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tears of the woman when she receives a proposal of marriage from the man she loves； we can understand why any averted circumstance； such as a threatened breach of the conventions； which would have led to embarrassment or humiliation； leads to a tendency to laughter； and why the recital of heroic deeds by association leads to tears； On the other hand； under the domination of acute diseases； of acute fear； or of great exhaustion； there is usually neither laughter nor crying because the nervous system is under the control of a dominating influence as a result of which the body is so exhausted that the excess of energy which alone can produce laughing or crying is lacking。
A remarkable study of the modification of laughter and crying by disease is found in that most interesting of diseasesexophthalmic goiter。 In this disease there is a low threshold to all stimuli。 That the very motor mechanism of which we have been speaking is involved； is shown by an enormous increase in its activity。 There is also an increase in the size of certain at least of the activating glandsthe thyroid and the adrenals are enlarged and overactive and the glycogen…producing function of the liver is stimulated。 The most striking phenomenon of this disease； however； is the remarkable lowering of the brain thresholds to stimuli。 In other words； in Graves' disease the nervous system and the activating glands the entire motor mechanismare in an exalted state of activity。
If this be true； then these patients should exhibit behavior precisely contrary to that of those suffering from acute infection； that is； they should be constantly clearing their systems of these superabundant energizing materials by crying or laughing； and this is precisely what happensthe flood…gates of tears are open much of the time in Graves' diseasea disease of the emotions。
We have already interpreted pain as a phenomenon of motor activity。 When pain does not lead to muscular activity it therefore frequently leads to crying or to moaning； just as tickling； which is equally an incentive to motor activity； results in laughter if it does not find full expression in action。
From the foregoing we infer that pain； the intense motor response to tickling； and emotional excitation are all primitive biologic reactions for the good of the individual； and that all have their origin in the operation of the great laws of evolution。 If to this inference we add the physiologic dictum that the nervous system always acts as a whole； and that it can respond to but one stimulus at a time； we can easily understand that while diverse causes may integrate the nervous system for a specific action； if the cause be suddenly removed； then the result of the integration of the nervous system may be； not a specific action； but an undesigned muscular action； such as crying or laughter。 Hence it is that laughter and crying may be evoked by diverse exciting causes。 The intensity of the laughter or of the crying depends upon the intensity of the stimulus and the dynamic state of the individual。
The linking together of these apparently widely separated phenomena by the simple law of the discharge of energy by association perhaps explains the association of an abnormal tendency to tears with an abnormally low threshold for pain （Fig。 36）。 In the neurasthenic； tears and pain are produced with abnormal facility。 Hence it is that； if a patient about to undergo a surgical operation is in a state of fear and dread before the operation； the threshold to all stimuli is lowered； and this lowered threshold will continue throughout the operation； even under inhalation anesthesia； because the stimulus produced by cutting sensitive tissue is transmitted to the brain just as readily as if the patient were not anesthetized。 In like manner； the brain may be sensitized by the administration of large doses of thyroid extract prior to operation； the threshold to injury in such a case continuing to be low to traumatic stimuli even under anesthesia。 Under the sensitizing influences of thyroid extract or of Graves' disease the effect of an injury； of an operation； or of emotional excitation is heightened。 The extent to which the threshold to pain or to any other excitant is affected by Graves' disease is illustrated by the almost fatal reaction which I once saw result from the mere pricking with a hypodermic needle of a patient with this disease。 As the result of a visit from a friend； the pulse…rate of a victim of this disease may increase twenty beats and his temperature rise markedly。 I have seen the mere suggestion of an operation produce collapse。 As the brain is thus remarkably sensitized in Graves' disease； we find that in these patients laughter； crying； emotional disturbances； and surgical shock are produced with remarkable facility。
I hope that even this admittedly crude and imperfect consideration of this subject will suggest the possibility of establishing a practical viewpoint as to the origin and purpose of pain； of tickling； and of such expressions of emotion as laughter and crying； and that it may help 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 individu