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p us to understand their significance in health and in disease。
THE RELATION BETWEEN THE PHYSICAL STATE OF THE BRAIN…CELLS AND BRAIN FUNCTIONSEXPERIMENTAL AND CLINICAL＇*＇
＇*＇ Address before The American Philosophical Society； April 18； 1913。
The brain in all animals （including man） is but the clearing…house for reactions to environment； for animals are essentially motor or neuromotor mechanisms； composed of many parts； it is true； but integrated by the nervous system。 Throughout the phylogenetic history of the race the stimuli of environment have driven this mechanism； whose seat of powerthe batteryis the brain。
Since all normal life depends upon the response of the brain to the daily stimuli； we should expect in health； as well as in disease； to find modifications of the functions and the physical state of the component parts of this central battery the brain…cells。 Although we must believe； then； that every reaction to stimuli； however slight； produces a corresponding change in the brain…cells； yet there are certain normal； that is； non…diseased； conditions which produce especially striking changes。 The cell changes due to the emotions； for example； are so similar； and in extreme conditions approach so closely to the changes produced by disease； that it is impossible to say where the normal ceases and the abnormal begins。
In view of the similarity of brain…cell changes it is not strange that in the clinic as well as in daily life； we are confronted constantly by outward manifestations which are so nearly identical that the true underlying cause of the condition in any individual case is too often overlooked or misunderstood。 In our laboratory experiments and in our clinical observations we have found that exhaustion produced by intense emotion； prolonged physical exertion； insomnia； intense fear； certain toxemias； hemorrhage； and the condition commonly denominated surgical shock； produce similar outward manifestations and identical brain…cell changes。
It is； therefore； the purpose of this paper to present the definite results of laboratory researches which show certain relations between alterations in brain functions and physical changes in the brain…cells。
Fear。Our experiments have shown that the brain…cell changes due to fear may be divided into two stages： First； that of hyperchromatism stimulation； second； that of hypochromatismexhaustion （Figs。 5 and 13）。 Hyperchromatism was shown only in the presence of the activating stimuli or within a very short time after they had been received。 This state gradually changed until the period of maximum exhaustion was reachedabout six hours later。 Then a process of reconstruction began and continued until the normal state was again reached。
Fatigue。Fatigue from overexertion produced in the brain…cells like changes to those produced by fear； these changes being proportional to the amount of exertion （Fig。 4）。 In the extreme stage of exhaustion from this cause we found that the total quantity of Nissl substance was enormously reduced。 When the exertion was too greatly prolonged； it took weeks or months for the cells to be restored to their normal condition。 We have proved； therefore； that in exhaustion resulting from emotion or from physical work a certain number of the brain…cells are permanently lost。 This is the probable explanation of the fact that an athlete or a race…horse trained to the point of highest efficiency can reach his maximum record but once in his life。 Under certain conditions； however； it is possible that； though some chromatin is forever lost； the remainder may be so remarkably developed that for a time at least it will compensate for that which is gone。
Hemorrhage。The loss of blood from any cause； if sufficient to reduce the blood…pressure； will occasion a change in the brain…cells； provided that the period of hypotension lasts for more than five minutes。 This time limit is a safeguard against permanent injury from the temporary hypotension which causes one to faint。 If the hemorrhage be long continued and the blood…pressure be low； there will be a permanent loss of some of the brain…cells。 This explains why an individual who has suffered from a prolonged hemorrhage will never again be restored to his original powers。
Drugs。According to their effect upon the brain…cells； drugs may be divided into three classes： First； those that stimulate the brain…cells to increased activity； as strychnin （Fig。 37）； second； those that chemically destroy the brain…cells； as alcohol and iodoform （Figs。 38 and 39）； third； those that suspend the functions of the cells without damaging them； as nitrous oxid； ether； morphin。 Our experiments have shown that the brain…cell changes induced by drugs of the first class are precisely the same as the cycle of changes produced by the emotions and by physical activity。 We have found that strychnin； according to the dosage； causes convulsions ending in exhaustion and death； excitation followed by lassitude； stimulation without notable after…results； or
｛illust。 caption = A； Section of Cerebellum of Normal Dog。 C； Section of Cerebellum of Dog after Repeated Doses of Strychnin。 FIG。 37。 BRAIN…CELLS SHOWING STAGE OF HYPERCHROMATISM FOLLOWED BY CHROMATOLYSIS RESULTING FROM THE CONTINUATION OF THE STIMULUS。 （Camera lucida drawings。）increased mental tone； while the brain…cells accurately display these physiologic alterations in proportional hyperchromatism in the active stages； and proportional chromatolysis in the stages of reaction。 The biologic and therapeutic application of this fact is as obvious as it is important。
In our experiments； alcohol in large and repeated dosage caused marked morphologic changes in the brain…cells which went as far even as the destruction of some of the cells （Fig。 39）。 Ether； on the other hand； even after five hours of administration； produced no observable destructive changes in the brain…cells。
The effect of iodoform was peculiarly interesting； as it was the only drug that produced a rise of temperature。 Its observed effect upon the brain…cells was that of wide…spread destruction。
Infections。In every observation regarding the effect of pyogenic infections on dogs and on man we found that they caused definite and demonstrable lesions in certain cells of the nervous system； the most marked changes being in the cortex and the cerebellum （Fig。 40）。 For example； in fatal infections resulting from bowel obstruction； in peritonitis； and in osteomyelitis； the real lesion is in the brain…cells。 We may； therefore； reasonably conclude that the lassitude； the diminished mental power； the excitability； irritability； restlessness； delirium； and unconsciousness which may be associated with acute infections； are due to physical changes in the brain…cells。
Graves' Disease。In Graves' disease the brain…cells show marked changes which are apparently the same as those produced by overwork； by the emotions； and by strychnin。 In the postmortem examination of one advanced case it was found that a large number of brain…cells were disintegrated beyond the power of recuperation； even had the patient lived。 This is undoubtedly the reason why a severe case of exophthalmic goiter susta