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production of fever。
That the stimulation of the brain…cells without gross activity of the skeletal muscles and without infection can produce heat is shown as follows：
（_a_） Fever is produced when animals are subjected to fear without any consequent exertion of the skeletal muscles。
（_b_） The temperature of the anxious friends of patients will rise while they await the outcome of an operation （Fig。 63）。
（_c_） The temperature and pulse of patients will rise as a result of the mere anticipation of a surgical operation （Fig。 64）。
（_d_） There are innumerable clinical observations as to the effect of emotional excitation on the temperature of patients。 A rise of a degree or more is a common result of a visit from a tactless friend。 There is a traditional Sunday increase of temperature in hospital wards。 Now the visitor does not bring and administer more infection to the patient to cause this rise； and the rise of temperature occurs even if the patient does not make the least muscular exertion as a result of the visit。 I once observed an average increase of one and one…eighth degrees of temperature in a ward of fifteen children as a result of a Fourth of July celebration。
Is the contribution of the brain to the production of heat due to the conversion of latent energy directly into heat； or does the brain produce heat principally by converting its latent energy into electricity or some similar form of transmissible energy which； through nerve connections； stimulates other organs and tissues； which in turn convert their stores of latent energy into heat？
According to Starling； when the connection between the brain and the muscles of an animal is severed by curare； by anesthetics； by the division of the cord and nerves； then the heat…producing power of the animal so modified is on a level with that of cold…blooded animals。 With cold the temperature falls； with heat it rises。 Such an animal has no more control over the conversion of latent energy into heat than it has over the conversion of latent energy into motion。
Electric stimulation done over a period of time causes brain…cell changes； and electric stimulation of the muscles causes a rise in temperature。
Summary of Brain…cell Studies
In our crossed circulation experiments we found that neither waste products nor metabolic poisons could be considered the principal cause of the brain…cell changes。 We found that in the production both of muscular action and of fever there were brain…cell changes which showed a quantita…tive relation to the temperature changes or to the muscular work done。 We observed that under deep morphinization the febrile response or the muscular work done was either diminished or eliminated and that the brain…cell changes were correspondingly diminished or eliminated。 We found also that brain…cell changes and muscular work followed electric stimulation alone。 I conclude； therefore； that the brain…cell changes are work changes。
We shall next consider other organs of the kinetic system in their relation to muscular activity； to emotion； to consciousness； to sleep； to hibernation； and to heat production。
The Adrenals
In our extensive study of the brain in its relation to the production of energy and the consequent exhaustion caused by fear and rage； by the injection of foreign proteins； of bacterial toxins； and of strychnin； by anaphylaxis； by the injection of thyroid extract； of adrenalin； and of morphin； we found that； with the exception of morphin； each of these agents produced identical changes in the brain…cells。 As we believed that the adrenals were intimately associated with the brain in its activities； we concluded that the adrenals also must have been affected by each of these agents。 To prove this relation； we administered the above…mentioned stimuli to animals and studied their effects upon the adrenals by functional； histologic； and surgical methods； the functional tests being made by Cannon's method。
Functional Study of the Adrenals。Our method of applying the Cannon test for adrenalin was as follows： （_a_） The blood of the animals was tested before the application of the stimulus。 If this test was negative； then （_b_） the stimulus was applied and the blood again tested。 If this second test was negative； a small amount of adrenalin was added。 If a positive reaction was then given； the negative result was accepted as conclusive。 （_c_） If the control test was negative； then the stimulus was given。 If the blood after stimulation gave a positive result for adrenalin； a second test of the same animal's blood was made twenty…five minutes or more later。 If the second test was negative； then the positive result of the first test was accepted as conclusive。
We have recorded 66 clear…cut experiments on dogs； which show that after fear and rage； after anaphylaxis； after injections of indol and skatol； of leucin and creatin； of the toxins of diphtheria and colon bacilli； of streptococci and staphylococci； of foreign proteins； and of strychnin； the Cannon test for adrenalin was positive。 The test was negative after trauma under anesthesia； and after intravenous injections of thyroid extract； of thyroglobin； and of the juices of various organs injected into the same animal from which the organs were taken。 Placental extract gave a positive test。 The test was sometimes positive after electric stimulation of the splanchnic nerves。 On the other hand； if the nerve supply to the adrenals had been previously divided； or if the adrenals had been previously excised； then the Cannon test was negative after the administration of each of the foregoing adequate stimuli。 Blood taken directly from the adrenal vein gave a positive result； but under deep morphinization the blood from the adrenal vein was negative； and under deep morphinization the foregoing adequate stimuli were negative。
In brief； the agencies that in our brain…cell studies were found to cause hyperchromatism followed by chromatolysis gave positive results in the Cannon test for adrenalin （Fig。 62）。 The one agent which was found to protect the brain against changes in the Nissl substance morphingave a negative result in the Cannon test for adrenalin。 After excision of the adrenals； or after division of their nerve supply； all Cannon tests for adrenalin were negative。
Histologic Study of the Adrenals。Histologic studies of the adrenals after the application of the adequate stimuli which gave positive results to the Cannon test for adrenalin are now in progress； and thus far the histologic studies corroborate the functional tests。
In hibernating woodchucks； the cells of the adrenal cortex were found to be vacuolated and shrunken。 In one hundred hours of insomnia； in surgical shock； in strong fear； in exhaustion from fighting； after peptone injections； in acute infections； the adrenals undergo histologic changes characteristic of exhaustion （Figs。 66 to 67）。
We have shown that brain and adrenal activity go hand in hand； that is； that the adrenal secretion activates the brain； and that the brain activates the adrenals。 The fundamental question which now arises is this： Are the brain and the adrenals interdependent？ A positive answer may be given to this question； for the evidence of the dependence of the brain upon the adrenals is as clear as is the evidence of the dependence of the adrenals upon the brain。 （1） After excision of the adrenals； the brain…cells undergo continuous histologic and functional deterioration until death。 During this time the brain progressively loses its power to respond to stimuli and there is also a progressive loss of muscular power and a diminution of body temperature。 （2） ｛illust。 caption = FIG。 66。In our crossed circulation experiments we found that adrenalin alone could cause increased brain activity； while histologically we know that adrenalin alone causes an increase of the Nissl substance。 An animal； both of whose adrenals had been excised； showed no hyperchromatism in the brain…cells after the injection of strychnin； toxins； foreign proteins； etc。 （3） When the adrenal nerve supply is divided （Cannon…Elliott）； then there is no increased adrenal activity in response to adequate stimuli。
From these studies we are forced to conclude not only that the brain and adrenals are interdependent； but that the brain is actually more dependent upon the adrenals than the adrenals upon the brain； since the brain deteriorates progressively to death without the adrenals； while the adrenal whose connection with the brain has been broken by the division of its nerve supply will still produce sufficient adrenalin to support life。
From the strong affinity of the brain…cells for adrenalin which was manifested in our experiments we may strongly suspect that the Nissl substance is a volatile； extremely unstable combination of certain elements of the brain…cells and adrenalin； because the adrenals alone do not take the Nissl stain and the brain deprived of adrenalin also does not take Nissl stain。 The consumption of the Nissl substance in the brain…cells is lessened or prevented by morphin； as is the output of adrenalin； and the consumption of the Nissl substance is also lessened or prevented by nitrous oxid。 But morphin does not prevent