The conference chairman asked for a statement of work done at the Laboratory of the Department of Psychiatry of the University of Illinois between September, 1941 and September, 1952. Shortly thereafter this was presented at Queen Square.
I am sorry that our work then left so many problems unsolved, and sorrier still that the subsequent 10 years have left them so nearly as they were that the Queen Square lecture needs no major alteration to bring it up to date.
The bulk of psychiatry's burden comes from biochemical disorders of the brain. Half of all patients have trouble with their brains. Two-thirds of them are psychotic, and two-thirds of these on first admission are tossed into the scrapbasket called schizophrenia, which might as well catch all postpartum, puerperal, and involutional psychoses. In 1941, I went to Illinois to join Gerty, hoping that our laboratory might discover the biochemical bases of some of these diseases. The respiratory quotient of the brain is nearly one. Dusser de Barenne had recorded it continuously and shown that, given sugar and insulin, it might exceed one. Hence he thought sugar turned to fat, liberating oxygen. Years later, our Department of Agriculture recorded, in pigs fed carbohydrates, a respiratory quotient of two, and DeWitt Stetten demonstrated the formation of fatty acids containing heavy hydrogen by giving heavy water and glucose to animals with plenty of insulin.
With Dusser de Barenne, Nims, and Stone at Yale, I had measured the pH of cortex as affected by its own activity. During the first fast phase of a local fit the area becomes alkaline some tenth of a pH unit and then swings acid by as much as three-tenths. As in peripheral nerve, alkalinity parallels release of ammonia. The acid swing initiates a vasodilation in which the veins run red. Santos, with Penfleld in Montreal, using Gibb's heated thermocouples, found, at this time in the fit, increased blood flow in cortex and thalamus.
I went to Chicago with J. Raymond Klein, where we froze the exposed brain suddenly by pouring liquid air on it and then analyzed it for various carbohydrate intermediate metabolites. We found a great accumulation of pyruvate and lactate, which could easily account for the observed acidity in fits. Biochemical textbooks of that period stated that nothing was known of the carbohydrate metabolism of brain, but in muscle — thus and so! In muscle, the utilization of carbohydrate begins by an anaerobic process, adding phosphate and splitting the molecule, step by step, to pyruvate which is in equilibrium with lactate. The energy released is captured by building adenosine triphosphate, and stored as phosphocreatine. About a tenth of it is obtained by the anaerobic steps leading to pyruvate. Lactate does not easily escape from brain to blood but, going back to pyruvate, enters the cyclical process to end as carbon dioxide and water, providing the remaining nine-tenths of the energy caught and stored as before. This process was proved, step by step, in my laboratory, by using various preparations of brain in Warburg until we knew that brain did everything that muscle was known to do. We found that, in fits, phosphocreatine was well-nigh exhausted before the concentration of adenosine triphosphate was much decreased. We thought that the exhaustion of stored energy might terminate the convulsion, but shorter seizures showed they stopped too soon.
Stone, on interrupting blood supply of brain or drowning in nitrogen, found the same rise in lactic acid and the same fall in phosphocreatine. Thus in the seizure, the utilization, by increased activity, outruns the increased total metabolism and, despite increased oxygen supply, overworks its anaerobic metabolism. But we also found that the utilization of glucose by anoxic brain increased eightfold and from eight to eightyfold in fits. To clinch this story, we measured the oxygen tension of the brain polarographically. It begins to fall at the beginning of the fit; and, despite an increased blood flow during the acid shift, it reaches its nadir somewhat later than the peak of acidity. This bespeaks the subsequent oxidation of accumulated acid metabolites.
To understand these reactions better, we measured the so-called redox potential in the cortex. During induced convulsions, it swung out of phase with the pH, so that the redox system communicating with the electrode did not include the hydrogen ion per se. The potential is affected in the right direction by intravenous injections of oxidized and reduced ascorbic acid. Its value lies in the range attributable to ascorbic acid, and it is cyanide-stable—even when the animal's cortex becomes isoelectric. Finally, in human spinal fluid, the potential of the noble metal electrode shifts with the shift of the ultraviolet ascorbic acid spectrum from reduction to oxidation and vice versa. As is now well known, ascorbic acid does play a role in the carbohydrate cycle; Ward and I found this potential fluctuating from moment to moment in Kopoloff's monkeys in that cortical region where fits arose. These facts are clear, but even now their interpretation is not.
At that time the mechanisms of pyruvate oxidation, via acetate and acetyl coenzyme A and the subsequent condensation of citrate, was elucidated by Lipmann, Novelli, Korkes, and Ochoa.
The Gibbses and Kety, by dissimilar methods, had shown that about a pint of blood per minute flows through a man's brain; that this can be doubled by breathing CO2 and halved by hyperventilating. We had found that the brain of cat or monkey heated its blood about a degree Fahrenheit in transit. Hence we may estimate that human brain dissipates about 24 watts, a figure which agrees with the best measurements of metabolism in Warburg and with the Gibbs’ measure of oxygen and carbohydrate uptake. None of us secured truly comparable direct measures of its metabolism during grand, mal convulsions.
James Bain began collaborating with Klein, Olsen, and the author. Interest in fits was on the manner in which they effect remission in schizophrenics. For the Medical Division of the Chemical Warfare Service we had been studying the action of sodium cyanide in titering out the cytochrome oxidase of the central nervous system. Its concentration is lowest in highest structures. By grading the dose, one is able to quench cerebral activity from above downward, until only the medulla remained active enough to conserve respiration. One milligram of sodium cyanide per kilogram of cat, dog, goat, monkey or man produces a decerebration with silent cortex and thalamus, opisthotonos and extension of all four limbs, just as if Sherrington had transected the midbrain. Magnus de Kleijn reflexes are then obtainable. In three minutes the subject is again normal and no damage has been done. The effects of cyanide on the carbohydrate cycle were found to be the same as those of fits and of hypoxia. We thought that these changes might be responsible for the therapeutic virtue of fits in schizophrenia; and we knew that it was less dangerous than convulsions induced electrically or by metrazol. Therefore, we decerebrated sixty-odd schizophrenia patients ten times each, without producing a remission in a single case, though we were subsequently able to snap some of these patients out of catatonia with a single metrazol convulsion or a couple of electrically induced ones. Clearly, then, the known changes in the metabolism of the brain were not sufficient to produce remissions. The question remained whether they were necessary.
To answer this I sought a seizure in which cerebral oxygen supply would be more than sufficient for any increase in metabolism, namely the hyperoxic convulsion which occurs after some 30 minutes respiration of three or more atmospheres of pure oxygen. Under the auspices of the Office of Naval Research, Seymour Stein built us a tank and invented a way of respiring paralyzed animals with pure oxygen, or any other gas we desired, at a constant and controllable volume per respiration and respirations per minute, when the rest of the tank was filled with pure nitrogen. This prevents fire and explosion, which heretofore had blocked such investigations. We found that the fits did indeed occur when the brain has a very high oxygen tension. Its pH showed the familiar acid swing, but we could not tell whether this was due to lactic acid or to an accumulation of carbon dioxide because of poor transport by blood surcharged with oxygen or by stasis in the lungs. We had instrumental difficulties in measuring the actual output of carbon dioxide. Stein went to carry on physiology for the Navy in Bethesda, where he had the equipment, but not the teamplay that he needed. So we do not know whether the overrunning of anaerobic metabolism is unnecessary as well as insufficient for therapy.
Electrophysiologists have long known that barbiturates retard repolarization of neurons. The energy comes from oxidation-reduction reactions producing adenosine triphosphate. Whatever the link between that energy and that potential, it is clear that if adenosine triphosphate is not produced at a sufficient rate, the energy for polarizing the membrane at a normal rate is wanting. Bain extracted mitochondria from brain and showed that these carried the full complement of enzymes for oxidation and for phosphorylation, sufficient to produce adenosine triphosphate at a normal rate. But barbiturates, in no greater concentration than anesthetic dose divided by body weight, uncoupled the reactions. Phosphorylation failed, while oxidation proceeded as before.
Two classic neurophysiological problems then required solution. We did not know how the central nervous system knows the sugar level in the blood, or the full story of how it controls that level. One thing was certain, it is not the sugar level in brain that determines the action by brain, for the brain can be fooled. Klein showed that several sugars failed to enter brain at any significant rate, yet their injection into animals produced a reaction by brain to lower the level of blood glucose. You'd think it an easy job to destroy the connections of all possible taste buds in the mouth and along the arteries so as to deprive the brain of these channels of information. Though I had teamplay with several excellent neurosurgeons, we never succeeded.
For this, and for clinical chores, we had developed teams of skillful technicians, who could sample blood in man or beast at prescribed times without a tourniquet to produce stagnation. One of them, Ellen Ridley, with various collaborators, trained a series of dogs so that they would lie on the table for hours unrestrained, to have blood drawn every few minutes, without showing fluctuation exceeding the error of the method. Among these, she selected those dogs that preferred a minute taste of Pablum flavored with a trace of meat extract to one of plain Pablum. These dogs routinely showed a substantial rise on tasting the bland Pablum and a greater one on tasting the flavored Pablum. She and Share trained and tested esophagotomised dogs in the same way, then fed them to so-called satiety. At the beginning of the feeding, blood sugar rose as it had from taste alone; but fell in a few minutes to a nadir 15 milligrams per cent, or more, below the fasting level. Such experiments cannot throw much light on mechanisms, but indicate that they are more complicated, and hence more prone to disorder, than I had naively supposed.
This is of clinical importance in certain neurotics whom we found to be significantly more sensitive to injected hormones, and other substances involved in carbohydrate regulation, than nurses, attendants or doctors on the same diet, and far more sensitive than psychotics. Franz Alexander discovered a small group of energetic people who, having crystallized their hopes around some narrow goal to which they could not proceed, experienced fatigue, slept too much, ate too much, and grew fat. They all suffered from so-called hypoglycemic symptoms, i.e., they felt faint, warm and sweaty within a few hours after eating. He sent them to me asking whether their parasympathetic system was overactive, for he and Portis had relieved these symptoms by atropine, in doses that they thought prevented vagally induced secretions of insulin. I confirmed Portis’ findings that the blood sugar of Alexander's patients, following injection of glucose, fell somewhat more rapidly and to a lower level than normal. Unlike most neurotics, these patients were only normally sensitive to insulin. I therefore suspected they might show the rise in the respiratory quotient which Dusser de Barenne and DeWitt Stetten had found with sugar plus insulin. I took normal controls under basal metabolic conditions, recorded rectal temperature continuously, and determined the basal metabolic rate, using a typical clinical instrument that measures only the rate at which oxygen is consumed. I then injected them with 0.6 cc. of 50 per cent glucose per kilogram and repeated the determination every few minutes until their blood sugar had returned to normal. Their temperature remained constant and they showed no change in oxygen consumption except as scatter within the error of the measure. When the same procedure was repeated on Alexander's patients, there was no change in temperature; but, during the time the sugar was disappearing from their blood, their oxygen uptake fell in some cases by as much as 30 per cent below the basal level. To make up for this failure to absorb oxygen from the tank they must have converted more than half of the injected sugar to fatty acid. Naturally, they got fat. This fall in oxygen uptake was prevented and the sugar tolerance curve was decreased to normal rate and amplitude by small doses of atropine.
The Coris had just shown that glucose plus adenosine triphoshate plus hexokinase gave glucose-6-phosphate and adenosine diphosphate; that this could be blocked by aqueous extracts of the anterior pituitary lobe; and that once so blocked, it could be unblocked by addition of insulin. Had normal brain required insulin for utilizing carbohydrate, I should have been excited; but I supposed simply that the pituitary factor never passed the blood-brain barrier. To the Coris’ reaction we shall return when it is relevant. For the moment let me lament my failure to discover how the brain regulates the blood sugar. Leimdorfer and I proved past peradventure that adrenalin injected into the subarachnoid space of beast and man produces no rise in blood pressure, but a great rise in blood sugar, analgesia, anesthesia and lethargy that lasts from hours to days according to the dose. The piqûre of Claude Bernard had remained unexplained for nearly a century. I had hoped to solve it by using intrathecal adrenalin instead of the piqûre, and destroying, one after another, all of the ways whereby brain might affect blood sugar. A. A. Ward and Oscar Sugar assisted me. We worked on cats and dogs. Removal of adrenals, sacculation of spinal cord above the thoraco-lumbar (sympathetic) outflow, bilateral section of the vagi high in the neck, and removal of the entire pituitary with gross damage to the ventral hypothalamus, singly and in combination — even all of them in the same dog or in the same cat — failed to prevent a rise in blood sugar induced by intrathecal adrenalin. We attempted, un-successfully, to cross-circulate a head so prepared from the body of a second beheaded dog, or even to maintain it with no connection with its own body save arteries and veins. Until someone succeeds, the chance remains that some part of the brain not destroyed by us serves as a gland of internal secretion to produce some unknown hyperglycemic factor. Until then the piqûre of Claude Bernard will remain a mystery.
Concerning this regulation as affected by emotional factors, or mere zest, I can only add that we made an enormous number of measurements on controls and neurotics, and found that neurotics fluctuate somewhat more than normals under resting conditions, that the fluctuations increase significantly when they are watching moving pictures and more when they are playing games like chess. But neurotics in the hands of analysts, however expensive it may have been to them, were no burden to taxpayers. Few of them inhabit our state hospitals. Hence they were less important to us than the great group of psychotics.
While Wagner Jauregg was growing famous for malaria as an antidote to general paresis, Meduna discovered the incompatibility of epilepsy and schizophrenia and initiated convulsive therapy. He found it worked only with those who had a primary clouding of the sensorium resembling a dream. Hence he calls these patients “oneirophrenic.” Meyer-Gross’ term for this state is “oneiroid Zustandt.” Langfeldt calls them “schizopheniform,” and Francis Braceland just “hot schiz.” Meduna compares shock therapy to kicking Swiss watches. It sometimes gets them going again but he does not like it and resents its use as a panacea. He therefore returned to the laboratory, first at Loyola Medical School, and then with us, to find out how fits worked, to seek a substitute for shock and to study the pathophysiology of the oneiroid “schiz.” With Gerty, Ursy, Braceland, and Vaichulis, he found that about two-thirds of all so-called schizophrenics, on their first admission, gave a diabetic response to the Exton-Rose (one-hour two-dose) glucose-tolerance test. Later he substituted an intravenous glucose-tolerance test, and showed that, following injection of a given amount of glucose, the rise to the five-minute value was significantly less in oneiroids than in normals, but that thereafter the curve fell at something like half the normal rate. The curve resembles that seen when there is damage to the liver.
He inaugurated an insulin tolerance test, giving 1/10 unit per kilogram, and sampling blood before injection, every five minutes after for 45 minutes, and thereafter at longer intervals. Normal controls show a fall to a nadir at least 50 per cent below fasting values within the first half-hour. Ten minutes later still, heart rate increases; and, at the 45-minute sample, blood sugar rises in the “Cannon spike.” The exact dose is unimportant; it can be multiplied or divided by eight without affecting the rate of fall or the nadir. In Meduna's patients, the nadir is always belated and never deep. The average slope is about half the normal, and increasing the dose does not increase it.
Perhaps the insulin resistance of oneirophrenics might have been guessed from Gellhorn's work. He removed pituitary, pancreas, and adrenals in rats, and injected a few drops of blood from excited medical students, producing a large rise in the rats’ blood sugar. But when he injected the same quantity of blood from excited insane patients, the blood sugar fell profoundly, sometimes to lethal values. This suggests that these patients have too much insulin in their circulation, and that their blood sugar is roughly normal only because their own insulin fails to take effect in them.
Meduna had also found, and others confirmed, that intraperitoneal injection of oneirophrenics’ blood into animals rendered them resistant to a subsequent dose of insulin. When he came to my laboratory, he was isolating from the urine of oneiroid patients a substance that could not be found in normal human urine. It precipitates at a pH about 4.2. It is soluble in 60 per cent acetone but insoluble in 80 per cent, and can be purified to some extent by repeating the extraction. A few milligrams of this crude extract are enough to double the blood sugar of a 250-gram rat. To secure uniform rats, we raised our own strains, and thereby decreased the scatter of our results. A hot oneirophrenic patient puts out enough of this material in 24 hours to double the blood sugar of seven 250-gram rats. We could never get it free enough from colored contaminants to be sure of biuret or Molisch reactions. It is unstable in alkaline solution. It had a habit of denaturing to a tar with which we could do nothing. Meduna's purest extracts were studied by a friend of his, who reported that small quantities were sufficient to block the Cori reaction, which then required large quantities of insulin to unblock it, and he thought it also blocked the invertase action. For this reason we studied liver functions, and found no abnormality except that, in a few of the oneiroid patients whom we studied carefully, the conversion of levulose to glucose seemed abnormally slow. We did encounter one wildly psychotic case with a fasting levulose of 12 milligram per cent and several milder cases with smaller amounts when there is normally none in man.
We asked Cretcher of the Mellon Institute to help in purification and identification of the hyperglycemic factor. He put Marcus Morgan on the trail of this material. Incredulous of our findings, Morgan ran his own controls and found none in the urine of the research fellows of the Institute, whereas in the urine of patients of the Western Psychiatric Institute he found a plentiful supply. By lyophilizing his precipitates he secured an almost colorless material that gave both biuret and Molisch reactions. Its stoechiometric analysis was appropriate for a protein, rich in phosphorus and fairly rich in sulphur. It did not seem in any way denatured; its Svedberg constant of 6.5 indicated a molecule of large size, with a gram molecular weight of about 100,000. Its infrared absorption spectrum was that of a typical protein. Its hyperglycemic potency per gram of animal, assayed on mice, was like Meduna's best, assayed on rats. On digestion with trypsin, Morgan obtained a smaller molecule, of Svedberg constant 2.75, or gram molecular weight of about 10,000, of still greater potency.
For ten years we had studied a few cases of catatonia who had spontaneous remissions, and a few who relapsed frequently but could be rendered temporarily symptom-free by electroshock or metrazol convulsions. On glucose tolerance tests, insulin tolerance tests, and assay of the hyperglycemic factor in urine, we found that the pathological findings paralleled the clinical picture very closely. From 12 to 72 hours before the clinical picture changed, the insulin tolerance test changed in the appropriate direction. This led us to suppose that, instead of being merely a telltale, the biochemical change might, in some obscure way, be causally related to the behavioral change. Had brain required insulin, the way would not have seemed obscure. We were preparing to test Morgan's purified hyperglycemic factor, at least on ourselves, to see whether we could produce the psychosis. How wrong we were you may judge from the following story.
Stephen Sherwood, then of the Middlesex Hospital, who had become disgusted with the poor results of leucotomy in catatonic patients, reasoned that if he could get cholinesterase into the right place it might help his patients, and, since enzymes, being proteins, could not pass from blood to brain, that he would have to put it into the ventricles. There it might lower the titer of acetylcholine in the spinal fluid and, so, in the adjacent tissue. He knew that Ingraham, Ranson, Magoun and many of us had made animals catatonic by symmetrical lesions dorsal and caudal to the corpora mammillaria, and that these lesions were near the third ventricle and the aqueduct of Sylvius. Presumably the lesions deafferented other cells in their vicinity. This, as Cannon and Rosenblueth have shown in other structures, should make the denervated cells more sensitive to acetylcholine and similar substances. He had at his disposal a small quantity of freeze-dried human erythrocyte stroma, which is rich in esterase and safe for intraventricular injection. His first patient had been catatonic for some six years. Shock therapy and leucotomy had not produced significant improvement, but she responded to intraventricular injection of the erythrocyte stroma with a remission lasting many months, during which she was relatively normal for her age. In other cases he tried intraventricular Flaxidril and other compounds which tend to block the action of acetylcholine. They worked briefly and poorly. He then came to America to work with me on beasts, and with Bay at Manteno State Hospital on catatonic patients.
We began by producing typical catatonic cats, à la Ingraham and Ranson. Bain prepared for us human cholinesterase of fairly high titer, but not completely purified, and by no means as potent in Warburg as the cholinesterase produced, purified and given to us by Nachmansohn, who made it from the electric organ of the eel. Intraventricular injection of either esterase promptly restored our catatonic cats to a normal, mobile, friendly state in which they ate spontaneously. The improvement lasted hours or days, the duration depending partly on the dose, partly on the size and antiquity of the lesion. As Nachmansohn had predicted, his eel cholinesterase was less effective than human esterase in the same gravimetric dose. Cats with small lesions eventually recover. In them and in those we had given a remission by cholinesterase, small intraventricular doses of acetylcholine, without observable effect on unoperated cats, immediately reinstated the catatonia.
After carefully checking eel cholinesterase on chronic animals, to be sure it was safe to inject it into human ventricles, we tried is on a few of the most hopeless cases at Manteno State Hospital. They had all been there for years, were typical burnt-out catatonics, and all of them were typically resistant to insulin action. In no case did we achieve anything resembling full recovery, but I think there was some clinical improvement in every case. The first observable effect in all of them was the prompt disappearance of their gray cyanosis and some peripheral dilitation, making it much easier to draw blood. This was promptly followed by a change in facial expression, most noticeable in the eyes, which now followed objects and looked into the face of the speaker. The waxy flexibility melted. They obeyed commands, answered questions, and sometimes spoke spontaneously. In every case the insulin tolerance test shifted toward the normal curve, but never reached it. In some cases, the improvement lasted only a day or two; in others, a few months. In one patient to whom we gave repeated injections, the glucose tolerance curve improved with each injection.
We then returned to my laboratory, obtained normal insulin tolerance curves on several monkeys, made them catatonic by lesions, found they had become resistant to insulin action and removed this resistance by intraventricular cholinesterase. Finally, we restored both catatonia and resistance to insulin by small intraventricular doses of acetylcholine which had no such effect on a normal monkey. Shortly after, I left Illinois.
When I left Illinois and psychiatry and said farewell to the problems, despite Ellen Ridley, this work ceased. I know of no one else who will carry on in my stead. The diseases called schizophrenia affect nearly two per cent of our population. They are responsible for more suffering and more prolonged illness than any other diseases. There should be not one, but a hundred teams at work on them. In the 10 succeeding years we might have had a chance of curing or preventing them; for schizophrenia even today looks the way diabetes did 40 years ago when I was a freshman in medical school.
Eliott B. Hague (Conference Chairman; Millard Fillmore Hospital, Buffalo, N.Y.): Thank you Dr. McCulloch. Before calling for discussion I feel that I should point out, and I'm sure that I am correct, that this material has not been published. Dr. McCulloch has given us a very clear picture of the trials and tribulations of the thoroughgoing scientist. However, there is one comment I would like to make now. It seems to me that there is a certain mutual relevance between McCulloch's pseudoneurotic patient and the hypothalamic patient of Reimann. I particularly wanted Reimann's material in our program tomorrow in order to make clear to the clinician that hypothalamic disease is a very real thing. Is there any discussion now?
O. C. Irwin: Dr. McCulloch, did you happen to indicate that you gave an anticholinergic to human catatonics and got a remission of the catatonia? Did I hear you correctly on that? I thought that somewhere along the line you had indicated the use of an anticholinergic; I mention this only because I would expect that if cholinesterase were to produce a remission that an anticholinergic such as atropine perhaps might also do the same by way of blocking the acetylcholine. Do you have any information on this point?
Warren S. McCulloch (Massachusetts Institute of Technology, Cambridge, Mass.): There have been quite a number of compounds tried out in England by Steven Sherwood before he came over here, Plaquinil and so on. Some of these had some beneficial effect, but very brief and very short lived.
O. C. Irwin : I might say in addition it is rather interesting that in the catalepsy produced in animals with phenothiazine drugs, one can abolish this very easily with an anticholinergic. However, the catalepsy produced by reserpine and I also believe morphine, will not be abolished by an anticholinergic ; there are differences here also.
Warren S. McCulloch : What is the location of your drug, intraventricular?
O. C. Irwin : No, this is strictly parenteral in this case.
Warren S. McCulloch : I mean where are you injecting your anticholinergics and so on?
O. C. Irwin : No, this is all parenteral.
Warren S. McCulloch : May I point out that these affairs are entirely different in their central action from what they are in their peripheral action. You can say for example, that atropine has almost diametrically the opposite effects if you give it intraventricularly than when you give it systematically.
O. C. Irwin : I see your point, yes.
Warren S. McCulloch : These tricks were first worked out by Harvey Cushing.
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