W.S. McCulloch


I had hoped to have something very exciting to say, but, as usual, I have run into a blind lead.

Because of Dr. Medunas perennial dislike for his firstborn, shock therapy, we have for years been trying, first, to make out how it worked, and thereafter to find a substitute for it. In the attempt to find out how it worked we used convulsant after convulsant and found with all of them the same general story as far as the shift in carbohydrate metabolism was concerned. With every seizure there was a fall in the energetic phosphate bonds phosphocreatine and adenosine triphosphateand with all convulsants there was an accumulation of lactic acid.

We then undertook to find other ways of producing the same chemical changes. We used cyanide which, to a lesser extent, causes the same shift in the carbohydrate metabolism of brain. That turned out to be of no use as an agent in curing patients.

Now, as it was clear that the peripheral motor seizure was of no value in curing patients, we wondered whether the cortical seizure was of any value, and we began to look for other agents. The literature disclosed that the compound which was known to produce seizures in the cerebellum contained chlorine atoms; we then began to look for other characteristics that might be useful. At that time we undertook an investigation of agenized breadstuffs, thinking these might have chlorines in a position beta to a nitrogen. Youat least the chemistsare more familiar with that story than I am. It turned out that while the NCF-breadstuffs initiated seizures in the cerebellum, they destroyed the cerebellar nuclei and were therefore useless. We then tried another group of compounds, the so-called nitrogen mustards, of which we investigated eighty in all. Those which are capable of producing seizures are bis beta chlor-nitrogen mustards, in which the remaining radical is more than a hydrogen. I am told by my friends in chemistry that this is the condition (that it should contain more than a mere hydrogen here) for its being able to be converted to a tetravalent nitrogen, and that we may be playing again with our old friend, the tetravalent nitrogen, cropping up in a new form.

The interesting point concerning all of the convulsants that start seizures in the cerebellum was that the seizures were precipitated by breathing carbon dioxide; whereas with every cortical convulsant that we have tried the seizure has been prevented by feeding carbon dioxide.

Investigation of the nitrogen mustards, however, proved to be a blind lead because these compounds also caused degeneration of the nuclei of the cerebellum (most marked in the nucleus dentatus) and were consequently of no use in experiments on man as possible substitutes for ordinary shock therapy.

I began looking for other agents. Among those tried was eserine. With this agent I did not know where the seizures would start. During the investigation with this compound a peculiar phenomenon was noted. Those of you who are electrically minded will remember a long series of experiments that Dusser de Barenne and I carried out in New Haven on the ancient problem of facilitation and on extinction. If an area of cortex is stimulated following a prior stimulation of the same area, a larger or a smaller response is obtained according to the interval between the first and second period of stimulation. If the cortex of an animal under barbiturates is eserinized and then stimulated electrically, it is found that the eserine has produced no change in the threshold to electrical stimulation. If that area is atropinized, it is found that there is no change in the threshold to electrical stimulation. Yet eserine in large doses is a good convulsant, and convulsions can be stopped with large doses of atropine, which a cat can tolerate in enormous amounts.

There are three known factors entering into the facilitation and extinction of the motor response to stimulation at one point in the cortex. The first of these, an obvious one, is concerned with after-discharge. If the initial stimulus stirs up an after-discharge, a greater response is obtained than if the second stimulus falls in the silence after the after-discharge. That after-discharge turned out to be difficult to dodge in an eserinized cortex. The second factor is that if many cells lying close together are stimulated repeatedly there results a large change in the pH of that area, it being initially alkaline and subsequently acid, the alkalinity being associated with increased and the acidity with decreased responsiveness.

By familiarity with a given preparation and careful study, one can dodge both the after-discharge and the pronounced change in the pH of the area; thus the remaining facilitation is associated merely with a negativity of the surface of that cortex, with respect to its depth, in the excited area and nowhere else.

If, now, that area of cortex is eserinized, it is found that the period of negativity endures more than twice as long, and that the time the response is facilitated is enormously protracted. If the area is atropinized, the period of facilitation and the period of surface negative are cut approximately in half, although the size of the first motor response is unaffected.

Placing an interpretation on the behavior of the cortical elements very similar to that demonstrated by Dr. Lloyd in the cord, we have here motor neurons with apical dendrites and basal dendrites, and an axon going elsewhere. If the cell is stimulated repeatedly, there are stirred up impulses which as they play out into the dendritic end of that cell cannot possibly go all the way to the end following the first impulse, because the length of the impulse increases as the fiber-diameter decreases and when it dies its sink fades slowly. The time of fading will be too long to allow the rapid succession of aftercoming impulses to proceed as far. The process will end in a relatively depolarized state of the dendrites. A period of positive after-potential should supervene in the axon, and there should be, because of these polarizations, a polarization of the cortexdendrite negative, axon positiveduring which time the clear negativity of the surface could be recorded. During this time the superior part of the cell, being somewhat depolarized, might be more excitable, but the axon in hyperpolarization could deliver a greater kick. This is a very neat and simple theory, and if it were true the role of eserine and acetylcholine in the process would be relatively uncomplicated.

We went, therefore, next to Lloyds preparation for the potentiation of the monosynaptic arc, and here we ran into a peculiar difficulty, which accounts for the fact that I have nothing exciting to report.

If the experimental animal is prepared by a high spinal transection, cutting only the dorsal roots in the lumbar enlargement necessary to reach the ventral roots, picking up the dorsal root or the motor nerve to be stimulated, and sectioning the ventral root and recording from it, it is found that the potentiation is enormously enhanced under eserine and reduced under atropine.

If, however, the cord is transected in the thoracic region and all of the dorsal roots, except the one to be stimulated or the one bringing impulses in from the muscle in question, are cut, and recordings are made from the motor root after it is cut, then there is obtained no change in potentiation on atropinization or on eserinization. In other words, at the present moment I can make neither head nor tail of the findings, and two preparations in which I can see no reason for any difference are giving diametrically opposite results.

This is the sort of obstacle I have encountered almost every time I have experimented with drugs in the spinal cord, above all with eserine, atropine, or DFP.



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Keywords: Seizure, Metabolism, Ignorance, Dislike, Changes, Triphosphate, Truth, Brain-Wise, Therapy

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1 Reprinted from The Biology of Mental Health and Disease (Report of the 27th annual conference on the Milbank Memorial Fund Symposium held in NYC, Nov. 13-16, 1950) Paul B. Koeber, Inc., Medical Book Dept, of Harper Bros. New York 16, NY, 1952, pp 177-179.