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 princ.i.p.al 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 quant.i.ta-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 a.s.sociated 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-- morphin--gave 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) {ill.u.s.t. 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 the action of adrenalin injected into the circulation, hence the control of morphin over energy expenditure is exerted directly on the brain-cells. Apparently morphin and nitrous oxid both act through this interference with oxidation in the brain. We, therefore, conclude that within a certain range of acidity of the blood adrenalin can unite with the brain-cells only through the mediation of oxygen, and that the combination of adrenalin, oxygen, and certain brain-cell const.i.tuents causes the electric discharge that produces heat and motion.

In this interrelation of the brain and the adrenals we have what is, perhaps, the master key to the automatic action of the body.

Through the special senses environmental stimuli reach the brain and cause it to liberate energy, which in turn activates certain other organs and tissues, among which are the adrenals. The increased output of adrenalin activates the brain to still greater activity, as a result of which again the entire sympathetic nervous system is further activated, as is manifested by increased heart action, more rapid respiration, raised blood-pressure, increased output of glycogen, increased power of the muscles to metabolize glucose, etc.

If this conclusion be well founded, we should find corroborative evidence in histologic changes in that great storehouse of potential energy, the liver, as a result of the application of each of the adequate stimuli which produced brain-cell and adrenal changes.

The Liver

Prolonged insomnia, prolonged physical exertion, infections, injections of toxins and of strychnin, rage and fear, physical injury under anesthesia, in fact, all the adequate stimuli which affected the brain and the adrenals, produced constant and identical histologic changes in the liver--the cells stained poorly, the cytoplasm was vacuolated, the nuclei were crenated, the cell membranes were irregular, the most marked changes occurring in the cells of the periphery of the lobules (Figs. 69 and 70). In prolonged insomnia the striking changes in the liver were repaired by one seance of sleep.

Are the histologic changes in the liver cells due to metabolism or toxic products, or are they "work" changes incident to the conversion of latent into kinetic energy? Are the brain, adrenals, and liver interdependent?

The following facts establish the answers to these queries:

(1) The duration of life after excision of the liver is about the same as after adrenalectomy--approximately eighteen hours.

(2) The amount of glycogen in the liver was diminished in all the experiments showing brain-adrenal activity; and when the histologic changes were repaired, the normal amount of glycogen was again found.

(3) In crossed circulation experiments changes were found in the liver of the animal whose brain received the stimulus.

From these premises we must consider that the brain, the adrenals, and the liver are mutually dependent on one another for the conversion of latent into kinetic energy. Each is a vital organ, each equally vital.

It may be said that excision of the brain may apparently cause death in less time than excision of the liver or adrenals, but this statement must be modified by our definition of death. If all the brain of an animal be removed by decapitation, its body may live on for at least eleven hours if its circulation be maintained by transfusion.

An animal may live for weeks or months after excision of the cerebral hemispheres and the cerebellum, while an overtransfused animal may live many hours, days even, after the destruction of the medulla.

It is possible even that the brain actually is a less vital organ than either the adrenals or the liver.

In our research to discover whether any other organs should be included with the brain, the adrenals, and the liver in this mutually interdependent relation, we hit upon an experiment which throws light upon this problem.

Groups of rabbits were gently kept awake for one hundred hours by relays of students, an experiment which steadily withdrew energy but caused not the slightest physical or emotional injury to any of them; no drug, toxin, or other agent was given to them; they were given sufficient food and drink. In brief, the internal and external environments of these animals were kept otherwise normal excepting for the gentle stimuli which insured continued wakefulness.

This protracted insomnia gradually exhausted the animals completely, some to the point of death even. Some of the survivors were killed immediately after the expiration of one hundred hours of wakefulness, others after varying intervals.

Histologic studies were made of every tissue and organ in the body.

Three organs, the brain, the adrenals, and the liver, and these three only, showed histologic changes. In these three organs the histologic changes were marked, and were almost wholly repaired by one seance of sleep.

In each instance these histologic changes were identical with those seen after physical exertion, emotions, toxins, etc.[*] It would appear, then, that these three organs take the stress of life-- the brain is the "battery," the adrenals the "oxydizer," and the liver the "gasoline tank." This clear-cut insomnia experiment corresponds precisely with our other brain-adrenal observations.

[*] Further studies have given evidence that the elimination of the acids resulting from energy-transformation as well as the conversion of energy stored in the kinetic organs causes histologic changes in the liver, the adrenals, and possibly in the brain.

With these three kinetic organs we may surely a.s.sociate also the "furnace," the muscles, in which the energy provided by the brain, adrenals, and liver, plus oxygen, is fabricated into heat and motion.

Benedict, in his monumental work on metabolism, has demonstrated that in the normal state, at least, variations in the heart-beat parallel variations in metabolism. He and others have shown also that all the energy of the body, whether evidenced by heat or by motion, is produced in the muscles. In the muscles, then, we find the fourth vital link in the kinetic chain. The muscles move the body, circulate the blood, effect respiration, and govern the body temperature.

They are the pa.s.sive servants of the brain-adrenal-liver syndrome.

Neither the brain, the adrenals, the liver, nor the muscles, however, nor all of these together, have the power to change the rate of the expenditure of energy; to make possible the increased expenditure in adolescence, in pregnancy, in courting, and mating, in infections.

No one of these organs, nor all of them together, can act as a pace-maker or sensitizer. The brain acts immediately in response to the stimuli of the moment; the adrenals respond instantly to the fickle brain and the effects of their actions are fleeting; the liver contains fuel only and cannot activate, and the muscles in turn act as the great furnace in which the final transformation into available energy is made. The Thyroid

Another organ--the thyroid--has the special power of governing the RATE OF DISCHARGE of energy; in other words, the thyroid is the pace-maker. Unfortunately, the thyroid cannot be studied to advantage either functionally or histologically, for there is as yet no available test for thyroid secretion in the blood as there is for adrenalin, and thyroid activity is not attended by striking histologic changes.

Therefore the only laboratory studies which have been satisfactory thus far are those by which the iodin content of the thyroid has been established. Iodin is stored in the colloid lacunae of the thyroid and, in combination with certain proteins, is the active agent of the thyroid.

Beebe has shown that electric stimulation of the nerve supply of the thyroid diminishes the amount of iodin which it contains, and it is known that in the hyperactive thyroid in Graves' disease the iodin content is diminished. The meagerness of laboratory studies, however, is amply compensated by the observations which the surgeon has been able to make on a vast scale--observations which are as definite as are the results of laboratory experiments.

The brain-cells and the adrenals are securely, concealed from the eye of the clinician, hence the changes produced in them by different causes escape his notice, but the thyroid has always been closely scrutinized by him. The clinician knows that every one of the above-mentioned causes of increased brain-cell, adrenal, liver and muscle activity may cause an increase in the activity of both the normal or the enlarged thyroid; and lie knows only too well that in a given case of exophthalmic goiter the same stimuli which excite the brain, the adrenals, the liver, and the muscles to increased activity will also aggravate this disease.

The function of the thyroid in the kinetic chain is best evidenced, however, by its role in the production of fever. Fever results from the administration of thyroid extract alone in large doses.

In the hyperactivity of the thyroid in exophthalmic goiter one sees a marked tendency to fever, in severe cases there is daily fever.