Book - The brain of the tiger salamander 6
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Herrick CJ. The Brain of the Tiger Salamander (1948) The University Of Chicago Press, Chicago, Illinois.
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Part I. General Description and Interpretation 1. Salamander Brains | 2. Form and Brain Subdivisions | 3. Histological Structure | 4. Regional Analysis | 5. Functional Analysis, Central and Peripheral | 6. Physiological Interpretations | VII. The Origin and Significance of Cerebral Cortex | VIII. General Principles of Morphogenesis Part 2. Survey of Internal Structure 9. Spinal Cord and Bulbo-spinal Junction | 10. Cranial Nerves | 11. Medulla Oblongata | 12. Cerebellum | 13. Isthmus | 14. Interpeduncular Nucleus | 15. Midbrain | 16. Optic and Visual-motor Systems | 17. Diencephalon | 18. Habenula and Connections | 19. Cerebral Hemispheres | 20. Systems of Fibers | 21. Commissures | Bibliography | Illustrations | salamander
Chapter VI Physiological Interpretations
APPARATUS OF ANALYSIS AND SYNTHESIS
IN A primitive brain like that of Amblystoma the stable framework of localized centers and tracts performs functions that are primarily analytic. The sense organs are analyzers, each attuned to respond to some particular kind of energy. The sensory systems of peripheral nerves and the related internal sensory tracts are parts of the analytic apparatus, in so far as their functional continuity with the peripheral organs of the several modalities of sense can be traced.
On the motor side similar conditions prevail. The neuromotor apparatus is organized in functional systems, each of which is adapted to call forth the appropriate sequence of action in a particular group of synergic muscles. These units are as truly analyzers as are those of the sensory systems, though in an inverse sense. Out of the total repertoire of possible movements, those, and only those, are selected which give the appropriate action. The efferent fibers are grouped, the members of each group being so bound together by central internuclear connections that they act as a functional unit adapted for the execution of some particular component of behavior, such as locomotion, conjugate movements of the eyeballs, seizing and swallowing food, and so on.
The several sensory systems are so interconnected within the sensory zone as to react mutually with one another. They form a dynamic system so organized that all discharges from this zone are resultants of this interaction. This interplay has pattern. The various modalities of sense are not discharged into a single common pool of equipotential tissue. The sensory components of the nerves are segregated, more or less completely, so that related systems converge into dominant centers of adjustment— exteroceptors in the tectum, proprioceptors in the cerebellum, olfacto-visceral systems in the hypothalamus, olfacto-somatic systems in the habenula, and so on.
A review of the internal architecture of the adult brain of Amblystoma suggests that the specifications of the general plan are drawn in terms of current action. The elaboration of the analytic apparatus on the sensory side is carried only so far as is requisite to facilitate responses to any combination of sensory stimuli in patterns determined by the appropriate use of such motor equipment as the animal possesses. In species with simpler action systems the central analytic apparatus is less elaborate; in species endowed with more complicated motor organs the central architecture is more elaborate. In all species the peripheral sensory equipment determines the architectural plan of the primary centers of the sensory zone; internally of this level the details of the plan are shaped by two additional factors : first, the motor equipment available and, second, the amount and quality of the apparatus of correlation and integration required for the most efficient use of such sensory excitations as the animal experiences. The cross-connections between the sensory and motor zones are quite direct and simple in early embryological stages, so arranged as to provide uniform stereotyped responses to oft recurring situations. But as development advances these connections become more and more complicated, an intermediate apparatus of correlation is interpolated, and, correlated with this, the behavior becomes more diversified and unpredictable.
In the sequence of development of behavior patterns this change can be accurately dated. For instance, in Amblystoma between the early swimming and early feeding stages, at about Harrison's stage 40, the swimming movements, which in younger stages are perfectly co-ordinated by the bulbo-spinal central apparatus alone, lose this autonomy, and participation of the midbrain is essential for the maintenance of efficient swimming, as was mentioned on page 62 in describing experiments by Detwiler ('45, '46). It is during this period that tecto-bulbar and tecto-spinal connections of essentially adult pattern are established ('39, p. 112). In human fetal development there is a similar critical period at about 14 weeks of menstrual age (Hooker, '44, p. 29). At this time the upper levels of the cerebrum acquire functional connections with the lower brain stem, and the behavior shows a corresponding change. "The fetus is no longer marionette-like or mechanical in the character of its movements, which are now graceful and fluid, as they are in the new-born."
Synthesis and integration may be effected in various ways. The most evident nervous structures employed here are the internuclear tracts which form a complicated web of conductors, which interconnect the analytic units with one another so that the entire complex forms an integrated equilibrated system. This is the apparatus of the stable heritable components of the action system — the reflexes and instincts. A second integrating apparatus is found in the allpervasive neuropil, and a third in specialized derivatives of the latter, the associational tissues locally differentiated in the brain stem and reaching maximal development in the cerebral cortex.
The total behavior of neuromuscular type emerged within a preexisting bodily organization, which maintained the unity of the individual by nonnervous apparatus. The nervous system is from its first appearance a totalizing apparatus. Local differentiations of tissue for the analysis of sensory experience and of motor responses arise within this integrated structure, and local reflexes similarly emerged within a total neuromuscular pattern of action adapted to maintain the unity of the organization. As development advanced, the mechanisms of the local reflexes acquired increasing autonomy, but they are never completely emancipated from some control in the interest of the behavior of the body as a whole. The organic unity of the whole is preserved while local specificity is in process of development, and this unitary control is never lost during the normal life of the individual.
THE STIMULUS-EESPONSE FORMULA
The stimulus-response formula has wide application and great usefulness as a basic concept in physiology and psychology, but its apparent simplicity is illusory and has tended to divert attention from essential features of even the simplest patterns of behavior. This I have illustrated ('44a) by an examination of the simplest reflex connection known in Amblystoma — from retina to ocular muscles by way of the basal optic tract.
The late G. E. Coghill, during a productive period of foi'ty years, studied the development of the action system of Amblystoma and the correlated processes of bodily growth. These researches have demonstrated beyond question that in this animal the neuromuscular system is so organized in prefunctional stages that, when first activated from the sensory zone, the resulting movement is a total response of all the musculature that is mature enough to respond to nervous excitation. These "total patterns" of activity are not disorderly, and they become progressively more complicated while the apparatus of local reflexes ("partial patterns") is slowly differentiated within the larger frame of the total pattern. The development of both the total pattern and the partial patterns is initiated centrally, and throughout Hfe all of them are under some measure of unified central control so that the body acts as an integrated whole with diverse specialization of its parts (Coghill, '29; Herrick, '29). Coghill's contributions of factual observations and the principles derived from them have been critically reviewed by the writer in a book ('48), to which the reader is referred.
The patterning of these orderly movements is determined by the intrinsic structure of the nervous system. This structural pattern is not built up during early development under the influence of sensory excitations, for in the embryo the motor and sensory systems attain functional capacity independently of each other; and when central connection between the sensory zone and the motor zone is made, the first motor responses to excitation exhibit an orderly sequence, the pattern of which is predetermined by the inherited organization then matured (Coghill '29, p. 87; '30, Paper IX, p. 345; '31, Paper X, pp. 158, 166). This early structural differentiation goes on independently of any stimulus-response type of activity, though the latter may modify the pattern of subsequent development. This is a principle of wide import, applicable not only in lower vertebrates but in higher forms as well (Coghill, '40), including man (Hooker, '44). The stimulus-response mechanism is not a primary factor in embryogenesis; it is a secondary acquisition.
REFLEX AND INHIBITION
It has been pointed out that the functions of the sensory and motor zones are fundamentally analytic — analysis of environmental influences and analysis of performance in adjustment to those influences. How the units of the analytic apparatus are actually related so as to insure the appropriate correlated action of the separate parts is the key problem, which must be resolved before animal (and human) behavior can be approached scientifically in other than a descriptive way. Good progress has been registered. The sensory and motor analytic apparatus has been exhaustively studied and well described; and this was the appropriate place to begin, for these organs are most accessible to observation and experiment. Because these systems of peripheral end-organs and the related pathways of conduction and centers of control are, in the human nervous system, obviously interconnected in stable and definitely localized patterns, it was natural to use this structural framework as the point of departure in the elaboration of the hypothetical superstructure of current doctrines of reflexology. But reflexes can be conditioned, and this name for a well-known physiological fact is for the neurologist scarcely more than a symbol of complete ignorance of the mechanisms actually employed.
The several reflexes have been so closely colligated with specific details of central architecture that the reflex arc came to be regarded as the primary unit of nervous organization, and it was assumed that the increasing complexity of the upper levels of the brain in higher vertebrates has been brought about by progressively more intricate interconnections among these elementary units. The integrative action of the nervous system was conceived in terms of the definition of mathematical integration — "the making up or composition of a whole by adding together or combining the separate parts or elements." This conception leaves unexplained how any additive process of this sort can result in such a unique centrally controlled unitary organization as we actually observe, capable of conditioning the reflexes in terms of individual experience (learning), of abstracting some common features of mixed experience and synthesizing these into quite original patterns of response, and of maintaining some measure of "spontaneous" or self-determined directive control.
A far more serious charge against traditional doctrines of reflexology is the observed fact that in the development of Ambly stoma the early responses to external stimulation are not local reflexes but total movements of the entire available musculature. The integrated total pattern precedes in time the appearance of the partial patterns. These are individuated within the total pattern; they are integral parts of it, and for an appreciable time they are subordinate to it. Even in the adult animal the local partial patterns are not completely emancipated from control by the body as a whole. It is, indeed, impossible to find in this brain any sharply defined, well-insulated reflex arcs.
What happens during the emergence of specific reflexes from the total reactions is, first, the development of an increasing number of collateral branches of the primary axons and the central linkage of sensory and motor pathways in ever more complicated patterns. Then, second, in the adjusting centers additional neurons are differentiated, the axons of which take longer or shorter courses, branching freely and participating in the formation of a nervous feltwork of extraordinary complexity. These neurons are not concerned primarily with specific reflexes but with the co-ordination and Integration of all movements. Some parts of this intricate fabric, generally witli thicker fibers, more or less well fasciculated, activate mass movements of primitive type, and other parts control local reflexes as these are individuated. But these systems of fibers are not segregated in comjjletely insulated reflex arcs. They are interconnected by collateral branches with one another and with the interstitial neuropil. There are lines of preferential discharge, but whether any one of them is actually fired depends on numberless factors of peripheral stimulation and central excitatory state.
The phylogenetic history is parallel. The further down we go toward the primitive ancestral vertebrates, the less clear evidence do we find of definitely localized reflex arcs, and the overt behavior tends more toward mass movements of total-pattern type.
It must be borne in mind that the development of the individual does not exactly recapitulate the phylogenetic development (Hooker, '44, pp. 15, 33). The pattern of the sequence of structural changes' which take place during prefunctional stages of growth is determined by the organization of the germ plasm and the interaction of the genetic factors with one another. This organization, in turn, has been determined during preceding evolutionary history in adaptation to the environment and habitus of the species in question. In broad lines the history of ancestral development is repeated in the growth of the embryo, but cenogenetic modifications of it may appear in adaptation to changing conditions, as illustrated, for instance, by the appearance of some local reflexes earlier in mammals than in amphibians.
The structural organization of the brain sets off in sharp relief a few important general physiological principles. First, it is to be noted that the "resting" nervous system is not inert. The body acts before it reacts. There is always some spontaneous — that is, centrally excited — activity, and the importance of this factor increases as we ascend the phylogenetic scale. There is always intrinsic activity, as demonstrated, for instance, by the Berger rhythms, and it is always acted upon by numberless extrinsic agencies. When an excitation is received from the periphery, there results a change in the central excitatory state both locally and diffusely, which involves both activation and inhibition.
Another general principle may be mentioned here. The flow of nervous impulses from receptor to effector is not one-way traffic.
The excitation of a peripheral sense organ may be followed by an efferent discharge back to the receptor. An instructive illustration of this is seen in the auditory apparatus of mammals. Excitation of the cochlea is followed by an efferent return to the tensor tympani and stapedius muscles and also to the cochlea itself (the latter pathway recently demonstrated by Rasmussen, '46). Almost all contracting muscles report back to the center by a system of proprioceptive fibers. The central nervous system is full of similar reciprocating systems. Many of the fasciculated tracts of Ambly stoma are two-way conductors, transmitting in both directions, and there are numberless illustrations of a circular type of connection, efferent fibers of one center activating another, which has a return path, perhaps by a devious route, back to the first center. A neuropil may be interpolated in any of these types of circuit. The thalamo-cortical connections of the human brain are of this sort, exhibiting what Campion and Elliot Smith ('34) have aptly named a "thalamo-cortical circulation," a circulation not of blood but of nervous transmission. All parts of the cerebral hemispheres are in similar reciprocal interconnection, as has recently been emphasized and illustrated by Papez ('44).
Here reference may be made to Dewey's ('96) stimulating analysis of the reflex-arc concept or, as he prefers to say, the "organic circuit" concept. This he elaborated in terms of psychology, and nearly twenty years later I made this comment about it ('13«) :
"Let us see how it may be applied to biological behavior. The simple reflex is commonly regarded as a causal sequence: given the gun (a physiologically adaptive structure), load the gun (the constructive metabolic process), aim, pull the trigger (application of the stimulus), discharge the projectile (physiological response), hit the mark (satisfaction of the organic need). All of the factors may be related as members of a simple mechanical causal sequence except the aim. For this in our illustration a glance backward is necessary. An adaptive simple reflex is adaptive because of a pre-established series of functional sequences which have been biologically determined by natural selection or some other evolutionary process. This gives the reaction a definite aim or objective purpose. In short, the aim, like the gun, is provided by biological evolution and the whole process is implicit in the structurefunction organization which is characteristic of the species and whose nature and
origin we need not here further inquire into The aim (biological purpose) is
so inwrought into the course of the process that it cannot be dissociated. Each step is an integral part of a unitary adaptive process to serve a definite biological end, and the animal's motor acts are not satisfying to him unless they follow this predetermined sequence, though he himself may have no clear idea of the aim. These reactions are typically organic circuits Always the process is not a simple sequence of distinct elements, but rather a series of reactions, each of which is shaped by the interactions of external stimuli and a preformed or innate structure which has been adapted by biological factors to modify the response to the stimuli in accordance with a purpose, which from the standpoint of an outside observer is teleological, i.e., adapted to conserve the welfare of the species."
This apparent teleology is commented upon in chapter viii. Since the passage just quoted was written, control of gunfire by radar has been perfected, thus reinforcing our analogy at one weak spot. In the reflex the "aim" does not precede the stimulus that pulls the trigger; it is automatically adjusted to the stimulus as in radar. But this automatism in both cases is dependent upon the presence of a preformed structure adapted to provide it.
Our analysis of the adult structure of the brain of Amblystoma confirms and supplements the conclusions reached by Coghill from his study of the development of the same species. His major contribution, as I see it, was the demonstration of the primacy of the integrative factors in the development of behavior patterns and of some of the features of structural growth during the individuation of local partial patterns within the larger total pattern. The adult structure of the brain of Amblystoma is in perfect conformity with the conclusions to which he was led. One of these conclusions should receive special emphasis here, for it clarifies our conception of what the reflex is in general, and in particular it helps us over some hard places in our attempt to discover the actual mechanisms involved in the individuation of local reflex patterns within the frame of the total pattern.
In the central resolution of forces which eventuates in some particular pattern of overt movement there is always an inhibitory factor (Coghill, '36, '43). In discussing the individuation of partial patterns (local reflexes) from the total pattern, he wrote ('40, p. 45):
"Individuation is obviously the result of organized inhibition
The major division of the total pattern must be under inhibition when a part acquires independence of action, and the same part can be inhibited while the major segment of the total pattern acts. So that the whole individual probably acts in every response, either in an excitatory or inhibitor}^ way," This he generalized in the following statement ('30, p. 639):
"For an appreciable period before a particular receptor field acquires specificity in relation to an appropriate local reflex its stimulation inhibits the total reaction. Inhibition, accordingly, through stimulation of the exteroceptive field, begins as a total pattern. It is then in a field of total inhibition that the local reflex emerges. The reflex may, therefore, be regarded as a total behavior pattern which consists of two components, one overt or excitatory, the other covert or inhibitory. The essential anatomical basis for this is (1) in the mechanism of the total pattern of action, or primary motor system, and (2) in the mechanism of the local reflex, or secondary motor system; the mechanism of the total pattern being inhibited and that of the reflex excited. But since inhibition is not a static condition but a mode of action, the mechanism of the total pattern must be regarded as participating in every local reflex."
This conception of the reflex as involving a factor of inhibition of the total pattern Hnked with excitation of the partial pattern is fruitful. Total inhibition plays a more obvious role in the overt behavior of amphibians than in most other animals, not only in embryogenesis of behavior but also in the adult. This was emphasized by Whitman ('99) in his classic description of the behavior of Necturus. In my manuscript notes of a conference with Dr. Coghill on January 1, 1929, I find a record of his remarks which is here transcribed.
"The first neurons to differentiate in Amljlystoma are in the floor-plate. These and others adjacent form the primary motor column, the dominant function of which is activation of muscles of the same side for mass movement of the trunk and limbs and inhibition of the musculature of the opposite side which is in the same phase of locomotor movement. In later stages, when mechanisms of specific local reflexes emerge, residual neurons in the region of the floorplate maintain their functional importance for mass movements as activators of the whole somatic motor apparatus. They may prime this neuromotor system, putting it into a subliminal excitatory state in advance of its patterned activation.
"At an age which immediately precedes the first feeding reactions and before it is possible to open the mouth and swallow, the larva will react to a moving object in front of the eyes by a total reaction, a leap forward. It cannot seize the object. The general activator mechanism here comes to overt expression before the specific local reflex patterns are mature enough to function. After feeding activities have matured there is a similar general activation, accompanied by inhibition, as illustrated by the 'regarding' reaction [p. 38]. A larva which had been feeding for several days was stimulated by moving a hair slowly across the field of vision. The animal responded by moving the head slowly following the hair. The head is bent to the side, with rotation of the eyes, movement of the fore limbs, and adduction of both hind limbs. When the hair was not too far distant, the animal finally, at the end of this 'regarding' reaction, jumped after it. Here there is a clear distinction between what Sherrington calls the anticipatory phase and the consummatory phase of the reaction, and evidently in the anticipatory phase inhibition plays the major role. This is obvious also in almost all adult behavior of these animals."
The mechanism of central inhibition is still obscure. There is some evidence that a nervous impulse impinging upon a central neuron may, on occasion, activate the element, or under other conditions of central excitatory state, strength, or timing of the afferent flow it may inhibit activity ui process. Whether or not this is true, it is well known that a central neuron may exhibit a large variety of types of synaptic junctions, differing in histological structure, electrical properties, and perhaps also in chemical reactivity. These afferent fibers may come from widely separated regions with diverse functions, and the impulses delivered may differ in intensity and temporal rhythm. Bodian's description ('37, '4'2) of axon endings on Mauthner's cell of the medulla oblongata shows four main types of synaptic contact which vary from 0.5 to 7/i in extent, with a wide variety of arrangements. There are between four and five hundred of these endings on a single cell, and the presumption is legitimate that these diverse structures are correlated with significant differences in electrical and chemical properties, including the timing of the pulses of transmission. It has been suggested that some of the influences transmitted across the synaptic junctions are excitatory and that others are inhibitory. Synaptic junctions on dendrites are in some cases structurally different from those on the axon hillock or axon, and they may be activated from different sources. Some observers believe that excitation of dendrites is excitatory and of axons is inhibitory, a supposition supported with physiological evidence by Gesell and Hansen ('45, p. 156). In their theory of the electronic mechanism of activation and inhibition, these functions are viewed as basically similar, activation being associated with an increasing, and inhibition with a decreasing, intensity of the electronic current. The connections of horizontal cells of the retina as described by Polyak ('41, p. 385) suggest to him a different inhibitory apparatus. The horizontal cells may exert an inhibitory influence upon the synapses between the rods and cones and the bipolar cells, that is, the synapses of the horizontal cells may function as "countersynapses" to the photoreceptor-bipolar synapses.
Whatever may be the mechanism employed in central inhibition, it is clear that in some parts of the brain excitatory functions predominate, in other parts inhibitory functions. Noteworthy examples of the latter are (1) the head of the caudate nucleus (Fulton, '43, p. 456) ; (2) a region in the reticular formation of the medulla oblongata explored by Magoun ('44) ; and (3) certain specific zones of the cerebral cortex (areas 4^, ^s, 19s, and some others) which are known as "suppressor bands." In all these cases, excitatory and inhibitory fields are intimately related physiologically in such a way as to secure appropriate balance of activation and inhibition of the members of synergic systems of muscles in proper sequence.
The role of general inhibition in the patterning of behavior has been under investigation for several years by Beritoff and his colleagues. The first half of the fifth volume of the Transactions of his institute is devoted to studies on the nature of general inhibition and its role in the co-ordination of cortical activity and reflex reactions of the spinal cord. Beritoff believes that the neuropil possesses an inhibitory function — slow changes in voltage, expressing the active state of the neuropil, show an anelectrotonic effect on the cellular bodies, lowering excitability in them and weakening the excitation. The evidence is drawn from both somatic and visceral stimulation. He writes ('43, p. 142) : "Thus, during each reflex reaction in the visceral organs, taking place in response to a stimulation of the interoceptors and of visceral afferent fibers, just exactly as during somatic reflexes, the spinal cord acts as a whole, making the given reflex local and every spinal reflex reaction entire by means of general inhibition." This is essentially the same as Coghill's position as stated in the preceding quotations. In other articles in the same volume the role of the neuropil in a great variety of spontaneous and stimulated activities of the brain is emphasized by Beritoff.
The neuropil as a whole is not, in my view, a specific inhibitor. It may partipciate on occasion in either excitation or inhibition, and in the inhibitory phase it acts as part of the covert component of the reflex or of mass action, as the case may be, in Coghill's analysis as quoted above. In my discussion of the habenular system (chap, xviii) and the interpeduncular nucleus (chap, xiv) I have ventured to suggest a possible mechanism through which general inhibition effected in the interpeduncular neuropil may operate in the facilitation of both mass movement and local reflexes. On this hypothesis this local band of neuropil must be able to act as a specific inhibitor in Beritoff's sense.
The amphibian neuropil in its various forms . is structurally adapted for a considerable variety of functions of different grades of specialization. There is generally a diffuse spread of terminals, so that a single incoming fiber may activate many neurons of the second order. If the receptive tissue is homogeneous, this provides for simple central summation. If the receptive tissue is heterogeneous, as in most sensoiy fields, this arrangement facilitates mass movement of the musculature or total patterns of action. If many fibers converge upon a single neuron, the threshold of central excitation is lowered, as in the mitral cells of the olfactory bulb and in the *'motor pool," as this concept has been developed by Sherrington. If the activated motor pool is large, with wide distribution of the efferent fibers, complicated integrated mass movement may result. If the pool is small, with a single final common path, a local reflex may follow. If the outlet comprises a number of open channels with different connections and physiological properties, there is provision for discriminative response, the selection being made (presumably) in terms of the central excitatory state of the components of the system ('42, p. 295).
It has been objected that the preceding comments on the limitations of current doctrines of reflexology are based upon the amphibian organization, which is aberrant and degenerate and therefore not typical or significant in the interpretation of the behavior of higher animals. But, even so, the Amphibia live well-ordered lives, and their behavior conforms in basic patterns with that of other vertebrates. We want to know how they behave as they do. Accepting the current view that Amblystoma is a retrograde descendant of some more highly specialized ancestor now extinct and that some of its characters are aberrant, yet the evidence seems to me adequate that such retrogression as may have occurred has been toward a generalized form ancestral to modern amphibians and mammals.
Conclusion. — I have assembled in these pages some factual description of observed structure, together with speculative interpretations of its probable physiological significance. The organic structure here under consideration is not something vague and ill-defined. Its anatomical distribution, histological organization, and fibrous connections can be described with precision. Not until this has been done can our imperfect knowledge of its functions be advanced by experiments designed to reveal its physiological properties.
In a discussion of "localized functions and integrating functions" more than a decade ago ('34a), the significance of neuropil in the evolution of cerebral structure was summarized in these words :
"The neuropil is the mother tissue from which liave been derived both the specialized centers and tracts which execute the refined movements of the local reflexes and the more general web which binds these local activities together and integrates the behavior. It retains something of embryonic plasticity and so is available as a source of raw material for two very dift'erent lines of specialization — first, toward the structural heterogeneity requisite for the execution of localized reflex and associational functions, and, second, toward the more generalized and dispersed apparatus of total or organismic functions of tonicity, summation, reinforcement, facilitation, inhibition, 'spontaneity,' constitutional disposition and temperament, and extra-reflex activities in general."
PRINCIPLES OF LOCALIZATION OF FUNCTION
The gi-eat advances that have been made in the diagnosis and treatment of nervous diseases have been due in large measure to the more accurate mapping of the structural features of the nervous system and recognition of the specific functions of its several parts. Before a disorder can be successfully treated we must know what it is and where it is. The most notable triumphs in this medical field have been registered with those diseases whose situs can be recognized and then subjected to appropriate therapy or surgery. Even a systemic disorder like anemia has localization in blood corpuscles and blood-forming organs; and a general infection, like poliomyelitis, spreads in preferential paths determined by the histochemical structure of the tissue. The stable heritable tissues of the nervous system are most accessible to this kind of inquiry, of diagnosis, and of treatment; conquest of the unlocalized disorders has been retarded.
Some kinds of disorder, particularly those of primary concern to psychiatrists, have resisted all attempts at localization in accordance with conventional principles, and in the field of physiology the concept of local reflex arcs has limited application. The various attempts to elaborate a comprehensive account of animal and human behavior in terms of conventional reflexology have broken down. These conspicuous failures have led some competent authorities to question the over-all significance of localization in space of nervous functions and to search for other principles in the realm of pure dynamics or chemical interaction or some as yet unknown factors which operate quite independently of stable structural patterns. But no nervous tissue is structurally homogeneous or physiologically equipotential. In this connection it is interesting to note that Lashley, the leading advocate of the equipotentiality of the nervous tissues, has given us clear demonstration of point-to-point projection of retinal loci upon the lateral geniculate body and the cerebral cortex of the rat (Lashley, '34, '34a). This is the most refined anatomical localization of function known. In a later communication ('41) he demonstrated a very precise projection of the thalamic nuclei upon the cerebral cortex and added: "A functional interpretation of the spatial arrangement of the thalamo-cortical connections is not justified on anatomic grounds alone for any sensory system."
Somewhere between the extreme views of rigid localization in spatial patterns and a labile physiological equipotentiality a practicable working conception of the meaning of the structural configuration will be found. Clearly, the nervous system does not operate, even in the case of the simplest known reflex, on the mechanical principles of an automatic telephone exchange. We get only confusion by oversimplification of the problem. On the other hand, there are no disembodied functions, and the apparatus that performs functions has locus in space and time. Our problem is, first, to observe what is done and then to find out wliere and when it is done and how.
The observed spatial arrangements are not meaningless, and their functional interpretation is possible and fruitful, as evidenced by their practical utility in medical diagnosis and treatment. These structural patterns are stable and heritable. Their phylogenetic development can be traced, and in broad outline this has been done. But as these patterns are followed backward in the evolutionary series they become, not more simple and sharply defined, but less so, until in the most primitive and generalized vertebrates they tend to disappear in a more nearly homogeneous matrix. This would seem to support the view that localization of function is a secondary acquisition, derived from a primitive equipotentiality. With certain important qualifications, this is probably true; and if we follow in phylogeny the differentiation of local centers and their connecting tracts in correlation with types of function performed, the significance of localization appears. The problems of cerebral localization have usually been attacked in mammals and especially in man, where clinical applications are vitally important. Let us approach the subject from the other end of the phyletic series and look for the inception of localization patterns in primitive animals.
In the simplest known organisms localization of function is minimal and transient. In ameba any part of the cytoplasm may on occasion perform any function of which the organism is capable. There is a local differentiation of nucleus from cytoplasm, but in some bacteria even this localization disappears. A surface-interior pattern is always present, but the physical substance may shift from one to the other of these zones. In primitive multicellular species, ectoderm and entoderm were early differentiated — a specialization which persists throughout the animal kingdom as manifested in the basic distinction between somatic and visceral organs, a structural differentiation that has physiological meaning. Further specialization advanced more rapidly in somatic organs than in visceral, and in the former more rapidly on the sensory side than on the motor side. This again has physiological significance because the acute problems of subsistence involve adjustments to surroundings. The primitive motor responses are mass movements, but the surface of the body is exposed to a manifold of diverse stimuli which must be analyzed, and, accordingly, diverse organs of sense were locally differentiated. The course of this differentiation followed this rule: from the generalized and equipotential to the special and local. Thus in some primitive eyeless forms the entire skin is sensitive to light, in others only the most commonly exposed surfaces of it; and in the leech, Clepsine, Whitman ('92) found that a single animal exhibited all transitions from a series of segmentally arranged sense organs of generalized function in the posterior part of the body to well-formed eyes at the anterior end.
As I have elsewhere pointed out ('29), in the most simply organized vertebrates, the hagfishes, as described by Jansen ('30) and Conel ('29, '31), the brain is organized around two dominant sensory systems — olfactory and cutaneous — and the other special senses are in various stages of arrest or degeneration in correlation with a semiparasitic habit. Without eyes, jaws, or limbs, the visible behavior is reduced to a simple system of mass movements. Within the brain there is little local differentiation except for the primary sensory and motor fields directly connected with the peripheral end-organs, and yet this brain is the adjusting mechanism of a very rigid system of simple movements.
Larval Amblystoma is similar, though here the specialization of tissue is further advanced, and there is progressive advancement in representatives of later phylogenetic stages. The principle of progressive transformation from the general and dispersed to the specific and local applies throughout phylogenetic development; it is a general principle of embryogenesis (Weiss, '39, p. 288) ; it is clearly exemplified in human development, as has been demonstrated on the physiologic side by Hooker ('44) and on the structural side by Humphrey ('44, p. 39); and it appears in the course of conditioning reflexes (CoghiU, '30).
In the phylogenetic history of vertebrates the basic pattern of sensory equipment was apparently laid down very early, with no radical changes except at the transition from aquatic to terrestrial life. And at this period of transition from fish to tetrapod the neuromotor apparatus experienced even more radical transformation, with elaboration of local reflexes which supplement and largely replace the more primitive mass movements.
In amphibian development this history is recapitulated in the long
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period which cidminates at metamorphosis; and during this period the texture of the brain undergoes two divergent Hues of differentiation of tissue in correlation with the expansion of two types of activity, the analytic and the synthetic, as described in the pi-eceding section. The structural arrangement of the analytic apparatus is, in its main features, predetermined in the hereditary organization; it is stable and approximately the same in all members of the species. The intervening synthetic and integrating apparatus, on the other hand, is less rigid and is more labile in function. The pattern of its performance will vary from moment to moment in adjustment to every change in sensory and motor activity and every fluctuation of central excitatory state. But in even the most primitive vertebrates some cross-connections between sensory and motor zones, which are interrupted in the intermediate zone of correlation, are laid down in the stable, heritable structure. These serve the standardized ("instinctive") patterns of behavior, and the arrangement of these connections is determined more by the motor equipment of the animal than by the sensory equipment (Crosby and Woodburne, '38; Woodburne, '39).
From these considerations it follows that the concept of localization of function must not be formulated in static terms. It is localization of action, and the spatial pattern of this localization reflects every change in the character of the action. The structural pattern of this localization is more stable at the afferent and efferent endpoints of the system, and it becomes less so as we pass inward from these fixed points. The apparatus of standardized behavior like reflex is more rigidly localized than is that of more labile individually modifiable behavior.
Two types of structure which have just been contrasted may be characterized as unspecialized or generalized, and locally differentiated in specific stable and heritable patterns. The second was probably derived phylogenetically from the first, and in higher animals both of them exhibit progressive differentiation of structure in divergent directions. Some examples of these two types of cerebral architecture will next be cited, beginning with the second, which has been investigated in more detail.
SPECIFIC LOCALIZED STRUCTURE
An early stage in the evolution of localized conductors of specific sensory systems is illustrated by the connections of the lemniscus systems described in chapter xi. These tracts of Ambly stoma are not well separated, and in the aggregate they comprise a rather dispersed collection of ascending fibers loosely assembled in several tracts, which are distinguished more by their general fields of origin and termination than by the functions which they serve. It is to be borne in mind that this low level of functional specificity of the secondary tracts is not correlated with a corresponding generalized structure and function of sense organs and related peripheral nerves. These organs, though different from those of higher animals, are highly specialized and as sharply localized. The correlation, on the contrary, is with the generalized character of the motor responses evoked. In higher animals with a wider range of motor capacities the functional specificity of the lemniscus tracts becomes more precise.
During the process of differentiation of these more specific tracts they retain collateral connections along the entire course, so that they continue to perform integrative functions similar to those of the less specialized ancestral pattern. In this connection we quote a passage from Dr. Papez ('36) :
"In tracing the central connections of any one of the main afferent systems in the vertebrates one gains the impression that there is a progressive pliyletic tendency of each system to enter into connections with all the important segments of the central organ. In this way there arises a totally integrated anatomical pattern common to all the receptorial systems in spite of the wide diversity of the receptors, their individual pathways and their interpolated centers. This central integration is not essentially of a reflex nature and cannot be appropriately described as a chain of reflex connections insomuch as each level has a highly individual structural organization designed primarily for the production of distinctive organic functions."
Papez appropriately emphasizes the integrating action of these long conductors; it seems to me, however, that his conception of "a progressive phyletic tendency of each system to enter into connections with all the important segments" in the interest of integration is a reversal of the actual course of phyletic history. These collateral connections are more numerous and more dispersed in lower forms than in higher. The integration is primary, and the analysis is secondary. It is true that the primary integration is not subordinated in the course of phylogeny; it is accentuated; but the apparatus employed is radically changed. Dispersed nonspecific connections are progressively replaced by localized specific structures, which are so interrelated as to work together harmoniously in the performance of standardized patterns of behavior. And, in addition to this, higher centers are elaborated, notably in the cortex, which progressively acquire dominant control of the total action system.
The phylogenetic history of the differentiation of the visual-motor
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system also illustrates the principle just stated. In most vertebrates the eyes are the dominant organs concerned with the orientation of the body and its members in space. The visual apparatus within the brain, accordingly, exhibits the most precise localization of function, and the refinement of this localization increases progressively in the phyletic series.
In Amblystoma the fibers of the optic tracts are widely spread in the brain stem, in marked contrast with those of other sensory systems, which tend to converge into a single receptive field. There is no evidence that this dispersal of fibers of retinal origin to the tectum, pretectal nucleus, thalamus, hypothalamus, and cerebral peduncle is correlated with any specificity of visual function. The explanation of this central spread of retinal fibers is to be sought on the motor side of the arc, that is, it is determined primarily by the nature of the response to be evoked.
In the Amphibia all these visual areas are centers of correlation, for in all of them optic terminals are mingled with those of other systems. Within this class, however, as we pass from generalized urodeles to specialized anurans, there is a conspicuous trend toward segregation of some terminals of the optic nerve in the tectum and lateral geniculate body of the thalamus. This trend culminates in mammals and is correlated with the differentiation of the visual area of the cerebral cortex, until in primates, as pointed out by Clark ('43), the retinal-geniculate-cortical pathway provides a very precise point-to-point projection of the visual field upon the cerebral cortex, and "there is no possibility that these impulses can be disturbed and modified 'en route' by other, unrelated, types of nervous
impulse In other words, the cerebral cortex receives retinal
impulses in a remarkably pure and unadulterated form."
The highly specialized optic tecta of some lower vertebrates exhibit two types of specific localized structure, which differ in form and physiological significance. There is, first, an arrangement of sensory terminals spread superficially in mosaic pattern. This provides for point-to-point projection of retinal loci upon the tectum and perhaps for other forms of sensory localization. In the second place, there is a pattern of lamination at different depths from the surface. These laminae differ somewhat in their sensory connections, and the sensory influence is stronger in the moi-e superficial members of the series. The arrangement of the deeper layers seems to be determined primarily by the directions taken by their efferent fibers. The mosaic pattern is primarily in terms of sensory analysis, the lamination pattern in terms of sensory correlation superficially and of motor analysis in the deeper layers. The cerebral cortex of mammals also exhibits both mosaic and laminated patterns of localization and in far more complex designs (Huber and Crosby, '33, '34).
Specific structure of this analytic type, with well-defined localization in both gray and white substance, increases in amount as we pass from lower to higher animals in the phyletic series; and this increment progresses from the sensory and motor periphery inward toward the upper cerebral levels, where the apparatus of integration and synthesis is most elaborately developed. In submammalian brains the amount of myelin present at successive levels of the brain stem is a rough indicator of the relative mass of tissue of this analytic type.
This type of tissue, as pointed out above, predominates in the most primitive vertebrate brains. With advancing differentiation, we observe specialization of this tissue in three directions. (1) Some of it retains its primitive generalized structure with little change. In urodeles this is true of a large proportion of it; in mammals it survives in the periventricular system of cells and fibers of the diencephalon and mesencephalon and in some other regions. (2) A progressively larger proportion of this tissue is transformed into specifically localized structures, as just described. (3) Another large proportion of it is transformed into the relatively unspecialized tissues of the intermediate zone of correlation and its highly elaborated derivatives in the suprasegmental apparatus of the cerebellar and cerebral cortex.
Doubtless all parts of the body participate in the total integration and the determination of general attitudes and types of response, but the brain exercises dominant control over overt behavior and orders it in the interest of the welfare of the body as a whole. The apparatus of these totalizing functions evidently includes many diverse components, of which one of the most obvious is the neuropil, which in primitive vertebrates pervades the entire brain, so that activity in any part of it may affect the whole fabric, as elsewhere described. This dispersed tissue 's not homogeneous, and it is not equipotential. It is doubtless always active and in diverse ways in different places at different times. Such localization of function as it exhibits can best be conceived in dynamic terms, that is, in terms of what intercurrent nervous volleys act upon it in momentarily changing places, rhythms, and intensities. We are dealing here with an equilibrated dynamic system comprising many activated fields in interaction, and
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this interplay is in patterns quite different from those of the stable, locally differentiated centers and tracts. It is more labile, and the patterns of performance are not stereotyped. Nevertheless, these fields are not structurally identical, and each one has distinctive physiological properties correlated with these histological differences.
Each field of neuropil differs from others in internal texture, in the source of afferent fibers, and in the distribution of efferents. A local field may be sharply segregated, as in the ventrolateral neuropil of the peduncle and the ventral interpeduncular neuropil, or it may interpenetrate tissue of the specific localized systems, as in the corpus striatum and optic tectum. The pattern of this localization is different structurally and physiologically from that of the specific systems of cells and fibers, and the two patterns of localization may both be present in the same block of tissue in primitive brains. In higher vertebrates these local differences are accentuated, the segregation of the synthetic apparatus is carried further, and its tissue is locally differentiated in a radically different way from that of the analytic apparatus, as is best exhibited in the associational tissue of the human cerebral cortex.
The "field" concept has been much exploited of late in several contexts, and it is fruitful, as applied, for instance, by Weiss ('39, p. 289) in general embryology and by Agar ('43, chap, ii) in general biology. As applied psychologically in Gestalt it has been difficult for the structurally minded neurologist to transfer the dynamic formulations into the biological frame of reference; but there is a structural "ground" within which every "configuration" of experience is set, and the primitive neuropil, together with its specialized derivatives, is one important component of the organic substrate of the "gestalt qualities." The "field" as here conceived is an organized living structure in action, some components of which we recognize as stable architecture and some as fluctuations in the excitatory state of the structural fabric. This structure has visible organization, and its properties are open to investigation anatomically and physiologically ('34a; '42, p. 293).
TWO CONCEPTS OF LOCALIZATION
The two kinds of structure which have just been considered perform functions which are localized according to different principles, a distinction which has been generally ignored. The specialized analytic structures have stable arrangement in space, and their functions have corresponding localization in three-dimensional mosaic patterns. The functions of the generalized structures are, in the main,
90 'IIIE IJHAIN OF THE TKiEK SALAMANDER
syntlu'tic rtillicr than Jiiuilylic, and they arc usually descrihod in dynamic terms in which a fourth dimension a time factor — plays an important pail. Yet this ef|nilil)rated dynann'c system is not disembodied, and its component parts have locus in space and time. These loci, or fields, may have some degree of permanence with characteristic structural organization, as in the so-called "association centers" of the cortex, or they may fluctuate as ever changing patterns of linkage of the o})erating neui-ons. As Papez ('44) expresses it: "The anatomical structures are stable, the function is labile, depending on numbers of cells and their excitable or refractory states at any particular time." Many of these synthesizing patterns are repetitive, as in habit and memory. Though the actual structures involved may not be identical in successive repetitions, the i)attern of performance is similar, that is, it recurs in conformity with an enduring "schema" (to employ Henry Head's term), or the engram of conventional teiininology. Doubtless the engram has a structural (or chemical .f*) counterpart, but we do not know what it is.
The stable localization of the structural fields is contrasted with the evanescent localization of the i)attern of their combination at each repetition of the schema. It is possible to find out where the tissue is that yields these dynamic schemata and to delimit it; but these limits cannot be circumscribed on the surface of the brain in simple mosaic patterns. "^I'he manifestation of any schema at a particular time is always a function of a configuration of nervous elements, which has location in space. But a very similar schema may at another time be exhibited by a different structural configuration, whose locus in space is by no means identical with the first ('30a).
It has recently been shown by Lashley and Clark ('46) that cortical structure is variable to a degree not hitherto appreciated in different individuals of the same species of monkey, and it is probable that the range of this variability will be found to be still greater in any human population. They conclude that "marked local variations in cell size and density among individuals of the same species may constitute a basis for individual difi'erence in behavior"; but they challenge the validity of the criteria in current use for parcellation of the cortex into functionally specific areas, except for rather large areas of projection. This is supported by the experiments of Murphy and Gellhorn ('45) and the observations of Bailey and von Bonin ('4(5).