Bodily Changes in Pain, Hunger, Fear and Rage

was lowered from 120 to 100 millimeters of mer- cury (A), there was no appreciable decrease in the height of contraction; when lowered to 90 Figure 17. — The arrows indicate the points at which the thorax began to be compressed in order to lessen the output of blood from the heart. millimeters (B), there resulted a decrease of 2.4 per cent; when to 80 millimeters of mercury (C), a decrease of 7 per cent; and when to 70 milli- meters (D), a decrease of 17.3 per cent. Results similar to those represented in Fig. 17 were ob- tained by pulling on a string looped about the

aorta just above its iliac branches, thus lessening the flow to the hind limbs. The region of 90 to 100 millimeters of mercury may therefore be regarded as the critical region at which a falling blood pressure begins to be ac- companied by a concurrent lessening of the effi- ciency of muscular contraction, when the muscle is kept in continued activity. It is at that region that the blood flow is dangerously near to being inadequate. An Explanationotjth^ Effects op Varying the Arterul ""■ Pressure

How are these effects of ^ucreasing and decreas- ing the arterial blood pressure most reasonably explained? There is abundant evidence that fa- tigue products accumulate in a muscle which is doing work, and also that these metabolites inter- fere with efficient contraction. As Eanke ^ long ago demonstrated, if a muscle, deprived of circu- lating blood, is fatigued to a standstill, and then the circulation is restored, the muscle again re- sponds for a short time to stimulation, because the waste has been neutralized or swept away by the fresh blood. When the blood pressure is at its normal height for warm-blooded animals (about 120 millimeters of mercury, see Fig. 13), the flow appears to be adequate to wash out the depressive metabolites, at least in the single muscle

pressuTe_praduQ©s-%at4ittte-S level. On the other hand, when the pressure is abnormally low, the flow is inadequate, and the waste products are permitted to accumulate^ahd clog the action of the muscle. Under such circum- stances a rise of pressure has a. very striking bene- ficial effect. It is noteworthy that the best results of adre- nin on fatigued muscle reported by previous ob- servers were obtained from studies on cold-blooded animals. In these animals the circulation is main- tained normally by an arterial pressure about one- third that of warm-blooded animals. Injection of adrenin in an amount which would not shut off the blood supply would, by greatly raising the arterial pressure, markedly increase the circulation of blood in the active muscle. In short, the conditions in cold-blooded animals are quite like those in the pithed mammal with an arterial pressure of about 50 millimeters of mercury (see Fig. 16). Under these conditions the improved circulation causes a remarkable recovery from fatigue. That notable results of adrenin on fatigue are observed in warm-blooded animals only, when they are deeply anaesthetized or are ^epriVed of the medulla was claimed by Panella.* He apparently believed that in normal mammalian conditions adrenia has little effect because quickly destroyed, whereas in

the cold-blooded animals, and in mammals whose respiratory, circulatory, and thermogenic states are made similar to the cold-blooded by anaesthesia or pithing, the contrary is true. In accordance with our observations of the effects of blood pres- sure on fatigued muscle, we would explain Panel- la's results not as he has done but as due to two factors. First, the efficiency of the muscle, when blood pressure is low, follows the ups and downs of pressure much more directly than when the pressure is high. And second, a given dose of adrenin always raises a low blood pressure in atonic vessels. The improvement of circulation is capable of explaining, therefore, the main re- sults obtained in cold-blooded animals and in pithed mammals.

Oliver and Schafer reported unusually effective contractions in muscles removed from the body after adrenal extract had been injected. As shown in Fig. 16, however, the fact that the circulation had teen improved results in continued greater effi- ciency of the contracting muscle. Oliver and Scha- fer's observation may reasonably be accounted for on this basis. The Value of Increased Arterial Pressure m Pain and Strong Emotion As stated in a previous paragraph, there is evi- dence that the vessels supplying a muscle dilate

when the muscle becomes active. And although the normal blood pressure (about 120 millimeters of mercury) may be able to keep adequately sup- plied with blood the single muscle used in our in- vestigation, a higher pressure might be required when more muscles are involved in activity, for a more widely spread dilation might then reduce the pressure to the point at which there would be insufficient circulation in active organs. Further- more, with many muscles active, the amount of waste would be greatly augmented, and the need for abundant blood supply would thereby to a like degree be increased. For both reasons a rise of general arterial pressure would prove advan- tageous. The high pressure developed in excite- ment and pain, therefore, might be specially ser- viceable in the muscular activities which are likely to accompany excitement and pain.

Tn connection with the foregoing considerations, the action of adrenin on the distribution of blood in the body is highly interesting. By measuring alterations in the volume of various viscera and the limbs, Oliver and Schafer ^ proved that the viscera of the splanchnic area — e. g., the spleen, the kidneys, and the intestines — suffer a consider- able decrease of volume when adrenin is adminis- tered, whereas the limbs into which the blood is forced from the splanchnic region actually in- crease in size. The action of adrenin indicates the

relative degrees of sympathetic innervations. In other words, at times of pain and excitement sym- pathetic discharges, probably aided by the adrenal secretion simultaneously liberated, will drive the blood out of the vegetative organs of the interior, which serve the routine needs of the body, into the skeletal muscles which have to meet by extra action the urgent demands of struggle or escape. But there are exceptions to the general state- "nient thai •by'Sdrenin the viscera are emptied of their blood, ^t is well known that adrenin has a vasodilator, not a vasoconstrictor, action on the arteries of the heart; it is well known also that adrenin affects the vessels of the brain and the lungs only slightly if at all. From this evidence we may infer that sympathetic impulses, though causing constriction of the arteries of the abdomi- nal viscera, have no effective influence on those of the pulmonary and intracranial areas and actually increase the blood supply to the heart. Thus the absolutely and immediately essential organs — those the ancients called the "tripod of life" — the heart, the lungs, the brain (as well as its instru- ments, the skeletal muscles) — are in times jjf, ex- citement abundantly supplied with blood taken from organs of less importance in criticar"in6- inents. This shifting of the blood so that there is an assured adequate supply to structures" eSMntlal for the preservation of the individual may reason-

ably be interpreted as a fact of prime biological significance. It willJbej'Msgjd . in .its.,.pr,ape]j- setti-ng- / when the_otb.eX-,eziclence of bodily changes in pain I and excitement have. been. presented. ^ As a muscle approaches its fatigue level, its con- tractions are decreased in height. Higher contrac- tions will again be elicited if the stimulus is in- creased. Although these phenomena are well known, no adequate analysis of their causes has been advanced. A number of factors are probably operative in decreasing the height of contraction : (1) The using up of available energy-producing material; (2) the accumulation of metabolites in the fatigued muscle; (3) polarization of the nerve at the point of repeated electrical stimulation ; and (4) a decrease of irritability. It may be that there are interactions between these factors within the muscle, e. g., the second may cause the fourth.

Variations of the Threshold Stimulus as a Measure of Irritability The last of the factors mentioned above — the effect of fatigue on the irritability of the nerve- muscle combination, or on the muscle alone — can be tested by determining variations in the least stimulus capable of causing the slightest contrac- tion, the so-called "threshold stimulus." As the irritability lessens, the threshold ' stimulus must necessarily be higher. The height of the threshold is therefore a measure of irritability. How does fatigue affect the irritability of nerve-muscle and muscle ? How is the irritability of fatigued struc- tures affected by rest? How is it influenced by adrenin or by adrenal secretion? Answers to these questions were sought in researches carried on by C. M. Gruber ^ in 1913.

The neuro-muscular arrangements used in these researches were in many respects similar to those already described in the account of experiments by Nice and myself. To avoid the influence of an anesthetic some of the animals were decerebrated under ether and then used as in the experiments in which urethane was the anesthetic. The nerve (the peroneus communis) supplying the tibialis an- ticus muscle was bared and severed ; and near the cut end shielded platinum electrodes were applied. These electrodes were used in fatiguing the muscle. Between these electrodes and the muscle other platinum electrodes could be quickly applied to de- termine the threshold stimulus and the tissue re- sistance. These second electrodes were removed

except wlien in use, and when replaced were set always in the same position. Care was taken, be- fore replacing them, to wipe off moisture on the nerve or on the platinum points. For determining the threshold stimulus of the muscle the skin and other overlying tissues were cut away from the tibialis anticus in two places about 5 centimeters apart. Through these open- ings platinum needle electrodes could be thrust into the muscle whenever readings were to be taken. Local polarization was avoided by rein- serting the needles into fresh points on the exposed areas whenever new readings were to be taken.

The tendon of the tibialis anticus was attached, as in the previous experiments, by a strong thread passing about pulleys to a lever which when lifted stretched a spring. During the determination of the threshold the spring was detached from the lever, so that only the pull of the lever itself (about 15 grams) was exerted on the muscle. The method of measuring the stimulating value of the electric current which was used in testing the threshold was that devised by E. Gr. Martin* of the Harvard Laboratory — a method by which the strength of an induced electric shock is calculable in definite units. If the tissue resistance enters

* For a full account of Dr. Martin's method of calculating' the strength of electric stimuli, see Martin : The Measurement of Induction Shocks, New York, 1912. into the calculation these are called ^ units. When the threshold of the nerve-muscle was taken, the apparatus for the determination was connected with the nerve through the electrodes nearer the muscle. They were separated from the fatiguing electrodes by more than 3 centimeters, and ar- ranged so that the kathode was next the muscle. When the threshold of the muscle was taken direct- ly the apparatus was connected with the muscle through platinum needle electrodes thrust into it. The position of the secondary coil of the inducto- rium, in every case, was read by moving it away from the primary coil until the very smallest pos- sible contraction of the muscle was obtained. Four of these readings were made, one with tissue resist- ance, the others with 10,000, 20,000, and 30,000 ohms additional resistance in the secondary cir- cuit. Only break shocks were employed — the make shocks were short-circuited. Immediately after the determination of the position of the sec- ondary coil, and before the electrodes were re- moved or disconnected, three readings of the tis- sue resistance were made. From these data four values for /3 were calculated.

The strength of the primary current for deter- mining the threshold of the nerve-muscle was usu- ally .01 ampere, but in a few cases .05 ampere was used. For normal muscle it was .05 ampere and for denervated muscle 1.0 ampere. The inducto- rium, which was used throughout, had a secondary resistance of 1400 ohms. This was added to the average tissue resistance in making corrections — corrections were made also for core magnetiza- ti on. The Lessening op Neuro-musculae Irritability by Fatigue The threshold for the peroneus communis nerve in decerebrate animals varied from 0.319 to 2.96 units, with an average in sixteen experiments of 1.179.* This average is the same as that found by E. L. Porter ^ for the radial nerve in the spinal cat. For animals under urethane anesthesia a higher average was obtained. In these it varied from .644 to 7.05, or an average in ten experiments of 3.081.

The threshold for the tibialis anticus muscle varied in the decerebrate animals from 6.75 units to 33.07, or an average in fifteen experiments of 18.8. Ten experiments were performed under ure- thane anesthesia and the threshold varied from 12.53 to 54.9, with an average of 29.84 j3 units. From these results it is evident that anesthesia notably affects the threshold. E. L. Porter proved, by experiments carried on in the Harvard Physiological Laboratory, that the threshold of an undisturbed nerve-muscle remains

* For the detailed data of these and other quantitative ex- periments, the reader should consult the tables in the original papers. constant for hours, and his observation was con- firmed by Gruber (see Fig. 19). If, therefore, after fatigue, a change exists in the threshold, this change is necessarily the result of alterations set up by the fatigue process in the nerve-muscle or muscle. After fatigue the threshold of the nerve-muscle, in sixteen decerebrate animals, increased from an average of 1.179 to 3.34 — an increase of 183 per cent. In ten animals under urethane anesthesia the threshold after fatigue increased from a nor- mal average of 3.08 to 9.408 — an increase of 208 per cent.

An equal increase in the threshold stimulus was obtained from the normal muscle directly. In de- cerebrate animals the normal threshold of 18.8 units was increased by fatigue to 69.54, or an in- crease of 274 per cent. With urethane anesthesia the threshold increased from 29.849 to 66.238, or an increase of 122 per cent. Fig. 18, plotted from the data of one of the many experiments, shows the relative heights of the threshold before and after fatigue. The corre- spondence of the two readings of the threshold, one from the nerve supplying the muscle and the other from the muscle directly, served as a check on the electrodes. The broken line in the figure repre- sents the threshold (in units) of the nerve-muscle, and the continuous line that of the muscle. The

threshold values of the nerve-muscle have been magnified ten times in order to bring the two rec- ords close together. In this experiment the thresh- FiGTJEE 18. — A record plotted from the data of one experiment. The time intervals in minutes are registered on the abscissa; the value of the threshold in units is registered on the ordinate. The continuous line is the record of the muscle, the broken Une that of the nerve-muscle. The values for the nerve-muscle have been magnified ten times, those for the muscle are normal.

(2) Fatigue thresholds after one hour's work, hfting 120 grams 240 times a minute. old of the muscle after fatigue (i.e., at 2) is 167 per cent higher than the normal threshold (at 1), while that of the nerve-muscle after fatigue is 30.5 per cent higher than its normal. Evidently a direct relation exists between the duration of work and the increase of threshold. For instance, the threshold is higher after a muscle is fatigued for two hours than it is at the end of

the first hour. The relation between the work done and the threshold is not so clear. In some animals the thresholds were higher after 120 grams had been lifted 120 times a minute for 30 minutes than they were in others in which 200 grams had been lifted 240 times a minute for the same period. The muscle in the latter instances did almost four times as much work, yet the threshold was lower. The difference may be due to the general condi- tion of the animal.

A few experiments were performed on animals in which the nerve supplying the muscle was cut seven to fourteen days previous to the experiment. The muscle, therefore, had within it no living nerve fibres. The average normal threshold for the denervated muscle in 6 animals was 61.28 units. As in the normal muscle, the percentage increase due to fatigue was large. The Slow Eestoration of Fatigued Muscle to Normal Ireitability by Eest That rest decreases the fatigue threshold of both nerve-muscle and muscle can be seen in Fig. 18. The time taken for total recovery, however, is de- pendent upon the amount of work done, but this change, like that of fatigue, varies widely with different individuals. In some animals the thresh- old returned to normal in 15 minutes; in others, in which the same amount of work was done, it was

still above normal even after 2 hours of rest. This may be due to the condition of the animals — in some the metabolites are probably eliminated more rapidly than in others. There were also variations in the rate of restoration of the normal threshold when tested on the nerve and when tested on the muscle in the same animal. In Fig. 18 (at 3) the nerve-muscle returned to normal in 30 miautes, whereas the muscle (at 4) after an hour's rest had not returned to normal by a few /3 units. This, however, is not typical of all nerve-muscles and muscles. The opposite condition — that in which the muscle returned to normal before the nerve- muscle — occurred in as many cases as did the con- dition just cited. The failure of the two tissues to alter uniformly in the same direction may be ex- plained as due to variations in the location of the electrodes when thrust into the muscle at different times (e. g., whether near nerve filaments or not). The results from observations made on the nerve are more likely to be uniform and reliable than are those from the muscle.

The time required for the restoration of the threshold from fatigue to normal, in denervated muscles, is approximately the same as that for the normal muscle. The Quick Eestoration of Fatigued Husole to Normal Irritability by AoRENDf The foregoing observations showed that fatigue raises the normal threshold of a muscle, on the av- erage, between 100 and 200 per cent (it may be in- creased more than 600 per cent) ; that this increase is dependent on the time the muscle works, but also varies with the animal ; that rest, 15 minutes to 2 hours, restores the normal irritability ; and that ^ this recovery of the threshold depends upon the time given to rest, the duration of the work, and also upon the condition of the animal. The prob- lem which was next attacked by Gruber was that of learning whether the higher contractions of fa- tigued muscle after splanchnic stimulation could be attributed to any influence which adrenal secre- tion might have in restoring the normal irritability. To gain insight iato the probabilities he tried first the effects of injecting slowly into the jugular vein physiological amounts of adrenin.*

The normal threshold of the peroneus communis nerve varied in the animals used in this series of observations from 0.35 to 5.45 units, with an aver- age in nine experiments of 1.3, a figure close to the 1.179 found in the earlier series on the effect of fatigue. For the tibialis anticus muscle, in which the nerve-endings were intact, the threshold varied * The form of adrenin used in these and in other injections was fresh adrenalin made by Parke, Davis & Co.

from 6.75 to 49.3 units, with an average in the nine experiments of 22.2. This is slightly higher than that cited for this same muscle in the earlier series. By fatigue the threshold of the nerve-muscle was increased from an average of 1.3 to an average of 3.3 units, an increase of 154 per cent. The muscle increased from an average of 22.2 to an average of 59.6, an increase of 169 per cent. After an injec- tion of 0.1 to 0.5 cubic centimeters of adrenin (1:100,000) the fatigue threshold was decreased ivithin five minutes in the nerve-muscle from an average of 3.3 to 1.8, a recovery of 75 per cent, and in the muscle from an average of 59.6 to 42.4, a re- covery of 46 per cent. To prove that this effect of adrenin is a counteraction of the effects of fatigue, Gruber determined the threshold for muscle and nerve-muscle in non-fatigued animals before and after adrenin injection. He found that in these cases no lowering of threshold occurred, a result in marked contrast with the pronounced and prompt lowering induced by this agent in muscles when fatigued.

Figs. 19 and 20, plotted from the data of two of the experiments, show the relative heights of the threshold before and after an injection of adrenin. The close correspondence of the two readings of the threshold, one from the nerve supplying the muscle, the other from the muscle directly, served to show that there was no fault in the electrodes. The continuous line in the Figures represents the threshold (in units) of the muscle, the broken line that of the nerve-muscle. The threshold of the nerve-muscle is magnified 100 times in Fig. 19 and 10 times in Fig. 20. In Fig. 19 (at 2 and 4) the threshold was taken after an intravenous injection of 0.1 and 0.2 cubic centimeter of adrenin respec- tively.

These examples show that adrenin does not af- fect the threshold of the normal non-fatigued mus- cle when tested either on the muscle directly or on the nerve-muscle. In Fig. 19 (at 3) the observa- tion taken after two hours of rest illustrates the constancy of the threshold under these circum- stances. In Fig. 19 the normal threshold was increased by fatigue (at 5) — the muscle had been pulling 120 times a minute for one hour on a spring hav- ing an initial tension of 120 grams — from 30.0 to 51.6 units, an increase of 72 per cent; and in the nerve-muscle from 0.62 to 0.89 units, an increase of 46 per cent. The threshold (at 6) was taken five minutes after injecting 0.1 cubic centimeter of adrenin (1:100,000). The thresh- old of the muscle was lowered from 51.6 to 38.0 units, a recovery of 62 per cent; that of the nerve-muscle from 0.89 to 0.79 units, a recovery of 37 per cent. After another injection of 0.5 cubic centimeter of adrenin the thresholds (at 7) were

taken; that of the nerve-muscle dropped to normal — 0.59 miits — a recovery of 100 per cent, and that Figure 19. — A record plotted from the data of one experiment. The time inter- vals in hours and minutes are represented on the abscissa; the values of the threshold in ;3 units are represented on the ordinate. The continuous line is the record of the muscle, the broken line that of the nerve- muscle. The nerve-muscle record is mag- nified 100 times; that of the muscle is nor- mal.