Middle- and long-latency auditory evoked responses recorded from the vertex of normal and chronically lesioned cats

Brain Research, 205 (1981) 91-109 © Elsevier/North-Holland Biomedical Press

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M I D D L E - A N D L O N G - L A T E N C Y A U D I T O R Y E V O K E D RESPONSES R E C O R D E D F R O M T H E V E R T E X OF N O R M A L A N D C H R O N I C A L L Y L E S I O N E D CATS

J. S. BUCHWALD, C. HINMAN, R. J. NORMAN, C.-M. HUANG and K. A. BROWN Department of Physiology, Mental Retardation Research Center, Brain Research Institute, School o f Medicine, University of CaliJbrnia, Los Angeles, Calif. 90024 (U.S.A.)

(Accepted January 3rd, 1980) Key words: middle-andlong-latencyauditoryevokedresponses--normallesionedcats--chronically lesioned cats

SUMMARY A prolonged sequence of auditory evoked potentials with latencies ranging from 1 to 250 msec was recorded f r o m the vertex of the awake restrained cat. This sequence was reproduceable within and across subjects and was not altered by complete neuromuscular paralysis. The effects of click rate, pentobarbital, and chronic lesions of a number of different brain areas were evaluated for each of the potentials. Vertex waves 1-5, previously shown to originate from generators in the primary auditory pathway of the brain stem, were followed by smaller and less well defined waves 6 and 7, with peak latencies in the 6-8 msec and 10-12 msec range respectively. These potentials were not abolished by fast click rates (i.e. up to 50/sec) nor by moderate levels of pentobarbital. Correlative extra- and intracranial studies indicated that wave 6 occurred in the same latency range as the medial geniculate body, pars principalis potential, and that wave 7 occurred in the same latency range as the primary ectosylvian cortical potential. The intracranial potentials showed click recovery functions and barbiturate resistance which were similar to those of waves 6 and 7, and wave 7 disappeared following aspiration of ectosylvian cortex. These data suggest that waves 6 and 7 reflect generators in medial geniculate body and ectosylvian gyrus. In contrast to the stability of potentials 1 through 7, the longer latency waves were relatively unstable. Wave A occurred in a latency range of 17-25 msec, wave B, 35-45 msec, wave C, 50-75 msec, and wave D, 150-200 msec. All of these waves showed marked amplitude fluctuations, disappeared as click rates increased to 10/sec, and were abolished by moderate levels of pentobarbital. After bilateral aspiration of middle suprasylvian gyrus, ectosylvian gyrus, or frontal lobes, wave A continued to appear. After hemispherectomy, which removed all cortex, basal ganglia and limbic

92 lobes, wave A was not abolished and appeared enhanced in one animal. Thus, the generator system of wave A appears to be largely independent of auditory cortex and adjacent association cortex, but may be modulated by other forebrain systems. Wave C continued to appear after aspiration of suprasylvian and ectosylvian gyri and after frontal lobectomy, but disappeared after hemispherectomy. Thus, wave C reflects a generator system which differs from that of wave A, but which also appears to be largely independent of the primary geniculo-cortical auditory pathway. These data suggest the following conclusions: waves 1 through 7, which show high fidelity, rate-resistant, barbiturate-insensitive acoustic transmission, appear to reflect activation of the primary auditory system from acoustic nerve to auditory cortex. Subsequent, longer-latency vertex potentials seem to be generated through other forebrain systems which receive auditory information in parallel from the brain stem, rather than serially from the primary geniculo-cortical pathway and association cortex relays. The relevance of data in the cat model to the human vertex potentials is discussed.

INTRODUCTION In response to acoustic stimuli, a prolonged series of evoked potentials can be recorded from the vertex of the awake human subject 12,29,36. These potentials, which extend from 1 to more than 250 msec after cessation of the acoustic signal, suggest that in addition to the rapid activation of primary sensory relays, slower brain circuits are also consistently brought into play as acoustic information is centrally processed. Insofar as these evoked potentials indicate discrete events in the total acoustic response, they provide probes of brain centers or systems which are involved in different aspects of hearing. For example, significant correlations occur between the amplitude of the N1-P2 evoked potentials and attention to the auditory signal 2s. Two hypotheses have been advanced regarding the origins of the human long-latency potentials based primarily on surface mapping studies. One postulates that auditory vertex potentials in the 10-200 msec latency range reflect protracted activation of primary auditory cortex, with subsequent diffuse activation of association cortex reflected in even longer latency responses 44. A contrasting hypothesis holds that responses in the 10-25 msec range reflect direct activation of primary auditory cortex, whereas later potentials reflect more diffuse activation through some parallel projection system, e.g. rostral reticular formation to medial thalamus to association cortex24,29,37. In previous studies, it has been shown that the short-latency auditory vertex potentials, i.e. those occurring within 6-7 msec, are similar in cat and human in terms of latency, stability, parametric functions of rate and intensity, and brain stem origin 6,13,15,16,19,21,22,25,29,31,4°. Correlative extracranial and intracranial experiments in the cat suggest that each response reflects a major, although not necessarily sole, anatomical generatorl,6,2x,25,30, 34 and that all of these responses reflect a neuronal sub-type characterized by high response fidelity and a short recovery time constant 2°.

93 The objective of the present study was to define the sequence of longer-latency auditory evoked potentials which can be consistently recorded from the vertex of the awake, restrained cat and to characterize each of the responses in terms of stability, recovery cycle, barbiturate sensitivity, and neuroanatomical substrate. More specifically, we sought to determine whether there is a functional grouping of the vertex potentials along parametric dimensions and whether the longer-latency potentials occur in series or in parallel with activation of the primary auditory cortex. MATERIALS AND METHODS Middle- and long-latency evoked responses were studied in 28 unanesthetized adult cats. All cats behaviorally oriented to auditory stimuli, and otoscopic examination indicated normal external ear canals. Prior to recording, a head mount was implanted on the skull. Animals were anesthetized with 35 mg/kg sodium pentobarbital, placed in a stereotaxic head-holder and the skull was bared. A stainless-steel screw (size 2-56) was implanted at ATa just lateral to the midline (the 'vertex' electrode) and 3 linked screws were embedded in dental cement in the frontal sinus. In addition, a screw overlying the primary auditory cortex of the middle ectosylvian gyrus (A9, L15) was implanted in 3 cats. Leads from the screws were terminated in a small connector mounted on the skull. Eight animals in which depth recordings were to be carried out were additionally outfitted with a skull-well overlying the medial geniculate body which was covered by a removable Teflon shield. On all cats, two aluminum sleeves were stereotactically mounted in cement on the front and back of the skull to hold the head motionless during recording sessions and to provide stereotaxic orientation for depth recordings in the awake cat. The animals were given one week to recover from this surgical procedure before recordings commenced. At the time of recording, the cat was fastened securely in a canvas bag to prevent excessive movement. Stereotactically oriented bars, which projected medially from the stereotaxic frame, were screwed into the implanted skull sleeves to immobilize the head. All recordings were carried out in a sound isolation chamber (Industrial Acoustics) with the cat positioned at a fixed location within the chamber and the sound source at a constant 15 cm in front of the nose. Acoustic stimuli consisted of 0.1 msec square wave clicks delivered through a Shure (Model 533 SA) microphone driven as a speaker. This acoustic output was calibrated with a Bruel and Kjaer (Model 4144) condensor microphone located 15 cm from the sound source in the same free field as that used experimentally. The peak to peak amplitude value of this acoustic output, recorded through the calibrated condensor microphone, converted to 80 dB SPL. Activity was led from the vertex screw referenced to the paw, neck, pinna or frontal sinus and differentially recorded through a Grass P511 amplifier (10-3000 Hz filter settings) with 100 kDalton amplification. Depth recordings through the same system were made with a concentric electrode (30-gauge stainless-steel wire within 21gauge stainless-steel tubing) stereotacticaUy lowered to the medial geniculate body, pars principalis, with barrel to wire and barrel to pinna reference configurations. The

94 amplified potentials were averaged on-line with a DEC PDP 11-10 computer or recorded at 7½ IPS on an Ampex 1300 FM tape recorder for bter analysis. Responses were averaged in 25 trial blocks over a 50 trial procedure, with alternate trials comprising each average. Superimposition of these plots provided an index of waveform repeatability., A 250 msec sampling period was used. One thousand sampled points were distributed non-linearly through the interval with an initial interval of 40 #sec and an exponentially increasing interval between successive points. EEG activity was continuously monitored and behavioral observations were made through a one-way glass on the door of the recording chamber. After 2-3 initial periods of habituation, the cats were quiet but awake with desynchronized EEG activity in all sessions reported. A number of recording configurations were used to determine the relative neutrality of various 'reference' sites. A forepaw electrode referenced to the tail recorded no evoked potentials although large E K G artifacts were present. When the forepaw electrode was referenced to a neck or pinna electrode no evoked potentials were recorded although E M G activity often occurred (Fig. 1C). The forepaw electrode recorded against frontal sinus resulted in small or no evoked potentials. Thus, relatively neutral reference sites were tail, forepaw, neck, pinna, and, to a lesser extent, frontal sinus. The vertex electrode referenced to any of these locations resulted in a clearly defined sequence of auditory evoked responses. In all recordings reported, the vertex electrode was referenced to pinna or frontal sinus. In some animals, a chronic tracheal fistula was established to permit repeated artificial respiration during recordings under neuromuscular paralysis, a procedure described in detail elsewhere 5. Following intraperitoneal injection of gallamine triethicdide (Flaxedil, 10 mg/kg), complete paralysis was indicated by absence of eyeblink and loss of respiration. The animal was artificially respired at a rate of 18 strokes/min using a tidal volume which maintained the pupils at a 2-3 mm diameter with brisk dilation to an arousal stimulus. These recording sessions were completed within one hour of initial paralysis; usually the animal was off the respirator and breathing normally within 4 h following Flaxedil injection. In other sessions, sodium pentobarbital was injected intraperitoneally (35 mg/kg) and recordings were carried out under surgical levels of anesthesia, i.e. after withdrawal reflexes disappeared. All lesion surgery subsequent to the initial series of recordings was carried out under pentobarbital anesthesia (35 mg/kg) with aseptic procedures. Hemispherectomies were performed in 3 cats. Both cerebral hemispheres were separated from the thalamus at the level of the internal capsule using suction and blunt dissection. The middle cerebral artery was ligated and the entire hemisphere removed. A more detailed description of the surgical procedure, post-operative nursing care, and the general behavior of this chronic preparation has been published elsewhere ~6. Subpial aspiration of auditory cortex in the middle ectosylvian gyrus (areas AI, AII and EP) was carried out bilaterally in 3 cats. Aspiration of auditory association cortex in the middle suprasylvian gyrus42 was carried out bilaterally in 2 cats. Bilateral aspiration of the inferior colliculus was carried out in 2 cats. A posterior approach was utilized with midline aspiration of the rostral portion of the

95 cerebellar vermis until the inferior colliculi could be visualized and then aspirated. In 2 additional cats, only the vermal region of the cerebellum was aspirated as a control procedure. All groups were maintained for a prolonged post-operative period which ranged from a few weeks to more than one year. Recordings were made throughout the survival time. The animals were killed with an overdose of pentobarbital and immediately perfused with 1 0 ~ buffered formalin. The brains were embedded in gelatin and 80 # m sections were cut and stained with cresyl violet. Reconstructions of the lesions were made by projecting slides containing the area of lesion onto appropriate brain atlas section. Depth recording loci were identified by plotting the electrode tracks and recording sites on relevant brain atlas sections. RESULTS

Normative data In the quiet but unanesthetized, waking cat, click stimulation produced a prolonged series of auditory evoked potentials which were repeatedly recorded from the vertex. The first 5 waves occurred within 7 msec. These waves, termed the auditory brain stem responses (ABRs), reflect generator loci in the primary auditory pathway from the level of the acoustic nerve to inferior colliculusl,6,21,25,30, 34. Subsequent to

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The initial 5 ABR waves were followed by additional positive components within the latency range of 6-12 msec. A positive peak at 6-8 msec, wave 6 in Fig. 1, was followed by a less clearly resolved peak at 19-12 msec, wave 7. Earlier studies indicated that only waves 1-5 remained after mid-collicular decerebration 6. We were interested, therefore, in correlating waves 6 and 7 with forebrain levels of the primary auditory pathway. Recordings of local evoked responses were made from medial geniculate body, pars principalis, and middle ectosylvian gyrus in 8 animals concurrently with vertex recordings (Fig. 2). The peak latency range of both the pars principalis and wave 6 potentials was 6-8 msec, while the peak latency range of both the middle ectosylvian cortex and wave 7 potentials was 10 to 12 msec. Click rates of 5/sec and slower produced little change in the amplitude of waves 6 and 7. At 10-20/sec moderate decrements occurred but neither wave 6 or 7 was abolished until click rates exceeded 50/sec. Concurrent recordings from the pars principalis and ectosylvian cortex showed parallel clik rate effects (Fig. 2). In summary, evoked potentials locally recorded from the medial geniculate body, pars principalis, and middle ectosylvian gyrus showed the same latency ranges as waves 6 and 7 recorded from the vertex and all of these potentials followed click rates up to 20/sec with only moderate changes in amplitude.

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Longer-latency vertex potentials Wave A. Wave A appeared as a relatively broad positive potential, usually emerging from a preceding negativity, with a peak latency range of 17-25 msec (Fig. 1). Often wave A was followed by a large negative trough. In contrast to the shorterlatency potentials, wave A showed frequent amplitude fluctuations. It often, but not invariably, increased when the chamber door was opened and the cat spoken to. Wave B. Usually emerging from the negative trough subsequent to wave A, wave B occurred infrequently as a positive wave with a peak latency between 35 and 45 msec

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(Fig. 1). Wave B was considerably more erratic than wave A a n d was often absent o n one day b u t present o n another. Wave C. A p p e a r i n g as a b r o a d positivity, usually larger in a m p l i t u d e t h a n wave A or B, wave C showed a peak latency in the 50-75 msec range (Fig. 1). Wave C was the

99 most uniformly present of the longer-latency potentials; it was observed in all cats studied and only rarely was it missing on any particular day. Wave D. Much less consistent than waves A and C, wave D appeared as a large, long duration positivity at 150 to 200 msec (Fig. 1).

EfJects of click rate All of the longer-latency potentials showed marked amplitude decrements as click rates increased from 1/sec to 5/sec (Fig. 3). At rates of 10/sec these potentials disappeared, in contrast to the ABRs and waves 6 and 7. Effects of neuromuscular paralysis In order to determine whether the sequence of vertex potentials contained E M G components, recording sessions were carried out in 6 animals before and during neuromuscular paralysis. All of the potentials described above were observed during complete paralysis, as well as in the unparalyzed state (Figs. 1B, 5). VERTEX 4

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Fig. 5. Effects of primary auditory cortex and association cortex aspiration on vertex-evoked responses. During complete neuromuscular paralysis (+op trace) the potentials were essentially unchanged from their appearance in the awake, restrained cat. During pentobarbital anesthesia (second trace) wave 7 showed a transient increase and a large negative trough replaced wave A. These effects disappeared when the animal recovered from the drug and the potentials again resembled the top trace. During the week following aspiration of suprasylvian cortex (cross-hatched area on diagram) wave 7 showed persistent enhancement and both waves A and C were present (third trace, 6 days post-operative). Following subsequent aspiration of ectosylvian cortex (striped area, with fringe damage indicated by stipples), wave 7 disappeared while waves A and C continued to be present (fourth trace, 7 days postoperative).

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Effects of pentobarbital In most animals a series of recordings was made which commenced soon after barbiturate injection (35 mg/kg i.p.) and continued until no reflex paw withdrawal occurred. Waves 6 and 7 showed no consistent change in latency or amplitude. In contrast, the longer latency waves rapidly diminished under light anesthesia and disappeared prior to surgical levels, yielding a deep negative trough at 17-25 msec (Fig. 4).

Lesion data A number of lesion procedures were carried out to determine which brain regions or systems were most relevant to the potentials just described. Because waves B and D were so inconstant in the normal animal, they will not be discussed with these lesion data.

Cortical aspirations Suprasylvian gyrus. Aspiration of the middle and ventral aspects of the suprasylvian gyrus was carried out bilaterally in two eats. Brain histology in both animals indicated complete loss of cortex from the surface of the middle suprasylvian gyrus; cortical remnants were inconsistently present in the depths of the surrounding sulci. Recordings from both animals made over a 6 day post-operative period indicated a marked increase in the amplitude of wave 7 whereas waves A and C appeared unchanged from their pre-operative condition (Fig. 5). Thus, neither wave A nor C required suprasylvian cortex while wave 7 appeared enhanced as a consequence of its aspiration.

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Ectosylvian gyrus. One week after r e m o v a l o f s u p r a s y l v i a n cortex a s e c o n d a s p i r a t i o n p r o c e d u r e was carried out on the two cats discussed above. T h e cortex o f the ectosylvian gyrus, including areas A I , E P and the u p p e r p a r t o f A l l , was a l m o s t totally r e m o v e d bilaterally in b o t h a n i m a l s ; cortical r e m n a n t s r e m a i n e d in the ectosylvian sulcus. R e c o r d i n g s over a two week p o s t - o p e r a t i v e p e r i o d showed s i m i l a r results in b o t h animals. The p r e v i o u s l y e n h a n c e d wave 7 was a b o l i s h e d (Fig. 5). I n contrast, waves A a n d C c o n t i n u e d to a p p e a r in the a p p r o p r i a t e latency zones (Fig. 5). These o b s e r v a t i o n s were confirmed in a t h i r d a n i m a l in which areas A I , EP a n d m o s t o f A I I were a s p i r a t e d bilaterally. Both waves A a n d C c o n t i n u e d to be r e c o r d e d over a two week p o s t - o p e r a t i v e p e r i o d a l t h o u g h wave 7 d i s a p p e a r e d . These d a t a i n d i c a t e d t h a t a u d i t o r y cortex was essential for wave 7 b u t n o t for waves A o r C.

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Fig. 8. Effects of inferior colliculus aspiration on the vertex potentials. Tissue removed by aspiration indicated by striped areas on the diagram. All of the inferior colliculus caudal to level P 2.58 and most of the central nucleus rostral to this level were completely removed. Recordings 6 days after collicular aspiration compared with the pre-operative vertex responses showed no change in waves A or C.

Frontal lobectomy Since frontal cortex has been implicated in the generation of long-latency evoked potentials zS, the frontal lobes were bilaterally removed in one animal. Post-mortem examination indicated that no tissue remained rostral to the level of the cruciate sulcus and sigmoid gyrus (Fig. 6). Recordings over a two week post-operative period showed that both waves A and C remained essentially unchanged f r o m their pre-operative appearance (Fig. 6).

Hemispherectomy Because neither wave A nor C was abolished by aspiration of primary auditory cortex, suprasylvian association cortex, or frontal lobes, more radical surgery was subsequently carried out. The cerebral hemispheres, including all the cortex, the limbic lobes, and basal ganglia, were bilaterally removed in 3 cats. No tissue rostral to the diencephalon remained and post-mortem histology indicated extensive retrograde degeneration in the primary sensory nuclei of the thalamus. Post-operative recordings were made over a period of 6 months to one year. None of the animals showed consistent evoked potentials at latencies longer than 25 msec. In contrast, a large positive potential was observed in the 15-25 msec latency range in all the animals and was extremely prominent in one animal (Fig. 7).

103 In order to compare this potential to wave A, which in intact cats appeared in this same latency zone, the parametric procedures used to characterize wave A were repeated. The potential showed a marked decrease in amplitude at click rates faster than l/sec (Fig. 7). When the hemispherectomized animal was briefly aroused, the amplitude of the wave increased, while under pentobarbital (35 mg/kg) it completely disappeared (Fig. 7). In these parametric dimensions, i.e. click rate, arousal, and barbiturate effects, the large positive wave showed changes that were identical to those of wave A in the intact cat. These data suggest that wave C but not wave A is dependent upon a system primarily within the cerebral hemispheres, insofar as wave C but not wave A disappeared following hemispherectomy. Components within the hemispheres may also importantly influence wave A; indeed, the abnormally large amplitude of the potential in one of the hemispherectomized animals suggests that suppression of the wave A system may normally occur.

Inferior colliculus aspiration Since wave A persisted even after bilateral removal of the cerebral hemispheres, with subsequent extensive retrograde degeneration in the medial geniculate body, additional aspiration procedures were carried out to determine whether the inferior colliculus was essential for wave*A, either by projecting to a non-geniculate,"e.g.

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Fig. 9. Effects of inferior colliculus aspiration on the vertex potentials. Tissue removed by aspiration is indicated by striped areas on the diagrams. All of the inferior colliculus caudal to level P1 a and most of the colliculus rostral to this level was completely removed. A small bridge of tissue between the colliculus and medial geniculate body remained intact on the right. Eight days after collicular aspiration waves A and C continued to be recorded and showed characteristic decrements as the click rate increased to 5/sec.

104 tegmental, generator system or by providing an intrinsic collicular system of wave A generation. Bilateral aspiration of the inferior colliculus was carried out in two cats. In one animal, most of the central nucleus was aspirated bilaterally although a small medial and ventro-lateral portion remained intact. Post-operative recordings from this animal were carried out over a 2 week period (Fig. 8). Waves A and C were essentially unchanged from their pre-operative appearance, indicating that neither wave required the central nucleus. In a second cat, a more extensive aspiration included the collicular commissure, central nucleus, and most of the external nucleus (Fig. 9). On the left, the brachium of the colliculus was aspirated up to the medial geniculate body. On the right, a fragment of the external nucleus, the ventrolateral central nucleus and most of the brachium were spared. In the right medial geniculate body, a small potential with a peak latency of 7 msec was recorded as the electrode passed into the pars principalis, indicating that some collicular-geniculate transmission persisted. On the left side no potentials were recorded at comparable geniculate sites. Vertex potentials from this cat were recorded over a 2 week post-operative period (Fig. 9). Waves A and C were less consistent than in the intact cat, but both showed normal latencies and rate effects. This result suggests that a brain stem outflow other than the collicular projections to the medial geniculate body, pars principalis, may be important for the generation of waves A and C.

Cerebellar vermis aspiration As a control procedure for the inferior colliculus experiments, the anterior portion of the cerebellar vermis was aspirated in two cats. This duplicated the cerebellar damage which occurred in the posterior approach used to visualize the inferior colliculi. Over a two week post-operative recording period, the vertex potentials showed no change from their pre-operative appearance. DISCUSSION Data obtained in this study show that a prolonged series of evoked potentials can be recorded from the vertex of the awake, restrained cat which in a general way resembles the sequence of vertex potentials recorded from the awake human subject. In both cases it is clear that the shorter-latency potentials are stable, highly consistent events in contrast to the unpredictable amplitude and latency fluctuations typical of the longer latency responses. In the cat, the auditory brain stem responses, waves 1-5, and waves 6 and 7 occurred within 15 msec after click stimulation. While the definition of vertex waves 6 and 7 was less sharp than that of waves 1-5, the entire sequence could be recorded as a relatively consistent pattern in any one subject. As was true for waves 1-5, waves 6 and 7 showed short recovery time constants with little response degradation until click rates exceeded 10/sec. All 7 waves persisted with minimal changes in amplitude and latency during barbiturate anesthesia. The origins of waves 6 and 7 are suggested from a variety of data in this and

105 other studies. Our correlative extracranial and intracranial recordings indicated that both the latency and parametric characteristics of vertex wave 7 were mirrored in the 10-12 msec potentials of the auditory cortex. In other studies, potentials recorded from auditory cortex with these latencies were considered locally generated as they disappeared following lesions at the electrode site44 and reversed with depth recording 7. The present results indicated that vertex wave 7 was abolished by aspiration of the ectosylvian gyrus (Fig. 5). Taken together these data suggest that direct activation of primary auditory cortex in the awake cat results in a large amplitude 10-12 msec evoked potential which is volume-conducted to the vertex as the small and often poorly defined wave 7. The 6-8 msec vertex response recorded in the present study as wave 6 has been noted in other extracranial recordings from the awake cat with more laterally placed electrodes 7. Its latency is similar to that previously reported for medial geniculate body primary evoked potentials14, z2 as well as for medial geniculate unit responses in the unanesthetized catZ,aL Our correlative recordings from vertex and medial geniculate body indicated that the maximal amplitude pars principalis reversal potential also had a 6-8 msec latency and showed the same parametric characteristics as did wave 6. Following complete transection of the brain stem just rostral to the inferior colliculus, wave 6 was not recorded (nor were any of the subsequent vertex potentials)% These data suggest that wave 6 largely reflects volume conducted activation of the medial geniculate body, pars principalis. Overall, waves 1-7 in the cat appear to reflect high-fidelity, rate-resistant, barbiturate-insensitive acoustic transmission mediated by the primary auditory system from acoustic nerve to primary auditory cortex. This sequence is similar to the human vertex sequence which extends through wave P0. Wave P0 and the shorter latency human vertex waves I, II, III, IV, V, VI and VII, are stable during fluctuations in attention 2s and arousal22, z7 and are markedly more resistant to fast click rates than are the longer-latency vertex potentials13,15,27,29, zl. On the basis of verified brain lesions, human vertex potentials I through V are generally considered to reflect generators within the pontine-midbrain auditory pathway ~9,4°, with the IV-V complex in the human believed to correspond to wave 4 in the cat zs, while waves VI and VII are associated with upper midbrain and thalamic levels of generation 4°,43. Wave P0 occurs with a peak latency in the 12-13 msec range 28,29, which is similar to the latency of evoked potentials recorded directly from the primary auditory area (AI) of human patients during surgery under local anesthesia%lO, 3a. These cortical potentials show stable morphology and similar latencies and waveforms across subjects 9,~0,33. Insofar as experimental data in the present study strongly suggest that the cat vertex wave 7 reflects the auditory cortex primary evoked potential, the human vertex wave P0 may also primarily reflect the AI cortical response. Thus, as reflections of pontine-midbrain activation, the I through VI sequence in the human would appear to be comparable to the I through V sequence in the cat. If waves VII and P0 in human reflect primary thalamo-cortical auditory activation, they would then be generally comparable to waves 6 and 7 in the cat. In contrast to the stability of waves 1-7 in the awake cat, our data indicated that

106 the longer-latency waves were relatively unstable within and across subjects, and showed marked amplitude fluctuations which could not be related to any obvious environmental factors. Under complete neuromuscular paralysis the vertex potentials appeared no different than in the non-paralyzed animals, so that the variability of the longer latency components could not be attributed to waxing and waning muscle potentials. Moderate levels of barbiturate anesthesia further differentiated the series of potentials subsequent to wave 7 from the earlier potentials. All of the later positive potentials disappeared and were superceded by a large amplitude, broad negative through with a peak latency around 20 msec. In previous studies of potentials recorded from auditory cortex of the awake cat, a positive potential with 15-28 msec peak latency was found to follow the primary 11-14 msec cortical potential 7,23,41. The shorter-latency primary cortical response was stable 11,~3,41,47, and only moderately affected by click rates of 5-10/sec 11,41,47, or barbiturate anesthesia7, 23, while the longer-latency 15-28 msec positivity was quite variable in the awake cat7,23,41 and disappeared under barbiturate anesthesia 7,23, or with 5-10/sec clicks41. After ectosylvian cortical lesions sufficient to abolish the primary response, the 15-28 msec response remained 41. Our data appear to extend these results insofar as wave A, with the same latency range and parametric characteristics as the later 'cortical' potential, did not disappear after removal of ectosylvian cortex, after aspiration of suprasylvian association cortex, or after hemispherectomy with complete loss of cortex, basal ganglia and limbic lobes. Correlative extracranial and intracranial recordings of wave A and related depth responses in the awake cat have suggested that this generator system extends as a restricted pathway through the medial-rostral midbrain reticular formation to the intralaminar thalamic nuclei centralis lateralis and centre medianum4,17, ~s. Evoked potential and single unit responses occur in this pathway in the same 17-25 msec latency range as that of wave A, and show the same parametric effects of barbiturate and click rate ~7. Thus, wave A appears to reflect a reticulo-thalamic system of auditory information processing which is largely independent of primary auditory cortex and adjacent association cortex, but which may be modulated by other forebrain systems. In the human sequence of vertex potentials, wave Pa appears as a positive peak in the 25-35 msec range~6, 29. In patients under local anesthesia a small positivity with this latency range has been recorded from the posterior superior temporal gyrus and parietal and frontal operculumS,9, in contrast to the earlier 13-16 msec potentials recorded from auditory cortex (AI)9,10, 33 with the latency range of P026,29. Moreover, responses in the 25-35 msec latency range continued to be recorded from surface electrodes after complete removal of the transverse temporal gyri of Heschl 7. These data suggest certain similarities between wave Pa in the human and wave A in the cat. Additional studies are clearly needed to test the hypothesis of a similar generator system for these waves in cat and human. While wave A in the cat was not abolished following hemispherectomy, wave C disappeared and showed no clear recovery over post-operative periods of 6-12 months. Thus, wave C appears to reflect a generator system which differs from that of

107 wave A. On the other hand, wave C did n o t require intact auditory or suprasylvian association cortex and therefore appears to reflect an additional auditory processing system in parallel with the primary thalamo-cortical pathway. In the h u m a n , wave P1 shows a latency range o f 50-70 msec12, 29 and a marked sensitivity to fast click rates 29, both of which are characteristic o f wave C. The extent to which these waves share additional parametric features requires further investigation. I n summary, the middle- and long-latency vertex potentials in the awake cat seem to be generated differentially t h r o u g h several forebrain systems which receive auditory information in parallel f r o m the brain stem, rather than serially f r o m the primary thalamo-cortical pathway t h r o u g h association cortex relays. The parametric separation o f the early, middle- and long-latency potentials and their general similarity to the sequence recorded in h u m a n suggest that the cat model m a y provide a valuable tool for further assessment o f the prolonged series o f events in central auditory processing, b o t h in terms o f anatomical origins and functional significance. ACKNOWLEDGEMENT This work was supported by U S P H S Grants MH24344, H D 05958 and HD04612.

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