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.