- Email: [email protected]
Effects of Primary Auditory Cortex Lesions on Middle Latency Responses in Awake Cats
Auris'Nasus'Larynx (Tokyo) 20.155-165 (1993)
EFFECTS OF PRIMARY AUDITORY CORTEX LESIONS ON MIDDLE LATENCY RESPONSES IN AWAKE CATS Lee Suk KIM, M.D., Kimitaka KAGA, M.D.,* Toshihiro TsuzuKu,** and Akira UNO** Department of Otolaryngology, Seoul National University School of Medicine, Seoul, Korea Faculty of Medicine, The University of Tokyo, Tokyo, Japan Department of Otolaryngology, Teikyo University School of Medicine, Tokyo, Japan
* Department of Otolaryngology,
**
In order to clarify the role of the primary auditory cortex (AI) on middle latency responses (MLRs), we recorded the auditory evoked potentials (AEPs) from the vertex and the right and left AI areas of the skull simultaneously before and after creating serial lesions of the AIs contralateral and ipsilateral to the stimulated ear in 7 awake cats. The auditory brainstem responses (ABRs) and MLRs recorded from the vertex in normal awake cats revealed the presence of peaks 1-8, NA and PA within the analysis time of 50 msec. After there were serial AI lesions, (1) all the peaks remained at nearly the same latencies, (2) the amplitude of the NA was decreased significantly, that of the PA was slightly decreased and those of peaks 6, 7 and 8 were variable, and (3) the difference between the effects of the first operation (contralateral AI) and the second operation (ipsilateral AI) was not statistically significant. These findings indicated that the main, prominent effect of bilateral AI lesions on MLRs in the awake cat is a significant decrease in the NA amplitude. Middle latency responses (MLRs) are vertex-recorded auditory evoked responses (AEPs) detectable from 9-10 to 50-80 msec in humans. 1•4 The origin of the MLR has been the source of continuing debate, and the development of a clinical testing technique has been seriously hampered. In patients with unilateral temporal lobe lesions involving the primary auditory cortex (AI), hemispheric asymmetry of the P A of the MLR has been described, and the bilateral temporal lobes are considered to be the source of the PA. 5,6 In some patients with bilateral lesions of the AI, the PA of the MLR has been shown to be abolished. 7-9 In contrast, in other patients also with bilateral lesions, the PA has remained intact. 10-12 In studies on animal lesions, Kaga et al 13 showed that the cat "PA" is generated by the AI contralateral to the stimulated ear in the chloralose-urethane--anesthetized cat. On the other hand, Buchwald et al 14 showed that the AI is the generator of wave 7 in Received for publication January 6, 1993 155
156
L. S. KIM, K. KAGA, T. TSUZUKU, et al
the awake cat. These conflicting results from human and animal studies raise questions over the role of the AI in the generation of MLR. Comparisons among studies are also complicated by methodologic differences such as the recording site and the type of anesthesia employed. The aim of the present study was to clarify the role of the AI in MLRs. For this purpose, we recorded the AEPs from the vertex of the skull on the right and left AI areas at sites before and after creating serial lesions of the contralateral and ipsilateral AIs in awake cats. METHODS
Seven adult cats weighing 2.5-3.5 kg were used in this study. All cats were behaviorally well oriented to auditory stimuli, and their external auditory canals appeared normal under otoscopic examination. Each cat was anesthetized with 35 mg/kg sodium pentobarbital (Nembutal) injected intraperitoneally, placed in a stereotaxic apparatus, and the skull was exposed. A stainless steel screw was implanted stereotaxically at A7 just lateral to the midline (the "vertex" electrode), and two screws overlying the right and left AIs (the "AI" electrodes) were implanted in the skull bone. Leads from the screws terminated through a small connector mounted on the skull. Two aluminum sleeves were then mounted with dental cement on the front and back of the skull to hold the head motionless during recording. At the time of recording, each cat was comfortably secured in a canvas bag to prevent excessive movement. Horizontal bars projecting medially from the stereotaxic frame were screwed into the implanted aluminum sleeves to immobilize the head. Before the start of any recording, the cats had been earlier trained to become accustomed to this procedure in a sound isolation chamber for a period of 1 or 2 weeks. Under Nembutal anesthesia, the first operation was performed, consisting of subpial aspiration of the auditory cortex in the middle ectosylvian gyrus (areas AI and parts A, DP, All, and p 15 ) contralateral to the stimulated ear (contralateral AI lesion state). Then, 1 or 2 weeks after the first operation, the second operation on the ipsilateral auditory cortex was carried out (bilateral AI lesioning state). After surgery, stainless steel screw electrodes were again implanted in the reconstructed skull overlying the previous AI area in order to compare the AEPs from the AI electrodes before and after creating AI lesions in three cats. AEPs were recorded in awake cats from the vertex electrode and the contralateral and ipsilateral AI electrodes referenced to the mastoid ipsilateral to the stimulated ear simultaneously in three different phases, i.e., before the operation, and 1 week after both the first and second operations. The acoustic stimuli were broad-band clicks (0.1 msec square wave) alternating in polarity and presented monaurally at a rate of 2/sec through a headphone (RION AD 06) in contact with the cat's ear. The stimulus intensity was 110dB peak-equivalent SPL (re: 20PA)
AI LESIONING ON CAT MLR
157
which was about 55-65 dB (SL) above the thresholds of the 7 cats. Broad-band masking (40 dB less intense than the clicks) was presented to the contralateral ear to eliminate any crossover due to bone conduction. The EEG was differentially amplified and band-pass was filtered (lo-l,OOOHz, 12 dB/octave). Averages and replications were obtained for each condition using a signal averager (l00 trials/ average) with an analysis epoch of 50 msec. Averaging was discontinued when the EEG showed artifacts or myogenic contamination. After completing all recordings, the cats were deeply anesthetized with Nembutal and perfused through the left ventricle of the heart with normal saline followed by 10% formalin. The perfused brains were inspected grossly, photographed, and sectioned coronally including the lesion sites. Gross and microscopic examinations of the fixed brains showed that the lesions were at the middle ectosylvian gyrus including the AI and parts of A, DP, All, and plS without involvement of the subcortical area. The following measurements were made for the responses utilizing the cursors of the signal averager: latencies of the peaks, absolute amplitudes of peaks 6, 7, and 8 with respect to peak Nl (negative peak between peak 1 and peak 2), and peak-to-peak amplitudes of 8-NA and NA-PA. RESULTS
Typical MLRs in normal awake cats and anesthetized cats The ABRs (auditory brain stem responses) and MLRs recorded from the
VERTEX CAT +6
NA
o Fig. I.
10
20
30
40
50 msec
The typical ABRs and MLRs of the vertex recordings in two normal awake cats.
L. S. KIM, K. KAGA, T. TSUZUKU, et al
158
CAT #5
- - AWAKE . H., NEMBUTAL PA
VERTEX
CONTRA. AI
Pl._
o
10
IPSI. AI
20
30
40
50 msec
Fig. 2. The cat ABRs and MLRs recorded from the vertex electrode (VERTEX), contralateral AI electrode (CONTRA. AI), and ipsilateral AI electrode (IPS!. AI) elicited by left click stimulation in an awake state and a Nembutal-anesthetized state.
vertex in normal awake cats are shown in Fig. 1. Peaks 1-8, NA, and PA were observed within the analysis time of 50 msec. Figure 2 illustrates the cat ABRs and MLRs obtained from 3 recording sites in an awake state and in a Nembutalanesthetized state. In contrast with the ABRs, the MLRs of the vertex recording were very different from those of the contralateral and ipsilateral AI recordings in the awake state, and they were also different from the AEPs in the Nembutalanesthetized state. This indicated that the results of MLR studies in cats should be interpreted by the data for the vertex recording in an awake state. MLRs (vertex) and AI recordings before and after causing serial AI lesions Figure 3 demonstrates the typical vertex potentials in an awake cat before and after there are contralateral and bilateral AI lesions. It shows that all the peaks were present after there was an AI lesion. Table 1 lists the mean values and standard deviations of MLR and ABR peak latencies for the 7 cats before and after causing serial AI lesions. Since the mean latencies of peaks 4 and 5 in the three phases were the same, the cats were considered to be under similar conditions of stimulus intensity. As illustrated in Table 1, none of the peaks from peak 6 to PA were changed significantly in latency after there was an AI lesion. Figure 4 shows the AEPs from 3 recording sites in three different phase~ of cat #7. In the contralateral and ipsilateral AI recordings, the large PI and the following small wave disappeared after contralateral and bilateral (ipsilatet:al) AI lesions, respectively, were formed. Figure 5 demonstrates the loss of bilateral
AI LESIONING ON CAT MLR
159
CAT #5 : VERTEX PREOP. CONTRA.AI OP. BllAT.AIOP .
.......... _... -... -
I
NA
o
10
30
20
SpY
50 msec
40
Fig. 3. The typical ABRs and MLRs of the preoperative (PREOP.) state and following a contralateral AI lesion (CONTRA. AI OP.) and bilateral AI lesions (BILAT. AI OP.) in an awake cat. Note that all the peaks are present after there is an AI lesion. Table I.
Preoperative and postoperative peak latencies [msec, mean (SD)].
PREOP. CONTRA. AI OP. BILAT. AI OP.
4
5
6
7
8
NA
PA
3.64 (0.20) 3.55 (0.16) 3.59 (0.19)
4.81 (0.28) 4.68 (0.24) 4.74 (0.28)
6.21 (0.41 ) 6.02 (0.54 ) 6.00 (0.44)
7.73 (0.63) 7.73 (0.74 ) 7.56 (0.65)
9.51 (0.52) 9.23 (0.58) 9.21 (0.69)
14.21 ( 1.39)
21.60 (2.34 ) 19.80 (0.07) 19.94 ( 1.60)
l3.10 (0.83) 12.90 (0.37)
auditory cortices of cat #7 after the formation of bilateral AI lesion. The post-Iesioning change in the AI recordings, which was the disappearance of PI and the following small wave, corresponded to the portion ranging from peak 6 to P A in the vertex recordings. These peaks of the vertex recordings were present with the same latency but they changed in amplitude after there were serial AI lesions. As seen in Figs. 3 and 4, peaks 6, 7, and 8 were small ones and the general slope of peaks 6, 7, and 8 was changed after surgery, which was considered to be due to the change in the underlying slow component. From this viewpoint, the absolute amplitudes of peaks 6, 7, and 8 were measured with respect to the peak Nl which was relatively stable (Table 2). Although the mean amplitudes of these three peaks were similar in the three phases, the amplitudes were somewhat variable, as indicated by the large standard deviations which were obtained.
L. S. KIM, K. KAGA, T. TSUZUKU, et al
160
CAT # 7
- - PREOP . . CONTRA.AI OP. -.. ----- BILAT.AI OP.
VERTEX
#~
... .....
... - - - - -
CONTRA. AI
o
10
20
30
40
... ~
.
I
I
10)'Y
20)'V
50 msec
Fig. 4. The auditory evoked potentials recorded from the vertex electrode (VERTEX), ipsilateral AI electrode (IPS!. AI), and contralateral AI electrode (CONTRA. AI) in the preoperative (PREOP.) state and following a contralateral AI lesion (CONTRA. AI OP.) and bilateral AI lesions (BILAT. AI OP.) in an awake cat (#7). Note the relationship between the NA wave and the PI waves.
Fig. 5. The coronary section of the brain of cat #7 demonstrates loss of bilateral auditory cortices after the forming of bilateral AI lesions. The white arrows indicate the lesion sites of the right and left auditory cortices.
Figure 6 shows the mean peak-to-peak amplitudes of 8-NA and NA-PA in the three phases. Statistical analysis of these amplitudes showed a significant difference between the preoperative group and the bilateral AI operation group (Table 3). The amplitudes of NA and PA were decreased significantly after there was an AI lesion. The amplitude of PA, however, may have decreased slightly because the
AI LESIONING ON CAT MLR Table 2.
161
Absolute amplitudes* of peaks 6,7, and 8 (n =7) [V, mean (SD)].
PREOP. CONTRA. AI OP. BILAT. AI OP.
6
7
8
3.94 (2.20) 3.60 (2.49) 3.46 (2.17)
2.16 (1.88) 1.97 (1.74) 1.86 (1.73)
-0.09 (2.73) -0.15 (1.76) -0.67 (1.63)
* Amplitudes with respect to peak NI.
• : 8-NA
fIlV)
o : NA-PA
10
5
o
L -_ _
~
____
~
+-__
____
PREOP. CONTRA. BILAT. AIOP. AIOP.
Fig. 6. The mean peak-to-peak amplitudes of 8-NA and NA-PA in the preoperative (PREOP.) state and after a contralateral AI lesion (CONTRA. AI OP.) in awake cats. Table 3.
Peak-to-peak amplitudes analyses of 8-NA and NA-PA (n =7). 8-NA
NA-'PA
PREOP. vs. CONTRA. AI OP.
PREOP. vs. BILAT. AI OP.
PREOP. vs. CONTRA. AI OP.
PREOP. vs. BILAT. AI OP.
p >0.05
p<0.OO5
P >0.05
p
Probability* * Paired t-test.
reduction in the NA-PA amplitude appeared to be mostly a function of the change of NA. As seen in Fig. 6, the difference between the effects of the first operation (contralateral AI) and the second operation (ipsilateral AI) was not statistically significant (p >0.05).
162
L. S. KIM , K. KAGA, T. TSUZUKU, et al
DISCUSSION
Our present data showed that after the formation of bilateral AI lesions in awake cats, all the peaks remained at nearly the same latencies, the amplitude of NA decreased significantly, the amplitude of PA decreased slightly and the amplitudes of peaks 6, 7, and 8 were variable. These findings suggest that direct activation of the contralateral and ipsilateral AI in the awake cat results in large positive waves, PIs at 12-15 msec, in AI recordings, which were volume-conducted to the vertex as the NA following peak 8. In this study, the auditory evoked potentials recorded from the AI electrodes showed peaks 1-6 of ABR and a small negative deflection around 8- 9 msec followed by a large surface positive peak, PI at 12-15 msec, which is considered to be locally generated, as previous studies have described. 14, 16.17 Wolpaw 17 reported that average spike latencies at llOdB SPL for 151 single units of the AI in awake cats ranged from 5 to 30 msec (most being less than 20 msec) , and that the amplitude of the initial positive peak, Plat 12-16 msec, of an epidural recording at the AI was directly proportional to the unit response at middle stimulus levels. In barbiturate-anesthetized cats, Phillips and Irvine l8 recorded the responses of single neurons in the physiologically defined AI at a latency of 8.5-20.8 msec. In their study, the range of the latencies of the AI in awake and anesthetized cats indicated that the PI observed in the AI recording in our present study (see Figs. 1 and 4) reflects the primary auditory cortex response in cats. In the present study, the principal effect of there being bilateral AI lesions on the MLRs in awake cats was the significant decrease of the NA amplitude, which correlates well with the fact that the latency range of the NA largely corresponds to that of PI. It appears to be contradictory that a negative wave (NA) could be recorded from the vertex electrode at a similar latency to the large positive waves (PIs) from the AI electrodes bilaterally. This may be explained by using the concept of an electrical vector, as for the cardiac vector in an ECG. 19 In the cat, the AI is located on the lateral aspect of each hemisphere below the suprasylvian sulcus ls • 2o and this AI has a surface-positive dipole.!3 If the direction of the electrical vector (dipole) is slightly caudal to the horizontal plane, a large positive peak could be recorded at the AI, although a small negative peak could be recorded at the vertex due to the caudal direction of the resultant vector of the right and left electrical vectors. Seen from this viewpoint, the disappearance of large positive waves (P Is) in the bilateral AI recordings can result in the reduction of the amplitude of the negative wave (NA) in the recording at the vertex. In cat #7 (Fig. 4), the PI of the contralateral AI recording was larger than that of the ipsilateral AI recording, and this may have been due to the dominant pathway being contralateral to the stimulated ear with the precise electrode location
AI LESIONING ON CAT MLR
163
overlying the AI. The wave pattern of the ipsilateral AI recording was changed after there was a contralateral AI lesion. This may be accounted for by the disappearance of the far-field electrical potential (P 1 of the contralateral AI recording) and the influence of the cortico-cortical connection. 21 It is generally considered that the presence of a contralateral AI lesion may affect AEPs to a much greater extent than an ipsilateral one. In this study, however, there was no statistical evidence to support this hypothesis, probably because of functional and anatomical variations existing among the cats, so that a greater number of cats than those used in this experiment would seem to be necessary to validate this point. Buchwald et al 14 reported that vertex wave 7 was abolished by aspiration of the bilateral ectosylvian gyri in awake cats. The peak latency of their wave 7 was 10 msec, which is remarkably longer than the latency of our peak 7 at 7-8 msec, but is close to the latency of our peak 8 at 9-lOmsec. In our study, however, neither peak 7 nor peak 8 was abolished but showed various changes in amplitude following aspiration of the bilateral ectosylvian gyri. It is unclear how these discrepancies could have resulted from the same ablation studies of the MLRs in awake cats. Kaga et al 13 reported that the generator of the cat "PA" was the contralateral AI in chloralose-urethane-anesthetized cats. Their MLR configuration which showed a large positive peak was very different from our MLRs of the vertex recordings in awake cats because of the pharmacological action of chloralose-urethane, which is well known to cause marked augmentation of the sensory cortices. In the present study, Nembutal also markedly changed the MLR configuration. Therefore, the states of the cats, awake or anesthetized, should be considered in evaluating the data from MLR studies. The PA wave in humans shows latency, recovery cycle and state-dependent properties 3 that are similar to those of wave "A" in the cat. 22,23 Abnormalities in human PAs are associated with subcortical lesions, not necessarily with the primary auditory cortex,12 while our present study showed that the AI is not the main generator of the PAin cats. The amplitude of a human PAis known to be significantly decreased in general anesthesia with halothane 24 and enflurane/ 5 and the cat PA was observed to disappear in general anesthesia with Nembutal, as seen in Fig. 2. These data suggest that the human PA could be analogous to the cat PA. Our results, taken together with those mentioned above, suggest that the primary auditory cortex in humans could be the generator of Po, NA, and/or PA of the human MLR. The authors gratefully acknowledge the help received in the course of this study from Mr. Osamu Motoyoshi and Miss Yoshiko Hiyama.
164
L. S. KIM, K. KAGA, T. TSUZUKU, et al
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.
13. 14. 15. 16. 17. 18. 19. 20.
21.
22.
Geisler CD, Frishkof LS, Rosenblith WA: Extracranial responses to acoustic clicks in man. Science 128:1210-1211, 1958. Goldstein R, Rodman LB: Early components of averaged evoked responses to rapidly repeated auditory stimuli. J Speech Hear Res 10:697-705, 1967. Picton TW, Hillyard SA, Krausz HI, et al: Human auditory evoked potentials. I. Evaluation of components. Electroenceph Clin Neurophysiol 36:178-190, 1974. Ozdamar 0, Kraus N: Auditory middle-latency responses in human. Audiology 22:34-49, 1983. Kraus N, Ozdamar 0, Hier D, et al: Auditory middle latency responses (MLRs) in patients with cortical lesions. Electroenceph Clin Neurophysiol 54:275-287, 1982. Kiley P, Paccioretti D, Wilson AF: Effects of cortical lesions on middle-latency auditory evoked responses (MLRs). Electroenceph Clin Neurophysiol 66:108-120, 1987. Graham J, Greenwood R, Lecky B: Cortical deafness: a case report and review of the literature. J Neurol Sci 48:35-49, 1980. Shindo M, Kaga K, Tanaka Y: Auditory agnosia following bilateral temporal lobe lesions-report of a case (in Japanese with English abstract). No to Shinkei 33:139-147, 1981. Ozdamar 0, Kraus N, Curry F: Auditory brain stem and middle latency responses in a patient with cortical deafness. Electroenceph Clin Neurophysiol 53:224-230, 1982. Parving A, Salomon G, Elberling C, et al: Middle components of the auditory evoked responses in bilateral temporal lobe lesions. Scand Audiol 9:161-167, 1980. Woods DL, Knight RT, Neville HJ: Bitemporal lesions dissociate auditory evoked potentials and perception. Electroenceph Clin Neurophysiol 57:208-220, 1984. Woods DL, Clayworth CC, Knight RT, et al: Generators of middle- and long-latency auditory evoked potentials: implications from studies of patients with bitemporal lesions. Electroenceph Clin Neurophysiol 68:132-148, 1987. Kaga K, Hink RF, Shinoda Y, et al: Evidence for a primary cortical origin of a middle-latency auditory evoked potential in cats. Electroenceph Clin Neurophysiol 50:254-266, 1980. Buchwald JS, Hinman C, Norman RJ, et al: Middle- and long-latency auditory evoked responses recorded from the vertex of normal and chronically lesioned cats. Brain Res 205:91-109, 1981. Reale RA, Imig TJ: Tonotopic organization in auditory cortex of the cat. J Comp Neuroll92:265291, 1980. Teas DE, Kiang NY: Evoked responses from the auditory cortex. Exp Neurol 10:91-119, 1964. Wolpaw JR: Single unit activity vs. amplitude of the epidural evoked potentials in primary auditory cortex of awake cats. Electroenceph Clin Neurophysiol 47:372-376, 1979. Phillips DP, Irvine DRF: Responses of single neurons in physiologically defined primary auditory cortex (AI) of the cat: frequency tuning and responses to intensity. J NeurophysioI45:48-58, 1981. Goldman MJ: The cardiac vector. Goldman MJ (ed): Principles of Clinical Electrocardiography. 11th ed, Maruzen Asian ed, Chap 4, pp 29-35, LANGE Med. Pub., Tokyo, 1982. Woolsey CN: Organization of cortical auditory system: a review and a synthesis. Rasmussen GL, Windle WF (eds): Neural Mechanism of the Auditory and Vestibular Systems. pp 165-180, Thomas, Springfield, IL, 1960. Imig TJ, Reale RA, Brugge JF, et al: Topography of cortico-cortical connections related to tonotopic and binaural maps of cat auditory cortex. Lepore F, Ptito M, Jasper HH (eds): Two Hemispheres-Dne Brain: Functions of the Corpus Callosum. pp 103-115, Alan R. Liss, New York, 1986. Hinman CL, Buchwald JS: Depth evoked potential and single unit correlates of vertex midlatency auditory evoked responses. Brain Res 264:57-67, 1983.
AI LESIONING ON CAT MLR 23. 24. 25.
165
Buchwald JS: Auditory evoked responses in clinical populations and in the cat. Auris Nasus Larynx (Tokyo) 10:87-95, 1983. James MFM, Thornton C, Jones JG: Halothane anesthesia changes the early components of the auditory evoked responses in man. Br J Anaesth 54:787, 1982. Thornton C, Catley DM, Jordan C, et al: Enfturane anaesthesia causes graded changes in the brainstem and early cortical auditory evoked response in man. Br J Anaesth 55:479-485, 1983.
Request reprints to:
Dr. K. Kaga, Department of Otolaryngology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan
EFFECTS OF PRIMARY AUDITORY CORTEX LESIONS ON MIDDLE LATENCY RESPONSES IN AWAKE CATS Lee Suk KIM, M.D., Kimitaka KAGA, M.D.,* Toshihiro TsuzuKu,** and Akira UNO** Department of Otolaryngology, Seoul National University School of Medicine, Seoul, Korea Faculty of Medicine, The University of Tokyo, Tokyo, Japan Department of Otolaryngology, Teikyo University School of Medicine, Tokyo, Japan
* Department of Otolaryngology,
**
In order to clarify the role of the primary auditory cortex (AI) on middle latency responses (MLRs), we recorded the auditory evoked potentials (AEPs) from the vertex and the right and left AI areas of the skull simultaneously before and after creating serial lesions of the AIs contralateral and ipsilateral to the stimulated ear in 7 awake cats. The auditory brainstem responses (ABRs) and MLRs recorded from the vertex in normal awake cats revealed the presence of peaks 1-8, NA and PA within the analysis time of 50 msec. After there were serial AI lesions, (1) all the peaks remained at nearly the same latencies, (2) the amplitude of the NA was decreased significantly, that of the PA was slightly decreased and those of peaks 6, 7 and 8 were variable, and (3) the difference between the effects of the first operation (contralateral AI) and the second operation (ipsilateral AI) was not statistically significant. These findings indicated that the main, prominent effect of bilateral AI lesions on MLRs in the awake cat is a significant decrease in the NA amplitude. Middle latency responses (MLRs) are vertex-recorded auditory evoked responses (AEPs) detectable from 9-10 to 50-80 msec in humans. 1•4 The origin of the MLR has been the source of continuing debate, and the development of a clinical testing technique has been seriously hampered. In patients with unilateral temporal lobe lesions involving the primary auditory cortex (AI), hemispheric asymmetry of the P A of the MLR has been described, and the bilateral temporal lobes are considered to be the source of the PA. 5,6 In some patients with bilateral lesions of the AI, the PA of the MLR has been shown to be abolished. 7-9 In contrast, in other patients also with bilateral lesions, the PA has remained intact. 10-12 In studies on animal lesions, Kaga et al 13 showed that the cat "PA" is generated by the AI contralateral to the stimulated ear in the chloralose-urethane--anesthetized cat. On the other hand, Buchwald et al 14 showed that the AI is the generator of wave 7 in Received for publication January 6, 1993 155
156
L. S. KIM, K. KAGA, T. TSUZUKU, et al
the awake cat. These conflicting results from human and animal studies raise questions over the role of the AI in the generation of MLR. Comparisons among studies are also complicated by methodologic differences such as the recording site and the type of anesthesia employed. The aim of the present study was to clarify the role of the AI in MLRs. For this purpose, we recorded the AEPs from the vertex of the skull on the right and left AI areas at sites before and after creating serial lesions of the contralateral and ipsilateral AIs in awake cats. METHODS
Seven adult cats weighing 2.5-3.5 kg were used in this study. All cats were behaviorally well oriented to auditory stimuli, and their external auditory canals appeared normal under otoscopic examination. Each cat was anesthetized with 35 mg/kg sodium pentobarbital (Nembutal) injected intraperitoneally, placed in a stereotaxic apparatus, and the skull was exposed. A stainless steel screw was implanted stereotaxically at A7 just lateral to the midline (the "vertex" electrode), and two screws overlying the right and left AIs (the "AI" electrodes) were implanted in the skull bone. Leads from the screws terminated through a small connector mounted on the skull. Two aluminum sleeves were then mounted with dental cement on the front and back of the skull to hold the head motionless during recording. At the time of recording, each cat was comfortably secured in a canvas bag to prevent excessive movement. Horizontal bars projecting medially from the stereotaxic frame were screwed into the implanted aluminum sleeves to immobilize the head. Before the start of any recording, the cats had been earlier trained to become accustomed to this procedure in a sound isolation chamber for a period of 1 or 2 weeks. Under Nembutal anesthesia, the first operation was performed, consisting of subpial aspiration of the auditory cortex in the middle ectosylvian gyrus (areas AI and parts A, DP, All, and p 15 ) contralateral to the stimulated ear (contralateral AI lesion state). Then, 1 or 2 weeks after the first operation, the second operation on the ipsilateral auditory cortex was carried out (bilateral AI lesioning state). After surgery, stainless steel screw electrodes were again implanted in the reconstructed skull overlying the previous AI area in order to compare the AEPs from the AI electrodes before and after creating AI lesions in three cats. AEPs were recorded in awake cats from the vertex electrode and the contralateral and ipsilateral AI electrodes referenced to the mastoid ipsilateral to the stimulated ear simultaneously in three different phases, i.e., before the operation, and 1 week after both the first and second operations. The acoustic stimuli were broad-band clicks (0.1 msec square wave) alternating in polarity and presented monaurally at a rate of 2/sec through a headphone (RION AD 06) in contact with the cat's ear. The stimulus intensity was 110dB peak-equivalent SPL (re: 20PA)
AI LESIONING ON CAT MLR
157
which was about 55-65 dB (SL) above the thresholds of the 7 cats. Broad-band masking (40 dB less intense than the clicks) was presented to the contralateral ear to eliminate any crossover due to bone conduction. The EEG was differentially amplified and band-pass was filtered (lo-l,OOOHz, 12 dB/octave). Averages and replications were obtained for each condition using a signal averager (l00 trials/ average) with an analysis epoch of 50 msec. Averaging was discontinued when the EEG showed artifacts or myogenic contamination. After completing all recordings, the cats were deeply anesthetized with Nembutal and perfused through the left ventricle of the heart with normal saline followed by 10% formalin. The perfused brains were inspected grossly, photographed, and sectioned coronally including the lesion sites. Gross and microscopic examinations of the fixed brains showed that the lesions were at the middle ectosylvian gyrus including the AI and parts of A, DP, All, and plS without involvement of the subcortical area. The following measurements were made for the responses utilizing the cursors of the signal averager: latencies of the peaks, absolute amplitudes of peaks 6, 7, and 8 with respect to peak Nl (negative peak between peak 1 and peak 2), and peak-to-peak amplitudes of 8-NA and NA-PA. RESULTS
Typical MLRs in normal awake cats and anesthetized cats The ABRs (auditory brain stem responses) and MLRs recorded from the
VERTEX CAT +6
NA
o Fig. I.
10
20
30
40
50 msec
The typical ABRs and MLRs of the vertex recordings in two normal awake cats.
L. S. KIM, K. KAGA, T. TSUZUKU, et al
158
CAT #5
- - AWAKE . H., NEMBUTAL PA
VERTEX
CONTRA. AI
Pl._
o
10
IPSI. AI
20
30
40
50 msec
Fig. 2. The cat ABRs and MLRs recorded from the vertex electrode (VERTEX), contralateral AI electrode (CONTRA. AI), and ipsilateral AI electrode (IPS!. AI) elicited by left click stimulation in an awake state and a Nembutal-anesthetized state.
vertex in normal awake cats are shown in Fig. 1. Peaks 1-8, NA, and PA were observed within the analysis time of 50 msec. Figure 2 illustrates the cat ABRs and MLRs obtained from 3 recording sites in an awake state and in a Nembutalanesthetized state. In contrast with the ABRs, the MLRs of the vertex recording were very different from those of the contralateral and ipsilateral AI recordings in the awake state, and they were also different from the AEPs in the Nembutalanesthetized state. This indicated that the results of MLR studies in cats should be interpreted by the data for the vertex recording in an awake state. MLRs (vertex) and AI recordings before and after causing serial AI lesions Figure 3 demonstrates the typical vertex potentials in an awake cat before and after there are contralateral and bilateral AI lesions. It shows that all the peaks were present after there was an AI lesion. Table 1 lists the mean values and standard deviations of MLR and ABR peak latencies for the 7 cats before and after causing serial AI lesions. Since the mean latencies of peaks 4 and 5 in the three phases were the same, the cats were considered to be under similar conditions of stimulus intensity. As illustrated in Table 1, none of the peaks from peak 6 to PA were changed significantly in latency after there was an AI lesion. Figure 4 shows the AEPs from 3 recording sites in three different phase~ of cat #7. In the contralateral and ipsilateral AI recordings, the large PI and the following small wave disappeared after contralateral and bilateral (ipsilatet:al) AI lesions, respectively, were formed. Figure 5 demonstrates the loss of bilateral
AI LESIONING ON CAT MLR
159
CAT #5 : VERTEX PREOP. CONTRA.AI OP. BllAT.AIOP .
.......... _... -... -
I
NA
o
10
30
20
SpY
50 msec
40
Fig. 3. The typical ABRs and MLRs of the preoperative (PREOP.) state and following a contralateral AI lesion (CONTRA. AI OP.) and bilateral AI lesions (BILAT. AI OP.) in an awake cat. Note that all the peaks are present after there is an AI lesion. Table I.
Preoperative and postoperative peak latencies [msec, mean (SD)].
PREOP. CONTRA. AI OP. BILAT. AI OP.
4
5
6
7
8
NA
PA
3.64 (0.20) 3.55 (0.16) 3.59 (0.19)
4.81 (0.28) 4.68 (0.24) 4.74 (0.28)
6.21 (0.41 ) 6.02 (0.54 ) 6.00 (0.44)
7.73 (0.63) 7.73 (0.74 ) 7.56 (0.65)
9.51 (0.52) 9.23 (0.58) 9.21 (0.69)
14.21 ( 1.39)
21.60 (2.34 ) 19.80 (0.07) 19.94 ( 1.60)
l3.10 (0.83) 12.90 (0.37)
auditory cortices of cat #7 after the formation of bilateral AI lesion. The post-Iesioning change in the AI recordings, which was the disappearance of PI and the following small wave, corresponded to the portion ranging from peak 6 to P A in the vertex recordings. These peaks of the vertex recordings were present with the same latency but they changed in amplitude after there were serial AI lesions. As seen in Figs. 3 and 4, peaks 6, 7, and 8 were small ones and the general slope of peaks 6, 7, and 8 was changed after surgery, which was considered to be due to the change in the underlying slow component. From this viewpoint, the absolute amplitudes of peaks 6, 7, and 8 were measured with respect to the peak Nl which was relatively stable (Table 2). Although the mean amplitudes of these three peaks were similar in the three phases, the amplitudes were somewhat variable, as indicated by the large standard deviations which were obtained.
L. S. KIM, K. KAGA, T. TSUZUKU, et al
160
CAT # 7
- - PREOP . . CONTRA.AI OP. -.. ----- BILAT.AI OP.
VERTEX
#~
... .....
... - - - - -
CONTRA. AI
o
10
20
30
40
... ~
.
I
I
10)'Y
20)'V
50 msec
Fig. 4. The auditory evoked potentials recorded from the vertex electrode (VERTEX), ipsilateral AI electrode (IPS!. AI), and contralateral AI electrode (CONTRA. AI) in the preoperative (PREOP.) state and following a contralateral AI lesion (CONTRA. AI OP.) and bilateral AI lesions (BILAT. AI OP.) in an awake cat (#7). Note the relationship between the NA wave and the PI waves.
Fig. 5. The coronary section of the brain of cat #7 demonstrates loss of bilateral auditory cortices after the forming of bilateral AI lesions. The white arrows indicate the lesion sites of the right and left auditory cortices.
Figure 6 shows the mean peak-to-peak amplitudes of 8-NA and NA-PA in the three phases. Statistical analysis of these amplitudes showed a significant difference between the preoperative group and the bilateral AI operation group (Table 3). The amplitudes of NA and PA were decreased significantly after there was an AI lesion. The amplitude of PA, however, may have decreased slightly because the
AI LESIONING ON CAT MLR Table 2.
161
Absolute amplitudes* of peaks 6,7, and 8 (n =7) [V, mean (SD)].
PREOP. CONTRA. AI OP. BILAT. AI OP.
6
7
8
3.94 (2.20) 3.60 (2.49) 3.46 (2.17)
2.16 (1.88) 1.97 (1.74) 1.86 (1.73)
-0.09 (2.73) -0.15 (1.76) -0.67 (1.63)
* Amplitudes with respect to peak NI.
• : 8-NA
fIlV)
o : NA-PA
10
5
o
L -_ _
~
____
~
+-__
____
PREOP. CONTRA. BILAT. AIOP. AIOP.
Fig. 6. The mean peak-to-peak amplitudes of 8-NA and NA-PA in the preoperative (PREOP.) state and after a contralateral AI lesion (CONTRA. AI OP.) in awake cats. Table 3.
Peak-to-peak amplitudes analyses of 8-NA and NA-PA (n =7). 8-NA
NA-'PA
PREOP. vs. CONTRA. AI OP.
PREOP. vs. BILAT. AI OP.
PREOP. vs. CONTRA. AI OP.
PREOP. vs. BILAT. AI OP.
p >0.05
p<0.OO5
P >0.05
p
Probability* * Paired t-test.
reduction in the NA-PA amplitude appeared to be mostly a function of the change of NA. As seen in Fig. 6, the difference between the effects of the first operation (contralateral AI) and the second operation (ipsilateral AI) was not statistically significant (p >0.05).
162
L. S. KIM , K. KAGA, T. TSUZUKU, et al
DISCUSSION
Our present data showed that after the formation of bilateral AI lesions in awake cats, all the peaks remained at nearly the same latencies, the amplitude of NA decreased significantly, the amplitude of PA decreased slightly and the amplitudes of peaks 6, 7, and 8 were variable. These findings suggest that direct activation of the contralateral and ipsilateral AI in the awake cat results in large positive waves, PIs at 12-15 msec, in AI recordings, which were volume-conducted to the vertex as the NA following peak 8. In this study, the auditory evoked potentials recorded from the AI electrodes showed peaks 1-6 of ABR and a small negative deflection around 8- 9 msec followed by a large surface positive peak, PI at 12-15 msec, which is considered to be locally generated, as previous studies have described. 14, 16.17 Wolpaw 17 reported that average spike latencies at llOdB SPL for 151 single units of the AI in awake cats ranged from 5 to 30 msec (most being less than 20 msec) , and that the amplitude of the initial positive peak, Plat 12-16 msec, of an epidural recording at the AI was directly proportional to the unit response at middle stimulus levels. In barbiturate-anesthetized cats, Phillips and Irvine l8 recorded the responses of single neurons in the physiologically defined AI at a latency of 8.5-20.8 msec. In their study, the range of the latencies of the AI in awake and anesthetized cats indicated that the PI observed in the AI recording in our present study (see Figs. 1 and 4) reflects the primary auditory cortex response in cats. In the present study, the principal effect of there being bilateral AI lesions on the MLRs in awake cats was the significant decrease of the NA amplitude, which correlates well with the fact that the latency range of the NA largely corresponds to that of PI. It appears to be contradictory that a negative wave (NA) could be recorded from the vertex electrode at a similar latency to the large positive waves (PIs) from the AI electrodes bilaterally. This may be explained by using the concept of an electrical vector, as for the cardiac vector in an ECG. 19 In the cat, the AI is located on the lateral aspect of each hemisphere below the suprasylvian sulcus ls • 2o and this AI has a surface-positive dipole.!3 If the direction of the electrical vector (dipole) is slightly caudal to the horizontal plane, a large positive peak could be recorded at the AI, although a small negative peak could be recorded at the vertex due to the caudal direction of the resultant vector of the right and left electrical vectors. Seen from this viewpoint, the disappearance of large positive waves (P Is) in the bilateral AI recordings can result in the reduction of the amplitude of the negative wave (NA) in the recording at the vertex. In cat #7 (Fig. 4), the PI of the contralateral AI recording was larger than that of the ipsilateral AI recording, and this may have been due to the dominant pathway being contralateral to the stimulated ear with the precise electrode location
AI LESIONING ON CAT MLR
163
overlying the AI. The wave pattern of the ipsilateral AI recording was changed after there was a contralateral AI lesion. This may be accounted for by the disappearance of the far-field electrical potential (P 1 of the contralateral AI recording) and the influence of the cortico-cortical connection. 21 It is generally considered that the presence of a contralateral AI lesion may affect AEPs to a much greater extent than an ipsilateral one. In this study, however, there was no statistical evidence to support this hypothesis, probably because of functional and anatomical variations existing among the cats, so that a greater number of cats than those used in this experiment would seem to be necessary to validate this point. Buchwald et al 14 reported that vertex wave 7 was abolished by aspiration of the bilateral ectosylvian gyri in awake cats. The peak latency of their wave 7 was 10 msec, which is remarkably longer than the latency of our peak 7 at 7-8 msec, but is close to the latency of our peak 8 at 9-lOmsec. In our study, however, neither peak 7 nor peak 8 was abolished but showed various changes in amplitude following aspiration of the bilateral ectosylvian gyri. It is unclear how these discrepancies could have resulted from the same ablation studies of the MLRs in awake cats. Kaga et al 13 reported that the generator of the cat "PA" was the contralateral AI in chloralose-urethane-anesthetized cats. Their MLR configuration which showed a large positive peak was very different from our MLRs of the vertex recordings in awake cats because of the pharmacological action of chloralose-urethane, which is well known to cause marked augmentation of the sensory cortices. In the present study, Nembutal also markedly changed the MLR configuration. Therefore, the states of the cats, awake or anesthetized, should be considered in evaluating the data from MLR studies. The PA wave in humans shows latency, recovery cycle and state-dependent properties 3 that are similar to those of wave "A" in the cat. 22,23 Abnormalities in human PAs are associated with subcortical lesions, not necessarily with the primary auditory cortex,12 while our present study showed that the AI is not the main generator of the PAin cats. The amplitude of a human PAis known to be significantly decreased in general anesthesia with halothane 24 and enflurane/ 5 and the cat PA was observed to disappear in general anesthesia with Nembutal, as seen in Fig. 2. These data suggest that the human PA could be analogous to the cat PA. Our results, taken together with those mentioned above, suggest that the primary auditory cortex in humans could be the generator of Po, NA, and/or PA of the human MLR. The authors gratefully acknowledge the help received in the course of this study from Mr. Osamu Motoyoshi and Miss Yoshiko Hiyama.
164
L. S. KIM, K. KAGA, T. TSUZUKU, et al
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.
13. 14. 15. 16. 17. 18. 19. 20.
21.
22.
Geisler CD, Frishkof LS, Rosenblith WA: Extracranial responses to acoustic clicks in man. Science 128:1210-1211, 1958. Goldstein R, Rodman LB: Early components of averaged evoked responses to rapidly repeated auditory stimuli. J Speech Hear Res 10:697-705, 1967. Picton TW, Hillyard SA, Krausz HI, et al: Human auditory evoked potentials. I. Evaluation of components. Electroenceph Clin Neurophysiol 36:178-190, 1974. Ozdamar 0, Kraus N: Auditory middle-latency responses in human. Audiology 22:34-49, 1983. Kraus N, Ozdamar 0, Hier D, et al: Auditory middle latency responses (MLRs) in patients with cortical lesions. Electroenceph Clin Neurophysiol 54:275-287, 1982. Kiley P, Paccioretti D, Wilson AF: Effects of cortical lesions on middle-latency auditory evoked responses (MLRs). Electroenceph Clin Neurophysiol 66:108-120, 1987. Graham J, Greenwood R, Lecky B: Cortical deafness: a case report and review of the literature. J Neurol Sci 48:35-49, 1980. Shindo M, Kaga K, Tanaka Y: Auditory agnosia following bilateral temporal lobe lesions-report of a case (in Japanese with English abstract). No to Shinkei 33:139-147, 1981. Ozdamar 0, Kraus N, Curry F: Auditory brain stem and middle latency responses in a patient with cortical deafness. Electroenceph Clin Neurophysiol 53:224-230, 1982. Parving A, Salomon G, Elberling C, et al: Middle components of the auditory evoked responses in bilateral temporal lobe lesions. Scand Audiol 9:161-167, 1980. Woods DL, Knight RT, Neville HJ: Bitemporal lesions dissociate auditory evoked potentials and perception. Electroenceph Clin Neurophysiol 57:208-220, 1984. Woods DL, Clayworth CC, Knight RT, et al: Generators of middle- and long-latency auditory evoked potentials: implications from studies of patients with bitemporal lesions. Electroenceph Clin Neurophysiol 68:132-148, 1987. Kaga K, Hink RF, Shinoda Y, et al: Evidence for a primary cortical origin of a middle-latency auditory evoked potential in cats. Electroenceph Clin Neurophysiol 50:254-266, 1980. Buchwald JS, Hinman C, Norman RJ, et al: Middle- and long-latency auditory evoked responses recorded from the vertex of normal and chronically lesioned cats. Brain Res 205:91-109, 1981. Reale RA, Imig TJ: Tonotopic organization in auditory cortex of the cat. J Comp Neuroll92:265291, 1980. Teas DE, Kiang NY: Evoked responses from the auditory cortex. Exp Neurol 10:91-119, 1964. Wolpaw JR: Single unit activity vs. amplitude of the epidural evoked potentials in primary auditory cortex of awake cats. Electroenceph Clin Neurophysiol 47:372-376, 1979. Phillips DP, Irvine DRF: Responses of single neurons in physiologically defined primary auditory cortex (AI) of the cat: frequency tuning and responses to intensity. J NeurophysioI45:48-58, 1981. Goldman MJ: The cardiac vector. Goldman MJ (ed): Principles of Clinical Electrocardiography. 11th ed, Maruzen Asian ed, Chap 4, pp 29-35, LANGE Med. Pub., Tokyo, 1982. Woolsey CN: Organization of cortical auditory system: a review and a synthesis. Rasmussen GL, Windle WF (eds): Neural Mechanism of the Auditory and Vestibular Systems. pp 165-180, Thomas, Springfield, IL, 1960. Imig TJ, Reale RA, Brugge JF, et al: Topography of cortico-cortical connections related to tonotopic and binaural maps of cat auditory cortex. Lepore F, Ptito M, Jasper HH (eds): Two Hemispheres-Dne Brain: Functions of the Corpus Callosum. pp 103-115, Alan R. Liss, New York, 1986. Hinman CL, Buchwald JS: Depth evoked potential and single unit correlates of vertex midlatency auditory evoked responses. Brain Res 264:57-67, 1983.
AI LESIONING ON CAT MLR 23. 24. 25.
165
Buchwald JS: Auditory evoked responses in clinical populations and in the cat. Auris Nasus Larynx (Tokyo) 10:87-95, 1983. James MFM, Thornton C, Jones JG: Halothane anesthesia changes the early components of the auditory evoked responses in man. Br J Anaesth 54:787, 1982. Thornton C, Catley DM, Jordan C, et al: Enfturane anaesthesia causes graded changes in the brainstem and early cortical auditory evoked response in man. Br J Anaesth 55:479-485, 1983.
Request reprints to:
Dr. K. Kaga, Department of Otolaryngology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan