AVERAGED EVOKED POTENTIALS IN CATS WITH LESIONS OF AUDITORY PATHWAY
ROBERT A. GOLDENBERG and ARTHUR J. DERBYSHIRE
University of Illinois, Chicago, IUinois Averaged evoked activity was recorded from needle electrodes placed at the vertex of the calvaria and adjacent to each bulla in anesthetized cats in response to click stimuli. The portion of the response from 0 to 10 msec was analyzed. Activity during the first 3 msee was greatly reduced on the side ipsilateral to a lesion involving destruction of the cochlea or section of the eighth nerve and its blood vessels. Activity after 4 msec was greatly reduced on the side ipsilateral to destruction of the cochlear nuclei. No effect was found with destruction of both inferior colliculi. The bulla-vertex evoked responses were also compared to those recorded from the round window. The results support the premise that change in the waveform of the early evoked potential can be used to determine site of loss of acoustic information along the auditory pathway.
The evoked potential generated in response to auditory stimuli has been studied for many years. Fifteen individual potential waves can be identified in the averaged responses (Picton et al., 1974). Only recently has attention turned to the study of the very early portion of the evoked response, specifically those waves having latencies of less than 10 msec (Jewett et al., 1970). The early portion of the evoked response is smaller in amplitude than the later response components (Goldstein, 1973), but it exhibits properties that are proving useful in clinical electroencephalic audiometry (Mendel and Goldstein, 1971). These include long-term stability, resistance to habituation, perseverance during sleep, and relative independence from level of anesthesia or state of consciousness. The very early evoked potentials, which are thought to arise from brainstem sources, have already been used to clinically assess hearing in human infants and adults (Hecox and Galambos, 1974). Previous work is based upon the concept that the evoked responses are generated by a progressive activation of the auditory pathway. The neural origin of this response has been established, however the specific contribution of individual components of the auditory pathway has not been determined (Picton et al., 1974). While it may be possible to associate a given wave with activity in a distinct portion of the auditory system, it seems unlikely that any but the earliest of waves will represent exclusively the activity of a specific nucleus or tract (Jewett and Williston, 1971; Ruhm, Walker, and Flanigan, 1967). A destructive lesion along this pathway should elicit an observable 420
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change in the evoked response at a particular time segment, if each component of the response is functionally associated with a specific anatomical locus. The purpose of this study was 1~odemonstrate the effects of lesions at specific sites along the auditory pathway in cats, and to determine if such lesions produce a predictable alteration in the waveform of the very early portion of the evoked potential. MATERIALS
AND M E T H O D S
Healthy adult cats were anesthetized with pentobarbital at a rate of 20 mg per kg, tracheotomized, and placed in a head-holder. The pentobarbital was given as one initial intraperitoneal injection and supplemented with additional small increments as needed to maintain a satisfactory plane of anesthesia. Because the early evoked response is relatively independent os pentothal anesthesia, assisted ventilation and close monitoring of vital signs was not necessary. Both mastoid bullae were opened to expose the round windows for manipulation or direcl~ recording. Three needle electrodes were inserted through the scalp: one at the vertex, one at the right bulla, and one at the left bulla. The electrode tip was inserted into the subcutaneous tissue just posterior to each bulla, and the skin and soft tissue over the bulla were dosed prior to recording. A ground electrode was placed in the muscle of the tracheotomy incision. Clicks were used as stimuli. As schematized in Figure 1, these were gen-
SQUARE, WAVE GENERATOR
D-u:, DRIVER
25 FT. HOSE
SPEAKER GROUND
INTERVAL TIMER
I CRO]
I COMPUTER 12K
GENERATOR
/ MAGNETIC TAPE
A----~
D
CONVERTER
Ix-Y
PLOTTER
FIGURE 1. Instrumentation used in the experiment. GOLDENBERG, DERBYSHIRE.Potentials in Cats with Lesions 421
Downloaded From: https://jslhr.pubs.asha.org/ by a Univ of Auckland User on 03/31/2018 Terms of Use: https://pubs.asha.org/ss/rights_and_permissions.aspx
erated by a laboratory stimulator (Grass $5), shaped in an active filter with a bandpass between 4000 and 10,000 Hz, amplified and sent to a driver speaker. The speaker generated dicks at one end of a 25-foot hose, and conveyed the acoustic energy to a sound field in an IAC booth. A sound level meter was positioned to record the amplitude and waveform configuration of the stimulus at a position in the test booth corresponding to the location of the cat's ear. Using the sound level meter, it was determined that the maximal energy in the click stimulus was at frequencies between 2000 and 4000 Hz, and that a 3000 Hz sinusoidal stimulus matched in amplitude to the click produced a level of 80 dB SPL (re: 0.0002 /zbar). This corresponds to approximately 60 dB sensation level for normal-hearing adults in the same sound field, and was the only level used in the study. It should be noted that, while the hose undoubtedly influenced the waveform of the click stimulus, its use was thought to be advisable because approximately 25 msec was required for the sound to traverse the hose. This 25 msec delay between application of the electrical stimulus to the driver speaker and the arrival of the stimulus at the cat's ear placed the stimulus electrical artifact outside of the time zone being collected in the computer for averaging. The interval between stimuli was irregular, as determined by a randomnoise generator triggering an interval timer, which, in turn, triggered the stimulator. The minimal interval between stimuli was 70 msec, and the maximal interval was 500 msec. Two potential patterns were derived, one from vertex to left mastoid, and one from vertex to right mastoid. These two potentials were amplified in a preamplifier and DC driver amplifier. The filters of the preamplifiers were set to 10 Hz for the low-frequency cutoff ( - 3 dB) and 3 k Hz for the highfrequency cutoff. The gain was set at 30/zV per cm. The amplified potentials were monitored on a cathode ray oscilloscope and sent to an analog-to-digital converter (Digital Equipment Corporation AX08) and digital computer (Digital Equipment Corporation PDP8/I). The sampling rate of the analog to digital converter was 5 k Hz (one bin per 200/xsec), and a total of 700 bins comprised a given sample. This sampling rate was thought to be sufficient to determine the existence of response components having spectral energy up to approximately 2500 Hz, an upper-frequency limit such as that used previously with human subjects (Jewett and Williston, 1971). Rather than plotting records of responses as mean-voltage vs time, the records were normalized according to procedures used to obtain Z-scores, and are plotted as Z-scores vs time. The Z-score for each point is determined by obtaining an average of 700 responses, subtracting the average at each point from the mean of the points sampled prior to the stimulus, and dividing this difference by the standard deviation of the distribution of prestimulus points. When an ensemble average is developed in this fashion, records with high noise level have a low weighting in the ensemble. Three individual normalized responses were accumulated for each experimental condition. These were accumulated, and the resulting response was plotted as the graphic representa422 Journal o~ Speech and Hearing Research
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18 420-429 1975
tion of the evoked response. In some cases, the difference (arithmetic) between ensemble averages was computed and plotted. Negativity of the bulla electrode relative to the vertex electrode was recorded as down in all tracings. The recordings obtained from the roundwindow site were reversed, that is, negativity of the round-window electrode was recorded as up. The experimental protocol was to collect a set of data with both right and left auditory pathways intact, and to follow this with data collected subsequent to unilateral and then bilateral lesions. Cochlear destruction was accomplished by direct visualization of the promontory, and surgical destruction via a blunt probe inserted through the oval or round window. The eighth nerve was sectioned with a sharp knife that transected both the nerve and associated blood vessels under direct visualization after retraction of the cerebellum. Destruction of the cochlear nucleus was accomplished with a commercially available lesion maker. Placement of the lesion was determined with stereotaxic coordinates. Confirmation of the specific lesion was made by histological examination. Destruction of the inferior colliculus was accomplished under direct visualization after retraction of the cerebral hemisphere(s) and removal of the tentorium. Lesions of the inferior colliculus were also confirmed histologically. A total of 21 cats were studied in this manner. RESULTS The evoked potential with an intact auditory pathway consists of a single slow wave that has a duration of 7 to 9 msec, begins 0.5 to 1.0 msec after the arrival of the stimulus, and has a maximal amplitude of 4 to 8 standard deviations (SD). This is illustrated in Figure 2. Superimposed on this single slow wave are multiple (four to five) fast waves that have a duration of 0.5 msec or more, and amplitudes of 1 to 8 SDs. Both the slow and fast components were present in all but two ears tested, but the multiple fast waves were more variable than the slow wave with respect to amplitude and latency. In all cases, the time of the maximal voltage of an individual response component was accepted as the measure of the latency of that response. With a unilateral cochlear lesion (see Figure 2) there is a delay of 3 msec in the onset of the negative wave recorded from the same side as the lesion. After this delay, the negative wave reaches its maximal amplitude abruptly, and it persists until approximately 10 msec following stimulus arrival. Superimposed fast activity like that observed for an intact pathway is observable in the remainder of the negative wave. With a unilateral eighth nerve lesion on the side of the recording, a 3-reset delay in the onset of the negative wave was also observed. As in the case of the cochlear lesion, the wave reached its maximum amplitude abruptly and had a duration of 7 msec, ending approximately 10 msec after stimulus arrival. This is shown in the third panel in Figure 2. GOLDENBERG, DERBYSHIRE:Potentials in Cats with Lesions 423
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1
No Lesion
Cochlear Lesion
C Nucleus Lesion
O o CO N
Auditory Nerve Lesion
O O
Inferior Colliculus Lesion
r
iI
I%1
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2
3
4
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8
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4
5
6
7
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10
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(msec)
FIcuRF. 2. Response ensembles obtained from the bulla/vertex recording site ipsilateral to the indicated lesions. The ordinate of each graph shows the Z score corresponding to each response. The line intersecting the graphs at 0 time corresponds to the time-of-arrival of the acoustic stimulus at the ear. Bulla negativity is plotted downward.
Destruction o f the cochlear nucleus resulted in a different distortion of the response. Following ablation ipsilateral to the recording site, the negative deflection began at 1 msec, reached a maximum amplitude at 2 msec, and continued until 4 msec. At 4 msec the waveform abruptly turned positive and appeared to persist until 10 msee or more. This is illustrated in the fourth panel in Figure 2, and the reversal of the negative wave is thought to represent a loss of activity of the cochlear nucleus. The portion of the response up to 4 msec is, likewise, thought to represent activity of the cochlea and eighth nerve. Destruction of one inferior co]liculus did not alter the waveform of the response to any significant amount up to 10 msec following stimulus arrival. An example of this is shown in Figure 2. The negative wave began at essentially the same point in time as in the no-lesion condition, reached a maximum amplitude at i to 2 msec and exhibited a total duration extending to approximately 10 msec. Of the four discrete lesions, cochlear, auditory nerve, cochlear nucleus, and inferior colliculus, only two (cochlear and auditory nerve) may be considered to be unilateral. This is underscored by examination of responses obtained from recording sites contralateral and ipsilateral to the site of the lesion. In Figure 3 (A), the evoked potential obtained from the right bulla after a lesion of the left cochlea is shown. The response is similar to that obtained when no lesion was introduced. Figure 3 (B) shows the evoked potential obtained from the left bulla following the left cochlear destruction. The expected 3-msec 424
1ournal of Speech and Hearing Research
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18
420-429
1975
4IA
Contralateral Lesion
2 0 2 4
J
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Ipsilateral
Lesion
2 4 6 A-B
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3
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4 5 6 7 8 9 Time (milliseconds)
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12
FIGURE 3. Response ensembles obtained from the bulla/vertex recording site contralateral and ipsilateral to lesions of the auditory nerve. Tracing (C) shows the difference between tracings A and B. Tracing (D) shows the ensemble associated with bilateral lesions. The ordinate of each graph shows the Z-score corresponding to each response. The line intersecting the graphs at 0 time corresponds to the time-of-arrival of the acoustic stimulus at the ear. Bulla negativity is plotted downward.
GOLDENBERG, DERBYSHIRE: Potentials in Cats with Lesions 425
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delay in response onset is apparent. The tracing in Figure 3 (C) shows the arithmetic difference between the evoked potentials in 3 (A) and 3 (B), and emphasizes that the potential coincident with the ipsilateral lesion does not have the early negative component shown in 3 (A), but does have a somewhat greater negative component in the 3.5- to 8-msec time period. Bilateral lesions produced the following general results. Bilateral destruction of the cochleae resulted in a complete absence of response. An example of this is shown in Figure 3 (D). Similarly, bilateral section of the auditory nerves resulted in a complete absence of a response. Bilateral lesions were not accomplished in the cochlear nuclei. Bilateral destruction of tlae inferior colliculi did not alter the basic waveform up to the tenth msec following stimulus arrival, except for some differences in amplitude, timing, and number of fast-wave response components. To further elucidate the basis for the very early portion of the responses obtained from the bulla/vertex recording sites, these were compared to responses obtained from a ball electrode placed on the round window (RW). Figure 4 shows the response ensemble obtained from a bulla/vertex recording,
4~ IBulla .... ipsilateral
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4
5
6
7
8
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IZ
(msec)
Time
(msec)
FIGURE 4. Comparison of bulla/vertex and round-window (RW) recordings with and without ipsilateral lesions. The top tracing shows the response ensemble for-the bulla/ vertex recording, and the second tracing, the RW recording for the normal ear. The lower two tracings are from the bulla/vertex and RW sites following a lesion to the ipsilateral cochlea. The ordinate of each graph shows the Z-score corresponding to each response. The line intersecting the graphs at 0 time corresponds to the time-of-arrival of the acoustic stimulus at the ear. Bulla negativity is plotted downward. RW negativity is plotted upward. and the second coordinates show the RW response obtained from the same preparation. (Recall that the RW response polarity is inverted relative to the responses obtained from the bulla due to our instrumentation.) The biphasic component occurring between 0 and 1 msec in the RW record has the same 426 Journal of Speech and Hearing Research
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18 420-429 1975
shape as the acoustic stimulus recorded with the monitoring sound level meter placed 4 cm lateral to the ear. This suggests that the first component of the RW response is the cochlear microphonic. The component that follows the biphasic response at approximately 2 msec is probably the N1 component of the action potential of the auditory nerve. Its latency corresponds to the occurrence of a negative component in the bulla/vertex recording from the same side (see top portion of the figure). The third and fourth graphs in Figure 4 provide a means of comparing bulla/vertex and RW recordings with ipsilateral lesions. The bulla/vertex recording shows the anticipated 3 msec delay to onset of the evoked response. No response is evident in the RW recording. Thus, one may conclude that the loss of the cochlear microphonic and N1 components in the RW recording correlates with the loss of the first 3 msec of the response observed at the bulla/vertex site, and that cochlearauditory nerve activity comprises the initial 3 msec of the bulla/vertex response. DISCUSSION The purpose of this study was to analyze the early portion (under 10 msec) of the auditory evoked response in cats to determine if a known lesion of the auditory pathway could produce a demonstrable and temporally locatable change in the wave form of the evoked response. Two general components were identified in the responses obtained from the bulla: (1) a relatively slow negative component and (2) rapid fast components. The conventional description of five major deflections suggested by Jewett and Williston (1971, p. 683) was not used in this study, however, the fast components observed in this study approximate the five major deflections described by them. The early fast components (0-3 msec) were shown to be eliminated in recordings ipsilateral to lesions of the auditory nerve and cochlea. The slow component occurring later than 4 msec was eliminated in ipsilateral recordings following lesions of the cochlear nucleus. Finally, bilateral lesions of the inferior colliculus did not eliminate either of the general types of response (fast or slow components), but did seem to result in increased variability of the amplitude and timing of the fast components. A comparison of the round window response with the evoked potential was made in an attempt to further establish the fact that it was actually the auditory pathway activity that was under observation. The correlation observed between round-window and mastoid/vertex responses with lesions substantiates the neural origin of the response. Two primary characteristics of the ascending auditory system should be noted. There are numerous synaptic stations along the pathway and there are many opportunities at which bilateral innervation may occur. Therefore, a lesion of the cochlea or auditory nerve can be considered unilateral; however, lesions central to and including the cochlear nucleus cannot be considered to be unilateral. The data from this study substantiate this axiom. A unilateral GOLDENBERG,DERBYSHIRE:Potentials in Cats with Lesions 427
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lesion of the cochlea or the auditory nerve causes a loss of the earliest compohent of the evoked response on the side ipsilateral to the lesion, but not contralateral to it. The remaining components of the response must derive from that portion of the auditory pathway that has bilateral innervation. A reversal of the negative wave exhibited with a lesion in the cochlear nucleus reflects the alteration in the auditory pathway, but after bilateral representation occurs. Indeed, it was interesting to observe that the evoked response generated from the side opposite the ablated cochlear nucleus exhibited a marked increase in amplitude. The reasons for this can only be speculative, such as loss of inhibition, or a change in the complex electrical geometry from which the response was obtained. The lack of any alteration of the evoked response in the first 10 msec after ablation of one or both inferior colliculi cannot be readily explained. Because all ascending fibers pass through the inferior colliculi, ablation of both might be expected to modify the response considerably. This assumption also finds support in the fact the responses evoked from the inferior colliculus in laboratory animals fall well within the 0-10 msec epoch under scrutiny in the present study (Wickelgren, 1968). As Davis (1973) has indicated, the precise identification of specific structures underlying the later components of the response continues to pose an elusive problem. The observations presented in this study strongly support the concept that the cochlea-auditory nerve-cochlear nucleus complex is the site of origin of the auditory evoked potential components having a latency between 1 and 4 msec. Further investigation with diotic/dichotic stimuli and known lesions would appear t o b e the most promising approach to aid in defining the later components of the response. ACKNOWLEDGMENT Requests for reprints should be directed to Robert A. Goldenberg, Department of Otolaryngology, Abraham Lincoln School of Medicine, University of Illinois, Chicago, Illinois 60612. REFERENCES DAvis, H., Classes of auditory evoked responses. Audiology, 12, 464-469 (1973). GOLI)SrEXN,R., Electroencephalic audiometry. In J. Jerger (Ed.), Modern Developments in Audiology. (2nd ed.) New York: Academic (1973). H~.cox, K., and GXLAMBOS,R., Brainstem auditory evoked responses in human infants and adults. Arch. Otolaryn., 99, 30-33 (1974). JV.WETT, D., ROMANO, H., and WmLISTON, J. S., Human auditory evoked responses: Possible brain stem components detected on the scalp. Sc/ence, 167, 1517-1518 (1970). JEWETT, D., and WmLISTON,J. S., Auditory evoked far fields averaged from the scalp of humans. Brain, 94, 681-696 (1971). MENDEL, M. I., and GOLDSTEIN,R., Effect of sleep on the early components of the averaged electroencephalic response. Arch. Ohr. Nas. Kehlikheilk., 198, 110-117 (1971). PICTON, T. W., HmLYAlaD, S. A., KtaAosz, H. I., and GXLAMBOS,R., Human auditory evoked potentials. I. Evaluation of components, Electroenceph. clin. Neurophysiol., 36, 179-190 (1974). 428 lournal of Speech and Hearing Research
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18 420-429 1975
Run-M, H., WALKER, E., and FLANXGAN,H., Acoustically evoked potentials in man: Mediation of early components. Laryngoscope, 77, 806-827 (1967). WICKELCREN, W. O., Effect of state of arousal on click-evoked responses in cats. ]. Neurophysiol., 31, 757-768 (1968). Received May 8, 1974. Accepted March 1, 1975.
GOLDENBERG,DERBYSHIRE: Potentials in Cats with Lesions 429
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ROBERT A. GOLDENBERG and ARTHUR J. DERBYSHIRE
University of Illinois, Chicago, IUinois Averaged evoked activity was recorded from needle electrodes placed at the vertex of the calvaria and adjacent to each bulla in anesthetized cats in response to click stimuli. The portion of the response from 0 to 10 msec was analyzed. Activity during the first 3 msee was greatly reduced on the side ipsilateral to a lesion involving destruction of the cochlea or section of the eighth nerve and its blood vessels. Activity after 4 msec was greatly reduced on the side ipsilateral to destruction of the cochlear nuclei. No effect was found with destruction of both inferior colliculi. The bulla-vertex evoked responses were also compared to those recorded from the round window. The results support the premise that change in the waveform of the early evoked potential can be used to determine site of loss of acoustic information along the auditory pathway.
The evoked potential generated in response to auditory stimuli has been studied for many years. Fifteen individual potential waves can be identified in the averaged responses (Picton et al., 1974). Only recently has attention turned to the study of the very early portion of the evoked response, specifically those waves having latencies of less than 10 msec (Jewett et al., 1970). The early portion of the evoked response is smaller in amplitude than the later response components (Goldstein, 1973), but it exhibits properties that are proving useful in clinical electroencephalic audiometry (Mendel and Goldstein, 1971). These include long-term stability, resistance to habituation, perseverance during sleep, and relative independence from level of anesthesia or state of consciousness. The very early evoked potentials, which are thought to arise from brainstem sources, have already been used to clinically assess hearing in human infants and adults (Hecox and Galambos, 1974). Previous work is based upon the concept that the evoked responses are generated by a progressive activation of the auditory pathway. The neural origin of this response has been established, however the specific contribution of individual components of the auditory pathway has not been determined (Picton et al., 1974). While it may be possible to associate a given wave with activity in a distinct portion of the auditory system, it seems unlikely that any but the earliest of waves will represent exclusively the activity of a specific nucleus or tract (Jewett and Williston, 1971; Ruhm, Walker, and Flanigan, 1967). A destructive lesion along this pathway should elicit an observable 420
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change in the evoked response at a particular time segment, if each component of the response is functionally associated with a specific anatomical locus. The purpose of this study was 1~odemonstrate the effects of lesions at specific sites along the auditory pathway in cats, and to determine if such lesions produce a predictable alteration in the waveform of the very early portion of the evoked potential. MATERIALS
AND M E T H O D S
Healthy adult cats were anesthetized with pentobarbital at a rate of 20 mg per kg, tracheotomized, and placed in a head-holder. The pentobarbital was given as one initial intraperitoneal injection and supplemented with additional small increments as needed to maintain a satisfactory plane of anesthesia. Because the early evoked response is relatively independent os pentothal anesthesia, assisted ventilation and close monitoring of vital signs was not necessary. Both mastoid bullae were opened to expose the round windows for manipulation or direcl~ recording. Three needle electrodes were inserted through the scalp: one at the vertex, one at the right bulla, and one at the left bulla. The electrode tip was inserted into the subcutaneous tissue just posterior to each bulla, and the skin and soft tissue over the bulla were dosed prior to recording. A ground electrode was placed in the muscle of the tracheotomy incision. Clicks were used as stimuli. As schematized in Figure 1, these were gen-
SQUARE, WAVE GENERATOR
D-u:, DRIVER
25 FT. HOSE
SPEAKER GROUND
INTERVAL TIMER
I CRO]
I COMPUTER 12K
GENERATOR
/ MAGNETIC TAPE
A----~
D
CONVERTER
Ix-Y
PLOTTER
FIGURE 1. Instrumentation used in the experiment. GOLDENBERG, DERBYSHIRE.Potentials in Cats with Lesions 421
Downloaded From: https://jslhr.pubs.asha.org/ by a Univ of Auckland User on 03/31/2018 Terms of Use: https://pubs.asha.org/ss/rights_and_permissions.aspx
erated by a laboratory stimulator (Grass $5), shaped in an active filter with a bandpass between 4000 and 10,000 Hz, amplified and sent to a driver speaker. The speaker generated dicks at one end of a 25-foot hose, and conveyed the acoustic energy to a sound field in an IAC booth. A sound level meter was positioned to record the amplitude and waveform configuration of the stimulus at a position in the test booth corresponding to the location of the cat's ear. Using the sound level meter, it was determined that the maximal energy in the click stimulus was at frequencies between 2000 and 4000 Hz, and that a 3000 Hz sinusoidal stimulus matched in amplitude to the click produced a level of 80 dB SPL (re: 0.0002 /zbar). This corresponds to approximately 60 dB sensation level for normal-hearing adults in the same sound field, and was the only level used in the study. It should be noted that, while the hose undoubtedly influenced the waveform of the click stimulus, its use was thought to be advisable because approximately 25 msec was required for the sound to traverse the hose. This 25 msec delay between application of the electrical stimulus to the driver speaker and the arrival of the stimulus at the cat's ear placed the stimulus electrical artifact outside of the time zone being collected in the computer for averaging. The interval between stimuli was irregular, as determined by a randomnoise generator triggering an interval timer, which, in turn, triggered the stimulator. The minimal interval between stimuli was 70 msec, and the maximal interval was 500 msec. Two potential patterns were derived, one from vertex to left mastoid, and one from vertex to right mastoid. These two potentials were amplified in a preamplifier and DC driver amplifier. The filters of the preamplifiers were set to 10 Hz for the low-frequency cutoff ( - 3 dB) and 3 k Hz for the highfrequency cutoff. The gain was set at 30/zV per cm. The amplified potentials were monitored on a cathode ray oscilloscope and sent to an analog-to-digital converter (Digital Equipment Corporation AX08) and digital computer (Digital Equipment Corporation PDP8/I). The sampling rate of the analog to digital converter was 5 k Hz (one bin per 200/xsec), and a total of 700 bins comprised a given sample. This sampling rate was thought to be sufficient to determine the existence of response components having spectral energy up to approximately 2500 Hz, an upper-frequency limit such as that used previously with human subjects (Jewett and Williston, 1971). Rather than plotting records of responses as mean-voltage vs time, the records were normalized according to procedures used to obtain Z-scores, and are plotted as Z-scores vs time. The Z-score for each point is determined by obtaining an average of 700 responses, subtracting the average at each point from the mean of the points sampled prior to the stimulus, and dividing this difference by the standard deviation of the distribution of prestimulus points. When an ensemble average is developed in this fashion, records with high noise level have a low weighting in the ensemble. Three individual normalized responses were accumulated for each experimental condition. These were accumulated, and the resulting response was plotted as the graphic representa422 Journal o~ Speech and Hearing Research
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18 420-429 1975
tion of the evoked response. In some cases, the difference (arithmetic) between ensemble averages was computed and plotted. Negativity of the bulla electrode relative to the vertex electrode was recorded as down in all tracings. The recordings obtained from the roundwindow site were reversed, that is, negativity of the round-window electrode was recorded as up. The experimental protocol was to collect a set of data with both right and left auditory pathways intact, and to follow this with data collected subsequent to unilateral and then bilateral lesions. Cochlear destruction was accomplished by direct visualization of the promontory, and surgical destruction via a blunt probe inserted through the oval or round window. The eighth nerve was sectioned with a sharp knife that transected both the nerve and associated blood vessels under direct visualization after retraction of the cerebellum. Destruction of the cochlear nucleus was accomplished with a commercially available lesion maker. Placement of the lesion was determined with stereotaxic coordinates. Confirmation of the specific lesion was made by histological examination. Destruction of the inferior colliculus was accomplished under direct visualization after retraction of the cerebral hemisphere(s) and removal of the tentorium. Lesions of the inferior colliculus were also confirmed histologically. A total of 21 cats were studied in this manner. RESULTS The evoked potential with an intact auditory pathway consists of a single slow wave that has a duration of 7 to 9 msec, begins 0.5 to 1.0 msec after the arrival of the stimulus, and has a maximal amplitude of 4 to 8 standard deviations (SD). This is illustrated in Figure 2. Superimposed on this single slow wave are multiple (four to five) fast waves that have a duration of 0.5 msec or more, and amplitudes of 1 to 8 SDs. Both the slow and fast components were present in all but two ears tested, but the multiple fast waves were more variable than the slow wave with respect to amplitude and latency. In all cases, the time of the maximal voltage of an individual response component was accepted as the measure of the latency of that response. With a unilateral cochlear lesion (see Figure 2) there is a delay of 3 msec in the onset of the negative wave recorded from the same side as the lesion. After this delay, the negative wave reaches its maximal amplitude abruptly, and it persists until approximately 10 msec following stimulus arrival. Superimposed fast activity like that observed for an intact pathway is observable in the remainder of the negative wave. With a unilateral eighth nerve lesion on the side of the recording, a 3-reset delay in the onset of the negative wave was also observed. As in the case of the cochlear lesion, the wave reached its maximum amplitude abruptly and had a duration of 7 msec, ending approximately 10 msec after stimulus arrival. This is shown in the third panel in Figure 2. GOLDENBERG, DERBYSHIRE:Potentials in Cats with Lesions 423
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1
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FIcuRF. 2. Response ensembles obtained from the bulla/vertex recording site ipsilateral to the indicated lesions. The ordinate of each graph shows the Z score corresponding to each response. The line intersecting the graphs at 0 time corresponds to the time-of-arrival of the acoustic stimulus at the ear. Bulla negativity is plotted downward.
Destruction o f the cochlear nucleus resulted in a different distortion of the response. Following ablation ipsilateral to the recording site, the negative deflection began at 1 msec, reached a maximum amplitude at 2 msec, and continued until 4 msec. At 4 msec the waveform abruptly turned positive and appeared to persist until 10 msee or more. This is illustrated in the fourth panel in Figure 2, and the reversal of the negative wave is thought to represent a loss of activity of the cochlear nucleus. The portion of the response up to 4 msec is, likewise, thought to represent activity of the cochlea and eighth nerve. Destruction of one inferior co]liculus did not alter the waveform of the response to any significant amount up to 10 msec following stimulus arrival. An example of this is shown in Figure 2. The negative wave began at essentially the same point in time as in the no-lesion condition, reached a maximum amplitude at i to 2 msec and exhibited a total duration extending to approximately 10 msec. Of the four discrete lesions, cochlear, auditory nerve, cochlear nucleus, and inferior colliculus, only two (cochlear and auditory nerve) may be considered to be unilateral. This is underscored by examination of responses obtained from recording sites contralateral and ipsilateral to the site of the lesion. In Figure 3 (A), the evoked potential obtained from the right bulla after a lesion of the left cochlea is shown. The response is similar to that obtained when no lesion was introduced. Figure 3 (B) shows the evoked potential obtained from the left bulla following the left cochlear destruction. The expected 3-msec 424
1ournal of Speech and Hearing Research
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18
420-429
1975
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FIGURE 3. Response ensembles obtained from the bulla/vertex recording site contralateral and ipsilateral to lesions of the auditory nerve. Tracing (C) shows the difference between tracings A and B. Tracing (D) shows the ensemble associated with bilateral lesions. The ordinate of each graph shows the Z-score corresponding to each response. The line intersecting the graphs at 0 time corresponds to the time-of-arrival of the acoustic stimulus at the ear. Bulla negativity is plotted downward.
GOLDENBERG, DERBYSHIRE: Potentials in Cats with Lesions 425
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delay in response onset is apparent. The tracing in Figure 3 (C) shows the arithmetic difference between the evoked potentials in 3 (A) and 3 (B), and emphasizes that the potential coincident with the ipsilateral lesion does not have the early negative component shown in 3 (A), but does have a somewhat greater negative component in the 3.5- to 8-msec time period. Bilateral lesions produced the following general results. Bilateral destruction of the cochleae resulted in a complete absence of response. An example of this is shown in Figure 3 (D). Similarly, bilateral section of the auditory nerves resulted in a complete absence of a response. Bilateral lesions were not accomplished in the cochlear nuclei. Bilateral destruction of tlae inferior colliculi did not alter the basic waveform up to the tenth msec following stimulus arrival, except for some differences in amplitude, timing, and number of fast-wave response components. To further elucidate the basis for the very early portion of the responses obtained from the bulla/vertex recording sites, these were compared to responses obtained from a ball electrode placed on the round window (RW). Figure 4 shows the response ensemble obtained from a bulla/vertex recording,
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FIGURE 4. Comparison of bulla/vertex and round-window (RW) recordings with and without ipsilateral lesions. The top tracing shows the response ensemble for-the bulla/ vertex recording, and the second tracing, the RW recording for the normal ear. The lower two tracings are from the bulla/vertex and RW sites following a lesion to the ipsilateral cochlea. The ordinate of each graph shows the Z-score corresponding to each response. The line intersecting the graphs at 0 time corresponds to the time-of-arrival of the acoustic stimulus at the ear. Bulla negativity is plotted downward. RW negativity is plotted upward. and the second coordinates show the RW response obtained from the same preparation. (Recall that the RW response polarity is inverted relative to the responses obtained from the bulla due to our instrumentation.) The biphasic component occurring between 0 and 1 msec in the RW record has the same 426 Journal of Speech and Hearing Research
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18 420-429 1975
shape as the acoustic stimulus recorded with the monitoring sound level meter placed 4 cm lateral to the ear. This suggests that the first component of the RW response is the cochlear microphonic. The component that follows the biphasic response at approximately 2 msec is probably the N1 component of the action potential of the auditory nerve. Its latency corresponds to the occurrence of a negative component in the bulla/vertex recording from the same side (see top portion of the figure). The third and fourth graphs in Figure 4 provide a means of comparing bulla/vertex and RW recordings with ipsilateral lesions. The bulla/vertex recording shows the anticipated 3 msec delay to onset of the evoked response. No response is evident in the RW recording. Thus, one may conclude that the loss of the cochlear microphonic and N1 components in the RW recording correlates with the loss of the first 3 msec of the response observed at the bulla/vertex site, and that cochlearauditory nerve activity comprises the initial 3 msec of the bulla/vertex response. DISCUSSION The purpose of this study was to analyze the early portion (under 10 msec) of the auditory evoked response in cats to determine if a known lesion of the auditory pathway could produce a demonstrable and temporally locatable change in the wave form of the evoked response. Two general components were identified in the responses obtained from the bulla: (1) a relatively slow negative component and (2) rapid fast components. The conventional description of five major deflections suggested by Jewett and Williston (1971, p. 683) was not used in this study, however, the fast components observed in this study approximate the five major deflections described by them. The early fast components (0-3 msec) were shown to be eliminated in recordings ipsilateral to lesions of the auditory nerve and cochlea. The slow component occurring later than 4 msec was eliminated in ipsilateral recordings following lesions of the cochlear nucleus. Finally, bilateral lesions of the inferior colliculus did not eliminate either of the general types of response (fast or slow components), but did seem to result in increased variability of the amplitude and timing of the fast components. A comparison of the round window response with the evoked potential was made in an attempt to further establish the fact that it was actually the auditory pathway activity that was under observation. The correlation observed between round-window and mastoid/vertex responses with lesions substantiates the neural origin of the response. Two primary characteristics of the ascending auditory system should be noted. There are numerous synaptic stations along the pathway and there are many opportunities at which bilateral innervation may occur. Therefore, a lesion of the cochlea or auditory nerve can be considered unilateral; however, lesions central to and including the cochlear nucleus cannot be considered to be unilateral. The data from this study substantiate this axiom. A unilateral GOLDENBERG,DERBYSHIRE:Potentials in Cats with Lesions 427
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lesion of the cochlea or the auditory nerve causes a loss of the earliest compohent of the evoked response on the side ipsilateral to the lesion, but not contralateral to it. The remaining components of the response must derive from that portion of the auditory pathway that has bilateral innervation. A reversal of the negative wave exhibited with a lesion in the cochlear nucleus reflects the alteration in the auditory pathway, but after bilateral representation occurs. Indeed, it was interesting to observe that the evoked response generated from the side opposite the ablated cochlear nucleus exhibited a marked increase in amplitude. The reasons for this can only be speculative, such as loss of inhibition, or a change in the complex electrical geometry from which the response was obtained. The lack of any alteration of the evoked response in the first 10 msec after ablation of one or both inferior colliculi cannot be readily explained. Because all ascending fibers pass through the inferior colliculi, ablation of both might be expected to modify the response considerably. This assumption also finds support in the fact the responses evoked from the inferior colliculus in laboratory animals fall well within the 0-10 msec epoch under scrutiny in the present study (Wickelgren, 1968). As Davis (1973) has indicated, the precise identification of specific structures underlying the later components of the response continues to pose an elusive problem. The observations presented in this study strongly support the concept that the cochlea-auditory nerve-cochlear nucleus complex is the site of origin of the auditory evoked potential components having a latency between 1 and 4 msec. Further investigation with diotic/dichotic stimuli and known lesions would appear t o b e the most promising approach to aid in defining the later components of the response. ACKNOWLEDGMENT Requests for reprints should be directed to Robert A. Goldenberg, Department of Otolaryngology, Abraham Lincoln School of Medicine, University of Illinois, Chicago, Illinois 60612. REFERENCES DAvis, H., Classes of auditory evoked responses. Audiology, 12, 464-469 (1973). GOLI)SrEXN,R., Electroencephalic audiometry. In J. Jerger (Ed.), Modern Developments in Audiology. (2nd ed.) New York: Academic (1973). H~.cox, K., and GXLAMBOS,R., Brainstem auditory evoked responses in human infants and adults. Arch. Otolaryn., 99, 30-33 (1974). JV.WETT, D., ROMANO, H., and WmLISTON, J. S., Human auditory evoked responses: Possible brain stem components detected on the scalp. Sc/ence, 167, 1517-1518 (1970). JEWETT, D., and WmLISTON,J. S., Auditory evoked far fields averaged from the scalp of humans. Brain, 94, 681-696 (1971). MENDEL, M. I., and GOLDSTEIN,R., Effect of sleep on the early components of the averaged electroencephalic response. Arch. Ohr. Nas. Kehlikheilk., 198, 110-117 (1971). PICTON, T. W., HmLYAlaD, S. A., KtaAosz, H. I., and GXLAMBOS,R., Human auditory evoked potentials. I. Evaluation of components, Electroenceph. clin. Neurophysiol., 36, 179-190 (1974). 428 lournal of Speech and Hearing Research
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18 420-429 1975
Run-M, H., WALKER, E., and FLANXGAN,H., Acoustically evoked potentials in man: Mediation of early components. Laryngoscope, 77, 806-827 (1967). WICKELCREN, W. O., Effect of state of arousal on click-evoked responses in cats. ]. Neurophysiol., 31, 757-768 (1968). Received May 8, 1974. Accepted March 1, 1975.
GOLDENBERG,DERBYSHIRE: Potentials in Cats with Lesions 429
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