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.