Refractory phase in cerebral mechanisms.

1. 1. Stimulation of the sciatic nerve in cats under deep barbiturate narcosis has previously been shown to evoke a primary electric response in the sensory leg area of the cortex and a secondary discharge, more widespread in the cortex, with latencies from 30 to 80 msec. When a series of stimuli is applied at more than about 5 per sec., each stimulus evokes a primary response, but only the first evokes the secondary discharge. A rest of at least 0.2 sec. is needed before another stimulus can evoke the discharge. 2. 2. This behavior resembles the Wedensky inhibition in peripheral nerve, in which when a series of impulses so frequent that each one after the first falls in the relative refractory phase and is therfire subnormal, a partial block in the nerve will stop all but the first (full-sized) impulse. The experiiments described herein were designed to determine the effect of varying the depth of narcosis on the properties of the primary response, on the time of recovery of responsiveness in the sensory discharge (S. D.) mechanism, and on the critical stimulus frequency requisite to maintain blockingof the S.D. It was hoped that such information might aid in estimating whether the block could be interpreted as essentially a Wedensky effect.v 3. 3. The quantitative estimation of the depth of narcosis became a major issue. For this purpose we recorded respiration, blood pressure and spontaneous electric waves in the cortex, graded them on an empirical percentage scale, and designated their average the “functional mean” — a convenient measure of the depression of the cerebrum and the vital centers. We studied the effects of injection of dial in urethane and of nembutal on the functional mean and the rate of recovery as the effect of the drug wore off, and by trial and error arrived at formulae that gave fairly good correlation of estimated narcotic concentration with observed depression of functional mean (fig. 2). 4. 4. Analysis of blood samples by spectrophotometry when nembutal alone was used, showed that the actual concentration of the drug in the blood was nearly what we had estimated for the active tissues, and further gave evidence that the concentration of the narcotic was not in itself enough too account for the depression of activity after narcosis had been in progress more than 4 or 5 hours (fig. 3). The observations of Beecher and Moyer suggest that increased CO2 in the blood may be the explanation. 5. 5. Increasing the depth of narcosis greatly prolonged the apparent refractory phase of the S.D. mechanism, and correspondingly decreased the critical frequency above which repeated stimuli held the S.D. in abeyance as long as they were continued (figs. 4 and 5). The primary response. localized in the sensori-motor area, was much less reduced by deep narcosis, as to size and the frequency with which it could be evoked. 6. 6. Alternation between large and small excursions was occasionally found in both primary response and S.D. In each case it can be explained as due to slow recovery from refractory phase such that the excitatory effect of the afferent volley is subliminal at the time of the second stimulus, but is adequate when the third volley arrives. 7. 7. In some experiments a distinct wave (“X spike”) appeared between the primary response and the S.D. Its behavior at various stimulus frequencies and levels of narcosis differed from that of both primary and S.D. Like them it sometimes showed alternation. 8. 8. Reducing body temperature greatly increased the latencies and duration of responses and the recovery times. In the later experiments temperature was carefully maintained above 35°C. 9. 9. We explored the possibility that during S.D. block a sudden increase in stimulus frequency might cause facilitation that would break through the block, as has been found by Wiersma in the crustacean nervous system. The results were dominantly negative, but with a few cases in moderate narcosis the sudden increase in frequency appeared to be the cause of a cortical wave. The atypical form of the wave and its long latency led us to believe that it came from some cerebral mechanism other than that involved in the S.D. 10. 10. The threshold of afferent stimuli required to evoke the S.D. is in general little higher than the A-fiber threhold. In at least one experiment we found the S.D. threshold consistently higher, and closer to the maximal value for A fibers. This suggests that convergence of many impulses may sometimes be necessary to evoke S.D. 11. 11. When narcosis was deep enough to lower blood pressure, arterial injection that restored b.p. nearly to normal raised the level of cerebral activity, but not enough to indicate that depression was due solely to lowered blood pressure. Clearly the barbiturates depress cerebral function by direct action as well. 12. 12. Experiments on three rabbits showed much the same effects as those on cats, but because the margin between quiescence of the cortex and death is much smaller than in cats, the most significant features of deepening narcosis could not be clearly shown. 13. 13. Two experiments were performed on isolated frog sciatic nerves, with alcohol in a narcotizing chamber, to demonstrate for purposes of comparison the classical Wedensky inhibition under conditions similar to those that obtained in Adrian's analysis of that phenomenon (fig. 12). 14. 14. As to the question whether our observations on cortical responses to afferent stimuli can be explained on the basis of a Wedensky effect, it is pointed out that the disparity in time relations between the cerebral events and the Wedensky effect in a nerve trunk do not necessarily preclude this explanation. A hypothetical schema is presented (fig. 13), in which the relations of the refractory periods and thresholds of its components could most simply account for complete and incomplete Wedensky effects, as well as alternation of cortical responses, without recourse to more complex inhibitory or humoral blocking phenomena. The S.D. focus of this schema is assumed to be one of the sources of spontaneous cortical electrical activity. It is postulated that under light or no anesthesia, this focus is driven by afferent impulses reaching it over interneurones (I N in fig. 13). Under barbiturate narcosis, function in these interneurones is depressed, as suggested by Bremer, and as a consequence there occurs the quiescence in the cortex which renders the properties of the S.D. clearly observable.