电刺激对豚鼠听神经兴奋性影响
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摘要
电刺激对豚鼠听神经兴奋性影响
目的
1、研制用于电刺激听神经方波刺激器。2、了解EABR和cABR的相互关系并比较其异同。3、通过记录EABR幅值变化来评估高速率电刺激对听神经兴奋性影响。4、通过记录EABR幅值变化评估不同电刺激强度对听神经兴奋性影响。5、通过记录EABR阈值变化来探导植入刺激电极在豚鼠耳蜗鼓阶内的位置对听神经兴奋性影响。6、通过记录EABR阈值变化搞清楚内耳外淋巴“枯竭”状态对听神经兴奋性影响。
方法
1、应用智能控制的非常实用的独立单片机系统研制用于电刺激听神经方波刺激器。 2、受试动物进入全麻状态后，记录完短声刺激诱发听觉脑干电位，作耳后切口，用电钻磨开豚鼠双耳的上鼓室和后鼓室，暴露豚鼠耳蜗的圆窗，切开圆窗膜，标准电极插入鼓阶大约4mm,两个蜗尖电极作为刺激电极，切开圆窗用压碎颞肌封住。随机选择一耳作为刺激耳，另外一耳作为对照耳，不论是刺激耳还是对照耳都安装上标准电极。刺激电极在整个测试过程中保持不动。在保持刺激强度处在正常临床水平（EABR阈值上6dB）情况下，用四种不同的电刺激速率200PPS(n=14)、400 PPS(n=10)、1000 PPS(n=11)、2000 PPS(n=10) 急性刺激45只听力正常豚鼠鼓阶内电极2小时，记录急性刺激前和急性刺激后三小时内EABR，通过比较急性刺激前和急性刺激后EABR的I波幅值的变化来评估不同电刺激速率对听神经兴奋性影响(t 检验)。3、用三种不同的刺激强度[正常临床水平：EABR阈值上6dB(n=35)或12dB(n=32)，明显高于临床水平：EABR阈值上18dB(n=30)]电荷平衡双相脉冲电流（charge- balanced biphasic current pulse）连续分别急性刺激97只听力正常豚鼠鼓阶内电极2小时，刺激速率分别为200、400、1000PPS，通过比较急性刺激前和刺激后3小时内电刺激脑干诱发
电位I波幅值的变化(t 检验)来评估不同电刺激强度对听神经兴奋性影响。4、为了搞清楚内耳外淋巴“枯竭”状态对听神经兴奋性影响，在手术显微镜帮助下，小心把标准刺激电极放在靠近蜗轴位置，待园窗重新出现外淋巴后，用压碎的肌肉轻轻封住圆窗口。然后用波宽为50μs／phase、刺激速率为30次／秒电荷平衡双相脉冲电流刺激受试动物鼓阶内的靠近蜗尖的电极对（1/2），记录二次EABR阈值，取均值。然后把明胶海绵做成直径约为1mm，长约为4cm小的圆柱形，把一端放入前庭阶持续吸干外淋巴，直到显微镜下见鼓阶外淋巴消失，模拟外淋巴“枯竭”状，用以上类似方法记录电极对（1/2）的二次EABR阈值，取均值，比较前后两次EABR阈值的变化(t 检验)。5、为了探导植入刺激电极在豚鼠耳蜗鼓阶内的位置对听神经兴奋性影响，首先，在手术显微镜帮助下，小心把标准刺激电极放在靠近蜗轴位置，待园窗重新出现外淋巴后，用压碎的肌肉轻轻封住园窗口，记录电极对（1/2）的二次EABR阈值，取均值。然后取出刺激电极，再次植入电极靠近耳蜗鼓阶的外侧壁，待鼓阶浸满外淋巴后，记录电极对（1/2）的二次EABR阈值，取均值，然后比较前后二次记录到的EABR阈值变化(t 检验)。
电刺激诱发听觉脑干电位（electrically evoked auditory brainstem response, EABR）主要用来监测听神经的兴奋状态。受试豚鼠置入声电屏蔽房间内，实行差分记录，记录电极为头顶或者前额：＋，颈：－，腹：地。选择由外部阴极刺激触发Nicolet Spirit Evoked Potential System仪器（U.S.A）记录EABR，记录到的反应放大10５，通过选择放大器参数中抑制电刺激伪迹、50Hz速率电流干扰按纽复选框抑制电刺激伪迹，带通滤波范围（150赫兹~3000赫兹），采样率为20千赫兹，采样时间为12.5ms，叠加次数为500。刺激电流速率为30PPS，脉宽/相位为50μs。刺激电极为标准电极中靠近蜗顶两个电极（电极对1/2）。
EABR阈值：III波的幅值至少为0.15μV时，刺激最低的电流值，用于决定阈值的电流每次升降幅度为0.05 mA。幅值：I波幅值为I波的波峰和接着波谷之间距离即Ｐ１－Ｎ１。潜伏期：刺激开始到I波波峰时间。
由于各个动物之间绝对EABR幅值常常不同，为了便于比较各个不同动物之间EABR幅值，急性刺激后不同观察时间段记录到的EABR幅值分别除以急性刺激前记录到的EABR幅值，取百分值作统计分析。用t 检验比较急性刺激前后EABR
幅值和阈值差异是否有显著性意义。
为了防止动物的全身生理状态改变对动物急性刺激后ＥＡＢＲ幅值改变有影响，对照耳的ＥＡＢＲ的I波幅值急性刺激前后要处于95%的可信区间内。在此实验中绝大多数动物在测试时间内幅值稳定，只有5只豚鼠对照耳的幅值发生显著性变异，从数据中剔除。
结果
1、用于刺激听神经方波刺激器有三个主要性能指标，脉宽／相位：２５μs／phase、５０μs／phase、１００μs／phase；电流强度：５０μＡ~４０００μＡ（每５０μＡ一档上、下可调）；频率：３０次／秒、２００次／秒、４００次／秒、１０００次／秒、１２００次／秒、２０００次／秒，此系统由于本身安装有电子开关，不管刺激频率有多快，在两个刺激电极之间每次刺激后都要发生短路，尽可能减少高频刺激下刺激电极之间残留净电荷，其特点有人机界面友好，性能稳定
The effect of electrical stimulation on excitability of the auditory nerve in guinea pig
Objective
1. To develop a rectangular pulse stimulator for electrical stimulation of auditory nerve. 2. To clarify the correlation between EABRs and cABRs. 3. To assess the effect of high rate electrical stimulation on excitability of the auditory nerve by recording the change of amplitude of the electrically evoked auditory brainstem responses (EABRs) 4. To evaluate the effect of stimulus intensity on excitability of the auditory nerve via recording the change of amplitude of the electrically evoked auditory brainstem responses (EABRs) of guinea pig. 5. To investigate the influence of electrode position within scala tympani of the guinea pig on neural excitability while recording the change of threshold of electrically evoked auditory brainstem responses(EABRs). 6. To clarify the situation concerning the effects of less perilymph in the scala tympani of guinea pig on neural excitability via recording the change of threshold of electrically evoked auditory brainstem responses (EABRs).
Methods
1. A rectangular pulse stimulator for electrical stimulation of auditory nerve was developed using intelligence-controlled and practical Single Chip Micyoco system. 2. After click evoked auditory brainstem responses (cABRs) were recorded in the anesthetic guinea pigs, both bullae
were exposed and the round window membranes incised. A standard electrode array was carefully inserted a distance of approximately 4mm into the scala tympani of both the experimental cochlea and the control cochlea. The most apical electrodes were used as stimulating electrodes. The round window was then sealed with crushed muscle. The electrode arrays were maintained in the same position throughout the experiment. While the stimulus intensities were kept constant in the normal clinical level (6dB above EABR threshold), four stimulus rates of 200(n=14), 400(n=10), 1000(n=11), 2000(n=10) pulses/s(PPS) were each delivered to bipolar electrodes in scala tympani of 45 guinea pigs for 2h acute electrical stimulation.Threshold and wave I amplitudes of EABRs were recorded for periods of 3h following 2h of acute stimulation. By comparing the pre-stimulus amplitudes of wave I in EABRs with the post-stimulus one（t- test）, the effect of high-rate electrical stimulation on the excitability of auditory nerve was assessed. 3. With acute electrical stimulation using stimulus intensities within normal clinical levels [6dB(n=35) or 12dB(n=32) above EABR threshold] or significantly above normal clinical levels[18dB above EABR threshold(n=30)] at different stimulus rate of 200, 400, 1000 pulses/s(PPS) the effect of different stimulus intensity on the excitability of auditory nerve was evaluated by recording the stimulus induced amplitude changes of wave I. 4. With the aid of an operating microscope, the standard electrode array was placed in the specific location adjacent to the modiolus under visual control. After perilymph was again observed at the round window, the electrode entry point was then sealed by gently placing crushed muscle around the electrode array. The stimuli used to evoke EABRs(the probe current) consisted of 50μs per phase biphasic current pulse presented at 30 PPS. The two most apical electrodes were used as stimulating electrodes.
The threshold was defined as the average of two EABR threshold recordings. Following the completion of EABR threshold recordings, the crushed muscle seal was removed, perilymph was continuously aspirated from basal turn by placing the end of 1mm（?）×4cm（L）sponge in the scala vestibule , until the perilymph in the scala tympani was found disappearing under the operating microscope. Then the averaged EABR threshold was again recorded as done before. The situation concerning the effect of less perilymph in the guinea pig scala tympani on neural excitability was clarified by comparing the pre- and post- EABR threshold (t-test). 5. First, with the help of operating micros
目的
1、研制用于电刺激听神经方波刺激器。2、了解EABR和cABR的相互关系并比较其异同。3、通过记录EABR幅值变化来评估高速率电刺激对听神经兴奋性影响。4、通过记录EABR幅值变化评估不同电刺激强度对听神经兴奋性影响。5、通过记录EABR阈值变化来探导植入刺激电极在豚鼠耳蜗鼓阶内的位置对听神经兴奋性影响。6、通过记录EABR阈值变化搞清楚内耳外淋巴“枯竭”状态对听神经兴奋性影响。
方法
1、应用智能控制的非常实用的独立单片机系统研制用于电刺激听神经方波刺激器。 2、受试动物进入全麻状态后，记录完短声刺激诱发听觉脑干电位，作耳后切口，用电钻磨开豚鼠双耳的上鼓室和后鼓室，暴露豚鼠耳蜗的圆窗，切开圆窗膜，标准电极插入鼓阶大约4mm,两个蜗尖电极作为刺激电极，切开圆窗用压碎颞肌封住。随机选择一耳作为刺激耳，另外一耳作为对照耳，不论是刺激耳还是对照耳都安装上标准电极。刺激电极在整个测试过程中保持不动。在保持刺激强度处在正常临床水平（EABR阈值上6dB）情况下，用四种不同的电刺激速率200PPS(n=14)、400 PPS(n=10)、1000 PPS(n=11)、2000 PPS(n=10) 急性刺激45只听力正常豚鼠鼓阶内电极2小时，记录急性刺激前和急性刺激后三小时内EABR，通过比较急性刺激前和急性刺激后EABR的I波幅值的变化来评估不同电刺激速率对听神经兴奋性影响(t 检验)。3、用三种不同的刺激强度[正常临床水平：EABR阈值上6dB(n=35)或12dB(n=32)，明显高于临床水平：EABR阈值上18dB(n=30)]电荷平衡双相脉冲电流（charge- balanced biphasic current pulse）连续分别急性刺激97只听力正常豚鼠鼓阶内电极2小时，刺激速率分别为200、400、1000PPS，通过比较急性刺激前和刺激后3小时内电刺激脑干诱发
电位I波幅值的变化(t 检验)来评估不同电刺激强度对听神经兴奋性影响。4、为了搞清楚内耳外淋巴“枯竭”状态对听神经兴奋性影响，在手术显微镜帮助下，小心把标准刺激电极放在靠近蜗轴位置，待园窗重新出现外淋巴后，用压碎的肌肉轻轻封住圆窗口。然后用波宽为50μs／phase、刺激速率为30次／秒电荷平衡双相脉冲电流刺激受试动物鼓阶内的靠近蜗尖的电极对（1/2），记录二次EABR阈值，取均值。然后把明胶海绵做成直径约为1mm，长约为4cm小的圆柱形，把一端放入前庭阶持续吸干外淋巴，直到显微镜下见鼓阶外淋巴消失，模拟外淋巴“枯竭”状，用以上类似方法记录电极对（1/2）的二次EABR阈值，取均值，比较前后两次EABR阈值的变化(t 检验)。5、为了探导植入刺激电极在豚鼠耳蜗鼓阶内的位置对听神经兴奋性影响，首先，在手术显微镜帮助下，小心把标准刺激电极放在靠近蜗轴位置，待园窗重新出现外淋巴后，用压碎的肌肉轻轻封住园窗口，记录电极对（1/2）的二次EABR阈值，取均值。然后取出刺激电极，再次植入电极靠近耳蜗鼓阶的外侧壁，待鼓阶浸满外淋巴后，记录电极对（1/2）的二次EABR阈值，取均值，然后比较前后二次记录到的EABR阈值变化(t 检验)。
电刺激诱发听觉脑干电位（electrically evoked auditory brainstem response, EABR）主要用来监测听神经的兴奋状态。受试豚鼠置入声电屏蔽房间内，实行差分记录，记录电极为头顶或者前额：＋，颈：－，腹：地。选择由外部阴极刺激触发Nicolet Spirit Evoked Potential System仪器（U.S.A）记录EABR，记录到的反应放大10５，通过选择放大器参数中抑制电刺激伪迹、50Hz速率电流干扰按纽复选框抑制电刺激伪迹，带通滤波范围（150赫兹~3000赫兹），采样率为20千赫兹，采样时间为12.5ms，叠加次数为500。刺激电流速率为30PPS，脉宽/相位为50μs。刺激电极为标准电极中靠近蜗顶两个电极（电极对1/2）。
EABR阈值：III波的幅值至少为0.15μV时，刺激最低的电流值，用于决定阈值的电流每次升降幅度为0.05 mA。幅值：I波幅值为I波的波峰和接着波谷之间距离即Ｐ１－Ｎ１。潜伏期：刺激开始到I波波峰时间。
由于各个动物之间绝对EABR幅值常常不同，为了便于比较各个不同动物之间EABR幅值，急性刺激后不同观察时间段记录到的EABR幅值分别除以急性刺激前记录到的EABR幅值，取百分值作统计分析。用t 检验比较急性刺激前后EABR
幅值和阈值差异是否有显著性意义。
为了防止动物的全身生理状态改变对动物急性刺激后ＥＡＢＲ幅值改变有影响，对照耳的ＥＡＢＲ的I波幅值急性刺激前后要处于95%的可信区间内。在此实验中绝大多数动物在测试时间内幅值稳定，只有5只豚鼠对照耳的幅值发生显著性变异，从数据中剔除。
结果
1、用于刺激听神经方波刺激器有三个主要性能指标，脉宽／相位：２５μs／phase、５０μs／phase、１００μs／phase；电流强度：５０μＡ~４０００μＡ（每５０μＡ一档上、下可调）；频率：３０次／秒、２００次／秒、４００次／秒、１０００次／秒、１２００次／秒、２０００次／秒，此系统由于本身安装有电子开关，不管刺激频率有多快，在两个刺激电极之间每次刺激后都要发生短路，尽可能减少高频刺激下刺激电极之间残留净电荷，其特点有人机界面友好，性能稳定
The effect of electrical stimulation on excitability of the auditory nerve in guinea pig
Objective
1. To develop a rectangular pulse stimulator for electrical stimulation of auditory nerve. 2. To clarify the correlation between EABRs and cABRs. 3. To assess the effect of high rate electrical stimulation on excitability of the auditory nerve by recording the change of amplitude of the electrically evoked auditory brainstem responses (EABRs) 4. To evaluate the effect of stimulus intensity on excitability of the auditory nerve via recording the change of amplitude of the electrically evoked auditory brainstem responses (EABRs) of guinea pig. 5. To investigate the influence of electrode position within scala tympani of the guinea pig on neural excitability while recording the change of threshold of electrically evoked auditory brainstem responses(EABRs). 6. To clarify the situation concerning the effects of less perilymph in the scala tympani of guinea pig on neural excitability via recording the change of threshold of electrically evoked auditory brainstem responses (EABRs).
Methods
1. A rectangular pulse stimulator for electrical stimulation of auditory nerve was developed using intelligence-controlled and practical Single Chip Micyoco system. 2. After click evoked auditory brainstem responses (cABRs) were recorded in the anesthetic guinea pigs, both bullae
were exposed and the round window membranes incised. A standard electrode array was carefully inserted a distance of approximately 4mm into the scala tympani of both the experimental cochlea and the control cochlea. The most apical electrodes were used as stimulating electrodes. The round window was then sealed with crushed muscle. The electrode arrays were maintained in the same position throughout the experiment. While the stimulus intensities were kept constant in the normal clinical level (6dB above EABR threshold), four stimulus rates of 200(n=14), 400(n=10), 1000(n=11), 2000(n=10) pulses/s(PPS) were each delivered to bipolar electrodes in scala tympani of 45 guinea pigs for 2h acute electrical stimulation.Threshold and wave I amplitudes of EABRs were recorded for periods of 3h following 2h of acute stimulation. By comparing the pre-stimulus amplitudes of wave I in EABRs with the post-stimulus one（t- test）, the effect of high-rate electrical stimulation on the excitability of auditory nerve was assessed. 3. With acute electrical stimulation using stimulus intensities within normal clinical levels [6dB(n=35) or 12dB(n=32) above EABR threshold] or significantly above normal clinical levels[18dB above EABR threshold(n=30)] at different stimulus rate of 200, 400, 1000 pulses/s(PPS) the effect of different stimulus intensity on the excitability of auditory nerve was evaluated by recording the stimulus induced amplitude changes of wave I. 4. With the aid of an operating microscope, the standard electrode array was placed in the specific location adjacent to the modiolus under visual control. After perilymph was again observed at the round window, the electrode entry point was then sealed by gently placing crushed muscle around the electrode array. The stimuli used to evoke EABRs(the probe current) consisted of 50μs per phase biphasic current pulse presented at 30 PPS. The two most apical electrodes were used as stimulating electrodes.
The threshold was defined as the average of two EABR threshold recordings. Following the completion of EABR threshold recordings, the crushed muscle seal was removed, perilymph was continuously aspirated from basal turn by placing the end of 1mm（?）×4cm（L）sponge in the scala vestibule , until the perilymph in the scala tympani was found disappearing under the operating microscope. Then the averaged EABR threshold was again recorded as done before. The situation concerning the effect of less perilymph in the guinea pig scala tympani on neural excitability was clarified by comparing the pre- and post- EABR threshold (t-test). 5. First, with the help of operating micros
引文
1 McDermott HJ, Vandali AE, van Hoesel RJM, et al. A portable programmable digital sound processor for cochlear implant research. IEEE Trans. Rehabil. Eng, 1993,1(2):94-100
2 Wilson BS, Finley CC, Lawson DT, et al . Better speech recognition with cochlear implants. Nature, 1991;352:236~238
3 Huang CQ, Shepherd RK. Reduction in excitability of the auditory nerve following electrical stimulation at high stimulus rates. IV. Effects of stimulus intensity. Hear Res, 1999;132:60-68
4 Huang CQ, Shepherd RK. Reduction in excitability of the auditory nerve following electrical stimulation at high stimulus rates: V. Effects of electrode surface area. Hear Res, 2000;146(1-2):57-71
5 Tykocinski MT, Shepherd RK and Clark GM. Reduction in excitability of the auditory nerve following electrical stimulation at high stimulus rates. Hear Res, 1995;88:124~142
6 Mitchell A, Miller JM, Finger PA, et al. Effect of chronic high-rate electrical stimulation on the cochlea and eight nerve in the deafened guinea pig. Hear Res,1997;105:30-43
7 Xu J, Shepherd RK, Millard RE, et al. Chronic electrical stimulation of the auditory nerve at high stimulus rates: a physiological and histopathological study. Hear Res,1997;105:1-29
8 Huang CQ, Shepherd RK, Seligman PM, et al. Reduction in excitability of the auditory nerve following acute electrical stimulation at high stimulus rates: III. Capacitive versus non-capacitive coupling of the stimulating electrodes. Hear Res, 1998;116(1-2):55-64
9 王正敏. 病理内耳外淋巴新生的临床研究.中华耳鼻咽喉杂志.1994; 29(1):58
10 Shepherd RK, Hatsushika S, Clark GM. Electrical stimulation of
the auditory nerve: the effect of electrode position on neural excitation. Hear Res ，1993 ，66(1):108-20
11 Huang CQ, Carter PM, Shepherd RK. Stimulus induced pH changes in cochlear implants :an in vitro and in vivo study. Annals of Biomedical Engineering, 2001,29:791-802
12 Macaulay RB. Estimated range of current levels used by nucleus implantees. Cochlear Technical Memo no.71, 1995
13 Killian MJP, Klis SFL, Smoorenburg GF. Adaptation in the compound action potential response of the guinea pig VIIIth nerve to electric stimulation. Hear Res ,1994;81:66-82
14 Melcher JR, Kiang NYS. Generators of the brainstem auditory evoked potential in cat III: identified cell populations. Hear Res,1996;93:52-71
15 Vischer M, Haenggeli A, Zhang J, et al. Effect of high-frequency electrical stimulation of the auditory nerve in an animal model of cochlear implants. Am J Otol,1997;18:S27-S29
16 Kim-Lee MH, Stokes BT, Anderson DK. Intracellular calcium dynamics and cerebral injury: modeling various insults in vitro. Brain Res. 1993; 613: 156-159
17 Shepherd RK, Clark GM. Effect of high electrical stimulus intensities on the auditory nerve using brain stem response audiometry. Ann. Otol. Rhinol. Laryngol. Suppl. 1987; 128(96):50-53
18 Black RC, Clark GM, O'Leary SJ, et al. Intracochlear electrical stimulation of normal and deaf cats investigated using brainstem response audiometry. Acta Otolaryngol. Suppl.1983;399:5-17
19 McAnally KI, Clark GM, Syka J. Hair cell mediated responses of the auditory nerve to electrical stimulation of the cochlea in the cat. Hear Res.1993;67:55-68
20 McAnally KI, Brown M, Clark GM. Estimating mechanical responses to pulsatile electrical stimulation of the cochlea. Hear Res.1997;106:146-153
21 Kennedy DW. Multichannel intracochlear electrodes: mechanism of insertion trauma. Laryngoscope .1987;97:42-9
22 Tykocinski M, Cohen LT, Pyman BC, et al. Comparison of electrode position in the human cochlea using various perimodiolar electrode arrays. Am J Otol 2000; 21(2): 205-11
23 Tykocinski M, Saunders E, Cohen LT,et al. The contour electrode array: safety study and initial patient trials of a new perimodiolar design. Otol Neurotol, 2001 ;22(1):33-41
24 Badi AN, Hillman T,Shelton C, et al. A technique for implantation of a 3-dimensional penetrating electrode array in the modiolar nerve of cats and humans. Arch Otolaryngol Head Neck Surg,2002;128(9):1019-25
25 Frijns JHM, Briaire JJ, Grote JJ. The importance of human cochlear anatomy for the results of modiolus-hugging multichannel cochlear implants.Otology& Neurotology,2001; 22:340-349
26 Spelman FA. Determination of tissue impedances of the inner ear: Models and measurements. In: Miller JM, Spelman FA. Cochar Implant: Models of the Electrically Stimulated Ear. New York:Springer-Verlag. 1990;35-51
27 Finley CC, Wilson BS and White MW. Models of neural responsiveness to electrical stimulation . In: Miller JM, Spelman FA. Cochlear Implant: Models of the Electrically Stimulated Ear. New York :Springer-Verlag. 1990;55-91
28 Geisler CD. Electrical characteristic of cochlear tissues. In: Miller JM, Spelman FA. Cochlear Implant: Models of the Electrically Stimulated Ear. New York:Springer-Verlag. 1990;7-15
2 Wilson BS, Finley CC, Lawson DT, et al . Better speech recognition with cochlear implants. Nature, 1991;352:236~238
3 Huang CQ, Shepherd RK. Reduction in excitability of the auditory nerve following electrical stimulation at high stimulus rates. IV. Effects of stimulus intensity. Hear Res, 1999;132:60-68
4 Huang CQ, Shepherd RK. Reduction in excitability of the auditory nerve following electrical stimulation at high stimulus rates: V. Effects of electrode surface area. Hear Res, 2000;146(1-2):57-71
5 Tykocinski MT, Shepherd RK and Clark GM. Reduction in excitability of the auditory nerve following electrical stimulation at high stimulus rates. Hear Res, 1995;88:124~142
6 Mitchell A, Miller JM, Finger PA, et al. Effect of chronic high-rate electrical stimulation on the cochlea and eight nerve in the deafened guinea pig. Hear Res,1997;105:30-43
7 Xu J, Shepherd RK, Millard RE, et al. Chronic electrical stimulation of the auditory nerve at high stimulus rates: a physiological and histopathological study. Hear Res,1997;105:1-29
8 Huang CQ, Shepherd RK, Seligman PM, et al. Reduction in excitability of the auditory nerve following acute electrical stimulation at high stimulus rates: III. Capacitive versus non-capacitive coupling of the stimulating electrodes. Hear Res, 1998;116(1-2):55-64
9 王正敏. 病理内耳外淋巴新生的临床研究.中华耳鼻咽喉杂志.1994; 29(1):58
10 Shepherd RK, Hatsushika S, Clark GM. Electrical stimulation of
the auditory nerve: the effect of electrode position on neural excitation. Hear Res ，1993 ，66(1):108-20
11 Huang CQ, Carter PM, Shepherd RK. Stimulus induced pH changes in cochlear implants :an in vitro and in vivo study. Annals of Biomedical Engineering, 2001,29:791-802
12 Macaulay RB. Estimated range of current levels used by nucleus implantees. Cochlear Technical Memo no.71, 1995
13 Killian MJP, Klis SFL, Smoorenburg GF. Adaptation in the compound action potential response of the guinea pig VIIIth nerve to electric stimulation. Hear Res ,1994;81:66-82
14 Melcher JR, Kiang NYS. Generators of the brainstem auditory evoked potential in cat III: identified cell populations. Hear Res,1996;93:52-71
15 Vischer M, Haenggeli A, Zhang J, et al. Effect of high-frequency electrical stimulation of the auditory nerve in an animal model of cochlear implants. Am J Otol,1997;18:S27-S29
16 Kim-Lee MH, Stokes BT, Anderson DK. Intracellular calcium dynamics and cerebral injury: modeling various insults in vitro. Brain Res. 1993; 613: 156-159
17 Shepherd RK, Clark GM. Effect of high electrical stimulus intensities on the auditory nerve using brain stem response audiometry. Ann. Otol. Rhinol. Laryngol. Suppl. 1987; 128(96):50-53
18 Black RC, Clark GM, O'Leary SJ, et al. Intracochlear electrical stimulation of normal and deaf cats investigated using brainstem response audiometry. Acta Otolaryngol. Suppl.1983;399:5-17
19 McAnally KI, Clark GM, Syka J. Hair cell mediated responses of the auditory nerve to electrical stimulation of the cochlea in the cat. Hear Res.1993;67:55-68
20 McAnally KI, Brown M, Clark GM. Estimating mechanical responses to pulsatile electrical stimulation of the cochlea. Hear Res.1997;106:146-153
21 Kennedy DW. Multichannel intracochlear electrodes: mechanism of insertion trauma. Laryngoscope .1987;97:42-9
22 Tykocinski M, Cohen LT, Pyman BC, et al. Comparison of electrode position in the human cochlea using various perimodiolar electrode arrays. Am J Otol 2000; 21(2): 205-11
23 Tykocinski M, Saunders E, Cohen LT,et al. The contour electrode array: safety study and initial patient trials of a new perimodiolar design. Otol Neurotol, 2001 ;22(1):33-41
24 Badi AN, Hillman T,Shelton C, et al. A technique for implantation of a 3-dimensional penetrating electrode array in the modiolar nerve of cats and humans. Arch Otolaryngol Head Neck Surg,2002;128(9):1019-25
25 Frijns JHM, Briaire JJ, Grote JJ. The importance of human cochlear anatomy for the results of modiolus-hugging multichannel cochlear implants.Otology& Neurotology,2001; 22:340-349
26 Spelman FA. Determination of tissue impedances of the inner ear: Models and measurements. In: Miller JM, Spelman FA. Cochar Implant: Models of the Electrically Stimulated Ear. New York:Springer-Verlag. 1990;35-51
27 Finley CC, Wilson BS and White MW. Models of neural responsiveness to electrical stimulation . In: Miller JM, Spelman FA. Cochlear Implant: Models of the Electrically Stimulated Ear. New York :Springer-Verlag. 1990;55-91
28 Geisler CD. Electrical characteristic of cochlear tissues. In: Miller JM, Spelman FA. Cochlear Implant: Models of the Electrically Stimulated Ear. New York:Springer-Verlag. 1990;7-15