A Bipolar Theory of Living Processes

Besides the tissues included in the table, measurements have been made of the thyroid, the adrenals, the kidneys and the spleen. The variation in these measurements was so great that no averages for these tissues have been made and it remains to discover some method by which accurate measurements of these tissues and increased accuracy in the measurement of the spinal cord, of the heart and of voluntary muscle may be secured. It will be noted that with the exception of the spinal cord, the order of magnitude of the conductivity values of the tissues included in Table 6 never varied.

It was the initial plan to establish a normal range of the conductivity of the various tissues to be used as the basis of comparison for the tissues of all subsequently treated animals. Accident, however, showed the futility of this plan. During the period in which groups I to III were measured (November, 1918, to February, 1919), the animals had been kept in airy, cool quarters in the country, and provided with an open air run. In April they were removed to a typical animal room which, although well lighted and ventilated, was a great contrast to the former quarters. The effect upon the animals which were

transferred is indicated by the measurements of group IV. The measurements of this group as well as of all treated animals among those that were transferred from the country quarters have been discarded since the great discrepancy between these measurements and those in the earlier as well as in the later groups illustrates most strikingly the effect of variations in environment, season, etc. In this instance the effect of moving and of the changed environment was sufficient to put the animals in the abnormal class, although at autopsy no sign of disease could be discovered. We then began securing animals from a dealer in the country in small groups so that the measurements of all treated animals could

Range of electrical conductivity of various normal rabbit tissues arranged in the order of magnitude of their conductivity values *On account of the wide range of the individual measurements of the heart muscle and the fact that in our earliest series its conductivity appeared to be higher, its place in this table may be questioned. be compared with the measurements of normal animals of the same group. No conclusions have been drawn from findings in any series unless the difference between the electrical conductivity of the organ in the treated animal and the average measurement of the normal organ in the same group has been greater than the established average deviation of the normal measurements in that group.

It will be noted that throughout these researches, there has been no exception to what appears to be the normal relationship between the cerebrum and the cerebellum in the adult animal; i.e., in every adult animal the conductivity of the cerebrum has been greater than that of the cerebellum. This constant relationship was observed also by Doctor Obear in his preliminary studies. In order to discover whether or not this relation is a characteristic of adult life only, series of fetuses and of young rabbits were measured, and the significant observation was made that in fetuses and imme-

Relation between the electrical conductivity of the cerebrum and of the cerebellum іп fetuses and іп young rabbits diately after birth the conductivity of the cerebellum was higher than that of the cerebrum. In most of the fetuses measured the conductivity of the cerebellum was as high as in the average adult, while the conductivity of the cerebrum in the fetus and in the newborn rabbits was far below normal. The rise of the conductivity of the cerebrum to the normal level apparently coincides with the emerging of the young rabbit from the nest and the inauguration of its conscious life as an independent individual (Table 7). As will be noted in the table, the conductivity of the liver of the fetus is far below that of the normal adult, but apparently rises | to the normal level at birth. It should be noted that on account of the very small size of the fetal cerebellum, it was necessary to use a special electrode and minute glass tubes, so that the possibility of error in the measurements of the cerebellum was greater than in the case of the cerebrum.

Ап interesting corollary to these observations in rabbits may be noted here. Permission was granted for securing sections of the brains of two patients who died in the hospital on the same day. One died from carcinoma of the stomach and had been conscious until death; the other had been unconscious for days before his death, which was caused by a brain tumor. As is shown by Table 8, in the patient conscious until death, the conductivities of the cerebrum and the cerebellum while low, undoubtedly as the result of the exhaustion ef prolonged disease, nevertheless preserved the relationship observed in all our adult animals; viz. the conductivity of the cerebrum was higher than that of the cerebellum. In the patient who had been unconscious, this relationship was reversed, the conductivity of the cerebellum being higher than that of the cerebrum. It will be noted also that

in this case the value of the conductivity of the cerebellum is very high. A number of measurements have been made to determine whether or not there is a regional variation in the conductivity of the cere- Comparison between the relative conductivities of the cerebrum and of the cerebellum of each of two patients—one conscious until death and one unconscious for days before death LLL edo oe qose eoe ut brum. While these preliminary studies are suggestive, the only result which seems sufficiently established to be noted here is the relation between the conductivities of the gray and of the white matter. As shown by Table 9, in every measurement thus far made,

Relation between the electrical conductivity of the gray matter and of the white matter of the cerebrum the conductivity of the gray matter has been markedly higher than that of the white matter. ELECTRICAL CONDUCTIVITY OF THE BRAIN AND THE LIVER. In selecting the types of exhaustion to be included in this research, we were guided by previous researches in order that we might discover whether or not any measurable relation could be established between the histological changes observed in exhaustion, in particular those in the brain, and the electrical conductivity. That this correlation might be fairly made, we have been constantly guided by the data of the previous researches in the treatment of the animals, dosage, protraction of stimulation, etc.

I. Insomnia. Thirteen Belgian hares of weights varying from 1.414 to 2.588 kgm. were kept awake continuously for 96 hours. During this time they were confined in а large airy room and were given abundant food and water. 'lhe animals were kept awake by constant but gentle prodding; they were not hurt in any way, nor at any time did they manifest any discomfort beyond their attempts to settle into corners where they might be left alone. Most of the animals ate and drank freely throughout the insomnia period. Table 10 gives the weight and temperature of each at the beginning and at the end of the period of insomnia.

Effect of prolonged. insommia—96 howrs—upon the weight and temperature of rabbits At the end of the insomnia period four of the rabbits were killed at once and conductivity measurements made. Four were put into а darkened room and left undisturbed for 6 hours, when they in turn were killed and conductivity measurements made. Тһе remaining four were kept undisturbed for from 7 to 14 days. The average conductivities of the cerebrum, cerebellum and liver in each of these groups are shown in Table 11.

II. Fright and exertion. Each of six rabbits was frightened until exhausted by a dog which kept them in a state of intense nervous excitement by barking and thwarted attacks until they were prostrated by the resultant exhaustion. The effect upon the conductivity of the brain and the liver is shown in Table 12 (a). ПІ. Adrenalin—repeated doses. Repeated doses—2 to 3—of 1-1000 adrenalin (P. D. & Co.) were given to each of 8 rabbits at intervals of from 10 to 20 minutes according to the degree of reaction. The average dose—intravenous—was 0.4 сс. per kgm.; to two rabbits twice this dose was given intramuscularly. Typical changes in pulse and respiration were produced in each animal with ultimate prostration. The conductivity changes are shown in Table 12 (e).

IV. Surgical shock. Each of six rabbits was subjected, under ether, to severe trauma of the intestines and abdominal walls for periods of from 30 to 45 minutes. The resultant conductivity changes are shown in Table 12 (с). V. Prolonged ether and prolonged nitrous oxid anesthesia. Six rabbits were subjected to 4 hours’ continuous ether anesthesia ; and six to continuous nitrous oxid anesthesia of the same duration with resultant conductivity changes which are shown in Table 12 (h) and (i).

VI. Thyroid feeding. Six rabbits in fine general condition and of approximately equal weight were each given 5 grains of thyroid extract daily for 3 weeks. All but one showed at first a loss of appetite, with a later increased appetite but a continued loss of weight. With the exception of the one referred to above, which seemed to thrive, the fur of all became rough and coarse in appearance and was shed abundantly; they became nervous and excitable; the eyes were staring in appearance; the skin felt hot to the touch although the clinical thermometer showed no change in temperature. In brief, the animals manifested the typical signs of thyroid intoxication. The probable reason for the exception of the one rabbit noted above appeared at autopsy, which showed a minute and pale thyroid gland as compared with enlarged vascular glands in each of the others.

The losses of weight in each animal were as follows: 18 per cent, 29 per cent, 15 per cent, 36.6 per cent, with a loss of but 4.5 per cent in the exceptional one. One animal died after 2 weeks, with a loss in weight of 33.8 per cent. At the termination of 3 weeks the animals were killed and conductivity measurements made (Table 12 (f)). It should be noted that in this group the thyroid feeding was protracted until the stage of exhaustion had been reached. Earlier effects are described in a later section.

VII. Hydrochloric acid. In each of four rabbits 1 cc. of hydrochlorie acid—10 per cent—-was injected in the femoral vein. Each showed an immediate reaction registered in circulatory and respiratory changes, convulsive movements and prostration. The animals were killed in from four to twelve minutes after the injection and conductivity measurements made (Table 12 (g)). VIII. Strychnin. On account of the wide variation in the response of individual rabbits to strychnin, in this series in which it was desired to produce a massive effect the dosage varied from the just tetanic (0.155 mgm. per kgm. intravenous, Sollman) to the just fatal (0.36 mgm. per kgm. intravenous, Sollman), the dose being repeated if required to produce suffieient reaction. Five animals were included in the series. In each a reaction varying from a general tremor to severe convulsions was produced.

While on account of the variation in dosage and clinical results this is not considered a satisfactory series, the contrast in the conductivity findings to those in a subsequent series in which the incipient effects were noted, is so marked that the series has been included (Table 12 (j)). Summary. А study of Table 12 shows that in each type of exhaustion there included the conductivity of the cerebrum and of the cerebellum was diminished and the conductivity of the liver was increased except in exhaustion due to thyroid feeding in which case the average conductivity of the liver was unchanged from the normal. With the exception of exhaustion produced by adrenalin injection and by prolonged nitrous oxid anesthesia, in every instance the average conductivity of the cerebrum in exhaustion fell below the lowest individual normal measurement included in the normal group with which comparison is made. If one allows for the average deviation of the cerebellum and of the liver in both the exhausted and the normal animal, in certain instances the apparent change in exhaustion falls within those limits, nevertheless the marked downward tendency in the cerebrum and the cerebellum, and the upward tendency in the liver are obvious.

ELECTRICAL CONDUOTIVITY OF THE BRAIN AND THE LIVER. Previous researches and clinical observations had indicated the presence of an incipient stage of shock marked by hyperchromatism of the brain cells as compared with hypochromatism after shock had become established. 'lo determine whether or not a corresponding early increase in the electric conductivity of the brain precedes the ultimate decreased conductivity after the state of exhaustion or shock is established, a number of studies of the incipient effects of some of the shock-producing agents noted above was made.

I. Incipient effects of intense trauma. Under light ether anesthesia two groups of rabbits were subjected to extreme shockproducing manipulations for periods of 1 and of 5 minutes respectively. They were killed immediately and electric conductivity measurements made (Table 13 (a)). Incipient effects of strychnin. Each of five rabbits was given а fatal dose (0.36 mgm. per kgm.) intravenously and killed 1 minute after the injection (Table 13 (d)).

Incipient effects of adrenalin. Each of three rabbits was given an intravenous injection of 0.4 сс. per kg. of 1-1000 adrenalin (Р. D. & Co.) and killed 1 minute later (Table 13 (e)). Incipient effects of ether and of nitrous ovid anesthesia. To one of two groups of rabbits ether was administered for from 2 to 5 minutes; nitrous oxid being administered to the other group for like periods. Each animal was killed just at the termination of the first stage of anesthesia—the stage of excitement (Table 13 (b and с)).

Diphtheria toxin. To various groups of rabbits twice the lethal dose of diphtheria toxin (P. D. & Co.) was given intravenously, the animals being killed at intervals varying from 5 minutes to 1 hour after the dose was received. The progressive effects are shown in Table 14. Summary. With every exhaustion-producing agent studied, the initial effect was an increased conductivity of the cerebrum followed by a decrease to below the normal when the stage of exhaustion was reached. The early effect of stimulation upon the cerebellum appeared to vary, but a study of the clinical behavior of the animals, especially of the initiation of the respiratory and circulatory changes, together with an examination of the individual measurements, would seem to indicate that a like unvarying rule exists in the case of the cerebellum, but that the protraction of the incipient stage is shorter than in the case of the cerebrum. Many additional experiments are required to establish this point.

A study of the individual measurements of the liver would appear to. indicate an immediate tendency to decrease followed by an increase to above the normal. LIVER. The control of infection by morphin, so strikingly illustrated by the Alonzo Clark treatment of peritonitis, and the comparison of the histologic effects of diphtheria toxin alone and in the presence of morphin, led us to perform a series of experiments to determine whether or not the protective effect of morphin would be manifested by any diminution of the conductivity changes produced by diphtheria toxin alone.

Coincidentally with the series of experiments described above in which the rabbits were killed 4 hours after the intravenous injection of twice the lethal dose of diphtheria toxin, to each of another group 5 grains of morphin were given hypodermically in two doses, 1 hour apart; twice the lethal dose of diphtheria toxin being given intravenously 15 minutes after the second dose of morphin was received. The animals were killed 4 hours after receiving the diphtheria toxin.

To each of a third group morphin alone was administered as above, and the animals killed 4 hours after the second dose. The conductivity measurements are given in Table 15. THE BRAIN AND THE LIVER. In a preceding section we have shown that the late effects of thyroid feeding are identical with the late effects of other exhaustion-producing agents. Three later series of experiments were performed to discover the earlier effects of thyroid feeding and what, if any, effect upon the conductivity of the brain is produced by adrenalin in the presence of thyroidism, or of iodism.

The results of these series are shown in Tables 16 and 17, in which have been included also for ready comparison the effects of thyroid feeding to the point of exhaustion, and the immediate effect of the injection of adrenalin. The animals included in Table 16, series II and III, had been given 2 to 3 grains of thyroid extract daily for a period of 4 weeks. 1$ wil be noted that while thyroid extract alone increases the conductivity of the cerebrum and of the cerebellum, the injection of adrenalin in the thyroid-fed animals produced a tendency to return toward or below the normal.

In Table 17 the same contrast in the effects of iodoform and of iodoform plus the injection of adrenalin upon the conductivity of the cerebrum and of the cerebellum will be noted; i.e., iodoform alone increases the conductivity of the brain, this effect tending to be neutralized by adrenalin. орллођцо штлоүро 5714 aynydjns wnisaubow Јо рир ayoydjns wmsaubow jo әәә ou? jo woswDdwo;) Each of the animals in the iodoform series had received an intraperitoneal injection of 75 grams of iodoform introduced through a small abdominal opening. The incision was closed and the animals killed on the following day. Each showed febrile phenomena.

"There was an early rise of temperature of from 0.4 to 1.3? С. which was persistent in all but three of the cases; in those three the temperature dropped to from 0.1 to 1.0? 0. below the initial temperature. That the increased conductivity produced by iodoform cannot be due to the permeation of the tissues by the iodin is shown in series II, Table 17, in which, while the conductivity of the cerebrum and of the cerebellum is markedly increased, the conductivity of the liver is practically unchanged.

Ап essential corollary to these experiments would be the measurement of the conductivity of the brain in thyroidectomized animals after the injection of iodoform. ELECTRICAL CONDUCTIVITY OF THE BRAIN AND THE LIVER. In each of 6 rabbits 10 сс. of a saturated solution of sodium bicarbonate were slowly injected through the marginal ear vein. Each animal was killed 2 hours after the injection and sections taken for conductivity measurements. As will be seen in Table 18, the injection of sodium bicarbonate inereased the conductivity of the brain and decreased the conductivity of the liver, while the injection of hydrochlorie acid, as de- Scribed in а preceding section of this report, decreased the conductivity of the brain and increased the conductivity of the liver.

AGENTS UPON THE ELEOTRIO CONDUCTIVITY OF THE BRAIN. In this section are included a number of preliminary studies. Мо comment is made, as they should be extended before any conclusions can be drawn. The indications are sufficiently shown in Tables 19 and 20.! I. Magnesium sulphate—calcium chloride. То each of four rabbits 6 cc. per kgm. of a 25 per cent solution of magnesium sulphate was given intramuscularly. The animals were killed onehalf hour after the anesthesia was complete and sections taken for conductivity measurements. |

То each of another group of four rabbits a like dose of magne- 1Sollman's Laboratory Guide in Pharmacology was used as a guide in determining the dosage in each group of experiments included in this sium sulphate was given, followed, one-half hour after anesthesia was complete, by the intravenous injection of 8 ce. per kgm. of a 3 per cent solution of calcium chlorid. In each case the animal became completely conscious almost immediately after the calcium chlorid injection. It was killed at once and conductivity measurements made.