Adaptation of evoked auditory potentials: A midbrain through frontal lobe map in the unanesthetized cat

BRAIN RESEARCH

121

A D A P T A T I O N OF E V O K E D A U D I T O R Y P O T E N T I A L S : A M I D B R A 1 N T H R O U G H F R O N T A L LOBE M A P IN T H E U N A N E S T H E T I Z E D CAT

S. L. JAFFE*, P. F. BOURLIER ANDW. D. HAGAMEN Department of Anatomy, Cornell University Medical College, New York, N. 1I. (U.S.A.)

(Accepted March 12th, 1969)

INTRODUCTION A decrement in amplitude of evoked potentials during acoustic habituation to a repeated click or short tone has been observed in the auditory cortex and direct auditory projection system 1,a--a,7,s,l°-12,1a,t6,18-2a,26. This response has also been recorded from certain structures outside of the direct auditory pathway 7,s,13,19,2°. In most of these experiments, a significant decrement in amplitude was reported only after hours or days of repetitive stimulation. However, in some studies, this decrement was noted to occur very rapidlyl,4,5,1o, 13,1s,19,26. Although most investigators chose stimulus rates of 1/sec or slower, rates as high as 10 and 80/sec were used18, 26. Both the terms adaptation and habituation have been used to denote the decrease in amplitude of evoked potentials during repetitive stimulation. We have referred to this decrement in amplitude as adaptation, using habituation to describe only the behavioral event. This distinction is not purely arbitrary since amplitudes have also been observed to increase during acoustic habituation 20. It should be noted that adaptation as described here is considered a result of central integration, and is to be differentiated from adaptation resulting from electrochemical 'fatigue'. Since the experimental conditions used in previous investigations varied, we believed that a thorough exploration of the brain with detailed characterization of the adaptation phenomenon was the necessary next step in elucidating the electrophysiological mechanism underlying auditory habituation. Since habituation as evidenced by the disappearance of orienting responses can occur after a few clicks, adaptation occurring after a comparable number of stimuli should be the significant electrical event 21. Dunlop et al. 4 and Webster et al. 26 observed that the greatest change in amplitude occurred within the 1st rain of stimulation and that this de-

* Present address: Department of Neurology, University of Virginia School of Medicine, Charlottesville, Va., U.S.A. Brain Research, 15 (1969) 121-136

crement was most pronounced at their highest repetition rate (10/sec). In the present study stimulus rates of 1, 2, 5, 10, 20/sec were used, and attention was focused on adaptation occurring within the first 60 sec of stimulation. METHODS

Twenty adult cats were used in this study. Routine post-mortem examination revealed severe otitis media in one cat and massive intracerebral bleeding in another. Therefore, data on only 18 cats was analyzed. In each experiment, the animal was first anesthetized intravenously with sodium pentobarbital. A spinal transccnon (C7-C8) and a craniotomy were performed under asepnc conditions. The cervical incision was permanently sutured, and the craniotomy incision was closed temporarily with Michel clips. The cat was allowed to recover for at least 24 h from the effects of anesthesia and surgery. At the end of this period, anesthesia was induced by a single intravenous injection of 1.5 ml of a 2.5% solution of sodium thiopental. The animal was then placed in the Horsley-Clarke apparatus, points of pressure having been infiltrated with lidocaine to avoid painful stimuli, Recording was begun 2 h after the thiopental was administered. Concentric bipolar stainless steel electrodes were used. These consisted of a 20 gauge outer barrel and 28 gauge inner barrel with the tip protruding I ram. Electrode impedance was approximately 50,000 ~2. Electrodes were connected to an Offner Type R Dynograph. Preamplifier and amplifier settings were 0.5 mV/cm and × 0.02 respectively. Click stimuli generated by an electrical square wave of 0.2 msec duration were delivered simultaneously by 6 ~2 Argonne 408 earphones attached to hollow ear bars. The click intensity at the ear bar outlet was 60 db. Recordings were made at each point using stimulus rates of 1,2, 5. 10 and 20 clicks'sec. After piercing the pia, the tip of the electrode was maneuvered to a point just within the cortical substance. This vertical coordinate was recorded and testing was begun. The electrode was advanced in 1 mm steps and withdrawn when within 1-2 mm of the ventral surface of the brain. Exploration extended from P2 to A21 and from the midline to 12 mm lateral to the midline. However, in any one cat electrode paths were separated by at least 4 mm. At the completion of testing, the cat was deeply anesthetized with an intravenous injection of sodium pentobarbital. Small electrolytic lesions were made in order to determine dorsoventral shrinkage due to dehydration. The animal was then perfused with isotonic saline followed by 10~o formalin. The brain was embedded in celtoidin and serially sectioned to allow localization of the electrode paths. Sections were stained alternately by Weil and Nissl methods. The position of each point tested was calculated by using the previously noted vertical coordinates of the top of the cortex. the bottom of the electrode path, and the site of the electrolytic lesion. These points were then replotted on tracings of histological sections, 1 mm apart, of a standard cat brain which has served as our stereotaxic atlas z2. From these sections, the composite version appearing in Figs. 2-15 was produced. Every point in these figures was plotted within the anatomic structure where it had been found originally, even Brain Research, 15 (1969) 121- 136

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Brain Research, 15 (1969) 121-136

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though this might have necessitated a slight change in the remaining two stereotaxic coordinates. RESULTS

There were 4628 points tested. Evoked auditory potentials were recorded from 1134. At 333 points, the potentials did not adapt at any of the repetition rates (Fig. IA). At 411 points, there was paltial adaptation, i.e., the amplitude of the evoked potentials decreased initially with subsequent potentials remaining constant at the lower amplitude level. At 390 points, the adaptation was complete, i.e., the evoked potentials disappeared within 60 sec. Two types of partial adaptation were recognized (Figs. 1B and C). In B the amplitude decrement is gradual. In C, there is an abrupt decrease in amplitude after the first evoked potential. When both patterns were recorded from the same point, the abrupt type occurred at the more rapid stimulus rates. Two types of complete adaptation were recognized (Figs. I D and El). In D, the evoked potential becomes indistinguishable from the background activity following a gradual fall in amplitude. In E, only the first stimulus produces a distinguishable potential. Both Et and E,_, are examples of complete adaptation occurring abruptly and have been recorded from the same point although the rates of stimulation are different (t0/sec and 20/sec respectively). The phenomenon illustrated in Fig. 1F appears closely related to complete adaptation and has been included in this category for the brain sections, Figs. 2-15. Although potentials were evoked at a low stimulus repetition rate (F1), not even an initial potential was observed (F2) at higher rates tested at the same point. Thus this phenomenon appeared dependent upon an increase in the frequency of stimulation. Moreover, evoked potentials always disappeared at the high click repetition rates (10 and 20/sec), and the potentials present at the lower repetition rates demonstrated complete adaptation patterns as in Figs. 1D or E. Generally, an increase in the stimulus repetition rate was accompanied by more pronounced adaptation, i.e., greater amplitude decrement after a fewer number of clicks. In most structures where adaptation occurred, one of the following sequences could be observed at a single point: no adaptation to partial adaptation; or partial to complete adaptation; or no adaptation, to partial, to complete adaptation. For example in the anteromedial caudate, no adaptation was recorded at I click/sec, partial adaptation at 2/sec, complete adaptation as in Fig. 1D at 5/sec, and complete adaptation as in Fig. 1E at 10/sec and 20/sec. But there were potentials in other structures that demonstrated partial adaptation at 1/sec and continued to do so at 20/sec. In some structures potentials adapted completely at 1 click/see. However, adaptation never became less pronounced as the stimulus repetition rate increased. Although in most structures the occurrence of a specific adaptation pattern was not dependent on a particular stimulus rate, certain structures did demonstrate this relationship. In the pericruciate cortex, partial adaptation as in Fig. I B always occurred at 2 clicks/sec, complete adaptation as in Fig. 1D always occurred at 5/sec Brain Research, 15 (1969) 121-136

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and as in Fig. I E at 10 clicks/sec. In the suprasplenial gyrus, complete adaptation as in Fig. 1E always occurred at 2 clicks/sec. In the cingulate gyrus, complete adaptation as in Fig. 1E always occurred at 5 clicks/sec. Tested points have been plotted in Figs. 2-15. A small number of points have not been included because of space limitations at certain locations (e.g., in lemniscal structures at A1). Amplitudes have been divided into four ranges based on naturally

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generated groupings (see key to symbols, Fig. 2). The amplitudes of 10 evoked potentials produced by a 1/sec click rate were measured and averaged to determine the voltage symbolized at each point. If adaptation occurred at 1 click/see, the amplitude of the first evoked potential was used. The range of amplitudes in structures of the direct auditory pathway was comparable to the range in structures outside of this pathway, i.e., 3-320 #V versus 3-374 #V. The adaptation pattern represented at each point is the most complete pattern recorded throughout the range of stimulus rates. Thus if a potential adapted partially at 5 clicks/see and completely at 20/see, the point was represented as complete adaptation. One potential was recorded at the rostral margin of the lateral geniculate nucleus (Fig. 7) less than 1 mm from the nucleus reticularis. The anatomical isolation of this potential and its similarity in terms of amplitude and adaptation to those in the nucleus reticularis suggests this structure as a more likely source. However, several auditory potentials were recorded in other structures of the direct visual pathway. In general the more rostral the structure whether lemniscal or extralemniscal, the more numerous were the potentials exhibiting adaptation. Large amplitude auditory potentials demonstrating partial and complete adaptation defined a region in the ventral thalamus and adjacent subthalamus which extended from A6 to A1 I and from lateral coordinates 2-5 mm (Figs. 5-10). Potentials from the nucleus reticularis had similar adaptation characteristics. In the medialis dorsalis, auditory potentials were found only at A8. In the case of cortical potentials from the auditory areas (after WoolseyZS), all the recognized adaptation patterns occurred in each area although there were small subdivisions where the patterns were homogeneous. DISCUSSION

Macroelectrode recording poses obvious difficulties in precisely localizing electrical activity. In areas as the thalamus where fiber tracts and nuclei are interspersed, electrical activity has been arbitrarily assigned to nuclear areas. Electrical spread appeared to be minimal since large amplitude, non-adapting potentials were lost by a 1 mm advancement of the electrode. Thus, most structures were clearly defined in terms of their electrical activity, and in addition results were consistent from animal to animal. The middle ear muscles have been considered an important part of the mechanism responsible for adaptationL In this study these muscles were not sectioned, and yet during multiple electrode recordings, no adaptation was observed at one point while complete adaptation was simultaneously recorded at another. The role of the middle ear muscles has also been minimized by other investigations. Adaptation has been observed in the first-order neuron without change in the cochlear microphonics 1°,16, and cochlear microphonic shifts have not corresponded to recorded adaptation 9. In this investigation the animal has been immobilized to enable the auditory stimulus to reach both ears simultaneously and be of equal intensity binaurally. Brain Research, 15 (1969) 121-136

A D A P T A T I O N OF E V O K E D A U D I T O R Y POTENTIALS

133

As has been reported elsewhere, a reduction in intensity and an increase in latency of a click stimulus in relation to one ear as compared to the other (proposed cues for sound localization2a), will result in an amplitude decrement of the evoked potentials at many points contralateral, and occasionally ipsilateral, to that ear t4. Movement of the cat's head in a sound field created by a distant speaker could thus produce an amplitude pattern mimicing adaptation. In fact, two studies have reported a decrease in the amplitude of evoked auditory potentials during repetitive stimulation only when the animals were moving~, 24. Transmission of evoked auditory potentials from the motor cortex to the pyramids has been reportedL Most potentials we recorded from pyramidal and extrapyramidal structures adapted either completely or partially. However, there were a number of non-adapting potentials in the cerebral peduncle, internal capsule, ventral part of the nucleus reticularis, globus pallidus, and putamen. These may represent direct radiations from the medial geniculate where minimal adaptation was recorded, since fibers from this nucleus have been histologically demonstrated to traverse all 5 structures 27. Auditory potentials were also recorded in structures of the direct visual system including the optic tract and optic radiations. Although their significance was not discussed, auditory potentials have previously been recorded from the dorsal portion of the optic tract2L As proposed in an earlier investigation for explaining the occurrence of auditory potentials in the optic radiation 20, both optic structures are in close proximity to the auditory radiation. However, although electrical spread might account for potentials recorded at the periphery of the optic tract, those deep within the structure appear to be intrinsic. The significance of that type of complete adaptation which depends upon an increase in the stimulus repetition rate (see Fig. 1F) is not clear. The possibility that this pattern is an artifact, i.e., that the position of the electrode changed due to slight shifting of the brain substance after puncture, is remote since potentials never appeared at an initially negative point. A more probable explanation necessitates assuming a prolonged inhibitory effect13. Although there was usually a 1-min delay between the onset of one series of clicks and the next, this delay may not have been sufficient to allow diminution of the inhibitory effect in certain areas. Thus no potential would be generated from those areas by the next series of clicks. Perhaps the most suitable explanation is based on latency differences of afferent potentials. Frequencydependent, complete adaptation was often recorded in the middle suprasylvian gyrus where auditory potentials have latencies of approximately I00 msec 2s. At repetition rates of 10 and 20 clicks/sec, a low-latency control system could respond to the second afferent signal (corresponding to the second click) emitting an inhibitory impulse which would reach the gyrus before the first, slowly-ascending, afferent signal. Thus, the activity of high latency signals could be completely blocked by rapidly ascending inhibitory influences. This adaptation phenomenon cannot be dismissed simply by assuming that a 10/sec repetition rate is too rapid for potentials with 100 msec latencies. Obviously areas with such prolonged latencies could not produce evoked potentials which followed at 10 or 20/sec stimulus rates, but at least an initial potential would be observed. Brain Research, 15 (1969) 121-136

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Of the lemniscal structures investigated, potentials in the medial geniculate and the inferior colliculus demonstrated partial adaptation, more potentials adapting in the more rostral structure. Adaptation had been previously observed in both structures, with a significant decrement reported only after a minimum of 30 clicks 4,a,15,z°. Originally, extralemniscal potentials which adapted alter I-3 clicks were contrasted with lemniscal potentials which adapted at a much slower rate >. The partial adaptation we observed in lemniscal structures occurred after the same number of clicks (1-5) as in extralemniscal structures. However, most temniscal adaptation was recorded when the stimulus repetition rate was 10 or 20/sec, while most extralemniscal potentials adapted at the lower, more conventional rates. This disparity between the two systems at low stimulus rates undoubtedly produced the original contrast. Habituation, the learning process in which an animal recognizes the insignificance of a repeated stimulus extraneous to his life functions, must be monitored by observing the changes in physical activity directed towards the stimulus. Since this activity disappears after 2-10 clicks, the adaptation which has been recorded within such a stimulus interval would appear to be an electrophysiological correlate of auditory habituation. Adaptation reported after thousands of clicks does not appear related to this learning process since the behavioural importance of the stimulus would have been long lost to the animal 17. This late amplitude decrement more likely reflects a subsequent phenomenon in which the animal focuses attention away from a stimulus which he has already learned is insignificant. SUMMARY

Adaptation patterns of auditory potentials were investigated with stereotaxically oriented concentric bipolar electrodes at 4628 points in the brains of 18 unanesthetized but restrained cats. Binaural click stimuli were presented at rates of 1,2, 5, 10 and 20/sec through hollow ear bars. The results are presented as a map from P2-A21. Evoked auditory potentials were recorded in both lemniscal and extralemniscal structures. Adaptation, the decrement in amplitude of evoked potentials observed upon repetitive stimulation, was most pronounced during the first few clicks. This rapidly occurring decrement was considered most closely correlated with the learning process of habituation. Two major patterns of adaptation were observed: partial and complete. No potentials in the lemniscal structures adapted completely although some in the inferior colliculus and medial geniculate adapted partially. Many potentials recorded in extralemniscal structures adapted completely. Most extralemniscal structures exhibited non-adapting as well as adapting potentials. However, certain 'non-auditory' cortical areas only produced potentials which adapted completely, and certain thalamic nuclei as well as the subthalamus only produced potentials which adapted completely or partially. Contrary to earlier studies, potentials in lemniscal and extralemniscal structures adapted after a similar number of stimulus repetitions. Brain Research, 15 (1969) t21-136

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ADAPTATION OF EVOKED AUDITORY POTENTIALS ACKNOWLEDGEMEN3 S

This research was supported by U.S. Public Health Service Grant MH-01386. W e w i s h to t h a n k M i s s K. R o t h w e l l f o r t h e a c c o m p a n y i n g i l l u s t r a t i o n s .

REFERENCES 1 ARTEMIEV, V. V., Evoked cortical auditory potentials in anesthetized and in unanesthetized animals, Fiziol. Zh. (Leningrad), 37 (1951) 688-702. 2 BUSER, P., ASCHER, P., BRUNER, J., JASSIK-GERSCHENFELD, D., AND SINDBERG, R., Aspects of sensorimotor reverberation to acoustic and visual stimuli. In G. MoRuzzI, A. FESSARD AND H. H. JASPER (Eds.), Brain Mechanisms, Progress in Brain Research, Vol. 1, Elsevier, Amsterdam, 1963, pp. 294-324. 3 DESMEDT, J. E., Neurophysiological mechanisms controlling acoustic input. In G. L. RASMUSSEN AND W. F. WINDLE (Eds.), Neural Mechanisms (!1the Auditory and Vestibular Systems, Thomas, Springfield, I11., 1960, pp. 152 164.. 4 DUNLOP, C., McLACHLAN, E. M., WEBSTER, W. R., AND DAY, R. H., Auditory habituation in cats as a function of stimulus intensity, Nature (Lond.), 203 (1964) 874-875. 5 DUNLOP, C., WEBSTER, W., AND DAY, R., Amplitude changes of evoked potentials at the inferior colliculus during acoustic habituation, J. audit. Res., 4 (1964) 159 169. 6 DUNLOP, C., WEBSTER, W. R., AND SIMONS, L. A., Effect of attention on evoked responses in the classical auditory pathway, Nature (Lond.), 206 (1965) 1048 1050. 7 GALAMBOS, R., Studies of the auditory system with implanted electrodes. In G. L. RASMUSSEN AND W. F. WINDLE (Eds.), Neurological Mechanisms of the Auditoo' and Vestibular Systems, ~fhomas, Springfield, 111., 1960, pp. 137-151. 8 GALAMBOS,R., SHEATZ, G., AND VERNIER, V. G., Electrophysiological correlates of a conditioned response in cats, Science, 123 (1956) 376 377. 9 GALIN, D., Auditory nuclei: distinctive response patterns to white noise and tones in unanestbetized cats, Science, 146 (1964) 270 272. 10 GARCiA-AUSTT, E., Influence of the states of awareness upon sensory evoked potentials, Electroenceph, clin. Neurophysiol., Suppl. 24 (1963) 76 89. 11 GERSHUNI, G. V., KOZHEVNIKOV, V. A., MARUSEVA, A. M., AVAKYAN, R. V., RAD|ONOVA, E. A., ALTMAN, J. A., AND SOROKA, V. 1., Modifications in electrical responses of the auditory system in different states of the higher nervous activity, Electroenceph. clin. Neurophysiol., Suppl. 13 (1960) 115-124. 12 HERNANDEZ-PEON,R., AND SCHERRER, H., Habituation to acoustic stimuli in the cochlear nucleus, Fed. Proc., 14 (1955) 71. 13 HORN, G., AND HILL, R. M., Responsiveness to sensory stimulation of units in the superior colliculus and subjacent tectotegmental regions of the rabbit, Exp. Neurol., 14 (1966) 199 223. 14 JAFFE, S. L., AND HAGAMEN, W. D., Electrophysiological correlates of sound localization in extralemniscal structures, Anat. Rec., 160 (1968) 475 476. 15 JASPER, H. H., Studies of non-specific effects upon electrical responses in sensory systems. In G. MORUZZI, A. FESSARDAND H. H. JASPER (Eds.), Brain Mechanisms, Progress in Brain Research, Vol. 1, Elsevier, Amsterdam, 1963, pp. 272 286. 16 JOUVET, M., ET HERN~NDEZ-PEdN, R., M6canismes neurophysiologiques concernant l'habituation, l'attention, et le conditionnenrent, Electroenceph. clin. Neurophysiol., Suppl. 6 (1957) 39 49. 17 KEy, B. J., Correlation of behavior with changes in amplitude of cortical potentials evoked during habituation by auditory stimuli, Nature (Lond.), 207 (1965) 441. 18 LIEBBRANDT, C. C., The significance of the olivo-cochlear bundle for the adaptation mechanism of the inner ear, Aeta oto-laryng. (Stockh.), 59 (1965) 124 132. 19 LIFSCHITZ, W., PALESTINI, M., AND ARMENGOL, V., Habituation in lemniscal and extralemniscal system, XX1 hTt. Congr. Physiol. Sci., 1959, p. 164. 20 MARSH, J. T., McCARTHY, D. A., SHEATZ, G., AND GALAMBOS, R., Habituation and evoked auditory potentials, Electroenceph. clin. Neurophysiol., 13 (1961) 224-234. 21 MARSH, J. T., AND WORDEN, E. G., Auditory potentials during acoustic habituation: cochlear nucleus, cerebellum, and auditory cortex, Electroenceph. clin. Neurophysiol., 17 (1964) 685-692.

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22 O'DONOHUE, N. F., AND HAGAMEN, W. D., A map of the cat brain for regions producing selfstimulation and unilateral inattention, Brain Research, 5 (1967) 289-305. 23 ROSENZWEIG, M. R., Development of research on the physiological mechanisms (~f auditory localization, Psychol. Bull., 58 (1961) 376-389. 24 STARR, A., Influence of motor activity on click-evoked responses in the auditory pathway of waking cats, Exp. Neurol., 10 (1964) 191-204. 25 STARZL, T. E., TAYLOR, C. W., AND MAGOUN, H. W., Collateral afferent excitation of reticular formation of brain stem, J. Neurophysiol., 14 (1951) 479-496. 26 WEBSTER, W. R., DUNLOP, C. W., SIMONS, L. A., AND AITKIN, L. M., Auditory habituation: a test of a centrifugal and peripheral theory, Science, 148 (1965) 654-656. 27 WOOLLARD, H. H., AND HARPMAN, A.~ The cortical projections of the medial geniculate body, J. NeuroL Psychiat., 2 (1939) 35-44. 28 WOOLSEY, C., Organization of cortical auditory system. In G. L. RASMUSSENAND W. F. WINDLE (Eds.), Neural Mechanislns of the Auditory and Vestibular Systems, Thomas, Springfield, II1., 1960, pp. 179-180.

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