The effects of electroconvulsive shock on the collicular auditory potential

The Effects of Electroconvulsive Shock on the Collicular Auditory Potential Nigel A. Shaw Key Words: Auditory evoked potential, depression, electroconvulsive shock, generalized seizure activity, inferior colliculus, rat BIOL PSYCHIATRY 1 9 9 6 ; 3 9 : 2 2 3 - 2 2 6

Introduction The induction of generalized seizure activity (GSA) by electroconvulsive therapy (ECT) remains the most effective treatment for severe depressive illness, being superior to antidepressant medication in its rapidity and efficacy of action and in its comparative lack of side effects (Weiner 1984; Crowe 1984; Potter and Rudorfer 1993). What is particularly lacking and is essential to an understanding of its mode of action is a knowledge of its acute neurophysiological effects (Fraser 1982). Sensory evoked potentials (EPs) have the capacity to provide discrete snapshots of cerebral activity during the ictal and immediate postictal period. By recording EPs from different sensory systems and from different locations within a sensory pathway, it should be possible to construct a model of the physiology of acute seizure activity, which should ultimately provide insights into the mechanisms and site of action of ECT. The brainstem auditory evoked potential (BAEP) is a measure of activity from the cochlea to the lateral lemniscus (Hall 1992). When the BAEP has been recorded from patients undergoing ECT, it was found that the waveform remained intact even during the acute ictal phase (Weiner et al 1981; Small et al 1981). More rigorously controlled animal experiments have confirmed this finding (Shaw 1986a); however, no attempt appears to have been made to assess the impact of ECT on activity generated in more central parts of the auditory pathway such as the inferior colliculus. Although the inferior colliculus is an important way Prom the Department of Physiology,Schoolof Medicine,Universityof Auckland, Auckland, New Zealand. Address reprint requests to Professor Nigel A. Shaw, Department of Physiology, School of Medicine,Universityof Auckland, Private Bag 92019, Auckland 1, New Zealand, Received April 10, 1995; revisedJuly 17, 1995. © 1996 Societyof BiologicalPsychiatry

station and integration center for auditory information, collicular activity cannot be reliably recorded from the human skull. In contrast, with an animal such as the rat, an epidural electrode can be inserted directly over the inferior colliculus and a robust, well-defined collicular auditory evoked potential (COLLAEP) can normally be recorded. In the present experiment, therefore, the effects of electroconvulsive shock (ECS) were examined on an auditory response arising from the midbrain of the rat.

Methods and Materials Subjects were 16 male albino rats (300-350 g). One week prior to the experiment, each subject had four small stainless steel screws inserted in the skull while under pentobarbital anesthesia (60 mg/kg). Screws did not penetrate the dura, and were insulated and secured with dental cement. One screw was implanted over the inferior colliculus (2 mm lateral to the lambda). Two screws were inserted sequentially along the nasal bone. A fourth electrode was implanted elsewhere in the dorsal skull. On the experimental day, each animal was initially curarized with a dose of d-tubocurarine chloride (4 mg/kg). As soon as signs of neuromuscular blockade became apparent, the subject was connected to a respirator and artificially ventilated at a rate of 55 strokes per minute, each of 15 mL/kg. Animals were attached to the respirator via a mask constructed of the mouthpiece end of a balloon which fitted snugly over the animal's snout. The mask was secured to the animal by lodging the bottom part behind the upper incisors and the top part over the more distal of the nasal bone screws. Electrocardiogram (ECG) electrodes were attached and stroke rate and volume of the ventilator were adjusted (if necessary) to maintain a normal heart rate 0006-3223/96/$15.00 SSDI 0006-3223(95)00434-3

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(350-450 bpm). EP electrodes were then attached. The active lead was connected to the screw inserted over the inferior colliculus. The reference lead was connected to the second of the nasal bone screws. The ground lead was connected to the remaining skull screw. Several baseline COLLAEPs were then recorded. In some subjects, the COLLAEP could not be reproducibly recorded because of interference from the temporally and spatially contiguous cerebellar and thalamic auditory evoked potentials. In such cases, the experiment was abandoned forthwith. COLLAEPs were recorded using a Medelec MS6. Analysis time was 50 msec and sampling interval 50 Ixsec. Sixty-four responses were averaged to obtain each COLLAEP. Bandpass of the amplifiers was set to 3.2-320 Hz. This is the optimal setting to record the COLLAEP. If the low-pass filter is raised beyond 320 Hz, the waveform will become increasingly distorted by the high-frequency activity of the BAEP. Stimuli were rarefaction clicks of 0.1 msec duration transduced by a TDH-39 headphone. They were delivered monaurally at a rate of 3/sec directly into the external auditory meatus via a thin plastic tube. Intensity of the click was 104 dB peak equivalent sound pressure level. Following the baseline recordings, GSA was induced by transmitting a brief electric current (80 mA for 600 msec) via miniature bulldog clips attached to the animal's ears. The insides of the clips were filled with electrode paste. This magnitude of ECS will induce tonic-clonic seizures in the awake nonparalyzed animal lasting approximately 1 min accompanied by a period of unconsciousness and loss of reflex activity for up to 3 min (Shaw 1985). Because of the delay in reconnecting the animal to the recording equipment plus the temporary blocking of the averaging process by the high-voltage epileptiform activity, the first COLLAEP recording following the induction of GSA usually began about 10-15 sec after the administration of ECS. A second COLLAEP was recorded at 60 sec and subsequent COLLAEPs were obtained at 2, 3, 4, 6, 8, and 10 min. The animal was then immediately euthanized with an overdose of pentobarbital.

Results An example of the COLLAEP recorded from an awake rat is shown in the baseline (Before ECS) illustration in Figure 1. The principal component of the waveform is a positivity that according to its peak latency is labeled P6. The evidence that P6 is of midbrain origin is summarized elsewhere (Funai and Funasaka 1983; Angelo and Moiler 1990; Shaw 1993). Considering its latency, it seems most likely that P6 arises in or near the nucleus of the inferior colliculus. P6 is followed by a negative trough but no later component was reproducibly present. In the present study, only the P6 component was systematically analyzed. Judging by the illustration in Figure 1, it is apparent that ECS had only a minimal and transitory effect on the COLLAEP. Even during the ictal phase, immediately after the induction of GSA, the COLLAEP was preserved with only a slight distortion to its waveform. The principal abnormality consisted of a small diminution in amplitude associated with a minor increase in latency. Normal waveform morphology was rapidly regained.

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Figure 1. An example of the effects of electroconvulsive shock (ECS) on the collicular auditory evoked potential (COLLAEP). The baseline (Before ECS) potential was recorded just prior to the induction of generalized seizure activity. Subsequent COLLAEPs were recorded at the times indicated after ECS. In the baseline example, the principal component of the COLLAEP (P6) is identified with its actual latency (msec) in parentheses. In the remaining COLLAEPs, only the latencies are indicated. Note the inflection on the rising phase of the COLLAEP, which precedes P6 by about 2 msec. This is the cerebellar auditory evoked potential. Group amplitude and latency data for all subjects are summarized in Figure 2. This confirms the finding in the individual subject in Figure 1 that the COLLAEP is largely immune to the effects of ECS. Overall, there was an increase in the latency of P6 of 0.5 msec mirrored by a decrease in its amplitude of 2.7 ixV. Near normal baseline values were restored within 2-3 min.

Discussion Comparatively little is known about the acute physiology of seizure activity. Earlier reports from both humans and animals demonstrated that auditory activity arising from the cochlea, eighth nerve, and brainstem nuclei were virtually immune to ECS (Weiner et al 1981; Small et al 1981; Shaw 1986a, 1988). The present set of recordings has proven that even more centrally generated activity is similarly resistant to the effects of ECS. This

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Figure 2. Mean latency and amplitude ( _ 1 SD) of the P6 component of the collicular auditory evoked potential at the times indicated following electroconvulsive shock (ECS). Amplitudes were calculated by referring them to a zero baseline comprising the first millisecond of the waveform. The wide SDs of the amplitude data indicate the variability among animals in the voltage of the P6 component. implies that synaptic transmission within the more caudal part of the auditory system is not susceptible to disruption by GSA to any significant extent. This might seem anomalous considering that epileptiform activity induced by ECS seems to be just as prevalent within the midbrain and brainstem as it is elsewhere within the brain (Kasprow et al 1985). It is sometimes assumed that the various amnesic, anesthetic, and therapeutic consequences of ECS are mediated by a generalized impairment of

ongoing neural transmission, but the present findings offer little support to this notion. Nevertheless, it has been demonstrated that ECS does cause a severe disruption of the afferent signal at some level within the central somatosensory pathways (Shaw 1985). Assuming that a similar dysfunction also occurs within the central auditory pathways, the present findings suggest that this must take place either within the diencephalon or at the cortex. This conclusion is relevant to at least two problems regarding the site of action of ECS. First is the question of how GSA causes an instantaneous loss of consciousness, a phenomenon sometimes described as electrical stunning. Conventional anesthetics, such as the barbiturates, are thought to cause depression of synaptic transmission within the brainstem involving both specific and nonspecific (reticular) pathways (Angel 1977); however, ECS may induce loss of consciousness by an entirely different mechanism of action, and this would be consistent with the observation that whereas ECS does not alter the BAEP waveform (e.g., Shaw 1986a), barbiturate anesthetics do (Shapiro et al 1984; Shaw 1986b). One possibility is that ECS simply blocks the sensory signal at an as yet unknown location, so rendering the cortex insensible. If this theory is correct, then the present findings indicate that the sensory signal must penetrate to levels higher than the midbrain before functional deafferentation occurs. A second question involves the processes by which ECT alleviates severe depressive illness. Various explanations have been proposed but one of the most detailed is the neuroendocrine theory, which suggests that the release of hypothalamic peptides may underlie the therapeutic effects of ECT (Fink 1980). The neuroendocrine theory is derived from the centrencephalic hypothesis concerning the etiology of generalized seizures (Penfield and Jasper 1954), and predicts that the principal site of impact of ECT must lie within the diencephalon. This is because of the presumed role of the thalamus in the initiation, elaboration, and synchronization of GSA. Abnormal electrical discharges arising from the diencephalon should prevent the formation of thalamic EPs but not necessarily affect EPs generated more caudally. The preservation of the COLLAEP following ECS is therefore, at the least, compatible with the neuroendocrine theory. This work was supported by the Maurice and Phyllis Paykel Trust and the Deafness Research Foundation of New Zealand. The author thanks Paul Hill, Jack Sinclair, Peter Thorne, and Bruce Smaill for their advice and support, and Christine Rosendaie for preparation of the manuscript.

References Angel A (1977): Processing of sensory information. Prog Neurobiol 9:1-122.

Fink M (1980): A neuroendocrine theory of convulsive therapy. Trends Neurosci 3:25-27.

Angelo R, Moiler AR (1990): Responses from the inferior colliculus in the rat to tone bursts and amplitude-modulated continuous tones. Audiology 29:336-346.

Fraser M (1982): ECT: A Clinical Guide. Chichester, England: John Wiley.

Crowe RR (1984): Electroconvulsive therapy--A current perspective. N Engl J Med 311 : 163-167.

Funai H, Funasaka S (1983): Experimental study on the effects of inferior colliculus lesions upon auditory brain stem response. Audiology 22:9-19.

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Hall JW (1992): Handbook of Auditory Evoked Responses. Boston: Allyn and Bacon. Kasprow WJ, Schachtman TR, Miller RR (1985): A retrograde gradient for disruption of a conditioned aversion to drinking cold water by ECS administered during the CS-US interval. Physiol Behav 34:879-882. Penfield W, Jasper H (1954): Epilepsy and the Functional Anatomy of the Human Brain. Boston: Little, Brown and Co. Potter WZ, Rudorfer MV (1993): Electroconvulsive therapy--A modem medical procedure. N Engl J Med 328:882-883. Shapiro SM, Moiler AR, Shiu GK (1984): Brain-stem auditory evoked potentials in rats with high-dose pentobarbital. Electroencephalogr Clin Neurophysiol 58:266-276. Shaw NA (1985): Effect of electroconvulsive shock on the somatosensory evoked potential in the rat. Exp Neurol 90: 566 -579. Shaw NA (1986a): The effects of electroconvulsive shock on the brain stem auditory evoked potential in the rat. Biol Psychiatry 21:1327-1331.

Brief Reports

Shaw NA (1986b): The effect of pentobarbital on the auditory evoked response in the brainstem of the rat. Neuropharmacology 25:63-69. Shaw NA (1988): Effect of electroconvulsive shock on the slow components of the brain stem auditory evoked potential. Exp Neurol 100:242-247. Shaw NA (1993): Auditory evoked potentials recorded from different skull locations in the rat. Int J Neurosci 70:277-283. Small JG, Milstein V, Kellams JJ, Small IF (1981): Auditory brain stem evoked responses in hospitalized patients undergoing drug treatment or ECT. Biol Psychiatry 16:287-290. Weiner RD (1984): Does electroconvulsive therapy cause brain damage? Behav Brain Sci 7:1-53. Weiner RD, Erwin CW, Weber BA (1981): Acute effects of electroconvulsive therapy on brainstem auditory-evoked potentials. Electroencephalogr Clin Neurophysiol 52:202-204.