Effect of hydrocortisone on electrical activity, arousal thresholds and evoked potentials in the brains of chronically implanted rabbits

462

JOURNAL OF THE NEUROLOGICAL SCIENCES

Effect of Hydrocortisone on Electrical Activity, Arousal Thresholds and Evoked Potentials in the Brains of Chronically Implanted Rabbits S. F E L D M A N AND J. M. DAVIDSON Department of Nervous Diseases (Laboratory of Experimental Neurology), Hadassah University Hospital and the Hebrew University, Hadassah Medical School, Jerusalem (Israel) (Received 17 March, 1965)

INTRODUCTION

Recent clinical and experimental data suggest that the adrenocortical hormones play a role in central nervous system function. Though the evidence points to a general regulatory effect of the adrenal cortex on brain excitability, the glucocorticoids in particular have been shown to have a distinct excitatory influence on the central nervous system (WOODBURY 1958). Most studies related to this problem have dealt with thresholds of electrical or drug-induced convulsions, and few data are yet available on the electrophysiology of the central effects of these hormones. Previous investigations on the effect of adrenocortical hormones on evoked potentials in the brain stem were performed on acute preparations (FELDMAN et al. 1961). The present study deals with the effect of hydrocortisone on electrical activity and arousal thresholds, as well as on evoked potentials and their recovery cycles in chronically implanted unanesthetized animals. MATERIALSAND METHODS Experiments were performed on 12 rabbits 2.2-3.7 kg in weight. Under pentobarbital anesthesia concentric bipolar electrodes were introduced stereotaxically (SAWYER et al. 1954) into the hippocampus, amygdala, septum, preoptic area, ventromedian hypothalamus, posterior hypothalamus and the midbrain reticular formation. Two stainless steel screws inserted through the skull served as anterior and posterior cortical electrodes, and one placed over the frontal sinus served as an indifferent electrode. Commencing 2-4 weeks postoperatively, when recovery from surgery appeared complete and constant EEG records were obtained, 50 experiments were performed on these animals. Studies included recordings of the EEG, measurements of arousal thresholds following midbrain reticular formation stimulation and of evoked potentials following subcortical stimulation, and determinations of the recovery cycles of J. neurol. Sci. (1966) 3:462-472

EFFECT OF HYDROCORTISONE ON THE BRAINS OF CHRONICALLY IMPLANTED RABBITS

463

evoked potentials. Following a 2-4 hour period of control observations either 10-25 mg of hydrocortisone succinate (Solucortef of Upjohn) in 1 ml saline, or saline alone, was injected into an ear vein and the results observed for another 2-6 hours. In some experiments saline injection or venepuncture was performed first, and several hours later the hormone was administered. During experimentation, rabbits were kept in a large sound proof box equipped with a one way mirror, permitting observation by the investigator of the behaviour of the unrestrained animals. With the purpose of obtaining a stable control baseline, the studies on arousal thresholds were performed in rabbits which were made drowsy by running them on a treadmill for a few hours before the experiment was started. Single stimuli of 5-10 V, 0.1-1 msec duration were delivered from a Grass stimulator, and the resulting evoked potentials were recorded bipolarly, displayed on a Tektronix 502 oscilloscope and photographed with a Grass oscilloscope camera. Photic stimuli were delivered from a Grass photostimulator. Excitability cycles were studied by delivering paired stimuli at varying intervals between stimuli. EEG activity was recorded bipolarly on a Schwartzer 8-channel electroencephalograph. Arousal reactions were produced by stimulating the midbrain reticular formation with pulses at a frequency of 250 c/s and a duration of 1 msec for 5 sec. Atthe end of all experiments the brains were removed, fixed in formalin, sectioned at 80/~, stained and position of the electrodes was confirmed.

RESULTS

E E G activity

A number of changes in EEG activity were noted following hydrocortisone injection. In 5 rabbits, a prolonged electrical arousal appeared within several minutes after hydrocortisone injection and continued up to an hour thereafter. This reaction took the form of 0-activity recorded mainly in the limbic cortex, hippocampus, ventromedian hypothalamus, septum and midbrain reticular formation. The phenomenon was not observed in the same animals when saline alone was administered. During the prolonged hydrocortisone-induced arousal the animals were quiet, and occasionally lay on the floor of the cage. In the majority of animals, however, the arousal phenomenon was of short duration and led within a few minutes to a generalized slowing of electrical activity from v to ~ frequencies, usually 3-3.5 c/s, but occasionally as slow as 0.75-1 c/s. This slowing continued for about half an hour. Another phenomenon observed was the appearance or accentuation of a previously existing fast activity (35--40 c/s) in the amygdala, which continued for more than one hour (Fig. 1). Spikes in the hippocampus, hypothalamus, amygdala and septum appeared within 20-30 min after hydrocortisone injection in 6 animals. This effect was not usually noted in the midbrain reticular formation. The most pronounced effect of hydrocortisone injection was the appearance in 6 rabbits of convulsive electrical activity consisting of high amplitude spikes or delta waves in the ventromedian hypothalamus and septum, followed occasionally by electrical silence. These localized seizures which could be reproduced in the same rabbit and in one instance could be repeated in four different experiments, appeared J. neurol. Sci. (1966) 3:462-472

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s. FELDMAN, J. M. DAVIDSON

half to one hour following hydrocortisone injection. They either remained localized to these structures or there was a spread of epileptic activity to posterior hypothalamus and hippocampus with bursts appearing in some or all cortical and subcortical leads (Fig. 2). The localized epileptic attacks appeared without prior brain stimulation, but

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Fig. 1. A: control record; B: one minute after 20 mg hydrocortisone injection. Note: depression of the activity in LPO and great increase in fast activity (35-40/sec) in AMYG. C: 27 min after hydrocortisone. Note: AMYG fast activity and sharp waves in LPO and SPT indicative of a seizure activity. The localized seizures lasted for 30 sec and the fast AMYG activity continued for over an hour. Abbreviations: AC, anterior cortex; AMYG, amygdala; HIPP, dorsal hippocampus; LPO, lateral preoptic area; PC, posterior cortex; PHYP, posterior hypothalamus; MRF, midbrain reticular formation; SPT, septum; VMH, ventromedian hypothalamus.

in at least two instances followed a short stimulus to subcortical structures (Fig. 3). N o behavioural seizures were observed in the animals during the electrical epileptic activity. N o significant E E G changes were observed in the animals following saline injection. Single subcortical stimuli which evoked little or no after-discharges before hydrocortisone injection, produced a marked fast spike activity in various leads after h o r m o n e administration (Fig. 4). J. neurol. Sci. (1966) 3:462~,72

EFFECT OF HYDROCORTISONEON THE BRAINSOF CHRONICALLYIMPLANTEDRABBITS 465 A r o u s a l thresholds

Arousal thresholds were studied in ten experiments performed on four rabbits. A number of determinations were made during 3-4 hours and when the threshold was found to be constant, in 5 experiments 25 mg hydrocortisone and in 5 experiments c

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Fig. 2. A: control record; B: 46 min after 12 mg hydrocortisone. Note: fast activity in the VMH and AC and spikes in PHYP. C: 68 min after hydrocortisone. Increased spike activity in PHYP, increase in amplitude and appearance of seizure discharges in VMH. D: 69 min after hydrocortisone. Note: synchronic epileptic discharge in VMH, HIPP and AC which terminates the attack. For abbreviations, see Fig. 1. normal saline were injected. After this the threshold was tested for another 3-4 hours. The threshold was found to be surprisingly constant ( + 0 . 2 V) and no change occurred following injection of either hydrocortisone or saline. E v o k e d potentials

The latency of the evoked potentials varied according to the position of the stimulating and recording electrodes. Some of the responses recorded in the septum following midbrain reticular stimulation were of long latency (10-20 msec) but in most cases the latency was about 5 msec. Also short latency (3--4 msec) projections were demonstrated from the midbrain to the anterior hypothalamus and preoptic area. The responses in the hypothalamus after septal stimulation were of 5-10 msec latency. In 7 out of 9 experiments performed, an increase in the amplitude of the evoked potentials or one of their components appeared following a latent period of a few minutes after the injection of hydrocortisone. This increase lasted usually for half to J. neurol. Sci. (1966) 3:462-472

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EFFECT OF HYDROCORTISONE ON THE BRAINS OF CHRONICALLY IMPLANTED RABBITS 467

one hour after which amplitudes tended to return to the previous values. Such an increase in amplitude was observed in evoked potentials which were obtained by stimulating the midbrain reticular formation and recording in the septum and hippocampus and in the hypothalamus after septal (Fig. 5) or midbrain reticular formation (Fig. 6) stimulation. Similarly, photic responses in the anterior hypothalamus were enhanced by hydrocortisone (Fig. 6).

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Fig. 4. EEG responses following single stimuli of the septum, at increasing voltages, before and 80 rain after the administration of 25 mg hydrocortisone. Note: particularly in the VMH, after-discharges of high voltage fast activity after hydrocortisone (Hc), when compared with control records (C). For abbreviations, see Fig. 1.

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(1966) 3:462-472

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s. FELDMAN, J. M. DAVIDSON

The excitability cycle in these subcortical regions was found to be quite short, showing complete recovery at stimulus separations as short as 10-20 msec with occasional peaks of facilitation. In five out of nine experiments there was a further enhancement of neuronal excitability or a shortening of the recovery period following hydrocortisone injection, when compared with the recovery cycle before hormone administration (Fig. 7).

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Fig. 6. Evoked potentials in the ventromedian hypothalarnus (VMH) following midbrain reticular formation (MRF) and photic stimuli before and following the administration of 25 mg hydrocortisone. Note the appearance and increase in amplitude of a long latency response. Calibration signal: 10 msee and 100 #V.

DISCUSSION The excitatory effect of glucocorticoid hormones on the central nervous system has been well documented both in experimental and in clinical studies. Cortisone and hydrocortisone markedly increased brain electrical excitability in rats, as manifested by lowering of electroshock thresholds (WoODBURY 1958) and increase in metrazol sensitivity (ToRvA AND WOLFF 1951). In dogs, cortisone and ACTH decreased the thresholds of seizures induced by cerebral cortical stimulation (PASOUNI 1952) and shortened the latency and increased the severity of 'agene' induced seizures (COSTA AND BOt~VCASTLE 1952). The few experimental electrophysiological observations reported lmv¢ djmlt mostly with hormone-induced changes in the cortical EEG. In these studies an increase in voltage, spiking and paroxysmal runs of low-frequency high-voltage waves were observed (GRENELL AND MCCAWLEY 1947; TORDA AND WOLFF 1952). Recently large amounts of compound S have been shown to cause an initial epileptic activity in the amygdala and hippocampus in cats (HEUSER AND EIDELBERG 1961). The clinical observations on changes in the electrical activity of the brain in humans J. neurol. Sci. 0966) 3:462-472

EFFECT OF HYDROCORTISONE ON THE BRAINS OF CHRONICALLY IMPLANTED RABBITS 469 H y d ro cortisone

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Fig. 7. Effect of hydrocortisone on neuronal recovery in the posterior hypothalamus following double stimulation of the septum, at varying intervals: examples from the recovery cycle and a graph plotted to demonstrate the neuronal recovery of the initial positive wave (broken line) before and following the administration of 25 mg hydrocortisone. T.R., test response, and the number of msec indicating the separation between two stimuli. Note the enhanced facilitation of the recovery cycle. Calibration signal: I00 ttV.

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a p p e a r a n c e o f s l o w w a v e activity w i t h g e n e r a l i z e d bursts a n d greater r e s p o n s i v e n e s s to p h o t i c d r i v i n g i n d i c a t i v e o f epileptic t e n d e n c y (HOEFER AND GLASER 1950; STREIFLER J. neurol. Sci. (,1966) 3:462J,72

470

S. F E L D M A N , J. M. D A V I D S O N

AND FELDMAN 1953; LOEWENBERGWAYNE AND BOYLE 1953). This effect was much more pronounced in epileptic patients with previously abnormal EEG's (GLASER AND MERRITT 1952; GLASER e t al. 1955). These EEG changes are undoubtedly related to the well known, though infrequent appearance of frank epileptic attacks (DORFMAN e t al. 1951; LOEWENBERGWAYNE 1954) and even status epilepticus and death (GEPPERT e t al. 1952) though some of these patients were receiving the adrenocortical therapy for conditions which by themselves do not cause convulsive phenomena (GLASER 1953). We have previously reported (FELDMAN e t al. 1961) acute experiments on cats in which intravenous hydrocortisone succinate caused an increase in amplitude of the long latency potentials evoked by sciatic nerve stimulation in the thalamic intrataminar nuclei, the anteromedian hypothalamus and midbrain reticular formation. These effects were interpreted as lowering of thresholds of synaptic transmission and consequently involvement of more units in the response, as a result of the hormone administration. Increases in evoked potentials have also been observed following the administration of convulsive drugs (OKuMA 1960) and concomitant with the development of focal cortical epileptogenesis (WroTE e t al. 1960). The ability of hydrocortisone to enhance evoked responses in the brain has been confirmed in the present experiments in chronically implanted animals. Another manifestation of the facilitation of synaptic transmission was the enhancement of neuronal recovery after the hormone administration. Evidence that adrenocortical hormones play a role in synaptic transmission was also found in our previous studies in which increased conduction time and delayed neuronal recovery was demonstrated in the brainstem of adrenalectomized cats (FELDMAN 1962). These results were recently confirmed in chronically implanted animals (CHAMBERSet al. 1963). The mechanism of action of the adrenocortical hormones on the central nervous system has been discussed by WOODnURY (1958). In acute experiments, changes in cation distribution between extra- and intracellular fluids have been correlated with corticoid-induced decreases in electroshock threshold, but the changes in brain electrolytes were not found when the threshold decreases were produced by chronic administration of corticoids. The suggestion (WOODBURY 1958) that the corticosteroid effects are mediated by a lowering of brain GABA has not been substantiated by other investigators (HEuSER AND EIDELBERG 1961). Clinical reports indicate that there is also no correlation between the appearance of electrical and clinical epileptic phenomena and either biochemical or anatomical changes (HOEFER AND GLASER 1950; PINE e t al. 1951; GEPPERT e t al, 1952). It is thus evident that there is no satisfactory explanation for the enhanced central nervous system excitability following adrenocortical administration. This effect may be due therefore to a direct hormonal action on diencephalic centers which regulate brain electrical activity and are known to be related to epileptic phenomena (STREIFLERAND FELDMAN 1953). This proposal is supported by the changes in the subcortical evoked potentials as well as by the appearance of localized epileptic discharges in the hypothalamus and septum following hydrocortisone administration. Though no behavioral convulsions were observed under our experimental conditions, the building up of local epileptic activity into high voltage bursts in cortical and subcortical leads, in the form of centrencephalic disJ. neurol. Sci. (1966) 3 : 462-472

EFFECT OF HYDROCORTISONEON THE BRAINS OF CHRONICALLY IMPLANTED RABBITS 471 charges (PENFIELD AND JASPER 1954), is certainly indicative of epileptic phenomena which are capable of producing generalized convulsions. The facilitation of evoked potentials and enhanced neuronal recovery in the forebrain structures following hydrocortisone administration may have been due either to an excitatory effect of the hormone on these regions, or to suppression of inhibitory influences, possibly coming from the midbrain reticular formation. The latter area is, in fact, known to be inhibitory both to the diffuse tbalamic projection system (EVARTS AND MAGOUN 1957) and to the hypothalamus (FELDMAN1962). Our present observations that hydrocortisone does not alter the arousal thresholds following stimulation of the midbrain reticular formation, and the lack of initial electrical phenomena in this region following hormone administration, do not support an important role for the reticular formation in the hydrocortisone-induced electrical phenomena. In view of the major role played by the diencephalic and limbic circuits in emotional behaviour (BRADY 1960), it is not unlikely that the hormonal effects on these structures are also responsible for the psychiatric phenomena observed in patients receiving adrenocortical therapy (QUARTON et al. 1955).

ACKNOWLEDGEMENTS

This investigation was supported by Grant No. 244 from the National Multiple Sclerosis Society, and by National Institutes of Health, Bethesda (Agreement 4X5108). The technical assistance of MRS. S. ALPERN and MR. N. KONFORTI is gratefully acknowledged.

SUMMARY

The effects of intravenously administered hydrocortisone succinate on cortical and subcortical electrical activity, arousal thresholds, evoked potentials and their neuronal recovery were studied in the brains of unrestrained rabbits with chronically implanted electrodes in the cortex, hippocampus, amygdala, septum, hypothalamus and midbrain reticular formation. Hydrocortisone caused in various animals the appearance of prolonged electrical arousal, generalized slowing, spikes, fast activity in the amygdala and localized epileptic discharges in the ventromedian hypothalamus and septum. These were followed by spread of seizure activity to other structures and generalized bursts of epileptic activity. No behavioural seizures were observed in these animals. The hormone caused an increase in the amplitude of potentials evoked by central and photic stimulation in these forebrain regions. Hormone administration also enhanced neuronal excitability and shortened the recovery cycle of these responses. Hydrocortisone had no effect on electrical arousal thresholds following high frequency stimulation of the reticular formation. The clinical and experimental literature on central nervous system effects of adrenocortical hormones and their mode of action is briefly reviewed. The present results would suggest that the adrenocortical hormones affect the central nervous system through their direct action on forebrain and related limbic structures. J. neurol. Sci.

(1966) 3:462-472

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