The Agglomeration Theory of Sleep

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Naturwiss., 18, 778 (1930); Wierl, R., Phys. Zeit., 31, 366 (1930); Wierl, R., Ann. Phys., [5] 8, 521 (1931); Wierl, R., Ann. Phys., [5] 13, 453 (1932). 2 Debye, P., Ann. Phys., 46, 809 (1915). 3Mott, N. F., Proc. Roy. Soc. (London), A127, 658 (1930). 4 Thomson, G. P., Proc. Roy. Soc. (London),. A117, 600 (1928); Thomson, G. P., Proc. Roy. Soc. (London), A119, 651 (1928). e Hultgren, R., Phys. Rev., 40, 891 (1932). 6 Pauling, L., J. Am. Chem. Soc., 49, 765 (1927).

THE AGGLOMERATION THEORY OF SLEEP* By WILDER D. BANCROFT AND JOHN E. RUTZLER, JR.** BAKER CHBMIcAL LABORATORY, CORNELL UNIVERSITY

Read before the Academy, Tuesday, November 15, 1932

Hollingworthl says that "normal sleep shows so many differences from the states of stupor and insensibility induced by anesthetics, narcotics and other drugs, that the resemblance between the two conditions must be regarded as superficial." Hollingworth represents a minority. Most physiologists and psychologists consider that sleep due to chloroform, morphine, alcohol and other drugs, is identical in principle with ordinary sleep,2 though differing of course in detail. If this is true, sleep must be due in part to a reversible agglomeration of some proteins in the centers of consciousness, wherever these may be. Many agglomeration theories of sleep have been advanced; but they have all been rejected on the ground that one would necessarily stay awake until the agglomerating agent reaches a certain concentration and would necessarily go to sleep as soon as that concentration was exceeded. Since not going to sleep is a matter of choice within certain limits, it was assumed that no agglomeration theory can be right. The flaw in the reasoning is that people have overlooked the effect due to the irritability of the sensory nerves. The more irritated these nerves are, the higher must be the concentration of the agglomerating agent necessary to overbalance the effect due to the sensory nerves and thus to produce sleep. It was a curious error to make, because everybody knows the extraordinary effect of external stimuli in keeping men awake. Laird and Mullers say: "Soldiers on a forced march feel they can go no farther. They are on the verge of falling by the road from sheer exhaustion. An officer comes along. He cheers them with a few words. The regimental band breaks out with a stirring Sousa- rhythm-and without rest the men become refreshed and march briskly off many more miles." If the fatigue becomes great enough, it is almost impossible to keep men awake. There would come a time

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when the soldiers in question would drop to the ground asleep if the company halted for a moment. Soothing irritated nerves should and does make it possible for people to go to sleep quite regardless whether this is done by keeping the room dark and quiet or by administering drugs. It has long been the practice to give bromides either alone or in conjunction with a hypnotic. It has always been recognized that the bromide is a sedative and not a hypnotic; but people seem to have stopped there. Of course sodium rhodanate- is more effective than sodium bromide. As people grow older they usually sleep less, even though they need more sleep because they recuperate more slowly than their juniors. In many cases this inability to sleep well is due to irritated nerves and consequently we have been very successful by giving such people small amounts of sodium rhodanate in a glass of water every week or two. I take it myself and now sleep about seven hours a night instead of about four. Caffein irritates the sensory nerves and some people, including myself, cannot sleep if they drink coffee in the evening. In my own case I can counteract the effect of coffee by taking double the usual dose of sodium rhodanate in a glass of water after dinner. I have never tried this on anybody else and I have never tried putting the sodium rhodanate in the coffee. The sodium rhodanate does not put people to sleep any more than darkening the bedroom does; but it makes possible their going to sleep or staying asleep. Our work on drug addiction has shown that there is no longer anything to fear from habit-forming drugs. In extreme cases of sleeplessness, associated with neuroses, it is possible to give hypnotics, and to counteract their effect on the sensory nerves by suitable administration of sodium rhodanate. It is too soon to make a definite statement; but it looks as though sleeplessness should be a thing of the past for people who are not tuberculous and who do not have too weak hearts or kidneys. Any method of eliminating disturbances will make it easier to go to sleep. One of my friends stops thinking when he goes to bed and goes promptly to sleep. I do not question the principle involved; but I have never been very successful in applying it. On the other hand many of us will go to sleep in the evening over certain books whereas we keep awake without any apparent effort when we play contract. Napoleon was probably a man who was always tired to the point of sleep and who had the power to ignore at will most external and internal disturbances. Consequently he could drop off to sleep at any moment. Dubois4 believes that such people have a relatively large amount of carbon dioxide in the arterial blood; but this has not yet been proved, nor has it been proved that this is the only factor. If the sensory nerves are too irritated, sleep becomes almost impossible.

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Ordinary doses of morphine have very little effect on patients in the acute manic stage. Sodium rhodanate would probably be more effective and would certainly not have the aggravating effect on the psychosis that sodium amytal has. Dr. Gutsell has given sodium rhodanate intravenously to a man suffering from an acute attack of sciatica and the man was sound asleep inside of half an hour. Incidentally, it cured the sciatica. It sounds like foolishness to say that a man can become so tired that he cannot keep awake and yet can sometimes be too tired to sleep. The two statements refer to different conditions. If there is sufficient agglomeration of the centers of consciousness, stimulation of the sensory nerves will have very little effect. If the fatigue involves a large increase in the irritability of the sensory nerves, the man will be kept awake by these nerves, even though the fatigue of the centers of consciousness would put him to sleep under ordinary conditions. While a little sodium rhodanate will quiet the nerves and make sleep possible, more may start peptizing the proteins of the centers of consciousness and make sleep more difficult. Various medical men have tried to repeat our experiments on the antagonism between ether, sodium amytal or morphine, and sodium rhodanate and have obtained results diametrically opposed to ours, the animals coming out of the ether, sodium amytal or morphine more slowly when given sodium rhodanate. This is just the result the medical men should get if they administered too little rhodanate, an error which they would be practically -certain to make. Physicians have recently obtained good results in bringing patients out of narcolepsy by administering ephedrine, a peptizing agent. Equally good results could undoubtedly be obtained with sodium rhodanate. An objection that has been urged against all agglomeration theories of sleep is that some people will wake with one noise and others with another; also that some people can wake pretty accurately at a given hour.5 These are really matters of conditioned reflexes, the particular stimulus to which one is conditioned acting like a loud-speaker. My wife used to wake the moment one of the children cried, while I slept through a good deal of noise. On the other hand, I woke instantly if any of the children walked in their sleep, and my wife never heard them at all. Indians will wake at sounds and wild animals at scents that dwellers in a city would never notice, while some of us can sleep through the noise made by the milkman. When most of us try to wake at six to catch an early train, we wake up every hour or two all through the night, showing an unregulated irritability of the sensory nerves. Why we should get these outbreaks has nothing to do with sleep, because the same phenomena can and do occur when one is awake-if one is doing something interesting and has to catch a train before the end of the evening. I know a man who has apparently an absolute sense of time. He can tell time to within about five minutes

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day or night. Laird and Muller6 say that William Jenny in London can tell the time of day or night within three minutes; but average mortals are off an hour or more. Having a clock in the room to strike the hours while we sleep increases accuracy by employing our so-called subconscious mind. We do not know what the agglomerating substance or group of substances is. Lactic acid plays a part but apparently not the whole part. Dubois7 thinks that carbon dioxide is the important thing; but he has not yet convinced other people. Until the physiological chemists can be of more assistance than they are now, it will be wise to designate by X the substance or group of substances which causes sleep by producing reversible agglomeration of some of the proteins in the unspecified centers of consciousness. Having decided that X will put people to sleep unless prevented by the state of their sensory nerves, what makes people wake up? Most of us wake before we are driven to it by hunger, thirst or digestive necessities. Consequently there must be the production during sleep of an excess of some substance---possibly adrenalin-which irritates the sensory nerves enough to wake-us. In the case of nightmare, it is very probably adrenalin. Let us call this hypothetical substance Y. Since wakefulness in the middle of the night can often be counteracted by sitting up in bed and reading for an hour, it looks as though the excess of Y was decomposed by the extra metabolism due to sitting up and reading. Hibernation of warm-blooded animals differs from ordinary sleep chiefly in that the temperature regulation is thrown out of balance, the hibernating animal assuming pretty closely the temperature of his surroundings. Dubois8 thinks that the cause of this break-down of the temperature regulation is excess of carbonic acid. Something similar is said to occur in all anesthetized animals. Leaving this out of account, the rest of it seems fairly simple to a person like myself who has no firsthand knowledge of the subject. With the fall of body temperature the rate of metabolism becomes very low and there may easily be insufficient production of Y to wake the animal. Dubois says that the marmot wakes every four or five weeks to urinate and defecate. This waking is not due to over-production of Y and the animal goes to sleep again. When warmer weather comes, the rate of metabolism goes up and the animal wakes just as any sleeping animal does. He also wakes when the temperature goes too low. My guess is that he is waked by shivering. Most of us have waked slowly at night and have taken a long time, sometimes an hour, to find out that we woke because we were chilly. Once the animal is awakened, the rate of metabolism goes up and the body temperature likewise. Hibernation in times of drought is probably due to reversible agglomeration at the higher concentration. It is not yet clear why the rate of me-

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tabolism falls off; but this is probably due to poisoning of the catalytic oxidation. The snails of the French vineyards secrete membranes' relatively rich in calcium phosphate which close the orifice of the shell. An interesting question comes up in connection with psychotic patients suffering from dementia praecox catatonia. The psychosis is due unquestionably to an over-dispersed state, and we must therefore conclude either that the sleep of such patients is theoretically quite different from ordinary sleep or that the centers of consciousness may be over-agglomerated while some centers of thinking are over-dispersed. So far as I can learn, these patients do sleep normally as a rule. Consequently one portion of the brain must be over-agglomerated at times, even though another portion of the brain is over-dispersed. Unless one identifies internal inhibition with reversible agglomeration of proteins, it is difficult to see what one can do with Pavlov's theory of sleep.'0 "Sleep and what we call internal inhibition are one and the same process. The fundamental condition of the appearance and development of internal inhibition and sleep is exactly the same. It consists in the more or less prolonged or many times repeated isolated action of a conditioned stimulus producing stimulation of the cellular structures in the cortex. In all cases of internal inhibition which were discussed in the fourth to the seventh lectures drowsiness and sleep were met with continually. In the case of extinction of a conditioned reflex some animals even at the first extinction showed not only a disappearance of the conditioned secretory and corresponding motor reaction but also a great dullness as compared with the normal state of the animal before the extinction. Repetition of extinctions, in the course of a number of days, even if all the conditioned stimuli were reinforced in between, led in every case to an obvious drowsiness and even sleep of the animal in its stand, though no such symptoms had ever previously been observed.... "At this point the following question naturally arises: If sleep coincides so closely in its appearance and disappearance with internal inhibition, how is it that the latter plays such an extremely important part during the alert state of the animal, serving for the most delicate physiological mechanism of equilibration of the higher organism with its environment? To my mind all the facts which have been given in the preceding lectures dispose at once of the apparent contradiction. Internal inhibition during the alert state is nothing but a scattered sleep, sleep of separate groups of cellular structures; and sleep itself is nothing but internal inhibition which is widely irradiated, extending over the whole mass of the hemispheres and involving the lower centers of the brain as well. Thus internal inhibition in the alert state of the animal represents a regional distribution of sleep which is kept within bounds by the antagonistic nervous process of excitation."

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Sleep is then due to a reversible coagulation of some of the proteins of the centers of consciousness by a substance or group of substances which we will call X and which is produced during work. The coagulating effect of X can be counteracted to some extent by the effect due to the irritability of the sensory nerves. A peptizing agent, such as sodium rhodanate, will decrease this irritability and thereby make sleep possible, though not causing it. A larger dose of the peptizing agent may act also on the centers of consciousness and thereby prevent sleep. Use is made of this when counteracting morphine. During sleep there is excess production of a substance or group of substances which we will call Y-possibly adrenalin-and which irritates the sensory nerves, waking the sleeper eventually unless he is waked sooner by some other cause-hunger, thirst, digestive disturbances, light on the face, or an alarm clock, for instance. * This work was done under the program now being carried out at Cornell University and supported in part by a grant from the Heckscher Foundation for the Advancement of Research established by August Heckscher at Cornell University. ** ELI LILLY RESEARCH FELLOW. 1 Hollingworth, The Psychology of Thought, 38 (1926). 2 Pieron, "Le problWme physiologique du sommeil," 145, 147, 192, 193, 247 (1913); Dubois; "Physiologie compar6e de la marmotte," 27, 28, 44, 235, 248 (1896). 3 Laird and Muller, Sleep, 57 (1930). 4 Dubois, loc. cit., 76 (1896). 5 Pi&ron, loc. cit., 432 (1913). 6 Laird and Muller, loc. cit., 124 (1930). 7 Dubois, loc. cit., 248 (1896). 8 Dubois, loc. cit., 240, 249 (1896). 9 Marguerite Bellion, Recherches experimentales sur l'hibernation de l'escargot, 23

(1909). 10 Pavlov, Conditioned Reflexes, 251, 253 (1927).

THE ZERO POINT ENERG Y A ND THE SEPARA TION OF ISOTOPES By HENRY EYRMG FRICK CHEMICAL LABORATORY OF PRINCETON UNIVERSITY Communicated November 29, 1932

The very interesting research of Washburn and Urey' has shown that as water is electrolyzed the residual portion grows richer in H2. The purpose of the present note is again to point out the effect of the zero point energy on reaction rates2 and to show that the greater zero point energy of the lighter isotope effectually aids it in passing over the potential