Part 11

The cycle of greatest kinetic energy for physiologic ends is the period of reproduction. In the female especially there is a cycle of increased activity just prior to her development into the procreative state. During this time secondary sexual characters are developed-- the pelvis expands, the ovaries and the uterus grow rapidly, the mammary glands develop. Again in this period of increasing speed in the expenditure of energy we find the thyroid, the adrenals, and the hypophysis also in rapid growth. Without the normal development of the ovary, the thyroid, and the hypophysis, neither the male nor the female can develop the secondary sexual characters, nor do they develop sexual desire nor show seasonal cycles of activity, nor can they procreate. The secondary sexual characters--sexual desire, fertility--may be developed at will, for example, by feeding thyroid products from alien species to the individual deprived of the thyroid.

At the close of the child-bearing period there is a permanent diminution of the speed of energy discharge, for energy is no longer needed as it was for the self-preservation of the offspring before adolescence, and for the propagation of the species during the procreative period. Unless other factors intervene, this reduction in speed is progressive until senescent death. The diminished size of the thyroid of the aged bears testimony to the part the activating organs bear in the general decline.

We have now referred to variations in the rate of discharge of energy in different species; in individuals of the same species; in cycles in the same individual--such as the seasons of food supply, the periods of wakefulness and of sleep, the procreative period, and we have spoken of those variations caused artificially by thyroid feeding, thus far having confined our discussion to the conversion for adaptive purposes of latent into kinetic energy in muscular and in procreative action. We shall now consider the conversion of latent into kinetic energy in the production of heat,[*] and endeavor to answer the questions which arise at once: Is there one mechanism for the conversion of latent energy into heat and another mechanism for its conversion into muscular action? What is the adaptive advantage of fever in infection?

The Purpose and the Mechanism of Heat Production in Infections

Vaughan has shown that the presence in the body of any alien protein causes an increased production of heat, and that there is no difference between the production of fever by foreign proteins and by infections. Before the day of the hypodermic needle and of experimental medicine, the foreign proteins found in the body outside the alimentary tract were brought in by invading microorganisms. Such organisms interfered with and destroyed the host. The body, therefore, was forced to evolve a means of protection against these hostile organisms. The increased metabolism and fever in infection might operate as a protection in two ways--the increased fever, by interfering with bacterial growth, and the increased metabolism, by breaking up the bacteria. Bacteriologists have taught us that bacteria grow best at the normal temperature of the body, hence fever must interfere with bacterial growth. With each rise of one degree centigrade the chemical activity of the body is increased 10 per cent. In acute infections there is aversion to food and frequently there is vomiting. In fever, then, we have diminished intake of energy, but an increased output of energy--hence the available potential energy in the body is rapidly consumed. This may be an adaptation for the purpose of breaking up the foreign protein molecules composing the bacteria. Thus the body may be purified by a chemical combustion so furious that frequently the host itself is destroyed. The problems of immunity are not considered here.

As to the mechanism which produces fever, we postulate that it is the same mechanism as that which produces muscular activity. Muscular activity is produced by the conversion of latent energy into motion, and fever is produced largely in the muscles by the conversion of latent energy into heat. We should, therefore, find similar changes in the brain, the adrenals, the thyroid, and the liver, whatever may be the purpose of the conversion of energy-- whether for running, for fighting, for the expression of emotion, or for combating infection.

We shall first present experimental and clinical evidence which tends to show what part is played by the brain in the production of both muscular and febrile action, and later we shall discuss the parts played by the adrenals, the thyroid, and the liver. Histologic Changes in the Brain-cells in Relation to the Maintenance of Consciousness and to the Production of the Emotions, Muscular Activity, and Fever

We have studied the brain-cells in human cases of fever, and in animals after prolonged insomnia; after the injection of the toxins of gonococci, of streptococci, of staphylococci, and of colon, tetanus, diphtheria, and typhoid bacilli; and after the injection of foreign proteins, of indol and skatol, of leucin, and of peptones. We have studied the brains of animals which had been activated in varying degrees up to the point of complete exhaustion by running, by fighting, by rage and fear, by physical injury, and by the injection of strychnin (Figs. 2, 4, 5, and 37). We have studied the brains of salmon at the mouth of the Columbia River and at its headwater (Fig. 55); the brains of electric fish, the storage batteries of which had been partially discharged, and of those the batteries of which had been completely discharged; the brains of woodchucks in hibernation and after fighting; the brains of humans who had died from anemia resulting from hemorrhage, from acidosis, from eclampsia, from cancer and 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.