Trophic Action

TROPHIC ACTION. The concept of T. d. of the nervous system penetrated physiology from clinical practice. Practicing physicians constantly encountered facts that indicated that the nutrition of organs and tissues is in some definite dependence on the nervous system. This included nutritional disorders that appeared with various lesions of the nervous system, both central and peripheral, and both with lesions associated with organic pathological processes in the nervous system and with accidental injuries to it. On one hand, this refers to general phenomena of obesity or emaciation, general phenomena of hypertrophy or atrophy of muscular tissue with complete preservation of other types of tissues; then to trophic phenomena on the skin in the form of keratoses, disorders of glandular activity, abnormal hair growth, abnormal nail growth, formation of local dystrophic phenomena in the form of ulcers on mucous membranes or on the skin, necrosis, etc. A large number of such phenomena, sometimes very severe, running a rapid course, was noted by practicing physicians and described as "trophic disorders." In the vast majority of cases in the presence of these trophic disorders, it was possible to discover one or another lesion of the nervous system. Then it was striking that sometimes these trophic disorders appeared without direct damage or lesion of the nervous system itself, but as a result of various pathological processes occurring in distant parts of the body, on the periphery. It arose quite naturally to assume that these trophic disorders could result from reflex action through the central nervous system. Older physicians formed the view that these trophic disorders in various tissues and organs must be based on the presence of special nerve fibers that manage the regulation of nutrition of organs and tissues. Thus, from the doctrine of T. d. of the nervous system grew the doctrine of the trophic nervous system as an independent division of the nervous system, as an independent type of nerve fibers exclusively managing the regulation of metabolism. Such a view we encounter in physicians approximately until the second half of the 19th century, when with the development of clinical observations, with their clarification thanks to precisely based patho-anatomical autopsies and thanks to experimental research, the question underwent a sharp turn. The matter went so far that the doctrine of the trophic nervous system as such seemed to have been put to an end. In this question, several phases are observed, and now we are experiencing precisely an era of reverse tendencies, an era when a whole series of facts forces a return to the old doctrine of the trophic nervous system and not only to recognize the existence of trophic influences of the nervous system, but also to admit the existence of special fibers, which predominantly or exclusively manage the regulation of tissue nutrition and physico-chemical state of tissues. As for the fact of trophic influences of the nervous system itself, it was essentially never questioned, because in the most difficult times for the doctrine of the trophic nervous system, one still had to deal with facts, and clinical practice at every step indicated that certain diseases of the nervous system, either central or peripheral, moreover both in the efferent and in the afferent parts, are accompanied by a series of characteristic trophic disorders. The error consisted in that attempts to establish and substantiate the existence of trophic innervation were directed to the study of precisely these trophic disorders, and that all efforts were directed toward finding a special anatomical nerve substrate for the implementation of these trophic disorders, these dystrophies. On this path, great failures were obtained. First of all, it turned out that such a pronounced nutritional disorder as muscle atrophy in peripheral paralyses, atrophy accompanied by "reaction of degeneration" (i.e., perversion of the response to electrical irritation), is always associated with paralysis or with the loss of precisely the motor neuron, i.e., that neuron which causes the function of striated muscles. Precisely the lesion of the cells of the anterior horns of the gray matter of the spinal cord, the interruption of the anterior roots, or the interruption of motor fibers further on the periphery is the cause of degenerative atrophy of muscular tissue. From this it was concluded that in this case we are not dealing with a special trophic lesion, but with a trophic lesion associated with inactivity, with absence of work, and there was an attempt to explain this muscle atrophy as atrophy from disuse. Clinic, however, shows that if the musculature is placed in conditions under which it cannot actually perform its motor work, cannot function, then muscle atrophy develops, but without reaction of degeneration, so that atrophy from disuse sharply differs from degenerative atrophy associated with degeneration of the peripheral neuron. Thus, one had to speak of a special trophic influence of nerve fibers after all, but this trophic influence turned out to be inherent in those nerve fibers which cause the muscle to act and which are primarily "functional" nerves. Along with this, it was discovered that neither the cutting of sympathetic fibers approaching one or another extremity, nor the cutting of posterior root fibers carrying sensory and vasodilatory impulses to the same area of the body, are accompanied by atrophic phenomena in the muscles and all the more by reaction of degeneration. This dealt the first blow to the doctrine of trophic innervation. The trophic function had to be recognized, and the doctrine of special trophic fibers naturally fell away.

880 ACTION

It was subsequently discovered that severe cases of trophic lesions of the joints and skin coverings, which are observed in syringomyelia and in other organic diseases of the central nervous system, can be explained by a whole series of other factors besides the specific trophic influences of the nervous system. Indeed, attempts were made to analyze those trophic disorders that could easily be caused experimentally by the severing of peripheral nerves, for example, the severe trophic disorders observed on the side of the eye in the form of keratitis, in the form of inflammatory phenomena in the conjunctiva, in the form of complete disintegration of the eyeball, which occur when the trigeminal nerve is severed. All these disorders, upon experimental analysis, proved easier to explain not by trophic influences of special nerve fibers, but by a whole series of other factors. This moment of careful study of trophic influences coincided with the period of great scientific discoveries. Indeed, in the 1850s, Claude Bernard discovered the vaso-motor nerves. Then, during the same period, microorganisms were discovered, and their role as causative agents of various pathological processes, particularly purulent processes, was established. These two factors—changes in blood circulation under the influence of nervous influences and the possibility of causing pathological processes through bacterial infection—provided the basis for objecting to the concept of a trophic nervous system. The importance of trauma in the development of trophic disorders was also emphasized, and this was linked to the disorders of sensitivity that were often observed and had to be observed with certain lesions or artificial damage to nerve pathways. It turned out to be extremely easy to prevent a significant portion of trophic disorders or at least to weaken and alleviate their course by applying special bandages that protected the organ with a disabled or damaged nervous system from the penetration of infection, shielded it from harmful temperature disturbances that easily occur with circulatory disorders, and shielded it from mechanical trauma, which is inevitably strong when there is a loss of sensory innervation. The loss of sensitivity, which prevented the experimental animal from eliminating trauma, from protecting the organ from injury, bacterial infection, and circulatory disorders—these three factors proved to be so important in the implementation of dystrophic processes that the attention of all experimenters, both physiologists and pathologists, was directed to this triad of factors, which literally covered everything else, and therefore the direct trophic role of the nervous system was overshadowed. This was the reason why the question of the trophic nervous system was completely abandoned and fell out of the attention of researchers for entire decades. However, parallel to this, facts gradually accumulated which eventually had to lead to a return to the doctrine of the trophic nervous system. In the 1840s, it was first discovered by Volkmann in not a very convincing form, and then in a more convincing form by the Weber brothers, the influence of the vagus nerve on the cardiac muscle. It was shown that under the influence of irritation of the vagus nerve, the heart slows its rhythm, weakens its contractions, or even gives a complete temporary stoppage. A few years after this, it was discovered that irritation of the sympathetic fibers going to the heart is accompanied by an intensification of cardiac contractions and an increase in their rhythm. Thus, approximately at the same time when the vaso-motor nerves were discovered, such an exceptionally important moment was established as the regulation of the automatic work of the heart by the fibers of the vagus and sympathetic nerves. This fact could not but attract the special attention of researchers and could not but lead to a whole series of further works, the result of which was the establishment of the view that the cardiac muscle lacks functional innervation, i.e., innervation that would bring it into activity, that the activity proceeds automatically, can be observed and is observed in a distinct form after complete denervation or removal of the organ, but that at the same time there is an undeniable influence of the nervous system in the form of quantitative effects on the automatically proceeding process of cardiac activity. The analysis of facts in the very first years gave impetus to explain this influence of nerves on the function of the heart by a change in the basic properties of the heart muscle tissue. The first works in this direction were carried out and the corresponding conclusions were first made in Russia by I. P. Pavlov in 1886 and in the same year in England by Gaskell. Indeed, analyzing the influence of centrifugal nerves on cardiac activity, both of them, completely independently of each other, came to the conclusion that in this case we are not simply talking about an intensification or increase in cardiac activity, but that these effects must be considered as a result of a change in the basic functional properties of the cardiac muscle, a change in excitability, conductivity, and contractility of the cardiac muscle. The basis for this had to be, as I. P. Pavlov expressed it at the time, a change in the basic life properties of the cardiac muscle. And as early as 1886, in Pavlov's work, there slips the thought that obviously we are talking about some change in the nutrition of the cardiac muscle under the influence of nerves. It must be emphasized, however, that, under the impression of the doctrine of vaso-motor innervation, Pavlov at first tried to reduce the action of the vagus and sympathetic nerves to vaso-motor influences, i.e., influences on coronary circulation, and thought that perhaps the intensification and increase in cardiac activity upon irritation of the sympathetic nerve is the result of expansion of the coronary bed, while the inhibitory action of the vagus nerve is the result of constriction of the coronary vessels. Later these assumptions were confirmed. Indeed, the sympathetic nerve is a nerve that dilates, and the vagus constricts the coronary vessels, but at the same time it turned out that it is impossible to explain the characteristic influence of centrifugal nerves on the heart by their vaso-motor effect, because the vagus and sympathetic nerves exert a similar influence on the heart even in those animals that have no coronary circulation and the heart generally lacks its own circulatory system. For example, in amphibians, particularly in frogs, the heart is nourished from its cavities, and yet the effects of the nervous system are the same as in more highly organized animals. Pavlov took the point of view that we are talking about some regulation of the life properties of the heart in some other way, directly under the influence of the nervous system. Completely similarly, Gaskell, who worked from the beginning on cold-blooded animals, mainly on turtles and crocodiles, also came to the conclusion that the influence of the cardiac nerves is an influence on functional properties: a change in the refractory phase, a change in excitability, etc., and this must be based on a change in the course of assimilatory and dissimilatory (or anabolic and catabolic) processes. In this respect, Gaskell was a follower of the German school of Hermann and Hering, who considered the process of excitation in excitable tissues as a result of a disturbed relationship between the assimilation and dissimilation of certain materials. Gaskell at the same time made an attempt to confirm his view with the help of bio-electrical observations on the cardiac muscle. It was already known that in every excitable tissue, both nervous and muscular, differences in potential arise at the moment of activity, which give rise to the development of currents. At the same time, it was known that at rest, a damaged area of muscular tissue is electro-negative in relation to a normal area. If leads are taken to a galvanometer from a normal and a damaged area, the so-called current of rest is observed, which always has a definite direction—from the damaged area through the tissue to the normal area. When activity arises, this current of rest undergoes a negative fluctuation, i.e., the potential of the normal area falls during excitation. At that time, the view was established that this fall in potential is the result of the destruction of certain substances, a manifestation of a certain dissimilatory process. Hence arose the thought that the reverse phenomenon—assimilation, i.e., the construction of initial materials from breakdown products—should be accompanied by a positive fluctuation of the current of rest. In the first experiments, which could be made with the technique of that time, Gaskell obtained an indication that such a positive fluctuation of the current of rest does indeed arise in a stopped heart if the vagus nerve is irritated. Gaskell's data were disputed by a number of authors and were confirmed with impeccable technique only by A. F. Samoilov.

Engelmann brilliantly developed the question of changes in the functional properties of cardiac muscle under the influence of nerves and provided excellent criteria for their evaluation. ' Concentrating his attention on the study of digestive processes and performing various operations on the digestive canal, removing gland ducts, isolating segments of the intestine, blocking the stomach, pulling intestinal loops under the skin to observe their motor functions, I. P. Pavlov passed through his hands a huge amount of material from operated animals. Observing them day after day for long periods, he discovered that in many cases such operations, associated with unnatural tension of the internal organs, with the unnatural effect of external air on the mucous membranes, etc., lead to the emergence of certain pathological conditions in animals. He had to observe cases such as sudden fainting of the animal, accompanied by almost complete cessation of cardiac activity and breathing, a state of syncope, cooling of the animal. There were cases when there was a complete picture of apparent death. Pavlov mentions one case in which an animal with an isolated stomach according to Pavlov's method was fed and immediately after food fell into a state of syncope and seemed to have died. The animal was already taken to the table for dissection when it was noticed that the heartbeat resumed. The animal returned to a normal state. There were cases when operated animals (bringing a duodenal loop under the skin) showed complete atrophy of the muscle tissue. Then there were cases of ulcers on the mucous membrane of the tongue, again with tension of the duodenum. There were cases of ulcer formation on the limbs. In dogs, cases of ascending paralysis of the spinal cord were also observed, cases of psychosis—obvious violation of behavior and normal relationships with surrounding animals and people, accompanied by clear pathological-anatomical changes in the cerebral cortex. All these observations, made incidentally during the study of the digestive process, forced I. P. Pavlov in 1921 to make a 'categorical assertion that the old doctrine of the trophic nervous system was correct, that doctors and physiologists had wrongly rejected this correct point of view and overlook an extremely important mechanism constantly acting in the living organism. He began to assert that we must, along with centrifugal nerve fibers causing the function of one organ or another, along with vasoconstrictor nerves regulating the flow of nutritional materials, admit the existence of fibers which, as he says, most subtly regulate the process of nutrition in tissues and the relationships between tissue elements and their surrounding environment. Justifying his doctrine, Pavlov returned again to the doctrine of cardiac nerves and expressed the thought that the strengthening nerves of the heart, causing a change in the strength of cardiac contractions and changing, as had been predicted and later proven by Engelmann, the basic functional properties of cardiac muscle, and represent a typical example of trophic nerves. In the same year, Haskell, in his classic monograph on the involuntary nervous system, presenting the results of his many years of work on the autonomic nervous system, stated in categorical form that the influence which the sympathetic and vagus nerves exert on the heart cannot be considered otherwise than as trophic influences, i.e. that this is the direct regulation of tissue nutrition by nerve fibers. These assertions of both Haskell and Pavlov, however convincing they may be, still could not be considered proven, because a whole series of essential gaps remained that needed to be filled in order to categorically speak of the existence of a trophic nervous system and that the examples they provided are indeed typical examples of trophic innervation and that the phenomena they spoke of have some universal significance for the organism. An extremely important stage would be the proof that such influences can be observed and are observed in other tissues, in other organs. Data from various sides were presented in favor of the fact that the matter is similar with smooth muscle. Specifically for the smooth muscle of the intestine, uterus, ureters, and a whole series of other organs, for such special muscles as retractor penis in the dog, it was discovered that all these smooth muscle apparatuses, either maintaining tone or making rare rhythmic contractions, general or peristaltic, work automatically, independently of the presence of a connection with the central nervous system. However, centrifugal nerves going to these smooth muscle organs are always able to cause quantitative changes in them, i.e. cause either acceleration or slowing of the rhythm, or strengthening of peristaltic contractions, or their weakening; in tonically acting muscles, nerves cause either an increase or decrease in smooth muscle tone. Starting from 1921, Orbeli and his colleagues, on the basis of a number of facts, managed to establish that skeletal muscle receives two kinds of innervational influences—motor innervation, which causes the muscle to act, and sympathetic innervation, which has a regulatory character. The latter by itself never leads the muscle to activity, never makes the muscle contract, but only exerts such an influence on the skeletal muscle as is reflected in the activity caused by the motor nerve. A careful analysis showed that in these cases we are talking about a change in the excitability thresholds of both the skeletal muscle itself and the innervating nerve, a change in the time characteristics (chronaxy), a change in the ability to hold more or less significant tension for a more or less significant period of time, a change in the ability to perform long-term rhythmic work, etc. Thus, a whole series of proofs was presented that with respect to skeletal muscle the sympathetic nervous system exerts an influence of the same order as was earlier discovered on the part of the autonomic nerves with respect to cardiac muscle; this proved the universality of this type of innervation with respect to all types of muscle tissue. With time, Orbeli and his colleagues managed to obtain data which indicate that the sympathetic nervous system causes similar changes in the functional properties of receptors, peripheral nerves, and the central nervous system (see Autonomic nervous system). The data of the Orbeli school in recent years find confirmation in a number of works from other laboratories.

both in the USSR and abroad (in the laboratories of Vojacek, Nikrasov, Ascher, Brücke and others). Thus, at the present time, for almost all tissues in the organism, the existence of such nerve apparatuses has been proven, which, without causing function or leading to activity of the organ, at the same time sharply affect the condition of this organ and thereby influence those functional activities that will be caused by corresponding causes. Without wishing to mix without sufficient grounds two categories of phenomena, namely the influence on functional properties and the influence on tissue nutrition, Orbeli proposed to use the name 'adaptive nervous system' for the nerve apparatuses that create those changes in functional properties which were first established for the heart, then for smooth muscle, and then also for skeletal muscle, the nervous system, and sensory organs. By this, Orbeli did not want to assert that these adaptive influences must be separated from trophic influences, but only wanted to emphasize that adaptive influences have already been proven indisputably and must have their own nomenclature, their own designation, and that until facts are discovered which would also indisputably speak of changes in the chemistry, physical properties, and physico-chemical state of tissues, it is better to avoid the term 'trophic.' Indeed, neither in Haskel's data nor in I. P. Pavlov's data were there factual proofs that these influences on functional properties are connected precisely with changes in metabolism or with changes in the chemistry of tissues. There were only indications that under the influence of nerves a positive fluctuation of the current of a stopped cardiac muscle can be observed. This one positive fluctuation by itself is not yet proof of essential chemical shifts. It represents an extremely valuable fact, but it is too little to consider the question finally resolved. And in this direction facts were established in the reverse order. If adaptive influences were first discovered on the cardiac muscle and later on the skeletal muscle, then the skeletal muscle proved to be the most convenient object for discovering the true trophic influence of the sympathetic nerves. In this respect, a number of facts have been obtained both in our country and in foreign laboratories under the influence of various initial hypotheses. All these facts complement each other well and fit into a single whole. In a number of foreign laboratories, it was discovered that when the sympathetic nerves are cut on one side, chemical changes can be observed in the muscles of the corresponding limb. Specifically, in the limbs, asymmetry was noted in the content of glycogen, lactacidogen, creatine, i.e. a whole series of chemical substances which are either the starting material for muscular work or products arising from muscular activity. There are facts indicating a disturbance in the course of oxidative processes on the sympathectomized limb (Magnus, Alslieben and colleagues, Stepanov). Furthermore, in Orbeli's laboratory, a series of works was carried out clarifying the intimate side of the influence of the sympathetic nerves on the muscle. Orbeli, by direct experiments with determination of gas exchange of an isolated curarized muscle, showed that when the sympathetic nerve is irritated, there is an increase in oxygen consumption by this muscle. Krestovnikov, by means of Tünberg's method, showed a sharp deviation in the course of oxidative processes in the substance of the muscles on the side where the sympathetic nerve was irritated. Then Orbeli and Tonnykh showed that a thermal injection causes an increase in temperature in cats precisely due to an increase in heat production in the muscles through the sympathetic nervous system. After complete sympathectomy, the injection does not cause an increase in temperature. Krepe and Streltsov established that the sympathetic nervous system influences the course of restitution of materials in muscle tissue that has performed prolonged motor work. As a criterion, electrometric titration was used. The vessels of the muscle were washed with a physiological solution of salt, and this solution, having passed through the muscle and washed out certain materials from it, was subjected to electrometric titration. Analysis of the electrometric titration curves showed that the content of buffer materials in the washout liquid sharply deviates if the muscle has performed work. Titration of portions of liquid taken at different times after work shows a gradual return to the original buffer values. Thus, there is a significant deviation, and then a return to normal. If immediately after completing work the sympathetic fibers going to the limb are irritated, it is found that in the first moments after irritation the electrometric titration curves are already very close to the original normal, i.e., when the sympathetic nerve is irritated, conditions are created that force the muscle tissue to return more quickly to the normal picture of bufferization. Analysis of the curves showed that the matter must be about an increase in either lactate or phosphate buffers. The direct follow-up, carried out by Kreps, Verzhbinskaya, Borsuk, Mikheleson, and Streltsov by means of microchemical determination of the content of lactic acid and various phosphorus fractions in the muscle itself, led the authors to assert that under the influence of irritation of the sympathetic nerve there is an increase in the content of pyrophosphate fractions of phosphorus, i.e., accumulation of that very fraction of phosphorus which to the greatest extent can serve as a buffer material and maintain the constancy of the reaction of muscle tissue despite the accumulation of acidic products. What was proposed on the basis of the electrometric curve found confirmation in the data of microchemical analysis. In parallel with this, a study of the physical properties of the muscle was made by Lebedinsky, who discovered changes in electrical conductivity. Electrical conductivity was measured with respect to high-frequency alternating currents, and both ohmic and capacitive resistance were taken into account, as had previously been done for the skin in Gildemeister's works; just as in the frog's skin, in the muscle, irritation of sympathetic fibers changes both types of resistance. Then Lebedinsky and Mikheleson N. I. made an assessment of the elastic-viscous properties of muscle tissue by the method of torsional oscillations. It was discovered that under the influence of the sympathetic nerves certain shifts occur, namely changes in the viscosity of muscle substance. Finally, it is necessary to mention the results of histological studies of frog and cat muscles, carried out by Hering and Langelaan a year after the cutting of the corresponding postganglionic sympathetic fibers: an increase in the content of nuclei (10% higher than the control side) and accumulation of sarcoplasmic substance were found without deviations in the fibrillar apparatus. Thus, the doctrine of the trophic influence of the sympathetic nervous system on skeletal muscle, that sympathetic fibers, without causing any function, any contraction, at the same time are regulators of trophics, i.e., regulators of nutrition, regulators of the relationship between muscle and environment, regulators of oxygen absorption, permeability, elastic-viscous properties, is indisputably proven. It was natural to return to the cardiac muscle and to check whether analogous influences exist there, whether it is possible to admit there a connection between changes in functional properties and changes in physical or chemical state. In this respect, in Orbeli's laboratory in recent years data have accumulated which speak of the fact that changes in electrical conductivity of the same order and character as have been proven for skeletal muscle also take place in the cardiac muscle when the vagus and sympathetic nerves are irritated. Just as on functional properties, these nerves act on electrical conductivity in the opposite direction (Aleksanyan and Mikaleva). Thus we come to the conclusion that we must not look for trophic innervation, but for functional innervation. It is precisely that type of innervation which pushes the organ to work, forces the organ to work, that represents a particular case, while the more universal significance is that trophic innervation of which we are now speaking. If we turn to comparative-physiological data, then here the fact is established that in a number of animal forms, even in the case of organs of external behavior which can be compared with our skeletal musculature, there is the presence of a certain automatism or local peripheral call to activity under the influence of direct mechanical or physical irritations, and the nervous system is an apparatus which changes the functional state of the muscle or the functional state of subordinate nerve nodes, and thus must be recognized as analogous rather to that innervation of which we speak than to motor innervation. Thus in the experimental material obtained on higher animals and in the comparative-physiological material we find confirmation of the thought that the development of the nervous system and management from the side of the nervous system over tissues is carried out by two fundamentally different paths. One influence of the nervous system is the regulation of chemistry, regulation of physical properties, functional state of organs, and the other is the call of the organ to work. Depending on with which organ or with which representative of the animal kingdom we have to deal, we always encounter the predominance of one or the other type of innervation.

Each of them deserves attention, since each plays a role in the regulation of organ function, in the development of individual pathological symptoms. Thus, the question of trophic innervation, which arose in the clinic based on observations of dystrophic processes, has collapsed upon experimental study of dystrophic processes. In the development of dystrophic processes, so many other no less important and at the same time more gross factors play a role that the problem TROPHIC ACTION

The significance of trophic influence has remained obscure. We find proof of trorophic innervation not in dystrophies, but in the normal course of physiological processes. Trophic innervation is interesting not so much for the fact that under its influence, with the presence of additional factors, trophic disorders can occur, but for the fact that the entire daily process of life of our organs is under the control of a certain trophic regulation. It is characteristic of trophic innervation that it does not give anything that could not also occur without it. We are not talking about calling forth qualitatively new properties, about the emergence of new phenomena, but about the quantitative regulation of what occurs autogenously in tissues even without this system. If this is not kept in mind, one can always draw erroneous conclusions regarding the role and significance of trophic innervation. Authors who imagine that when the trophic nerve is interrupted, all tissue nutrition should cease are mistaken—of course this does not happen. Nor are those right who believe that after cutting the trophic nerves, some uncontrollable chaos of trophic processes should occur, because the trophic nerves allegedly inhibit the trophic function. The processes go on quite well and coordinated even without these trophic nerves. But it is not difficult to grasp that these automatically occurring processes undergo significant quantitative shifts in one direction or another under the influence of nerves coming from special departments of the central nervous system. As for how and under what circumstances these trophic influences can be called forth, here, as in all other cases, we have to admit the possibility of central excitation of the brain nuclei of these nerve fibers and then the possibility of reflex calling forth of these phenomena from one or another peripheral receptor apparatus. If we take as a criterion the influences which the sympathetic nervous system exerts on skeletal muscle, on cardiac muscle, on sense organs and nerve centers, then in all these cases the picture turns out to be similar. We now have convincing data which testify that all these effects can be caused not only by artificial irritation of peripheral branches of the sympathetic nerve, but also by irritation of certain central foci. In recent years many facts have accumulated which testify that in the brain, in the subthalamic region, precisely in the tuber cinereum, there is a focus giving rise to all sympathetic influences (Kag-plus and Kreidel, Cannon and others). In 1929 three Canadian authors (Beatty, Brow and Long) succeeded, through experiments with degeneration, to trace the paths which, starting from the tuber cinereum, descend through the region of the pons, quadrigemina and medulla oblongata into the spinal cord and come into contact with the cells of the lateral horns of gray matter, i.e., with those cellular formations which have long been recognized as the cell bodies of preganglionic sympathetic neurons. This was established in higher animals—dogs and cats. The same relationships exist in cold-blooded animals. In the frog the same thalamic region is the focus from which all sympathetic influences can be obtained. 8«9 In the laboratories of Orbeli a large series of works was carried out which showed that, by irritating the thalamic region with a crystal of table salt by the Sechenov method, one can cause acceleration of cardiac activity, closure of renal glomeruli, narrowing of skin vessels, contraction of skin pigment cells (probably as a result of narrowing of vessels), change in skin potentials, and finally all those special effects which have been described above in relation to skeletal muscle and spinal cord, namely, increase in working capacity of tired muscles, change in chronaxy of nerve and muscle, acceleration of rigor, etc. These same effects can be caused under certain conditions from the spinal cord, for example by poisoning the spinal preparation with strychnine one can on the periphery cause all sympathetic effects, in particular changes in the isolated skeletal muscle connected with the central nervous system only by means of sympathetic nerve fibers. Thus the possibility of central calling forth of phenomena is beyond doubt. Next arises the question, whether in physiological conditions there are occasions for the nerve centers to be excited directly. In this respect there is a very widespread doctrine that carbonic acid is an excitant of nerve centers, in particular of the respiratory center. With increased accumulation of carbon dioxide in the blood there occurs an exciting influence on the motor centers, on the centers regulating cardiac activity and all other sympathetic and parasympathetic centers. The irritating influence on centers is also ascribed to anoxemia. In recent time there are a number of indications of serious changes in the state of the central and peripheral nervous system under the influence of anoxemia. These data prompted A. M. Vorobiev to investigate the influence of anoxemia on the chronaxy of motor nerves. It turned out that with weak degrees of anoxemia there occurs a sharp shortening, and with great degrees a sharp lengthening of the chronaxy of the sciatic nerve in the frog. These effects can be obtained also after removal of the large hemispheres (in thalamic frogs), but disappear after removal of the thalamic region. Further analysis showed that they can occur when somatic nerves are disconnected and connection with the brain is maintained by means of only sympathetic fibers and are absent within the tested conditions if the sympathetic paths are cut but all somatic connections are preserved, just exactly as in experiments with irritation of the thalamic region with a crystal of table salt. However, in recent years doubts are expressed as to how carbonic acid (or the increased concentration of hydrogen ions associated with its accumulation) acts, whether it acts directly on central formations or reflexly, irritating some peripheral receptors. In particular, a large role is attributed to that special group of receptors which is located in the aorta and in the region of the branching of the carotid artery into internal and external branches. In the initial part of the internal carotid artery there is an expansion (sinus caroticus) filled with special receptor apparatuses. To it is adjoined a special organ—the glomus caroticus, which for a long time was considered an endocrine organ. At present it has been clarified (Del Castro) that it is a bundle of receptors surrounded by capillary vessels. Both groups of receptors are connected with centripetal fibers of the so-called sinus nerve from the composition of the glossopharyngeal nerve (IX pair). A number of authors asserts that along these fibers impulses are conducted which arise in the sinus caroticus under the influence of mechanical changes in the vascular system or in the glomus caroticus under the influence of chemical and physical (e.g., thermal) shifts. At present the question remains open as to in exactly which cases we must admit direct central irritation of the brain substance and in which—irritation of it from peripheral intravascular receptors. If we speak of trophic influence, of regulation of one or another side of metabolism, then one can imagine regulation of individual sides of fat, water metabolism. The dominant doctrine until recent time asserted that in the central nervous system we must imagine nerve elements sensitive to disturbance of the chemical composition of the blood, precisely in relation to these individual components. There are authors who believe that in the region of the medulla oblongata there are centers of sugar metabolism, fat metabolism, protein metabolism, etc. Against this doctrine there are a number of weighty objections (Bogolyubets). At present time this doctrine can undergo significant changes: it is easier to imagine the presence of special sensitive elements in the walls of blood vessels. If one recalls that the sinus caroticus and glomus caroticus are innervated by the same n. glossopharyngeus which innervates the oral cavity with its chemoreceptors, then it is easy to imagine in this vascular reflexogenic field various receptor formations which will react to changes in the chemical composition of the blood. This finds its justification also in the history of development of the carotid body. Next arises the question, whether there is proof that adaptational-trophic influences can be caused reflexly from some receptors. In this respect we have a large old material testifying that characteristic influences on the heart can be caused from the entire skin surface and from the abdominal organs (experiment of Golts with a blow to the intestine, experiments of Engelmann who caused various changes in functional properties of the heart, applying qualitatively and quantitatively different irritants to the surface of the frog's skin). Orbeli succeeded in showing that increase in working capacity of tired muscle, change in thresholds of excitability of muscle, change in chronaxy of muscle and motor nerves, acceleration of rigor can be caused reflexly, through the sympathetic nervous system, when applying the most moderate ordinary irritations to the skin surface of the frog.

In relation to warm-blooded animals, it has also been possible to establish that changes in the state of receptors and in the state of the central nervous system can be caused reflexively, both through the spinal cord and through the thalamic area (Orbeli). Should these trophic reflex influences have a generalized or localized character? In this regard, there are two possibilities. On the one hand, with the entire central nervous system present, the possibility of generalized influence is ensured. The sympathetic nervous system has universal distribution, and in all those cases where the tuber cinereum or the spinal cord as a whole is brought into an active state, we simultaneously observe the appearance of sympathetic effects throughout the body. This is facilitated by the fact that sympathetic fibers of the n. splanchnici lead to the release of adrenaline into the blood, which has a general effect on all organs with sympathetic innervation. But there is also the possibility of transmission of influences through the peripheral parts of the sympathetic system beyond the central nervous system, due to the fact that postganglionic axons of the sympathetic system branch and spread their collaterals very far. Here we encounter a whole series of segmental connections that ensure, within each metamere of the body, mutual connection between the skin coverings, muscles, and certain segments of internal organs, embryologically related to this metamere, through the processes of the same nerve cell. As a result of this, the possibility arises of obtaining intrasegmental relationships between the skin coverings, muscles, and internal organs even after the removal of the entire central nervous system. One can think that under normal conditions within metameres, such trophic phenomena can occur without the participation of the central nervous system. Under certain conditions, intrasegmental and monosegmental influences are conceivable, which lead to the presence of segmental trophic phenomena. Not without reason does clinical practice more often encounter the fact of isolated occurrence of trophic disorders in one or another segments. This segmentarity can be determined, in addition to the branching of processes of the sympathetic system and the interaction of organs belonging to one metamere, also by the fact that posterior root fibers, which apparently also possess a certain trophic action, have a segmental distribution on the periphery, l. Orbeli. Nervous trophic action. The question of nervous trophic action was first raised by pathology and clinical medicine more than 100 years ago. At the present time, this question has been most fully developed experimentally and theoretically in the laboratories and clinics of Prof. A. D. Speransky. This doctrine occupies the attention of broad scientific and practical circles not only of physicians but also of biologists. In connection with broad generalizations, it is put forward as a monistic problem in the construction of the theory of medicine. At different stages of its development, the doctrine of nervous trophic action encountered active opposition. This is also the case at the present time, and the oppositional mood stems from a number of fundamental positions regarding the understanding of the relationships between medicine and biology, between modern physiology and clinical medicine, etc. Not all modern medicine arose from modern biology, since medicine is a much more ancient system than scientific physiology. Modern physiology studies fragments of processes in accessible conditions and artificially created conditions. Medicine deals with life in all its aggregate of simple and complex manifestations with those exceptional combinations that only nature can compose. 'Modern physiology continues to live mainly by the analysis of the process, while medicine has always been interested only in synthesis' (Speransky). - The main controversy around questions of nervous trophic action has also unfolded in the plane of affirmation or negation of a certain substrate in the form of a trophic nerve cell and accounting for the process within the framework of physiological study. These fundamental viewpoints still cannot be considered complete at the present time, and undoubtedly further research into questions of nervous trophic action with greater sharpness will continue this historical controversy. In order to better understand the development of the doctrine of nervous trophic action, it is necessary to give a brief history of the question in Speransky's interpretation. The beginning of the entire matter of nervous trophic action should be considered the experiments of Magendie (1824), who, by damaging the intracranial parts of the trigeminal nerve in rabbits, noted in them a sequential disease of the eyes in the form of keratitis. These experiments were repeated by Samuel, Meissner, Schiff, Kirchner, and others. As a result of irritation or damage to the intracranial parts of the trigeminal nerve, on the side of the injury in rabbits, conjunctivitis and keratitis appeared, sometimes with perforation of the cornea. Some considered the inflammatory changes in the eyes a direct consequence of nerve trauma and saw here a manifestation of a special trophic function of the nervous system. Others sought explanations simply in the violation of eye sensitivity, which increased the percentage of its accidental injuries. As a result of numerous experimental and clinical works, Samuel created a whole theory, set forth in his book 'Die trophischen Nerven' (1860), in which he asserts the existence in the organism of a special trophic nervous system and gives a general scheme of its distribution and work. This theory did not receive general recognition, however Charcot, after a certain time, again quite categorically spoke in favor of the connection of certain chronic local disorders with a violation of nervous function. He also asserted that 'in pathology there is nothing as firmly established as trophic disorders on the basis of damage to nerve centers or nerves.' The analysis of the consequences of nerve injuries after the war of the Northern and Southern American states by the physicians Mitchell, Morhouse, and Kine showed the development of dystrophic phenomena in tissues after nerve injuries, which was also interpreted as a special form of nerve reactions. The discovery of secretory nerves by Ludwig in 1851 and the works of Heidenhain on the analysis of the nervous side of the secretory process with indisputable certainty affirm the presence of trophic nerve fibers and even attempt to prove the presence of trophic fibers in the composition of the sympathetic nerve. Claude Bernard's classic experiment with a sugar injection also with indisputable proof demonstrates the active participation of the nervous system in the process of regulating metabolism. The dissertations of V. I. Razumovsky on the topic of atrophic processes in bones after nerve section (1884) and I. P. Pavlov on the accelerating nerves of the heart (1885) are milestones in the field of studying nervous trophic action. A series of works of Spiss on the study of the effect of anesthetizing substances on the course of certain pathological processes (1901-06) went in the same direction.- A new form of approach to questions of nervous trophic action began to be created in connection with the study of the physiology and morphology of the autonomic nervous system, starting with the observations of Gaskell, Langley, Sherrington, and others, and the development of questions of surgery on the autonomic nervous system by Leriche and others further advanced the development of this problem and the clarification of the trophic function. The experience of the world war with numerous injuries to the nervous system gave enormous material for the proof of nervous trophic action, and the specific clinical material revived past ideas about this doctrine. Speransky establishes four main historical stages in the doctrine of nervous trophic action, namely: one direction-Samuel and Charcot with a number of other clinicians; the second direction-Claude Bernard and his experiments to clarify the role of the nervous system in metabolism; the third direction-physiological-Ludwig, Heidenhain, and I. P. Pavlov; the fourth direction-Levi. The first direction was mainly followed by clinical research studying the nature of trophic consequences of nerve injuries; in this, some worked with a bias toward intervention on sympathetic nodes and pathways (Leriche, Mattei Corn, and others), while others concentrated their attention on parts of the central nervous system (Shamov, Molotkov, Bruening). The research of A. G. Molotkov with nerve section above and below the site of neuroma showed that section below the neuroma did not change the course of the chronically non-healing ulcer and other trophic lesions of the lower extremities. The same operation, performed above this point, cured this disease sometimes in a remarkably short time. Similar observations were conducted by Polenov, A. S. Vishnevsky, and others. A number of theoretical works from the field of general pathology also contributed to strengthening the view of the nervous system as the starting point in the development of certain pathological processes on the periphery. Here it is necessary to note the works of Soviet scientists - Abrikosov, Davydovsky, Burdenko, Mogilnitsky, Vail, and the German pathologist Ricker.-The starting point of the second direction was Claude Bernard's sugar injection; these works concerned the clarification of the role of the nervous system in general metabolism. Numerous facts from the field of pathology of the subcortical ganglia of the brain, pathophysiological experiments with chemical and morphological researches with indisputable clarity revealed the role of the nervous system in the physiology and pathology of carbohydrate, water-salt, fat, and protein metabolism.

Among the main authors who developed this direction, one should name Ashner, Karpus, Kreidl, Marinesco, Trendelenburg, Eckhardt, Levi, Dresel, Asher, Kraus, Zondek, Biedl, Cushing, Förster, Burdenko, Mogilnitsky, Pines, Alpern, and others. The third direction in the study of nervous trophics, the beginning of which was laid by Ludwig, Heidenhain, and I. P. Pavlov, aimed to study the influence of the nervous system on local metabolism in tissues by applying physiological methods. Among the works of this direction, it is necessary to mention Babkin's research, which, using the method of conditioned reflexes, showed that despite the section of the sympathetic nervous system of the salivary gland, the composition of saliva with different types of conditioned stimuli remains different and still connected with those unconditioned reflexes, the signal for which is this conditioned stimulus. The works of Alpern and his colleagues detailed and developed the data of Heidenhain's experiments on the question of the direct nervous influence on the qualitative composition of the secretion of the salivary glands. The research of G. I. Stepanov, Magnus-Alsleben, and Hoffman aimed to study the influence of the sympathetic nervous system on the vital staining of striated muscles in frogs. In 1913, Bukey published his observations on the sympathetic innervation of skeletal muscles, and as early as 1895, Timofeev traced the sympathetic fibers within the Pacinian corpuscles. The research of de Bur and L. A. Orbeli independently showed the direct influence of the sympathetic nervous system on the tone of striated muscle. In subsequent works, Orbeli and his colleagues clarified the influence of the autonomic nervous system on the work of the central nervous system, sense organs, and other functions. The fourth group of works [whose starting point were the well-known experiments of Levi (1923) on Vagus- and Sympathicusstoff] is connected with the active state of a particular nerve. The mentioned experiments testify both to the existence of a special neuro-humoral form of regulation of physiological processes in the body, and with even greater force affirm the idea that the nervous influence on the chemistry of tissues is indeed direct. Spersky, giving a historical outline of the development of nervous trophics, quite rightly points out that the discovery of secretory nerves was a factor affirming the concept of neurotrophic functions, since 'a nerve is secretory only because it is trophic, because one cannot exist without the other.' The doctrine of nervous trophics, in his view, breaks down into the history of the doctrine and the history of misunderstandings. One of the essential misunderstandings was and is still that many want to see and understand nervous trophics as a special, completely new nervous function, different from those previously known, all the more so since all previous ideas about such functions of the nervous system as motor, sensory, and secretory were connected with their strict localization and the presence of a corresponding center. By analogy with this, some demanded that the nervous trophic function should represent a certain morphological substrate with its clear localization. Among other misunderstandings, one should include the statements of individual physiologists who believe that to prove certain functions, one should not resort to pathological processes as an indicator, as is particularly the case with respect to the doctrine of nervous trophics. Acad. I. P. Pavlov is one of those physiologists who recognize the scientific validity of an indicator taken from the field of pathology. A whole series of severe pathological changes in various organs in dogs that have undergone various operations in the area of the gastrointestinal tract are interpreted by him as dystrophic processes resulting from damage to the nerve apparatuses. If one abandons the idea of a nervous function as always strictly isolated and assumes that the neurotrophic component is part of all without exception processes, then no concept of an organ, its structure and function is possible without studying its nervous relationships. If one then recalls that the question of the influence of the nervous system on the course of physicochemical processes in the body has been resolved positively, then the correctness of such a statement is beyond any doubt. Attempts by some theorists and clinicians to attribute nervous trophics only to the autonomic nervous system are hardly justified, since the autonomic nervous system itself is intimately involved in the entire nerve network. One cannot, therefore, represent it as some kind of parallel existing system with its strictly delimited function. Clinical facts show that with damage to any nerve point, we encounter a whole series of dystrophic and atrophic conditions in various tissues and organs. Each of the affected nerve elements, wherever it is located, involves other healthy nerve parts in the process, creating for a time or forever new centers of pathological processes. From this it was concluded that 'any nerve point, excluding peripheral nerve formations, is part of the trophic nervous system, actively connected with the processes of nervous trophics. The autonomic nervous system is only a special case of those forms of physiological relationships that were known under the name of nervous trophics' (Spersky). Numerous experimental data and their verification on clinical material have undoubtedly shown that the neurotrophic process or the nervous form of control of physicochemical phenomena in a complex organism exists and that this process has both general significance for the whole organism and particular significance for each organ. The merit of Spersky is that he approached the understanding of nervous trophics not from any one of the above-mentioned positions, but taking into account the entire process as a whole. Having passed through a series of stages of experimental work in the laboratory and clinic, Spersky's research covered all departments of general pathology and ultimately led to the creation of the basic provisions of the general theory of medicine. This became possible from the moment it was possible to establish and show that neurotrophic disorders do not mark a special circle of processes, that they are part of all without exception pathological phenomena, cannot be extracted from them and therefore do not and cannot constitute a separate chapter in pathology. The doctrine of nervous trophics as it is synthesized by Spersky shows that this new direction seeks to solve the task of creating a unified theory of medicine and to give a concrete representation of the leading link in the various pathological processes, establishing a fundamental unification of countless individual pathological forms into a single system. Inevitably, this monistic principle also reinterprets the problem of therapeutic intervention. All the above-mentioned historical currents in the problem of nervous trophics, which were only partial currents, are now united for the first time.