W.S. McCulloch


Half a century ago, Dusser de Barenne, in a series of definitive experiments, made local strychninization a tool for analysis of the functional organization of nervous activity. He showed that it failed to evoke responses when applied to nerve, white matter or dorsal ganglia, but succeeded in grey matter, where axonal arbors terminate on neurons. In the ventrical horn of the spinal cord it evoked twitching; in the dorsal horn, hyper-reflexes; thereby indicating that its effect on function depended on its anatomical position in the central nervous system.

This enabled him to explore sensory mechanisms that previously were only to be inferred from the behavioral effects of lesions. He found that local strychninization of the dorsal-root entrance zone in a single segment of the cord induced hyperaesthesia and paraesthesia, causing the beast to accuse and attack the corresponding dermatome and thus to permit him to map the sensory fields of spinal segments. Moreover, he found that on homolateral hemisection immediately cephalic to the strychninization, or contralateral hemisection several segments higher, the beast accused the contralateral dermatome, an alloaesthesia too familiar in man after section of the spino-thalamic tracts for causalgea or phantom limb pain.

Dusser de Barenne next explored the sensory cortex of the dog, mapping the part accused by the beast on the precise position of the strychnine. This exploration of cortex and thalamus culminated in his collaboration with 0. G. Sager, when I had the good fortune to observe their procedure and the behavior of their cats and monkeys. For surface applications they used one or a few square millimeters of filter paper dipped in a saturated solution of strychnine salt in a paste of toluidine blue to locate its position post mortem. The method enabled them to distinguish between the first somatic cortex which produced contralateral symptoms, and the second somatic, which produced bilateral symptoms. For structure in the depths they used a similar mixture in a hypodermic, having a fine needle, its plunger driven by a micrometer and its barrel aligned and positioned in relation to landmarks on the skull. As with the cortex, so with the thalamus they were able to map the part accused on the particular site of strychnine which they located post mortem by taking the brain up in agar, chilling it, and sectioning it promptly.

The relation of these sites to the cortical areas for the corresponding parts of the body was soon confirmed by Earl Walker's study of thalamic retrograde degenerations following localized cortical ablations. But one of their findings is still ahead of anatomy, that strychninization of the central median, which in the cat yields sensory symptoms, in the monkey yields none. The method surely deserves to be applied to the centroencephalon.

With the development of facile recording of the synchronized discharge elicited by local strychninization, and propagated over the axons arising there, the emphasis shifted to rapid mapping of cortico-cortical, cortico-cerebellar and cortico-centroencephalic paths. This, the strychneuronography, pursued by many of us, is just now beginning to serve clinically in N. Geschwind's analysis of the agnosias, aproxias and aphasias.

The delay may in large part be due to the absence in primates, other than man, of that last in nature of cortical areas, the angular gyrus on which converge signals for all three secondary receptive areas, auditory, somatic, and visual. Nothing is known of the effects of local strychninization of human cortex.

In the hundred years since Palmer's conviction for murder with strychnine, only a few untoward accidents have confirmed the clinical results of its systemic action in man. It evokes violent spasms in response to touch, tap, flash and sudden sound while the conscious patient is not hallucinated, retains the perception of form and the ability to answer questions. One might be tempted to seek an explanation of this syndrome in the difference between the extremely localized response of primary receptive areas, (e.g., area 17) as opposed to the large areas affected by local strychninization of the motor cortex, but it is more prudent to attempt an explanation not so limited to particularities of structure.

To put it simply, one might say that strychnine causes otherwise graded responses to occur in an all-or-none manner, and at a threshold lower than that normally required to elicit a maximum response. This description fits not only the whole man or beast but the isolated spinal cord, and is true of general and of local strychninization. It is in sharp contrast with the picture produced by depressant drugs, such as barbiturates, amphetamine which combats it, and even with spinal shock; for these, which may enhance some reflexes and depress others, show still the gradation of the response with gradation of the stimulus. Lettvin has noted that we are familiar with only two states resembling strychninization, one elicited by chloralose, reckoned an anesthetic; the other, that produced by spinal transection one hour after decerebration. In these, as in strychninization, whether thresholds are raised, lowered or unaltered, the responses when they are evoked are typically all or none.

In photography we encounter a similar phenomenon in films which, whether they are more or less sensitive to light, enhances the contrast so that the greys are lost in a picture that is black and white.

Yet, it will be better to explain the process in electrical engineering terms as being due to compression of the dynamic range, or a steepening of the gain curve for two reasons first because all neurons are highly nonlinear oscillators, capable of coupling, and second, because the coupling of structures as a result of strychnine is clearly electrical. The first is generally admitted and the second has been attested by many observers, for, under systemic strychninization the repetitive and the elicited discharges can cross a transection of all neuroanatomical paths if the cut surfaces are approximated, and can be prevented by introducing an insulator, e.g., mica, between them. This holds for the spinal cord (Bremer), the olfactory bulb (Gerard), and I have seen it on the cortex.

Certain observations have at times tempted me to oversimplify explanations of the action of strychnine. During the period of facilitation of a cortical focus following electrical stimulation, and at a focus of epileptic discharge caused by impinging, the hyper-responsive or explosive area is several millivolts negative to the depth. The same holds for a strychninized area by the time it is discharging synchronous propagated spines. Since similar voltages applied or appearing in the superficial waves of the cortex are known to be related to the activity of deep cells with long apical dendrites, there is clearly some effective component underlying all of these phenomena.

There is, however, no simple or linear relation between membrane potential, membrane impedance or transmembrane current in neurons that can unequivocally account for these phenomena, whereas the electrical coupling remains obvious, and is obviously associated with the potential.

The simplest assumption, namely that strychninization, or other procedures producing such a voltage gradient, lower the threshold of the neurons in the area, is certainly false, as is best seen in the spinal cord where it has been regularly observed on strychninization that the direct response to an electrical impulse from electrodes in the motor neuron pool occurs at the same threshold and, for constant stimulus, of the same size, whereas the indirect response is vastly augmented.

Under these circumstances, we looked for a physiological process resembling strychninization and found it in the potentiation of Lloyd that follows tetanization of the dorsal root. Here many electrical phenomena are similar: (a) the impulses are slowed and perhaps augmented by both; (b) the electrotonic image, DR1, DR2, and DR3, seen in a passive root neighboring the active dorsal root, potentiated or tetanized, are in both cases augmented, and the two are occlusive; (c) the potentiated active dorsal root evokes a highly enhanced reflex, as it does in the strychninized cord, i.e., in both, there is a much greater change in the size of the reflex for a given change of size in the stimulus than there is under normal conditions; and, (d) reflex excitation and reflex inhibition are heightened in the same way by both. Not only are the inhibitors of reciprocal innervation enhanced, but bulboreticular inhibition can hold in abeyance the strychnine convulsion.

From these considerations it is clear, with respect to the action of strychnine, that none of our ordinary terms, excitement, facilitator, inhibition or inhibitor, etc. are of any significance. We are compelled to look for more basic physical notions. Let us look, therefore, at the synchronization of axonal discharges which it characteristically produces.

These discharges consist of closely timed repetitive bursts of voltage so nearly synchronous, even in neighboring roots, as to preclude entrainment by reflexive or even multisynaptic chains of neurons in series. Nor need they be due to such structures, for we know that mere electrical connection is sufficient. If, as we must expect of nonlinear oscillators of high gain and steep gain curve, the axonal volley puts forth electrical pulses into the medium, these must at once affect all axonal terminal arbors approaching the neurons and perforce lock them into synchrony. This one, Lettvin's hypothesis, has clearly the weight of evidence in its favor, and can be checked by further experiment.

Lettvin's other hypothesis has already been verified. He proposed that, under ordinary conditions, an afferent volley occupied only a small fraction of the terminal arborization of its excited axons, but that on potentiation or strychninization it might have access to many more. This can be inferred from our experiments, mapping the current flow in the spinal cord produced by an afferent volley, and is clinched by study of collisions of impulses in the conjunction of dorsal root and dorsal column. These convince us that an entering volley has an inconstant effect on succeeding neurons not only because of supposed fluctuations in synaptic threshold but also because of changes in the number of terminals accessible to the afferent volley. Moreover, we, and others, have found that small polarizing currents do affect the efficiency of transmission from the parent axons to their terminal arbors. Thus, contrary to most investigators, we hold that the increased gain in a reflex, produced by potentiation or strychnine, is due to the greater efficiency of afferent impulses in occupying the available arbors.

Our account of the general action of strychnine makes little of exact anatomical considerations. We believe this proper, because of the conditions determining the dorsal-root reflex, the efferent volley of dorsal roots following ventral-root stimulation in the frog, the demonstration of an efferent-root volley following an antidromic volley to the ventral root, and our own observation of afferent-root volleys following strychninization of the Nucleus of Gracilis or Cureatus. All point to the ability of electrical events to affect neighboring structures regardless of the minutiae of synaptic connections. This is the very property that we know to be enhanced by strychnine. We may, therefore, summarize our present explanation of the action of strychnine as follows.

Strychnine elicits nervous activity only when it has access to nervous tissue in which axons terminate on neurons. For this reason, it has proved most useful in exploring the sensory functions of nervous activity and in mapping the connections of sundry parts of the nervous system. Its action cannot be accounted for in terms of pharmacological centers or properties as excitatory, inhibitory, etc., but must be sought in terms of how it alters local conditions. These are best understood by regarding neurons as non-linear oscillators which, when gain is high and gain curve steep, because of electrical coupling, are swept into synchronous discharge. Strychnine affects processes promoting electrical coupling even in the face of anatomical disruption, provided only that electrical continuity is preserved. Either by direct action on axonal arbors or by alterations of polarization of tissues, it allows afferent impulses to occupy a greater fraction of terminal arbors, thereby steepening the gain curve and producing, instead of responses graded as inputs are graded, responses that are all-or-none.

It is on this property that the clinical, physiological and anatomical advantages of strychninization all depend.



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Keywords: Cord, Half, Strychninization, Ganglia, Horn, Matter, Arbors, Looms

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1 Reprinted from Revue Roumaine de Neurologie, 1966, 3, 1:89-23