A Bipolar Theory of Living Processes

Fig. 41.—Early and late effects of strychnin poisoning on the electric conductivity of the brain and of the liver. is evidenced by an increased output of adrenalin; a marked in- стеазе in blood-pressure; and a complete cycle of changes in the brain cells, first a stage of hyperchromatism, then a stage of chromatolysis, and finally, in some cells, swelling, rupture of the nuclear and the cell membranes, and final death of the cells. (Fig. 40.) These changes in the brain cells are paralleled by changes in the electric conductivity of the brain— first an increased conductivity followed by a decrease which is in direct relation to the degree of exhaustion. (Fig. 41.) During the period of stimulation the oxidative capacity of the brain varies in direct relation to the clinical effects. (Fig. 42.)

We may assume that the stimulus from tetanus toxin, which is known to pass up the axis cylinder, passes along the axis cylinders of the nerve fibers until it reaches the synaptic junction, and closes the circuit, thus causing a contraction. It would appear that closing the circuit at the synapse “pegs the bell,” so that a vast muscular area becomes in effect one pole of a great battery, the other pole being the brain, and the nerves the connecting wires, the circuit of which is closed by the action of the tetanus toxin.

If physiologic activity is the equivalent of electric stimulation, then electricity is apparently the means by which cells are organized, for, as Mathews points out, if the eyelids of puppies be kept closed, the related brain cells will not be developed. If the nerve supply to muscles is cut off, the muscle cells become disorganized; but electricity will reorganize them. When limbs are fractured or soft parts injured, voluntary exercise best reorganizes the muscles and nerve cells from the disorganization of disuse. Children who are not allowed to play do not develop strongly; that is to say, their muscles are not organized by the electric energy of exercise. If groups of

muscles are not used, they are not so well organized and become weak. It is probable that play and exercise set in motion electric forces by means of which children are systematically built up into all-round physical efficiency. Next in value to voluntary exercise, which exercises the driving nerve cell as well as the driven muscle, is electric stimulation of the muscle. Electric stimulation restores the muscle quite as well as voluntary stimulation, but electric stimulation does not as readily reorganize and build up the de teriorated nerve cells.

These points have been abundantly proved by clinical experience, especially by the results of the treatment of the multitude of cripples produced by the world war. When an animal or a man is given unlimited ether anesthesia, several striking phenomena are observed. First, there is a period of excitement; second, a period of quiet anesthesia; third, a period of profound anesthesia, ending in death. Period of Excitement.—During the period of excitement, the subject tends to struggle, the face is flushed, there are sweating, moderate or violent muscular action, rapid respiration, dilated pupils, elevated blood-pressure, accelerated pulse, inereased output of adrenalin, hyperchromatism of the brain cells; the consumption of oxygen may be increased up to 150 per eent; of carbon dioxid up to 325 per cent (Alexander and Cserna)?; the H-ion concentration of the blood is increased ; the electric conductivity of the brain is increased; the temperature of the brain is increased.

Osterhout,* Overton, Meyer,? Lillie” and other observers have shown that ether anesthesia in lighter doses increases the permeability of the semi-permeable membranes of cells to the passage of ions. The activity of cells is governed by the state of permeability of their membranes to ions. This increased permeability renders the brain extremely excitable in light ether anesthesia, and therefore it drives the organism to perform more work, as has been shown by Alexander and Oserna,® by our observations of hyperchromatism, by Elliott’s demonstration of diminished adrenal content,® and by our demonstration of increased adrenalin output. The clinician sees striking evidence of this increased. activation of the brain in the behavior of his patient under light ether. In cases of hyperthyroidism, the increased activation of the first stage of ether anesthesia is especially marked.

The clinical phenomena and the experimental findings lead us to suppose that ether causes a greatly increased production of electric energy, which escapes readily through the lowered resistance of the cell boundaries and of the synapses, and in consequence we may presume that heavy charges of electricity are freed from the cells, and run over the open nerve paths leading to the various muscles and glands. The muscular and glandular responses are as free from purposeful action as in a convulsion, but if the victim is held or injured during this stage then the electric action current is led over the corresponding facilitated paths and is concentrated on the muscles required for action, and other muscles become idle. If no contact directs the current then the outflow of energy is as general as in an epileptic convulsion; there are contractions of all the muscles; increased secretion of the salivary and the mucous glands; and increased sweating. |

Аз we have stated, if the patient is restrained or injured during the first stage of anesthesia, then the muscles that usually respond receive all the collective electric force of the brain, and show almost supernatural power. If the anesthetic is withdrawn at this stage, the permeability of the cells returns to the normal, the struggle ceases, the flush fades from the face, the sweating ceases and the secretion of saliva and mueus rapidly becomes normal, the museles come under voluntary control and are quiet. Тһе individual appears normal with the exception of a slight fatigue.

Stage of Even Anesthesia.—lf the administration of the anesthetie 18 steadily continued through the stage of excitement, or if the amount is increased, the period of struggle soon passes into a stage of complete relaxation, The face remains flushed, Fic. 43.—Early and late effects of ether anesthesia on the electric conductivity of the brain and of the liver. although less so than in the stage of excitement; the eyes are less suffused; the skin is less moist; the saliva and mucus are less abundant. The H-ion concentration of the blood increases

with the increase of anesthesia. In this stage physical injury and restraint cause no marked muscular response. This is in accord with the findings in our electric conductivity measurements, which showed a decreased conductivity ot the cerebrum in deep ether anesthesia, as contrasted with the Ета, 44.—Comparative effects of prolonged ether and of prolonged nitrous oxid anesthesia on the temperature of the brain. increased conductivity in the stage of excitement. (Fig. 43.) Measurements of the temperature of the brain show that following a brief rise in the initial stage the temperature falls progressively. (Fig. 44, A.) Moreover, as has been shown by Lillie,;? McClendon !! and others, during the stage of complete anesthesia the permeability of the cell and synaptie membranes

to the passage of ions is decreased in contrast to the increased permeability of the stage of excitement. It seems probable that anesthesia is due to a block in the synaptic membranes like that which is supposed to occur in sleep, the difference being that in sleep the synaptic block is at once overcome by stimuli, hence is adaptive; whereas in anesthesia, the block is physical and non-adaptive. For this reason stimuli do not wholly awaken the patient, but nevertheless the afferent impulses reach the brain cells and stimulate them without purpose—exhausting the brain just as if no anesthetic had been given.

Profound Anesthesia: Death.—lf the anesthesia is pushed still further, a point of saturation is reached at which the H-ion concentration of the blood passes the neutral point. This is the fatal point, for when the anesthetic causes actual acidity of the blood, death takes place immediately. Death, we assume, is due to the loss of difference in potential in the autonomie and sympathetie systems, as well as in the cerebrospinal system; hence, electrie impulses cannot pass, and life ends.

The several parts of the brain differ greatly in their response to ether. It would be expected that the brain as a whole would be more markedly affected than other tissue, such, for example, as muscle, because the brain contains a greater proportion of lipoids, which are especially affected by ether. We would expect also that the order in which the different portions of the brain are affeeted would depend upon their relative irritability —the more irritable portions being affected first. This we find is true, for first consciousness is lost, then muscular activity, while the centers governing respiration and circulation are but slightly altered. Were the muscle cells more sensitive to anesthetics than the brain cells, then the function of the voluntary and of the involuntary muscular systems would fail before the funetion of the brain, and man would be paralyzed while conscious, as in curare poisoning; and since the respiratory and the circulatory muscles would fail, unconsciousness and death would follow the museular paralysis, and no such state as anesthesia could be established. It is because of this difference between the muscle cells and the brain cells that anesthesia and not death is first produced by inhalation anesthesia.

When ether anesthesia is continued for four or more hours, these outstanding facts are noted: 3. The brain cells, the liver cells and the adrenal cells show the same cytologic changes as are seen in exhaustion from other causes. 6. The electric conductivity of the brain is decreased; the electric conductivity of the liver is increased. 8. The individual is in a state of exhaustion, requiring a period of time for recovery about equal to that required for recovery from an equal degree of exhaustion from other causes.

In nitrous oxid-oxygen anesthesia, there is apparently an interference with the power of the brain cells to respond to stimulation by increased oxidation. This is demonstrated by the diminished response of the brain to the injection of adrenalin as shown by the slight increase in temperature as compared with the increase in temperature in normal animals and in animals under ether anesthesia. Therefore, the brain cells are able to respond to trauma and other stimuli only in inverse proportion to the depth of the anesthesia. The brain cells, therefore, are protected against shock. This is demonstrated by the hyperehromatie or normal appearance of the brain cells after prolonged nitrous oxid anesthesia; and by their normal appearance after shock-producing trauma under nitrous oxidoxygen anesthesia as compared with their disintegration after like trauma under ether anesthesia. lt is demonstrated also by the faet that the temperature of the brain is progressively decreased by long ether anesthesia, while it remains practically unchanged by nitrous oxid-oxygen anesthesia. (Fig. 49, B.)

These findings are in accord with the bipolar theory and with the conception that the brain is the primary seat of injury from excessive stimulation. The effect of nitrous oxid is somewhat comparable to that of sleep, as our experiments have shown. Because of the action of nitrous oxid on the intracellular oxidation, its use is fraught with danger unless it is skillfully administered, An animal may be much more quickly killed with nitrous oxid than with ether.

The essential content of the specific product of the thyroid gland is iodin. Jodin increases the electric conductivity of living tissue; iodin increases permeability; iodin increases the oxidative capacity of the brain. It is known that stimulation of the nerve supply of the thyroid causes a discharge of its iodized product; hence, we may suppose that the output of iodin is in part at least under the control of the nervous system. In hyperthyroidism there is marked nervous activity. Cannon states that adrenalin activates the thyroid gland." We assume that the stimulated gland throws out large amounts of activating 1odin, which by so much facilitates permeability, increases the oxidative сара- city of the central nervous system, hence increases the activation of the entire organism including the activation of the thyroid itself and of the adrenals. Oxidation is the basic process in metabolism; adrenalin increases oxidation; iodin increases electric conductance, hence increases metabolism.

Therefore, through the mediation of the nervous system, a reciprocal interaction is established among the thyroid, the adrenals, and the nervous system. Тот alone, adrenalin alone, thyroid extract alone, emotion, exertion, or infection alone, each causes a “kinetic drive" with phenomena similar to those of hyperthyroidism. | If the foregoing interpretation be correct, then the drive of hyperthyroidism should be diminished by lessening the activity of any one of the three interacting organs—of the brain, by rest cure; of the thyroid, by its resection; of the adrenals, by the removal of a portion of their tissue, though up to the present time evidence of the positive value of the last-named procedure is still incomplete.

Nothing in surgery is more striking than the immediate benefit of the surgical treatment of hyperthyroidism. In the expression of the disease, in the behavior before, during and after operation, the patient with hyperthyroidism presents notable evidence in support of the bipolar theory. The effect on the organism of the injection of foreign proteins, as shown by Vaughan, is similar to, if not identical with, the effect of infections. The mechanism of the action of the infections may therefore be regarded as the same as the mechanism of foreign protein reactions.

The injection of excessive amounts of foreign protein and the absorption of the toxins of infection produce similar effects, and involve certain essential parts of the same mechanism as the emotions and muscular exertion. This statement is based on the following phenomena: Each produces an increased output of adrenalin, a first stage of hyperchromatism of the braincells, followed later by chromatolysis, increased thyroid activity, increased body temperature. As a result of each, if excess fatigue is produced, the mechanism may be acutely worn down and completely overcome in death. The organism may be partly reduced by any one of these causes, carried further by another, and finally broken by still another. Their effects are interchangeable. Each produces increased electric conductivity of the brain in the acute phase, and in the stage of exhaustion a decreased electric conductivity of the brain. Each produces increased nervousness, and lowering of thresholds to other stimuli.

The first practical question 1s this: Is the response of the organism to an infection an imposed injurious mode of attack by the invading mieroórganism as a means of killing man and other animals, or is this response one of the evolved means by which man and animals defend themselves against the attacking mieroórganisms? Assuming it to be the latter, let us analyze the mechanism of this counter defense of man against the microorganism in the light of the bipolar theory. If our theory is correct we must point out the sequence of events

from the absorption of the toxin through the period of furious response to recovery or death, and point out the mechanisms which are involved. We must show that electric energy fabricated in the brain is an essential factor in the reaction. We must show that the muscles participate actively; that the adrenals are active; that the thyroid participates. We must show why a rise of temperature is of benefit; why there is no sweating in the first stage; why there may be chills. We must show why the temperature falls during the night. We must show why there is nervousness, loss of mental power, loss of muscular power. And last, and certainly not of least importance, we must show why, in an acute, overwhelming infection, there is shock and collapse, with diminished instead of increased metabolism as in the earlier stages; and why, under such circumstances, death is usually inevitable.

The Participation of the Brain.—It is common knowledge that deep narcotization with morphin reduces the power of the brain to drive the organism to transform potential energy into heat or into mental or muscular work or to express emotion. We may suppose that for the same reason morphin prevents the electric fish from transforming energy into electricity. In infections, morphin diminishes fever. In the acute phase following the injection of toxins, there is an increase in the conductivity of the brain; in the later stages there is a depression— morphin minimizes these changes.

The injection of foreign proteins, or of bacterial toxins, causes first hyperchromatism of the brain cells and later chromatolysis; but deep narcotization with morphin diminishes or prevents both the anaphylactic and the foreign protein systemic response and to the same degree prevents the changes in the brain cells. Anaphylaxis and foreign proteins and bacterial toxins cause an increased output of adrenalin.|* Deep narcotization by morphin prevents both. The significance of this point is that the nerves drive the adrenal glands to increase their output. This is proved by the fact that when the nerve supply to the adrenal glands is first severed, and no morphin is given, the output of adrenalin is not increased by the injection of foreign proteins, toxins, etc.

In patients in whom the brain cells are disintegrating as in enfeebled aged individuals, but slight fever is produced by even fatal infection. The highest fever and the most vigorous systemic response occur in the earlier periods of life when the brain is most active. After decapitation, or when the muscles are cut off from connection with the brain, there is no febrile response to the injection of toxins. It would seem, therefore, that the brain cells respond to the presence of foreign proteins or of toxins by increased oxidation, thus causing an increased fabrication of electric energy which in turn drives the organism to make a febrile defense.

The Participation of the Muscles.—That the muscles are the | principal mechanisms activated by the brain in the response to infection is suggested by the facts that (1) they produce from 50 to 75 per cent of the heat of the body; (2) they show fatigue and histologic change as a result of high fever; (3) they are the active agencies in chills. The Participation of the Adrenals—As has been shown by Elliott," the output of adrenalin is increased by foreign proteins, toxins, ete.

The injection of adrenalin causes virtually all the phenomena of infection or of the injection of a foreign protein. In fevers, therefore, we may suppose that the dilated pupils, the flushed skin, the dilated nostrils, the opened air passages, the pounding heart, the elevated blood-pressure, as well as the fever itself, result in part from the action of adrenalin. Adrenalin alone causes leucocytosis, a phenomenon which is usually present in fever. In Addison’s disease in which there is an adrenal insufficiency, the body temperature is subnormal. In this disease the defense of the organism against infection is diminished as is evidenced in part by the lessened rise in temperature.

The Participation of the Thyroid.—In myxedema, the body temperature is subnormal; and, though myxedematous subjects succumb to infections, they show little febrile reaction. In hyperthyroidism, infections cause abnormally high temperatures. Jodin alone causes most of the systemic symptoms of an infection. It is almost impossible to differentiate between an acute infection and iodoform poisoning, After operations for hyperthyroidism one cannot distinguish with accuracy between the febrile reaction facilitated by the activation of the organism by the hyperactive thyroid and the activation due to an acute infection.

In hyperthyroidism there is a state of abnormal iodin facilitation, 1.е., as we suppose, electric facilitation, and even an acute cold may cause a violent febrile response which may prove fatal. In chronic infections, and even in prolonged acute infections such as tuberculosis, the thyroid is frequently hyperplastic. In hyperthyroidism the thyroid is hypersensitive, hence hyperresponsive. Its enlargement is frequently demonstrable during an acute infection. Tonsillitis may cause the thyroid to enlarge and to remain enlarged; after the removal of infected tonsils, the thyroid sometimes returns promptly to its normal size.

In acute infections, often in chronic infections, therefore, the individual is obviously under the influence of increased thyroid activity. One of the evidences of this is the nervous state of the patient, which is but an indication that the nerve pathways have been facilitated by iodin for the more ready passage of the electric driving force. In cases of hyperthyroidism, the nervousness is similar to that which is characteristic of all infections. The restlessness, the tossing and the sleeplessness may be regarded as phenomena of the facilitation of the electric conductivity by iodin and adrenalin.