the stimulus has upon the substances in the living system. One can
only appreciate the nature of stimulation in relation to the vital
conditions and without considering the nature of the action of the
stimuli on the living substance. It is true that every stimulus is
followed by an alteration in living processes, but this is to be
expected when one clearly understands the nature of vital conditions.
A stimulus is in all cases an alteration in vital conditions and, in
that each of the vital conditions is necessary for the continuance
of life, it follows of necessity that every alteration in the vital
conditions, so intimately connected with the living processes, will
also be followed by an alteration in the processes occurring in the
living system. In short, response is produced. Nevertheless, a definite
alteration of an external vital condition, depending upon the state
of other vital conditions, that is, according to the state of living
substance at the moment, can produce quite opposite effects. Although
it may appear expedient to include in the conception of stimulation in
given instances, distinctions between stimuli according to the nature
of their effects upon the living substance, in all cases the conception
must under all circumstances be so formulated that it comprises _all_
alterations in the external vital conditions, either positive or
negative, that is to say, an increase or decrease, an augmentation or
diminution in those factors, acting as vital conditions.

Besides the quality there is another highly important factor to be
considered in the study of every alteration in the living process,
namely, its _amount_. The chemical concentration of the medium,
temperature, amount of light, the static and osmotic pressure may
undergo more or less variation. The electric stimulus can rise from
zero to great intensity and from great intensity can fall to zero. The
extent of the alteration determines the intensity of the stimulus.
In relation to the intensity, a differentiation of stimulation has
been introduced, which is not dependent upon the absolute intensity
of the stimulus, that is, upon the extent of the alterations in the
external vital conditions, but the intensity of the response that
can be observed. One refers frequently to threshold stimulation,
to stimulation beneath the threshold, to submaximal, maximal and
supermaximal stimulation. Such a classification is in many ways very
valuable. It is not only of practical value for the establishment of
definite intensities of stimulation, but also for the study of the
state of irritability in the living organisms.

_The threshold of stimulation_ furnishes roughly a standard for the
degree of irritability of a living system. The threshold value of a
stimulus is then that degree of intensity which is just sufficient
to bring about a perceptible response. The threshold of stimulation
is low, that is, the irritability is great, when the intensity of
the threshold stimulus is small; the threshold is high, that is, the
irritability of a system is small, if the intensity of the threshold
stimulus is great. All intensities of stimuli beneath the threshold
are sub-threshold stimuli. Here a point must not be overlooked, which
in older physiology did not generally meet with sufficient attention.
From the fact that the sub-threshold stimuli produce no apparent
effects, the wrong deduction must not be made, that they have no effect
whatsoever. The conception of the threshold of stimulation originated
in the field of muscle physiology and that of the special senses.
Here the indicator of the response is, on the one hand, contraction
of the muscles, and on the other, conscious sensation. There was a
great temptation to consider the stimulus altogether ineffectual, if
it produced no conscious sensation or no contraction of the muscle.
Today with our finer and more sensitive indicators for the study of
the alterations in the living substance, we know in reality that
sub-threshold stimuli, which produce no apparent effect in the living
substance, can have an effect in reality.

I will call your attention later to the fact that these sub-threshold
stimuli play a very important rôle under certain conditions in the
activities of the central nervous system. It only depends upon the
sensitivity of our special senses, or the indicators used for this
purpose, as to whether the alterations can be observed or not. The
conception of the threshold of stimulation, therefore, has meaning
only when used in relation to a certain indicator. The threshold of
the same living system may be different for different indicators.
When we use the term threshold we must necessarily know the indicator
employed in its determination. The threshold stimulus produces only
barely perceptible effects. The amount of response in most living
substances increases with the intensity to a certain limit. If this
limit is reached, that is, if the response is maximal, the stimulus
of the weakest strength necessary to produce this result is termed
the _maximal stimulus_, whereas all intensities lying between the
threshold and the maximal stimulus are termed _submaximal stimuli_. If
the intensity of the stimulus is increased _above_ that of the maximal,
the response, as in the case of the muscle, does not increase, and
therefore one could say that all intensities above the maximal could
also be called maximal stimuli.

In realty, however, the response to stimuli of different intensities
is never equal, even though it may appear so, when measured by
an indicator, as for instance, the height of the maximal muscle
contractions. This is clearly shown, for example, when the electrical
stimulus is increased far beyond that intensity which is necessary
to produce maximal effect. Injury is thereby produced, which is
manifested, for instance, in the muscle contraction by the nature of
its course and also by its height. One is, therefore, justified in
a certain sense in calling the intensities of the stimulus, which
are above the value which barely produces maximal contraction,
“_supermaximal stimuli_,” notwithstanding this is logically far from
being a happy expression. The term “maximal stimulus,” then, is limited
to the intensity of the stimulus which just produces a maximal effect.
I wish to point out this distinction between maximal and supermaximal
stimulus, as there is often a lack of clearness in the use of these
terms.

In that the nomenclature of intensity of stimulation is based upon the
intensity of response, the question arises as to the _relation between
the intensity of stimulus and the amount of response_. It is well known
that this question has met in one special field of physiology with a
very detailed and comprehensive treatment. I allude to the teaching
concerning sensation. _Ernst Heinrich Weber_[21] first called attention
to the relation between increase in sensation and that of the stimulus
in the case of the sense of touch. His observations, which have been
formulated into “_Weber’s law_,” have been the object of animated
discussion. A presentation of this law is the following: “The amount
of pressure necessary to produce a perceptible increase of sensation
always bears the same ratio to the amount of the stimulus already
applied.”

  [21] _Weber_: “Annotationes anatomicæ et physiologicæ.” Lips.
  1851. The same: “Der Tastsinn und das Gemeingefühl,” in Wagner’s
  Handwörterbuch d. Physiologie Bd. III. 2. Braunschweig 1846.

If in accordance with _Ziehen_[22] we designate the relative increase
in pressure to that already applied, which is necessary to produce
a perceptible increase in sensation, as the _threshold of relative
differentiation_, we can formulate the law in the simplest way thus:
The _relative threshold of differentiation is constant_. _Fechner_,[23]
who indeed attempted to apply this law, applicable to the sense of
pressure, to all the other special senses, has given us a mathematical
formula, based on the assumption that the just perceptible increase of
sensation has the same value at all levels. By this assumption he was
able to establish for the first time a relation between the intensity
of sensation and that of stimulus, for it follows that “_the sensation
increases in intensity in arithmetical progression, whereas the
intensity of the stimulus increases in geometrical progression_.” From
this _Fechner has_ worked out a psychophysical formula, which today is
generally termed the _Fechner law_. This is the law: _The intensity of
sensation varies with the logarithm of the intensity of the stimulus._

  [22] _Ziehen_: “Leitfaden der physiologischen Psychologie in 15
  Vorlesungen.” VI Auflage. Jena 1902.

  [23] _Fechner_: “Elemente der Psychophysik.” Leipzig 1860. 2 Auflage
  1889.

Soon the _Weber_ as well as the _Fechner_ law had been extended over
the whole field of sensation and stimulation. In this connection
_Preyer_[24] has formulated his “myophysical law,” which states
that there is the same relation between strength of stimulus and
the intensity of response of the muscle as is laid down by the
_Fechner_ law for stimulation and sensation. _Pfeffer_[25] has
found that _Weber’s_ law applied also to the relations of the
chemotaxis of bacteria, to the intensity of the chemical stimulus,
and likewise the attempt has been made to show that all living
substances respond in the manner laid down by the _Weber-Fechner
law_. Unfortunately the innumerable investigations in this field have
shown more and more clearly that it is not possible to formulate a
general mathematical law, which strictly fixes the relations of the
intensity of the stimulus and the intensity of response. Even in
the field of the physiology of the special senses many voices have
opposed the general application of the _Weber_ and the _Fechner law_.
_Lotze_, _G. Meissner_, _Dohrn_, _Hering_, _Biedermann_ and _Löwitt_,
_Funke_ and numerous other investigators have already demonstrated
for some decades, partly by means of critical inquiry, partly by
experimentation, that these laws are not strictly valid. Above all
these experiments have shown that logarithmic relations are not
tenable and likewise are not applicable to very strong stimuli. The
assumption made by _Fechner_, that is, the acceptance that all barely
perceptible increases of sensation have an equal value, has been set
aside as incorrect, and with this his mathematical formulation within
those boundaries of intensity of the stimulus, in which the _Weber_
law has proven itself valid, must also be abandoned. That which we can
say today with certainty concerning the relation between the intensity
of stimulus and the amount of response is as follows: A law generally
applicable to the relation between the strength of the stimulus and the
amount of response cannot be mathematically formulated. For a great
number of living systems the rule which holds for the intensity of
stimulation within certain boundaries is the following: With increase
of the intensity of stimulation the _response_ at first increases
rapidly and later more and more slowly.

  [24] _Preyer_: “Das myophysische Gesetz.” Jena 1874.

  [25] _Pfeffer_: “Ueber chemotaktische Bewegungen von Bacterien,
  Flagellaten und Volvocineen.” Untersuchungen aus dem botanischen
  Institut zu Tübingen. Bd. II, 1888.

This rule of course only applies within the boundaries of the
intensity between the threshold of stimulation and maximal stimulus.
The interval, however, between these intensities varies considerably
in different living substances. In this connection there are several
forms of living substance which call for our special attention. In
these the surprising condition seems to exist, that the interval
between the threshold and the maximal stimulus is zero; that is,
every stimulus which acts at all always produces a maximal response.
_Bowditch_[26] first observed this behavior in the frog’s heart and
this has also been confirmed by _Kronecker_.[27] The induction current
produces, as _Bowditch_ says, either a contraction or nothing. If
the former, it is the strongest contraction which can be produced
by an induction shock at the given time. Here for the first time a
constancy of response was discovered which has been termed the _all or
none law_. _McWilliams_[28] has later verified the same fact for the
mammalian heart. _Gotch_[29] has also arrived at the same conclusion
in connection with the nerve. He states that “the comparison of
submaximal with maximal responses shows that although there is an
obvious difference in the amount of E. M. F., there is little or no
difference between such time relations as the moment of commencement,
the moment of culmination of E. M. F. and the rate at which E. M. F.
disappears.” Further: “the rate of propagation of the excitatory wave
is the same whether this is maximal or submaximal.” He likewise assumes
that the “all or none law” is applicable to the constituent fibers, and
that the variations in the strength of response with weak and strong
stimulation are brought about in the first instance by stimulation of
a few, in the latter by a greater number of fibers in the nerve trunk.
The same conclusion has been reached by _Keith Lucas_[30] for the
single cross-striated fiber of the skeletal muscle, founded on the fact
that by direct stimulation of a bundle of curarized muscle fibers,
the contraction only increases inconstantly and not regularly with the
increasing intensity of the stimulus. This is only comprehensible if
one takes into consideration that, with the increasing intensity of
the stimulus, a greater and greater number of fibers are stimulated.
_Keith Lucas_[31] came to the same conclusion in the case of the
muscle stimulated indirectly through the nerve. He, therefore, sees,
because of the nature of the response of the single muscle cell, no
difference between heart muscle and skeletal muscle. The “_all or
none law_” applies to the individual muscle cells of both kinds. The
difference between the heart and skeletal muscle, according to him,
lies in the fact that in the heart the individual muscle cells in their
totality stand together as conductors of excitation, whereas in the
skeletal muscle the individual muscle fibers are separated, as far as
conduction of excitation is concerned, by the sarcolemma. Finally, the
recent investigations of _Vészi_[32] with strychnine poisoned ganglia
cells of the posterior horns of the spinal cord, have made it appear
probable that “the all or none law” can be applied likewise to the
individual ganglion cell. He draws this conclusion not only from the
fact that all reflex contractions of a muscle of a strychninized frog
are maximal, whether they are produced by weak or strong stimuli, but
also especially because of the loss in the strychninized spinal cord
of the capacity of the summation of irritability. The normal spinal
cord does not reflexly respond at all to weak single stimuli, but
responds to equally weak faradic stimulation very readily. Therefore,
the threshold lies very high for the individual induction shock and
very low for faradic shocks. But these differences are equalized in the
strychninized frog. This seems intelligible, when we assume that the
strychninized cell responds to every stimulus, to which it responds
at all, to the maximal extent which is permitted at that moment by
its stored up energy, otherwise the excitation would necessarily be
summated by faradic stimulation.

  [26] _Bowditch_: “Ueber die Eigentümlichkeiten der Reizbarkeit,
  welche die Muskelfasern des Herzens zeigen.” In Arbeiten aus der
  physiologischen Anstalt zu Leipzig VI. Jahrgang 1872.

  [27] _Kronecker_: “Das characteristische Merkmal der
  Herzmuskelbewegung.” In Beiträge zur Anat. und Physiol. Als. Festgabe
  Carl Ludwig gewidmet von seinen Schülern. Leipzig 1874.

  [28] _McWilliams_: “On the rhythm of the mammalian heart.” Journal of
  Physiology, Vol. IX, 1888.

  [29] _Gotch_: “The submaximal electrical response of nerve to a
  single stimulus.” Journal of Physiology, Vol. XXVIII, 1902.

  [30] _Keith Lucas_: “On the graduation of activity in a skeletal
  muscle fibre.” Journal of Physiology, Vol. XXXIII, 1905–06.

  [31] _Keith Lucas_: “The all or none contraction of skeletal muscle
  fibre.” Journal of Physiology, Vol. XXXVIII, 1909.

  [32] _Vészi_: “Zur Frage des Alles oder Nichts-Gesetzes beim
  Strychninfrosch.” Zeitschrift für allgemeine Physiologie Bd. XII,
  1911.

Such are the instances to which one has up to the present applied
the “all or none law.” The question if, as a matter of fact, such a
condition has ever been realized in any living substance has until now
found no final answer. Most authors, who accept the validity of the
“all or none law” for certain living substances, do so with a certain
reserve and speak only of the possibility or probability of such
behavior. The subject has, however, as will be shown later, a great
and even vital interest in another direction. For this reason I should
prefer to postpone the treatment of the same to a later occasion. Here
I wish simply to say, that _if_ the “all or none law” is valid in a
strict sense for certain structures, then there exists no general
constancy of the relations of the intensity of the stimulation and the
amount of response, applicable to all living organisms.

We will now return from this digression concerning the relations
between the intensity of the stimulus and the response, to the
further characterization of the properties of the stimulus. Besides
the quality, the direction and the intensity of every alteration in
vital conditions, an equally important factor is the duration of
the alteration. The time relations, under which a deviation of the
external vital conditions takes place, present immense and manifold
variations in nature. In many cases the change is very complicated, as
for instance, the alteration of the static pressure or the temperature
under the influence of air or water currents, the osmotic pressure
or chemical factors in diffusion currents, and the light intensity
produced by the movement of clouds. These very irregular alterations
have practically little interest for us. Here we are concerned rather
with the differentiation of the time alterations of the processes of
the simplest fundamental types, which are of importance in studying
the course of the reaction. For it is of such simple elements that the
complicated and irregular alterations of the above-mentioned kinds are
composed.

The simplest form of an individual change in the external vital
conditions would be a regular and constant alteration of intensity
which can be graphically represented as a straight line, wherein the
intensities are the ordinates and the time the abscissa. (Figure
3, A.) A regularly rising pressure would, for instance, represent a
stimulus in its simplest form. But such forms of stimuli are only very
rare in nature and are also experimentally very difficult to produce.
It is, for example, not easy to give the _electrical_ stimulus, so much
used for experimental purposes, this form. _Fleichl_ and _v. Kries_
have only accomplished this by means of complicated apparatus. The
usual _form of the individual stimulus_ is not a straight line, but a
logarithmic curve. (Figure 3, B.) The alteration hardly ever progresses
with equal rapidity from its beginning until it reaches its highest
point, but as a rule, with decreasing rapidity. This is the usual
course of alterations of concentration, also of chemical and osmotic
stimuli, of changes of temperature and of electric stimulation.

[Illustration: _A_

_B_

Fig. 3.]

The _rapidity of alterations_ in vital conditions has quite an
important influence on the development of the response to stimulation.
It is well known that if a constant current, which reaches its highest
intensity rapidly, is permitted to act upon a muscle, the effect
differs from that following the application of a current of the same
intensity but in which this is reached very slowly. In the first case
there is a sudden strong twitch, in the second none at all. In spite
of this there can be no doubt whatever of the current in the last case
being effective. That the muscle is also excited when the current is
slowly increased is shown by the contracture, which grows more and more
plainly perceptible with the increasing intensity of the current and
in higher intensities by the so-called _Porret’s_ phenomenon, which
consists in a curious wave-like movement of the muscle-substance. In
reference to the rapidity of the alterations in the factors which
act as stimuli, the behavior varies greatly. Many stimuli because of
their nature never have a steep ascent or descent of intensity, as, for
instance, alterations in the concentrations of soluble substances, that
is, chemical or osmotic stimuli; likewise temperature variations may be
mentioned. They always act relatively slowly. On the contrary there are
forms of stimuli which have now a rapid, now a slow, ascent or descent
of their intensity, such as the photic and mechanical stimuli. Finally,
there are other stimuli that nearly always show a very abrupt change of
intensity, such as the electrical form.

The most important factor to be considered in producing the response
to variations of intensity, is not the _absolute rapidity_, but rather
the _relative rapidity_; that is, the rapidity in relation to the
characteristic rapidity of reaction of the particular living substance
concerned. The rapidity of the reaction to stimuli is very different
in various forms of living substance. On the one hand, we have forms
reacting very quickly, as the nerve and the striated muscle; on the
other, those which respond very slowly, such as a great number of
unicellular organisms. Between these are a great number of living
substances which, as far as the rapidity of the reaction is concerned,
occupy intermediate positions of every varying degree. It is clear
that the adequate stimuli for slowly reacting substances must be those
having also a slow change of intensity; for quickly reacting, those
having a rapid change of intensity.[33] If a nerve muscle preparation
is simulated with the single induction shock, the “break” as well as
the “make” shock has effect. But even here a difference is noticeable.
The “make” shock has a weaker effect than the “break” shock. This
difference is due to the difference of abruptness in its course, which
when the current is made is less than that of opening, for, when the
current is made, the ascent of the primary current is retarded by
the extra current flowing in the opposite direction, whereas, when
broken, with the fall of the intensity of the primary current, the
extra current in the primary coil flows in the same direction. In
consequence of this there is a perceptible difference in the rapidity
of the alteration of the “make” and “break” shocks. (Figure 4.)

  [33] Vergl. _Julius Schott_: “Ein Beiträg zur electrischen Reigung
  des quergestreiften Muskels von seinen Nerven aus.” Pflügers Archiv
  Bd. 48, 1891.

[Illustration: Fig. 4.

Course of induction shocks. 1 and 2 make and break of the primary
current. 1_{1} and 2_{1} make and break induction shocks. (After
_Hermann_.)]

Now slowly reacting forms of living substance, such as certain
foraminifera, in which the extended pseudopods are stimulated with
single induction shocks, the break as well as the make shocks are
wholly without effect, as both take place far too quickly for the
slow responsivity of these organisms. I have made such observations
on various forms of foraminifera of the Red Sea, on _Orbitolites_,
_Amphistegina_ and others. The movement of granules in the pseudopods
is not influenced by the induction shocks in the least. It also
continues without interruption when the pseudopods are extended. Even
with the strongest induction shocks at my disposal I could _not_ induce
them to contract; the faradic current, also, the intensity of which
I found quite unbearable, remained utterly without effect.[34] These
two extreme cases, the nerve and the foraminifera, show plainly that
the effect of a stimulus is not produced by the absolute rapidity of
the increase of intensity, but is solely influenced by the relative
rapidity of the same.

  [34] _Max Verworn_: “Untersuchungen über die polare Erregung der
  lebendigen Substanz durch den constanten Strom.” III Mitteilung,
  Pflügers Arch. Bd. 62, 1896.

[Illustration:

  A      B      C

Fig. 5.]

A further point for consideration in the duration of an alteration in
a vital condition in producing a stimulant action is the _length of
time the stimulus remains after reaching its highest point_. In the
forms of stimuli occurring in nature the duration of the alteration
after reaching its highest level can vary considerably. The stimulus
may remain indefinitely at a certain level, when this is once reached.
(Figure 5, A.) The alteration likewise persists. This would be the
case, for instance, with the changes of concentration in the transfer
of an organism from fresh into sea water. The alteration can also,
however, immediately after attaining its highest level, return, so that
the original state is at once reestablished. (Figure 5, B and C.) Here
it is a case of a quick deviation in the external vital conditions. A
_sudden jar_ would be a case in point. Between these two extremes we
have all variations in the duration of all natural and experimental
forms of single stimuli.

Now we arrive at the question: Has a prolonged stimulation really a
prolonged effect? This question might seem superfluous, as from a
conditional standpoint it is self-evident that every alteration in
any one of the conditions of a system is followed by an alteration in
the system. But this very question played an important rôle in older
physiology and led to prolonged discussions for the reason that a
special case was taken into consideration in this connection, which
at that time was not clearly understood. _Du Bois-Reymond_,[35] as a
result of his investigations on the nerve muscle preparation of the
frog, formulated a law of nerve excitation, according to which it is
not the _absolute value_ of the intensity of the constant current which
produces an excitation of the nerve and contraction of its muscle, but
an alteration of the intensity from one moment to another. The more
rapidly these changes are produced, the greater is the excitation.
His arguments were based upon the fact that a contraction can only
take place on the “making” or “breaking,” or by rapidly strengthening
or weakening the constant current; it is possible to subject a nerve
muscle preparation to a current of considerable strength without a
muscle contraction resulting, provided it is slowly increased. One
might be disposed to conclude from this that the constant current,
when showing no fluctuations, has no stimulating effect whatsoever.
Should this observation be carried even further and the attempt made to
extend it into a general law of excitation by assuming that the effects
of stimulation are only produced by variations in the intensity, not
by its continued duration, one would commit the error of judging the
occurrence of a stimulus only by the unsatisfactory criterion of an
abrupt muscle contraction. Today we know with positiveness that a
continued effect also exists during the uninterrupted flowing of a
constant current in nerve or muscle, though much weaker, however, than
in the case of the excitations produced by sudden fluctuations of the
intensity. This is shown in the nerve by an altered excitability, which
continues at the poles during the whole duration of the current. In
the region of the anode the excitability is diminished, in that of
the cathode it is increased. An excitation can also be demonstrated
which extends from the cathode through the nerve, which can easily
be detected by sufficiently delicate methods. Among other effects of
prolonged stimulation is that of cathodal contracture, which remains
localized in the region of the cathode and which excitation persists
as long as the current continues. This permanent excitation can be
particularly well observed in the single cells of the rhizopods. If a
constant current is allowed to flow through an _Actinosphærium_,[36]
the straight, smooth, ray-shaped pseudopods of the cell body at the
moment of “making,” show evidence of contraction by being drawn _in_,
particularly those directed towards the anodic and in less degree also
those towards the cathodic pole. This excitation, greatest at the time
of “making” of the current, though diminishing rapidly in intensity
during its continuance, remains, however, to a less degree, and leads
to a progressive disintegration of the protoplasm on the side towards
the anode, which lasts until the current is again broken. (Figure 6.)
Thus even though there can be no doubt, on the one hand, that the
effect of stimulation, which appears at the moment of the entrance,
is to produce alterations, which develop very rapidly, and that by a
continuation of this state there is a more or less rapid fall to a low
level; on the other hand, it is just as certain that the alterations
in the living system persist throughout the duration of the changed
external conditions, or to put it more concisely: the effect of the
stimulus never wholly disappears unless the changes in the external
vital conditions return to their original state.

  [35] _Du Bois-Reymond_: “Untersuchungen über tierische electricität.”
  Bd. I. Berlin 1848, p. 258.

  [36] _Kühue_: “Untersuchungen über das Protoplasma und die
  Contractilität.” Leipzig 1864. _Max Verworn_: “Die polare Erregung
  der Protisten durch der galvanischen Strom.” Pflügers Arch. Bd. 35,
  45, 1889.

[Illustration: Fig. 6.

_Actinosphaerium eichhornii._ Four stages showing the progressive
influence of a constant current. Protoplasmic disintegration at the
side toward the anode.]

But more, an effect of the stimulus cannot indeed take place _without_
a certain duration of stimulation, which is related in _its_ turn to
the rapidity of reaction of particular living system. This can be much
more readily observed in more slowly reacting substances. _Fick_[37]
first proved this fact on the muscle of the _Anodonta_. I have also
been able to demonstrate the same fact in the slowly reacting sea
rhizopods[38] by the use of the constant current. When _Orbitolites_
is stimulated with a constant current lasting approximately the tenth
of a second, no response is seen in its extended pseudopods, which
are directed towards the poles. The same is the case if the induction
current is employed. Only when the constant current of the uniform
strength lasts approximately .05 seconds, a barely perceptible response
occurs, manifested by the sudden stoppage of the centrifugal flowing of
granules in the anodic pseudopods, which, however, after the lapse of
one to three seconds continues again unaltered. Should the duration of
the constant current be still further prolonged, typical symptoms of
contraction are seen being manifested by a heaping up of the protoplasm
in the pseudopods in the form of spindles and balls, whilst the
protoplasm flows in a centripetal direction towards the central cell
body. (Figure 7.)

  [37] _A. Fick_: “Beiträge zur vergleichenden Physiologie der
  irritablen Substanzen.” Braunschweig 1863.

  The same: “Untersuchungen über die electrische Nervenreizung.”
  Braunschweig 1864.

  [38] _Max Verworn_: “Untersuchungen über die polare Erregung der
  lebendigen Substanz,” etc. III Pflügers Arch. Bd. 62, 1896.

Two effects can be realized by the alteration in the living system as
the result of prolonged stimulation. Either a new state of equilibrium
is established by the prolonged action, or sooner or later death
develops. In considering both results, however, we will ignore for
the present the fact that every living system in the absence of
such prolonged stimulation is always in a state of change, i.e.,
development. Only with this restriction can an equilibrium of the
living system be spoken of.

[Illustration:

  A      Fig. 7.      B

_Orbitolites complanatus._ A--Before stimulation. B--Under influence of
a constant current.]

It is sometimes the case that under the influence of a stimulus a new
equilibrium is developed, which may remain as long as the stimulus
persists. This most frequently occurs as a result of _weak_ stimuli.
That which is usually termed “individual adaptation” belongs in this
category. Likewise some of the natural and artificial immunizations may
also be included. The continued stimulation in such cases of adaptation
as we learned before in the example of _Amœba limax_ and _radiosa_ or
_Branchipus stagnalis_ and _Artemia salina_ becomes a vital condition
for the living substance in its new state.

The other result, namely, that of death ensuing sooner or later, is
most frequently produced by stronger stimulation. Through the effect of
the prolonged stimulation, the change in the living system is so great
that all harmonious interaction of the various processes of life become
after a time impossible. The disturbance of this equilibrium after a
longer or shorter time becomes so great that life ceases. By far the
greater number of all diseases furnish examples of this kind. Disease
is nothing else but reaction to stimulation. Should a constant stimulus
persist and if the development of a new equilibrium of this system is
not established, the result is premature death.

In most cases, as, for instance, the nerve impulses which move
toward an organ, or better still the electrical stimuli as used for
experimental purposes, it is not a question of a permanent but of a
temporary alteration in the external vital conditions. The stimulus
starts, then ceases after a longer or shorter period. In this way
there is added to the deviation at the start also the alteration at
its termination. The latter takes place with different degrees of
rapidity, in a manner analogous to that of the initial alteration,
and can bring about response. With this the curve of the duration of
the course of the stimulus becomes somewhat more complicated and in
consequence a like effect is observed in the response. The “making,”
duration and “breaking” of the constant current furnishes the example
of this type. The “making” of the current being a quick alteration
calls forth a strong and sudden excitation (in the muscle contraction);
the continuation of the current maintains weak excitation of equal
intensity (in the muscle a continued contraction) and the “breaking,”
being a sudden alteration, is followed again by a stronger excitation
(in the muscle a contraction). The duration of the change can, however,
be so short that its intensity does not remain at two periods of
time at the same height, but instead the ascent of the intensity is
immediately followed by its descent to zero. Induction shocks of short
duration, the duration of which have been observed more in detail
especially by _Grützner_,[39] offer typical examples. Here a single
effect of the stimulus results from the rise and fall of the intensity
curve. Hence the induction shocks as momentary stimuli are universally
used for experimental purposes.

  [39] _Grützner_: “Über die Reizwirkungen der Stöhrer’schen Maschine
  auf Nerv und Muskel.” Pflügers Arch. Bd. 41, 1887.

In contrast to the single stimuli, which find their ideal in induction
shocks, another form of stimulation should receive our attention,
namely, the series of stimuli which produce a rhythmical alteration
of vital conditions. These show among their complex combination of
simultaneous and successive actions of their single stimuli relatively
the simplest and most easily understood regularity in their effects.
They are of particular interest, because they develop in the normal
physiological happenings of the animal body in the form of rhythmical
intermittent impulses of the nervous system.

Here again it is self-evident that with regard to the course of
response, we must first consider the character of the single stimulus
of the series, and this must be done from all those standpoints
already here discussed. However, a new factor is met with here, that
is, the frequency of the single stimuli of the series, or that which
has the same meaning, the duration of the intervals between them.
This is a feature upon which the result of stimulation depends in a
very high degree. But here, too, however, it is not a case of the
absolute frequency of the single stimulus, but simply of the relative
frequency in regard to the rapidity of reaction of the particular
living system. I should like to remark here that it is of greatest
importance whether the interval between the two single stimuli of the
series is sufficiently long or not to allow the living system time
to completely recover from the effect of the _preceding_ stimulus.
In the cases, for instance, where we have recovery, we have the same
rhythm of stimulation as that of response. When recovery _does not_
occur, interferences of the response are developed, which are of great
physiological importance, with the analysis of which we shall later
on find occasion to occupy ourselves in detail. The physiological
example for these stimuli is the rhythmical discharge of impulses of
the nerve centers; the physical method, which is most widely used for
experiments, is the faradic current.

It is apparent that the question of frequency must again be combined
with all those factors previously discussed in connection with the
_single_ stimulus. In consequence another complication arises and
with this another point must be taken into consideration, namely, the
fact that the duration of the single stimulus in a series undergoes
alteration by increasing frequency beyond a certain limit. Beyond
this limit the duration of the single stimulus must become less and
less. As the result of the fact that stimulation is, as we have seen,
dependent on the duration of stimulus, it is evident that, depending
upon the rapidity of response of the living system, sooner or later
the rhythmical stimulation must become ineffectual. Nevertheless,
this effect of shortening the duration of the single stimulus can be
compensated by a corresponding increase of its intensity. In this
connection _Nernst_[40] showed a very simple relation for induction
currents of higher frequency of interruption, which furnishes a law
according to which such a compensation takes place. In conjunction
with _Barratt_ he found, namely, that the intensity must increase
proportionately to the square root of the number of single stimuli if
the threshold value of the stimulus is to be maintained, that is, I :
√m = const., in which _I_ is the intensity of the current and _m_ the
frequency of interruptions. The limits of the validity of this law
cannot at present be conclusively established.

  [40] _Nernst und Barratt_: “Ueber electrische Nervenreizung durch
  Wechselströme.” Zeitschrift für Electrochemie 1904.

This exhausts the small number of elementary factors concerned in the
course of the stimulation, and which are of importance in considering
its effect. The combination of the different varieties of these single
factors, that is, the nature, the direction, the intensity, the
rapidity, the duration and number of alterations in the external vital
conditions of the organism produce the enormous variety of effects of
stimulation which we observe in the living world.




CHAPTER IV

THE GENERAL EFFECT OF STIMULATION

 _Contents_: Various examples of the effects of stimulation. Metabolism
 of rest and metabolism of stimulation. Metabolic equilibrium.
 Disturbances of equilibrium by stimuli. Quantitative and qualitative
 alterations of the metabolism of rest under the influence of stimuli.
 Excitation and depression. Specific energy of living substance.
 Qualitative alterations of the specific metabolism and their relations
 to pathology. Functional and cytoplastic stimuli. Relations of the
 cytoplastic effects of stimuli to the functional. Hypertrophy of
 activity and atrophy of inactivity. Metabolic alterations during
 growth of the cell. Primary and secondary effects of stimulation.
 Scheme of effects of stimulation.


In the foregoing lectures we have had occasion to touch more or less
often on the subject of the effects of the stimuli. This was the
case, however, only when it appeared necessary to obtain a systematic
knowledge of the stimuli and the differentiation of the individual
factors. We will now proceed to consider the effect of stimulation in a
more systematic manner. The conditional method of observation, however,
will remain our guide.

We have already pointed out the relations between the conception of
stimulation and that of vital conditions, now we will consider that of
the effect of stimulation with that of vital processes. Nevertheless,
the _effect_ of stimulation being a manifestation of the vital process
is not, therefore, in opposition to the latter as such. Hence the
question presents itself as to the connections between vital process
and the effect of stimulation.

When we study the motile flagellate infusorium _Peranema_ swimming
undisturbed in water, we observe that the swimming movements are
absolutely regular in character. The elongated cell body remains
unaltered in shape. The long flagellum is extended in a perfectly
straight line in the axis of the body and only the extreme end lashes
with regularity through the water (Figure 8, A). There is majestic
grace in this perfect uniformity of motion. The picture suddenly alters
the moment the _Peranema_ is influenced by the slightest jar. The whole
flagellum at once executes a few violent movements (Figure 8, B), the
body draws together, soon stretches itself again and swims immediately
after, in another direction, with the same majestic calm as before.

[Illustration: Fig. 8.

_Peranema._ A--Swimming in non-stimulated condition. B--Mechanically
stimulated at the end of the flagellum.]

Another instance. A number of fertilized eggs of the sea urchin are
placed in a watch glass in sea water. The temperature of the water
should correspond with the mean temperature in which the animals live
in the sea, averaging about 15° C. The eggs begin to form grooves and
to develop slowly by progressive division. In another glass we observe
a second sample of fertilized eggs of the same kind and under the same
conditions, but in this case we increase the temperature to 25° C. The
increased temperature brings about a decided increase of segmentation
and the same stage of development is reached in less than half the
time. The increased temperature, therefore, increases the development.
Further we take a third sample of the same urchin eggs in a watch glass
with sea water of 15° C. and add a little sea water mixed with ether.
The development of the eggs now comes to a standstill. The narcotic has
produced an inhibition of development.

To quote another instance. _Bacterium phosphorescens_ having been bred
upon a putrid fish are exposed in the culture fluid to the air. In the
dark the bacteria give forth a phosphorescent light. Then the culture
fluid containing the bacteria is put into a glass receptacle, which can
be rendered air-tight and all oxygen excluded. After a short time the
light formation ceases completely. The absence of oxygen has here had
a depressing effect and it is only after air has been again introduced
that light is once more produced.

Lastly, an example from the group of mammals may be cited. The
metabolism of a dog in complete rest is examined for a prolonged length
of time and we ascertain the values of the oxygen consumption, the
carbon dioxide production, and the nitrogen elimination in the urine.
Under the same nutritive conditions the animal is then allowed to
work from time to time in a treadmill. During these working periods
impulses of excitation are continually conducted to the muscles from
the nervous system. It is now found that under the influence of the
constantly recurring stimuli the quantity of nitrogen in the urine has
only very slightly augmented, whereas the consumption of oxygen and the
production of carbon dioxide has markedly increased.

What conclusions can be drawn from these instances of response to
stimuli, of which any number could still be quoted? They show us, first
of all, that a state or process existing under given conditions, is
altered by the influence of the stimulus. This is a fact, however,
which could be expected from the beginning and is self-evident, for
stimuli are alterations in the vital conditions, and when these are
altered the state of the system or the happenings thereof must also
alter. The question with which we are here more closely concerned,
however, is a somewhat more detailed characterization of the state
or process itself, as well as that of alterations produced by the
influence of the stimulus. The instances of response to stimuli already
cited furnish us with information in both kinds.

In all these examples, the living processes occur with equal constancy
and unaltered rapidity, provided a stimulus is not operative. Here,
however, the gradual alterations, the result of development, must
not be overlooked. An excellent example of this is seen in the eggs
of sea urchin, where the development is readily perceptible. In all
these instances, however, the condition is immediately changed by the
influence of the stimulus. The previous state of constancy in the vital
process is disturbed. The rapidity of its course is changed, being
either increased or decreased, and the specific vital manifestations
concerned are, therefore, augmented or diminished. We will now study
the vital process with the methods of chemical investigation and
consider the problem from the standpoint of metabolism. It may be
noted here, that other methods, such as the transformation of energy
or changes of form of the living system, would serve equally well as
indicators for this purpose. In every instance there is a uniformity
of the processes; the difference, however, is in the nature of the
indicators and the terms used. The methods and the terms used in
chemical investigation and description reach proportionately much
deeper than those employed when the transformation, energy or the
variations of form of the organisms are studied, and permit of the
finest differentiation of the processes. The atomistic terminology
is, for this reason, preëminently fitted for the description of vital
processes. When we study the vital process metabolically, we can, as
shown in the above-mentioned instance, divide the processes into a
_metabolism of stimulation_ in contradistinction to a _metabolism of
rest_.

The comprehension of _the metabolism of rest_ demands a closer
consideration. On closer observation we must say that this much-used
conception is merely an abstraction nowhere realized in a strict sense.
In truth, there is nowhere in nature a metabolism of rest. No cell
exists which in a mathematical sense remains for even two successive
moments under absolutely the same external conditions. If we imagine
a single living cell of the simplest kind living in a fluid nutritive
medium, and if we suppose its body and surroundings so magnified that
the single molecules and atoms were respectively of the size of cannon
and rifle balls, the boundary between cell and medium would represent
a battlefield, on which a heavy bombardment is constantly taking
place. The rain of shot of food and oxygen molecules penetrating into
the cell from the medium, would produce an explosion in the existing
ammunition depots, now at one point, now at another, creating great
breaches through which new masses of shot would reach the interior.
The fragments of these exploding molecules would be flung out here
and there into the medium and would stem, now at this, now at that
point the besieging masses of shot. In this wild confusion on the
whole boundary line between cell and medium there can be no question
of rest or even equilibrium at any point. The human mind, superior to
the material world as we may deem it, is yet always dependent upon
the results of experience, and even in its highest flights cannot
become wholly emancipated from the concrete objects. For this reason
it is of great purport to conceive processes whose dimensions cannot
be observed even microscopically, as enlarged and transformed to that
method of expression most familiar to the human mind, namely, in the
field of optical presentation. This method is of great help in aiding
our understanding, and likewise here, even in the resting state, the
cell is constantly exposed to local effects of stimulation, now at one
point, now at the other. The conception of the metabolism of rest is,
therefore, in a strict sense fiction.

Nevertheless, the conception of the metabolism of rest as an
abstraction can be of value provided always that it is strictly
and definitely limited. It must, for instance, not be applied to
short periods of time. The continued local and temporary responses
to stimulation constitute a mean value which, although composed
of numberless small sub-threshold responses, we can still call a
metabolism of rest. Weak stimuli have, however, as already seen,
the property, provided their influence is constant, of effecting an
adaptation to the stimulus on the part of the living organism, so
that the stimulus becomes a vital condition for this state of the
organism. Hence the continued existence of a vital process resulting
from the constant action of stimulation is made possible. That which
we are in the habit of calling metabolism of rest, would, therefore,
be metabolism of stimulation, but one that is characterized by a
constantly existing metabolic equilibrium.

This “_equilibrium of metabolism_” distinguishes the metabolism of
rest from that form which is developed in response to temporary
stimulation, in that every temporary stimulation has the effect that
it disturbs the existing metabolic equilibrium for a longer or shorter
time. This disturbance of the equilibrium of metabolism can in contrast
to the metabolism of rest be termed “_metabolism of stimulation_.”
In this, but only in this sense, can these two conceptions be placed
in opposition and used to characterize the processes in the living
organism. The conception of the metabolism of stimulation must always
stand in relation to that of an equilibrium of metabolism characterized
by a constantly existing metabolism of rest, just as the conception
of stimulus can likewise only be defined relatively to that of vital
conditions.

Nevertheless, the conception of the equilibrium of metabolism requires
a somewhat more accurate definition before we can feel justified in
using this term. Definitions are always trite, nevertheless they
are the basis of all our thinking and a definite understanding is
impossible unless we first clearly fix their contents. The history of
theology and philosophy even to the most recent times furnishes a long
line of instances in which the most eminent minds, for the want of
fixed definitions of the conceptions which they made use of, failed to
find a mutual basis for their ideas. Without a sharp definition every
conception is a mere word, which each individual, according to his
personal experiences and views, endows with a different meaning. To
such conceptions we may apply Mephisto’s ironical comment to his pupil:

  “Mit Worten lässt sich trefflich streiten,
  Mit Worten ein System bereiten.”

The natural sciences, if they are to retain their reputation for
exactness and precision, require the strictest and clearest definitions
of all conceptions. If we seek to penetrate more deeply into the
varied happenings in concrete conditions, we must reconcile ourselves
to dry pedantic definitions. In the case of that of the equilibrium
of metabolism indeed we have before us one of the most important
conceptions in physiology.

The justification to speak of an equilibrium of metabolism arises from
investigations of metabolism in mammals. The classical experiments of
the previous century, as is well known, have shown that in the adult
mammal receiving a necessary quantity of nourishment and in a state of
rest, the intake and outgo of the constituent elements are the same.
The carbon, hydrogen, nitrogen, oxygen, sulphur, phosphorus, etc.,
taken in during a lengthened period in the form of food and respired
air, appear again in equal quantity, in other combinations, in the
products of excretion of the organisms. Calorimetric experiments
likewise show an equilibrium of the consumption and elimination of
energy. If there thus exists an equilibrium of metabolism for the
whole cell community, it is clear that the same must also apply
to the individual cell, that is, for all living substance. The
quantitative relations of the foodstuffs taken _in_, and the excreted
metabolic products given _off_, are, however, merely a standard of the
metabolism. We know that the former are used to build up new living
substance and that the latter represent the result of disintegration
of that previously existing living substance; for we find, as in the
case of the plant, complicated protein combinations, which are built up
from comparatively simple constituents of the food and are again broken
down into comparatively simple substances. And so the building up and
breaking down processes form the two great processes of metabolism,
which with _Hering_[41] we can briefly call “_assimilation_” and
“_dissimilation_.” In the terms assimilation and dissimilation are
comprised the sum of _all_ processes of construction and disintegration
in the living organism. It is apparent that equilibrium of metabolism
occurs when assimilation and dissimilation are equal. The formula A : D,
that is, the relation of the sum of all assimilation to the sum
of that of all dissimilative processes, is a factor of fundamental
importance in the study of the course of the vital processes, for upon
its value depends individual vital manifestation, and, in fact, the
continuation of life. I have, therefore, designated the formula A = D
“_Biotonus_.” The equilibrium of metabolism would then be characterized
by the biotonus[42] of a living organism being equal to _one_. This
would be the metabolism of rest of a system, whilst its metabolism of
stimulation would consist in an alteration of the _biotonus_. But is
this state of living substance strictly speaking ever realized?

  [41] _E. Hering_: “Zur Theorie der Vorgänge in der lebendigen
  Substanz.” In Lotos, Bd. 9, Prag. 1888.

  [42] _Max Verworn_: “Allgemeine Physiologie. Ein Grundriss der Lehre
  vom Leben.” V. Aufl. Jena 1909.

In considering the nature of the equilibrium of metabolism one factor
has been disregarded which must be taken into account at every point;
this is growth. Growth changes, although varying more or less, are
never absent during the life of the organism. An equilibrium of
metabolism never exists in a strictly mathematical sense, and here
again we are working with a conception which is faulty, because it is
an abstraction, originating from experience with rather too restricted
boundaries. But an error of which one is aware is not dangerous.
In mathematics we also consciously reckon with errors, without the
result being altered. In the before mentioned cases the equilibrium of
metabolism was maintained, because the investigations involved only a
short time in an adult mammal. In the adult mammal the growth processes
occur very slowly, so that alterations within a relatively short time
are not demonstrated.

If it were possible to subject the adult mammal to metabolic or
calorimetric experiments, extending for years, it would be found that
the intake would be qualitatively and quantitatively different at the
end of the investigation and that the same would apply to the outgo.
In the growing egg cell this takes place with much more rapidity. In
the organism which rapidly grows, it can be seen at once that the
quantity of the outgo of the products of disintegration cannot be equal
to that of the intake of foodstuffs. If biotonus were equal to one,
the organism could not grow. Equilibrium of metabolism can only be
understood when we take into consideration a period of time in which
the alterations in growth take place with such imperceptible slowness
that the resultant error is inconsiderably minute. This period of
time is of greatly varying length in different living organisms and
this fact must be taken into account in every living form. Only with
this restriction can we justify the use of the term “equilibrium of
metabolism.” Then, however, its use is of great value.

The _metabolism of stimulation_ is then a disturbance of the metabolism
of rest, that is, a disturbance of the equilibrium of metabolism
through the effect of stimuli.

The question here follows: Is there a _constancy of this interruption
of the equilibrium of rest produced by the stimulus_ which can be
formulated into a general law? To begin with, the number of possible
responses are greater than the variety of forms of living substance,
for every living organism with its specific properties can undergo
alteration in its metabolism in various directions. Thereby results an
infinite number of manifold reactions to stimuli. However, in answer to
the question, in which direction the change in the specific metabolism
of rest in response to a stimulus takes place, we find a comparatively
simple scheme of general reaction. All phenomena can change in their
rapidity as well as in their nature. That is quantitatively and
qualitatively. In this way the specific vital process of an organism
can be altered by the stimulus, on the one hand, in its rapidity; on
the other, in the manner of its action.

The majority of all temporary responses to stimuli consist in
_alterations of rapidity of the vital process_, and form either a
quickening or retardation of its course. The former is manifested in a
strengthening or an increase, the latter in a decrease or repression
of the specific action of the living organism. The stimuli have the
same effect as in the case of the catalysers in chemical processes.
According to _Ostwald’s_[43] well-known definition of catalysis
a catalyser is a substance which, without appearing in the final
product of a chemical reaction, alters its rapidity. This group of
reactions can, therefore, be referred to as “_catalytic stimulation and
response_.” When the response consists in _increase_, we speak, in a
physiological sense, of an excitation, and when there is decrease in
the vital processes, we speak of a depression.

  [43] _Ostwald_: “Ueber Katalyse.” Verhandl. d. Ges. Deutscher Naturf.
  und Aerzte zu Hamburg 1901.

The conception of _excitation_ and _depression_ are purely empirical.
They are terms for real things, referring, in fact, simply to
alterations in rapidity of life process, which can be as readily
observed as the process itself. I wish to lay particular stress on
this fact, for the reason that _Cremer_[44] has recently made the
extraordinary statement that I have introduced hypothetical processes
into the definition of the conception of excitation. I have always
considered excitation as merely an increase or change of intensity of
the specific actions of a living system, and as such is an established
process without a _trace_ of the hypothetical element.[45] If, however,
the excitation process is to be regarded as something _absolute_,
as a mysterious state _sui generis_, which is entirely independent
and totally unlike the metabolism of rest, then, of course, it would
appear utterly incomprehensible and would be without purpose. As an
_absolute_ process excitation is merely a meaningless word. Excitation
and depression are _relative_ conceptions and can only acquire meaning
when the process which is excitated or depressed is more closely
defined. This is the specific vital process of a given organism, and
the two conceptions only have meaning in relation to it. The conception
of the vital process, however, is one directly gained from experience.
However complex or difficult to analyze the process may be, it still
is as little hypothetical as that of the combustion of carbon into
carbon dioxide, or the revolving of the earth around the sun. It can
be looked upon as something positive and real. Quite another question
is the manner in which we are to consider the mechanism of the vital
process. In analyzing this mechanism we cannot, at least in the
present state of our knowledge, entirely dispense with hypothesis. But
these hypotheses are in no way involved in the _definition_ of the
process of excitation. If we look upon every excitation or depression
produced by a stimulus as an alteration in rapidity in the specific
vital process of a given organism, we are thereby expressing the same
fact which _Johannes Müller_ has termed “_specific energy_.” We give,
however, the doctrine of specific energy a more general application
in so far as it comprehends not only the increase but likewise the
decrease of activity in response to stimuli. _Johannes Müller’s_
doctrine of specific energy of the living substance at all times has
been the subject of most animated discussion. When I refer here to the
specific energy of living substance, it is with the knowledge that
_Johannes Müller_ did not use this expression of “living substance” in
this connection. He was already acquainted, however, as we have seen,
with the fact of the existence of the specific energy of all living
structures. For appertaining to the muscle he says: “This is universal
in all organic reaction.” The reason why the doctrine of _sense energy_
has become of importance in the discussion of the specific energy of
the living substance, is in consequence of the theoretical interest,
resulting from its connection with the nature of the specific energy
of our _sense substances_. The controversies on this subject are still
far from settled.[46] Indeed, according to the special philosophical
standpoint taken by an observer, the existence of a specific energy of
the senses is acknowledged or disputed. For any one acquainted with
the general physiological reaction to stimuli, such a discussion is
wholly without purport. The sense substances have as a matter of course
in common with all living substances their specific energy, that is,
the influence of stimuli can produce an increase or decrease of their
specific vital processes. “Specific energy” of “sense substance” in
this sense is like that of all other living substances, a fact. In that
the psychical capability of these sense substances, in which we include
not only the peripheral, but also the central portion, are dependent
upon their specific vital processes, it must be self-evident that the
excitation and the suppression of sense sensation can be brought about
by adequate and inadequate stimuli, no matter what one may think of
the relations between physical and psychical phenomena.

  [44] _Cremer_: “Die allgemeine Physiologie der Nerven.” In Nagels
  Handbuch der Physiologie des Menschen. Bd. IV, Braunschweig 1909.

  [45] In the first edition of my “_General Physiology_” in 1895 I
  have sharply and clearly defined it as such, stating in formulating
  the general law of stimulation: that every excitation is an increase
  either of individual parts or the whole of vital phenomena,
  depression every decrease in the individual part or the whole of
  vital phenomena.

  [46] Compare: _Rudolf Weinmann_: “Die Lehre von den specifischen
  Sinnesenergien.” Hamburg 1895.

  Further: _Eugen Minkowski_: “Zur Müllerschen Lehre von den
  specifischen Sinnesenergien.” In Zeitschrift f. Sinnesphysiologie,
  Bd. 45, 1911.

The only debatable question is that concerning the limits of the
validity of the doctrine of the specific energy of living substances.
This question will involve our attention when we have analyzed somewhat
more closely the happenings in the living substance taking place under
the influence of stimuli. We will, therefore, return later on to a
more detailed consideration of the last question. Nevertheless, we
will here refer to a fact which, upon a superficial observation, seems
to restrict the validity of the conception of the specific energy of
living substance.

In contrast to those reactions to stimuli, which consist merely in the
changes of a rapidity of the specific vital process, are another group
of reactions in which the influence of stimuli leads to qualitative
alterations in the specific vital process. In these instances, the
influence of the stimulus directs the metabolism of rest into new
channels, so that chemical processes occur in the cell, which under
ordinary circumstances do not take place. This group of reactions,
which I wish to term “metamorphic stimulation and response,” are
chiefly observed where weak stimuli act continuously upon the living
substance. These are essentially weak chemical stimuli, which last
for a prolonged period or frequently reoccur in the life of the cell
community. Examples of this are found in the continual ingestion of
alcohol and other poisons by the human being, or in the formation of
metabolic products of bacteria, etc. The majority of _chronic_ diseases
belong to this group of reactions; disease being simply response to
stimulation. Disease is life under altered vital conditions and altered
vital conditions are stimuli. This simple and self-evident fact shows
the immense importance which the knowledge of the general laws of the
physiology of stimulation has for pathology. The pathologist, who
does not wish to confine his observations to a purely superficial
symptomatology or a merely histological morphology, must seek above
all to penetrate as deeply as possible into the nature of the general
reactions to stimulation in the living organism. It is the essential
point which meets him everywhere. In spite of their great interest
for pathology, however, it is just these qualitative alterations of
the normal vital process produced by continuous stimulation which
have up to now been least analyzed. In this field we expect much from
pathological investigation which alone has the immense amount of
material at its command. This will take place only when pathology adds
to the almost exclusively histological direction of investigation, that
also of experimental physiology. It is true that the problems of the
qualitative alterations of a vital process by chronic stimulation are
much more complicated than those of the rapid responses to temporary
stimuli, consisting simply in mere alterations of rapidity of the
specific vital process. An understanding of the nature of the former
can only be expected when a deeper knowledge of the latter is gained,
for, as will be seen presently, there is the closest relation between
the two groups.

The reactions to catalytic stimuli of short duration, which produce
merely an alteration of rapidity in the specific phenomena of a living
organism, show on a closer analysis the interesting fact, that it is
not always the _entire_ metabolic processes of the cell which are
perceptibly quickened, but that only certain constituent processes
of the same are affected by the action of excitation. This is the
_more_ noticeable, as, considering the close correlation which all
the individual links of the chain of metabolism bear to each other,
it is to be expected that the alteration in rapidity of _one_ would
be followed at once by a corresponding change in all the others. An
example of the case in question, in which a special constituent process
may be predominately affected, is that of the specific activity of a
muscle which is repeatedly stimulated by nervous impulses. Since the
classical investigation of _Fick_ and _Wislicenus_[47] on themselves,
and of _Voit_[48] on the dog, we know that the nitrogen metabolism is
practically unaltered by the functional use of the muscle and there is
a remarkable increase only in the breaking down of the nitrogen-free
groups of the living substance. Sufficient importance has not as yet
been attached to this knowledge. This fact not only has a particular
interest for the much-discussed question of the source of muscle
energy, but also affords a deeper insight into the metabolic activity
of the living substance. It shows us that we must not imagine a purely
linear linking of the individual constituent metabolic processes,
but rather, at least at certain points, a branching formation, the
individual members spreading in various directions. An alteration in an
individual member can occur without an immediate change in the other
branches. This _would not_ be the case if there were only a linear
connection of the constituent processes, for the breaking of a single
member of the chain would be followed by a change in all the following
members.

  [47] _Fick und Wislicenus_: “Ueber die Entstehung der Muskelkraft.”
  Vierteljahresschrift d. Züricher Naturforschenden Gesellschaft. Bd.
  10, 1865.

  [48] _Voit_: “Ueber die Entwicklung der Lehre der Quelle der
  Muskelkraft and einiger Theile der Ernährung seit 25 Jahren.”
  Zeitschrift f. Biologie Bd. VI, 1870.

  Derselbe: Physiologie des allgemeinen Stoffwechsels u. d. Ernährung.
  In Hermanns Handbuch d. Physiologie, Bd. VI, 1881.

It shows us, further, that certain branches are more labile than
others. In the case referred to here, the branches of this system,
which bring about the nitrogen metabolism, are relatively _firm_ and
_stable_, the branches, which are disturbed by the stimulus producing
functional activity of the muscle, are particularly _labile_. I should
like in passing to call here your attention to the fact that as is
well known, _Ehrlich_,[49] in another field involving other conditions
and other experiences and considerations, has arrived in analogous
manner at his “side chain theory.” In order to have an expression for
those stimuli which involve rapid alteration of the labile constituent
processes and which are connected with the specific action of the
particular organism, I have called them “_functional stimuli_,” and
contrasted with them the “_cytoplastic stimuli_.” In the latter the
alterations produced include all the constituent processes extending
even to the stable processes of nitrogen changes, and sometimes extend
to complete disintegration and rebuilding of living substance.[50] To
the first group belong all adequate stimuli within certain limits of
duration and intensity, and the greater part of inadequate stimuli of
brief duration so long as they do not exceed a certain intensity.
To the latter group belong in general all the stronger adequate and
inadequate stimuli of prolonged duration; such as extreme temperature,
the stronger electric currents, constant alteration in the supply of
food, water, oxygen, the prolonged or stronger influence of extraneous
chemical matter, etc.

  [49] _Ehrlich_: “Das Sauerstoffbedürfniss des Organismus. Eine
  farbenanalytische Studie.” Berlin 1885. Compare further: _L.
  Aschoff_: “Ehrlich’s Seitenkettentheorie und ihre Anwendung auf die
  künstlichen Immunisierungsprozesse. Zusammenfassende Darstellung.”
  Zeitschr. f. allgemeine Physiologie, Bd. I, 1902.

  [50] _Max Verworn_: “Die Biogenhypothese. Eine
  kritisch-experimentelle Studie über die Vorgänge in der lebendigen
  Substanz.” Jena 1905.

Considering the close correlation of the individual part processes it
would appear very strange, however, if a single one of these could
undergo an alteration of its rapidity without the course of the rest
of the processes being in the least influenced. One cannot comprehend
such _absolute_ independence of a process brought about by functional
stimulation from all the other constituent processes, particularly when
this is of prolonged duration and involves to a considerable extent
the alterations in rapidity, for the individual constituent processes
are dependent in a high degree upon the quantity of the particular
chemical substances of which the living system is composed. The cycle
of the individual constituent processes of this system is determined in
the most delicate manner in its rapidity and extent, by the relative
quantities of the individual substances. Associated with an alteration
in the rapidity of an individual constituent process, there would also
be a relative alteration quantitatively of the substances. And with the
increase in the _quantity_ of the disintegration products, and also the
increase of the substances for their replacement, there would result,
during this time, an alteration in the amount of interaction of the
molecules of the other constituent processes, so that these processes
secondarily suffer an alteration in rapidity which is perceptible after
long continued involvement of the functional part of metabolism.

In fact, in the previously mentioned case of the functional stimulation
of the muscle, the proof has been furnished that a long-continued
increase of the functional metabolism is followed, although to a
less extent, by an increase in the entire cytoplastic metabolism.
_Argutinski_ showed this on himself in 1890 in _Pflüger’s_ laboratory.
He found, namely, that after the exertion of a long walk in a hilly
district, a considerable increase of nitrogen excretion in the urine
took place, which extended over the succeeding two or three days. This
increase of the nitrogen metabolism in its totality is not nearly as
great as that of the breaking down of nitrogen-free substances, but
it is, nevertheless, present and shows us that functional metabolism
cannot experience a lasting excitation without being followed by
secondary results in the entire cytoplastic metabolism. This fact
is even more strikingly illustrated in the alteration of the entire
volume of a living organism as produced by the lengthened duration
of functional stimulation. It has been long known, that the muscle
as the result of frequent functional excitation by means of adequate
nerve impulses, that is, prolonged activity, is considerably increased
in size, whereas in the absence of such it loses more and more in
volume. A hypertrophy of activity, produced by functional stimuli, and
the atrophy of inactivity, the result of the discontinuance of the
functional excitation, is universal and can be observed in the various
tissues of our body. We see it, for example, in the glands; we see
it in the skin and we see it in the elements of the nervous system.
_Berger_,[51] for instance, established the fact that the ganglion
cells of the optic lobe in the cerebrum of newborn dogs only reach
their full development when functionally excitated by adequate light
stimuli (Figure 9, B), coming from the eye, whereas they remain in the
embryonic state when these light stimuli are eliminated. (Figure 9, A.)
The cytoplastic increase of volume of the neurons under the influence
of functional stimuli is a fact of fundamental importance for the
entire happenings of the nervous system and forms the physiological
basis for reinforcement of reflexes, which, in its turn, is essential
for all acts of memory and intelligence. For the increase in volume of
the ganglion cell body is, when functionally activated, accompanied at
the same time by an increase of specific capabilities and the intensity
of discharge. Its excitation impulses can, therefore, be conducted
through a greater number of neurons, with which it is connected, than
would be the case if development of the volume of the ganglion cell
increased to a less extent.

  [51] _Berger_: “Experimentell-anatomische Studien über die durch
  den Mangel optischer Reize veranlassten Entwickelungschemmungen im
  Occipitallappen des Hundes and der Katze.” Arch. f. Psychiatrie, Bd.
  33, 1909.

[Illustration: A

B

Fig. 9.

A--Undeveloped ganglia cells in the optic lobe of a dog, the eyes of
which have been sewn up immediately after birth. B--Fully developed
ganglia cells in the same region of a normal dog of the same age.
(After _Berger_.)]

The increase in volume under the influence of stimuli further shows
the relation between the group of those solely catalytic effects
of stimulation consisting in mere alterations of rapidity of the
specific vital process, and that of the metamorphotic effects of
stimulation, which manifest themselves in qualitative alterations of
the vital process. Simple observation shows us that a qualitative
change of individual constituent processes must necessarily result
from the increase of volume of a cell, and that considering the close
correlation of all the individual processes a profound alteration of
the entire metabolism must be produced. I have already at another
place[52], [53] treated these conditions more in detail and will,
therefore, only briefly refer to them here. If we study the growth of a
ball-shaped cell, we find that the surface then increases as a square,
and the volume as the cube. It therefore follows that, by progressive
volume increase, the conditions for the interchange of substance with
the surrounding medium must become more and more unfavorable for
those cell portions situated in the interior, whereas those at the
exterior are at much greater advantage. This must lead to a constantly
increasing difference of the rapidity of the metabolic processes
between the peripheral and central portions. Accordingly, the intricate
interworkings of the individual constituent processes, the rapidity of
action of all which is intimately connected, are, therefore, followed
by corresponding alterations in the entire metabolism. Sooner or later
a stage is reached in which the individual constituent processes become
so limited that certain metabolic products, which previously were
broken down as soon as formed, can be no longer eliminated and remain
in the cell acting as foreign bodies. In this way the relative quantity
of the individual cell substances become more and more altered, and
as the course of chemical processes occurs in accordance with the
law of mass action, the whole metabolism is directed into another
channel, so that finally new constituent processes take place, which
were formerly not possible. These in their turn produce deep-seated
alterations of the relations of the cell to its surrounding medium,
etc. Hence this mere increase of volume of the cell in growth forms
the source of an infinite mass of alterations in the activities of
cell metabolism, which we briefly term its “_development_,” and which
by constant progression, leads either to a process of cell division,
and with this to a correction of existing disorder, or finally to
irreparable disturbances ending in death. In this way an inseparable
relation exists between increase of volume and the development of
living substance. We have seen, however, that the catalytic reactions
of stimulation, which at first only produce an alteration of rapidity
of the individual constituent processes, if of prolonged duration
or of frequent recurrence, secondarily effect a change of volume of
the entire living organism. One can, therefore, hardly reject the
conclusion that seeing the close interworkings of the individual part
process of metabolism, every change of rapidity of a single member,
if of prolonged duration or of frequent occurrence, must finally lead
to qualitative alterations of the entire metabolism. In consequence
there results an important dependence between catalytic stimulation and
metamorphic reaction. Indeed, it is not unlikely that the metamorphic
reactions, which are especially seen in the continued effect of weak
stimuli, result from alterations of rapidity, which the individual
members of the vital processes have primarily undergone from this
influence.

  [52] _Max Verworn_: “Die cellularphysiologische Grundlage des
  Gedächtnisses.” Zeitschrift f. allgemeine Physiologie, Bd. VI, 1907.

  [53] _Max Verworn_: “Allgemeine Physiologie.” V. Aufl. 1909, pages
  649–671.

It is perhaps expedient to cite a concrete instance in illustration.
A simple example is furnished by asphyxiation. If oxygen is withdrawn
from any living organism, the result is a depression of its oxydation
processes. Here there is primarily only a change in rapidity,
especially a retardation of oxydation processes. The metabolism,
however, proceeds, the disintegration of living substance continues,
although at a slower rate, but produces an accumulation of other
products. Whereas formerly during the existence of a sufficient supply
of oxygen an oxydative disintegration of nitrogen-free groups into
carbon dioxide and water took place, both of which could easily be
eliminated from the cell, the anaërobic disintegration furnishes only
complex products, having a higher carbon content, such as lactic acid,
fatty acids, aceton, etc. These, being more difficult to excrete from
the cell, accumulate. These asphyxiation products have in their turn a
depressing effect and so on. In this way the whole metabolism is forced
into a wrong course. The accumulation of fat in those tissue-cells
with an insufficient blood supply, as we have seen in the case of the
fat metamorphosis, is doubtless brought about in the same manner by
relative oxygen insufficiency. The fatty acids accumulate as products
of an incomplete combustion and combine with glycerine to form neutral
fats. In like manner it may be that the accumulation of amyloid
substance in amyloid metamorphosis, of lime salts in arteriosclerosis,
etc., is produced by a primary depression of the individual constituent
processes of the particular cells.

The relation here described, of the catalytic stimuli to the production
of the metamorphic processes, leads us to the distinctions between
primary and secondary effects of stimulation. Should the general fact
be established, which has up to now only been pointed out in individual
cases, that all the metamorphic processes are merely secondary results
of primary alterations in rapidity of individual metabolic constituent
processes, _then the primary reactions of every stimulus would consist
purely in the excitation or depression of the directly concerned
constituent_. Whether or not, as may be assumed, this primary effect
of stimulation applies to _all_ stimuli, is a question which only the
future can answer.

The metamorphic processes are not, however, the only secondary effects
of stimulation. The influence of long-continued excitation of the
functional constituent processes upon the entire cytoplastic metabolism
can be looked upon as a secondary response. Therefore, they may be
considered as a _secondary_ effect of stimulation which, in contrast to
this _primary excitation_, may be called the _secondary excitation_.

Further: While the secondary excitation and metamorphic processes
are generally produced by the continued existing effects of weak
stimulation, we also observe as the result of a stimulus of short
duration or frequently repeated at brief intervals, but otherwise
not exceeding the physiological limits of intensity, a secondary
effect, which plays a very important part in the activity of the
organism. I refer to fatigue. Here a secondary depression is developed
in connection with the primary excitation, for fatigue of a living
organism must be characterized as a depression of activity. This case
shows that we have to distinguish between a _primary depression_,
as for example, produced by temperature reduction, withdrawal of
food, deficiency of oxygen, etc., which occurs as a direct effect of
stimulation, and _secondary depression_, which as in fatigue is an
_indirect_ result of primary excitation.

After the cessation of a briefly catalytic stimulus, not exceeding the
physiological limit of intensity, another secondary result is observed,
which is of the greatest importance for the continued existence of the
living substance. The catalytic stimulus brings about a disturbance of
the equilibrium of metabolism, which after cessation of the stimulus is
reestablished by the living substance. In other words: recovery takes
place. This fundamental principle has been known for a long time as
the result of observation. If a skeletal muscle of our body has been
activated for a prolonged period by nerve impulses, until it has become
completely fatigued and incapable of work, a recovery takes place on
the cessation of these impulses and the muscle is again capable of
action. Likewise, as the result of strong mental activity during the
day, we are mentally fatigued in the evening; recovery, however, occurs
during the night, which results from the removal of the source of
activity. The next morning finds us refreshed. This restitution occurs
in every cell, and the return of its former capability of action,
which had disappeared under the influence of stimulation, shows that
compensation has taken place of the metabolism of rest, disturbed
by the effects of the stimulus. _Hering_[54] has aptly termed this
restitution as “_the internal self-regulation of metabolism_.” All
recovery after disease is based on this self-regulation. The physician
simply provides, by means of therapy, for the possibility of its taking
place. Healing itself is brought about by the organism. “_Natura sanat,
medicus curat._”

  [54] _Ewald Hering_: “Zur Theorie der Vorgänge in der lebendigen
  Substanz.” In Lotos, Bd. 19, Prag. 1888.

Finally, a third kind of secondary effect of stimulation claims
our interest. This is the _secondary extension of the result of
stimulation_ from the part of a living organism directly and primarily
affected by the stimulus, to the surrounding structures. All living
substance has the capability of conducting an excitation, which is
produced locally through a catalytic stimulus, to a neighboring part,
not directly affected by the stimulus. It finds its highest development
in the nerve, but in no living structure is it completely absent. This
capability has been frequently termed “_conductivity of stimulation_.”
It is more precise, however, to speak of conductivity of excitation,
for it is not the primary influencing external stimulus which is
conducted in the living substance, but the excitation which it has
produced. I have intentionally considered only the excitating effects
of stimulation, and not those of the depressing reactions, as only
excitations, not depressions, are conducted by the living substance.
These questions, however, demand a closer analysis. Here we were
concerned only with a survey of the general effects of stimulation. If
I, therefore, once more summarize the results which have been gained,
this is most clearly demonstrated by the following scheme:

                    PRIMARY EFFECTS OF STIMULATION

                      Excitation      Depression

              Functional      Cytoplastic      Functional

                   SECONDARY EFFECTS OF STIMULATION

            Secondary excitation       Secondary depression

  Conduction of excitation, Metamorphic processes, Self-regulation of
                               metabolism

This, however, is simply a scheme, like all other schemes, having for
its purpose a superficial survey of the subject.

It brings to some extent order into the overwhelming mass of manifold
effects of stimulation but tells us nothing of the mechanism and
genesis. Our further task must, therefore, be a more thorough analysis
of this field.




CHAPTER V

THE ANALYSIS OF THE PROCESS OF EXCITATION

 _Contents_: Indicators for the investigation of the process of
 excitation. Latent period. The question of the existence of
 assimilatory excitations. Dissimilatory excitations. Excitations of
 the partial components of functional metabolism. Production of energy
 in the chemical splitting up processes. Oxydative and anoxydative
 disintegration. Theory of oxydative disintegration. Dependence
 of irritability on oxygen. Experiments on unicellular organisms,
 nerve centers and nerve fibers. Restitution after disintegration by
 metabolic self-regulation. Organic reserve supplies of the cell.
 The question of a reserve supply of oxygen of the cell. Metabolic
 self-regulation as a form of the law of mass effect, and metabolic
 equilibrium as a condition of chemical equilibrium. Functional
 hypertrophy.


If it is true that all primary effects of stimulation consist either
in an excitation or depression of the metabolism, and that all other
effects of stimulation secondarily follow this primary alteration of
the metabolism of rest, then every thorough analysis of the mechanics
of reaction must have its beginning in the investigation of these
primary processes. I desire to adopt this method here and will analyze
somewhat further the _primary process of excitation_ and its immediate
and remote sequences. This will be followed later by the analysis of
the process of primary depression and its results.

The investigation of the more obscure processes in the living substance
places us in a difficult position, for their details cannot be
observed by the unaided senses. That which we can perceive is merely
the grosser vital action, consisting of a complex combination of the
individual processes, the total result of a multitude of different
components. For this reason the conception of excitation can only be
established by observations based upon the combined vital actions,
which are produced by the effect of stimulation upon the complex
system. In the beginning, the process of excitation was studied
exclusively on the muscle and nervous system. A physical factor served
as indicator, such as muscle contraction or production of electricity.
These showed, besides the direct and primary effect of stimulation,
the secondary process of conductivity. Even graphic registration is
merely an expression of the phenomena composed of a great mass of
individual elements. The visible course of the phenomena, as shown,
for instance, by the latent period by the ascent and descent of the
curve of contraction, represents as it were a reflected picture of the
actual excitation processes similar to an object seen in a distorting
mirror; the first and the last parts of the process are not even
perceptible. Later, when organ physiology was extended into a cell
physiology the processes of excitation were studied in numerous simple
organisms, such as the plant cell, the rhizopoda, the infusoria, etc.
Later, in this way, by the use of comparative methods many essential
facts were discovered. However, even the single cell, in spite of
its minuteness, is, compared with the size of a molecule, a gigantic
system, and it would be a grave error if we should consider this system
even in its simplest aspect as homogeneous. In order, therefore,
to analyze the vital activities in the cell, cell physiology must
endeavor to penetrate into molecular conditions. For this purpose the
indicators employed must be essentially of a chemical nature, capable
of magnifying the processes of molecular dimension to such a degree
that we are enabled to base conclusions upon these not otherwise
directly perceptible phenomena. To obtain a sufficient magnification we
must necessarily place somewhat larger quantities of living substance
under observation and apply a stimulus of such frequency or length
of duration that the chemical alterations as a result of excitation
are so increased as to be plainly perceptible with the aid of our
chemical indicators. Unfortunately, we do not possess specific chemical
indicators for every individual molecular constituent process of the
cell and so cannot dispose with the help of indicators of the combined
happenings in a greater quantity of living substance. It remains for
us to obtain data concerning the cycle of excitation processes in the
living substances by the aid of the combined employment of the most
varied kinds of physical as well as chemical indicators. If we use the
most varied types of living substance of widely differing properties,
showing us the greatest variety of vital manifestations, we may hope
by the use of comparative physiological methods, even though with
difficulty, to separate more and more the essential details of the
general processes of excitation. At present we are still at the very
beginning of this task and vast fields of unexplored regions are yet
before us. But it is the unknown which has a particular fascination,
especially if we succeed from time to time in making new advances.

If we suppose a living system in a state of metabolism of rest
influenced by an instantaneously excitating stimulus, the entire
course of excitation extends from the first alteration produced by
the stimulation until the complete restitution of the metabolic
equilibrium, and we will, therefore, differentiate individually the
successive stages of this whole process.

The very beginning of the chain of alterations produced by the
excitating stimulus cannot be studied by any indicator. The changes
must first reach a certain dimension by conduction from the point of
stimulation before they influence even the most delicate indicators.
The application of the stimulus is, therefore, followed at first by a
measurable “_latent period_,” in which the living substance remains
apparently at rest. This latent period has been particularly studied in
muscle. After its discovery by _Helmholtz_[55] it was made the object
of innumerable investigations and met with an interest which can only
be explained by the exactness of the methods employed. Among others
_Tigerstedt_[56] has made the most thorough study of the influence of
various factors on the duration of the latent period. These experiments
have established the fact that the duration of the latent period varies
according to the intensity of the stimulus, temperature, loading or
fatigue. This is apparent when it is understood that the amount of
the alterations produced by the stimulus must ascend from the value
zero to a certain height before the changes are perceptible, and that
under various conditions this amount is, on the one hand, attained
in different lengths of time and, on the other, must reach a varying
amount before it is perceptible by means of the indicator.

  [55] _Helmholtz_: “Messungen über den zeitlichen Verlauf der
  Zuckungen animalischer Muskeln and die Fortpflanzungsgeschwindigkeit
  der Reizung in den Nerven.” Archiv für Physiologie Jahrgang 1850.

  [56] _Robert Tigerstedt_: “Untersuchungen über die Latenzdauer der
  Muskelzuckung in ihrer Abhängigkeit von verschiedenen Variablen.”
  Arch. f. Physiologie Jahrgang 1885 Suppl.

The facts concerning the whole latent period and its dependence on
various factors would be incomprehensible if it were assumed that no
alterations whatever take place during the latent period although the
stimulus is already operative. In reality, the alterations following a
stimulus occur with imperceptible rapidity in the form of a molecular
interchange, and the latent period is simply an expression of the
fact that the primary alterations, being limited in nature, are not
registered by our indicators.

The question first arises, In what do these first imperceptible
alterations consist? _Nernst_[57] has evolved the theory for electric
stimulus, that the primary effect produced by the electric current is
an alteration in the ion concentration on the surface of the living
substance. In fact, we know that the surfaces of all protoplasm
possess the property of semi-permeable membranes and that changes
in the concentration of ions invariably occur when an electric
current flows through two electrolytes separated by a semi-permeable
membrane, in which the anions and cations have a different rapidity
of movement. It is apparent, therefore, that such an alteration in
the ion concentration must be followed by further chemical processes
in the living substance. According to the theory of _Nernst_ the
first impetus for all further alterations, which the electrical
stimulus brings about in the metabolism of rest, is the alteration
in the concentration of the ions on both sides of the semi-permeable
membrane, which represents the surface of the protoplasm. In view of
the present findings of physical chemistry, objections can hardly be
made to this theory of _Nernst’s_. It is a question, however, in how
far this theory, especially established for the _electric_ stimuli,
can be applied to other forms of stimuli and their action. It cannot
be denied that the degree of dissociation of an electrolyte can be
altered by very different factors, such as heat, light, chemical
processes, etc., and in that the surfaces of the protoplasm, acting
as semi-permeable membranes, bring about a selective action on the
passage of the ions, there arises the opportunity for the development
of difference of electrical potential on both sides, and for further
chemical alterations in the protoplasm. These observations, however,
require further experimental investigations in many fields, before
we are justified in extending the _Nernst_ theory of the manner of
action of the electric stimuli to a general explanation of the primary
alterations produced by all stimuli in the living substance. For the
present we must confine our observations to _those_ alterations which
are known to be responses to an excitating stimulus; these are the
chemical alterations in the metabolism of rest in the living substance.

  [57] _Nernst_: “Zur Theorie der electrischen Reizung.” Nachrichten
  der Königl. Gesellsch. d. Wissensch. zu Göttingen. Math. physik.
  Klasse 1899.

If it is asked, which members of the entire metabolic chain are
increased primarily by the stimulating excitation of a vital system, we
should not be able to answer this question generally for _all_ living
systems. To begin with, it appears highly probable that the various
forms of vital substances in this respect act quite differently. It is
to be regretted that, up to the present, this question has not been
treated from a comparative standpoint. This inquiry should be extended
to the greatest possible number of organisms. Still there is enough
material at hand, obtained from the muscles, glands, ganglion cells,
nerve fibers and plants, to show that the complexity is by no means so
great as one might at first assume.

In considering the two stages of metabolism, assimilation and
dissimilation, in their entirety, it appears as a very remarkable fact,
that nearly all stimuli produce primarily a _dissimilative_ excitation.
We are only acquainted with a primary _assimilative_ excitation,
that is, an augmentation of the building up processes, in short, the
_formation_ of living substance, occurring as a primary result of
stimulation, following increased introduction of _foodstuffs_ extending
over a prolonged length of time. With this exception it cannot be
proved that _any_ other stimuli, either especially those operative
in the activity of the animal organism or any of the physiological
nerve impulses which regulate the actions of the different organs and
tissues, bring about primarily an assimilative excitation, which leads
to an increase of new formation of living substance. The much-discussed
teaching of the existence of the trophic nerves has not given us a
single case in which there was positive proof that a nerve impulse
brought about a primarily assimilative excitation. I have endeavored
for nearly fifteen years to discover such a case. My efforts have
been, however, without avail. In the most recent critical review by
_Jensen_[58] on the subject of the trophic nerves, the same conclusion
is reached although certain facts, as, for instance, the excitation
of assimilative processes in the green plant cell, produced by light,
seems at the first glance to clearly demonstrate a primary excitation
of the building up processes resulting from a stimulation. Nevertheless
closer observation invariably shows that these conditions are much more
complicated and that primarily assimilative excitating reaction of
the stimulus cannot be conclusively shown. There remains, therefore,
as a primary assimilative excitating stimulus only the increased
introduction of nutrition in a living organism. This excitating effect
on the assimilative portion of metabolism is, as we shall see later, a
simple manifestation of the law of mass action.

  [58] _Paul Jensen_: “Das Problem der trophischen Nerven.”
  Medicinisch-naturwissen-schaftliches Archiv. Bd. II, 1910.

As a result manifold effects of excitating stimulation, which seemed
possible at a first glance, are already considerably restricted.
The great mass of excitating stimuli produce an acceleration of the
dissimilative processes of the metabolic chain. But here our former
observations have already shown that certain constituent processes
are especially responsive and very readily increase as a result
of the most varied adequate and inadequate stimuli. These are the
“_functional_” members of metabolism. These members are particularly
labile, so that they are always affected by every influence to which
the system is subjected in the form of a stimulus. The functional
portion of metabolism of the muscle, which is particularly labile
and is always primarily affected by stimulation, consists as
demonstrated in increase of formation of carbon dioxide and water, and
in the disintegration of the nitrogen-free groups. The innumerable
observations on metabolism during the stage of the activity of the
muscle, as those of _Hermann_, _v. Frey_, _Fletcher_, _Johannson_,
_Thunberg_, and many others on the individual muscle, and those
by _Voit_, _Fick_ and _Wislicenus_, _Pflüger_, _Rubner_, _Zuntz_,
_Lehmann_ and _Hagemann_, _Bernstein_ and _Löwy_ and others on the
muscle of the entire organisms, have sufficiently proved this fact.
However, we should not apply in detail the conditions existing in
the _muscle_ to _all_ living substance. Comparative methods show us,
rather, that the functional portion of metabolism is very differently
involved in various forms of living substance. The formation of carbon
dioxide and water is constant in nearly all forms of living substance.
We must, however, exclude certain micro-organisms, which have adapted
themselves to unusual vital conditions. Further, there appear in
some forms manifold special constituent processes consisting in a
disintegration of living substance which are in part converted into
very complex combinations. In the gland cells this type is represented
in an especially high degree. Here the functional disintegration leads
to excretion of proteins, glycoproteins, nucleoproteins, cholic acid,
enzymes of various kinds, all of which are complex and at the same time
nitrogenous organic combinations. This fact must not be lost sight
of. The origin of these special members, however, for the present is
completely unknown, while on the other hand, it is self-evident that
the general and constant constituents of the process of excitation
must claim a first place in our interest. It is just at this point,
therefore, that we must endeavor to penetrate somewhat more deeply into
the mechanism of the excitation process and analyze in greater detail
the acceleration of the functional constituent parts of metabolism
produced by the stimulus bringing about the formation of carbon dioxide
and water.

The question arises: _By what means is the particular labile state of
just this constituent part of functional metabolism conditioned?_ The
lability of the functional portion of metabolism, excitated by the
stimulus, resembles the processes in the disintegration of explosive
combinations. Iodide of nitrogen, for instance, in a manner similar
to the living substance in the state of the metabolism of rest,
constantly disintegrates even without the influence of an impact. The
disintegration is suddenly enormously increased by the result of a jar.
An explosion follows. In a like manner the functional metabolism of
rest is explosively excitated by the stimulus, the transformation of
the energy involved likewise bears a similar relation.

In both instances the transformation of energy, _constant_ in the
resting state, is by the impact of the stimulus suddenly increased.
The dynamic method of investigation of the excitation process with its
physical indicators, forms, therefore, in many respects an excellent
addition to the chemical analysis. A development, that is, exothermic
formation, of energy can only occur in a chemical process when the
chemical affinities which are to be combined are stronger than those
which have been separated. When this process is brought about by a
simple impact, the energy value of which bears no relation to that of
the quantity of energy in the process itself and which occurs with
explosive rapidity, then it can be simply a question of a liberation
process, that is, a process by which the impact brought about a
conversion of latent chemical energy into that of kinetic energy.
The comparison of the functional excitation process with that of an
explosion does not, therefore, consist in a merely superficial analogy,
but is founded on the same dynamic principles.

When we study the chemical process which occurs in the explosive
transformation of potential into kinetic energy we find two types of
chemical processes. The first type includes the synthetic processes.
For this, the synthesis of water from explosive gas may serve as a
simple example. Here the weaker affinities in comparatively simple
molecules (H + H and O + O) are separated and stronger affinities
are combined in the formation of more complicated molecules (H + O +
H). The second type represents the process of cleavage. As example
for the latter, the explosive disintegration of nitroglycerine may
be quoted. Here the atoms, held together in a complex molecule by
weaker affinities, are changed by transposition of nitroglycerine. For
instance, the hydrogen atoms loosely combined with carbon enter into
strong combinations with oxygen and the oxygen loosely combined with
the nitrogen enters into strong combination with carbon, so that water
and carbon dioxide are formed and nitrogen and oxygen set free.

[Illustration]

In the functional disintegration of living substance, the last type is
realized. Living substance contains loose complex combinations, and we
know that functional disintegration is accompanied by the consumption
of these organic combinations. In the functional disintegration of
muscle substance the nitrogen-free groups are concerned, and we must,
consequently, first consider the carbohydrates. However, without
further study we should not generalize from that which is true in
the case of muscle. There are other forms of living substances which
contain different combinations, which disintegrate as a result of the
contact of a stimulus and yield carbon dioxide. A clue as to which
combinations in individual cases undergo disintegration as a result
of excitating stimulation, is furnished by the metabolism of rest
in the particular substance. Plants and micro-organisms have been
investigated more thoroughly in this connection than animals. Plant
physiology has demonstrated that the material employed for the CO_{2}
formation and with it the production of energy is carbohydrate, but
that, on the other hand, various plant organisms and protistæ also use
a quantity of other substances, such as fats and protein, indeed even
such comparatively simple organic combinations as alcohol, formic acid
and methane. It may be accepted that in all these various instances of
excitation of the functional metabolism as a result of stimulation,
the specific respiratory material of the substance concerned is used
in greater amount in the decomposition and likewise invariably yields
carbon dioxide.

The point of most essential interest for the analysis of the excitation
processes is, above all, the _mechanism_ of the organic combustion and
the associated energy production. Here we may base our observations
on the disintegration of carbohydrates, which is most extensive in
the animal as well as in the vegetable kingdom. We may now ask how
dextrose, for instance, disintegrates in the living system into carbon
dioxide, for it is this, or a sugar of similar chemical nature, which
is generally concerned. Plant physiology, which here, as in many other
respects, is in advance of animal physiology, has indicated two ways
by which this can be accomplished in the living substance. One is
oxydative, the other, _an_oxydative disintegration.

In the _oxydative disintegration_ of dextrose, taking place in
aërobic organisms, if sufficient quantities of oxygen are present,
there occurs a splitting up of the carbohydrate molecule, as a result
of the introduction of oxygen, into simpler substances and finally
into carbon dioxide and water, just as the dextrose molecule, when
subjected to oxydative processes, is split up into simpler molecules.
In the living substance the oxydases play the important rôle of oxygen
carriers. It cannot be denied, however, that up to now no carbohydrate
splitting oxydases have been obtained from living substance. This,
of course, does not prove its nonexistence. But this deserves
consideration in connection with an assumption very widely spread
among plant physiologists in regard to the aërobic disintegration of
the carbohydrate molecule, which I shall touch upon presently. If we
suppose that oxydases exist, which bring about primarily the oxydative
disintegration of the dextrose molecule, its first point of attack
must obviously be sought in the aldehyde group. Here would be situated
the activator, as it were, for the whole carbon chain, from which, as
by a spark, the entire series of links would be ignited.

In an _anoxydative disintegration_ of dextrose as observed in
anaërobic as well as in aërobic organisms, provided the latter have
an insufficient supply of oxygen, the dextrose molecule, by enzymic
action as a result of the splitting off of carbon dioxide, is converted
into substances having a comparatively large carbon content. The
best-known example of this anoxydative disintegration is the formation
of alcohol by fermentation in which the dextrose molecule is split
up by the yeast into alcohol and carbon dioxide. (C_{6}H_{12}O_{6} =
2C_{2}H_{5}OH + 2CO_{2}.) Instead of the production of alcohol and
CO_{2} we may have other enzymic actions with the formation of other
carbon-containing disintegration products, such as lactic acid, fatty
acids, hydrogen, etc. Of course in such an anoxydative disintegration,
which does not lead to the formation of such simple combinations as
carbon dioxide and water, the _quantity_ of energy set free is much
less in amount than in complete _oxydative_ decomposition, the energy
production of the alcohol fermentation being only 11 per cent of the
latter. In order to produce the same amount of energy as in the former,
a much greater number of molecules is required. We find, therefore,
that the anoxydative type of disintegration develops either only where
the respiratory substances are present in sufficient amounts, as for
instance, in the case of yeast cells, existing in nutritive solutions
rich in sugar; or where the chemical and energy transformations occur
only to a limited extent, as, for example, in the presence of low
temperature. In this respect _Pütter_[59] has demonstrated in the
leech that at a higher temperature, the oxydative, at a lower, the
anoxydative, decomposition predominates. These are important facts
in that they show us the superiority of oxydative to that of the
anoxydative disintegration in the cell economy. This is of particular
interest when we consider those organisms in which great demands are
made upon the capability of movement, above all, in homothermous
forms, the metabolism of which takes place on a continuously high
level. For this reason, in homothermous animals the respiration of
oxygen is the almost exclusive source of energy production.

  [59] _A Pütter_: “Der Stoffwechsel des Blutegels (Hirudo medicinalis
  L).” I Theil. Zeitschrift für allgemeine Physiologie Bd. VI, 1907. II
  Teil. ebenda Bd. VII, 1908.

The previously mentioned facts make it clear that in one and the same
form of living substance both oxydative and anoxydative decomposition
processes are found, depending upon the conditions. This does not
apply merely to the individual organic forms, such as the facultative
anaërobic organisms, but generally to all aërobic living substance.
If oxygen is withdrawn from an aërobic organism the disintegration
does not cease in consequence. In place of the oxydative we have
anoxydative decomposition. The various aërobic organisms are, however,
adapted in very different degrees to the possibility of an anaërobic
existence. While the facultative anaërobic organisms can continue to
exist without oxygen, the homothermous animals become asphyxiated in
a very short time in the absence of oxygen, in that they are poisoned
by the products of the anoxydative decomposition, which are eliminated
with much more difficulty than carbon dioxide and water. The fact,
however, that disintegration also continues in an anoxydative form,
if oxygen is withdrawn, has given rise to the thought, which has been
accepted especially by plant physiologists with great readiness, that
the decomposition of organic respiratory substances of the aërobic
organisms invariably takes place in two stages; in that the dextrose
molecule--to again use this as an example--is split up first by an
enzyme into larger fragments, which then in the second stage of the
process undergo combustion to the formation of carbon dioxide and
water. Such a possibility cannot be repudiated. I wish, however, to
state that one should be very reluctant in generalization of this
assumption for all aërobic organisms. The types of metabolism in
the different organisms are so manifold and of such immense variety
that we should be very careful in our generalizations before being
in possession of material extending over a great number of groups of
organisms. Above all, it does not seem justifiable to also accept
this type for life existing at higher temperatures, and still less
to apply it to those instances in which the production of energy
following stimulation is suddenly increased to great amounts. Let us
suppose that the disintegration process occurs in two phases, the first
of which after the type of the fermentation of dextrose separates
the molecule into larger fragments, while in the second phase these
fragments are split up through oxydation into the formation of carbon
dioxide and water. We can then say with certainty that in the first
stage only a comparatively _small_ amount of energy production occurs,
for energy production by enzymic processes of this kind is never
great; the second phase, on the other hand, must be associated with
a very considerable energy production, for by the addition of oxygen
and the formation of carbon dioxide and water the strongest affinities
possible are combined. With this assumption in certain cases, as, for
instance, in the sudden production of energy in muscle contraction,
which necessarily occurs in the purely oxydative phase of the whole
process, the view is forced upon us, that, in these cases, the entrance
of oxygen into the molecule from the very beginning, even the first
impact, produces oxydative decomposition of the whole molecule. The
view that, in the reactions of warm-blooded animals, which occur with
great rapidity and considerable energy production, the oxygen primarily
explosively breaks up the whole carbon chain, certainly presents no
more difficulties than the supposition that the simpler substances
are attacked secondarily, provided sufficient oxygen be present.
This method would be obviously the simplest. This is, however, mere
speculation and a definite decision between the two possibilities
cannot be made at present. However, whether the process takes place in
two phases, an anoxydative and an oxydative, or simply in an oxydative
phase, in _any case, the sudden discharge of energy in the aërobic
organism set free by the stimulus, is brought about by the addition of
oxygen_.

This is a highly important fact and as such requires the most thorough
confirmation, and is best accomplished by the investigation of the
state of excitation of aërobic substances on the withdrawal of oxygen.
Experience gained by observation in this respect on a great number
of living substances shows that excitability decreases upon the
withdrawal of oxygen. In this connection I should like to cite some
particularly significant instances.

[Illustration: A

B

Fig. 10.

_Rhizoplasma kaiseri._ A--Under normal conditions. B--In an atmosphere
of pure hydrogen.]

During a sojourn at the Red Sea in 1894–95 I was able to establish this
dependence in the single-celled organism, the _Rhizoplasma Kaiseri_,
a large naked orange-colored rhizopod. (Figure 10, A.) Mechanical
stimulation, which under normal vital conditions of these organisms
brings about contraction in the long-branched pseudopods, becomes
ineffective with a cessation of the movement of protoplasm, when
oxygen is removed and is replaced by a stream of hydrogen. (Figure
10, B.) With renewed introduction of oxygen there is a return of the
protoplasmic movement and entire recovery takes place.

This dependence of irritability upon oxygen is most clearly
demonstrated in the _nerve centers_. For this purpose I have employed
the spinal cord of the frog.[60] A canula is introduced and fixed
into the aorta of the animal and the blood is replaced by a current
of oxygen-free saline solution. The centers of the spinal cord are
thereby wholly isolated from the supply of oxygen. The indicator for
the irritability here used is reflex excitation from the skin to the
gastrocnemius, or better, stimulation of the central stump of the
sciatic nerve with single induction shocks, bringing about reflex
response of the triceps. The reflex may be considerably augmented by
increasing the reflex excitability of the spinal cord by poisoning
the animal with strychnine. On testing the reflex excitability at the
beginning of the experiment it will be found that the reaction to
each individual stimulus consists, in consequence of the strychnine
poisoning, of a long-continued maximal tetanus. The longer the
deficiency of oxygen continues, the briefer become the tetanic
reflex contractions following a single stimulus. Soon reflex tetanic
responses are merely short single contractions, which decrease more
and more with the continuance of oxygen deficiency. Finally, the same
stimuli which previously produced strong tetanic contractions of
long duration are altogether without effect. Although by increasing
the intensity of stimulation brief contractions can again be brought
about, irritability decreases more and more, until at last even the
strongest stimuli remain without result. If the oxygen-free saline
solution is now replaced by one saturated with oxygen, or blood of the
ox, rendered arterial, the excitability returns within a few minutes
and soon reaches the maximal height which it possessed under the
influence of the strychnine poison. Even the weakest single stimuli now
again produce tetanus. The same process reoccurs, if the fluid used
for transfusion containing oxygen is again replaced by an oxygen-free
saline solution. In this way, by repeated change of the perfusing
fluid, we can demonstrate in the most positive manner this alteration
in irritability, the result of the alternate presence and removal of
oxygen. This is perhaps the best example of the close dependence of
irritability on oxygen.

  [60] _Max Verworn_: “Ermüdung Erschöpfung und Erholung der nervösen
  Centren des Rückenmarks. Ein Beitrag zur Kenntniss der Lebensvorgänge
  in den Neuronen.” Archiv. f. Anat. u. Physiologie. physiol. Abteil.
  1900 Suppl.

  The same: “Ermüdung und Erholung.” In Berliner Klin. Wochenschrift
  1901.

This same fact can be observed with equal clearness in the nerve. At my
suggestion _H. v. Baeyer_[61] showed as the result of investigations
made in the Göttingen laboratory the dependence of irritability of the
nerve upon oxygen for the first time. By employing as the method the
ascertainment of the threshold of stimulation I then made a closer
study of the alterations in irritability during asphyxiation. These
observations were soon after continued by _Fröhlich_.[62] The method
is as follows: the nerve of a nerve-muscle preparation of the frog
is drawn through a glass chamber which is made completely air-tight
and containing platinum electrodes. The air in the chamber is then
displaced by a stream of pure nitrogen. (Figure 11.) On testing that
part of the nerve situated within the glass chamber with single break
induction shocks it can be observed that its irritability, measured by
the threshold of stimulation for muscle contraction, decreases more and
more, until after the lapse of some hours, the stimulation required is
so strong as to reach the region of the “Stromschleifengrenze.” If in
place of the stream of nitrogen, air or pure oxygen is now allowed to
flow through the chamber, the nerve recovers almost instantaneously.
Within the space of a minute its irritability has risen again to
its full height and the same experiment, with the same result, can
be repeated. Finally, as _Fillié_[63] has shown, the like result is
obtained when the nerve is asphyxiated in a fluid medium.

  [61] _H. v. Baeyer_: “Das Sauerstoffbedürfniss des Nerven.”
  Zeitschrift f. allgemeine Physiologie Bd. II, 1903.

  [62] _Fr. W. Fröhlich_: “Das Sauerstoffbedürfniss des Nerven.”
  Zeitschrift f. allgem. Physiologie Bd. III, 1904.

  [63] _H. Fillié_: “Studien über die Erstickung des Nerven in
  Flüsigkeiten.” Zeitschrift f. allgemeine Physiologie, Bd. VIII, 1908.

[Illustration: Fig. 11.

Arrangement for asphyxiating the nerve. A--Gasometer containing pure
nitrogen. B and B_{1}--Vessels for washing the gas. C--Ether chamber
for eventual experiments with narcosis. D, D_{1} and E--Glass faucets.
F--Moist chamber. G--Asphyxiation chamber. H and H_{1}--Two pairs of
electrodes over which the nerve is laid. I--Nerve muscle preparation. ]

All these facts, the number of which indeed could be increased greatly
for other aërobic forms, suffice to establish the fundamental
importance of oxygen to the maintenance of irritability of living
substance. _Oxygen is of greatest importance for a high degree of
irritability in all aërobic organisms._ All living systems which are
characterized by a great capability of activity and evince strong
responses under the influence of stimulation, such as the vertebrates
and insects, are necessarily aërobic, whereas the living organisms
of pronounced anaërobic character, as some bacteria, yeast cells,
parasitic organisms, etc., manifest on the average much less capability
of activity.

Finally, to briefly summarize the foregoing, the following picture
presents itself of disintegration produced by a momentarily acting
stimulus. It is immaterial how the stimulus produces an excitating
effect in the given case, whether through changes in the ion
concentration of the living system, by increase of intramolecular
atomic movement or in any other manner, it invariably accelerates
the disintegration of the complex molecules concerned in functional
metabolism, the nature of which varies in the special cases. In the
great majority of instances nitrogen-free organic combinations serve as
material for the functional constituent members of metabolic processes.
In the anaërobic organisms this decomposition takes place anoxydatively
with the coöperation of enzymic processes, and as larger fragments
generally result from the disintegration of the complex molecule,
the production of energy is accordingly smaller. The disintegration
of aërobic organisms, on the other hand, occurs in the form of an
oxydative splitting up of the complex molecules into carbon dioxide
and water so that the production of energy attains a high value.
The details concerning the manner in which the individual stages of
this decomposition take place and the interactions by which its end
products are reached is at present beyond our knowledge. It would be a
mistake to generalize in this connection from the behavior of certain
groups of organisms. The assumption that under certain conditions the
disintegration occurs in two phases, the splitting up resulting from
enzymic action of the complex molecule into larger fragments, followed
by an oxydative splitting up of these into carbon dioxide and water,
can in no case as yet be justifiably applied to all conditions and all
aërobic organisms. This is more or less the impression which we derive
of the functional excitation process as seen today.

Under normal conditions the functional excitation is at once followed
by a succession of secondary processes, the “_self-regulation of
metabolism_.” Self-regulation after a functional excitation is a fact
demonstrated by experience. But in what manner does it take place in
detail?

As the functional constituent members of metabolism involve a
disintegration of the nitrogen-free atom groups, the functional
self-regulation must necessarily furnish in sufficient quantity and
in proper form the carbon, hydrogen and oxygen atoms, which have
been removed in the production of carbon dioxide and water. This is
accomplished, as is well known, by the food and the intake of oxygen.
It is of importance to the maintenance of living substance that after
every functional activity it is as soon as possible again capable of
reaction. Therefore, it is absolutely necessary that this material is
in the proper place, where building up is essential, and is at the same
time constantly in proper form. Indeed, the restitution of the original
state follows under favorable conditions with lightning rapidity,
although varying in different forms of living substance. This occurs in
the nerve in an extremely short time. From this it might be supposed
that the living system by accumulating a store of the necessary
compensation substances in suitable form, had made itself independent
to a certain degree of the frequently varying supply of material
obtained from the medium.

This may be held as the proper view, first with regard to compensation
substances. The fact that living organisms can under some conditions
remain for a lengthened period in a state of starvation, without losing
their capability of activity, can only be explained by the presence
of a great quantity of reserve supplies of compensation substances.
In the course of work in the laboratory every physiologist has become
acquainted with the fact that frogs which have been kept without food
for a year, although much reduced in weight, are still capable of some
muscular activity.

[Illustration: A

B

Fig. 12.

Motor ganglia cells from the spinal cord of the frog. A--In normal
state. B--After an asphyxiation lasting 8 to 9 hours. (After _Gordon
Holmes_.)]

[Illustration: Fig. 13

_Paramecium aurelia._ A--In normal state. B--In a state of starvation.]

Organs and tissue, which are cut off from all food supply through the
blood and lymph, may remain active for many hours. _H. v. Baeyer_[64]
has shown that the ganglion cells in the frog, in which saline
solution was transfused at room temperature and containing no trace of
organic substances and where irritability has been increased to the
maximal by means of strychnine, were capable of strenuous work for
nine or ten hours before losing responsivity. The nerves and muscles
of the animal retain their excitability for even a longer period
under the same conditions. Indeed, we have histological evidence of
the existence of organic reserve material in the various cells in
the form of embedded bodies in the protoplasm. As for instance the
disappearance of the _Nissl_ granules in the ganglion cells following
great activity,[65] (Figure 12), or that of the granules in infusoria
cells during starvation.[66] (Figure 13.) We assume that a certain
amount of organic foodstuffs in a state properly prepared is present in
the cell. As the amount of these prepared substances is consumed, new
quantities of stores, having undergone various preparatory processes,
among which the enzymic actions may be considered to play a chief rôle,
are brought into that form in which they appear suited to fill the gap
produced by disintegration. Plant physiologists in particular have here
again furnished us with some essential data for the assumption of
the existence of such processes which regulate the transformation of
reserve substances as well as its extent. _Pfeffer_[67] has found in
several fungi and bacteria that there exists a compensation between the
diastatic breaking down of the carbohydrates stored as reserve material
and the quantity of dextrose introduced. He further found that the more
the reserve substance is split up into dextrose the less of the latter
is introduced from without and _vice versa_. _De Bary_[68] some time
ago also observed in the _bacillus amylobacter_ an analogous relation
between the enzymatic cellular digestion and the quantity of dextrose
introduced with the food. An equilibrium, therefore, exists between
the required amount of dextrose and the extent of enzymic splitting up
processes of the reserve material. A great number of similar processes
have been observed. Even though the details of the whole preparatory
assimilative processes are beyond our knowledge we can still say with
certainty that, on the one hand, everywhere great quantities of organic
reserve substances are always present in the cell, and on the other,
that these substances are subjected to a transformation into suitable
material for building-up processes, the extent of which is controlled
according to need, by the processes of self-regulation.

  [64] _H. v. Baeyer_: “Zur Kenntniss des Stoffwechsels in den nervösen
  Centren.” Zeitschr. f. allgem. Physiol. Bd. I, 1902.

  [65] _Gustav Mann_: “Histological changes induced in sympathetic
  motor and sensory nerve cells by functional activity.” In Journ. of
  Anat. and Physiol. 1894. Further: _Gordon Holmes_: “On morphological
  changes in exhausted ganglion cells.” Zeitschrift f. allgem. Physiol.
  Bd. II, 1903.

  [66] _Wallengren_: “Inanitionserscheinungen der Zelle.” Zeitschrift
  f. allgem. Physiol. Bd. I, 1902.

  [67] _W. Pfeffer_: “Ueber die regulatorische Bildung von Diastase.”
  In der math. phys. Klasse d. Königl. Sächs Ges. d. Wiss. zu Leipzig
  1896.

  [68] _De Bary_: “Sur la fermentation de la cellulose.” In Bull. de la
  Soc. bot. de France 1879.

Entirely different is the question if the cell also possesses a
reserve store of oxygen. In this respect views have widely differed,
and even today no conformity of opinions has been arrived at. The
fact that many purely aërobic organisms and tissues can exist under
complete exclusion of oxygen for a longer or shorter period, retaining
their excitability and producing carbon dioxide, has for a long time
led a great number of investigators, such as _Liebig_, _Matteucci_,
_Engelmann_, _Pettenkofer_ and _Voit_, _Claude Bernard_, _Verworn_,
_H. v. Baeyer_ and others, to the supposition that a reserve store
of oxygen must exist in the living substance which maintains its
excitability for a time. More recent information, however, of the
transition of the oxydative to the anoxydative disintegration under
a deficiency of oxygen, as can be observed in plants and certain
invertebrate animals, indicates that here also there is the possibility
of another explanation of these facts. Various attempts have been made
to solve the problem if reserve oxygen is present in the cell or not.
The experiments of _Rosenthal_,[69] carried out with his respiration
calorimeter, seemed to point directly to an oxygen reserve in the
organism of the mammal. He observed that during respiration in an
atmosphere rich in oxygen the respiratory quotient (CO_{2} : O_{2})
became lower than in ordinary air, that is, that oxygen, and that
indeed in considerable quantity, must be retained in the organism.
Nevertheless _Falloise_[70] found that when rabbits, which had
been kept in an atmosphere containing 80 per cent of oxygen, were
asphyxiated, the time necessary to produce death was no longer than in
animals which had been kept previously in ordinary air. The correctness
of the observations of _Rosenthal_ have been disputed by _Durig_.[71]
_Winterstein_[72] also, employing the microrespiration methods of
_Thunberg_ upon the spinal cord of the frog, believed that he had found
proof that an oxygen reserve cannot take place. He reasoned thus: If
the cells of the spinal cord contain reserve oxygen, which is used up
when pure nitrogen only is breathed, then it necessarily follows that
after reintroduction of oxygen, following asphyxiation, a definite
quantity must be stored up again as reserve. In consequence, the
respiratory quotient following the intake of oxygen after asphyxiation
should be smaller than when the animal is in air. He found, however,
that the respiratory quotient does not essentially change and concluded
from this that storage of oxygen does not take place. In these
experiments, however, there exists no certain indicator as to the state
of the spinal cord during asphyxiation and recovery in the given case.
The spinal cord may be severely injured and even undergo degeneration
during asphyxiation, and the recovery following the reintroduction of
oxygen may be either incomplete or nil, without there being a method
for its determination. Apart from this, _Lesser_[73] has already
emphasized, in opposition to these experiments, that the respiratory
quotient in recovery is no criterion to guide us. It is immaterial
whether during asphyxiation oxygen respiration occurs following a
reserve supply, or that an anoxydative formation of carbon dioxide has
taken place, for in both instances the respiratory quotient would be
less _after_ asphyxiation when there is again an oxygen supply. It is,
therefore, quite impossible to decide the question by the employment
of this method. For this reason _Lesser_ has attempted to solve the
problem by means of quite another method, and was convinced that he
had refuted finally the belief in the existence of reserve oxygen. His
method consists in the employment of the _Bunsen_ ice calorimeter, by
which he determines the heat production of frogs, kept first in air,
then in nitrogen, and at the end of each experiment ascertaining the
amount of output of carbon dioxide, respectively in air and nitrogen.
He found that the quantity of heat, calculated in terms of 100 grms.
body weight per hour, produced in nitrogen was considerably less than
that under corresponding conditions in air, but that the production
of carbon dioxide, on the other hand, during the first hours in
nitrogen was doubled in amount, as compared to that in air. From this
he concludes that the carbon dioxide formation in nitrogen must be
different from that in air, as it is associated with a reduced heat
production. In other words, carbon dioxide formation, while the animal
is in a nitrogen atmosphere, does not have its origin in oxydative
processes at the cost of stored up oxygen. I regret that I am unable to
accept these arguments as conclusive evidence against the assumption
of an oxygen reserve, as this question cannot be decided by the use of
such methods. _Lesser_ does not measure the amount of carbon dioxide
until the end of his experiments, that is, he learns merely the
entire carbon dioxide production during a period of many hours. No
conclusions can be drawn from this as to the conditions existing in the
first period of time, directly after the animals have been subjected
to an atmosphere of nitrogen. It is quite possible that subsequent to
the change to nitrogen an oxydative carbon dioxide formation may have
continued in decreasing degree, without this being shown in the final
result. The problem of the existence of a reserve supply of oxygen is
in no way solved by these experiments.

  [69] _Rosenthal_: “Untersuchungen über den respiratorischen
  Stoffwechsel.” Arch. f. Anat. u. Physiologie physiolog. Abt. 1902 und
  Suppl. 1902.

  [70] _Falloise_: “Influence de la réspiration d’une atmosphère
  suroxygéné sur l’absorption d’oxygène.” Traveaux du laborat. de
  physiol. de L. Fredéric Liège, T. VI.

  [71] _Durig_: “Ueber Aufnahme und Verbrauch von Sauerstoff bei
  Aenderung seines Partialdruckes in der Alveolarluft.” Arch. f. Anat.
  u. Physiol. physiol. Abt. 1903 Suppl.

  [72] _Winterstein_: “Ueber den Mechanismus der Gewebeatmung.”
  Zeitschr. f. allgem. Physiol. Bd. VI, 1907.

  [73] _Lesser_: “Die Wärmeabgabe der Frösche in Luft and
  sauerstofffreien Medien. Ein experimenteller Beweis dass die CO_{2}
  Production der Frösche im sauerstofffreien Raum nicht auf Kosten
  gespeicherten Sauerstoffs geschieht.” Zeitschr. f. Biologie Bd. 51,
  1908.

In assuming the presence of a reserve supply of oxygen in the cell we
must above all entertain no false conception as to its amount. This
must be, as I have often had occasion to emphasize, exceedingly small
and in no way comparable with the great masses of organic reserve
substances contained in the cell. The assumption, especially for the
_nerve centers_ of the frog, that the excitability remains after
complete exclusion of oxygen must be looked upon as demonstrating a
reserve supply of oxygen, would oblige one to suppose the presence of
such a small store of oxygen that it would be completely exhausted
by continued activity in room temperature within ten to twenty-five
minutes. Strychninized frogs, in which the blood has been replaced
by an oxygen-free saline solution, lose, as I have shown,[74] their
excitability completely within ten to twenty-five minutes after the
blood has been displaced. Nevertheless the assumption of the existence
of a small oxygen supply in the cell can hardly be evaded. It must not
be imagined that the moment the blood of the frog has been replaced
with an oxygen-free solution, there is not a trace of oxygen left in
the organism. Were such the case, the irritability, if measured by the
extent of the response, would sink _momentarily_ to a very low level,
for the anoxydative disintegration processes are associated with an
incomparably smaller production of energy than those of oxydative
disintegration. We see, however, that the irritability in the muscles,
nerves and nerve centers of the frog even after the complete withdrawal
of oxygen at first remains practically at the former height and only
very gradually decreases. Above all it would seem to me to be in the
interest of the preservation of the organism and especially of those
parts in which there is a high energy production and particularly those
substances in which energy production predominates, that the material
necessary for its formation is always at its disposal in sufficient
quantity. Otherwise the capability of action of the organism would be
impaired at every moment or at least suffer great fluctuations.

  [74] _Max Verworn_: “Ermüdung, Erschöpfung and Erholung der nervösen
  Centra des Rückenmarks.” Arch. f. Anat. u. Physiol. physiol. Abt.
  Suppl. 1900.

In accordance with this we must suppose that under physiological
conditions all those substances required to replace the disintegrated
molecules are always present in the cell in sufficient quantity and
suitable form to replace at once those lost by excitation. Further,
without doubt, in the organism which is always aërobic, oxygen must
be present in certain quantities to assure at any moment oxygen
replacement following oxydative disintegration, to guarantee sufficient
amount for succeeding stimulation.

A further question arises: How is it that the material lost in
disintegration is always replaced in just sufficient quantity to
establish the metabolic equilibrium? In short, how are we to understand
in a mechanical sense the self-regulation of metabolism?

In the preservation of metabolic equilibrium, we have a process before
us, the principle of which is nowadays restricted to living substance.
In my “Biogen hypothesis,”[75] I have associated the self-regulation
of metabolism with the chemical equilibrium in interreacting masses.
I have considered the metabolic self-regulation as the expression of
the formation of a mass equilibrium between the quantity of foodstuffs
and the quantity of a hypothetical combination of living substance,
the _biogen_, which continuously disintegrates and builds up again of
its own accord. In fact, however, we have in the chemical equilibrium
of reacting mixtures in the non-living world, a principle which is
completely analogous to the self-regulation in living substance. The
chemical facts are, indeed, well known. If we take the classical
example of the formation of ethylacetat from acetic acid and alcohol,
we have a case of an inanimate system, in which the amounts of the
reacting substances are in constant equilibrium. The reaction following
the mixture of equal amounts of alcohol and acetic acid is as follows:

  [75] _Max Verworn_: “Die Biogenhypothese.” Jena 1903. Compare also
  _Max Verworn_: “Allgemeine Physiologie.” V. Aufl. Jena 1909.

  1/3 Mol. C_{2}H_{5}OH + 1/3 Mol. CH_{3}COOH
  = 2/3 Mol. CH_{3}COOC_{2}H_{5} + 2/3 Mol. H_{2}O.

In this reaction there is an alteration only in the absolute quantity
of the individual constituents but never in the relative amount. In the
living system we have a completely analogous instance, which apart from
its course differs from the inanimate example merely in the following
points: In the first place, certain quantities of substances reacting
on each other are continually introduced into and certain reaction
products continually removed from the living system. Secondly, the
reacting mixture of the living substance is not homogeneous, and at
the same time is more complicated than that of the inanimate example.
Thirdly, the sum total of the reaction is not reversible in its
entirety. The question arises, should any essential difference between
metabolic self-regulation and the maintenance of chemical equilibrium
be assumed upon this statement? I must confess that this does not
appear to me to be the case. The fact that organisms exist in a stream
of substances by which their nutrition is introduced and the metabolic
products removed, cannot have any influence on the state of equilibrium
so long as the conditions are again and again replaced in the same
manner. The equilibrium can only be influenced when the introduction
of foodstuffs or the output of metabolic products is changed in value.
Then they occur as the inanimate example, when various amounts of
material are brought together. A new equilibrium takes place, having
a higher or a lower mass level. This is also true in the living
substance, in growth and in atrophy. The equilibrium is disturbed as
happens in the inanimate reacting mixture, where different quantities
of reacting substances are brought together. In both instances we
have in principle a conformity of behavior of the inanimate and
the living system. Secondly, as far as the greater complexity and
inhomogeneity of the living reacting mixture is concerned, it is
self-evident that this likewise does not constitute an essential
difference, for we are acquainted with conditions of equilibrium in
chemical reactions possessing a number of members and in inhomogeneous
mixtures. Finally, the fact that the reaction in the living system
is not totally reversible, forms no barrier to the assumption in
principle of metabolic self-regulation as a chemical equilibrium. It
is quite possible to conceive of a chemical equilibrium in a reacting
mixture, of which only certain constituent processes are reversible,
without the totality of the reactions as a whole being necessarily so.
Let us assume, by way of example, that the assimilative processes of
the metabolic chain are reversible, then under constant quantitative
relations of foodstuffs, following every disintegration of assimilative
products with removal of the decomposition products, the same amount
of assimilatory processes is required for building up. And this is
just that which we observe in metabolic equilibrium. Accordingly,
we may look upon the metabolic equilibrium as a special, although a
very highly complicated, instance of chemical equilibrium, and we
may explain the metabolic self-regulation following a dissimilative
excitation of the same, by those principles on which the rebuilding of
chemical equilibrium is founded. It is true that the special details
of this process can be differentiated in only that degree in which it
is possible to penetrate at all into the details of metabolism of the
given cell form. In this, as is well known, the advance is extremely
slow.

The rebuilding process following decomposition of living substance
in response to an excitating stimulus consists not merely in
compensation for the decomposed atom groups but also in the removal
of disintegration products. This removal can be accomplished, in
so far as simple chemical substances such as carbon dioxide and
water are concerned, by diffusion. Observations have shown that the
semi-permeable protoplasm surface is pervious to water and carbon
dioxide. The latter can, therefore, depending upon the amount of
concentration, be eliminated from the living substance. Output of water
likewise takes place in so far as the specific water content of the
living substance is exceeded and which is osmotically regulated by its
amount of salt content. When, finally, osmotic pressure within the
living cell and in the surrounding medium is equal, the interchange
of water ceases. All these processes are explained by diffusion.
Self-regulation takes place in this regard simply by osmotic means.
The conditions in respect to those decomposition products consisting
in more complicated organic combinations, such as lactic acid, fatty
acids and nitrogen derivatives of protein disintegration, are somewhat
different in that the protoplasm surface possesses the property of
hindering the passage of these substances into the medium. These are,
as is well known, first transformed by secondary chemical processes
into transfusable substances. In this transference the oxydative
decomposition with the formation of simpler substances plays the most
important rôle, so that the substances thereby formed, namely, carbon
dioxide, water and ammonia, are osmotically eliminated as the result of
the selective permeability of the surface of the protoplasm. In this
way the living cell rids itself of the useless products of metabolism.

Finally, the question remains, is the original state, as it existed
before the influence of the stimulus, really completely recovered by
metabolic self-regulation, or does even individual excitation of brief
duration produce a continued change in the protoplasm? It is quite
impossible to prove that such an effect follows the momentarily acting
single stimulus, if stimulation has not exceeded the physiological
limits of intensity. Should it exist, it must be imperceptible.
Nevertheless, it ought to be possible by frequently repeated
application of the stimulus to increase this which is imperceptible to
an extent in which it is perceptible. This is, indeed, the case and
is manifested as we have already seen in the increase of the volume
of living substance by frequently recurring functional excitation. We
can, therefore, assume with great probability that even the momentarily
acting individual stimulus produces, although not perceptible _per se_,
lasting effect in the cell. The functional excitation must be followed
secondarily by an increase of the assimilative phase of the entire
cytoplastic metabolism. Otherwise the taking place of the increase
of volume of the living system following frequent excitation of the
functional constituent members of metabolism, is unintelligible.
But how are we to interpret these secondary results from a physical
standpoint? First of all, it must be stated that we do not know of
such hypertrophy following activity in unicellular organisms, but only
in the tissues and organs of multi-cellular forms, in muscles, nerve
cells, glands, etc. In the cell community of the vertebrates, however,
the studies on the relations between activity and the blood supply of
the particular tissue or organ furnish a physical interpretation for
the existence of the functional hypertrophy. The active portions show a
dilation of the blood vessels, therefore an increased supply of blood
and consequently an increase in the circulation of lymph. In other
words: the supply of nourishment to the individual cell and the removal
of the metabolic products in a unit of time is increased. The preceding
discussion of the dependence of the conditions of equilibrium upon the
quantitative relations of the reacting substances makes it clear that
under these conditions a metabolic equilibrium on a higher quantitative
level must occur; that is, the living substance must increase in amount
just as in the inanimate example the absolute amount of the æthylacetat
increases if more alcohol and acetic acid are introduced to an equal
degree. Some time ago[76] I expressed the opinion that the increase
of the blood supply in a functionally active organ must be based on a
physical self-regulation, which takes place as a result of the fact
that metabolic products of the tissue cells influence the cells of
the vessel walls in that part, so that the vessels dilate and more
lymph is formed. In the meantime this has been proved to be indeed
the case. _Schwarz und Lemberger_[77] and _Ishikawa_[78] have shown
that especially the weak acids, which are produced in larger amount
as a result of strong activity of the cells, bring about vessels’
dilation. By the demonstration of this highly important process
of self-regulation the last link has been added for the physical
understanding of the hypertrophy of activity of the tissue cells by
continued functional excitation. Whether or not the same applies to
the single living cell, if the unicellular organism likewise undergoes
a quantitative increase by a continuous functional excitation, and
if the single cell possesses in itself a corresponding mechanism of
self-regulation similar to the cell community in the vertebrates,
cannot be answered, for concerning all these problems information is
lacking for the present.

  [76] _Max Verworn_: “Die cellularphysiologische Grundlage des
  Gedächtnisses.” Zeitschr. f. allgem. Physiol. Bd. VI, 1907.

  [77] _Schwarz und Lemberger_: “Über die Wirkung Kleinster Säuremengen
  auf die Blutgefässe.” Pflügers Arch. Bd. 141, 1911.

  [78] These investigations have not yet been published.




CHAPTER VI

CONDUCTIVITY

 _Contents_: Only processes of excitation are conducted, not processes
 of depression. Conduction of excitation in its two extreme instances.
 Conduction in undifferentiated pseudopod protoplasm of rhizopoda.
 Conduction of excitation with decrement of intensity and rapidity.
 Conduction of excitation in the nerve. Rapidity of conduction of
 excitation without decrement. Relation between irritability and
 conductivity. Conduction of excitation with decrement of the nerve
 after artificial depression of irritability by narcosis. Theory of the
 decrementless conduction of the normal nerve. Proof of the validity of
 the “all or none law” in the medullated nerve. Theory of the process
 of the conductivity of excitation. Theory of core model (Kernleiter).
 Electrochemical theory of conduction based on the properties of
 semi-permeable surfaces.


When the response to a stimulus is studied in a living system, whether
it be a single cell, a tissue, or a complex organism, the indicator
used, either that of movement, current of action, production of certain
substances, the development of light, of heat or the alteration of
form, is the result of two distinct processes. The first of these is
primary excitation, brought about by the stimulus at a local point, and
the second is an extension of the excitation to the surrounding tissue.
We are not in a position to experimentally bring about a response
to stimulation, in which the primary excitation occurs and not the
secondary process, that of conductivity. All living substance contains
this property, although to a very different degree, as all living
substance possesses irritability, and this presents the condition not
only for the taking place of the process of excitation but also that of
its conduction.

If I here speak only specifically of the conduction of excitation
instead of the conductivity of response to stimulation this is not
only primarily for the reason that we intend especially to analyze the
conductivity of excitation on this occasion, but also because no other
effects of stimulation except those of excitation can be conducted from
the part affected by the stimulus to the surroundings.

Although considered on theoretical grounds it appears more or less
improbable that depression is extended from the place of its origin,
it is very easy to convince one’s self experimentally of the fact
that depression following a stimulus is invariably localized to that
portion directly affected by the stimulus. The nerve furnishes a very
favorable object for this purpose. If a nerve muscle preparation of the
frog is made and introduced in the glass chamber previously described
containing platinum electrodes, and another pair is applied to the
nerve between the chamber and the muscle, it is possible to subject
the stretch of nerve in the chamber to various agents, producing a
paralyzing effect. In this way it may be exposed to an atmosphere of
pure nitrogen for example, or to narcosis as by ether, chloroform,
carbon dioxide and other gases, to an increase in temperature or to
other agents, without these in any way affecting the irritability of
the nerve stretch situated over the electrode between the chamber and
the muscle. The contractions of the muscle, which are produced by
stimulation of the periphery region of the nerve with stimuli of a
definite strength, remain unaltered, even when the asphyxiated stretch
of nerve in the chamber is already completely degenerated. The central
depression of a ganglion cell of a motory neuron is likewise wholly
without influence on the degree of excitability of its nerve fiber, as
I was able to demonstrate[79] in the reflex inhibition of the motor
neurons of the spinal cord of the dog. (Figure 14.) That which is
conducted by the nerves is solely the process of excitation.

  [79] _Max Verworn_: “Zur Physiologie der nervösen
  Hemmungserscheinungen.” Arch. f. Anat. u. Physiol. physiol. Abt.
  Suppl. 1900.

It is our task to analyze in detail the conditions involved in the
conduction of excitation in order to obtain a deeper insight into the
physics of this process. A comparative survey of a series of various
types of living substance shows us that they differ in respect to the
conduction of excitation in the following points: In regard to the
rapidity with which the excitation is conducted, the extent of the area
over which it spreads, and the intensity with which it extends. These
conditions may be best illustrated by citing two extreme examples. The
one is formed by the rhizopods, the other by the nerve fibers. Between
these two extremes we have manifold gradations in the conditions of
conductivity. Not all cell forms are suitable objects for the study of
conductivity. There are forms of rhizopods which are as favorable to
investigation as the nerve; this is due to the fact that, although
they are often of microscopic dimensions, they possess elongated
fingerlike or threadlike pseudopods.

[Illustration: Fig. 14.

Contractions of the musculus extensor digitorum communis longus of the
dog, brought about by rhythmic stimulation of the nervus peroneus. The
muscle is in the condition of tonic excitation which proceeds from
the center. The arrows indicate the point where reflex inhibition of
the central tonus is produced. The height of the single contraction
undergoes no diminution. ]

Indeed, a rhizopod cell, with its straight, elongated pseudopods,
is preëminently fitted as an object of comparison with a neuron.
Although the difference in respect to the individual points is so
far-reaching, still, based on their outward morphological similarity
various physiological parallels in both are forced on our observation.
A comparison of the rhizopod cell with the neuron can consequently
guard us from many erroneous generalizations which we might be
inclined to deduce from a one-sided investigation of the nerve. This
is especially the case in regard to the conductivity of excitation,
which was formerly studied almost exclusively on the nerve and only
occasionally on the muscle, which offers similar conditions. The nerve,
in which the function of the conductivity of excitation is particularly
highly developed, was considered at the same time as the type in which
this process could be most readily analyzed, and from which it was
believed general information of the process of the conductivity of
excitation could first be gained. This view has led to serious errors,
as the nerve, resulting from the high development of its conductive
capability, shows quite one-sided specialized conditions, which can by
no means be transferred to other forms of living substance.

A very suitable object among rhizopods for the study of conductivity,
and which is everywhere easily procured, is _Difflugia_. This species
living in small pools has a delicate urn-shaped, pear-shaped or
flask-shaped capsule built up of sand grains, diatomes or material
produced by the organism itself. From the opening the protoplasm
extends often to a considerable length its finger-shaped hyaline
pseudopods. When _Difflugia_ is placed in a flat dish in water and
observed under the microscope, it is frequently seen to extend from the
opening long pseudopods in exactly opposite directions, which reach
for a considerable distance on the bottom. These offer particularly
favorable conditions for the study of the conduction of excitation.
When this animal is placed under a microscope, the pseudopods are
very readily stimulated at any position to a desired extent by means
of a sharp needle, to which fat has been previously applied and
subsequently the excess removed. The extension of the response from
one point toward the other can then be followed with great ease.
The pseudopod of the rhizopod has the great advantage over the
nerve that its excitation can be directly observed. The excitation
following weaker stimulation is manifested by a wrinkling of the
previously completely smooth surface; stronger stimulation produces
differentiation of the hyaline protoplasm to a strongly refractive
strand in the axis and a turbid myelinlike mass at the periphery, the
pseudopod at the same time retracting toward the central cell body. In
spite of all these occurrences being of microscopic dimensions, still
with some practice it is quite possible to experiment on them under the
microscope. In this way I found it comparatively simple to study the
fundamental principles of conductivity.[80]

  [80] _Max Verworn_: “Psycho-physiologische Protistenstudien.
  Experimentelle Untersuchungen.” Jena 1889.

[Illustration: Fig. 15.

_Difflugia urceolata._ A--Weak local stimulation at the end of a long
extended pseudopod. B--Stronger local stimulation applied to the end of
a long pseudopod.]

[Illustration: Fig. 16.

_Difflugia urceolata._ A--In non-stimulated condition. B--The same
individual locally stimulated in the middle of a long extended
pseudopod. The excitation spreads in both directions, centripetal as
well as centrifugal. ]

All these factors, the intensity with which the excitation extends from
the point of stimulation, the rapidity of the extension, and finally
the area over which conduction takes place, are manifestations of the
intensity of stimulus, and as such alter with these in corresponding
manner. If the end of a pseudopod is barely touched and thereby weakly
stimulated, the response is restricted to a slight wrinkling of the
surface, which slowly extends to the immediate neighborhood, whilst
the more distant parts of the pseudopod are not affected at all by
the excitation. (Figure 15, A.) On a stronger stimulation of the
pseudopod by slight pressure, the response is likewise stronger, and
the characteristic differentiation of the protoplasm, consisting in
the strongly refractive strand in the axis and the turbid myelinlike
outer mass, appears at the point of stimulation. From here a peculiar
alteration spreads gradually further over the pseudopod, in that
first upon its smooth surface a few myelinlike droplets are seen,
which become larger and with the development of the strand in the
axis, dissolve into a wrinkled mass on the surface. The further this
process extends from the point of stimulation, the weaker it becomes
and the more slowly it proceeds, until at last there is complete
disappearance. (Figure 15, B.) The pseudopod has at the same time
retracted to a considerable degree. If a still stronger stimulus is
applied by firm pressure at the end of the pseudopod the process takes
place with much greater violence. The differentiation of the protoplasm
spreads centripetally from the point of stimulation over the whole
pseudopod with great rapidity, and produces a quick retraction in the
same, then involves the oppositely directed pseudopod, in which it
then extends more and more slowly, until, proceeding in a centrifugal
direction, it is at last gradually completely obliterated. When strong
stimulation is applied, the process occurs with such rapidity that the
contraction of the pseudopod is almost twitchlike. As the rapidity of
the conduction alters within a wide limit according to the strength
of the stimulus and the distance from the point of stimulation, it
is self-evident that no constant figure can be stated. To give a
general idea of the rapidity, they might be estimated according to
observations I have made with second watch and ocular-micrometer as
from within a slight fraction to that of a millimeter in the second.
When a very long extended pseudopod is locally stimulated in the
middle, the response spreads from the point affected in both directions
diminishing in intensity and rapidity. The excitation extends equally
in all directions. (Figure 16.) These facts show very clearly that
in _Difflugia_ the excitation following a localized stimulus is
dependent on the intensity of the stimulus, and that according to
the degree of this, the wave progresses in either stronger, more
rapid and extended, or weaker, slower and more limited manner. With
the greater distance from the point of stimulation the excitation
undergoes an increasing decrement of its intensity and rapidity of
conduction. Different species of _Difflugia_ which I have investigated,
_Difflugia lobostoma_, _urceolata_, _pyriformis_, have shown a
complete conformity in this respect. A great number of other fresh
water and marine rhizopods, the pseudopods of which I have used for
analogous experiments, although differing in the manner of reaction
in regard to the extent and rapidity of the course of excitation,
manifest exactly the same fundamental principles. A very favorable
form is, for instance, the much smaller _Cyphoderia margaritacea_,
which is distinguished by a somewhat higher degree of excitability and
rapidity of reaction.[81] The long straightly extended pseudopods are
thinner and more threadlike than those of _Difflugia_ and show upon
stimulation as a result of their local excitation a simple contraction
into clumps of the stimulated protoplasm without the characteristic
differentiation of that of _Difflugia_. (Figure 17.) In the case of
the marine rhizopods, _Orbitolites_ (Figure 19), _Amphistegina_, etc.,
which I investigated at the Red Sea, the conduction of excitation takes
place also as in _Difflugia_ with a decrement of intensity and rapidity
becoming larger with the distance from the point of stimulation until
the wave of excitation is obliterated.

  [81] _Max Verworn_: “Die Bewegung der lebendigen Substanz.
  Eine vergleichend physiologische Untersuchung der
  Contractionserscheinungen.” Jena 1892.

[Illustration: Fig. 17.

_Cyphoderia margaritacea._ Result of localized mechanical stimulation
at the end of a long extended pseudopod. A, B, C--three successive
stages.]

[Illustration: Fig. 18.

_Cyphoderia margaritacea._ Result of localized mechanical stimulation
in the middle of a long extended pseudopod.]

[Illustration: Fig. 19.

A pseudopod of Orbitolites complanatus (cf. Fig. 7). _a_--In normal
condition. _b_--Severed by a cross section near the end. _b-f_--Five
successive stages of the effect. _b-d_--The pseudopod retracts by
centripetal flowing of the protoplasm contracted in the shape of
microscopic balls and spindles. _e_ and _f_--The pseudopod begins to
extend again. The centripetal flowing balls and spindles begin to
disappear. ]

A sharp contrast to this type is formed by the other extreme as
represented by that of the medullated nerve. As an indicator of the
course of excitation we will take the action current in an isolated
nerve of the frog. If this is stimulated at one end, we can test the
intensity of the conducted excitation by leading off the action current
from two points at varying distances from the one influenced by the
stimulus. Since the classical discovery of _Du Bois-Reymond_ of the
action current of the nerve, we know that in the fresh medullated
nerve, if observed under favorable experimental conditions, no
decrement of intensity of excitation during its course from the point
of stimulation along the length of the nerve can be demonstrated.[82]
If unpolarizable electrodes are applied to a nerve in such a position
that they are equidistant from the cross section and are connected with
apparatus for testing the current, it will be found that there exists
an “unwirksame Ableitung” in the sense of _Du Bois-Reymond_, that is,
in which there is no demarcation current. When a tetanizing current is
applied to one end of the nerve, no difference of potential between the
two nonpolarizable electrodes is observed, which indeed would be the
case if excitation with its current of action would have a decrement
on its way from one to the other point of leading _off_ the current.
_This fact, which has been repeatedly confirmed, shows us that the
medullated nerve, under normal conditions, conducts excitation without
a perceptible decrement of the intensity._

  [82] _Du Bois-Reymond_: “Untersuchungen über tierische Electricität.”
  II Band. 1849.

This specific property of a medullated nerve is in conformity with
the conditions in connection with the rapidity of conductivity. Since
_Helmholtz_[83] has devised the method for measuring the rapidity of
conduction in the nerve, this investigator himself and numerous others
have studied the rate in different nerves.[84] _Helmholtz_ found the
rate for motor nerves of the frog to be 27 meters per second, for
the sensory nerves of man 60 meters, and the motor nerves of man 34
meters. Other investigators have obtained quite different results;
_Hirsch_, for the sensory nerves of man, 34 meters; _Schelske_, for the
same, 25–33 meters; _De Jaager_, 26 meters; _v. Wittich_, 34–44 meters,
and _Kohlrausch_, 56–225 meters; _v. Wittich_ for the motor nerves of
man, 30 meters; _Piper_[85] finally in the most recent investigations
about 120 meters in the second.

  [83] _H. Helmholtz_: “Messungen über den zeitlichen Verlauf der
  Zuckung animalischer Muskeln und die Fortpflanzungsgeschwindigkeit
  der Reizung des Nerven.” Müller’s Archiv. 1850.

  The same: “Messungen über die Fortpflanzungsgeschwindigkeit der
  Reizung in den Nerven.” Zweite Reihe, Müller’s Arch. 1852.

  [84] Compare: _Hermann_: “Handbuch der Physiologie.” II, 1 Leipzig
  1879.

  [85] _Piper_: “Ueber die Leitungsgeschwindigkeit in dem markhaltigen
  menschlichen Nerven.”

  The same: “Weitere Mitteilungen über die Geschwindigkeit der
  Erregungsleitung im markhaltigen menschlichen Nerven.” Pflügers Arch.
  Bd. 127, 1909.

These differences may be explained in a _large_ measure by the variety
of the methods used, in part also by the difference in the structures.
The methods employed for the study of the velocity have also been used
to solve the question, whether the velocity of the excitation wave in
its course over the nerve meets with a decrement as it moves further
and further away from the point of stimulation. Here the endeavor was
made to study the difference in time of the latent period, which is
observed by the indicator, when the nerve is stimulated at two points
at different distances from the muscle, used as an indicator, or
from the wires leading the current to the indicator. The more recent
investigators, as _René Du Bois-Reymond_,[86] _Engelmann_,[87] _G.
Weiss_,[88] have arrived at the same conclusion, that the rate of
conductivity in the medullated nerve under normal conditions is the
same at all distances from the point of stimulation. (Figure 20.)

  [86] _R. Du Bois-Reymond_: “Ueber die Geschwindigkeit des
  Nervenprincips.” Arch. f. Anat. u. Physiol. physiol. Abt. Suppl. 1900.

  [87] _Engelmann_: “Graphische Untersuchungen über die
  Fortpflanzungsgeschwindigkeit der Nervenerregung.” Arch. f. Anat. u.
  Physiol. physiol. Abt. 1901.

  [88] _G. Weiss_: “La conductibilité et l’excitabilité des nerfs.” In
  Journ. de Physiol. et de Pathol. générale 1903.

The medullated nerve shows, therefore, under normal conditions
neither a decrement of its conductivity, nor of its _irritability_,
as the distance of the wave of excitation increases from that of the
position of stimulation; this means, in other words, that excitation is
conducted with the same intensity with which it is started, and with a
constant rate throughout the entire course of the nerve.

[Illustration: Fig. 20.

Curves of muscle contraction obtained by stimulation of 3 and 4 points
situated at equal distances from each other on the sciatic nerve of the
frog. The increase of length of the nerve stretch corresponds with an
equal increase of the latent period of contraction. From this follows,
that the rapidity of the wave of excitation is the same at all points
of the entire length of the nerve. (After _Engelmann_.) ]

There is, nevertheless, a third point of considerable difference
between the types of conduction of excitation in the rhizopods and
in the nerve. Whereas in the rhizopods the rapidity of conduction
is dependent upon the _intensity_ of the stimulus, it has been long
known as the result of investigation by _Rosenthal_, _Brücke_ and
_Lautenbach_ and at a more recent date by _Gotch_[89] and _Piper_,[90]
that in the nerve of the frog, as well as in man, the velocity is _not_
dependent upon the intensity of stimulation. (Figure 21.) Contrary
results have been obtained by a few early observers wherein the latent
period was shorter when the stimulation was strong. _Nicolai_[91]
explains this shortening of the latent period, resulting from the
application of strong electrical stimuli, to a spreading out of the
“Stromschleifen” from the point of application and consequently
there is a shortening of the stretch of nerve between the point of
stimulation and the indicator.

  [89] _Gotch_: “The submaximal electric response of nerve to a single
  stimulus.” Journal of Physiology, Vol. XXVIII, 1902.

  [90] _Piper_: Ueber die Leitungsgeschwindigkeit in den markhaltigen
  menschlichen Nerven. Pflügers Arch. Bd. 124, 1908, und Bd. 127, 1909.

  [91] _Nicolai_: “Ueber Ungleichförmigkeiten in der
  Fortpflanzungsgeschwindigkeit des Nervenprincips, nach Untersuchungen
  am marklosen Riechnerven des Hechts.” Arch. f. Physiologie 1905.

[Illustration: Fig. 21.

Course of the action current of the nerve. The thin line indicates the
action current produced by a weak, the thick line the action current
produced by a strong stimulus. The duration of the action current is
the same in both cases. (After _Gotch_.) ]

This conspicuous difference in the conduction of the two extreme types
of living substance, which we have already observed, arouses the
question as to what properties of living substance bring about these
differences. In order to answer this question, it is necessary, first
of all, to make some general statements concerning the processes of
conductivity.

As already emphasized, all living substance possesses the capability of
conducting excitations to a definite degree. We may, therefore, assume
that the same fundamental _property_ of conductivity exists in all
substances. A fact to be considered in the conduction of excitation, is
that the primary breaking down of the complex molecules at the position
of stimulation act in turn as exciting stimuli upon the neighboring
portion of the living substance, which in turn undergoes a similar
decomposition. And so this process continues. This fact is evident from
the observations on the process of excitation. But the nature of the
stimulus which produces the breaking down of the complex molecules
upon the surrounding molecules is a problem which can only be studied
later. Here only one point will be mentioned in advance concerning the
intensity of the stimulus. It is apparent from the experiments on the
rhizopods, that the greater the intensity of the stimulus the more
extensive must be the breaking down of the living substance. A stronger
primary stimulation must also secondarily produce a stronger stimulus
in the neighborhood. In other words: the _conduction of excitation_
is a function of irritability. The greater the irritability, that is,
the greater the number of molecules broken down in a unit of time
and space by a stimulus of a certain intensity, the greater also is
the conductivity of the living system, that is, the stronger, the
more rapidly and the further excitation is extended. Conductivity
of excitation is, therefore, unthinkable without irritability. Both
are inseparably connected. The conclusion forced upon us by this
chain of reasoning admits of no argument. Nevertheless the endeavor
has been made, because of certain evidence at hand, to show that
the property of conductivity could exist without irritability. A
number of authors, such as _Schiff_,[92] _Erb_,[93] _Grünhagen_,[94]
_Effron_,[95] _Hirschberg_[96] and _G. Weiss_,[97] have observed the
fact that in spite of a more or less strong decrease of _excitability_
of a stretch of nerve, stimuli applied above this stretch can still
produce a conduction of excitation through the affected part. They have
concluded from this that it is possible to separate the conductivity
from irritability. _Erb_ and _G. Weiss_ have even gone so far as
to directly express the opinion that capability of conduction and
irritability involve two different histological elements. In contrast
to this, other investigators, such as _Hermann_,[98] _Szpilmann_ and
_Luchsinger_,[99] _Gad_,[100] _Piotrowski_[101] and _Wedenski_,[102]
have more or less decidedly taken the stand that an actual separation
of irritability and of conductivity does not exist. The apparently
contradictory evidence as well as the conflicting theoretical views
have been cleared up by _Werigo_,[103] _Dendrinos_,[104] _Noll_[105]
and _Fröhlich_.[106] These investigators have shown that the length
of the narcotized stretch of the nerve plays an important rôle in the
obliteration of conductivity. It has been found by the application
of a stimulus above the narcotized stretch of nerve, that the longer
this stretch is, the less is the reduction of irritability which
obliterates the excitation wave reaching this area. Further: The
shorter the stretch, the greater must be the reduction in irritability
before this result is brought about. (Figure 22.) In other words, the
conductivity in the narcotized nerve is dependent upon the length and
the irritability of the narcotized stretch. From this observation the
important fact is evolved, that the wave of excitation meets with a
decrement of its intensity in the narcotized area. This decrement
becomes larger as the wave progresses through the involved stretch.
Further it is progressively increased as the amount of the irritability
is reduced. Finally, when the stretch is long enough, the wave of
excitation is obliterated. This important fact has been further
established by the experiments of _Boruttau_ and _Fröhlich_,[107] in
which they studied the intensity of the current of action, produced by
a wave of excitation, from two points in the narcotized stretch. The
wave of negative variation, brought about by the excitation, gradually
decreases in the narcotized stretch as the electrode is further removed
from the point of entrance. Beside a decrement of _intensity_, as
the investigations of _Fröhlich_[108] prove, the wave of excitation
shows a decrement of the velocity in the narcotized stretch. And it
is probable that the wave of excitation extends with _progressive_
reduction in the velocity, corresponding to the decrement of intensity.
The work of _Koike_[109] under the direction of _Garten_, in which the
conclusion arrived at is that the reduction in the velocity is the same
throughout the narcotized area, should not be accepted as conclusive
in spite of the delicate method employed. These investigations are
extremely difficult, being in the field of the most delicate of
present-day methods. The decrement, which the wave of excitation meets
with in its progress in the narcotized stretch, makes the conflicting
testimony concerning the apparent separation of irritability and
conductivity intelligible. It depends entirely upon the length of
the narcotized area, and the amount of reduction in irritability on
the one hand, and the strength of the stimulus used for testing the
irritability on the other, whether the conductivity will disappear
_before_ the irritability or _vice versa_. If I test the irritability
in the narcotized stretch with a weak stimulus, just slightly _above_
the threshold, then by slight reduction in the irritability complete
absence of response occurs, when the same stimulus is applied. This
occurs at a time when excitation reaches the narcotized area from
above and meets with a decrement so slight that it can pass through
the whole narcotized stretch, that is, when the narcotized stretch is
short enough. If I test the irritability of the narcotized area with a
strong stimulus, far above that of the threshold, irritability will be
found to be present at a time when the conductivity for the excitation,
coming from above, is already obliterated. This is due to the fact that
the decrement in the narcotized area is already great enough to bring
about the complete disappearance of the wave of excitation coming
from above. This, of course, only occurs provided the length of the
narcotized stretch is great enough. The separation of conductivity
and irritability is, therefore, only an apparent one. In reality, the
facts obtained from experimentation indicate that with the reduction of
irritability the decrement of the wave of excitation increases, whilst
the shorter the stretch, the smaller is the decrement. This shows that
_conductivity is a manifestation of irritability_.

  [92] _Schiff_: “Über die Verschiedenheit der Aufnahmsfähigkeit und
  Leitungsfähigkeit in dem peripherischen Nervensystem.” Henle u.
  Pflügers Zeitschr. 1866.

  [93] _Erb_: “Zur Pathologie und pathologischen Anatomie
  peripherischer Paralysen.” Deutsches Arch. f. Klin. Med. 1869.

  [94] _Grünhagen_: “Versuche über intermittierende Nervenreizung.”
  Pflügers Archiv. Bd. 6, 1872.--_Funke-Grünhagen._ Lehrbuch der
  Physiologie Bd. I, 1876.

  [95] _Effron_: “Beiträge zur allgemeinen Nervenphysiologie.” Pflügers
  Arch. Bd. 36, 1885.

  [96] _Hirschberg_: “In welcher Beziehung stehen Leitung und Erregung
  der Nervenfaser zu einander?” Pflügers Arch. Bd. 39, 1886.

  [97] _G. Weiss_: “La conductibilité et l’excitabilité des nerfs.”
  Journ. de physiol. et de pathol. générale. T. V. 1903.--“Influence
  des variations de temperature et des actions méchaniques sur
  l’excitabilité et la conductibilité des nerfs.” _Ibidem._

  [98] _Hermann_: “Handbuch der Physiologie.” Bd. II, I Leipzig 1879.

  [99] _Szpilmann und Luchsinger_: “Zur Beziehung von Leitungs- und
  Erregungsvermögen der Nervenfaser.” Pflügers Arch. Bd. 24, 1881.

  [100] _Gad_: “Ueber Trennung von Reizbarkeit und Leitungsfähigkeit
  des Nerven.” (Nach Versuchen des Herrn Sawyers) Arch. f. Anat. u.
  Physiol. physiol. Abt. 1888.

  Derselbe: “Ueber Leitungsfähigkeit und Reizbarkeit des Nerven in
  ihren Beziehungen zur Längs- und Querschnitts erregbarkeit.” Nach
  Versuchen des Herrn Piotrowski Arch. f. Anat. und Physiol. physiol.
  Abt. 1889.

  [101] _Piotrowski_: “Ueber Trennung von Reizbarkeit und
  Leitungsfähigkeit des Nerven.” Arch. f. Anat. u. Physiol. physiol.
  Abt. 1893.

  [102] _Wedenski_: “Die fundamentalen Eigenschaften des Nerven unter
  Einwirkung einiger Gifte.” Pflügers Arch. Bd. 82, 1900.

  The same: “Excitation, inhibition et narcose.” Compt. rendus du v.
  Congres internat. de Physiologie à Turin 1901.

  [103] _Werigo_: “Zur Frage über die Beziehungen zwischen Erregbarkeit
  und Leitungsfähigkeit des Nerven.” (Nach Versuchen von stud.
  Rajmist.) Pflügers Arch. Bd. 76, 1899.

  [104] _Dendrinos_: “Ueber das Leitungsvermögen des motorischen
  Froschnerven.”

  [105] _Noll_: “Ueber Erregbarkeit und Leitungsvermögen des
  motorischen Nerven unter dem Einfluss von Giften und Kälte.” Zeitsch.
  f. Allgem. Physiol. Bd. III, 1907.

  [106] _Fr. W. Fröhlich_: “Erregbarkeit und Leitfähigkeit des Nerven.”
  Zeitschr. f. allgem. Physiol. Bd. III, 1904.

  [107] _Boruttau und Fröhlich_: “Erregbarkeit und Leitfähigkeit des
  Nerven.” Zeitschrift f. allgem. Physiologie Bd. IV, 1904. The same:
  “Electropathologische Untersuchungen ueber die Veränderungen der
  Erregungswelle durch Schädigung des Nerven.” Pflügers Arch. Bd. 105,
  1904.

  [108] _Fröhlich_: “Die Verringerung der Fortpflanzungsgeschwindigkeit
  der Nervenerregung durch Narkose and Erstickung des Nerven.”
  Zeitschrift allgem. Physiologie Bd. III, 1904.

  [109] _Izuo Koike_: “Ueber die Fortleitung des Erregungsvorgangs in
  einer narkotisierten Nervenstrecke.” Zeitsch. f. Biologie Bd. 5, 1910.

[Illustration: Fig. 22.

Scheme of the decrement of the excitation wave in the narcotized
stretch of a nerve. A--The narcotized stretch (indicated by the cross
section of the chamber) is 30 mm. long. The ordinates of the dotted
lines indicate the amount of the decrement. If the decrement is slight
(upper dotted line), the excitation wave passes the narcotized stretch
and increases again on entering the normal stretch. If the decrement is
great (lower dotted line), the excitation wave is obliterated towards
the end of the narcotized stretch and the muscle remains at rest.
B--The narcotized stretch is 15 mm. long. The decrement is slight.
The excitation wave can therefore pass into the normal stretch and
here increase again. C--The narcotized stretch is 15 mm. long. The
decrement is great. The excitation wave is obliterated, therefore, in
the narcotized stretch, and the muscle remains at rest. ]

The facts just mentioned have, however, a much deeper meaning. They
show us that it is possible by means of narcosis to convert an extreme
type of a living system, with decrementless conductivity, into another
extreme type of living substance, in which excitation in its progress
meets with a strong decrement, like that seen in the rhizopods. The
same results may also be obtained by asphyxiation and other forms of
temporary and permanent injury of the nerve. We are, therefore, in the
fortunate position in the case of the medullated nerve of having a
substance to study, which, depending upon conditions which are under
our control, may become a type in which conductivity occurs with
or without the presence of a decrement. We can likewise reduce the
irritability to various degrees, producing all intermediate gradations
between the two extremes. This latter is particularly valuable in that
it permits us to study the conditions in one and the same substance
necessary to bring about the various peculiarities of conductivity. The
great differences in the conductivity of excitation are conditioned by
variations in the degree of irritability. If the irritability of the
nerve is at the normal level the wave of excitation progresses to the
end of the nerve without manifesting a decrement of its intensity or
rapidity.

If the level of irritability of the intact nerve is artificially
reduced, the wave of excitation meets with a greater decrement and
reduces in velocity, and in fact disappears the more quickly in the
stretch of nerve, as the reduction in irritability is increased.
These three factors, irritability, intensity and velocity of the
progress of the wave of excitation, are inseparable. All living
substances may be grouped according to their capability of conducting
excitation into a long series, starting with those possessing the
least irritability, as we found in the rhizopods, then those having
greater irritability, as the smooth muscle and ganglion cells, then
those with still greater irritability, as the striped muscle, and
finally those having the greatest degree of irritability, as the
medullated nerves of the warm-blooded animal. Should the processes of
excitation, as we saw, result from the energy production following the
disintegration of the labile molecules of the living substance, then
the degree of irritability is determined by the chemical constitution
of the disintegrating molecules, by the number of molecules which are
broken down in a definite space and a given time, and by the nature
of the disintegration itself. All of these individual components, if
we observe the problem from the physical standpoint, are manifested
by the quantity of energy production. The higher the irritability of
a living system, the greater is the amount of energy production in a
given time and space which the stimulus produces. This has particular
interest from the standpoint of the extreme cases of medullated nerves
of the vertebrates with their most highly developed conductivity,
and which will be analyzed in somewhat greater detail. How are we to
explain their decrementless conductivity? When we study the decrement
of the excitation wave in the series of living substances, before
alluded to, we see that this reduces with a progressive increase of
irritability. Consequently the extreme irritability of the nerve is
a manifestation of its decrementless conductivity. If we study the
course of a process of excitation and its conduction in its molecular
details, the fact of the decrementless conduction indicates that
in excitation, produced by a stimulus, the same number of specific
molecules capable of disintegration are broken down in the same manner
at every following cross section, as at the point of stimulation; or
in other words: an equal amount of energy is set free at every cross
section, which, in its turn, acts as stimulus to the next, etc. Such a
condition presupposes, however, in an elementary fiber of the nerve,
that by the conduction of the wave of excitation from cross section
to cross section, all those molecules capable of disintegration are
broken down. If it is assumed that the entire number of molecules
capable of disintegration do not break down, but only a certain per
cent. of the same, then it would not be possible to conceive of a
molecular structure of the nerve in which this would take place
without decrement of the wave of excitation. With the assumption of
a generally homogeneous molecular structure (Figure 23, a) of the
elementary fibers it would be entirely incomprehensible how, with the
decrementless extension of the excitation, individual molecules capable
of breaking down could escape disintegration. If, on the contrary, the
molecular structure is not homogeneous it only is possible to explain
a conduction, on each cross section of which an equal per cent. of
irritable molecules break down, by the hypothesis that the irritable
molecules are in their turn ordered in fiber-shaped series (Figure 23,
b) within the elementary fiber and are thus protected to a certain
degree from one another and from transverse conduction of excitation.
This hypothesis would, therefore, only mean that the elementary fiber
is not such in reality and would thus transfer the difficulty to
the ultimate fiber unit, for which a homogeneous molecular structure
would have to be presumed. In short, whatever may be the assumption on
which molecular structure of elementary fibers is based, the fact of
the decrementless conduction peremptorily demands, from the physical
standpoint, that from cross section to cross section the entire number
of irritable molecules are broken down. This conclusion is highly
important, for it indicates very clearly that the “all or none law” is
applicable to the nerve.

[Illustration: Fig. 23.]

This gives us occasion to return to the discussion of the question, if
living systems really exist which respond in accordance with the “all
or none law.” The medullated nerve forms an object particularly suited
to serve as a starting point for the treatment of this especially
important problem. The question arises in this connection, if the
validity of this law for the nerve can be tested by other means.

At first it would seem as if the application of the “all or none law”
to the nerve were in contradiction to the well-known fact that a
weak stimulation of the nerve produces a weak, a strong stimulation,
a strong response. In this connection _Gotch_[110] has pointed out,
as the result of experimental studies of the wave of activity of the
nerve, that the difference in response, following the application of
stimuli of varying strengths, is understandable from the fact that
threshold stimuli stimulate only a few of the fibers of the nerve
trunk, whereas progressively increasing the intensity of the current
involves more and more fibers. There can be no doubt that this factor
explains the difference in the strength of the response. Therefore, in
reality we do not find here a contradiction of the “all or none law.”
On the other hand, the fact that the nerve, in contradistinction to
many other forms of living substance, the ganglion cell, for example,
upon a weak stimulation does not show the phenomena of summation, even
when the stimuli follow each other in a rapid succession, indicates
very strongly that the weakest operable stimulus produces maximal
excitation, so that the response cannot be further increased. But
above all, there is a series of facts, which have been gained in the
Göttingen laboratory, which demonstrate apparently without doubt the
validity of the “all or none law” for the medullated nerve. These
observations I wish now to consider in greater detail.

  [110] _Gotch_: “The submaximal electrical response of nerve to a
  single stimulus.” Journal of Physiology, Vol. XXVIII, 1902.

If a nerve of a nerve muscle preparation is drawn through a specially
devised glass chamber so that the middle portion can be narcotized or
asphyxiated and the nerve so arranged that it rests upon a pair of
electrodes in the chamber and upon a second pair without the chamber
and centrally located, then the nerve can be narcotized or asphyxiated
and thereby the alterations in the irritability as well as the
conductivity can be followed. In order to obtain as distinct a picture
of this alteration as possible, I tested continuously the threshold of
stimulation, which just produced minimal contraction in the muscle, and
_Fröhlich_[111] continued these observations. As a result the following
very remarkable conditions were observed. During the increase of the
depth of narcosis or asphyxia the irritability sinks more and more with
regularity. The conductivity remains unaltered for a long time, as the
strength of the threshold stimulus is not changed until irritability
has fallen to a definite point. When this is reached, conductivity
disappears. (Figure 24.) The most important point in this connection,
however, is, that the conductivity disappears simultaneously and
practically momentarily for the excitation produced by both weak and
strong stimuli. When the stimulation at the electrode placed centrally
to the chamber does not bring about response for threshold stimuli,
maximal stimuli at the same time also become inoperative. This is a
very interesting point, the importance of which has not until now been
recognized. This fact is not in harmony with the view held until now,
that in the nerve fiber different strengths of stimuli bring about
excitation of different intensity, and are then conducted. Let us now
clearly comprehend this problem.

  [111] _Fröhlich_: “Erregbarkeit und Leitfähigkeit des Nerven.”
  Zeitschr. f. allgem. Physiologie, Bd. III, 1904.

[Illustration: Fig. 24.

Curves of the changes in irritability (p) and conductivity (c) of
a nerve under the influence of narcosis or asphyxiation. (After
_Fröhlich_.)]

We have already seen that the wave of excitation meets with a decrement
of its intensity in the narcotized stretch, which increases in
strength as the irritability diminishes. If the value of the threshold
is learned by stimulating the nerve at the electrodes centrally placed
to the chamber with minimal stimuli, it would necessarily follow that
this weak stimulus would bring about a corresponding weak excitation
of the individual fibers and the wave of excitation already in the
beginning of narcosis would be obliterated, for it would meet with a
decrement, the result of the reduction in the irritability. A wave of
excitation of minimal strength could under these conditions no longer
reach the muscle, even in the beginning of narcosis. In spite of this
the excitation, even when produced with threshold stimuli, passes
through for a long time, even when the irritability in the chamber is
greatly reduced, as shown by testing with the electrodes within the
chamber. This is not consistent with the assumption that a threshold
stimulus brings about the minimal excitation, even in the individual
nerve fiber. But further: with a definite decrease of irritability of
the narcotized stretch the capability of conductivity disappears, and
indeed simultaneously for the weakest as well as the strongest stimuli.
If it is assumed that weak stimuli bring about weak excitations in the
nerve fiber, it must most certainly be expected that on the cessation
of the response, weak stimuli applied at the central nerve end would
still, by slight increase of the intensity of stimulation, be followed
anew by reaction in the muscle. This is all the more to be expected,
because the irritability of the narcotized stretch, as shown by
stimulation with the electrodes inside the chamber, very gradually
decreases, so that within the chamber stimuli of moderate strength are
still effective. Instead the capability of conduction is completely
obliterated, and even the strongest stimuli, applied to the end of
the nerve, produce no response in the muscle. This in turn does not
agree with the assumption that the intensity of excitation varies with
the strength of the stimulus in the individual nerve fiber. The facts
here alluded to are, therefore, either not correct, or the intensity
of excitation in the individual nerve fibers is independent of the
strength of the stimulus, and the view which we have entertained up to
the present in this respect is incorrect.

[Illustration: Fig. 24.]

In order to examine these facts once more on an extensive scale, and
at the same time obtain an understanding of the development of the
decrement in the narcotized stretch, I have requested _Dr. Lodholz_ to
register as many accurate curves as possible in which the positions of
the secondary coil of an inductorium are the ordinates indicating the
threshold of stimulation at four points of a nerve stretch. Of these
points three are situated at prescribed distances from each other in
the narcotized or asphyxiated stretch; the fourth is centrally placed.
(Figure 24.) As might be expected the result was the same as in former
investigations. They show however even more strikingly the abruptness
of the disappearance of conductivity simultaneously for the weakest
and the strongest stimuli. The curve produced by the centrally placed
electrode remains at the same height for a considerable period, then
suddenly abruptly declines. Those of the electrodes within the chamber
likewise sink, at first slowly, then with increasing rapidity in
successive order corresponding to the distance which they are situated
from the point of exit of the nerve, so that the curve of the most
distant electrode reaches the abscissa first, that of the electrode
nearest the muscle in the chamber, last. The experiments demonstrate
with complete clearness that in contrast to all those points within the
affected stretch, where the conductivity, though already obliterated
for weaker stimuli, still exists for stronger, that with stimulation
of a point towards the center _above_ the affected stretch, conduction
ceases simultaneously for all different strengths of stimuli. This
last state at the points within the affected stretch might be ascribed
to the diminution of the excitability of this stretch, and the idea
entertained that the weak stimuli no longer produce excitation capable
of further conduction.

This assumption is contradicted, however, by the fact that subsequently
to the disappearance of the response at a point situated at the
_greatest distance_ from the place of exit, an effect of stimulation
can be obtained at the _nearest_ point to the exit with the same or
even less strength of the current. As the irritability in the affected
stretch is reduced at all points in equal measure, the fact of a weaker
stimulus becoming inoperative whilst a stronger remains effective can
only be attributed to the circumstance that the wave of excitation
set free at some point of the influenced stretch by a weaker stimulus
is sooner obliterated on its way to the muscle than that produced at
the same point by a stronger stimulus. These experiments, in which
the manifestations of the nerves in response to stimuli applied
centrally above the chamber in the normal stretch are compared to those
in response to a stimulus acting on the affected stretch, clearly
demonstrate the totally different effect in both cases. In stimulation
of the centrally situated normal stretch, the wave of excitation, which
enters from here into the influenced stretch, is obliterated at the
same point simultaneously for the weakest as well as for the strongest
stimulus; stimulation of the affected stretch, the wave of excitation
which is set free at one point by a weak stimulus, is obliterated
sooner and after passing through a shorter stretch than that which is
produced by a stronger stimulus. It is self-evident that in the first
instance, in which the stimulus acts on the centrally situated normal
stretch, the wave of excitation, thereby set free, must in passing
through the affected stretch undergo a decrement of its intensity. If,
therefore, the wave of excitation, coming from above, is obliterated
exactly at the same point, whether brought about by weak or strong
stimuli, the inevitable conclusion must be drawn that, whether either
a weak or a strong stimulus is operative, the wave of excitation must
have entered into the influenced stretch from the normal stretch with
exactly the same intensity. In other words: the weakest as well as the
strongest stimuli produce excitations of equal intensity in the normal
nerve, that is, the “_all or none law_” is _valid for the nerve_.

This information can no longer be doubted in the presence of such
evidence as was presented above. This indeed is a fact of far-reaching
importance in the understanding of the functional activity of our
nervous system, for it is evident that the difference of intensity in
the conduction of excitation is not, as has been assumed until now, the
result of the conduction of varying strengths of a single excitation
in the same elementary fibers, but rather the involvement of a various
number of fibers, and that a series of processes which we have to the
present attributed to the varying intensities are now to be explained
by difference in the duration and form of excitation. This gives us
an entirely different but nevertheless a more definite picture of the
physiological character of the processes in the nervous system. Still,
this question belongs to another chapter of physiology. Here we are
interested in the fact that we have in the nerve a form of living
substance, in which irritability has reached a high degree, and every
stimulus which is at all operative brings about disintegration of all
the material involved in excitation, and consequently the property of
conductivity in the nerve reaches the state of highest development
of all living structures, in that the medullated nerve conducts with
the greatest rapidity on the one hand, and on the other, there is
no decrement of the velocity and intensity of excitation. All these
characteristics: the existence of the “all or none law,” the rapidity
of the conduction of excitation, the absence of a decrement in the
velocity, the absence of a decrement of the intensity of the excitation
wave, the want of the capability of summation of excitation, are all
dependent upon one another, for they are the combined expression of
one and the same factor, that of the high state of irritability. When
the irritability is artificially reduced, then the nerve approaches
more and more, depending upon the amount of reduction, to the series
of living substances in which we found the protoplasm of the rhizopoda
to occupy the other extreme. Between the normal medullary nerve with
its maximal, and the pseudopods of the rhizopods with their minimal
capability of reaction, we find innumerable gradations in groups of
living substances. Whether or not other forms of living substances
follow the type of the nerve, whether for example the “all or none law”
can be applied to the skeletal muscle as the investigations of _Keith
Lucas_[112] seem to show, requires further investigation.

  [112] _Keith Lucas_: “On the gradation of activity in a skeletal
  muscle fiber.” Journal of Physiology, Vol. IX, 1888. The same: The
  “all or none” contractions of the amphibian skeletal muscle-fiber.
  Journ. of Physiology, Vol. XXXVIII, 1909.

Finally, there arises the important question as to the finer mechanism
of conductivity. The progression of excitation from cross section to
cross section in a living system is brought about by the decomposition
of the molecules in one region acting as a stimulus and producing
a disintegration of the molecules in another region, etc. We have
already seen that the intensity is dependent upon the amount of energy
produced by the disintegration of the molecules following the stimulus,
that is, upon the amount liberated in a definite space in a definite
time. The question which now arises is this: What form of energy is
produced by the stimulus at the point of stimulation, which acts upon
the neighboring molecules? The conduction of excitation is a property
of all living substance, and we may presume that this occurs in all
living systems in the same manner. If one examines the forms of energy
which are produced in a living substance by the breaking down of the
molecules, we find that chiefly three forms of energy may be taken in
consideration in the problem of conductivity: heat, electricity and
osmotic energy. Light cannot be looked upon as a form of energy which
is produced by all living substance, and the other forms of energy,
as the chemical energy and surface tension, remain local. At a first
glance one is inclined to assume that heat is the form of energy
which is liberated by the breaking down of the stimulated molecule
and which spreads to the neighboring molecules and brings about their
decomposition. For we know that heat facilitates dissociation, and the
analogy between living substance and explosive material is very close.
In both instances the decomposition, which extends over a great mass
of molecules, is accomplished by the heat produced in the breaking
down of a few molecules. In fact, the conduction of excitation of a
nerve can in many respects be compared with the burning of a fuse.[113]
Nevertheless, it must not be forgotten that this analogy, which on
first glance seems so apt, upon closer observation presents serious
difficulties. It can be experimentally shown that an increase in the
temperature in the living substance follows stimulation, but it is
also known that in momentary excitation following a single stimulus,
as in the muscle after the application of an induction shock, the heat
production is extremely small. This difficulty becomes particularly
apparent if we endeavor to gain an approximate idea of the numerical
proportions of the irritable, that is the disintegrating molecules to
the remaining mass of a living system. The water content above all
represents an enormous proportion. If we calculate this to be for
the nerve, for instance, roughly about 75 per cent., which is a low
estimate, only 25 per cent. of dry substances remain. Even of this
25 per cent. by far the largest part is apportioned to connective
tissue, for which 15 per cent. is certainly not too high a figure.
Neither can the remaining 10 per cent. of dry substances be regarded
as consisting entirely of molecules capable of decomposition. For in
this is also included the organic reserve material of the axis cylinder
protoplasm, which is doubtless of very considerable amount. Further,
the salts and products of disintegration, for which the estimate for
the sum total would probably not be too low if we assume the amount to
be equal to that of the group specially concerned in the process of
excitation. As, however, a constant metabolism of rest takes place,
these last molecules or atom groups are certainly not at the moment
of entrance of the stimulus in their entirety in a condition capable
of decomposition. It is quite certain, therefore, that we are still
overestimating the amount of the molecules capable of disintegration,
if we put them down as 5 per cent. of the entire nerve substance.
If we now suppose that this 5 per cent. of irritable molecules are
broken down as a result of stimulation, 95 per cent. of nonirritable
substance, separating these irritable molecules, must become heated to
such a degree by the disintegration of the latter that the amount of
heat suffices to bring about decomposition of the nearest surrounding
molecules or atom groups, for otherwise conduction of disintegration
could not take place in this manner. This condition presents a
serious difficulty for the assumption that heat is the form of energy
responsible for the conduction of disintegration. It is true that we
cannot reject this view at once as being completely incorrect, as the
possibility of conduction does not depend upon the absolute amount of
heat which reaches the next molecule capable of decomposition, but
upon the relative amount of heat in regard to the degree of lability
of the irritable molecules, of which we cannot even approximately make
an estimate. However, by a comparison with other highly explosive
substances, such as iodide of nitrogen, we find that a slight trace
of water applied to the iodide of nitrogen suffices to prevent the
extension of the disintegration process, and with this the explosion of
the whole mass. Nor does the view of _Pflüger_ remove this difficulty,
which assumes that the atom groups capable of breaking down are joined
together by a chemical linking of atoms to long fiber-shaped giant
molecules through the whole nerve fiber, for this assumption of a firm
structure can hardly be reconciled with the principles concerned of
metabolism.

  [113] Compare _Pflüger_: “Ueber die physiologische Verbrennung
  in den lebendigen Organismen.” In Pflügers Archiv. Bd. 10, 1875.
  Further: _L. Hermann_: “Handbuch der Physiologie, Bd. II, Allgemeine
  Nervenphysiologie,” 1879.

In consideration of this difficulty it seems easier to assign the
rôle of mediator of disintegration not to heat but to electricity.
Production of electricity is likewise a property of all living
substance. Differences of electrical potential between two points may
be equalized in the stretch by conduction through the intervening
space. Electricity would then fulfil the important conditions, which
must be demanded for the form of energy, acting as mediator for the
conduction of disintegration from cross section to cross section.

[Illustration: Fig. 25.

Model of a “Kernleiter.” A, B--Glass tube, with a number of side tubes
filled with saline solution, through which a wire is passed. _c_ and
_d_--Side tubes with electrodes for stimulation. _e_ and _f_--Tubes for
connection with a galvanometer. (After _Hermann_.) ]

Physiologists even at an early date, misled by the apparent likeness
in the conduction of excitation, especially in the nerve, to that of
electricity in a metal wire, regarded both processes as identical.
When, however, _Helmholtz_ first demonstrated experimentally the
rapidity of the conduction in the nerve, the thought that electrical
conduction was concerned, such as takes place in a metal wire, had to
be abandoned, as the velocity shows too great a difference in the two
cases.

[Illustration: Fig. 26.

Scheme of the conduction by local electric currents in a “Kernleiter.”
(After _Hermann_.)]

The observations, on the other hand, on the conductivity in the
so-called “core model,” seemed to offer another possibility of
attributing the conduction of excitation in the nerve to electric
processes. _Matteucci_, later _Hermann_ and finally _Boruttau_[114]
have endeavored to apply the results obtained when electricity is
introduced in a wire covered with a moist envelope (saline solution),
to the explanation of conductivity in the nerve. (Figure 25.) The fact
has been shown, that in such a model the application of electricity
to a point, as a result of polarization between the moist envelope
and the metal, produces a weak local current, which in turn disturbs
the electrical potential in the next cross section and consequently
a new local current is produced and so on through the whole length
of the wire. (Figure 26.) This fact, in connection with the apparent
similarity in the differentiation of the axial fibers and peripheral
envelope in the nerve, has led _Boruttau_ to apply the principles of
conductivity in the “core model” to that of the nerve. Then, however,
_Nernst_ and _Zeyneck_ brought forward their theory, according to which
the galvanic current is operative as a stimulus in that it brings
about an alteration in the concentration of the ions at the junction
of two different electrolites which, in turn, produce local currents.
_Boruttau_ then dropped the assumption of the existence of a simple
physical polarization between the wire and the envelope and replaced it
by the assumption of an alteration in the concentration of the ions at
this position. Thereby the “core model explanation” was already altered
in principle, in that only the differentiation of a central fibrilla
and a peripheral enveloping substance was appropriated. It seems to me
that this factor can likewise be considered as completely dispensable
and may, therefore, be omitted; thus nothing remains of the “core model
explanation” of the conduction of excitation in the nerve.

  [114] The enormously extensive literature on this subject up to the
  most recent date is quoted in _Cremer_: “Die allgemeine Physiologie
  der Nerven.” In _Nagels_ Handbuch der Physiologie des Menschen, Bd.
  IV, 1909. Braunschweig.

The results of continually increasing numbers of investigation in
recent times make it appear almost as a certainty that the elementary
fibrillæ in the axis cylinder are nothing else but skeletal substances.
_Wolff_,[115] _Verworn_[116] and others have first expressed the
view that the neurofibrillæ must be looked upon as skeletal fibers
for the soft neuroplasm, and more recently _Lenhossek_[117] and
especially _Goldschmidt_[118] have confirmed this assumption in detail.
_Goldschmidt_ has shown by extensive comparative studies of cell
mechanism the rôle played by the neurofibrillæ in a physical connection
as internal skeletal formations, and has proved at the same time, in
complete unanimity with other investigators, their continuity with
other undoubted skeletal fibrillæ. By this the numerous combinations
and speculations of _Apathy_ and _Bethe_ concerning the part taken by
the neurofibrillæ have been rendered untenable. In no case is there the
slightest justification to regard the apparent “Kernleiterstructur” of
the nerve as the principal condition for the process of conductivity,
for should we dispense completely with this point for the theory of the
conduction of the nerve, we can obtain, solely by the aid of the facts
known today in physical chemistry, the foundations for a theory of the
conductions of excitation which not merely renders the specific case of
the conduction of the nerve intelligible, but contains at the same time
the principles of the process of the conduction of excitation for all
living substance.

  [115] _M. Wolff_: “Ueber die fibrillaren Structuren in der Leber des
  Frosches.” Anatom. Anzeiger Bd. 26, 1905.

  [116] _Max Verworn_: “Bemerkungen zum heutigen Stand der
  Neuronlehre.” Medicin. Klinik, Jahrg. IV, 1908.

  [117] _M. v. Lenhossek_: “Ueber die physiologische Bedeutung der
  Neurofibrillen.” Anatom. Anzeiger Bd. 36, 1910.

  [118] _Richard Goldschmidt_: “Das Nervensystem von Ascaris
  lumbricoides und megalocephala. Ein Versuch in den Aufbau eines
  einfachen Nervensystems einzudringen.” III Teil. Festschrift zum 60
  Geburtstage Richard Hertwigs Bd. II, 1910, Jena.

[Illustration: Fig. 27.

Scheme of the foam structure of living substance. A--In
undifferentiated protoplasm. B--In fibrillae protoplasm.]

On the basis of investigation in the physical chemistry on the
properties of semi-permeable membranes, we know that such membranes
produce an elective effect on the diffusion of dissolved substances.
This is in the way that the two different solutions, separated by a
semi-permeable surface, do not follow the known laws of diffusion, but
are altered in that certain substances in contrast to their rapidity
of diffusion pass through the membrane or are prevented from entering
by the latter. This applies likewise to the two kinds of ions, which
are dissociated in diluted substances. If the surface exercises a
selection in the way, for instance, that the positive kations are
allowed to pass through, whilst the negative anions are held back, a
difference of potential must exist between the two. In this manner,
wherever two different solutions are separated from each other by a
semi-permeable surface, an opportunity occurs for the taking place
of galvanic currents. As we know, living protoplasm by reason of
its colloidal components possesses, in common with all colloidal
substances, on its surface the properties of semi-permeable membranes.
Between the cell and the medium, therefore, there is always the
opportunity for the occurrence of differences of electric potential.
But more. We likewise know that protoplasm itself represents a
mixture of colloid substances and actual solutions. Frequently, if
not always, living structure presents a morphological differentiation
of two types, when seen under the microscope, in the form of a foam
structure described by _Bütschli_. (Figures 27 and 28.) If we suppose
that with the disintegration of complex molecules, which we must assume
as taking place in the material of the walls of the protoplasm network,
substances are formed which are subjected to electrolytic dissociation,
the anions and kations hereby liberated must be diffused from the place
of their separation into the surroundings. Their diffusion, however,
is restricted by the protoplasmic network. The positive ions may pass
through, but the negative ions may not. As a result: the reticulated
substance is the seat of electric discharge, which in turn gives the
impact to the breaking down of new molecules and with this to the
occurrence of new potential differences, and so on, consequently the
disintegration is extended further and further through the connected
masses of the protoplasmic framework.

[Illustration: Fig. 28.

Protoplasm of different cells, showing foam structures. A--Pseudopod
of a marine rhizopod. The protoplasm only shows foam structure at the
point of stimulation. B--Epidermic cell of lumbricus. C--Nerve fiber.
D--Part of the cell body of a ganglia cell. (A-C after _Bütschli_, D
after _Held_.) ]

This theory, founded on facts gained entirely from investigation, would
involve those forms of energy which play the rôle of activator in the
extension of the breaking down of the molecule from cross section to
cross section, namely, the osmotic and the electrical energy. Based on
the general properties of physical chemistry and those of morphology
of the living substances, they would be applicable to all vital
systems. It would be premature to attempt to extend this assumption and
further develop its specific details, above all to make it responsible
for the specific differences in the process of the conduction of
excitation in various forms of living substance. For this our knowledge
of the properties of living substance is still far too incomplete.
Nevertheless, it furnishes us even now with various points of view
for the further analysis of a series of vital manifestations, as,
for instance, the facts concerning the production of electricity, of
galvanotaxis, chemotaxis and so on. This, however, exceeds the limits
of the task we have here mapped out. We are concerned here solely with
the general principle on which the conductivity of excitation in the
living substance is founded.




CHAPTER VII

THE REFRACTORY PERIOD AND FATIGUE

 _Contents_: Conception of specific irritability. Alteration of
 specific irritability during and after excitation. Refractory period
 in various forms of living substance. Absolute and relative refractory
 period. Curve of irritability during refractory period. Dependence of
 the duration of the refractory period on the rapidity of the course
 of the metabolic processes in the living substance. Dependence on
 temperature. Dependence on supply of oxygen. Theory of refractory
 period. Refractory period as basis of fatigue. Fatigue as a form of
 asphyxiation. Alterations of irritability and the course of excitation
 in fatigue. Recovery from fatigue. The rôle played by oxygen in
 recovery. Fatigue as an expression of the prolongation of the
 refractory period conditioned by the relative want of oxygen. Fatigue
 of the nerve.


Every living system possesses, as we know, a peculiar and
characteristic manner of reacting to stimulation. The muscle responds
with a contraction, the salivary cell with production of saliva, the
luminous cell with the emission of light. This is the _specific energy_
in the sense of _Johannes Müller_. Every living system is likewise
characterized by a certain degree of irritability, which can be
expressed by the threshold value of the stimulus at which the specific
reaction is just perceptible. This degree of irritability, by which
the system concerned is distinguished, may be termed its _specific
irritability_.

From the standpoint of the conditional method of investigation it is at
once apparent that specific energy, as well as specific irritability,
must be solely determined by the specific conditions existing in the
particular system. It follows from this that every alteration in
the conditions of the system, that is, every change of its state,
likewise entails a corresponding alteration of its specific energy and
its specific irritability. It is, therefore, self-evident that the
alteration of the state, which is undergone by the living system in
the process of excitation, brings about an alteration of its specific
irritability. Likewise as the original state of the system is restored
by the metabolic self-regulation after the course of an excitation, the
specific irritability of the system must be reestablished. The specific
irritability is, therefore, a property of the living system, which,
like the metabolic equilibrium, undergoes restitution by the process of
self-regulation after variation produced by a stimulus of any kind. It
is scarcely necessary to repeat each time that this is only applicable
within the physiological variations and for a limited period, during
which the alterations in development need not be considered.

These alterations of the specific irritability following an excitation
and their compensation through the metabolic self-regulation will now
claim our attention.

That the specific irritability of a living system undergoes a
diminution as the result of a stimulus of long duration has been
long known through the study of fatigue. This is especially so with
frequently recurring excitating stimuli. It is only within the last
decade, however, that the observation has been made in a few instances
that a single momentary excitation is likewise followed by such a
reduction of the specific irritability. But that this is a fact of
general physiological fundamental importance for the whole field
of response to stimulation in the living substance has only been
recognized within the last few years.

[Illustration: Fig. 29.

Eight series of heart contractions. The dotted lines _e_ show
the moment of an artificial stimulus. The artificial stimulus is
ineffective if it is applied before the height of a systole. The
artificial stimulus becomes the more effective in producing an extra
systole, followed by a compensatory pause, the later it is applied
after the height of the systolic contraction. (After _Marey_.) ]

In 1876 _Marey_[119] found that the irritability of the heart in
response to artificial stimulation was greatly reduced during the
systole, and that recovery took place during the following diastole.
(Figure 29.) This fact was already apparent from the observations made
by _Bowditch_[120] and _Kronecker_,[121] that by stimulation of the
isolated frog’s heart with single induction shocks, an artificial
systole can only be produced with certainty when the stimuli succeed
each other at certain intervals, which must be the longer as the
strength of the stimulation is weaker. _Marey_ calls this period
of reduced irritability “_phase réfractaire_” of the heart. The
refractory period of the heart has been made the subject of a great
number of investigations, especially by _Engelmann_ and his pupils.
It was _Engelmann_[122] especially who determined more exactly the
duration of the course of the refractory period. He found, namely, that
irritability disappears immediately before each systole and reappears
shortly before the beginning of the diastole, and again reaches its
original height at the end of the diastole. For a long time, however,
this refractory period was looked upon as a special peculiarity of the
heart. It was not until _Broca_ and _Richet_,[123] twenty years after
_Marey’s_ investigations, discovered an analogous refractory period for
the motor centers of the cerebral cortex of the dog. They first made
this observation on a dog affected with chorea, in which the choreic
movements rhythmically occurred in intervals of one second. They found
that after each movement electrical stimulation of the cortex remained
without result for about .5 seconds. During the next .25 seconds
stimulation was followed by a weak response and it was not until the
last .25 seconds before the next movement that a strong effect was
produced. They also found in the normal dog a refractory period after
every artificial stimulation equal to .1 second, so that the number of
contractions brought about by rhythmical electrical stimulation were
only ten per second. Following this, numerous other investigations of
the refractory period have been made on the central nervous system.
_Zwaardemaker_[124] and _Lans_ have observed a refractory period in
the eyelid reflex of the human being which, on stimulation of the
optic nerve, amounts to about .5–1 second; on the stimulation of
the trigeminus produced by blowing on the cornea on the other hand,
it is somewhat shorter, less than .25 seconds. _Zwaardemaker_[125]
also was able to demonstrate an analogous refractory period for the
swallowing reflex of the cat. Further a refractory period was found
and closely analyzed by _Verworn_[126] for the reflexes in the spinal
cord of the strychninized frog. _Dodge_[127] found a refractory period
in the knee jerk reflex of man. _Gotch_ and _Burch_[128] showed, by
two induction shocks following each other in quick succession, a
refractory period of the nerve, which is characterized by its extremely
brief duration. They found, depending upon the temperature, a period
of nonirritability of .001-.008 seconds after every stimulus. The
investigations of Miss _Buchanan_[129] lead us to conclude that there
is a refractory period for the cross striated skeletal muscle. Miss
_Buchanan_ stimulated the muscle at times through the nerve, at other
times directly after elimination of the nervous element, with very
frequent electrical stimuli (about 1000 in the second) and found by
means of the capillary electrometer a rhythmical reaction of the muscle
of about 50–100 excitation shocks per second. Likewise the _Ritter_
tetanus produced by the breaking of an increasing current proved to
be a rhythmical reaction of an analogous nature. In a more direct
manner _Keith Lucas_[130] has determined the refractory stage for the
musculus sartorius of the frog. He allowed two induction shocks to act
successively on the muscle at intervals of varied duration and then
registered the action currents by means of the capillary electrometer.
He then found that the second stimulus was ineffective for about .005
seconds after the application of the first stimulus. If the second
stimulus follows somewhat later, it produces a contraction which is
weaker and has a longer latent period the nearer the second stimulus
approaches the first in point of time. (Figure 30.) _Massart_[131]
and _Jennings_[132] likewise observed the existence of a refractory
period for the myoids of unicellular organisms brought about by
mechanical stimuli. _Massart_ attributes this cessation of reaction
to stimuli following each other at certain intervals, to fatigue, an
explanation which has been disputed by _Jennings_ as the result of
his investigations made on Stentor and Vorticella. _Jennings_ looks
upon the behavior of the infusoria rather as an “adaptation” to the
stimulus. _Pütter_ was the first to see in this the existence of a
refractory period. His experiments on Spirostomun ambiguum in 1900
showed a refractory period in the reaction to rhythmical mechanical
stimuli. I wish to state, however, that these observations of _Pütter_
have not as yet been published. Thus the existence of a refractory
period has even today been proved for a whole series of very different
kinds of substances.

  [119] _Marey_: “Des excitations artificielles du cœur.” Travaux du
  lab. de M. _Marey_ II, 1875. The same: “Des mouvements qui produit le
  cœur lorsqu’il est soumis à des excitations artificielles.” Comptes
  rendues de l’academie des sciences T. L. XXXII, 1876.

  [120] _Bowditch_: “Ueber die Eigenthümlichkeiten der Reizbarkeit
  welche die Muskelfasern des Herzens Zeigen.” Arbeiten aus der
  physiologischen Anstalt zu Leipzig, 1872.

  [121] _Kronecker_: “Das charakteristische Merkmal der
  Herzmuskelbewegung.” Beiträge zur Anatomie und Physiologie als
  Festgabe f. Carl Ludwig zum 15, Oct. 1874, gewidmet von seinen
  Schülern. Leipzig 1874.

  [122] _Th. W. Engelmann_: “Beobachtungen und Versuche am
  suspendierten Herzen III. Refractäre Phase und compensatorische Ruhe
  in ihrer Bedeutung für den Herzrhythmus.” Pflügers Arch. Bd. 59, 1895.

  [123] _Broca et Richet_: “Période réfractaire dans les centres
  nerveux.” Comptes rendus de l’academie des sciences 1897. Further
  _Richet_: “La vibration nerveuse.” Revue scientific Déc. 1899.

  [124] _Zwaardemaker und Lans_: “Ueber das Stadium relativer
  Unerregbarkeit als Ursache des intermittierenden Charakters des
  Lidschlagreflexes.” Centralblatt für Physiol. XIII, 1899.

  [125] _Zwaardemaker_: “Sur une phase réfractaire du reflex
  déglutition.” Arch. international de physiologie Vol. I, 1900.

  [126] _Max Verworn_: “Zur Kenntniss der physiologischen Wirkungen
  des Strychnins.” Arch. f. Anat. u. Physiol. physiol. Abth.,
  1900. “Ermüdung Erschöpfung and Erholung der nervösen Centra des
  Rückenmarks.” Ibidem, 1900. “Die Biogenhypothese.” Jena 1903. “Die
  Vorgänge in den Elementen des Nervensystems.” Zeitsch. f. allgem.
  Physiologie Bd. VI, 1907.

  [127] _Dodge_: “A systematic exploration of a normal knee jerk, its
  technique, the form of the muscle contraction, its amplitude, its
  latent time and its theory.” Zeitsch. f. allgem. Physiol. Bd. XII,
  1911.

  [128] _Gotch and Burch_: “The electrical response of nerve to two
  stimuli.” Journ. of Physiology, Vol. XXIV, 1899.

  [129] _Florence Buchanan_: “The electrical response of muscle in
  different kinds of persistent contraction.” Journ. of Physiology,
  Vol. XXVII, 1901–1902.

  [130] _Keith Lucas_: “On the refractory period of muscle and nerve.”
  Journ. of Physiology, Vol. XXXIX, 1909–1910.

  [131] _Massart_: Annales de l’Institut Pasteur 1901.

  [132] _Jennings_: “Studies on reactions to stimuli in unicellular
  organisms.” IX. American Journal of Physiology, 1902.

[Illustration: Fig. 30.

Curve of action current of the musculus sartorius excitated by two
successive stimuli (St. 1 and St. 2). The effect of the second stimulus
is the less and the latent period is the longer the more quickly the
first stimulus is followed by the second. (_Keith Lucas._) ]

We will now examine the alterations of irritability which are
perceptible during the refractory period to complete restitution of the
specific irritability of the particular system, and endeavor by the
analysis of their special conditions to render them comprehensible from
a physical standpoint of view.

The first fact to take into consideration is, that, as is shown in the
heart, the refractory period begins at the moment of the appearance
of the systolic excitation. The irritability of the heart is absent
and remains so until the excitation has reached its highest point,
that is, shortly before the beginning of the diastole. From this point
the restitution of irritability begins, which does not reach the
maximum until the end of the diastole. In other words: irritability
undergoes the greatest reduction by disintegration produced by the
stimulus and is restored by the metabolic self-regulation following the
decomposition.

This point of view enables us to interpret this state from a physical
standpoint. In this discussion on the relations between irritability
and the extension of excitation, I have taken the amount of energy
which is produced during the time unit and space unit in a living
system as the general standard for the degree of irritability, at the
same time duly regarding the individual components involved. This
amount of energy is determined in a given system by the quantity
of substance broken down by a stimulus of a given intensity. It
is, therefore, clear that during the time in which an increased
disintegration produced by a stimulus takes place, the irritability in
response to a second stimulus must be reduced, as during this period
the second stimulus has less of necessary decomposable substances
at its disposal, and at the same time there are more products of
disintegration in a given space. If a living organism is the subject
of consideration, to which the “all or none law” is applicable, as,
for instance, the heart at the moment of the beginning of excitation,
irritability is completely obliterated, as shown by the fact that the
second stimulus of any strength remains without response, for during
the excitation there is a complete breaking down of all the substances
capable of decomposition. If, on the contrary, a system is the subject
of observation, for which the “all or none law” is not valid, then
irritability is merely reduced but not wholly obliterated during an
excitation, and whether or not a response is obtained to the stimulus
depends upon its strength. To impress the relations between the degree
of irritability and the intensity of the stimulus, I have, therefore,
employed the term “_relative refractory period_” in contrast to the
“_absolute refractory period_,” in which irritability is obliterated
even for the strongest stimuli. It is self-evident that irritability
must again increase in the same degree as the restitution of the
living system by metabolic self-regulation takes place, for the
more molecules capable of disintegrating are restored and the more
products of disintegration removed, the more molecules necessary for
decomposition in the unit of space are attacked and broken down by the
stimulus. All these are self-evident facts which are in accordance
with the conception we have here developed of the course of the
process of excitation and its physical nature. But another important
point is evolved from the observations we have made of the nature of
the process of self-regulation. The process of self-regulation is
founded on the same principle as that which governs the taking place
of all chemical equilibrium, for metabolic equilibrium is merely a
special kind of a chemical equilibrium. The development of a chemical
equilibrium between reacting substances and reaction products has,
as known, a characteristic course in regard to its duration. If the
rapidity with which the equilibrium is reached is expressed by a curve
in which the abscissa represents the time, while the ordinates signify
the number of contacts of the interacting molecules, the rapidity
of reaction is altered with the approach to the equilibrium in the
form of a logarithmic curve; that is, the approach to the state of
equilibrium, which is represented by ordinate value zero, takes place
at first very rapidly, then with more and more decreasing speed, for
with the decrease of the number of reacting molecules and the increase
of the amount of products of reaction, the contact of the interacting
molecules and with this the opportunity for the reaction occurs
less and less frequently. Although the self-regulation of metabolic
equilibrium is by no means such a simple process as, for instance, that
of the well-known example of the forming of ethylester from acetic
acid and æthyl alcohol, we have still in every case to deal with the
taking place of a chemical mass equilibrium. Hence the progress to
the metabolic equilibrium must likewise correspond with a logarithmic
curve, i.e., restitution after a disturbance of the equilibrium must
take place at first rapidly, then at a constantly decreasing rate. For
reasons readily to be understood the special form of this restitution
curve has so far not been accurately ascertained for any kind of living
substance. Even in those cases where the restitution occurs very slowly
we meet with the difficulty that, when the tests are applied which
are necessary to determine the restitution at different intervals,
with each testing stimulus irritability is each time reduced. Hence
the construction of the restitution curve can only be achieved by
indirect means, and we must content ourselves with the ascertainment
of a smaller number of its points from which by interpolation its form
can be constructed. Indeed in this connection a certain number of
results have already been gained quite sufficient to experimentally
confirm the correctness of these types of curves, primarily obtained
by purely theoretical deductions. That irritability very gradually
reaches its maximal height has been already shown, as previously
mentioned by _Bowditch_[133] in his investigations on the influence
of rhythmical induction shocks on the apex of the heart of the frog.
He found that in order to produce response, the weaker the stimuli
the longer must be the intervals between them. It follows from this,
that after a discharge the irritability in response to strong stimuli
reappears more rapidly than for weak, i.e., that they only _gradually_
regain their maximum. The exact periods of time for the course of the
return of irritability for the heart have unfortunately not been so far
ascertained. On the other hand, the investigations of _Ishikawa_[134]
furnish the material for the construction of the restitution curve
for the centers of the spinal cord of the frog. _Ishikawa_ did not
employ the threshold of stimulation as an indicator for the course
of restitution, but used instead the duration of the reflex time
following on a stimulus of a certain strength. The reflex time is
greatly prolonged after an excitation of extended duration and only
regains its normal value in the same degree as restitution takes place.
By a great number of painstaking experiments _Ishikawa_ ascertained
the duration of the reflex time at intervals of thirty seconds to one
minute, and obtained figures which show that restitution does actually
take place, at first rapidly and then with constantly decreasing speed.
The detailed study of the course of self-regulation of the individual
forms of living substance will doubtless be more exactly determined
in the near future. But even at the present we are fully justified in
describing the form of restitution curve as a _logarithmic_ in type.
Therefore, a relative refractory period must be present in every
metabolic self-regulation after an excitation, during which stronger
stimuli produce response, while weaker are still without result. This
is a fact which, as we shall see later, is of fundamental importance
for the comprehension of the various kinds of interference responses to
stimuli.

  [133] _Bowditch_, 1. c.

  [134] _Hidetsurumaru Ishikawa_: “Ueber die scheinbare Bahnung.”
  Zeitschrift f. allgem. Physiologie Bd. XI, 1910.

From the information here gained on the nature and origin of the
refractory period the conclusion must inevitably be drawn that in all
living substance there must exist, directly following an excitation,
a period of time in which its irritability is reduced, that is, under
proper conditions a refractory period can be demonstrated for every
living organism. Every living system possessing irritability undergoes
a period of reduced irritability at the time of and subsequent to every
excitation, for every excitation momentarily decreases the amount of
products capable of disintegration and increases the disintegration
products in the unit of space. As restitution involves time, a
stimulus occurring in the phase preceding complete restitution cannot
break down the same quantity of molecules as would be the case after
the establishment of complete restitution, that is, the response is
weaker, the irritability is decreased. The refractory period during and
subsequent to excitation is as much a general property of the living
substance as irritability and metabolic self-regulation.

This conclusion appears so self-evident that it would seem hardly
to call for emphasis were it not that even at the present time the
view is still widely held that the refractory period is a special
characteristic of certain forms of living substance. This assumption
is explained on the one hand by the fact that our information
concerning the refractory period is still of comparatively recent
date and that few physiologists are in the habit of connecting
special observations with general physiological conceptions, but also
for the reason that some investigators have vainly tried to find a
refractory period in certain forms of living substance. _Langendorff_
and _Winterstein_,[135] for instance, have not succeeded in proving
a refractory period for the spinal cord of the frog. _Langendorff_
stimulated the central sciatic stump with two stimuli in quick
succession and used the contractions of the triceps as indicator of
the response. He found that when the stimuli, if consisting in either
single induction shocks or faradic shocks, followed each other even at
intervals of .004 seconds the second stimulus was still operative, this
being perceptible in an increase of the contraction or with greater
intervals of time in a summation of two contractions. _Winterstein_
concludes from this that the development of a refractory period after
a stimulation is not a general property of all nerve centers. If
the experiments of _Langendorff_ failed to show the presence of a
refractory period it is not for the reason that this does not take
place in the centers of the spinal cord but rather results from the
fact that the conditions for the investigation were not suited for its
demonstration. In fact, _Fröhlich_[136] and especially _Vészi_[137]
have incontestably proved the existence of relative refractory periods
in the normal spinal cord.

  [135] _Langendorff u. Winterstein_: “Beiträge zur Reflexlehre.”
  Pflüger’s Arch. Bd. 127, 1909.

  [136] _Fr. W. Fröhlich_: “Beiträge zur Analyse der Reflexfunction des
  Rückenmarks mit besonderer Berücksichtigung von Tonus, Bahnung und
  Hemmung.” Zeitschrift f. allgem. Physiologie Bd. IX, 1909.

  [137] _Julius Vészi_: “Der einfachste Reflexbogen im Rückenmark.”
  Zeitschr. f. allgem. Physiologie Bd. XI, 1910.

If the existence of the refractory period is based on the fact that
during the time of and subsequent to an excitation the quantity of
substances necessary for disintegration is decreased and that of
the breaking down products increased, and if it is limited by the
restitution of the substances required for decomposition and the
elimination of the disintegration products, its duration must be
dependent upon the length of these processes. All factors which
lessen the decomposition and hasten the metabolic self-regulation
must, therefore, shorten its duration. This is completely confirmed
by experimental investigations. As can be understood, the factors of
special interest for us are those which influence the duration of the
refractory period in the physiological occurrences of the organism.

One of these factors is temperature. As we know, the rapidity of
chemical reactions increases with ascending and decreases with falling
temperature. As in the disintegration as well as in the restitution,
processes are chemical in nature, it is to be expected that the
duration of the refractory period is influenced in like manner by
temperature. Indeed, _Kronecker_[138] found some time ago that in
the isolated frog’s heart a much more frequent rhythm of stimulation
is effective at a higher than at a lower temperature. When the heart
is stimulated at a temperature of 11–12° C. with twelve rhythmical
induction shocks in the second, every stimulus is operative and
produces a systole. If a stimulus of the same frequency is used at
a temperature of 5° C., the heart responds merely to every second
stimulus. This shows that the refractory period is of longer duration
at a lower than at a higher temperature.

  [138] _H. Kronecker_: “Das charakteristische Merkmal der
  Herzmuskelbewegung.” Beiträge zur Anatomie and Physiologie als
  Festgabe Carl Ludwig zum 15 October 1874 gewidmet. Leipzig 1874.

A factor of particular interest is the supply of oxygen, for we know
its fundamental importance in all aërobic organisms in the breaking
down of the living substance. The life of these organisms is primarily
dependent upon the supply of oxygen from without. Organic reserve
substances for restitution after disintegration are contained in ample
quantity in the reserve stores in the living cell substance, whereas
oxygen is present in very small quantities in relation to the former.
It is, therefore, self-evident that the rapidity of the breaking down
processes is very closely dependent upon the amount of available oxygen
at hand. Nevertheless it is not the absolute quantity but the relative
amount of oxygen in relation to the momentary requirement which is of
importance. For instance, the quantity of oxygen present may completely
suffice for the oxydative disintegration in the metabolism of rest or
at lower temperature, whereas the same amount would be much too small
to meet the demand increased by excitation or at higher temperature.
In the latter case “_a relative deficiency of oxygen_” occurs. I have
introduced the term “_relative deficiency of oxygen_”[139] for I have
found that a number of authors by neglecting the relations of the
available oxygen to that which is required at the moment have been
led to false conclusions. There is no living object so preëminently
fitted to demonstrate in such a striking manner the dependence of
the duration of the refractory period upon the supply of oxygen as
the spinal cord centers of the frog, when their irritability has been
increased to the maximum by strychnine.[140] Various observers, such
as _Loven_, _Buchanan_, _H. von Baeyer_ and others, investigated the
action current by the capillary electrometer. As a means of studying
the number of impulses in the strychnine tetanus, we can upon the basis
of their figures roughly assume the number of impulses to equal ten
per second at room temperature. In short, in the freshly strychninized
frog the duration of the refractory period is about .1 second. By means
of the method of artificial circulation already mentioned a deficiency
of oxygen can readily be brought about. It has been demonstrated that
the rhythmic in contrast to the continuous method of introduction
of circulatory fluid is superior in that the former reproduces more
closely the natural conditions of the circulation of the blood and
renders the smallest capillaries more permeable. In consequence I have
recently constructed a small appliance for artificial circulation,
which accomplishes this in a manner as simple as it is complete.
(Figure 31.)

[Illustration: Fig. 31.

Arrangement for an artificial circulation in the frog. A--Accumulator.
B--Metronom. C--Mercury key. D--Electromagnetic apparatus for
compressing the rubber tube: 1, wire spool with magnet; 2, anchor for
the magnet; 3, spiral spring which pulls back the anchor; 4, axis on
which the anchor turns; 5, plate for arresting the anchor. E--Vessel
containing saline solution. F--Slab of cork with frog. ]

The fluid flows from a vessel, E, provided with an outlet tube through
a thin rubber tube into a glass canula, which is introduced into the
general aorta of the frog, F. The tube is automatically occluded by the
rhythmical movement of the armative of an electromagnet, D, produced by
a metronome, B. The pressure of the circulating fluid can be readily
changed at will by varying the level of the vessel and the frequency
of the pulse by the rhythm of the metronome, which makes and breaks
the current to the electromagnet.[141] In this way it is possible
to artificially replace the normal circulation with satisfactory
exactitude and substitute for the blood, circulating in the vessels of
the frog, any desired fluid. If the entire quantity of blood of a frog
is displaced by a continuous stream of oxygen-free saline solution and
a weak strychnine solution is injected with a Pravaz syringe, a violent
strychnine tetanus appears after the lapse of a few seconds. (Figure
32, A.) If the artificial circulation with oxygen-free saline solution
is now contained in the rhythm of the natural heart beat, the further
reactions can then be readily observed. The first long-continued
tetanic attack, which can be produced by a slight touch of the skin,
is followed by a whole series of tetanic convulsions of prolonged
duration, which are repeatedly followed by periods of exhaustion. I
wish to emphasize this fact once more, as it appears to me as not
without interest for the understanding of the question of reserve
substances.

[Illustration: Fig. 32.

Muscle curve of strychnine tetanus in a frog with artificial
oxygen-free circulation. Lower line indicates seconds. Upper line
indicates stimulation by induction shocks. A--A single shock produces
a long tetanic contraction. B--In a more advanced stage each shock
produces a tetanus only of short duration. C--In a still more advanced
stage each shock brings about only a single contraction if the stimuli
do not succeed each other too rapidly. If they succeed more rapidly,
as, for instance, in a faradic current, only the first shock is
effective. ]

If we assume that at the moment when the entire amount of blood is
removed from the vascular system, no oxygen remains in the cells of the
spinal cord and muscle, then disintegration of the living substance
could from this instant take place exclusively anoxydatively, and there
would be no further oxydative breaking down into carbon dioxide and
water. The energy production compared in equal number of molecules,
taking the figures of _Lesser_ for the fermentation of sugar, would
approximately amount to about 3.8 per cent. of that of the energy
production in the oxydative disintegration of dextrose into carbon
dioxide and water. In reality, however, the tetanic convulsions are
at first exactly as violent as in the frog with a normal circulation.
There simply remains the assumption, therefore, that either the
disintegration as soon as it becomes _an_oxydative involves relatively
greater number of molecules than would be the case if it were oxydative
in nature, or to suppose that even after the complete displacement
of the blood a certain, though relatively small, amount of oxygen is
present in the cells which for a short time suffices for the taking
place of oxydative disintegration and with this an almost maximal
production of energy which naturally decreases as the oxygen is
consumed. It seems to me that the latter supposition contains more
probability than the first. To return, however, from this observation
to a further consideration of the animal we are studying, we see how
the complete tetanic convulsions in the refractory period which we
assumed to be .1 second are gradually transformed into incomplete
tetanus. After a time the tetanic convulsions become shorter after each
stimulus (Figure 32, B) and permit us to distinguish their individual
movements, even though the latter at first succeed each other still
very rapidly. Gradually this incomplete tetanic convulsion assumes the
form of a short series of individual contractions, distinctly separated
from each other and soon a stage is reached in which each reaction
to a peripheral stimulus consists merely in a single contraction.
(Figure 32, C.) The refractory period is, however, even now less than
a second. Nevertheless, with a further continuation of the experiment,
the refractory period becomes more and more prolonged, so that stimuli
succeeding each other at intervals of less than a second are without
effect. It is possible at this stage, as _Tiedemann_[142] did, to
graphically record the reactions. He severed the sciatic nerve on one
side and stimulated its central stump, at the same time connecting the
triceps with a writing lever. It is then found that when the single
induction shocks follow each other at intervals of a second or more
every stimulus produces a contraction, but that on the contrary only
the first stimulus of a rhythmical series is operative and all those
succeeding ineffectual, if the stimuli follow each other at shorter
intervals. The refractory period becomes, however, more and more
prolonged. The rhythm of the stimulus must become continually slower
if each individual stimulus is to remain effective. If the rhythm is
even slightly too rapid only the first few stimuli of a rhythmical
series are effective and this with decreasing response and later no
contraction at all is observed. With a further continuance of the
experiment, the stimuli are only effective when following each other
at long intervals. It is necessary that a period of recovery lasting
several seconds must take place before the following stimulus can
meet with response. (Figure 33.) The refractory period can gradually
be prolonged for the space of a minute or longer, until finally
irritability does not reappear at all, and even the strongest stimuli
fail to produce the least contraction. The continuous manner in which
the refractory period is, in the absence of oxygen, more and more
prolonged until eventually a prolonged state of nonirritability is
developed, can be better followed by observing the experiment than when
described in words. If at this stage instead of the oxygen-free saline
solution, defibered blood of the ox shaken in air or a saline solution
saturated with oxygen is circulated in the frog, restitution is often
within a few minutes so complete that tetanic attacks are once more
produced by a single stimulus, that is, the refractory period has from
being practically nil returned to the normal. This experiment can be
repeated several times on the same animal. It is invariably found that
the refractory period is prolonged by the withdrawal of oxygen and
shortened with a renewed supply.

  [139] _Max Verworn_: “Allgemeine Physiologie.” V. Auflage. Jena 1909.

  [140] _Max Verworn_: “Ermüdung Erschöpfung und Erholung der nervösen
  Centra des Rückenmarks.” Arch. f. Anat. u. Physiol. physiol. Abt.
  Suppl. 1900. The same: Ermüdung und Erholung. Berliner Klin.
  Wochenschrift 1901.

  [141] As I have not yet described this method elsewhere the above
  figure will suffice for demonstration.

  [142] _Tiedemann_: “Untersuchungen über das absolute
  Refractäerstadium and die Hemmungsvorgaenge im Rückenmark des
  Strychninfrosches.” Zeitschrift f. allgem. Physiologie Bd. X, 1910.

[Illustration: Fig. 33.

Development of the refractory period in the spinal cord of a
strychninized frog. Lower line indicates seconds; upper line stimuli.
Of a series of stimuli only the first ones are operative with
decreasing effect. ]

I have described this experiment somewhat in detail as it contains
facts which are the key for the comprehension of a general
physiological process of paramount importance. I refer to fatigue. The
refractory period and fatigue are inseparably connected, for fatigue is
founded on the existence of the refractory period and is an expression
of prolongation of the former, brought about by want of oxygen. This is
shown at once by closer analysis. It is here necessary to differentiate
somewhat more in detail the factors which bring about the _prolongation
of the refractory period in deficiency of oxygen_.

If we first turn our attention to the normal refractory period
which occurs in a system in metabolic equilibrium of rest in direct
connection with dissimilatory excitation, following a momentary
stimulus, we find that reduction of irritability or, more exactly
expressed, the lessening of the response is, as we have seen,
determined by the time involved in the metabolic decomposition and
recovery. Both these processes require time and until their completion
the quantity of substance demanded for the oxydative disintegration
is decreased in a given space, and every stimulus must consequently
be followed by a weaker response. Our conceptions of the physical
details of these processes depend essentially upon the question, if
the oxydative disintegration itself in the given living system occurs
in one single phase, in that the oxygen is the activator for the
oxydative splitting up of the carbon chain, or if this takes place in
two periods, in which the carbon chain is first anoxydatively split
up into larger fragments by the stimulus, which are then seized upon
by the oxygen to be split up into carbon dioxide and water. As we
have seen, this question must remain for the present undecided as far
as the metabolism of rest as well as the excitation produced by a
single momentary stimulus is concerned. It is highly probable that a
uniformity of the process for all living systems does not exist. We
are, therefore, not justified in assuming that these special chemical
processes resulting from single stimuli are uniform throughout the
refractory period.

On the contrary it is different in the case of oxygen deficiency. Here
we see with increasing want of oxygen a constantly increasing duration
of the refractory period, a prolongation which may be attributed to the
retardation of the oxydative disintegration. It is necessary, however,
that we now study more clearly these alterations brought about by the
deficiency of oxygen.

If we follow the course of the changes from that of the normal state of
equilibrium of metabolism, wherein oxygen is sufficient to bring about
complete disintegration of the molecules to the formation of carbon
dioxide and water, we must assume in spite of the great explosive
rapidity of this process on the basis of our chemical knowledge, that
first a series of intermediate products are produced before finally
the end products are formed. In this way the oxydative disintegration
produced by a stimulus becomes more and more prolonged by an increasing
want of oxygen. If, as I have previously suggested, the amount of
energy which is liberated in a given space and time by an excitating
stimulus is taken as a standard of irritability, it is apparent that
the more the oxydative disintegration following a stimulus is retarded,
the greater must be the decrease in irritability. The less oxygen there
is at disposal and the more incomplete the oxydative breaking down,
the smaller is the degree of irritability, the weaker the response and
the slower the return of irritability after every stimulus. In other
words, with the increasing deficiency of oxygen, the response is not
merely reduced for every stimulus, but the duration of the refractory
period is likewise progressively prolonged until finally with an
absolute want of oxygen, constant and complete depression takes place.
In the genesis of this process another factor, however, has the same
effect.

While with a sufficient supply of oxygen disintegration leads to the
formation of carbon dioxide and water, therefore to end products, which
can quickly and easily be removed by diffusion, the want of oxygen
produces complex products of incomplete combustion and finally of
anoxydative decomposition, such as lactic acid, fatty acids and even
more complex substances in constantly increasing quantities. These
products permeate the protoplasmic surfaces with great difficulty,
if at all, and as they cannot subsequently be oxydatively split up,
constantly accumulate. These asphyxiation substances, as they may be
briefly termed, produce a depressing effect on further disintegration.
This can be experimentally demonstrated.

For this purpose I have modified the experiment previously described
in the way that after every introduction into the blood of oxygen-free
saline solution and after the injection of strychnine, the artificial
circulation was stopped so that stagnation of the oxygen-free saline
solution took place in the vascular system. The processes then occurred
in exactly the same manner with the exception that the state of
non-irritability appeared somewhat earlier. If after the beginning of
complete depression artificial circulation with oxygen-free saline
solution was again started, a certain degree of recovery took place
within one or more minutes. The stimuli were once more effective
and produced a number of contractions. At times, several single
contractions, following each other in more or less quick succession,
could be brought about. But complete recovery or the appearance of even
incomplete tetanic convulsions was never again obtained, whereas by
the introduction of oxygen complete recovery could at once be brought
about. If, however, the circulation with oxygen-free saline solution
was continued, irritability gradually decreased. The refractory
periods after the individual stimuli became longer, and in spite of
continuous artificial circulation irritability _again_ disappeared.
The experiment shows that by the circulation of oxygen-free solution
irritability can simply be reduced up to a certain degree. This partial
restitution is produced by washing out the depressing metabolic
products. Being desirous to verify the results of this investigation
with greater exactitude I have requested _Dr. Lipschütz_[143] to repeat
the experiments, taking the utmost possible precaution in respect to
the absolute exclusion of oxygen. _Lipschütz_ has tested the normal
saline solution made oxygen free with the sensitive _Winkler_ method,
in which the slightest trace of oxygen is shown by the oxydation of
manganous chloride to manganic chloride in which the latter in a
saline solution sets free an amount of iodide from iodide of potassium
corresponding to that of the consumed oxygen. These experiments of
_Lipschütz_ have shown that even with the absolute exclusion of the
slightest trace of oxygen a partial recovery can be brought about by
artificial circulation. There can be, therefore, no doubt that recovery
is actually founded on the removal of the depressing asphyxiation
substances by artificial circulation. Moreover _Fillié_[144] has
previously succeeded in the laboratory at Göttingen in obtaining
by the same methods a corresponding result for the nerve. In both
cases the experiments are extremely complicated and must be carried
out with the most painstaking care. The depressing influence of the
asphyxiation products need not be regarded as a specific effect of
poisoning. It can be solely an expression of mass relations, if we
assume that the anoxydative decomposition is controlled by a chemical
equilibrium between masses capable of disintegrating and products of
the disintegration. It is not possible to give any detailed account
as to the part taken by accumulating asphyxiation substances in
the prolongation of the refractory period. Indeed, we must for the
present relinquish the attempt to delimitate quantitatively the part
taken by the individual constituent processes in the symptoms of
depression resulting from the deficiency of oxygen. We can merely
say, the individual alterations produced by the want of oxygen, that
is, the restriction and retardation of the oxydative disintegration,
the corresponding increase of the anoxydative decomposition and the
accumulation of the products of incomplete oxydation and anoxydative
breaking down have the same influence in that they decrease the
strength of the response and retard the rapidity of the decomposition
process. These are the general effects perceptible in the refractory
period by the deficiency of oxygen.

  [143] _Alexander Lipschütz_: “Ermüdung und Erholung des Rückenmarks.”
  Zeitschr. f. allgem. Physiologie Bd. VIII, 1908.

  [144] _Fillié_: “Studien über die Erstickung und Erholung des Nerven
  in Flüssigkeiten.” Zeitschr. f. allgem. Physiologie Bd. VIII, 1908.

The establishment of these facts of the dependence of the refractory
period upon oxygen are of the utmost importance for the genesis
of fatigue, for the state of fatigue in all aërobic organisms is
invariably brought about by deficiency of oxygen. In other words:
_fatigue is invariably asphyxiation_. A deficiency of organic
reserve substances never occurs in fatigue before the effect of
oxygen deficiency leads to complete depression, for the quantity of
organic reserve substances at the disposal of the cells is greater
comparatively than that of oxygen. This is shown by transfusion
experiments in which the time involved before complete paralysis was
brought about in the frog by the introduction of an oxygen-free saline
solution was ascertained and compared with the period which elapsed
before complete paralysis took place, when the same solution saturated
with oxygen was used.

Although the previously described experiments on the strychninized
frog show clearly the relations of fatigue to the refractory period, I
should, nevertheless, like to illustrate them somewhat further.

The state of fatigue as it is developed in a living system by a
continuous functional activity is characterized by a series of symptoms
which can be best studied in the fatigue of the muscle, the nervous
centers, and the peripheral nerves.

If the muscle of the frog is isolated and rhythmically stimulated
with single induction shocks and the muscle contractions graphically
recorded, it will be found that the first perceptible alteration during
the course of stimulation is the increasing height in the curve,
which appears directly after the first contraction and becomes more
and more noticeable after every succeeding one. With the isolated
apex preparation of the frog’s heart an effect is produced which
_Bowditch_[145] has termed the “Treppe” and _Tiegel_,[146] _Minot_[147]
and others have obtained the same result for the skeletal muscle. The
_Treppe_ has been often regarded as an expression of increasing of
capability of the muscle following each succeeding stimulus in spite of
the fact that it is physiologically incomprehensible that an isolated
muscle can become more capable by increased demands. _Fröhlich_[148]
first threw light on this seeming contradiction by showing that the
increase in height of the muscle contraction in the _Treppe_ is in
reality the first indication of the beginning of fatigue, and _Fr.
Lee_[149] arrived at the same result. The increase in height of the
contraction curve depends upon the retardation of the course of
contraction. As the contraction extends over the muscle substance in
the form of a wave, a longer stretch of the muscle will be in a state
of contraction when the wave is more extended than when it is shorter,
that is, the shortening of the muscle will be greater, the contraction
curve higher, when the wave is more extended. With increasing fatigue
the retardation in the course of contraction, as _Rollet_[150] already
has shown, becomes continuously greater. (Figure 34.) The consequence
of this retardation in the course of contraction is, therefore,
perceptible in the rhythmically activated muscle in the form of
contracture. As fatigue increases, the muscle requires an increasing
length of time to relax to its full extent and in consequence the
period between the two stimuli is very soon insufficient for this to
occur. There remains a certain amount of shortening, when the next
contraction begins. This characteristic extension of the individual
contraction curve of the fatigued muscle is an expression of the
retardation of the oxydative disintegrating processes and of the
_Treppe_. It shows us that fatigue is perceptible to a slight degree
even after the first excitation. After every succeeding stimulus
the oxydative decomposition in the fatigued muscle is increasingly
prolonged. It is, therefore, self-evident that the capability of
action of the muscle likewise becomes less with increasing fatigue.
Every state of fatigue is, in fact, distinguished by the decrease of
response. This is perceptible in the later stages by the decline of
the height of contraction. Hence all symptoms of fatigue which we
observe form the expression of one single process; it is the constantly
increasing slowness of oxydative disintegration with increasing fatigue.

  [145] _Bowditch_: “Ueber die Eigenthümlichkeiten der Reizbarkeit,
  welche die Muskelfasern des Herzens zeigen.” Arbeiten aus der
  physiologischen Anstalt zu Leipzig VI Jahrgang 1871, Leipzig 1872.

  [146] _Tiegel_: “Ueber den Einfluss einiger willkürlichen
  Veränderungen auf die Zuckungshöhe des untermaximal gereizten
  Muskels.” Arbeiten aus der physiol. Anst. zu Leipzig X Jahrgang 1875,
  Leipzig 1876.

  [147] Minot: “Experiments on tetanus.” Journ. of Anat. and Physiol.
  Vol. XII.

  [148] _Fr. W. Fröhlich_: “Ueber die scheinbare Steigerung der
  Leistungsfähigkeit des quergestreiften Muskels im Beginn der
  Ermüdung. (Muskel Treppe), der Kohlensäurewirkung und der Wirkung
  anderer Narcotica (Aether, Alkohol).” Zeitschr. f. allgem.
  Physiologie Bd. V, 1905.

  [149] _Frederic S. Lee_: “The cause of the Treppe.” Americ. Journ. of
  Physiol. Vol. XVIII, 1907.

  [150] _Alexander Rollet_: “Ueber die Veränderlichkeit des
  Zuckungsverlaufs quergestreifter Muskeln bei fortgesetzter
  periodischer Erregung und bei der Erholung nach derselben.” Pflügers
  Arch. Bd. 64, 1896.

[Illustration: Fig. 34.

Series of muscle curves graphically recorded one over the other,
showing the retardation in the course of contraction with increasing
fatigue. (After _Rollet_.) ]

Exactly similar conditions as those of the muscle are seen in the
central nervous system. The reflex contraction of the triceps of the
frog produced by stimulation of the central end of the sciatic nerve
with single induction shocks demonstrates clearly as _Ishikawa_[151]
has proved in certain stages of fatigue, an increase in height and a
strong relaxation which does not depend upon the fatigue of the muscle
but on that of the centers. If the fatigue is greater, the height of
the contraction then decreases, whereas the extension of the course
of relaxation increases further. The possibility of fatigue of the
muscle during these experiments was, of course, precluded by proper
precautionary measures. Irritability and the course of excitation in
fatigue of the centers show exactly the same alterations as developed
in fatigue of the muscle. The processes of oxydative breaking down
are retarded more and more with increasing fatigue, that is, fatigue
is characterized by exactly the same processes as is the prolongation
of the refractory period by the deficiency of oxygen, and likewise in
fatigue this retardation of the oxydative disintegration processes is
conditioned by the relative deficiency of oxygen. This is shown by the
rôle played by oxygen in recovery after fatigue.

  [151] _Hidetsurumaru Ishikawa_: “Ueber die scheinbare Bahnung.”
  Zeitschr. f. allgem. Physiologie Bd. XI, 1910.

It was found by _Hermann_[152] in 1867 and confirmed by Mademoiselle
_Joteyko_[153] in _Richet’s_ laboratory, that the isolated muscle
of the frog, which was completely nonirritable as the result of
fatigue, does not regain irritability in an oxygen-free medium,
but does so when oxygen is introduced. The previously described
experiments of artificial circulation in the frog show clearly how
dependent the centers are upon the oxygen supply for the restoration
of irritability. In consequence of the strychnine poisoning the
irritability of the centers is so enormously increased that the “all
or none law” is applicable to the centers of the spinal cord under
these conditions.[154] These are the best conditions for the production
of fatigue. One can readily demonstrate the importance of the oxygen
supply for the rapidity with which irritability returns after fatigue
if in the strychninized frog an artificial circulation is used, at
the same time varying on one hand the amount of oxygen, on the other
the activity of the centers. If a saline solution containing merely
a trace of oxygen is circulated, the centers recover very slowly
and incompletely after every fatigue. Subsequent to every reaction
produced by a stimulus, an increasing length of time is required until
irritability is so far recovered that a new stimulus can meet with
response. If, however, a saline solution is circulated which has been
saturated by being shaken with oxygen and is continuously in a pure
atmosphere of oxygen, recovery takes place in comparison with far
greater rapidity and completeness. If the supply of oxygen is ample and
the stimuli act at longer intervals on the frog, irritability always
is quickly restored in the periods of rest between the stimuli. With
continuous stimulation of quickly succeeding stimuli, irritability is
soon completely obliterated, even though an abundant oxygen supply be
present, and it is not until a pause is interpolated that oxygen is
capable of bringing about a recovery. By manifold variations of these
experiments the connection between fatigue and the refractory period
can be more and more clearly recognized. _Fatigue is simply the
refractory period prolonged by deficiency of oxygen._ In both cases
there is a diminution of irritability. In both cases this diminution
is conditioned by a retardation of oxydative disintegration following
every stimulation. In both cases it is the relative deficiency
of oxygen which produces this delay. In both cases the oxydative
decomposition can be quickened and irritability restored, that is,
the refractory period lessened and fatigue removed by a sufficient
supply of oxygen. The amount of oxygen which suffices to constantly
maintain the specific irritability of a living system in an undisturbed
metabolism of rest is not sufficient if the system is continuously
functionally activated by stimulation. The refractory period increases
after excitation and merges, although very gradually, finally into
permanent nonirritability, that is, into complete fatigue.

  [152] _Hermann_: “Untersuchungen über den Stoffwechsel der Muskeln
  ausgehend vom Gaswechsel derselben.” Berlin 1867.

  [153] _Joteyko_: “La fatigue et la respiration élémentaire du
  muscle.” Paris 1896.

  [154] _Julius Vészi_: “Zur Frage des Alles oder Nichts Gesetzes beim
  Strychninfrosch.” Zeitschr. fur allgem. Physiologie Bd. XII, 1911.

[Illustration: Fig. 35.

Double glass chamber for comparative experiments on fatigue of the
nerve (_n n_). A and B--Wires of the electrodes. (After _Thörner_.) ]

[Illustration: Fig. 36.

Curve of action current of two nerves, one of which is stimulated
(plain line) whilst the other remains at rest (dotted line). After
decrease of irritability of the stimulated nerve in nitrogen, oxygen is
introduced into the chamber and irritability increases again. Then the
previously resting nerve is stimulated in nitrogen and the stimulated
nerve remains at rest. (After _Thörner_.) ]

The knowledge that fatigue represents a prolonged refractory period
resulting from relative deficiency of oxygen has enabled me with the
aid of my coworkers to demonstrate the existence of fatigue and produce
the typical symptoms experimentally for a living tissue, which up to
then was considered indefatigable: I refer to the medullated nerve.
After having found that the condition necessary for the production of
fatigue in the nervous centers is a deficiency of oxygen, I arrived at
the conclusion that fatigue could only be obtained in the medullated
nerve when subjected to a deficiency of oxygen. Up to that time,
however, no consumption of oxygen was known for the nerve. It was,
therefore, necessary to first ascertain if the nerve possessed an
oxydative metabolism. At my request, _H. von Baeyer_ investigated
these questions. After many vain attempts to obtain absolutely pure
nitrogen, we finally succeeded in finding a method by which it is
possible to gain nitrogen gas, which is, one might almost say, in a
mathematical sense absolutely pure. It was then possible for _H. von
Baeyer_[155] to asphyxiate the nerve and subsequently to bring about
complete restoration by the introduction of oxygen. It was shown
that the nerve requires merely a minute quantity of oxygen and only
completely asphyxiates when the last trace of oxygen is removed,
and further that recovery takes place within a fraction of a minute
if the oxygen is again supplied. These experiments which have been
carried further by _Fröhlich_[156] were afterwards confirmed in other
laboratories,[157] and _form_ the basis for proving the existence of
fatigue of the medullated nerve. Shortly after, _Fröhlich_[158] was
able to demonstrate symptoms of fatigue in the medullated nerve. He
found that the refractory period of the nerve, which, as previously
mentioned, _Gotch_ and _Burch_ fixed at about .005 second duration,
was prolonged by oxygen deficiency to .1 second, so that stimuli
following each other oftener than ten times per minute produced
merely single initial contractions in the muscle concerned, that
is, in a series of stimuli of which the intervals are less than .1
per second, only the first produces response, whereas the following
occur in the refractory period, brought about by those preceding,
and are, therefore, inoperative. The nerve is fatigued by the quick
succession of stimuli. The normal nerve on the contrary invariably
responds, as known, to an even more rapid succession of stimuli with
a rhythmical excitation corresponding to the number of stimuli and
which is manifest in the muscle by a tetanus. This again confirmed the
identity of fatigue with the prolonged refractory period, conditioned
by the relative want of oxygen. It likewise explained the conditions
of the analogous behavior that _Wedensky_[159] had observed in the
narcotized nerve, but had neither recognized as manifestation of the
prolonged refractory period nor as fatigue. A further advance was made
by the investigations of _Thörner_. He placed two nerves of the same
frog in a double chamber under completely identical conditions with
the exception that one remained in a state of rest, whilst to the
other tetanic stimuli were applied. (Figure 35.) If this took place in
nitrogen, the irritability of the stimulated nerve invariably sank with
much greater velocity than that of the nonstimulated, whereas after an
introduction of oxygen, even when the stimulation was continuous, both
again recovered. In these experiments of _Thörner_[160] the action
current and not the muscle contraction served as indicator. Here the
fatigue of the medullated nerve brought about by the deficiency of
oxygen during prolonged stimulation is demonstrated in the most obvious
manner. (Figure 36.) _Thörner_[161] further succeeded by a continuous
stimulation of the nerve in obtaining even in atmospheric air the
indications of primary fatigue. The symptoms were exactly the same
as those characterizing fatigue of the muscle; the extension of the
course of excitation and, as a consequence of this, the appearance of
a summation of excitation produced by tetanic currents and a reduction
of irritability in response to single stimuli. The form of the curve,
resulting from alteration of irritability in fatigue and recovery,
likewise shows complete conformity with that of the muscle. (Figure
37.) Finally _Thörner_[162] proved that the nerve, when fatigued by
continuous tetanic stimulation in nitrogen, could also partially
recover in the latter if the stimulation was interrupted, whereas a
complete recovery could not take place unless a supply of oxygen was
introduced. (Figure 38.) This fact is in perfect accordance with the
relations found by _Verworn_, _Lipschütz_, in fatigue of the nervous
centers. It is the expression for the accumulation and removal of
fatigue substances, the depressing effect of which _Ranke_[163] first
established for the fatigued muscle. The fact that the nerve could also
partially recover in an atmosphere of nitrogen would seem to likewise
contain the proof that among the fatigue substances products in the
form of gas must be present. It is probable that an escape of carbon
dioxide has taken place.

  [155] _Hidetsurumaru Ishikawa_: “Ueber die scheinbare Bahnung.”
  Zeitschr. f. allgem. Physiologie Bd. III, 1904.

  [156] _Fr. W. Fröhlich_: “Das Sauerstoffbedürfniss des Nerven.”
  Zeitschr. f. allgem. Physiologie Bd. III, 1904.

  [157] _K. H. Baas_: “Zur Frage nach dem Sauerstoffbedürfniss des
  Froschnerven.” Pflügers Arch. Bd. 103, 1904.

_K. Frick_: “Die Abhängigkeit der Erregbarkeit des peripherischen
Nerven vom Sauerstoff.” Inaugural Dissertation vorgelegt der
medicinischen Facultät der Univers. Berlin (Aus dem physiologischen
Institut der Univers.). Berlin 1904.

_Uchtomsky und Dernoff_: “Zur Frage nach dem Sauerstoffbedürfniss der
Nerven.” Travaux du laboratoire de Physiologie a l’université de St.
Petersbourg II Année 1907.

  [158] _Fr. W. Fröhlich_: “Die Ermüdung des markhaltigen Nerven.”
  Zeitschr. f. allgem. Physiologie Bd. III, 1904.

  [159] _Wedensky_: “Die fundamentalen Eigenschaften des Nerven unter
  Einwirkung einiger Gifte.” Pflügers Arch. Bd. 82, 1900.

  The same: “Erregung, Hemmung und Narkose.” In the same place. Bd.
  100, 1903.

  [160] _Thörner_: “Die Ermüdung des markhaltigen Nerven.” Zeitschr. f.
  allgem. Physiologie Bd. VIII, 1908.

  [161] _Thörner_: “Weitere Untersuchungen über die Ermüdung des
  markhaltigen Nerven. Die Ermüdung in Luft und die scheinbare
  Erregbarkeitssteigerung.” Zeitschr. f. allgem. Physiologie Bd. X,
  1910.

  [162] _Thörner_: “Weitere Untersuchungen über die Ermüdung des
  markhaltigen Nerven. Die Ermüdung und Erholung unter Ausschluss von
  Sauerstoff.” Zeitschr. f. allgem. Physiologie Bd. X, 1910.

  [163] _Ranke_: “Untersuchungen über die chemischen Bedingungen der
  Ermüdung des Muskels.” Arch. f. Anat. u. Physiol. 1863 u. 1864.

[Illustration: A

Scheme showing course of fatigue (plain line) and recovery (dotted
line) of the nerve as it is manifested on testing the irritability
with tetanic stimuli, when fatigue and recovery alternate at equal
intervals. The curve shows at the beginning an apparent increase of
irritability corresponding to the “Treppe” of the muscle. (After
_Thörner_.) ]

[Illustration: B

Fig. 37.

Scheme showing course of fatigue (plain line) and recovery (dotted
line) on testing the irritability of the nerve by single induction
shocks. In fatigue irritability sinks at first rapidly, then more and
more slowly until a state of equilibrium is reached. Recovery shows the
same in reverse succession. (After _Thörner_.) ]

As a result of all these investigations, linked together in a
systematic series, the proof has now been obtained that the nerve like
all other living substances is fatigable. Its fatigue is solely the
manifestation of a prolonged refractory period and the extension of the
latter by continuous stimulation is, as in all aërobic substances, a
result of relative deficiency of oxygen.

[Illustration: Fig. 38.

Curve of irritability as demonstrated by action current of two nerves
in nitrogen, which are alternatively stimulated (plain line) and at
rest (dotted line). Recovery in nitrogen is always merely partial
and relative. It only increases on introduction of oxygen. (After
_Thörner_.) ]

To briefly summarize in conclusion, I will repeat that just as all
living systems show a refractory period after an excitation, in which
irritability is reduced, all living systems are likewise capable of
fatigue. Both are most intimately connected and are based fundamentally
on the facts of metabolism.

An excitating stimulus disturbs the metabolic equilibrium of rest
by suddenly bringing about increased decomposition of certain
substances. During and directly after the breaking down, irritability
is reduced in the same degree as the amount of substances required
for disintegration in response to a succeeding stimulus is decreased
and the quantity of the decomposition products is increased. This is
the refractory period. By the metabolic self-regulation in accordance
with the principle of chemical equilibrium, the original metabolic
equilibrium is restored after every excitation. Irritability,
therefore, increases in the same measure as this occurs, that is, in
the form of a logarithmic curve, until it again reaches the specific
degree of irritability of the particular system. The refractory period
diminishes. If the processes of disintegration and self-regulation are
delayed, either by want of substance necessary for breaking down or
the accumulation of decomposition substances, the refractory period is
prolonged and the response to every further stimulation decreased, that
is, the system is fatigued. In all aërobic organisms the retardation
of the course of excitation and self-regulation under a continuous
influence of stimuli is the result of the relative want of oxygen. The
processes of oxydative disintegration are prolonged and restricted by
relative deficiency of oxygen and merge more and more into anoxydative
decomposition. The products of incomplete oxydative and anoxydative
decomposition accumulate. Both factors decrease the strength of the
response after every stimulation. Thus the want of oxygen leads to
reduced activity. In the anaërobic organisms the refractory period and
symptoms of fatigue are, of course, produced by the relative deficiency
of other substances. Fatigue in the anaërobic systems has, however, so
far not been investigated. We advance very slowly, step by step, in
physiology, and, as in every science, an acquirement of a new knowledge
means a new problem. In this lies the inexhaustible charm of our
scientific research.




CHAPTER VIII

INTERFERENCE OF EXCITATIONS

 _Contents_: Examples of effects of interference of stimuli in
 unicellular organisms. Interference of galvanic and thermic stimuli in
 Paramecia. Interference of galvanic and thermic stimuli and narcotics.
 Interference of galvanic and mechanical stimuli. Interference of
 galvanotaxis and thigmotaxis in Paramecia and hypotrii infusoria.
 Real or homotop interference, apparent or heterotop interference. The
 two effects of homotop interference of excitations: Summation and
 inhibition of excitations. Theory of the processes of inhibition.
 _Hering-Gaskell_ theory. Inhibition as an expression of the refractory
 period. Individual possibilities of interference of two stimuli.
 Interference of an excitating and a depressing stimulus. Interference
 of two depressing stimuli. Interference of two excitating stimuli.
 Analysis of the interference of two excitations. Interference of two
 single stimuli. Conditions upon which the result of interference is
 dependent. Heterobole and isobole living systems. Intensity of the
 two stimuli. Interval between the stimuli. Specific irritability and
 rapidity of reaction of the living system. Latent period. Interference
 of single stimuli in a series. General scheme of the development
 of the effect of interference. Summation and inhibition. Apparent
 increase of irritability. Conditions of summation. Tonic excitations.
 Conditions of inhibition. Various types of inhibition. Interference of
 two series of stimuli. Relations in the nervous system. Peculiarities
 of the nerve fibers. Conversion of the nerve by relative fatigue from
 an isobolic into a heterobolic system.


Until now the mechanism of the single excitation has received the major
portion of our attention. It was not until we reached the subject
of the origin of fatigue that we became acquainted with the effects
of repeated stimulation. Here we found a case of interference of
individual excitations. But fatigue is simply a special instance of
such interference, for the subject of interference action occupies a
much greater field.

Every cell of the larger organisms, and more especially the single
celled organisms, is subjected to manifold stimuli. It is indeed,
quite common that two stimuli interfere with each other and manifold
effects follow, depending upon the specific reaction of the cell
and the quality, intensity and duration of the interfering stimuli.
Sometimes the interference effect is readily understandable from a
knowledge of the specific effect of the individual stimuli concerned.
At other times, however, the specific reaction seems entirely different
in nature than would be expected from a study of the effects of the
individual stimuli.

[Illustration: Fig. 39.

Galvanotaxis of Paramaecium aurelia.]

When I place a drop of Paramecium culture on a slide having on two
sides parallel pieces of baked clay which serve as electrodes and
allow a constant current of about .2 milliampère to flow through, it
will be seen that the infusoria at room temperature move toward the
negative pole at a rate averaging 1–1.4 mm. per second. (Figure 39.)
If I increase the temperature, the rate of movement is increased. Here
the galvanic and the thermal stimuli influence each other in such a
manner that the reaction to the galvanic is increased by the thermal
stimulation. This summation of excitation is readily understood on
the basis of the laws concerning the effect of temperature upon the
velocity of chemical change established by _van’t Hoff_. If, however,
the Paramecia are in a 1 per cent. alcoholic solution, then, as was
shown by _Nagai_,[164] the rapidity of movement following galvanic
stimulation is decidedly reduced. The interference effect between the
galvanic and chemical stimulation is, because of the depressing effect
of the latter, likewise readily understood.

  [164] _Nagai_: “Der Einfluss verschiedener Narcotica, Gase and Salze
  auf die Schwimmgeschwindigkeit von Paramæcium.” Zeitschr. f. allgem.
  Physiologie Bd. VI, 1907.

[Illustration: Fig. 40.

Thigmotaxis of Paramaecium aurelia. (After _Jennings_.)]

Greater difficulty meets us, however, in the following instance. The
forward movements of the Paramecia follow in consequence of the fact
that the individual cilia of the body lash more powerfully backward
than forward. If now the Paramecia, while moving forward, meet with a
resisting body, they withdraw sideways while executing a sudden strong
forward ciliary stroke. The strong mechanical stimulation brings about
retraction of the organism. Entirely different are the results when the
impact is weak. If Paramecia while slowly swimming touch a resisting
object with the anterior portion of the body, withdrawal does not
occur. The infusoria remain under proper conditions in contact with the
resistance, and the rhythmic activity of the cilia directly against
resistance, as well as those on the other side toward the posterior
portion of the body, are more or less inhibited. (Figure 40.) The
degree of inhibition brought about by this weak mechanical stimulation
may vary considerably. At times the cilia of the whole body suddenly
cease their movement. (Figure 41, A.) At other times, this cessation
is limited to the cilia in the anterior portion of the body (Figure
41, B), while the movements of those on the posterior portion of the
body are of less amplitude or are irregular and weak. In all cases
the infusorium remains quiescent in the water in contact with the
resistance, and it is not uncommon to find numerous individuals in
apposition with particles of ground, slimy detritus, plant fibers and
so forth. (Figure 41, C.) In short, the rhythmic activity of the cilia
of the Paramecia receiving their normal impulses of excitation from the
ectoplasm of the cell body interfere with strong mechanical stimuli
in such a manner that a negative thigmotaxis develops; following weak
mechanical stimuli a positive thigmotaxis results. Here is an instance
of the relation between the intensity of the stimulus and the manner in
which its effects interfere with an already existing excitation.

[Illustration:

  _A_      _B_      _C_

Fig. 41.

Thigmotaxis of Paramaecium aurelia.]

However, the strength of the inhibitory effect of a weak contact
stimulus upon another excitation is best appreciated when positive
thigmotaxis is interfered with by the effect of a thermal or galvanic
stimulus. _Jennings_[165] and especially _Pütter_[166] have, at my
request, more thoroughly investigated my original observations and
have given us a complete analysis of these interesting interference
effects. If the freely swimming Paramecia are subjected to a constantly
increasing temperature, the movements of these infusoria become more
and more active. At 30° C., the rapidity is very violent and at
about 37° C. they reach their maximal. If now the same experiment is
repeated with Paramecia which have in consequence of thigmotaxis fixed
themselves to particles of slime, the temperature may be increased to
30° C. without an observable effect. The infusoria remain throughout
in contact with the resistance. Only when the temperature is 37° C.
do they release their contact and move violently through the water.
If a drop containing Paramecia is placed on a slide, between parallel
pieces of fired clay which serve as electrodes, it will be seen that
some freely swim about, whereas others remain thigmotactically in
contact with particles of slime. When a constant current of about .2
of a milliampère is passed through, it is observed that the freely
swimming individuals hasten towards the cathode. Those attached
to objects, on the contrary, do not respond in this manner to the
electrical current. (Figure 42.) The intensity of the current can be
greatly increased without bringing about detachment of the individuals
from their position of fixation. The typical influence of the strong
current upon the movement of the cilia of the thigmotactically fixed
individuals can be clearly seen. Nevertheless, the inhibition, brought
about by the contact stimulus, predominates over that of the excitating
effect of the current, so that a freeing of the organisms from their
position does not occur. Not until the current becomes very strong is
the excitation thereby produced sufficient to bring about a separation
of the infusoria, whereupon they immediately swim toward the cathode.
In this interference between the contact stimulus, on the one hand,
and the thermal or galvanic on the other, the inhibitory effect of the
former may overpower the strong excitation of the latter.

  [165] _Herbert S. Jennings_: “Studies on reactions to stimuli
  in unicellular organisms. I. Reactions to chemical, osmotic and
  mechanical stimuli in the ciliate infusoria.” Journal of Physiology,
  Vol. XXI, 189 F.

  [166] _Pütter_: “Studien über Thigmotaxis bei Protisten.” Arch. f.
  Anat. and Physiologie, physiol. Abt. Suppl. 1900.

[Illustration: Fig. 42.

Interference of galvanotaxis and thigmotaxis in Paramaecium aurelia.
The individuals which are thigmotactically attached to slime particles
remain at rest while the freely swimming individuals move toward the
cathodic pole. ]

[Illustration: A

B

Fig. 43.

_Hypotrichous infusoria._ A--Stylonychia. B--Urostyla.]

Still more complex and striking is finally the following case of
interference between thigmotaxis and galvanotaxis. The hypotrichous
infusoria as _Stylonychia_, _Urostyla_, _Oxytricha_, etc., have a
marked functional and morphological differentiation of their cilia.
They possess a bow-like row of perioral cilia, which sweep in the food;
a number of cilia on the ventral surface used for locomotion by which
they move about upon objects in the water; a row of border cilia on
each side, which, during swimming, contribute the propelling force. The
perioral cilia also form the elements which bring about a screw-like
movement on the axis. They further possess several cilia, which
permit a rebounding of the organism, and finally certain forms have
anal cilia, which probably serve as breaks and to steer the organism.
(Figure 43.) Their usual mode of locomotion is that of creeping, moving
by means of the cilia on the ventral surface. These movements depend
upon the positive thigmotaxis of the cilia of locomotion. At the same
time there is inhibition of the cilia on the sides. When the infusoria
are excitated by a new stimulus, the cilia used for rebounding become
active, the body frees itself from its position of attachment and
begins to swim, wherein the cilia on the sides, as well as the perioral
cilia, act in the manner mentioned above. I have made the striking
observation that the hypotrichous infusoria respond differently to the
galvanic current, depending on whether they are swimming or in a fixed
position. If one places a drop of water with numerous Urostyla on a
slide between parallel pieces of fired clay which serve as electrodes,
it will be seen, upon the closing of a current, that all of the
individuals which are freely swimming and turning in a screw-like
manner around their axis, steer immediately toward the cathode, exactly
as in the case of the Paramecia. On the other hand, those which are
fixed to the bottom of the slide as a result of thigmotaxis, upon
closing of the current, make a short turn and assume a position wherein
the long axis is at right angles to the direction of the current, and
the perioral rim is directed toward the cathode. In this position they
move through the field. (Figure 44.) When the current is broken the
individuals draw backwards, distribute themselves and creep and swim
in all directions in the water. If during the course of the passage of
the current, an individual which has been swimming begins to creep, the
axis immediately assumes the position above described in the case of
the organisms which are in contact with the bottom and _vice versa_.
The thigmotaxis, therefore, influences galvanotactically swimming
organisms in a most characteristic manner. As a consequence of the
interference of thigmotaxis and galvanotaxis, the organisms move in
a direction transversely to the direction of the current. This most
striking reaction has been cleared up by _Pütter_,[167] the explanation
being based upon an accurate investigation of the mechanism of ciliary
activity. The galvanotactic swimming toward the cathode is explained
by the same principle as that applicable to all galvanotaxis.[168] As
a result of the excitation produced by the anode, the cell body must
assume a position wherein the border cilia, which are of greatest
importance in swimming, are equally stimulated on both sides of that
part of the body directed toward the anode. It is only in this position
that forward swimming is possible, for as a result of unsymmetrical
excitation of the border cilia a turning must at once occur, which
automatically brings about a resumption of the position of the long
axis. The perioral cilia bring about the screw-like movement around the
axis during swimming. It follows that the freely swimming individuals
must necessarily move towards the cathode. In the case of the
thigmotactically moving individuals the activity of the border cilia
is inhibited. The perioral and the locomotion cilia bring about the
assumption of the position of the axis, above described. The perioral
cilia during movement bring about a turning of the body on the vertical
axis toward the side opposite that of the orifice and it follows that
the body can occupy only that axial position wherein the perioral cilia
are least excitated. This is, however, only the case when the long axis
of the body is transverse to the direction of the current, and the
perioral cilia are directed toward the cathode, for stimulation arises
from the anode. The reason why the infusoria do not turn toward the
anode from this transverse position of the axis is to be found in the
fact that the anterior locomotion cilia are stimulated to a greater
extent by the turning toward the anode, and bring about a movement in
the contrary direction. The transverse position of the axis is thus
the result of an antagonistic action between the perioral and the
anterior locomotion cilia. It therefore follows that the characteristic
position, which is necessarily assumed by the thigmotactically creeping
individuals, is brought about by an interference action between tactile
and galvanic stimulation.

  [167] _Pütter_: l. c.

  [168] _Max Verworn_: “Allgemeine Physiologie.” V Aufl. Jena 1909.

[Illustration: Fig. 44.

_Urostyla grandis._ Interference of galvanotaxis and thigmotaxis. The
freely swimming individuals move towards the cathode (left side). The
creeping individuals move in transverse direction. ]

These, then, are a few examples of the interference action of various
stimuli on the single cell. They show us in part fairly simple, and
in part very complex states. It now behooves us to obtain a general
understanding of interference action, to learn the fundamental _laws_
in connection with these complex actions, to shell out, as it were, the
general factors involved in the special conditions. In this connection
the examples already referred to furnish all of the data necessary for
our first orientation. In the simple instance in which the effect of
galvanic stimulation was augmented by increase of temperature and again
in the case where there was a diminution of excitation resulting from
the alcohol, the interference of the two stimuli is consequent upon
the fact that the location of attack is the same. The constant current
acts upon a portion of the infusorium, which also responds to elevation
of temperature. We have a _real_, or, as I may term it, “_homotopic
interference_,” for it is an interference in which the general point of
attack is the same for both stimuli.

In contradistinction to this case, we have the examples of the
interference of thigmotaxis and galvanotaxis in the hypotrichous
infusoria. Here the effect of interference, the characteristic position
of the axis of the cell body, is brought about by the fact that the
galvanic stimulus affects different elements than the mechanical.
The turning of a creeping Stylonychia or Urostyla, when the current
is closed, in which the anterior portion of the body was previously
directed towards the anode, results from excitation of the perioral
cilia from the anodic pole. The mechanical stimulation, on the
contrary, exerts its effect upon the locomotion and border cilia. Only
when there is a turning of the anterior portion of the body towards the
anode, would the galvanic stimulus affect also the anterior locomotion
cilia and thereby counteract turning towards the anode. Therefore,
we have before us in this case of the assuming of a characteristic
position of the axis of the cell body the expression of an _apparent_,
or, as I prefer to express it, a “_heterotopic interference_,” in which
the two stimuli do not actually interfere in their action, but rather
influence the final result, in that the condition for the state of the
system in its totality is dependent upon its individual components.
This heterotopic interference is of particular importance in the
bringing about of the movements of the living system. The locomotion
of the animal and especially the direction is in part a manifestation
of heterotopic interference of response. At the same time, however,
especially in the coördinated movements of nervous origin, the
homotopic interference _also_ plays an important rôle and, not rarely,
is combined with heterotopic interference.

Although the physical analysis of heterotopic interference is extremely
attractive, we must, however, temporarily set aside its consideration,
for at this point the question arises as to what happens when there
is interference of two stimuli at the same point. In the heterotopic
interference the effect of each stimulus is the same as if it were
applied singly. In the homotopic interference the interfering effects
of stimulation influence each other.

The above examples of homotopic interference introduce us to the two
principal types of these manifold kinds of interference effects; the
excitation brought about by galvanic stimulation is summated by the
excitation produced by temperature. The other type consists of an
inhibition of one effect of stimulation brought about by another. The
depression produced by alcohol on the Paramecia weakens the excitation
of the galvanic current. These examples of the two principal types
of interference effects are quite simple; nevertheless, in other
cases, the conditions are very complex. This is especially true in
the field of nervous inhibition, so important in the functionation of
the nervous system, and which has presented the greatest difficulties
to physiological investigators until the last few years. That a
stimulus bringing about excitation in a ganglion cell can be inhibited
by another exciting stimulus, or that the development of excitation
in a ganglion cell may be prevented by another exciting stimulus
cannot be easily understood. The problem as to how two interfering
excitations can bring about inhibition is one that has received many
explanations. An interesting incident in the history of physiology is
that the first explanation of the principles of inhibitory processes
was close on the track of being a correct one, but was subsequently
abandoned by its originator. _Schiff_[169] (1858) has endeavored to
explain this inhibition as a manifestation of fatigue, and this idea
he defended with the greatest tenacity for a long time, until finally,
twenty-five years after, in a treatise which he called “Abschied von
der Ershöpfungstheorie,” he renounced the idea as untenable.

  [169] _M. Schiff_: “Lehrbuch der Physiologie des Menschen.” Bd. I,
  Lahr 1858.

Among other investigations, which since this time have been made
to explain the mechanism of inhibition, those of _Gaskell_,[170]
_Hering_[171] and _Meltzer_[172] have received widest consideration.
These theories are built upon the existence of the two phases of
metabolism, and assume that inhibition, in contradistinction to
dissimilatory excitation processes, depends upon an increase of
the assimilative processes. The principal evidence which _Gaskell_
advances is that when the vagus nerve of the tortoise heart, a
typical inhibitory nerve, is stimulated, a positive variation of the
demarcation current of the heart muscle occurs, whereas when a motor
nerve of a skeleton muscle is stimulated the attached muscle shows a
negative variation of the demarcation current. I must confess that
this explanation of inhibitory processes, from the standpoint of
an interpretation of processes in the living substance, seems very
plausible, and I have accepted this even in my address on excitation
and depression before the Frankfurter Naturforscher Versammlung.[173]
I have since then endeavored to obtain experimental evidence to
substantiate this theory, in that I attempted to prove that increase
of the assimilatory processes brought about by stimulation would be
associated with a reduction of the specific irritability. For this
purpose I have sought for such cases in which a stimulus primarily and
momentarily increases assimilative processes in a system in a state
of metabolic equilibrium. I was disappointed, when, after years of
investigation, I could not find such cases. There is only one kind
of stimulus of which we can say with positiveness that it primarily
increases the assimilative processes, that is, increased supply of
food. But here the increase in the processes of assimilation never
occurs momentarily, and indeed this increase is so extremely slight
that it can only be demonstrated over a long course of time. These
totally negative results of my investigation had awakened strong doubts
concerning the assimilation hypothesis of inhibition. Above all, this
explanation seemed to me to be impossible for the nervous system. I
searched, therefore, for another explanation for the processes of
inhibition in the nervous system. If the increase of energy production
resulting from the application of a stimulus is dependent upon an
excitation of a dissimilative nature, then one is justified to look
upon the reduction of functional energy production as an expression of
an antagonistic process to that of dissimilatory excitation. In this
respect the _Gaskell-Hering_ hypothesis of inhibition rests upon a
firm foundation. When, however, this hypothesis assumes an antagonism
between dissimilatory and assimilatory excitation, then it must not be
overlooked that a second antagonism is possible between dissimilatory
excitation and dissimilatory depression. The antagonism need not
involve the two types of metabolism, it may depend upon variations of
_one_ type. When, therefore, the hypothesis that inhibition is brought
about by assimilatory excitation meets with insuperable difficulties,
the possibility should be considered if it is not more likely
dependent upon dissimilatory depression. These reflections induced
me to investigate if conditions could not be produced experimentally
wherein dissimilatory depression could bring about inhibitory processes
in the nervous system. The most essential requirement was, that
dissimilatory depression should quickly develop and pass away with like
rapidity, for inhibition of the nervous system sets in momentarily
and disappears again momentarily. Another important requisite is,
that both interference stimuli are individually capable of producing
dissimilatory excitation, for the inhibitory processes of the nervous
type may be assumed to be the result of dissimilatory excitation which
produce by their interference inhibition, for the nerve fibers, as
already stated, are capable of conducting only dissimilatory excitation
to the responding organ. As I studied the problem in this manner,
it became clear to me that all the conditions necessary for the
genesis of inhibition are realized in the existence of the refractory
period, and that I had already produced inhibition by prolonging the
refractory period, by oxygen withdrawal, in the strychninized frog.
If we take a strychninized frog in which the refractory period has
been somewhat prolonged by oxygen withdrawal, so that the reaction
is simply a short reflex contraction, and rhythmically stimulate
the skin, a reaction is only obtained with the first few stimuli,
which reactions rapidly decrease until a stage is reached wherein
the succeeding stimuli are completely inoperative. (Figure 45.)[174]
This inhibition is demonstrated even more clearly by the following
experiment. Contractions of the triceps muscle of a strychninized
frog are recorded which reflexly follow from stimulation of the
central end of the cut sciatic nerve. Oxygen is withdrawn in the
manner already referred to. At the proper stage of oxygen deficiency,
rhythmic induction shocks applied to the central end of the nerve, the
interval between the individual stimuli of which being longer than the
duration of the refractory period, elicit reflex contractions of the
muscles of the posterior extremity on the opposite side following each
individual stimulus. If, however, in the same stage the central end of
the nerve is stimulated with induction shocks at intervals briefer than
the duration of the refractory period, a contraction is only observed
during the very beginning, being brought about by the _first_ stimulus,
whereas the subsequent stimuli are ineffective, the muscles remaining
at rest during their entire application. (Figure 46.) _Tiedemann_[175]
at a later date continued these observations and analyzed them more in
detail. In all these experiments, therefore, there is an interference
of the frequent stimulus, because each succeeding stimulus occurs in
the refractory period of the proceeding. In consequence there is a
strong reduction of irritability and reaction is absent. That is, the
centers during application of the frequent current are _inhibited_. If
cessation of stimulation by frequent shocks takes place, stimulation
by slowly succeeding individual shocks becomes effective again in a
few seconds. This is the simplest example of the process of inhibition
and by it I was led to seek in the refractory period the key of
the mechanisms of the process of inhibition. This principle once
recognized, further material for the more detailed working out and
extension of the theory was gathered from the experiences already
gained during the course of the preceding years in the researches on
fatigue and the refractory period in the nerve. Here it became apparent
that the processes resembling inhibition discovered by _Schiff_ in
the nerve preparation and which were studied anew at a later date by
_Wedenski_, _F. B. Hofmann_ and _Amaja_ and in part attributed by
_Hofmann_ to fatigue of the nerve endings, by _Fröhlich_ to fatigue
of the nerve itself, were in principle of the same nature as the
central inhibitions themselves. _Fröhlich_,[176] by his analysis of
the observations of _Richet_, _Luchsinger_, _Fick_, _Biedermann_ and
_Piotrowski_ on inhibition in the claw of the crab, then showed that
inhibition can be influenced by the alteration of the intensity of
the stimulus as well as its frequency. In a series of experimental
researches he could then demonstrate that the widely extended
antagonistic inhibitions and other special processes of inhibitions in
the centers could on the basis of the same principle be physiologically
explained. Here the supposition was confirmed that the development
of a relative refractory period plays a very important rôle in the
inhibition of the nervous centers. Thus, the relations of the processes
of inhibition to the refractory period, once established, their entire
field, up to then shrouded in darkness, has gradually in the course of
years been completely elucidated.

  [170] _Gaskell_: “On the innervation of the heart with especial
  reference to the heart of the tortoise.” Journ. of Physiology, Vol.
  IV, 1884.

  [171] _Ewald Hering_: “Zur Theorie der Vorgänge in der lebendigen
  Substanz.” Lotos IX. Prag 1888.

  [172] _Meltzer_: “Inhibition.” New York Medical Journal, 1899.

  [173] _Max Verworn_: “Erregung und Lähmung. Vortrag gehalten in der
  allgemeinen Sitz. der Gesellsch.” Deutsch. Naturf. u. Aerzte zu
  Frankfurt a. M. 1896. Verh. d. Ges. Deutsch. Nat. u. Aerzte 1896.

  [174] _Max Verworn_: “Zur Kenntniss der physiologischen Wirkungen des
  Strychnins.” Arch. f. Anat. u. Physiol. physiolog. Abth. 1900. The
  same: “Ermüdung, Erschöpfung and Erbolung.” Ibidem Suppl. 1900.

  [175] _Tiedemann_: “Untersuchungen über das absolute Refractärstadium
  und die Hemmungsvorgänge im Rückenmark des Strychninfrosches.”
  Zeitschr. f. allgem. Physiologie Bd. X, 1910.

  [176] _Fr. W. Fröhlich_: “Die Analyse der an der Krebsschere
  auftretenden Hemmungen.” Zeitschr. f. allgem. Physiologie Bd. VII,
  1907. The same: “Der Mechanismus der nervösen Hemmungsvorgänge.”
  Medizin. naturwiss. Arch. Bd. I, 1907. The same: “Beiträge
  zur Analyse der Reflexfunction des Rückenmarks mit besonderer
  Berücksichtigung von Tonus, Bahnung und Hemmung.” Zeitschr. f.
  allgem. Physiologie Bd. IX, 1909. The same: “Experimentelle Studien
  am Nervensystem der Mollusken 12. Summation und scheinbane Bahnung,
  Tonus, Hemmung und Rhythmus am Nervensystem von Aplysia limacina.”
  Zeitschr. f. allgem. Physiol. Bd. XI, 1910.

[Illustration: Fig. 45.

Lower line indicates stimuli.]

[Illustration: Fig. 46.

Reflex inhibition in the strychninized frog. Lower line indicates
seconds, upper line stimuli. When stimulation with single shocks at
longer intervals is applied, each single stimulus is effective. When
faradic stimulation is used, only the first stimulus is operative, and
during the further continuance of stimulation inhibition takes place in
the spinal cord. ]

Before going back to the cases of inhibition and explaining them by
this general principle, it is necessary that we penetrate more deeply
into the details of the characteristic course of the refractory period.
By this means we will find the conditions which universally determine
the interference in the effects of stimulation.

First of all, it is self-evident that the occurrence of interference
of stimulation in a living system can only take place when the
succeeding stimulus is applied before the effects of the previous
one have completely disappeared. Within the interval, however, which
is involved from the moment of the beginning of a stimulus until its
effect disappears through the self-regulation of metabolism, there is
the possibility of various interference results from stimulation.

If we take into consideration the various instances which can arise,
perhaps we may best start with that type wherein the first stimulation
produces depression, whereas the second has an exciting effect on
disintegration. In this type the response to the second stimulus is
weaker than when the second stimulus alone is applied. As a concrete
example of this type, we may refer to the interference of an induction
shock in a nerve during the relative want of oxygen. We arrange a
nerve of a nerve muscle preparation of a frog in a glass chamber,
as already described, and determine the threshold of stimulation of
the stretch within the chamber by the weakest induction shocks which
produce response. The oxygen is then removed and the effect on the
threshold determined. As shown by _Baeyer_ it is found that with
increasing asphyxia the threshold of stimulation for induction shocks
becomes continually higher. The irritability is likewise decreased.
This occurs, as the investigations of _Lodholz_ show, at first slowly,
then more and more rapidly. The curve of the decrease of irritability
has a logarithmic form. During the continuation of the depressing
stimulus, i.e., the want of oxygen, the exciting stimulus has less and
less effect. If oxygen is again brought in contact with the nerve,
irritability immediately returns to its original height. The cessation
of the depressing stimulus has, therefore, the effect that the exciting
stimulus again brings about its original response.

A second type of interference is produced when both stimuli bring
about depression. As an example, we may select the interference of
cold and deficiency of oxygen. If we assume, for instance, that each
of these stimuli of itself brings about only a partial reduction of
living processes and not a _complete_ suppression, then it would be
possible to think of a summation of both depressions. Nevertheless, the
conditions for the summation of depression have never been carefully
analyzed. Quantitative investigations upon the interference of
depressing stimuli are entirely lacking. One should not, however, in
physiology presuppose what may happen under certain given conditions
without first making the necessary experiments. The strength of
scientific investigation depends upon the fact that every deduction, no
matter how small, must be substantiated by experience before further
progress can be made. So, likewise, we must await the results of
thorough experimentation upon the interference of depressing stimuli
before we can establish a law. The conditions are not as simple as they
appear on first observation, for the point of attack of the various
kinds of the depressing stimuli upon the chain of metabolic processes
may be very different. In such a case it is not at once possible to
understand the results of the interference.

There is a third type in which two dissimilatory excitations interfere
with each other. Fortunately there is a great amount of experimental
data at our command so that today we have a clear understanding of
the essential points of the conditions necessary for the development
of summation of excitation on the one hand, and inhibition on the
other. If we take an instance of a momentary dissimilatory excitation
operating upon an aërobic system in metabolic equilibrium, it is
necessary to recall the two effects thereby produced. The stimulus
brings about an oxydative decomposition of the living substance.
Likewise there is a reduction of irritability. Both of these
alterations are the foundation of interference. Both processes have
a specific time of occurrence. The disintegration, determined by
energy production, reaches a maximum suddenly, then diminishes, at
first rapidly, then more and more slowly until the zero point is
reached. In an analogous manner the irritability abruptly reaches a
minimum, then increases rapidly, then more slowly, until it again
reaches its previous value. When we represent these processes by a
curve, they assume the following form. (Figure 47.) In this diagram
the abscissa is the time, the ordinate value zero is the level of the
metabolism of rest and the specific irritability. The points above the
abscissa represent disintegration, that is, energy production, those
under the abscissa, the reduction of irritability. A consideration
of the latent period may be omitted. At the end of the curve the
effect of stimulation may be assumed to have disappeared and the
state of metabolic equilibrium reestablished. If we base our further
observations upon this curve of excitation, we can study in them the
factors upon which responsivity is dependent when a second exciting
stimulus is operative during the course of the first.

[Illustration: Fig. 47.]

[Illustration: Fig. 48.]

[Illustration: Fig. 49.]

[Illustration: Fig. 50.]

It is from the beginning apparent that the response to the second
stimulus is determined by the intensity of the second stimulus in
relation to the degree of irritability which exists at the moment
when this is effective. This relation is dependent first upon the
absolute intensity of the second stimulus. In the following diagram the
intensity of the existing threshold value is fixed for convenience as
ordinates beneath the abscissa. If, for example, at the time point _x_,
a stimulus of weak intensity R_{1} acts, this stimulus being under the
existing threshold, produces no perceptible effect. (Figure 48.) If now
instead of a weak stimulus, one of stronger intensity acts at the time
point _x_, this stimulus will produce an appreciable response. (Figure
49.) If the second stimulus is of the same strength as the first,
this second stimulus will bring about relatively less disintegration,
because the system is then in a state in which irritability is still
reduced. But this lessened disintegration in that it summates the
excitation still existing as the result of the first stimulus can
produce an absolute increase of the height above that of the abscissa.
Here then we see the possibility of an increase of response resulting
from summation. Accordingly the increase of disintegration must occur
simultaneously with a diminution of irritability and this must fall
below the level of the reduction of irritability produced by the
first stimulus. This augmentation of the response through summation
above the level of that produced by the first stimulus acting upon an
unexcitated system is, however, connected with another condition. The
above example refers to systems in which weak stimuli bring about weak
response and strong stimuli strong response, that is, the response
is capable of increase. In systems in which the “all or none law” is
applicable, such an alteration in the absolute height of excitation,
as results in summation, is not possible. In order to characterize
these two types of living systems by a short expression rather than
by a long sentence, we will call the first a “_heterobolic system_,”
the latter in which the “all or none law” is operative an “_isobolic
system_.” The former term expresses various degrees of discharge
depending upon the intensity of the stimulus, the latter term refers to
the constancy of discharge following stimuli of various intensities.
Isobolic systems are in contradistinction to the heterobolic systems
not capable of summation. The response to the second stimulus of equal
intensity cannot be greater than that of the first, it may be equal
to the first (Figure 50) or be less in extent, but it can never be
greater than that resulting when a single stimulus is applied. These
facts have been known for a long time in the case of the heart muscle.
A word is necessary, however, concerning the effect of stimuli beneath
the threshold in heterobolic systems. We must here distinguish between
the _“ideal” threshold_, beneath which the influence of a stimulus
is nil, and the _threshold of perceptible effect_, beneath which a
stimulus apparently has no effect; nevertheless a weak effect does
occur, as is shown by succeeding reactions. This effect is manifested
by a sub-threshold disintegration and a corresponding slight reduction
of irritability. (Figure 51.) The presence of such a sub-threshold
effect is recognized by various facts as, for example, the summation of
the sub-threshold stimuli to production of a perceptible result. Thus
stimulation of a sensory spinal cord root with a single sub-threshold
induction shock will not produce any evidence of a reflex excitation,
whereas, when induction shocks of the same strength and of sufficient
frequency are applied, a strong reflex contraction results. The fact
that sub-threshold stimuli can bring about sub-threshold effects is
also important in consideration of the result of interference. The
relation between the intensity of the second stimulus and the degree
of irritability of the system, the intensity of the stimulus being
absolutely constant, depends, secondly, upon the momentary amount of
irritability which exists just at the time when the second stimulus
produces its effects. It is, therefore, clear that the response
produced by interference must also alter with the momentary degree of
irritability in a manner analogous with variations of the intensity
of the second stimulus. One must, therefore, know the factors which
control the momentary degree of excitation.

[Illustration: Fig. 51.

Effect of sub-threshold stimuli. _o_--Level of the ideal threshold.
_s_--Level of the threshold of perceptible effect.]

[Illustration: Fig. 52.]

The first factor to be considered is the moment of time in which the
second stimulus is applied, that is, the interval between the first
and the second stimulus. If, for example, a weak second stimulus
follows very quickly after the first, the stimulus will bring about
no response, as the system at the time of its application is in a
relative refractory period. (Figure 48.) The stimulus is, therefore,
under the threshold. If, however, a stimulus of the same strength is
applied somewhat later, when the irritability has already increased to
a somewhat greater extent, then at this moment the stimulus is above
that of the threshold and a response is obtained which, on account
of the state of irritability existing, is summated. (Figure 52.) But
further, it is not a question of the _absolute_ interval between
the stimuli, but rather to the _relative_ interval to the _specific
rapidity of the reaction of the living substance under consideration_.
There are living substances, as we have seen, in which the refractory
period is unusually short, as, for instance, the nerve. There are
other substances wherein this period lasts a considerable time after
stimulation, that is, before the irritability returns to the original
level, as, for example, the smooth muscle. Indeed, depending upon the
specific properties of a system, a short or a long interval is required
before a stimulus of a given intensity is again operative. Finally, in
one and the same living system the duration of the refractory period
can be very different, depending upon the _momentary state of the
system_. Above all we know that the refractory period is considerably
prolonged in fatigue and likewise after the influence of other agents,
as narcotics, lowering of the temperature, etc. In such states a second
stimulus remains inoperative when it follows at a definite interval
from the first, whereas under normal conditions the same stimulus
applied at the same interval would be operative.

Finally, there is another factor to be considered, namely, that the
latent period of the second stimulus is more and more prolonged as the
second stimulus approaches more closely to the absolute refractory
period of the first. In the above schemes the latent period was not
taken into consideration because practically for all the intervals
of stimulation considered at that time it could be assumed to be the
same. When, however, a decrease of the intervals between the individual
stimuli takes place, the prolongation of the latent period can then not
be overlooked, as it leads to a retardation of response. (Figures 29,
30.) This fact was shown in the classic investigations of _Marey_[177]
upon the refractory period of the heart, and more recently has been
the subject of study by _Samojloff_,[178] _Keith Lucas_[179] and
_Gotch_[180] in the muscle and nerve. These, then, are the essential
factors which bring about interference, and although there are special
details which deserve more close analysis, nevertheless, we are in a
position to attribute to them the origins of summation and inhibitory
processes, which occur in all living systems, especially the nervous
system.

  [177] _Marey_: “Des excitations artificielles du cœur.” Trav. du lab.
  de M. _Marey_ II, 1875. The same: “Des mouvements que produit le cœur
  lorsqu’il est soumis à des excitations artificielles.” Compt. rend.
  de l’acad. des sciences T. LXXXVII, 1876.

  [178] _Samojloff_: “Actionsströme bei summierten Muskelzuckungen.”
  Arch. f. Physiologie Suppl. 1908. The same: “Über die
  Actionsstromkurve des quergestreiften Muskels bei zwei rasch
  aufeinanderfolgenden Reizen.” Zentralblatt f. Physiol. 1910.

  [179] _Keith Lucas_: “On the refractory period of muscle and nerve.”
  Journ. of Physiology, XXXIX, 1909–10. The same: “On the recovery of
  muscle and nerve after the passage of a propagated disturbance.”
  _Ibid._ XXXXI, 1910–11.

  [180] _Gotch_: “The delay of the electrical response of nerve to a
  second stimulus.” Journ. of Physiology, XXXX, 1910.

For the analysis of summation and the inhibitory processes which occur
in the physiologically active organisms or which are experimentally
produced, a very important point should be observed, that is, the fact
that the stimuli which bring about these phenomena are practically
always a _series_ of _single_ stimuli. The nerve impulses, for example,
consist of a shorter or a longer series of single discharges which
follow each other in rapid rhythmic sequence. Here, then, we have the
conditions necessary for the production of interference effects when
these single stimuli follow each other with sufficient frequency and
also when there is the combined action of _two_ series.

[Illustration: Fig. 53.

Curve showing the general development of the effect produced by
interference of the stimuli of the same series in an heterobolic
system. The effect is first summation and then inhibition. _R_
indicates the intensity of the stimuli, _S_ the level of the threshold
of perceptible effect. ]

We will first direct our attention to the simplest case brought
about by an interference between the individual effects of stimuli
in the same series. We will study the effect, which here occurs,
in the accompanying diagram, which shows the facts involved in the
interference of _two_ stimuli of a _series_ of stimuli. (Figure 53.)
The curve shows the development of summation and inhibition. The single
stimuli of equal intensity follow at the same intervals, so that the
succeeding stimuli meet with an incomplete recovery of excitation
and accordingly a decreased state of irritability. In spite of the
diminution of the relative response to each stimulus the summation
of excitation brings about an absolute increase of the same. At the
same time the irritability decreases more and more, for after each
stimulation the oxydative disintegration as well as restitution require
a progressively greater time and a relative fatigue must, therefore,
necessarily develop. The summation, consequently, reaches its limit
very soon and then decreases progressively, for, as a result of the
increase of fatigue, the oxydative decomposition which occurs at
the instant of every stimulation reduces and with this the energy
production becomes less and less. The system is relatively refractory
for the given intensity of stimulus. Accordingly the response to
stimulation falls below the threshold of perceptible response
(dotted line S) and finally an equilibrium between disintegration
and restitution occurs, wherein the small amount of material used at
each stimulation by oxydative decomposition is again replaced before
the next stimulus. In other words, the irritability is reduced at
each stimulation to an amount equal to that of the recovery in the
interval. If this all takes place beneath the threshold of perceptible
response, the system during the continuance of the stimulation seems
responseless, that is, inhibited. The _inhibition_ consists then of a
reduction of irritability below the perceptible threshold of response
of the stimulus concerned. It depends upon a continued lessening of
dissimilative excitation to a low level through the delay of the
oxydative decomposition processes. The inhibition is according to
this a relative fatigue, which is conditioned, as is true of every
fatigue, by a lengthening of the refractory period following a relative
deficiency of oxygen. _The processes of inhibition are simply and
solely an expression of a refractory period persisting as a result of
dissimilatory excitating stimuli._

Accordingly the general conditions requisite for summation on the one
side and inhibition on the other may be formulated as follows:

A _summation_ may develop in a heterobolic system and by the use of
submaximal stimuli. It always develops when the following stimulus
is applied before there is complete recovery of excitation from the
previous stimulus. The absolute increase of excitation as a result of
summation is, however, limited by the diminution of irritability. By
continuation of the series of stimuli the state of equilibrium between
the amount of excitation and the irritability will be established
on a higher or lower level. There occurs then, depending on whether
the feeble persistent excitation remains above or below the level of
perceptible effect, either a tonus or an inhibition.

Summation can be transformed into inhibition by the continuance of
stimuli of constant intensity. The principles which underlie both
processes are in no way antagonistic and indeed are not separated by
distinct boundaries. The diagram here shown (Figure 53) illustrates
this development of summation and inhibition. The time required for
this development is in manifold ways influenced by variations of the
above-stated factors which control the occurrence of interference.
Thereby results an immense number of special cases which differentiate
themselves in characteristic manner depending on whether an isobolic or
heterobolic system is involved, depending on whether the irritability
of the system, as measured by the threshold of stimulation, is high or
low, depending on whether fatigability is great or small, depending
upon the intensity and frequency of the stimuli, etc. Analysis of every
instance shows us different combinations of the interaction of the
individual factors. It is, therefore, self-evident that we cannot here
analyze a greater number of these cases of summation and inhibition. I
wish only to refer to a few typical examples at this time.

It is known that summation of excitation in the normal nerve does not
occur. As already stated, the nerve is a system in which the “all
or none law” is operative. Such isobolic systems do not summate,
having no power of summation because each individual stimulus brings
about a maximum response. But we have seen that the nerve, as a
result of depressing factors, such as deficiency of oxygen, narcosis,
fatigue, etc., which decrease its irritability, can be transformed
from an isobolic into a heterobolic system. In this state the nerve
possesses the capability of summating excitations. _Waller_,[181]
_Boruttau_,[182] _Boruttau_ and _Fröhlich_,[183] _Thörner_[184] and
others have shown that the action current of the nerve during the
application of tetanic stimulation becomes decidedly greater during
a certain stage of narcosis or asphyxiation, so that the wave of
negative variation is higher than when the nerve is excitated by a
single induction shock. _Fröhlich_[185] first threw light upon this
subject in that he made the observation that here a principle is
involved which has far-reaching importance in the phenomena occurring
in the organism. He showed that as a result of fatigue, cold and
narcosis, etc., the course of excitation brought about by the single
stimulation undergoes retardation. These conditions within certain
limits become more favorable for the production of summation, because
each succeeding stimulus meets with a more incomplete recovery of
excitation than the one previously applied. In consequence of this, the
irritability of the system in the beginning of fatigue, or narcosis,
or immediately after the application of cold, is apparently increased.
This “_apparent excitation_,” as it was called by _Fröhlich_, depends,
however, in reality upon a beginning depression which is evident in
that the course of the individual excitations are lengthened by this
means. The irritability is likewise also reduced. _Reinecke_[186]
later studied in further detail the retardation of excitation in the
muscle and attributed to this the characteristic property shown in
muscle in the so-called “reaction of degeneration.” Fatigue, asphyxia,
cold, degeneration, in fact all factors which retard the course of
excitation, are favorable to the summation of excitation, provided
their influence does not exceed certain limits.

  [181] _Waller_: “Observations on isolated nerve.” Croonian Lecture,
  Philosophical transactions. 1897.

  [182] _Boruttau_: “Die Actionsströme und die Theorie der
  Nervenleitung.” Pflügers Arch. Bd. 84, 1901.

  [183] _Boruttau und Fröhlich_: “Electropathologische Untersuchungen.
  Ueber die Aenderung der Erregungswelle durch Schädigung des Nerven.”
  Pflügers Arch. Bd. 105, 1904.

  [184] _Thörner_: “Die Ermüdung des markhaltigen Nerven.” Zeitschr. f.
  allgem. Physiologie Bd. VIII, 1908, und Bd. N, 1910.

  [185] _Fr. W. Fröhlich_: “Ueber die scheinbare Steigerung der
  Leistungsfähigkeit des quergestreiften Muskels im Beginn der Ermüdung
  (Muskeltreppe), der Kohlensäurewirkung und Wirkung anderer Narkotica
  (Aether, Alkohol).” Zeitschr. f. allgem. Physiologie Bd. V, 1905.
  The same: “Das Princip der scheinbaren Erregbarkeitssteigerung.”
  Zeitschr. f. allgem. Physiologie Bd. IX, 1909.

  [186] _Fr. Reinecke_: “Ueber die Entartungsreaction und eine Reihe
  mit ihr verwandter Reactionen.” Zeitschr. f. allgem. Physiologie Bd.
  VIII, 1908.

Although the nerve as an isobolic system can only be rendered capable
of exhibiting summation when artificially influenced, there are other
forms of living substance which normally are systems with a slow
course of excitation, in which excitation may be summated, for this
type possesses at the same time a heterobolic character. For example,
a single mechanical excitation elicits a hardly perceptible response
in _Amœba_, _Actinosphærium_, _Orbitolites_. When it is perceptible
at all, there occurs a short interruption of the centrifugal movement
of the protoplasm. After a pause the movement of the protoplasm and
the stretching out of the pseudopods again return. But if the organism
is agitated one or more minutes by rhythmically shaking the edge of
the slide by a special device, as a result of the summation of weak
excitations there occurs a complete drawing in of the pseudopods and
the amœbæ become bell-shaped.[187] The ganglion cells also possess a
great capability for summation. We have already alluded to the fact
that single induction shocks below that of the threshold produce no
evident effect, whereas when rapidly repeated, summation occurs with
reflex reaction.

  [187] _Max Verworn_: “Psychophysiologische Protistenstudien.
  Experimentelle Untersuchungen.” Jena 1889.

  The same: “Die physiologische Bedeutung des Zellkerns.” Pflügers
  Arch. Bd. 51, 1892.

[Illustration: Fig. 54.

Development of tonus by interference of sub-threshold stimuli.
_S_--Level of the threshold of perceptible effect.]

The summation of sub-threshold excitation to a certain height offers
very favorable conditions for the development of _tonus_. (Figure
54.) This fact has been established for many kinds of centers
(cardio-inhibitory center, vasomotor center, etc.). During the
continuance of a series of stimuli, as we have already seen, an
equilibrium between disintegration and replacement soon takes place.
The level of this state of equilibrium depends upon the relative
intensity of the stimuli. It is lower in the case of strong and
higher in that of weak stimuli. This fact becomes apparent from the
researches of _Thörner_[188] on the fatigue of medullated nerves in
air. This investigator showed that during continued tetanic stimulation
of the nerve, the irritability fell to a certain level, at which it
remained so long as stimulation persisted. The irritability decreased
to a new level when the strength of the stimulus was increased. These
interesting experiments of _Thörner_ show that the level reached when
stimulation is continued is higher as the intensity is weaker. It is,
therefore, clear that this level in summation of stimulation beneath
the threshold can be above that of the threshold of perceptible
response, that is, a perceptible tonic excitation may result. In the
genesis of tonus in the muscle, there is another point to be taken into
consideration. Here we have a combination of a heterotopic interference
with a homotopic interference, for the total shortening of the muscle
is brought about in part by several contraction waves which occur at
various points at the same time and which follow each other, therefore
have a heterotopic sequence. If we consider a long stretch of muscle,
to one end of which a stimulus is applied, it will be found that
the contraction wave moves throughout the entire length. If after a
certain interval of time a second stimulus is applied, the resultant
wave moves along the muscle but does not necessarily homotopically
interfere with the first. In short, there are two waves of contraction
occurring coincidently in the muscle, the muscle is now more strongly
contracted. _Fröhlich_[189] has made the fact intelligible by this
means that tetanic shortening of a muscle is greater than that of
maximal shortening which can be produced by strong single stimulation.
This heterotopic interference dare not be overlooked in the genesis
of muscle tonus. If it is true, as appears from the investigations of
_Keith Lucas_,[190] that the “all or none law” applies to striated
muscle, then an increase of the contraction from homotopic summation
cannot occur, because an isobolic system cannot show an increase of its
already maximal excitation by summation. Such being the case, the tonic
shortening of striated muscle can only be explained as an expression of
a heterotopic interference.

  [188] _Thörner_: “Weitere Untersuchungen über die Ermüdung des
  markhaltigen Nerven. Die Ermüdung in Luft.” Zeitschr. f. allgem.
  Physiologie Bd. X, 1910.

  [189] _Fr. W. Fröhlich_: “Ueber die scheinbare Steigerung,” etc.
  Zeitschr. f. allgem. Physiol. Bd. V, 1905.

  [190] _Keith Lucas_: “On the gradation of activity in a skeletal
  muscle fiber.” Journ. of Physiology, Vol. XXXIII, 1905–06. The same:
  “The all or none law of contraction of the skeletal muscle-fiber.”
  Journ. of Physiology, Vol. XXXIII, 1909.

If we assume that the summation of sub-threshold stimulation, by
increasing excitation, brings about a state of equilibrium from below,
as it were, so also inhibition may be assumed to be the reverse, the
level of equilibrium being reached from above, as it were, by decrease
of the primary excitation from strong stimulation. This is expressed
in our general scheme of the development of summation and inhibition
resulting from the effect of a series of stimuli. At the same time
the first part of the curve to the fall of irritation to the level
of the sub-threshold equilibrium can be shortened to a minimum by
strong stimulation or greater frequency of the same, and we have then
the type of _inhibition with primary excitation_. As example of this
I wish to again recall the strychninized frog which was used in the
fundamental experiments for understanding of the theory of inhibition.
If we stimulate a sensory nerve of a strychninized frog, in which
the refractory period is already lengthened, with rhythmic single
induction shocks of slow frequency, the muscle arranged to make a
graphic record will show reflex contraction following each stimulus.
If, on the other hand, we apply a series of stimuli, consisting of
single stimuli rapidly repeated, contraction is produced only by the
first, or the first few stimuli (Figures 45 and 46, pages 202, 203).
For the succeeding stimuli the centers remain inhibited, because each
succeeding stimulus occurs in the refractory period of the former.
The origin of this inhibition shows us with particular clearness
how excitation produced by each single stimulus depending upon the
frequency of the same, falls rapidly or slowly beneath the threshold of
perceptible response. In this case, the state of equilibrium is reached
which is maintained by the following stimuli. That a single stimulus is
not entirely without effect upon this state of equilibrium follows from
the fact that during the continuation of the stimulus a recovery to the
point of observable response does not occur, whereas such is the case
immediately upon the discontinuation of the stimulus. In inhibition,
then, the dissimilatory excitation produced by a single stimulus falls
to a low level as a result of the reduction of irritability and remains
at this level continuously. _Inhibition as well as tonus is based
upon the development of a state of equilibrium between excitation and
recovery, or disintegration and restitution of the living substance
under the continuous effect of a rhythmic series of stimuli. They
differentiate themselves essentially by the height of this equilibrium,
which is dependent upon the intensity of the stimulus._

We have to the present considered only the _simplest_ conditions
existing as a result of the effect of a _single_ series of stimuli and
also of the interference of its individual members. These elementary
conditions are at the basis of an understanding of complicated
_interference effects which arise when two series of stimuli interact_.
In that these processes can be readily explained by the elementary
processes previously described, I will, therefore, dwell but briefly
on this subject. From the standpoint already taken it may be readily
presumed what will happen when two series of stimuli act upon the same
system.

When there is interference of _two series of stimuli_, there are
two resultant possibilities. In one type the stimuli of the one are
active simultaneously with that of the other. In this instance both
stimuli would act as a single stimulus of greater intensity, and we
have essentially the same condition as exists when a single series is
operative. Nevertheless, such cases are practically hardly realized
in the physiological happenings of the organism. More often a state
exists wherein the single stimuli of one series occur in the intervals
of the stimuli of the other. In these cases there is an increase in
the frequency of the stimuli applied in a given length of time. We
have here, then, in principle the same conditions as when a series
of greater frequency is operative. (Figure 55.) The effect of such
alteration in the frequency consists in an increase of the velocity
of the development of summation or inhibition, as the general scheme
(Figure 55) has shown us. Depending upon the special combination
of the factors involved in interference, we may have a summation
of the exciting effect of each series of stimuli or an inhibition
of one series by the exciting effects of the other series. If the
frequency of both series is essentially different, we may have here
the conditions for periodically increasing and decreasing excitations.
Nevertheless these conditions have not been systematically analyzed and
experimentally studied.

[Illustration: A B

Fig. 55.

Interference of two series of stimuli. A--Effect of the one series
alone. Development of tonus by summation. The dots below the curve
indicate the points of time at which the stimuli of the second series
will operate. B--Effect resulting from the interference of both series.
By the addition of the second series the frequency has been doubled.
The result consists in an inhibition. ]

The greatest number of instances of the interference of two series
of stimuli have been given to us by investigation of the physiology
of the nervous system. In the functionation of the nervous system
the fact that two series of stimuli from different tracks affect
the same ganglia plays a very important rôle. It is this to which
_Sherrington_[191] has alluded as “_the principle of the common path_.”
Where two nervous excitations involve the same paths, there arises
an interference of the effect of the two series of stimuli, for the
impulses in the nervous system, as already stated, possess a rhythmic
character. This principle has a broad application in the phenomena of
association in the cerebral cortex. The simpler and, therefore, the
most easily understood cases are, however, in the spinal cord. The
motor neurons of the anterior horns of the spinal cord are the junction
of a great number of tracks, for example, the sensory neurons of the
spinal cord at different levels, the neurons of the cerebellum, the
pyramidal tracks from the motor areas of the cerebral cortex, etc.
On the contrary, for example, the sensory neurons of the spinal cord
are strictly “_private_ paths” in the sense of _Sherrington_, for
excitation can enter by this means only from the special paths of the
spinal ganglia and, therefore, from the periphery. The motor neurons
of the anterior horns offer, therefore, excellent opportunities for
the experimental investigation of the interference of two series
of excitations which enter by different paths. The spinal cord
consequently has become a much-used object of investigation for this
purpose. In fact, we can observe and produce all types of interference
in the spinal cord. These conditions have been quite thoroughly
investigated by _Sherrington_[192] and his coworkers on the dog, and
_Fröhlich_,[193] _Vészi_,[194] _Tiedemann_[195] and _Satake_[196] on
the frog.

  [191] _Sherrington_: “Ueber das Zusammenwirken der Rückenmarksreflexe
  and das Princip der gemeinsamen Strecke.” Ergebnisse der Physiologie.
  Jahr. IV, 1905.

  [192] _Sherrington_: “The integrative action of the nervous system.”
  New York 1906.

  [193] _Fr. W. Fröhlich_: “Der Mechanismus der nervösen
  Hemmungsvorgänge.” Med. Natur. Arch. Bd. I, 1907. The same: “Beiträge
  zur Analyse der Reflexfunction des Rückenmarks, etc.” Zeitschr.
  f. allgem. Physiologie Bd. IX, 1909. The same: “Das Princip der
  scheinbaren Erregbarkeitssteigerung.” _Ibid._

  [194] _Julius Vészi_: “Der einfachste Reflexbogen im Rückenmark.”
  Zeitschr. für allgem. Physiol. Bd. IX, 1910.

  [195] _Tiedemann_: “Untersuchungen über das absolute Refractärstadium
  und die Hemmungsvorgänge im Rückenmark des Strychninfrosches.”
  Zeitschr. f. allgem. Physiologie Bd. X, 1910.

  [196] _Satake_: The researches are not yet published.

A _summation of two excitations_ was observed already by _Exner_. This
investigator connected the abductor pollicis of the rabbit with an
apparatus for making graphic records. He then stimulated first the paw
and then the motor areas of the cerebral cortex with faradic shocks,
the intensity of which was just sufficient to bring about perceptible
effect. If both stimuli were simultaneously operative, an increase in
the response was observed. Even when the stimuli were sub-threshold
in type, as a result of summation there was a perceptible muscle
contraction. (Figure 56.) _Exner_ had at that time referred to this
increase of the response as “Bahnung” (reinforcement). However, the
word “Bahnung” has more than one meaning, for processes of various
types are involved in this term. Thus writers have differentiated real
and apparent “Bahnungen.” On account of this lack of clearness in the
meaning of the term “Bahnung,” I wish to discard its use as it is not
at all essential. We will speak simply of a _summation of excitation_,
for here it is simply a question of summation of two excitations of the
motor cells of the spinal cord.

[Illustration: Fig. 56.

Summation of two excitations in the rabbit. The one proceeds from the
paw, the other from the motor sphere of the cerebral cortex. _S_--Time
in seconds. _Pf_--Stimulation of the paw. _H_--Stimulation of the motor
sphere. _M_--Contractions of the abductor pollicis. (After _Exner_.) ]

_Fröhlich_ has shown that summation of two excitations upon a motor
cell of the anterior horn coming by way of different paths is more
readily obtained when the stimuli are somewhat strong, or when the
duration of the excitation processes in the ganglion cells are somewhat
prolonged by fatigue.

[Illustration: A B

Fig. 57.

Summation of two excitations in the spinal cord produced by stimulation
of the ninth and tenth posterior root. Lower line indicates faradic
stimulation of the tenth, upper line of the ninth root. ]

[Illustration: A B

Fig. 58.]

[Illustration: Fig. 59.]

On the other hand, the conditions for the production of _inhibition_
are favored when the intensity of the series of stimuli is weak. Here
it is a question of the development of a relative refractory period for
the weak stimuli by increase in their frequency. A relative fatigue of
the motor ganglion cells for weak stimuli rapidly occurs, and there
develops a state of equilibrium beneath that of the threshold of
perceptible effect throughout the continuation of stimulation. _Vészi_
succeeded in isolating these types of summation and inhibition in the
spinal cord. His method consisted in cutting the posterior roots of
the spinal cord of the frog and stimulating faradically the central
ends, and at the same time graphically recording the response of the
gastrocnemius muscle. Upon faradic stimulation of the ninth posterior
root, one obtains tetanic reflex contraction of this muscle. When the
tenth posterior root is then stimulated, tetanus is also produced but
of somewhat shorter duration. If, while obtaining tetanus reflexly by
stimulation of the ninth root, a faradic current of short duration
and not too weak is applied to the tenth root, then a summation of
excitation occurs, an increase in the reflex contraction. (Figure
57, A and B.) When, on the other hand, the tenth root is stimulated
with weak shocks, one can obtain an increase of the tetanus of short
duration followed by inhibition. Here, as the result of interference,
we have an instance of inhibition with primary tetanus. (Figure 58.)
When the tenth root is stimulated with very weak shocks, inhibition
of the tetanus produced simultaneously from the ninth root occurs
without primary summation. (Figure 59.) The fact that two series of
stimuli, both of which produce dissimilative excitation, bring about
an inhibition by their combined action, is sufficient to show the
untenability of the _Gaskell-Hering_ hypothesis, that inhibitory
processes result from assimilatory excitation. It would be impossible
to understand how two dissimilatory exciting stimuli, by their
simultaneous action, could bring about assimilatory excitation. When
the eighth or the seventh root is stimulated with stronger faradic
shocks during the time when tetanus is produced reflexly by faradic
stimulation of the ninth, an inhibition is practically always obtained.
Indeed, faradic currents that are so weak as to be _far_ below the
threshold of perceptible response bring about when applied to the
seventh or eighth root a decided inhibition of the tetanus, brought
about by simultaneous stimulation of the ninth root. The inhibitory
effect of weak sub-threshold excitations are here particularly
apparent. This inhibition resulting from excitation far below that of
the threshold of perceptible response is a common occurrence in the
functional activities of the central nervous system. In various parts
of the nervous system, the excitation in its conduction is weakened
when passing through intervening ganglion stations so that it has
undergone a strong decrement before reaching the responding structure,
where an inhibitory effect may be manifested. In this connection it is
of interest that the reciprocal “antagonistic reflexes” discovered by
_Sherrington_,[197] who recognized their importance in the functional
processes of the nervous system, can be explained, as _Fröhlich_
showed, upon this principle of inhibition resulting from weakened
excitation. On the basis of numerous investigations in the Göttingen
laboratory as well as that of Bonn[198] we have come to look upon the
reflex arc in the spinal cord as consisting of the following elements:
a neurone in the spinal ganglion, a neurone in the posterior horn and
a motor neurone in the anterior horn. This is the most direct route
between the point of stimulation and that of the responding organ of
a unilateral reflex. (Figure 60.) It is known that the excitation
becomes weaker in passing from the entrance of the excitation into
the spinal cord to the motor elements of a lower level on the same
side or to those on the opposite side. In order to obtain a response a
stronger stimulus is necessary. Here the weakening of the excitation
as well as the prolongation of the reaction time is brought about by
the introduction of intercalated neurones. The reflex arc contains
more stations. (Figure 61.) If we accept the most plausible assumption
that the central connection of antagonistic muscles possesses
like relations, then the effects discovered by _Sherrington_ are
self-explanatory. In this case stimulation of the sensory path, which
brings about a strong reflex excitation of the motor neurons of the
anterior horns controlling a muscle, at the same time stimulates
the antagonistic muscle with sub-threshold stimuli. The result of
this as shown by the experiments of _Vészi_ is not a motor response
of the antagonists, but an inhibition if the motor neurons of the
antagonists are at the time in a state of excitation. It is, therefore,
understandable that reflex excitation of a muscle under normal
conditions of irritability has an inhibitory effect on its antagonist.

  [197] _Sherrington_: “Experimental note on two movements of the
  eye.” Journ. of Physiology XVII, 1895. The same: “On the reciprocal
  Innervation of antagonistic muscles.” Proceed. of the Royal Soc.,
  1897.

  [198] _Max Verworn_: “Die einfachsten Reflexwege im Rückenmark.”
  Zentralblatt f. Physiologie Bd. XXIII. _Tiedemann_: “Untersuchungen
  über das absolute Refractärstadium und die Hemmungsvorgänge im
  Rückenmark des Strychninfrosches.” Zeitschr. f. allgem. Physiologie
  Bd. X, 1910. _Julius Vészi_: “Der einfachste Reflexbogen im
  Rückenmark.” Zeitschr. f. allgem. Physiologie Bd. XI, 1910. _Oinuma_:
  “Ueber die asphyktische Lähmung des Rückenmarks strychninisierter
  Frösche.” Zeitschr. f. allgem. Physiol. Bd. XII, 1911. _Satake_: Not
  yet published.

[Illustration: Fig. 60.

Scheme of the simplest unilateral reflex arc of the spinal cord.]

[Illustration: Fig. 61.

Scheme of the simplest reflex arc from one to the other side, and from
a higher to a lower level.]

Finally, I wish to conclude this discussion on the origin of central
inhibition and its dependence upon the strength of the stimulus by
referring to a point which apparently is contradictory. We have already
met with the fact that series of stimuli by their interference in
the nervous system may have different effects depending upon their
intensity; if this is strong, we obtain summation of excitation, if
weak an inhibition. The question may be asked, how is it possible
that a weak stimulus can have a different effect when it is believed
that the nerve as an isobolic system responds to intensities of all
gradations to the same extent, namely, with maximum excitation? If the
“all or none law” is applicable, then the same intensity of excitation
is always carried to the centers and yet we see that various kinds of
responses follow various intensities of stimulation. Here, indeed, is a
difficulty which has not as yet been explained. Naturally between the
two facts there can be no contradiction. But the question arises, how
are we to bring them into harmony? Two entirely different possibilities
present themselves. If the various intensities of stimulation always
bring about excitation of the same strength and we see in spite of
this that various intensities of stimulation produce various kinds of
effects, then we must think of the possibility that various intensities
of stimulation bring about some other effect than that of variations in
intensity in the course of the wave of excitation. In this connection
variations in the time involved must be taken into consideration.
One might think that _strong_ stimuli may develop a longer wave of
excitation than such of _weak_ intensity. _Gotch_[199] tested these
questions experimentally with completely negative results. A single
strong stimulus does not result in an excitation differing in its
course from that of a weak stimulus. But there is another possibility
that requires testing. This was brought to light by the investigation
of _Thörner_[200] on the fatigue of the nerve. His investigations
showed that in a normal nerve in air the first typical beginning of
fatigue resulting from faradic stimulation can be demonstrated in the
characteristic summation of excitations. This is shown by the nerve
after fifteen minutes of stimulation with faradic shocks applied for
short intervals. The irritability, when tested with single induction
shocks, is at the same time reduced. Thereby the amount of fatigue of
the nerve, that is, the amount of the reduction of irritability, is
dependent upon the strength and frequency of stimulation producing
fatigue. When the nerve is stimulated with weak faradic shocks of a
slow rate of frequency, there is a slight or a complete absence of the
reduction of irritability. On the other hand, if the nerve is fatigued
with strong faradic shocks of great frequency, the irritability falls
very considerably. This shows that when the nerve is stimulated for a
longer time, even under conditions favorable to the supply of oxygen,
a diminution of irritability occurs and with it naturally an actual
diminution of the wave of excitation, a diminution the intensity of
which becomes greater as the strength of the stimulus increases. In
other words, long-continued faradic stimulation converts the nerve
from a system isobolic in character to that which is heterobolic
in that the intensity of the excitation which is conducted differs
depending upon the intensity of the stimulus. We have found other cases
in the investigation of the nervous system in which, as in fatigue,
an isobolic is converted into a heterobolic system. _Vészi_[201] has
shown that the centers of the strychninized frog, which are isobolic
in character, when fatigued by _weak_ faradic stimuli can be brought
to react again when the faradic stimulation is increased. According
to this and other experiments of a like nature, it is beyond doubt
that an isobolic system during the refractory period may assume a
heterobolic character, and only after completion of the refractory
period and entire recovery of the equilibrium of metabolism does
the isobolic character return. This permits us to understand the
characteristic properties of an isobolic system more accurately and
precisely than has thus far been possible. The “all or none law” with
its associated properties, such as the conductivity without decrement
and the incapability of summating excitations, have in a system of this
character only relative validity. They are realized only in the state
of an equilibrium of metabolism. Only when the stimuli follow each
other at intervals greater than the duration of the refractory period
is there a response of equal extent to stimuli of all intensities which
are above the threshold. During the refractory period and consequently
in fatigue, asphyxia, cooling and narcosis, etc., in short, in all
states in which the refractory period is prolonged this system loses
its isobolic properties and becomes heterobolic. In order that there
may not be a misunderstanding, we will consider more in detail the
capability in this state of summation of excitations. When we refer
to a summation of excitation of such a system under the influence of
one of these factors, we, of course, at no time mean an increase of
response beyond that of the degree of excitation which exists in an
isobolic system in a normal state consequent upon the application of
a single stimulus, for this degree of excitation is maximal. We refer
rather to a summation which has become reduced as a result of fatigue.

  [199] _Gotch_: “The submaximal electrical response of nerve to a
  single stimulus.” Journ. of Physiology, Vol. XXVIII, 1902.

  [200] _Thörner_: “Weitere Untersuchungen über die Ermüdung des
  markhaltigen Nerven: Die Ermüdung in Luft,” etc. Zeitschr. f. allgem.
  Physiologie Bd. X, 1910.

  [201] _Vészi_: “Zur Frage des Alles oder Nichtsgetzes beim
  Strychninfrosche.” Zeitschr. f. allgem. Physiologie Bd. XII, 1911.

On the basis of these facts it is readily understood when a level
of equilibrium of lower intensity has been reached that excitation
produced by weak faradic stimulation must have weaker effects than when
strong stimuli are applied, for when the system assumes a heterobolic
type as the result of relative fatigue weak stimuli bring about weak,
and strong, stronger excitation. Consequently, during interference
induced by a second series of excitations, in the first case we have
the conditions favorable for inhibition, in the second for those of
summation. If we also assume that this characteristic alteration of
the isobolic character of the elementary nerve fibers which has been
shown to occur in fatigue, as seen when continued faradic stimulation
is employed, develops immediately after the beginning of stimulation
then we can readily understand the various kinds of effects produced
by interference observed in the reflex response following weak and
strong faradic stimulation to the different nerves in spite of the
fact that the nerve in the state of rest is a system isobolic in type.
Experimental evidence, therefore, must be brought forward to show that
faradic stimulation of short duration produces the above-mentioned
alteration in the character of the system. _Thörner_ in his experiments
on the nerve stimulated it faradically at least four minutes and always
found after this that excitation was reduced. After shorter intervals
of stimulation _Thörner_ made no test of the state of excitation. It
is, however, highly probable that a reduction of excitation is much
more quickly reached. Indeed, we are unavoidably compelled to accept
the assumption that even after the first single stimulus of the faradic
current, alterations of a slight degree are present which, after
repeated stimulation, become constantly greater and give to the system
a heterobolic character. As a result of fatigue, as we have already
seen, the refractory period becomes more and more prolonged. As the
individual shocks in faradic stimulation follow each other at regular
intervals, a necessary consequence is that the shocks are operative
before the refractory period has completely disappeared, otherwise
_Thörner_ could not have obtained fatigue produced by continued
stimulation. The intervals of the individual shocks must be somewhat
shorter than the duration of the refractory period, even in fatigue
of a very slight degree. It is very interesting in this connection
that _Thörner_ invariably obtained positive evidences of fatigue by
the application of stimuli at the rate of 10–12 per second. When the
number of stimuli per second was less than this the above-mentioned
result was not always obtained. From this we can easily estimate the
refractory period of the nerve, which is present after reaching a state
of equilibrium under certain conditions. If we assume ten stimuli
per second to be the number required to produce slight fatigue when
stimulation is prolonged, we can conclude that the refractory period in
this state is somewhat longer than one tenth of a second. Even though
_Gotch_ in his investigations already cited placed the refractory
period of the normal nerve at about .005 second, this statement is in
no way contradictory to the figure which we have just given. _Gotch_
measured simply the duration of the absolute refractory period of
the normal nerve, in other words, the duration of the period in
which no excitation at all could be brought about. On the contrary,
my estimate, based upon the investigations of _Thörner_, refers to
the _total_ refractory period of the nerve, that is, to the point
of _complete_ recovery of the equilibrium of metabolism and of the
specific irritability. Experimental proof of this assumption is already
under way.

I have endeavored to show the elementary principles at the basis
of these extremely varied interference effects and to make a few
generalizations concerning the complicated conditions here concerned.
It has been shown that a great number of interference effects possess
characteristics in common if one takes into consideration the process
occurring in the course of a single excitation. The altered state
which exists in living substance until the complete disappearance of
excitation is the basis upon which to explain the altered effects
produced by a second stimulus. This state alters during the whole
course of the first stimulus until the original equilibrium of the
metabolism of rest is, by self-regulation, again reached. It is,
therefore, self-evident that the second stimulus must have different
effects depending upon the momentary state of the living system at the
time of its application. The state of the system differs depending on
the length of the interval in which the second stimulation follows the
first. The most important factor is the phase of the excitation period
and the reduction of irritability. The second important factor is the
intensity of the second stimulus; the relation of the two with each
other determines the response. But the specific properties of the given
systems must also be taken into consideration. It is important to know
if the living system possesses isobolic properties, that is, every
intensity of stimulation produces a _maximal_ liberation of energy, or
if it possesses a heterobolic character, that is, stimuli of different
strength bring about the liberation of _different_ amounts of energy.
It is further important to know the rapidity of reaction, whether the
system rapidly or slowly fatigues. In all cases it depends whether the
second stimulus produces a perceptible excitation or whether it occurs
in the refractory period and produces no perceptible effect. Upon
these factors depend the results of the interference of two rhythmic
series of stimuli, whether a summation or inhibition of excitation
takes place. Here is the key to the understanding of the great variety
of interference effects. By determination of these various factors in
a given case and their sequence, we can anticipate the nature of the
interference which will follow. The complex actions brought about by
the various factors, which we cannot at first clearly understand, can
be at once interpreted as soon as we convert them into their elements.




CHAPTER IX

THE PROCESSES OF DEPRESSION

 _Contents_: Necessity of cellular physiological analysis of toxic
 depressions by pharmacology. Apparent variety of processes of
 depression. Depression of oxydative disintegration as the most
 extended principle in the processes of depression. Asphyxiation,
 fatigue, heat depression, as a consequence of restriction of oxydative
 disintegration. Narcosis. Theories of narcosis. The alteration of
 specific irritability and conductivity in narcosis. Depression of
 oxydative processes in narcosis. Asphyxiation of living substance
 when oxygen is present during narcosis. Persistence of anoxydative
 disintegration in narcosis. Increase of the same by stimuli.
 Depression by narcosis as a form of acute asphyxiation. Hypothesis
 on the mechanism of depression of oxygen exchange by narcotics.
 Possibility of combining the facts with the observations of _Meyer_
 and _Overton_.


The processes of _excitation_ of all the effects of stimulation
are those which have invariably claimed place in the interest of
physiologists. The study of the processes of _depression_, on the other
hand, has remained more or less in the background. This is readily
understood when it is considered how much more apparent the processes
of excitation are than those of depression. Nevertheless, these latter
possess no less importance for the course of vital phenomena than
those of excitation. Without depression no excitation can take place
in the vital activity of the organism, for, as we have seen, every
excitation is secondarily followed by a refractory period. To this
must be added the great number of _primary_ depressions, directly
brought about by the most varied stimuli, such as cold, want of oxygen,
poisons, etc., without the presence of a preceding excitation. Thus
it is essential that the processes of depression should be studied
with no less interest than those of excitation, and it is much to be
desired that the former should receive a more detailed analysis than
has up to now been the case. Even as it is, extensive material has
been obtained for the analysis of this group of reactions. With the
closer study of the process of excitation the facts in connection with
the refractory period and fatigue make it necessary that the processes
of depression be taken into consideration. Toxicology and pharmacology
likewise furnish innumerable effects of depression produced by poisons
and drugs. Unfortunately the investigation of these reactions has
been in the main purely superficial. This arises from the recency of
the development of these sciences. Even later than physiology they
are only now beginning to extend their investigations, directed up
to the present to the grosser organic reactions, to the cellular
analysis of the effects of poisons. How rarely we find instances in
which the effect of some drug is studied at the point of attack and
systematically followed to the specific cell form, and its primary
excitating or depressing effect on this or that constituent process
of the metabolic activities ascertained. And how great, on the other
hand, is the number of “medicines” making their appearance each year
in pharmacology of which nothing further is known than a few secondary
effects on the action of the heart, the blood pressure, the secretion
and excretion and on some other outwardly perceptible organic actions!
This deplorable condition of present-day pharmacology must be ascribed
to the regrettable circumstances that pharmacological research is only
in a very small degree the result of careful investigations, carried
out by biologically and chemically trained pharmacologists, but is for
the most part undertaken at the instigation of chemical manufacturers.
This eager haste to obtain superficially practical results has lessened
in great degree the interest in the close and painstaking theoretical
analysis of reaction to poisons. Thus it happens that, in spite of the
numberless examples of the depressing effects of poisons discovered by
pharmacologists, it is only in rare instances that the physical nature
of these processes is more closely studied. Therefore, investigation
in pharmacology and toxicology in so far as they are carried out in a
purely scientific spirit and not influenced by the desire for merely
superficial results, may find here a wide field of research work, rich
in future promise. It is from such investigation that we may expect
an abundance of material for the closer analysis of the processes of
depression. For the present, however, we must restrict ourselves to the
consideration of some individual cases which have been studied somewhat
more in detail by physiologists.

Simple reflection shows the possibility that depression, that is,
the retardation of the normal vital processes, can be brought about
in various ways. As on the one hand the normal metabolism of rest is
composed of very numerous chemical constituent processes, and on the
other hand the closest interdependence exists between these individual
constituent processes, it follows that every factor which increases
or retards even one of these must secondarily influence the course of
the entire activity. Hence a wide range of possibilities exists for
the processes of depression. As the complicated works of a clock can,
by the stopping of a single moving part, be brought to a standstill,
so in like manner the metabolic activity can be depressed by very
different constituent members. In spite of this we have every reason to
assume that the greater number of all processes of depression result
from the primary effect of one or a few constituent members. A primary
simultaneous depression of all or at least of numerous constituent
processes of the entire metabolism may only be assumed as possible,
resulting from decrease of temperature within certain limits. But
even in the case of “_cold depression_” it is not probable, owing to
the great effect of every alteration in the relations of masses in
the cell, that depression is solely the manifestation of a _uniform_
retardation of all individual constituent metabolic processes. If,
therefore, the greater part of the processes of depression are brought
about by the primary effects of an individual constituent process,
then the possibility must be admitted that _any_ component of the
chain can by the means of some specific external influence form the
starting point for a depression. The number of the various kinds of
processes of depression would be, therefore, enormous. The knowledge
obtained up to the present shows, however, that this variety is not
quite as great as the above facts might lead one to expect. Even
though future investigation will certainly not do away with the
assumption of the existence of the most manifold physical types of
depression, the analysis of a few processes which have been studied
up to now demonstrates the singular fact that a number of these which
are brought about by quite different external factors, are based on
an absolute uniformity of their mechanism. As we have previously
seen, a certain constituent of the metabolic chain can be _excitated_
primarily by very different kinds of stimuli. In like manner there
exists in metabolic activity a certain point of predilection for
different kinds of stimuli, from which their _depressing_ effects
proceed. Here the highly interesting fact is shown that this point of
predilection, which represents that of the most frequent attack, is
the same for _excitating_ as for _depressing_ stimuli. These are the
_oxydative_ processes. As our knowledge of the reactions to stimuli in
anaërobic organisms is still almost nil it is not possible at present
to ascertain which component in the metabolism of these organisms,
adapted to life without oxygen, plays an analogous rôle to that of the
oxydative in aërobic systems. Our investigations must, therefore, be
restricted to the world of aërobic organisms. Here we have seen that
the different stimuli which produce an excitating effect invariably
increase the oxydative disintegration of the living system and we now
find that these constituent processes of metabolism likewise form a
point from which _depressing_ responses to stimuli very readily proceed.

The prototype of this group of processes of depression in which
this is manifested in a most striking manner, is that of a simple
_asphyxiation_ by the withdrawal of the oxygen supply from the
exterior. If the supply of oxygen is withheld from an aërobic organism,
oxydative disintegration is gradually found to be more and more
decreased and further breaking down takes place _an_oxydatively, as
oxydative decomposition forms the chief source of energy production,
and energy production consequently undergoes a gradual decrease.
Excitating stimuli, therefore, meet with less response than when a
sufficient supply of oxygen is present, that is, _irritability is
diminished_. As a result of this decrease, a corresponding decrement
in the extension of excitation takes place, which, in turn, is
likewise manifested by the restriction of the perceptible response
to stimulation. In the same degree in which oxydative disintegration
becomes less, _an_oxydative breaking down products are accumulated.
The accumulation of these products likewise plays a part in the
production of depression and increases the decrement in the conduction
of excitation. The decrease of energy production by decline of the
oxydative decomposition, as well as the accumulation of anoxydative
breaking down products, therefore, similarly reduce irritability;
that is, their effect is depressing. This whole series of processes,
which we have previously considered in detail, takes place on the
withdrawal of oxygen and leads to the depression of asphyxiation. It
can readily be observed in the most varied kinds of aërobic organisms
in rhizopods and infusoria, in plant and ganglion cells, but finds its
most complete demonstration in the nerves. Here these processes can be
easily produced with any rapidity desired, accordingly as a relative
or absolute want of oxygen is brought about. These same typical
results are likewise shown in numerous processes in which the external
conditions are quite different in nature.

We have previously become acquainted with such a case and studied
it in detail. This is the state of _fatigue_. Fatigue is a typical
state of depression, that is, a state in which the vital process is
retarded and irritability in response to stimuli correspondingly
decreased. Fatigue is, however, as we have found, the result of a
relative deficiency of oxygen. The amount of oxygen at disposal is not
sufficient to allow of disintegration, increased by constant functional
activity oxydatively taking place, to develop to its full extent. In
consequence the previously cited sequence of processes takes place. A
“depression of activity” is produced. Fatigue is true asphyxiation and
it is here evident that depression proceeds from the same constituent
processes of metabolism as excitation, brought about by a single
stimulus. Excitation produced by constant stimuli gradually merges
into depression as the amount of oxygen at disposal, even if augmented
in the intact organism by the increased blood supply, for instance,
is still insufficient to meet the demand made by the increased oxygen
consumption as a result of continuous functional activity.

A further very interesting example of depression produced by oxygen
deficiency is furnished by _heat depression_. It has long been known
that with increasing temperature the vital manifestations of all
poikilothermic organisms at first undergo a heightening of their
intensity. If, however, after a maximum is reached, the temperature is
still further increased a sudden depression sets in. The increase in
the rapidity of the vital process as a result of increased temperature
is readily understood when based on the well-known law discovered by
_van’t Hoff_. Numerous investigations on the rapidity of the course of
special vital manifestations, as, for instance the growth of the eggs
of the frog and sea urchin, the assimilation of carbon dioxide in green
plant cells, the number of vacuole pulsations in the infusoria cells,
the frequency of the heart rate of the frog and of the mammal, etc.,
have shown that their increase does in fact follow the _van’t Hoff_
law, being doubled or tripled in amount with every increase of ten
degrees of temperature. The genesis of depression produced by _heat_,
developed in different organisms at various heights of temperature,
requires a closer analysis. This depression takes place at temperatures
below that in which coagulation of proteins occurs. Therefore, under
certain conditions, with which we shall presently become acquainted, it
is capable of being recovered from, whereas in higher temperatures, in
which albumen coagulates, vital activity is permanently obliterated.
Depression produced by heat is, therefore, in itself not a necrobiotic
process, which, as such, must necessarily lead to death. But rather
like fatigue it must be looked upon as an asphyxiation process.
Its relations to oxygen exchange have been chiefly demonstrated by
_Winterstein_[202] by his investigations on the central nervous system
of frogs and on medusæ. He found that when placed in a heated chamber
in a temperature of 32–40° the activity and reflex excitability of
the frog are at first augmented. Within the lapse of a short time
this increase has become so great that the slightest touch produces
tetanic contractions, similar to those characteristic of strychnine
poisoning. Very soon, however, this state of high excitation is
followed by one of depression, in which no response to stimuli can be
obtained. The animal remains entirely motionless in any position in
which it is placed, in the same manner as a frog whose nerve centers
have been completely exhausted by strenuous activity. On the basis
of our knowledge of the rôle played by the deficiency of oxygen in
the bringing about of exhaustion the thought arose, if in this heat
depression exhaustion might not likewise be the result of oxygen
deficiency. This assumption has been most strikingly confirmed by the
investigations of _Winterstein_. It has been demonstrated that recovery
of the animal in a state of heat depression cannot be obtained by mere
cooling, but is only brought about when at the same time a renewed
oxygen supply is provided. For instance, a frog is depressed in the
warm chamber and even when a strychnine injection has been introduced,
does not show the slightest reaction to stimuli. In the warm water
bath artificial circulation is now applied in the previously described
manner with an oxygen-free saline solution at 30° C., so that the blood
is displaced and thus the renewed oxygen supply to the nervous centers
prevented. The animal can now be cooled and the warm saline solution
be replaced by a cooled one without the least recovery taking place.
If, however, blood of the ox with contained oxygen is substituted for
the oxygen-free saline solution, the frog shows signs of recovery
within a few minutes and after ten or fifteen minutes responds as a
result of the strychnine to the merest touch with tetanic contractions
of the whole body. By modifying these methods of investigation to a
certain extent _Bondy_[203] has confirmed these results to the fullest
extent. Later _Winterstein_ by quantitative determinations of oxygen
consumption on medusæ showed that at 30–35° C., at which temperature
heat depression sets in, the consumption of oxygen shows an increase
of about three and a half times compared to that in a temperature of
11–12° C. These facts show that we have in heat depression a process
which, as far as its genesis is concerned, is completely analogous to
that of fatigue. In fatigue, a relative want of oxygen is produced
by the increased consumption following functional activity, in heat
depression by the increase of the entire metabolism producing a
corresponding increase of oxygen requirement. In both instances we have
an excitation produced by external stimuli which result in an increase
in the amount of oxygen required, and in both instances the oxygen at
disposal is not sufficient to permanently meet the augmented demand.
In both types, therefore, decomposition must become more and more
anoxydative and the well-known series of processes is developed, which
find their expression in depression.

  [202] _H. Winterstein_: “Ueber die Wirkung der Wärme auf den Biotonus
  der Nervenzentren.” Zeitschr. f. allgem. Physiol. Bd. I, 1902. The
  same: “Wärmelähmung und Narkose.” _Ibid._

  [203] _Oskar Bondy_: “Untersuchungen über die
  Sauerstoffaufspeicherung in den Nervenzentren.” Zeitschr. f. allgem.
  Physiol. Bd. II, 1904.

In another direction likewise heat depression is of special interest,
that is, in regard to the theory of nature of the processes in the
living substance. According to the _van’t Hoff_ law we may assume that
every individual constituent metabolic process, if we imagine it as
isolated and taking place in a test tube, undergoes in more or less the
same degree as all others an increased rapidity of reaction as a result
of increased temperature. At the same time, in living substance we
find on the contrary that the _van’t Hoff_ law is only within certain
narrow limits more or less applicable to the sum total of all metabolic
processes. Beyond certain degrees of temperature no further increase
of the vital process takes place, instead a retardation occurs. The
analysis of depression produced by heat shows us in the clearest and
simplest manner the reason for this apparent deviation from the general
law of _van’t Hoff_. This reasoning is based on the fact that the
rapidity of reaction of a chemical process is not merely dependent upon
the temperature, but likewise upon the mass relations of the reacting
substances. In spite of the effect of the temperature in increasing
the rapidity of reactions, the process undergoes retardation which
extends to a complete cessation if the supply of material necessary
to its existence does not keep pace with the increase produced by
temperature. In the present instance the amount of reserve supplies for
the building up of the disintegrating molecules exists in abundance,
and it is merely the available oxygen which is in relatively a very
small quantity. As soon, however, as metabolism in its entirety, or
even merely in those parts in which oxygen is directly required, is
increased by whatever means, the oxydative processes would be the
first to fail and it must be from this point that the disturbance of
the harmony in the interacting of the individual metabolic processes
proceeds. This principle which we here see manifested in its simplest
form in the effect of temperature on oxygen exchange in the form of a
disturbance in the correlations of the individual constituent processes
based on an alteration of the mass relation and the rapidity of
reactions of individual members is, however, not merely restricted to
effects of temperature and the results quickly following on a relative
oxygen deficiency. It has, indeed, a much more general significance for
all manner of constituent metabolic processes, for it is applicable to
all nutrition and to all growth, and forms one of the most important
factors which influence the process of development, that is, the
gradual “metachronic” alterations in metabolism to which all living
systems are subjected as long as life endures.

A very extensive group of depression processes is produced by the
action of chemical stimuli. Among these the processes to which we apply
the collective term of “_narcosis_” must claim our special interest.
As is well known, an enormous number of substances of very different
chemical nature, such as carbon dioxide, alcohol, ether, chloroform,
chloral hydrate, etc., exist, which, possessing the property of
producing cessation of the vital activities in all living systems,
after withdrawal of their application, if it has not been too prolonged
or intense, permit a complete restoration to normal vitality. These are
the _general_ narcotics. Besides these there are a series of substances
which have a depressing effect only upon certain forms of living
substance, and which we may, therefore, term _special_ narcotics. As,
however, the particular nature of depression following the application
of chemical substances has hitherto been closely studied only in a
very few instances, we are not, at present, in a position to sharply
define the limitations of the conception of narcosis, a conception
which originally had hardly any further meaning than the production
of unconsciousness by chemical means. In the following discussion,
therefore, we shall deal merely with narcosis produced by the
well-known general narcotics, such as carbon dioxide, alcohol, ether,
chloroform, etc. From the time of the introduction of ether narcosis
into medical practice by _Jackson_ and _Morton_ in the year 1848 up to
the present day, the theory of this process has awakened the liveliest
interest. Many attempts have since been made to explain the physical
nature of this interesting process without, however, any generally
acknowledged theory of narcosis being established. I will refrain
from entering into these former theories in detail as they have been
exhaustively treated by _Overton_[204] in his studies on narcosis.

  [204] _E. Overton_: “Studien über die Narkose, zugleich ein Beitrag
  zur allgemeinen Pharmakologie.” Jena 1901.

In connection with our present observations, however, I will more
closely analyze the process itself, following the results of
investigations extending over more than ten years carried out by my
coworkers and myself. In these investigations it has been found that
narcosis belongs to this group of depressing processes. A satisfactory
theory of narcosis, however, and this I must explain from the first,
can even today not be arrived at. Such a theory would require the
ascertainment of all primary and secondary alterations produced by the
narcotic in the course of normal vital activity. For this, however, a
number of minute details are still lacking. Nevertheless, the careful
and detailed investigations during the last ten years have acquainted
us with a large number of alterations, which, acting as conditioning
factors for the process of narcosis, must be taken into consideration,
and which to a certain extent give us an idea of the mechanism of
this process. They are equally interesting from a theoretical as well
as from a practical point of view. The presentation will become more
detailed as more of such conditioning factors are established by the
deeper penetrating of future analysis. I will deal here with the facts
found up to the present and then proceed to the deductions which these
furnish for the theory of narcosis.

In the first place narcosis is stamped as a typical process of
depression, being characterized by a _decrease of irritability
with a corresponding decrement of the extent of excitation_. The
chief feature of all narcotized systems is, that in slight narcosis
excitating stimuli produce a greatly weakened excitation, and that in
deep narcosis no perceptible response is obtained. This can readily
be ascertained in the various forms of living substance. According
to the previous observations on the inseparable relations between
conduction of excitation and irritability, it is self-evident that
with decrease of irritability there must be a corresponding decrease
in the capability of the conduction of excitation from the point of
stimulation. This decrease in conductivity must, therefore, be the
greater the more irritability is reduced; that is, the deeper the
narcosis, the greater must be the decrement undergone by the wave
of excitation in its extension from the point of stimulation. These
facts can be observed in the highest perfection in the nerve, and
have, as we have seen, been demonstrated by the investigations of
_Werigo_, _Dendrinos_, _Noll_, _Boruttau_ and _Fröhlich_.[205] Upon
deeper analysis of this process of depression, the next task for the
investigator must be the ascertainment of the special components of the
metabolic activity, which are depressed as a result of the narcotic.

  [205] I have previously on another occasion briefly communicated the
  conclusions derived from the investigations made at the Göttingen
  laboratory by my coworkers and myself. Compare: _Max Verworn_: “Ueber
  Narkose.” Deutsche medicin. Wochenschrift, 1909.

As a consequence of the result of my investigations on fatigue, the
idea occurred to me to test if possibly oxygen exchange likewise
undergoes depression during narcosis. The spinal cord centers of the
frog, which had served me in ascertaining the rôle played by oxygen in
the bringing about of the depression of activity, appeared likewise
a favorable object for this investigation. Indeed, the question
if consumption of oxygen takes place during narcosis, could be
experimentally determined in direct connection with the investigations
on fatigue. This was based on the following consideration. If an
oxygen-free saline solution is introduced into the aorta of a frog and
in order to increase the activity of the spinal cord centers to the
maximum the animal is poisoned with strychnine, after a very short
time complete exhaustion takes place as a result of oxygen deficiency.
This exhaustion can only be removed by the introduction of oxygen. In
this condition the oxygen requirement of the centers is enormously
increased. If the centers are narcotized by adding a narcotic to the
oxygen-free circulating fluid in amounts which, as experience has
found, would produce complete loss of reaction in the normal animal,
for example, about 5 per cent. of alcohol, it can then be tested if, in
this state of narcosis, the centers are capable of oxygen consumption.
It is merely necessary to replace the oxygen-free saline solution
containing alcohol by blood rich in oxygen, containing alcohol in an
amount sufficient to continue the narcosis, but supplying an abundance
of oxygen. If, after this artificial circulation has lasted for a
sufficient period, the blood is then displaced by an oxygen-free saline
solution containing alcohol, and then this, in turn, is replaced by
an oxygen- and alcohol-free saline solution, so that cessation of the
narcosis is now produced, it can be ascertained by the responses of
the animal if consumption of the oxygen, when at the disposal of the
centers during narcosis, has taken place or not. If the former is the
case, then on the cessation of narcosis reflex contraction must occur
in the same manner as in every strychninized frog totally exhausted by
oxygen deficiency and into which a saline solution containing oxygen
is reintroduced. If during narcosis, on the other hand, oxygen has not
been consumed by the centers, depression must continue to be present
after cessation of narcosis. Testing the recovery of the animal on
the introduction of blood, rich in oxygen, serves as an indicator
for the vital activity and capability of recovery of the centers. A
great number of experiments based on this scheme of investigation
were undertaken at my request by _Winterstein_.[206] These were
carried out with alcohol, ether, chloroform and also carbon dioxide.
His experiments have shown in the most uniform manner that, in spite
of the requirement of oxygen by the centers being increased to its
highest extent, and notwithstanding the most ample oxygen supply
during narcosis, after cessation of the same and the introduction
of an oxygen-free saline solution _no trace of recovery occurred_,
whereas after a supply of oxygen was introduced tetanic contractions
reappeared at once. _During narcosis, therefore, the centers, in
spite of their great requirement of oxygen, lose their capability of
oxydative splitting up and consumption of oxygen._

  [206] _H. Winterstein_: “Zur Kenntniss der Narkose.” Zeitschr. für
  allgem. Physiol. Bd. I, 1902.

After the methods for asphyxiation of the _nerve_ had been worked
out and perfected the wish arose likewise to carry out for these
structures an analogous series of experiments to that employed for the
centers and based on the same chain of reasoning. These investigations
have the advantage of essentially simpler conditions. After having
convinced myself by experiments, that the results on the nerve were in
complete conformity with those on the spinal cord, at my suggestion
_Fröhlich_[207] repeated and continued these experiments on a more
extended scale. A nerve was asphyxiated by the previously described
method. This is accomplished in the simplest manner by the opening or
closing of stop cocks in the apparatus I have employed which permit of
pure nitrogen, or nitrogen with ether, and finally also oxygen with
ether or pure oxygen being conducted at will through the glass chamber.
If the nerve was so far depressed in pure nitrogen that conductivity
became obliterated for about two cm. of the asphyxiated stretch, it
was then narcotized in nitrogen. Following this oxygen with ether was
supplied for a time. Then the oxygen-ether mixture was displaced by
one of nitrogen and ether and finally by pure nitrogen. Even after
a prolonged period, a recovery in pure nitrogen never took place.
On the other hand, the nerve recovered at once, as soon as oxygen
without ether was introduced. The results of these investigations
are, therefore, completely in harmony with those undertaken by
_Winterstein_ on the nervous centers. They were later likewise
entirely confirmed by similar experiments of _Heaton_.[208] All these
investigations furnished the proof _that in narcosis, living substance,
notwithstanding even the greatest oxygen deficiency, is not capable of
producing oxydation, neither can consumption of oxygen take place, with
which, after cessation of the narcosis, oxydative splitting up can be
carried out_.

  [207] _Fr. W. Fröhlich_: “Zur Kenntniss der Narkose des Nerven.”
  Zeitschr. f. allgem. Physiol. Bd. III, 1904.

  [208] _Trevor B. Heaton_: “Zur Kenntniss der Narkose.” Zeitschr. f.
  allgem. Physiol. Bo. 1910.

Recently _Warburg_[209] has likewise found an oxydative depression
during narcosis in the eggs of the sea urchin and in the red corpuscles
of geese, and the same fact has lately been also demonstrated by
_Joannovics und Pick_[210] for the oxydative activity of the liver
cells of the dog.

  [209] _Otto Warburg_: “Ueber die Oxydationen in lebenden Zellen.”
  Zeitschr. f. physiol. Chemie Bd. 66, 1910. The same: “Ueber
  Beeinflussung der Oxydationen in lebenden Zellen nach Versuchen an
  roten Blutkörperchen.” Zeitschr. f. physiol. Chemie Bd. 69, 1910.

  [210] _Joannovics und Pick_: “Intravitale Oxydationshemmung in der
  Leber durch Narkotica.” Pflügers Arch. Bd. 140, 1911.

This fundamental establishment of the fact that narcosis prevents
oxydations in living substance is at once followed by the further
problem, in what _manner_ do the disintegration processes undergo
alterations during narcosis? _That_ they must be altered, and this
in the form of a reduced energy production, is clearly shown by the
decrease of irritability and the increase of the decrement of the
conduction of excitation. Both become the greater the deeper the
narcosis. The observations just discussed render these facts at
once self-evident. They follow as a simple and necessary result of
the elimination of the oxydative processes. If these are suppressed
further breaking down, if not influenced by addition of other factors,
proceeds anoxydatively. The previously observed series of processes is
developed, which invariably take place when oxygen deficiency occurs
and which produce in the clearest form the results of asphyxiation on
the withdrawal of oxygen supply. If, therefore, the disintegration
processes are not influenced in some other manner during narcosis,
they must then take place in the same way as in the withdrawal of the
oxygen supply. The question, if this is actually the case, can be
experimentally decided by comparing, on the one hand, the development
of the course of asphyxiation during narcosis, and on the other, the
withdrawal of the oxygen supply. We have carried out this comparison
for the spinal cord centers as well as for the medullated nerve. A
prolonged series of experiments have been made by _Bondy_[211] with the
apparatus constructed for this purpose by _Baglioni_.[212] Two frogs
under uniform conditions of temperature were submitted to artificial
circulation, the one merely with an oxygen-free fluid, the other with
the same, but with the addition of 5 per cent. of alcohol. In order
to render the least trace of irritability perceptible, responsivity
was increased in both animals by the employment of strychnine. It
then appeared that, on the average, irritability was obliterated in
the narcotized frog in about the same time as in the animal simply
asphyxiated. These experiments were controlled by introducing at their
conclusion a saline solution containing oxygen into both frogs and by
ascertaining the degree of recovery. In like manner _Fröhlich_[213] has
established the same fact for the nerve. The period of asphyxiation
for the nerve in a nitrogen-ether mixture is approximately the same
as in pure nitrogen. Analogous experiments have been carried out in
amœbæ by _Ishikawa_.[214] Here also it has been shown that living
substance becomes asphyxiated in narcosis and can finally recover only
when oxygen is supplied. In more than a hundred experiments _Ishikawa_
has, however, obtained the uniform result that amœbæ asphyxiate rather
sooner in narcosis than in pure nitrogen. The most striking experiments
are those which _Heaton_[215] has carried out on the nerve. Using
both sciatic nerves of the same frog, he passed each one through a
separate glass chamber, as previously described, and laid the central
stumps projecting from the chamber over a pair of platinum electrodes,
while the stretch within was likewise placed on platinum electrodes.
The muscles served as indicator of the capability of conduction and
irritability. The alterations thereof were tested by the ascertainment
of the threshold of stimulation. The nerve in the _one_ chamber
was then subjected to a pure nitrogen current, that in the _other_
merely to one of pure air with ether. In order to test the degree of
asphyxiation the air-ether current in the latter chamber was replaced
from time to time by an ether-nitrogen current, and then by one of pure
nitrogen, so that the narcosis was interrupted without the entrance of
oxygen being possible in the mean time. During this suspension of the
narcosis, the nerve recovered each time in nitrogen, its irritability
again increasing and its capability of conduction returning with every
test. However, recovery showed itself as less and less complete.
Finally irritability had sunk so low that the capability of conduction
disappeared entirely. At the end of the experiment as control, nitrogen
was displaced by air in the two chambers and in both nerves recovery
took place.

  [211] _Bondy_: “Untersuchungen über die Sauerstoffspeicherung in den
  Nervencentren.” Zeitschr. f. allgem. Physiol. Bd. III, 1904.

  [212] _Baglioni_: “Bezichungenzwishen physiologischer Wirkung und
  chemischer Constitution.” Zeitschr. f. allgem. Physiologie Bd. III,
  1904.

  [213] _Fr. W. Fröhlich_: “Zur Kenntniss der Narkose des Nerven.”
  Zeitschr. f. allgem. Physiologie Bd. III, 1904.

  [214] The experiments of _Ishikawa_ have not as yet been published.

  [215] _Trevors B. Heaton_: “Zur Kenntniss der Narkose.” Zeitschr. f.
  allgem. Physiologie Bd. X, 1910.

In both cases recovery could only be brought about by an introduction
of oxygen. From the sum of all these experiments it results that
during narcosis in air the nerve, even when a sufficiency of oxygen is
present, gradually asphyxiates and loses its capability of conduction,
and this in about the same length of time as the other nerve in pure
nitrogen. These investigations furnish two important facts for the
theory of narcosis. First, that in narcosis living substance becomes
asphyxiated notwithstanding the presence of an ample oxygen supply,
and secondly, that asphyxiation occurs in the same time, or somewhat
more rapidly, in pure nitrogen under otherwise similar conditions
than without narcosis. In other words, it is shown that the breaking
down processes of metabolism continue in narcosis as anoxydative
disintegration. _In narcosis, therefore, asphyxiation takes place with
approximately the same or a somewhat greater rapidity than that in an
oxygen-free medium._

The fact here established explains in the simplest manner the often
described observation that in the human being and in mammals during
prolonged anæsthesia typical products of insufficient combustion,
such as fatty acids, lactic acid and above all aceton, in not
inconsiderable quantities are eliminated, as the case may be, by the
urine or the respiratory air.[216] If, as has been shown by the
foregoing experiments, the processes of disintegration can continue
to anoxydatively take place during narcosis, the problem arises, if
this anoxydative breaking down can be further increased by excitating
stimuli. This question has been answered likewise by means of
experiments on the nerve made by _Heaton_.[217] The two sciatic nerves
of the same frog were drawn through a double glass chamber of the form
previously described so that each nerve lay on an electrode and with
the central stump protruding out of the chamber hanging likewise over
an electrode. As in the former instances the muscle contraction of the
shank again served as indicator. Both nerves were then subjected to
the same current of nitrogen-ether. When, as a result of the narcosis,
their irritability has sunk to the level of “stromschleifen” the
central stump of the one nerve was continuously stimulated with faradic
shocks during a prolonged period, while the other nerve remained at
rest. Finally, by displacement of the current of nitrogen-ether with
one of pure nitrogen, cessation of narcosis was brought about. It was
then seen that the irritability of the continuously stimulated nerve
showed a much greater decrease than that of the nonstimulated. The
control made by introduction of air demonstrated that both nerves
recovered in an oxygen supply. _There can, therefore, be no doubt,
by comparative experiments we find, that during narcosis anoxydative
disintegration can be still further increased by the action of stimuli._

  [216] For the very extensive literature on this subject see
  _Reicher_: “Chemischexperimentelle Studien zur Kenntniss der
  Narkose.” Zeitschr. f. klinische Medicin Bd. 65, 1908.

  [217] _Heaton_: l. c.

In view of this knowledge of the influence of narcotics on oxygen
exchange it may be considered as a firmly established fact, that
a process of depression is developed during narcosis, which can
be classified with the large group of depressions, resulting from
deficiency of oxygen. This is followed by the important problem, is it
possible to attribute the whole series of alterations, produced by the
narcotic, solely to this _one_ factor? In other words, is narcosis the
result of acute suppression of the oxydative processes?

If the individual symptoms which characterize narcosis are investigated
from this point of view, one must indeed confess that they are all
readily understood when regarded as the results of suppression of
the oxydative processes. Indeed, the disappearance of the perceptible
vital activities, the decrease of irritability, the restriction of the
conduction of excitation, the continuance of an anoxydative breaking
down, the recovery on cessation of narcosis, provided oxygen is
present, etc., in short, all the characteristics of narcosis so far
known must be expected and _demanded_ if a suppression of the oxydative
processes exists during narcosis.

There is only _one_ point which at the first glance would not seem to
agree entirely with the assumption. This is the fact that depression
sets in with a relatively greater rapidity in narcosis than when the
supply of oxygen is completely withdrawn. Depression of the centers
in the spinal cord, which begins in about five to ten minutes after
artificial circulation of an oxygen-free, alcohol-containing, saline
solution, is not brought about for more than an hour when the same
saline solution but without alcohol is introduced. This difference
is still more strikingly apparent in the nerve. The same degree of
depression, which is produced in the nerve in a nitrogen-ether mixture
within about _five_ minutes, is not reached in pure nitrogen without
ether until after the lapse of from _two_ to _four_ hours. In order
to investigate this relation somewhat more closely I have questioned
if it is possible for a living system, which has been narcotized to a
certain extent, to regain its irritability in a completely oxygen-free
medium, if cessation of the narcosis takes place after a period
essentially shorter than the time of asphyxiation of the system under
equal conditions. If the depression of narcosis is founded exclusively
on asphyxiation, it would be expected that no recovery could occur.
Experiments which I have made on the spinal cord centers as well as
on the peripheral nerves have, however, demonstrated exactly the
contrary. If a frog is subjected to an artificial circulation of an
oxygen-free saline solution containing 5 per cent. of alcohol until
reaction is lost, being certain of this by the injection of a weak
dose of strychnine, and if now a cessation of the narcosis is brought
about by the transfusion of oxygen-free saline solution, the centers
of the animal recover completely within ten to fifteen minutes, as
shown by typical strychnine tetanus. If a nerve is placed in a gas
chamber through which a mixture of nitrogen and ether is allowed to
flow until irritability is greatly decreased, and is then displaced by
pure nitrogen, irritability increases more or less completely according
to the time which has passed from the beginning of asphyxiation. This
investigation proves that living substance, even after the deepest
narcotic depression, may recover on cessation of the narcosis, although
in an entirely oxygen-free medium. _Fröhlich_, _Bondy_ and _Heaton_,
by the methods of their experiments above described, have proved this
fact in a great number of instances. On the other hand, _Ishikawa_
could not observe a pronounced recovery in amœbæ from narcosis in pure
nitrogen. But it is possible that here the difference is perhaps merely
quantitative.

What position should be taken in the face of these facts? Does recovery
of a deeply narcotized tissue in an oxygen-free medium really make
it difficult to suppose that narcosis is the result of an acute
suppression of the processes of oxydation? On closer view, it will be
found that this difficulty is merely apparent. In reality it is quite
possible to bring these facts into harmony with the assumption that
narcosis consists in a suppression of these processes. If one proceeds
from the supposition that living substance possesses a certain, even
though merely a small supply of oxygen in its interior, then it is at
once evident that a more or less complete recovery of irritability
from narcosis depression is possible, even in an oxygen-free medium.
It can take place at the cost of the oxygen still present in the
living substance and which during the narcosis, on account of the
suppression of the oxydation processes, could not be consumed. If
the presence of a certain oxygen reserve in living substance is
entirely set aside and a different explanation sought for the primary
continuance of irritability after a complete withdrawal of the oxygen
supply from without, the great difference of time in the setting in
of the depression in narcosis and that of the complete elimination
of the oxygen supply from without would make it necessary to assume
the processes occurring in narcosis are entirely different in nature.
The explanation that narcosis is the result of suppression of the
oxydative processes would indeed be out of the question in such a view.

The assumption, however, that in a living system at the same moment
when oxygen is removed from the neighborhood, let us say by a stream
of nitrogen, no oxygen would be present and that in consequence
every oxydative process must cease, contains so little probability
that I have rejected it on various occasions.[218] The way in which
irritability is lost in asphyxiation of the nerve likewise very clearly
demonstrates the untenability of this view. The recent investigations
of _Lodholz_[219] have shown that decrease of irritability takes
place after a sudden displacement of all oxygen from the surrounding
medium uniformly and gradually in the form of a logarithmic curve. If
at the moment of oxygen withdrawal from the outer medium, metabolism
became entirely anoxydative, the curve of irritability must under
all circumstances show a sudden _steep decline_ at this point,
and subsequent to this a further _slower_ decrease. For, as the
oxydative processes constitute by far the _chief_ part in the energy
production of living substance, the production of energy, and with
this irritability, would undergo considerable loss at the same moment
in which oxydative was replaced by anoxydative disintegration. The
curve of decrease of irritability during the transition period from
oxygen supply to oxygen withdrawal shows, on the contrary, a completely
uniform course and it is not until later that a very slow decline takes
place, which only after a prolonged time assumes increasing rapidity.
But the assumption that at the moment when the supply of oxygen ceases,
anoxydative breaking down could acquire such enormous dimensions that
it furnishes just exactly the same amount of energy as was before
supplied oxydatively, is a view which no one will seriously entertain.
In connection with this I wish to call attention to the experiments of
_Fröhlich_[220] in which he compared the time required for asphyxiation
to take place in the nerves, when, on the one hand, the frogs had
been kept several days previous to the experiment in temperature of
14–40° C., and on the other, in one merely a few degrees above zero.
He found that the nerves of the cooled frogs required on an average
twice or three times as long for their irritability to sink to the same
degree as those of the heated frog, although during the experiment
the same temperature was present in both. It was also shown that the
asphyxiation period was prolonged up to a certain limit, depending
upon the length of time the animals were kept at a low temperature. It
would seem to me that these facts admit of no other explanation than
that in a low temperature a greater amount of oxygen is stored in the
nerve than in high temperatures. From the standpoint that from the
moment of withdrawal of oxygen from without, disintegration likewise
takes place exclusively anoxydatively, these facts would be completely
incomprehensible. When, however, the assumption is made, and this
would appear to me as inevitable, that living substance contains in
itself a certain even though a very slight quantity of oxygen, which in
low temperature is greater, in a high temperature less, the recovery
from narcosis, when oxygen is withheld, is not at all surprising. The
comparatively rapid setting in of depression in narcosis finds a simple
explanation in the _violent_ manner in which the oxydative breaking
down, notwithstanding the presence of oxygen, is suddenly suppressed by
the flooding by the narcotic. Finally, this view receives unlooked-for
support by a group of facts which at the first glance would appear to
bear no relation whatever to the process of narcosis.

  [218] Compare lecture V; lecture VII.

  [219] The investigations have not yet been published.

  [220] _Fr. W. Frölich_: “Das Sauerstoffbedürfniss des Nerven.”
  Zeitschr. f. allgem. Physiol. Bd. III, 1904.

In a series of investigations on the mechanism of movement in naked
protoplasm,[221] I have pointed out the rôle played by oxygen in the
genesis of the amœboid protoplasm movement. We can distinguish two
antagonistic phases in the movement of amœboid cells, the expansion
phase and the contraction phase. The first consists in an increase,
the latter in a diminution of the surface, the mass remaining the
same. The expansion phase is manifested in the stretching out of the
pseudopods by a centrifugal outflowing of the protoplasm into the
surrounding medium, the contraction phase by the indrawing of the
pseudopods by the centripetal inflowing of the protoplasm to the cell
body. In total contraction, such as occurs, for instance, in strong
excitation following stimuli, the cell body becomes ball shaped.
In local contraction of the long thread or net-shaped outstretched
pseudopods of the sea rhizopoda, the protoplasm of the retracting
pseudopod forms balls and spindles. Considered from a physical point
of view the expansion phase of amœboid movement is an expression of
decrease, the contraction phase an increase of the surface tension.
I have shown that the factor which under physiological conditions
decreases the surface pressure and thereby brings about the expansion
phase is the introduction of oxygen into the living substance. With
removal of oxygen the stretching out of the pseudopods ceases. The cell
gradually draws in all pseudopods and assumes the shape of a ball.
On the reintroduction of oxygen the outflow of the pseudopods begins
anew. This fact can be observed in all amœboid cells. When, therefore,
consumption of oxygen and oxydative changes is suppressed during
narcosis it is to be expected that all naked protoplasm masses by being
narcotized lose their capability of assuming the expansion phase of
movement and contract into the shape of balls. Experimentation confirms
this deduction in the most striking manner. When amœbæ are placed in
a drop of water under the microscope in a gas cell through which air
and a little ether are allowed to flow, the pseudopod formation of the
amœbæ ceases within a few minutes and they all assume the shape of a
ball. (Figure 62.) In asphyxiation in pure nitrogen, the changes in the
amœbæ take place in exactly the same manner with the exception that in
this case a longer period ensues according to the size and activity of
the animals. About 20 to 60 minutes elapse before depression becomes
complete. If larger sea rhizopoda are narcotized in the same manner
all pseudopods are more or less retracted and the contained protoplasm
flows centripetally and contracts in the characteristic manner into
balls and spindles. (Figure 63.) If the narcosis is removed by
displacing the ether by pure air, the stretching out of the pseudopods
then begins anew, provided the narcosis has not been too deep or too
prolonged.

  [221] _Max Verworn_: “Die physiologische Bedeutung des Zellkerns.”
  Pflügers Arch. Bd. 51, 1891.

  The same: “Die Bewegung der lebendigen Substanz.
  Eine vergleichend-physiologische Untersuchung der
  Contractionserscheinungen.” Jena 1892.

  The same: “Allgemeine Physiologie.” V Auflage. Jena 1909. In the last
  place the same theory of the contraction movements with some new
  corrections is described.

[Illustration: _A_

_B_

Fig. 62.

Amoeba limax. _A_--In normal state. _B_--Narcotized by ether.]

[Illustration: Fig. 63.

Rhizoplasma Kaiseri. Effect of chloroform.]

In the face of all this evidence there can be indeed no further
barrier to the assumption that the symptoms in narcosis are a result
of a suppression of the oxydative processes. Nevertheless, I would
not at present venture to maintain that the entrance of the narcotic
into living substance produces no alterations whatever, except just
this oxydative suppression. For the present it seems to me that the
possibility is in no way precluded that the same process, which
is expressed in the oxydative suppression, is connected with other
alterations in the living substance, of which we are as yet ignorant.
As far as the effects of larger doses of narcotics are concerned, the
assumption that other alterations take place in the living substance
can in any case hardly be avoided. An application of larger quantities
of narcotics brings about destruction of the living system with great
rapidity. Here the alterations in the optical properties of the cell
are of such magnitude that the changes are directly perceptible under
the microscope. _Binz_[222] has observed such alterations in the nerve
cell and looked upon them as coagulation. In unicellular organisms
these optical alterations can readily be followed. If amœbæ, sea
rhizopods or infusoria are narcotized with stronger doses of ether or
chloroform, the protoplasm becomes opaque and granulated, it appears
darker than formerly and in many cases displays a yellowish brown color
in transmitted light. Cells altered in this way no longer recover
after removal of the narcotic. These intense and rapidly appearing
alterations of protoplasm resulting from the application of stronger
doses of the narcotic can scarcely be explained as simply the result of
a mere decrease of the oxydative processes. They would seem to consist
rather, as suggested by _Binz_, as coagulation, in an alteration of
the state of certain components of living substance. Whether these
alterations are already present in a correspondingly slight amount in
those degrees of narcosis after which complete recovery can take place
and further whether in this case they are in any way concerned in
bringing about the individual symptoms of the former, are questions the
decision of which must be left to future investigations. _Höber_[223]
indeed makes such an alteration of the colloidal state of the lipoid
the basis of a theory of narcosis. But such assumptions are scarcely
more than speculations. This is one of the points in which our present
knowledge is lacking.

  [222] _Binz_: “Vorlesungen über Pharmakologie für Aerzte und
  Studierende.” II Aufl. Berlin 1891.

  [223] _Höber_: “Beiträge zur physikalischen Chemie der Erregung
  und der Narkose.” Pflügers Arch. Bd. 120, 1907. The same: “Die
  physikalisch-chemischen Vorgänge der Erregung.” Sammelreferat.
  Zeitschr. f. allgem. Physiol. Bd. X, 1910.

Even if we restrict ourselves to the actually established alterations
produced by the narcotic in living substance, new problems present
themselves, the investigation of which requires further effort. Above
all, the question arises as to the finer mechanism of oxydative
depression. In what manner does the narcotic molecule, entering into
the living substance, suppress the oxydative processes? Here there are
very different possibilities to be taken into consideration and up to
the present in our investigations of a suppression of the oxydative
processes resulting from narcosis, we have stood on the firm ground
of assured facts. However, the discussion of the nature of this
suppression leads us into the domain of _hypothesis_. But without
hypothesis there can be no progress in knowledge. In all branches of
scientific research, working hypotheses are required for the obtainment
of new facts.

On closer reflection, there are chiefly _three_ possibilities, which,
considered from the standpoint of our present knowledge of the
processes in living substance, offer an explanation of the oxydative
suppression as a result of narcosis.

One of these possibilities is, that the _narcotic itself consumes
the oxygen which activates living substance_ and uses it for its
_individual_ oxydation, so that the specific oxydable material of
living substance receives less oxygen from the oxygen carriers. Based
on a series of interesting experiments this view has been recently
maintained by _Bürker_.[224] He observed that with the electrolysis
of acidulated water, to which a small per cent. of ether was added, a
much less amount of oxygen was at the anode than in one used as means
of control, containing acidulated water without ether. The oxygen was
replaced at the anode by oxydation products of the ether, such as
carbonic oxide, carbon dioxide, acetate aldehyde and acetic acid. In
experiments with various narcotics he likewise found that the stronger
the effect produced by narcosis, the greater the oxygen amount required
for the oxydation taking place of electrolysis. _Bürker_ applies these
results obtained for electrolysis to the processes in living substance
and takes the view that the narcotic seizes on the active oxygen, and
so withdraws it from the masses of living substance possessing a great
oxygen requirement. It cannot be denied that this conception of the
nature of certain narcotics deserves careful investigation. It seems
to me, however, that before considering it in the light of a serious
probability a grave difficulty would first have to be removed. In
living substance the narcotic would occur under conditions essentially
different from those existing during the experiment in the voltameter.
In the former case there would be the struggle for oxygen of the
specific oxydable cell masses to be met with. Considering the small
amount of chemical activity of the greater number of narcotics it would
appear at least doubtful if in this battle for supremacy the latter
would achieve a victory. For some narcotics, as, for instance, carbon
dioxide, this method of a depression of the oxydative processes would
have no bearing whatever. This is rather to be looked for in the
effects of oxydative suppression of the aldehydes, which _Warburg_[225]
has recently observed and investigated. Here, however, it is not a true
narcosis which is concerned.

  [224] _Bürker_: “Eine neue Theorie der Narkose.” Münchener Med.
  Wochenschrift, 1910.

  [225] _Warburg_: “Ueber Beeinflussung der Sauerstoffathmung. II
  Mitteilung. Eine Beziehung zur Constitution.” Zeitschr. f. physiolog.
  Chemie Bd. 71, 1911.

A second possibility of a suppression of oxydation would be the
_fixation of the molecules of the oxydable substances by chemical or
physical combinations_ in that they would lose their capability of
oxydative disintegration. Such a supposition would, however, likewise
contain but few elements of probability. As has been shown, an
anoxydative breaking down continues during narcosis, which, and this we
may assume with certainty, furnishes very different products in great
variety. These anoxydative disintegration products, as recovery on the
cessation of narcosis shows, are removed during recovery by oxydation.
If the effect of the narcotic consisted in the prevention in spite of
the presence of oxygen of the oxydation by combination, it would be
necessary to assume that the narcotic was bound to a mass of completely
heterogeneous substances, a conclusion we should find difficult to
entertain.

If, however, depression of the oxydative processes is founded neither
on the seizure of oxygen by the narcotic nor the fixation of oxydable
substances by the former, there remains the possibility _that the
narcotic suppresses the transmission of oxygen to these points
of consumption_. We assume that the oxygen transmission to those
points where its consumption takes place is carried out by special
substances, the existence of which has been established in the most
varied vegetable and animal cell forms. Unfortunately we only know
these oxygen-carrying substances by their effects. Of their chemical
constitution we have no knowledge, but we usually assume that the
transmission of oxygen occurs in the same manner as in catalytic
processes. On another occasion I have previously expressed the
suggestion,[226] that the narcotic suppresses oxydation by producing
incapability of the groups acting as oxygen carriers to carry out this
function. If we assume that the substances possessing the character
of oxygen carriers, which activate the molecular oxygen and so render
it capable of attacking the oxydable substances, lose this capability
under the influence of narcotics, this supposition would not only
make all of the facts of suppression of oxygen exchange in narcosis
comprehensible, considered from one point, but likewise, as careful
investigation has shown, be in complete harmony with all knowledge
obtained up to the present of the process of narcosis.

  [226] _Max Verworn_: “Ueber Narkose.” Deutsche med-Wochenschrift,
  1909.

Here is the point where the interesting observations of _Hans
Meyers_[227] and _Overton_[228] on the relations of the depressing
influence of narcotics to their solubility of fat and water may be
connected with the facts of the suppression of oxydation. _Meyer_
and _Overton_ have quite independently of each other made the same
observation, that the depressing effect of a narcotic is the greater,
the larger the coefficient of distribution between substances of a
fatty nature and water. Those narcotics produce the strongest effects
which are readily soluble in substances of a fatty nature, but not
easily so in water, that is, in which the coefficient distribution
between fat and water is very great. This law, which has been
demonstrated by _Meyer_ and _Overton_ for a large number of narcotic
processes, is in itself not a theory of narcosis, as has been often
erroneously assumed. It shows us, however, an important condition,
which must be considered in every theory of narcosis. It demonstrates
that it is the ease with which transmission in the lipoid occurs which
allows a substance to develop narcotic effects. These facts would seem
to indicate that the lipoids of the cell are connected in some way
or other with the exchange of oxygen. If we assume that the oxygen
carriers, the chemical constitution of which is so far not known, bear
the character of lipoids and belong, say, to the generally extended
group of phosphatides, there results at once an apparent connection
of the law established by _Meyer_ and _Overton_ with the nature of
narcosis.

  [227] _Hans Meyer_: “Welche Eigenschaft der Anaesthetica bedingt ihre
  narkotische Wirkung?” Arch. experimentelle Pathol. u. Pharmacol.
  Bd. 42, 1899. Further: _Fritz Baum_: “Ein physiologisch-chemischer
  Beitrag zur Theorie der Narkotica.” _Ibidem._

  [228] _Overton_: The first communication of the results obtained
  by _Overton_ were made by _Rost_: “Zur Theorie der Narkose” in the
  Naturwiss. Rundschau Jarhrg. 1899. _Overton_ has treated the subject
  in detail in his work, “Studien über die Narkose zugleich ein Beitrag
  zur allgemeinen Pharmakologie.” Jena 1901.

The depressing effect of the narcotic would then consist in producing
incapability of the lipoids transmitting oxygen to act as carriers of
the same, and it is, therefore, self-evident that the effect of the
narcotic would be the stronger the more readily it found entrance into
the lipoids. It is perhaps not without interest that in similar manner
_Mansfeld_[229] has attempted to establish a connection between the
facts which _Meyer_ and _Overton_ have found and those ascertained
by my coworkers and myself. He expressed the view that the lipoids
of the cells represent the channels followed by the oxygen on its
entrance, and that in consequence of their accumulation in the lipoids,
the narcotics bring about asphyxiation by physically obstructing the
transmission of the oxygen from the outer medium through the surface
layer of the lipoid into the protoplasm. The divergence in our views
is not essential in their nature, and I attach the less importance to
them as we find ourselves here, as I must again emphasize, on purely
hypothetical ground.

  [229] _Mansfeld_: “Narkose und Sauerstoffmangel.” Pflügers Arch. Bd.
  129, 1909.

In consideration of these observations we may perhaps establish the
following hypothesis of the effect of the oxydative suppression of
narcotics: The narcotics obstruct, either by absorption or loose
chemical combination the oxygen carriers of the cell and render them
incapable to activate the molecular oxygen. In consequence, oxydation
of the oxydable substances cannot take place and disintegration occurs
of an _an_oxydative form. The cell asphyxiates.

In conclusion I wish to warn against erroneous assumption that _all_
oxydative depressions by chemical substances are _narcosis_ and that
the mechanism is the same. It is true that a number of chemical
substances depress the processes of oxydation. But the latter can be
brought about in very varying ways. I would like to mention the effect
of oxydative depression of aldehydes. To this _Warburg_[230] has added
hydrocyanic acid, arsenic acid, ammonia and substitution compounds
of ammonia. These substances do not follow the _Meyer-Overton_ law of
the coefficient of distribution. We cannot consider them, therefore,
as narcotics. Future investigation will establish the existence of a
large number of substances belonging to this great group of oxydation
suppressing poisons, which are not narcotics. And it is likewise
certain that depressing substances will be found, the depressing
effects of which will not have their point of attack in the oxygen
exchange, but will be shown to exist in other constituents of the
metabolic chain. Our research in these fields, as already said, is
still in the first beginnings and its perspective reaches into infinite
space.

  [230] _Warburg_: “Ueber Beeinflussung der Sauerstoffatmung. II
  Mitteilung: Eine Beziehung zur Constitution.” Zeitschrift f. physiol.
  Chemie Bd. 71, 1911.




Spelling errors:

  possibilites → possibilities
  deliminated → delimitated
  equilibrum → equilibrium
  fur → für
  künstliche Immunisirungsprocesse → künstlichen Immunisierungsprozesse
  methan → methane
  aldehyd → aldehyde
  Rüchenmarks → Rückenmarks
  metronom → metronome
  irrritability → irritability
  tranverse → transverse
  the the → the
  Mittleilung → Mitteilung
  whereever → wherever
  oxdyative → oxydative
  anoxdyative → anoxydative

Spelling inconsistencies:

  ae/æ/e (inconsistent ligatures)
  cannot/can not
  cell-pathology/cell pathology (inconsistent hyphenation)
  æthyl/ethyl