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from other chronic diseases (Figs. 40 to 43, 56, 74, and 75). We have studied also the brains of animals after the excision of the adrenals, of the pancreas, and of the liver (Figs. 57 and 60).

 

In every instance the loss of vitality—that is, the loss of the normal power to convert potential into kinetic energy—

was accompanied by physical changes in the brain-cells (Figs. 45

and 46). The converse was also true, that is, the brain-cells of animals with normal vital power showed no histologic changes.

The changes in the brain-cells were identical whatever the cause.

The crucial question then becomes: Are these constant changes in the brain-cells the result of work done by the brain-cells in running, in fighting, in emotion, in fever? In other words, does the brain perform a definite role in the conversion of latent energy into fever or into muscular action; or are the brain-cell changes caused by the chemical products of metabolism? Happily, this crucial question was definitely answered by the following experiment: The circulations of two dogs were crossed in such a manner that the circulation of the head of one dog was anastomosed with the circulation of the body of another dog, and vice versa. A cord encircled the neck of each so firmly that the anastomosing circulation was blocked (Fig. 58). If the brain-cell changes were due to metabolic products, then when the body of dog “A” was injured, the brain of dog “A”

would be normal and the brain of dog “B” would show changes.

Our experiments showed brain-cell changes in the brain of the dog injured and no changes in the brain of the uninjured dog.

 

The injection of adrenalin causes striking brain-cell changes: first, a hyperchromatism, then a chromatolysis. Now if adrenalin caused these changes merely as a metabolic phenomenon and not as a “work” phenomenon, then the injection of adrenalin into the carotid artery of a crossed circulation dog would cause no change in its circulation and its respiration, since the brain thus injected is in exclusive vascular connection with the body of another dog.

In our experiment the blood-pressures of both dogs were recorded on a drum when adrenalin was injected into the common carotid.

The adrenalin caused a rise in blood-pressure, an increase in the force of cardiac contraction, increase in respiration, and a characteristic adrenalin rise in the blood-pressure of both dogs.

The rise was seen first in the dog whose brain alone received adrenalin and about a minute later in the dog whose body alone received adrenalin (Fig. 59). Histologic examinations of the brains of both dogs showed marked hyperchromatism in the brain receiving adrenalin, while the brain receiving no adrenalin showed no change.

Here is a clear-cut observation on the action of adrenalin on the brain, for both the functional and the histologic tests showed that adrenalin causes increased brain action.

The significance of this affinity of the brain for adrenalin begins to be seen when I call attention to the following striking facts: 1. Adrenalin alone causes hyperchromatism followed by chromatolysis, and in overdosage causes the destruction of some brain-cells.

 

2. When both adrenal glands are excised and no other factor is introduced, the Nissl substance progressively disappears from the brain-cells until death. This far-reaching point will be taken up later (Fig. 60).

 

Here our purpose is to discuss the cause of the brain-cell changes.

We have seen that in crossed brain and body circulation trauma causes changes in the cells of the brain which is disconnected from the traumatized body by its circulation, but which is connected with the traumatized body by the nervous system.

We have seen that adrenalin causes activation of the body connected with its brain by the nervous system, and histologic changes in the brain acted on directly by the adrenalin, but we found no notable brain-cell changes in the other brain through which the products of metabolism have circulated.

 

In the foregoing we find direct evidence that the products of metabolism are not the principal cause of the brain-cell changes.

We shall now present evidence to show that for the most part the brain-cell changes are “work” changes. What work? We postulate that it is the work by which the energy stored in the brain-cells is converted into electricity or some other form of transmissible energy which then activates certain glands and muscles, thus converting latent energy into beat and motion. It has chanced that certain other studies have given an analogous and convincing proof of this postulate.

In the electric fish a part of the muscular mechanism is replaced by a specialized structure for storing and discharging electricity.

We found “work” changes in the brain-cells of electric fish after all their electricity had been rapidly discharged (Fig. 61). We found further that electric fish could not discharge their electricity when under anesthesia, and clinically we know that under deep morphin narcosis, and under anesthesia, the production both of heat and of muscular action is hindered.

The action of morphin in lessening fever production is probably the result of its depressing influence on the brain-cells, because of which a diminished amount of their potential energy is converted into electricity and a diminished electric discharge from the brain to the muscles should diminish heat production proportionally.

We found by experiment that under deep morphinization brain-cell changes due to toxins could be largely prevented (Fig. 62); in human patients deep morphinization diminishes the production of muscular action and of fever and conserves life when it is threatened by acute infections. The contribution of the brain-cells to the production of heat is either the result of the direct conversion of their stored energy into heat, or of the conversion of their latent energy into electricity or a similar force, which in turn causes certain glands and muscles to convert latent energy into heat.

 

A further support to the postulate that the brain-cells contribute to the production of fever by sending impulses to the muscles is found in the effect of muscular exertion, or of other forms of motor stimulation, in the presence of a fever-producing infection.

Under such circumstances muscular exertion causes additional fever, and causes also added but identical changes in the brain-cells. Thyroid extract and iodin have the same effect as muscular exertion and infection in the production of fever and the production of brain-cell changes.

All this evidence is a strong argument in favor of the theory that certain constituents of the brain-cells are consumed in the work performed by the brain in the 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,

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