Original research paper
Impact of modulating phase duration on electrically evoked auditory brainstem responses obtained during cochlear implantation N-X Bonne1,2 , D Douchement 1,2, G Hosana 3, J Desruelles 1,2, P Fayoux3, I Ruzza 1,2, C Vincent 1,2 1
Department of Otology and Neurotology, University Hospital of Lille, Lille, France, 2Department of Audiophonology, University Hospital of Lille, Lille, France, 3Department of Pediatric Otolaryngology, Jeanne de Flandre Children Hospital, University Hospital of Lille, Lille, France Objective: To investigate the effect of increasing phase duration (pulse width, T-pulse) using a biphasic pulse composed of an initial anodic active phase followed by a balancing cathodic phase on the electrically evoked auditory brainstem responses (eABRs) recorded at the time of cochlear implantation. Design: eABRs recorded during 188 surgeries for cochlear implantation from 1999 to 2006 in a single center were retrospectively reviewed by two independent observers. All patients were fitted with a NEURELEC cochlear implant (CI) device, initially DIGISONIC® then DIGISONIC SP® (2004–2006). Result: Immediately following cochlear implantation, stimulation by the CI resulted in reliable wave III and V eABR waveforms (mean wave III latency 2.23 ± 0.38 ms SD and wave V latency 4.28 ± 0.42 ms SD). Latencies followed an apical to basal gradient (0.32 ms increase in mean eV latency and 0.12 ms for eIII latency). With increasing phase duration, wave III and wave V latencies significantly decreased in association with a shortening of the eIII–eV interwave gap, while amplitudes of both waves increased. Conclusion: The impact of increasing phase duration on latency and amplitude of brainstem responses in a large set of patients implanted with NEURELEC CIs was reported. Keywords: Electrically evoked auditory brainstem repsonses, Deafness, Cochlear implant
Introduction Cochlear implants (CIs) are used to bypass the damaged cochlea in severe-to-profound sensorineural hearing loss. A CI generates a controlled firing of groups of auditory nerve fibers through electrical stimulation of the spiral ganglion. In this study we used the MXM/NEURELEC DIGISONIC® CI device (Chouard et al., 1995a , 1995b). This device delivers biphasic pulse trains with sequential stimulation along the electrode array from base to apex. The biphasic pulse has an initial anodic active phase followed by a charge balancing cathodic phase realized through capacitive coupling. The nature of the pulse combined with coding by phase duration (i.e. pulse width, T-pulse) results in an electrical dynamic range
Correspondence to: Nicolas-Xavier Bonne, Otologie et Otoneurologie, Hôpital Roger Salengro, CHRU Lille – Avenue E Laine, Lille, Cedex 59037, France. Email: [email protected]
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of 30–100 dB associated with good perceptual loudness linearity (Gallego et al., 1999). Several objective tests allow assessment of the electrophysiological response to an electrical stimulus delivered to the cochlea: neural response telemetry, eighth nerve evoked compound action potentials, electrically evoked auditory brainstem responses (eABR), electrically evoked middle and late latency auditory responses (EMLR). The examination of eABR not only confirms the effective coupling between the array and the cochlea but also gives insight into the auditory pathway. Indeed it records the response along the auditory pathway, from the spiral ganglion to the midbrain, in response to an electrical stimulation delivered by the CI (van den Honert and Stypulkowski, 1986). eABR contains a series of one to three positive peaks (e.g. waves II, III, and V) occurring between 1 and 5 ms after presentation of the stimulus. Wave I is generally not visible because it is
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obscured by the stimulus artifact but would be expected to have a latency of approximately 0.75 ms (Firszt et al., 2002). The expected latency for wave V in response to a stimulus delivered at a high current level is between 3.5 and 4.0 ms and delays with decreasing stimulus’ amplitude (i.e. decreasing the current level). Wave V is the most robust component of the eABR recognizable on most implant electrodes and is observable at lower stimulus levels than other waves (Firszt et al., 2002). Studies referring to the evaluation of the MXM – NEURELEC DIGISONIC® CI device have successfully used eABR for objective testing of the auditory pathway following cochlear implantation (Herve et al., 1996; Gallego et al., 1999; Truy et al., 1998; Thai-Van et al., 2007). These studies focused on eABR change over time and correlation between electrophysiological responses and perceptional abilities in awake children. Meanwhile it remains unclear whether eABR would provide a reliable electrophysiologic testing of this device during cochlear implantation and under general anesthesia. The establishment of reliable stimulation parameters and filter settings in association to their corresponding expected eABR values would help in assessing the accurate function and placement of the electrode array. Ultimately, it would help in predicting the functional expectancies
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at the time of surgery. Indeed, a better knowledge of the initial response for each individual CI device may help to generate the initial mapping. Therefore, we aimed to evaluate the influence of varying a single stimulation parameter (T-pulse width) at different sites along the cochlea. Our secondary goal was to identify the reproducibility of intra-operative eABR recording at the time of cochlear implantation in a large population of early and late onset deafness.
Material and methods Study design This study provides a descriptive statistical analysis of per-operative intracochlear eABR obtained at two different phase durations (i.e. T-pulse widths) in three distinct locations of the cochlea. All eABRs recorded following the fitting of a MXM – NEURELEC DIGISONIC® CI at the time of surgery between 1999 and 2006 in the tertiary referral center of Otology & Neurotology University hospital of Lille, France were reviewed. One hundred and eighty eight patients were included in the study and 1128 eABR waveforms were subsequently included. The acquisition procedure was standardized as described below. All curves where reviewed independently by two experts and we excluded the following Table 2 Late onset deafness: clinical findings in 100 implanted patients
Table 1 Early onset deafness: clinical findings in 88 implanted patients
(n=) (n=)
Familial/genetic
Connexin 26
Usher Jervel & LangeNielsen Pendred Chromosomic (caryotype)
Non familial
Familial Metabolic disorder Infectious
Cardiac malformation
Obstetrical With associated inner ear malformation
Isolated large vestibular acqueduc Mondini Sever but not classified
Homozygote Heterozygote Yes but unknown
Inverted insertion of chromosome 1 and 3 Microdeletion in 22q11.2 Undetermined Hypothyroid Cytomegalovirus Congenital rubella Pneumococcal meningitis With hydrocephalus With vetebral anomaly Prematurity Small body weight
10 3 3 1 1
Familial/genetic
Connexin 26 Refsum disease NF2
Non familial
Familial Otologic condition
1 1
Autoimmune/ metabolic disorder
1 3 1 3 1 3
Infectious
Ototoxic 1 1 2 2 1
2 3
Traumatic With associated inner ear malformation
Homozygote Heterozygote Intracochlear schwannoma Undetermined Chronic otitis media Otospongiose Intralabyrinthine hemorrhage Sudden SNHL Insulin-dependent diabetes Fahr disease Crohn’s disease Magic syndrome Meningitis Syphilis Rubella Streptamycin Chemotherapy Reanimation care Noise induced Bilateral fracture
Isolated large vestibular aqueduct Mondini Sever but not classified
2 1 1 1 13 10 2
2 1 1 1 1 9 1 1 2 1 1 2 5 1
0 0
SNHL, sensory-neural hearing loss. NF2, neurofibromatosis type 2.
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from the analysis: any re-implantation procedures, all sets of curves without a clear and readable response, all curves with noticeable discrepancies by the two observers, absence of paired measurements for the same T-pulse in the analysis of stimulation position.
Subjects The study was realized in compliance with the institutional review board. All participants underwent eABR examinations as part of their regular clinical follow-up, and were not evaluated for the purpose of this study. These data are a retrospective collection of clinical evaluations. The study did not interfere either with the surgical decision with respect to device choice or with the routine standardized postoperative evaluation. Anonymity was respected. Clinical evaluation of the whole population allowed identification of a causative or precipitating pathology in 55% (104/188) listed in Tables 1 and 2. All were fitted unilaterally with a NEURELEC® CI device (124 CONVEX and 64 SP-20). The mean age at implantation was 22.9 years, ranging from 6 months to 80 years. Eighty-eight patients (46.8%) were deafened before the first year of life (early onset deafness). In this group, the implantation age was 2.9 ± 1.4 years. Forty-two deaf patients (22.3%) were genetically predisposed; 19 (10.1%) GJB2-related deafness were identified (12 of those 19 were homozygote carriers of the 35delG mutation). The preoperative imaging examination (MRI and CT-scan) revealed 20 innerear abnormalities, in which 7 were malformations, 4 were fibrosis and/or partial ossification, 5 were bilateral translabyrinthine fractures, and 2 were ostospongiosis, there was one intravestibular schwannoma occurring in the setting of neurofibromatosis type 2.
Technique used for intra-operative evoked potential recordings (Fig. 1) All patients were fitted with a CI under general anesthesia. Electrophysiological testing of the device and auditory pathway was performed at the end of the surgery when the patient was still in the operating room and under general anesthesia. An integrity test of all electrodes was performed and then followed with a numeric computerized record of eABR. The recording system was the Centaur USB (DeltaMed / Racia-Alvar, Le Bouscat, France). Recording started 200 μs after stimulation and was averaged over 1000 acquisitions. The gain of the amplifier was set at 100. Responses were pass band filtered between 160 and 1.6 kHz. The stimulus used in this study was a biphasic pulse train and the stimulation parameters were set as follows: the stimulation rate was 47 Hz and the amplitude of stimulation was set at 40 units for all DIGISONIC® CONVEX and 70 units for DIGISONIC® SP-20. Concerning the temporal
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parameters of the pulse, interphase gap was constant over all measurements and two values of pulse width (T-pulse) were tested to allow paired comparison. Three groups of electrodes (i.e. apical, middle, and basal) were stratified for analysis according to their anticipated location within the cochlea.
Data collection and statistical analysis Electrophysiological data were collected in an excel datasheet following two independent reviews of the collected eABR waveforms. The latency and amplitude values of wave III and wave V peaks at two durations of T-pulse for each group of electrode were collected. Groups were defined by the reviewers as follows: apical (18–20), middle (10–12), and basal (3–7). Surgical records were checked to ensure complete insertion of the array. Clinical features such as age at implantation, age at deafness, cause of deafness, imaging findings, and surgical findings were also collected. Values are given as mean ± SD or mean ± SEM, when unless otherwise specified. Statistical analyses were completed using SPSS 10.1 software. Parametric paired t-tests were used to compare values obtained for two durations of T-pulse, then two values for a given T-pulse at different sites of the cochlea, for multiple comparisons a one-way analysis of variance (ANOVA) with Bonferroni post-test analysis was used (Graphpad Prism 5.0). This approach was chosen to reduce skews and to improve the study of two parameters (e.g. T-pulse and site of stimulation).
Results Normative values We reviewed the sets of six supra-threshold eABR recordings obtained (using the single fixed amplitude and two different pulse durations) following 188 cochlear implantations. One thousand one hundred and twenty-eight such eABR recordings were eligible for review. Wave V was identified 738 times (738/ 1128, i.e. 68%), and wave III 682 times (682/1128, i.e. 60.5%). Average durations of T-pulse in eABR recordings with identifiable waves were 48.4 μs in the case of wave V and 48.2 μs in the case of wave III. There was no difference in T-pulse durations across the wave III-wave V groups (t-test, P = 0.84, ns). Overall latencies of wave V was found at an average of 4.28 ± 0.42 ms and 2.23 ± 0.38 ms for wave III (mean ± SD). Overall amplitudes were found to be 0.238 ± 0.19 μV (wave V) and 0.193 ± 0.16 μV (wave III) (mean ± SD).
Effect of increasing pulse width (T-pulse, Fig. 2) The effect of pulse width was studied by measuring the values of latencies and amplitudes obtained at two different durations of T-pulse for a given patient at the same intensity for each group of electrodes. The results are shown in Fig. 2A–B. Responses evoked by
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Figure 1 (A) Stimulogramme of the stimulus used throughout the series. (B) Electrically evoked auditory brainstem responses obtained at decreasing pulse width for a same intensity.
a shorter stimulus were recorded later and were lower in amplitude for both III and V (P < 0.0001, paired t-test). Also, we looked at the III–V gap at short and longer Tpulse durations to better localize the sites of integration along the auditory pathway. Overall, there was a significant reduction in III–V gap with a longer T-pulse durations (paired t-test, P < 0.001). This reduction in III–V results from a larger decrease in wave V latency relative to the decrease of wave III latency. Last we measured amplitude responses to stimulation and were able to identify an increase in amplitude with increasing Tpulse (paired t-test, P < 0.001).
Site of stimulation within the cochlea and eABR responses In order to identify the effects of the location of stimulation within the cochlea, paired-values obtained in a particular patient and for the same pulse duration in at least two electrode locations were processed for statistical analysis. Apical region results were compared
successively to the middle and basal regions. Ultimately the mid-cochlear and the basal groups were compared. A significant difference was found for latencies (Fig. 3A–C) and amplitudes between each group. A basal-to-apical gradient in latency was observed (0.32 ms increase in mean V latency and 0.12 ms for III latency). Amplitudes of waves III and V were larger in the apical compared with middle and basal groups.
eABR are susceptible to maturity of the auditory pathway prior cochlear implantation Last, we divided the cohort by age at the onset of deafness to compare the eABR in prelingual deafness versus post-lingual deafness. Therefore, we used a one-way ANOVA test with Bonferroni post-test analysis that allows multiple comparisons. We compared the latencies of waves III and V and the III–V interwave gap obtained at the most reliable site (e.g. apical). At the Apical level and for the longer durations of T-
Figure 2 Paired comparison: latencies and amplitudes of waves III and V are susceptible to the duration of the stimulus (Tpulse). Latencies and amplitudes are graphed using Box plot with whiskers 5–95 percentiles. (A) Increasing the T-pulse duration significantly shortened III and V latencies obtained in paired measurements (***P < 0.0001, paired t-test). (B) Similarly, amplitudes are higher when T-pulse is longer (***P < 0.0001, paired t-test).
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Figure 3 Stimulations delivered in similar conditions generate shorter eABR latencies and greater amplitudes in the apical compared with the mid-cochlear and basal regions (paired t-test). (A–C and D–F) Data are summarized using bar graph (mean ± SEM) and individual P values are specified on top of each capped line with the number of paired value available indicated below the line. The distribution follows an apical-to-basal gradient of latency.
pulse, the latency of waves V (P < 0.01, n = 162) and III (P < 0.05, n = 157) were significantly shorter for the post-lingually deafened. Interestingly, the III–V gap was also decreased (P < 0.05, n = 154) in the latter group. Furthermore, for shorter T-pulses, we identified a similar trend with shorter III–V interwave gaps in the post-lingual deafened group (P = ns, n = 159) as well as a shorter latency for wave V (P = ns) (Fig. 4).
Discussion In the reported study, we monitored eABR intraoperatively after fitting of a CI. The operating room is an unfavorable environment to record eABR because of
the increased sources of artifacts. Thus, it is not clear whether reproducible results can be obtained under such circumstances (including the effects of the cochleostomy). In addition, it is not established whether eABR results obtained in the operating room immediately during cochlear implantation are comparable to those obtained after healing of the cochleostomy, either in a standard clinical setting or in a laboratory. We studied eABR responsivity to increasing phase duration while under general anesthesia and at the time of first cochlear implantation. Hence, the results reported herein contribute to already existing data obtained later after surgery.
Figure 4 Consequence of auditory maturity on wave latency in response to the very first electrical stimulation. We divided our results into two groups regarding onset of the deafness: early onset deafness (EOD) vs. late onset deafness (LOD). Average latencies for waves III and V and interwave gap are represented as mean ± SEM. Individual P values are figured on top of ‘early onset deafness’ graph bar (Bonferroni test for multiple comparisons).
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We used biphasic pulse trains to stimulate the auditory nerve at different sites along the cochlea and recorded the more central evoked responses using eABRs. Using biphasic stimuli has the advantage of balancing the charge but is less efficient in activating nerve cells (Shepherd and Javel, 1997). This is in part due to the negative phase that counter balances the initial positive phase. As such, the interphase gap is an important parameter to consider and its influence over eABR and behavioral testing are well described (Macherey et al., 2008; Undurraga et al., 2012). First, we found that wave V is the most robust component of eABRs, consistent with previous reports from the literature (Firszt et al., 2002). Wave V is identifiable from most electrodes even for shorter Tpulse durations and for basal electrodes. Wave III is harder to identify, in particular in basal electrodes where the response is less consistent. In the eABR waveform, Latencies follow a decreasing gradient from the base to the apex of the array, associated with increasing amplitudes of eABR waveforms. This apical-to-basal gradient has been described using different CI technology and stimulation modalities (Miller et al., 1993; Firszt et al., 2002; Allum et al., 1990; Shallop et al., 1990). This gradient seems to be correlated to specific neural response properties and can be dependent on deafness etiology or spiral ganglion neuron survival (Prado-Guitierrez et al., 2006; Propst et al., 2006). It is well described that using a long phase-duration pulse reduces behavioral thresholds (Moon et al., 1993). Davids et al. (2008a, 2008b, 2008c) further investigated the consequence of varying pulse duration on eABR and EMLR in five paediatric CI recipients. They report that increasing the pulse duration results in a shortening of the III–V interwave gap. The authors consequently postulate that increases in the stimulus duration for any aspect of the stimulus phase including overall pulse train duration, interphase gap, and pulse width effectively reduce behavioral thresholds in CI users. In our study, we observe that increasing the pulse width (i.e. phase duration) reduces both the III–V interwave gap and individual latencies of wave III and V in patients with prelingual and postlingual deafness. Change in III–V interwave gap suggests an integration occurring at the brainstem level rather than from the peripheral auditory system. Therefore, temporal integration may be processed at the brainstem level. In fact, we also describe a decrease in wave III latency across patients suggesting that some integration could also exist between the level of the organ of Corti and superior olivary complex. The changes in latencies and interwave gap reported herein are consistent with experimental models using single auditory nerve fiber recordings in cats (Shepherd and Javel, 1997). However, the mechanism
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by which an increase in duration of the pulse acts to improve the thresholds is not perfectly understood. Theoretical studies modeling the mechanism of extra-cellular stimulation predict that nerve fibers are excited equally when increasing amplitude or duration of stimulation. This trend is captured by the so-called strength–duration curve which relates the response strength to the amount of injected charge Q = I × t. Strength–duration curves predict correctly that threshold is decreasing if stimulation pulse width increases. However, the assumptions behind the theory of strength duration (myelinated fibers of constant inter-node gap and simple stimulation geometry) are clearly not met in the clinical test where patients have variable nerve survival, peripheral process, and myelination degeneracy. In human studies, Davids et al. (2008b) suggest that longer duration pulses could activate multiple spikes in a single fiber and/ or induce more effective patterns of spikes across fibers. Some studies have suggested a relationship between the effects of pulse duration and neural survival, either in guinea pigs or in human (Miller et al., 1993; McKay and McDermott, 1999). Others hypothesized that neural demyelinization in consequence of prolonged deafness could result in increasing the time constant of the neural membrane causing longer time to reach the threshold potential for initiation of an action potential (Prado-Guitierrez et al., 2006). There is evidence that the maturational process of the auditory system relates to changes in eABR pattern (Thai-Van et al., 2007). For example, chronic electrical stimulation results in shortening the III–V interwave gap. Therefore, we aimed to compare at the scale of a population the latencies obtained for pre-lingually deafened patients in comparison to post-lingually deafened at a single time point. We choose to address this question by comparing the results obtained with identical parameters at the very first electrical stimulation of the pathway in both groups. Indeed, we describe significantly shorter latencies for waves V and III, and a shorter III–V gap at the apical level and for longer duration of T-pulse in the post-lingual deafened population. Further studies would be necessary to specifically address this point by gathering important information such as time of hearing deprivation and language skills before CI activation. Meanwhile our work is complementary to the literature, as a statistical model has been proposed to predict the maturational changes in wave V latency expected in CI users (Thai-Van et al., 2007). A new prospective study, with methodology based on this study but standardized, is warranted. Even though electrophysiological thresholds tend to be higher than behavioral comfort levels by 30–40 clinical current units (Pfingst, 1988; Smith et al.,
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1994; Hughes et al., 2001), a previous work found a significant correlation between eABR and perceptual thresholds, and demonstrated predictability of the loudness range in a population implanted with a DIGISONIC® CI (Gallego et al., 1999). Human studies suggest that eABR could be a powerful tool to predict speech recognition based on the wave III–V latency interval (Gallego et al., 1998). Indeed in the latter report, a small interval (1.44 ms) correlated with 100% speech recognition whereas 0% speech discrimination is obtained when the interval increased to 2.33 ms (Gallego et al., 1998). In conclusion, we can now provide normative values for intracochlear eABR registered during cochlear implantation under general anesthesia. These data will help in the fine assessment of implant function during CI surgery.
Disclaimer statements Contributors Nicolas-Xavier Bonne collected the data, did the statistical analysis, and wrote the article. Dorothée Douchement critically reviewed the manuscript. Grégory Hosana critically reviewed the manuscript. Julie Desruelles critically reviewed the manuscript. Pierre Fayoux critically reviewed the manuscript. Isabelle Ruzza and Christophe Vincent designed the study and reviewed the final manuscript. Funding This research has been funded by the University Hospital of Lille in full. Conflicts of interest None of the authors have conflicts of interest to disclose. Ethics approval Approval was felt to be unnecessary from the comity because it did not require specific experiments.
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Davids T., Valero J., Papsin B.C., Harrison R.V., Gordon K.A. 2008c. Effects of stimulus manipulation on electrophysiological responses of pediatric cochlear implant users. Part II: rate effects. Hear Res, 244: 15–24. Firszt J.B., Chambers R.D., Kraus N. 2002. Neurophysiology of cochlear implant users II: comparison among speech perception, dynamic range, and physiological measures. Ear Hear, 23: 516–531. Gallego S., Frachet B., Micheyl C., Truy E., Collet L. 1998. Cochlear implant performance and electrically-evoked auditory brain-stem response characteristics. Electroencephalogr Clin Neurophysiol, 108: 521–525. Gallego S., Garnier S., Micheyl C., Truy E., Morgon A., Collet L. 1999. Loudness growth functions and EABR characteristics in Digisonic cochlear implantees. Acta Otolaryngol, 119: 234–238. Herve T., Truy E., Durupt I., Collet L. 1996. A new stimulation strategy for recording electrical auditory evoked potentials in cochlear implant patients. Electroencephalogr Clin Neurophysiol, 100: 472–478. Hughes M.L., Vander Werff K.R., Brown C.J., Abbas P.J., Kelsay D.M., Teagle H.F., et al. 2001. A longitudinal study of electrode impedance, the electrically evoked compound action potential, and behavioral measures in nucleus 24 cochlear implant users. Ear Hear, 22: 471–486. Macherey O., Carlyon R.P., Van Wieringen A., Deeks J.M., Wouters J. 2008. Higher sensitivity of human auditory nerve fibers to positive electrical currents. J Assoc Res Otolaryngol, 9: 241–251. Mckay C.M., Mcdermott H.J. 1999. The perceptual effects of current pulse duration in electrical stimulation of the auditory nerve. J Acoust Soc Am, 106: 998–1009. Miller C.A., Abbas P.J., Brown C.J. 1993. Electrically evoked auditory brainstem response to stimulation of different sites in the cochlea. Hear Res, 66: 130–142. Moon A.K., Zwolan T.A., Pfingst B.E. 1993. Effects of phase duration on detection of electrical stimulation of the human cochlea. Hear Res, 67: 166–178. Pfingst B.E. 1988. Comparisons of psychophysical and neurophysiological studies of cochlear implants. Hear Res, 34: 243–251. Prado-Guitierrez P., Fewster L.M., Heasman J.M., Mckay C.M., Shepherd R.K. 2006. Effect of interphase gap and pulse duration on electrically evoked potentials is correlated with auditory nerve survival. Hear Res, 215: 47–55. Propst E.J., Papsin B.C., Stockley T.L., Harrison R.V., Gordon K.A. 2006. Auditory responses in cochlear implant users with and without GJB2 deafness. Laryngoscope, 116: 317–327. Shallop J.K., Beiter A.L., Goin D.W., Mischke R.E. 1990. Electrically evoked auditory brain stem responses (EABR) and middle latency responses (EMLR) obtained from patients with the nucleus multichannel cochlear implant. Ear Hear, 11: 5–15. Shepherd R.K., Javel E. 1997. Electrical stimulation of the auditory nerve. I. Correlation of physiological responses with cochlear status. Hear Res, 108: 112–144. Smith D.W., Finley C.C., Van Den Honert C., Olszyk V.B., Konrad K.E. 1994. Behavioral and electrophysiological responses to electrical stimulation in the cat. I. Absolute thresholds. Hear Res, 81: 1–10. Thai-Van H., Cozma S., Boutitie F., Disant F., Truy E., Collet L. 2007. The pattern of auditory brainstem response wave V maturation in cochlear-implanted children. Clin Neurophysiol, 118: 676–689. Truy E., Gallego S., Chanal J.M., Collet L., Morgon A. 1998. Correlation between electrical auditory brainstem response and perceptual thresholds in Digisonic cochlear implant users. Laryngoscope, 108: 554–559. Undurraga J.A., Carlyon R.P., Macherey O., Wouters J., Van Wieringen A. 2012. Spread of excitation varies for different electrical pulse shapes and stimulation modes in cochlear implants. Hear Res, 290: 21–36. Van Den Honert C., Stypulkowski P.H. 1986. Characterization of the electrically evoked auditory brainstem response (ABR) in cats and humans. Hear Res, 21: 109–126.
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Impact of modulating phase duration on electrically evoked auditory brainstem responses obtained during cochlear implantation N-X Bonne1,2 , D Douchement 1,2, G Hosana 3, J Desruelles 1,2, P Fayoux3, I Ruzza 1,2, C Vincent 1,2 1
Department of Otology and Neurotology, University Hospital of Lille, Lille, France, 2Department of Audiophonology, University Hospital of Lille, Lille, France, 3Department of Pediatric Otolaryngology, Jeanne de Flandre Children Hospital, University Hospital of Lille, Lille, France Objective: To investigate the effect of increasing phase duration (pulse width, T-pulse) using a biphasic pulse composed of an initial anodic active phase followed by a balancing cathodic phase on the electrically evoked auditory brainstem responses (eABRs) recorded at the time of cochlear implantation. Design: eABRs recorded during 188 surgeries for cochlear implantation from 1999 to 2006 in a single center were retrospectively reviewed by two independent observers. All patients were fitted with a NEURELEC cochlear implant (CI) device, initially DIGISONIC® then DIGISONIC SP® (2004–2006). Result: Immediately following cochlear implantation, stimulation by the CI resulted in reliable wave III and V eABR waveforms (mean wave III latency 2.23 ± 0.38 ms SD and wave V latency 4.28 ± 0.42 ms SD). Latencies followed an apical to basal gradient (0.32 ms increase in mean eV latency and 0.12 ms for eIII latency). With increasing phase duration, wave III and wave V latencies significantly decreased in association with a shortening of the eIII–eV interwave gap, while amplitudes of both waves increased. Conclusion: The impact of increasing phase duration on latency and amplitude of brainstem responses in a large set of patients implanted with NEURELEC CIs was reported. Keywords: Electrically evoked auditory brainstem repsonses, Deafness, Cochlear implant
Introduction Cochlear implants (CIs) are used to bypass the damaged cochlea in severe-to-profound sensorineural hearing loss. A CI generates a controlled firing of groups of auditory nerve fibers through electrical stimulation of the spiral ganglion. In this study we used the MXM/NEURELEC DIGISONIC® CI device (Chouard et al., 1995a , 1995b). This device delivers biphasic pulse trains with sequential stimulation along the electrode array from base to apex. The biphasic pulse has an initial anodic active phase followed by a charge balancing cathodic phase realized through capacitive coupling. The nature of the pulse combined with coding by phase duration (i.e. pulse width, T-pulse) results in an electrical dynamic range
Correspondence to: Nicolas-Xavier Bonne, Otologie et Otoneurologie, Hôpital Roger Salengro, CHRU Lille – Avenue E Laine, Lille, Cedex 59037, France. Email: [email protected]
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of 30–100 dB associated with good perceptual loudness linearity (Gallego et al., 1999). Several objective tests allow assessment of the electrophysiological response to an electrical stimulus delivered to the cochlea: neural response telemetry, eighth nerve evoked compound action potentials, electrically evoked auditory brainstem responses (eABR), electrically evoked middle and late latency auditory responses (EMLR). The examination of eABR not only confirms the effective coupling between the array and the cochlea but also gives insight into the auditory pathway. Indeed it records the response along the auditory pathway, from the spiral ganglion to the midbrain, in response to an electrical stimulation delivered by the CI (van den Honert and Stypulkowski, 1986). eABR contains a series of one to three positive peaks (e.g. waves II, III, and V) occurring between 1 and 5 ms after presentation of the stimulus. Wave I is generally not visible because it is
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obscured by the stimulus artifact but would be expected to have a latency of approximately 0.75 ms (Firszt et al., 2002). The expected latency for wave V in response to a stimulus delivered at a high current level is between 3.5 and 4.0 ms and delays with decreasing stimulus’ amplitude (i.e. decreasing the current level). Wave V is the most robust component of the eABR recognizable on most implant electrodes and is observable at lower stimulus levels than other waves (Firszt et al., 2002). Studies referring to the evaluation of the MXM – NEURELEC DIGISONIC® CI device have successfully used eABR for objective testing of the auditory pathway following cochlear implantation (Herve et al., 1996; Gallego et al., 1999; Truy et al., 1998; Thai-Van et al., 2007). These studies focused on eABR change over time and correlation between electrophysiological responses and perceptional abilities in awake children. Meanwhile it remains unclear whether eABR would provide a reliable electrophysiologic testing of this device during cochlear implantation and under general anesthesia. The establishment of reliable stimulation parameters and filter settings in association to their corresponding expected eABR values would help in assessing the accurate function and placement of the electrode array. Ultimately, it would help in predicting the functional expectancies
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at the time of surgery. Indeed, a better knowledge of the initial response for each individual CI device may help to generate the initial mapping. Therefore, we aimed to evaluate the influence of varying a single stimulation parameter (T-pulse width) at different sites along the cochlea. Our secondary goal was to identify the reproducibility of intra-operative eABR recording at the time of cochlear implantation in a large population of early and late onset deafness.
Material and methods Study design This study provides a descriptive statistical analysis of per-operative intracochlear eABR obtained at two different phase durations (i.e. T-pulse widths) in three distinct locations of the cochlea. All eABRs recorded following the fitting of a MXM – NEURELEC DIGISONIC® CI at the time of surgery between 1999 and 2006 in the tertiary referral center of Otology & Neurotology University hospital of Lille, France were reviewed. One hundred and eighty eight patients were included in the study and 1128 eABR waveforms were subsequently included. The acquisition procedure was standardized as described below. All curves where reviewed independently by two experts and we excluded the following Table 2 Late onset deafness: clinical findings in 100 implanted patients
Table 1 Early onset deafness: clinical findings in 88 implanted patients
(n=) (n=)
Familial/genetic
Connexin 26
Usher Jervel & LangeNielsen Pendred Chromosomic (caryotype)
Non familial
Familial Metabolic disorder Infectious
Cardiac malformation
Obstetrical With associated inner ear malformation
Isolated large vestibular acqueduc Mondini Sever but not classified
Homozygote Heterozygote Yes but unknown
Inverted insertion of chromosome 1 and 3 Microdeletion in 22q11.2 Undetermined Hypothyroid Cytomegalovirus Congenital rubella Pneumococcal meningitis With hydrocephalus With vetebral anomaly Prematurity Small body weight
10 3 3 1 1
Familial/genetic
Connexin 26 Refsum disease NF2
Non familial
Familial Otologic condition
1 1
Autoimmune/ metabolic disorder
1 3 1 3 1 3
Infectious
Ototoxic 1 1 2 2 1
2 3
Traumatic With associated inner ear malformation
Homozygote Heterozygote Intracochlear schwannoma Undetermined Chronic otitis media Otospongiose Intralabyrinthine hemorrhage Sudden SNHL Insulin-dependent diabetes Fahr disease Crohn’s disease Magic syndrome Meningitis Syphilis Rubella Streptamycin Chemotherapy Reanimation care Noise induced Bilateral fracture
Isolated large vestibular aqueduct Mondini Sever but not classified
2 1 1 1 13 10 2
2 1 1 1 1 9 1 1 2 1 1 2 5 1
0 0
SNHL, sensory-neural hearing loss. NF2, neurofibromatosis type 2.
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from the analysis: any re-implantation procedures, all sets of curves without a clear and readable response, all curves with noticeable discrepancies by the two observers, absence of paired measurements for the same T-pulse in the analysis of stimulation position.
Subjects The study was realized in compliance with the institutional review board. All participants underwent eABR examinations as part of their regular clinical follow-up, and were not evaluated for the purpose of this study. These data are a retrospective collection of clinical evaluations. The study did not interfere either with the surgical decision with respect to device choice or with the routine standardized postoperative evaluation. Anonymity was respected. Clinical evaluation of the whole population allowed identification of a causative or precipitating pathology in 55% (104/188) listed in Tables 1 and 2. All were fitted unilaterally with a NEURELEC® CI device (124 CONVEX and 64 SP-20). The mean age at implantation was 22.9 years, ranging from 6 months to 80 years. Eighty-eight patients (46.8%) were deafened before the first year of life (early onset deafness). In this group, the implantation age was 2.9 ± 1.4 years. Forty-two deaf patients (22.3%) were genetically predisposed; 19 (10.1%) GJB2-related deafness were identified (12 of those 19 were homozygote carriers of the 35delG mutation). The preoperative imaging examination (MRI and CT-scan) revealed 20 innerear abnormalities, in which 7 were malformations, 4 were fibrosis and/or partial ossification, 5 were bilateral translabyrinthine fractures, and 2 were ostospongiosis, there was one intravestibular schwannoma occurring in the setting of neurofibromatosis type 2.
Technique used for intra-operative evoked potential recordings (Fig. 1) All patients were fitted with a CI under general anesthesia. Electrophysiological testing of the device and auditory pathway was performed at the end of the surgery when the patient was still in the operating room and under general anesthesia. An integrity test of all electrodes was performed and then followed with a numeric computerized record of eABR. The recording system was the Centaur USB (DeltaMed / Racia-Alvar, Le Bouscat, France). Recording started 200 μs after stimulation and was averaged over 1000 acquisitions. The gain of the amplifier was set at 100. Responses were pass band filtered between 160 and 1.6 kHz. The stimulus used in this study was a biphasic pulse train and the stimulation parameters were set as follows: the stimulation rate was 47 Hz and the amplitude of stimulation was set at 40 units for all DIGISONIC® CONVEX and 70 units for DIGISONIC® SP-20. Concerning the temporal
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parameters of the pulse, interphase gap was constant over all measurements and two values of pulse width (T-pulse) were tested to allow paired comparison. Three groups of electrodes (i.e. apical, middle, and basal) were stratified for analysis according to their anticipated location within the cochlea.
Data collection and statistical analysis Electrophysiological data were collected in an excel datasheet following two independent reviews of the collected eABR waveforms. The latency and amplitude values of wave III and wave V peaks at two durations of T-pulse for each group of electrode were collected. Groups were defined by the reviewers as follows: apical (18–20), middle (10–12), and basal (3–7). Surgical records were checked to ensure complete insertion of the array. Clinical features such as age at implantation, age at deafness, cause of deafness, imaging findings, and surgical findings were also collected. Values are given as mean ± SD or mean ± SEM, when unless otherwise specified. Statistical analyses were completed using SPSS 10.1 software. Parametric paired t-tests were used to compare values obtained for two durations of T-pulse, then two values for a given T-pulse at different sites of the cochlea, for multiple comparisons a one-way analysis of variance (ANOVA) with Bonferroni post-test analysis was used (Graphpad Prism 5.0). This approach was chosen to reduce skews and to improve the study of two parameters (e.g. T-pulse and site of stimulation).
Results Normative values We reviewed the sets of six supra-threshold eABR recordings obtained (using the single fixed amplitude and two different pulse durations) following 188 cochlear implantations. One thousand one hundred and twenty-eight such eABR recordings were eligible for review. Wave V was identified 738 times (738/ 1128, i.e. 68%), and wave III 682 times (682/1128, i.e. 60.5%). Average durations of T-pulse in eABR recordings with identifiable waves were 48.4 μs in the case of wave V and 48.2 μs in the case of wave III. There was no difference in T-pulse durations across the wave III-wave V groups (t-test, P = 0.84, ns). Overall latencies of wave V was found at an average of 4.28 ± 0.42 ms and 2.23 ± 0.38 ms for wave III (mean ± SD). Overall amplitudes were found to be 0.238 ± 0.19 μV (wave V) and 0.193 ± 0.16 μV (wave III) (mean ± SD).
Effect of increasing pulse width (T-pulse, Fig. 2) The effect of pulse width was studied by measuring the values of latencies and amplitudes obtained at two different durations of T-pulse for a given patient at the same intensity for each group of electrodes. The results are shown in Fig. 2A–B. Responses evoked by
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Figure 1 (A) Stimulogramme of the stimulus used throughout the series. (B) Electrically evoked auditory brainstem responses obtained at decreasing pulse width for a same intensity.
a shorter stimulus were recorded later and were lower in amplitude for both III and V (P < 0.0001, paired t-test). Also, we looked at the III–V gap at short and longer Tpulse durations to better localize the sites of integration along the auditory pathway. Overall, there was a significant reduction in III–V gap with a longer T-pulse durations (paired t-test, P < 0.001). This reduction in III–V results from a larger decrease in wave V latency relative to the decrease of wave III latency. Last we measured amplitude responses to stimulation and were able to identify an increase in amplitude with increasing Tpulse (paired t-test, P < 0.001).
Site of stimulation within the cochlea and eABR responses In order to identify the effects of the location of stimulation within the cochlea, paired-values obtained in a particular patient and for the same pulse duration in at least two electrode locations were processed for statistical analysis. Apical region results were compared
successively to the middle and basal regions. Ultimately the mid-cochlear and the basal groups were compared. A significant difference was found for latencies (Fig. 3A–C) and amplitudes between each group. A basal-to-apical gradient in latency was observed (0.32 ms increase in mean V latency and 0.12 ms for III latency). Amplitudes of waves III and V were larger in the apical compared with middle and basal groups.
eABR are susceptible to maturity of the auditory pathway prior cochlear implantation Last, we divided the cohort by age at the onset of deafness to compare the eABR in prelingual deafness versus post-lingual deafness. Therefore, we used a one-way ANOVA test with Bonferroni post-test analysis that allows multiple comparisons. We compared the latencies of waves III and V and the III–V interwave gap obtained at the most reliable site (e.g. apical). At the Apical level and for the longer durations of T-
Figure 2 Paired comparison: latencies and amplitudes of waves III and V are susceptible to the duration of the stimulus (Tpulse). Latencies and amplitudes are graphed using Box plot with whiskers 5–95 percentiles. (A) Increasing the T-pulse duration significantly shortened III and V latencies obtained in paired measurements (***P < 0.0001, paired t-test). (B) Similarly, amplitudes are higher when T-pulse is longer (***P < 0.0001, paired t-test).
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Figure 3 Stimulations delivered in similar conditions generate shorter eABR latencies and greater amplitudes in the apical compared with the mid-cochlear and basal regions (paired t-test). (A–C and D–F) Data are summarized using bar graph (mean ± SEM) and individual P values are specified on top of each capped line with the number of paired value available indicated below the line. The distribution follows an apical-to-basal gradient of latency.
pulse, the latency of waves V (P < 0.01, n = 162) and III (P < 0.05, n = 157) were significantly shorter for the post-lingually deafened. Interestingly, the III–V gap was also decreased (P < 0.05, n = 154) in the latter group. Furthermore, for shorter T-pulses, we identified a similar trend with shorter III–V interwave gaps in the post-lingual deafened group (P = ns, n = 159) as well as a shorter latency for wave V (P = ns) (Fig. 4).
Discussion In the reported study, we monitored eABR intraoperatively after fitting of a CI. The operating room is an unfavorable environment to record eABR because of
the increased sources of artifacts. Thus, it is not clear whether reproducible results can be obtained under such circumstances (including the effects of the cochleostomy). In addition, it is not established whether eABR results obtained in the operating room immediately during cochlear implantation are comparable to those obtained after healing of the cochleostomy, either in a standard clinical setting or in a laboratory. We studied eABR responsivity to increasing phase duration while under general anesthesia and at the time of first cochlear implantation. Hence, the results reported herein contribute to already existing data obtained later after surgery.
Figure 4 Consequence of auditory maturity on wave latency in response to the very first electrical stimulation. We divided our results into two groups regarding onset of the deafness: early onset deafness (EOD) vs. late onset deafness (LOD). Average latencies for waves III and V and interwave gap are represented as mean ± SEM. Individual P values are figured on top of ‘early onset deafness’ graph bar (Bonferroni test for multiple comparisons).
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We used biphasic pulse trains to stimulate the auditory nerve at different sites along the cochlea and recorded the more central evoked responses using eABRs. Using biphasic stimuli has the advantage of balancing the charge but is less efficient in activating nerve cells (Shepherd and Javel, 1997). This is in part due to the negative phase that counter balances the initial positive phase. As such, the interphase gap is an important parameter to consider and its influence over eABR and behavioral testing are well described (Macherey et al., 2008; Undurraga et al., 2012). First, we found that wave V is the most robust component of eABRs, consistent with previous reports from the literature (Firszt et al., 2002). Wave V is identifiable from most electrodes even for shorter Tpulse durations and for basal electrodes. Wave III is harder to identify, in particular in basal electrodes where the response is less consistent. In the eABR waveform, Latencies follow a decreasing gradient from the base to the apex of the array, associated with increasing amplitudes of eABR waveforms. This apical-to-basal gradient has been described using different CI technology and stimulation modalities (Miller et al., 1993; Firszt et al., 2002; Allum et al., 1990; Shallop et al., 1990). This gradient seems to be correlated to specific neural response properties and can be dependent on deafness etiology or spiral ganglion neuron survival (Prado-Guitierrez et al., 2006; Propst et al., 2006). It is well described that using a long phase-duration pulse reduces behavioral thresholds (Moon et al., 1993). Davids et al. (2008a, 2008b, 2008c) further investigated the consequence of varying pulse duration on eABR and EMLR in five paediatric CI recipients. They report that increasing the pulse duration results in a shortening of the III–V interwave gap. The authors consequently postulate that increases in the stimulus duration for any aspect of the stimulus phase including overall pulse train duration, interphase gap, and pulse width effectively reduce behavioral thresholds in CI users. In our study, we observe that increasing the pulse width (i.e. phase duration) reduces both the III–V interwave gap and individual latencies of wave III and V in patients with prelingual and postlingual deafness. Change in III–V interwave gap suggests an integration occurring at the brainstem level rather than from the peripheral auditory system. Therefore, temporal integration may be processed at the brainstem level. In fact, we also describe a decrease in wave III latency across patients suggesting that some integration could also exist between the level of the organ of Corti and superior olivary complex. The changes in latencies and interwave gap reported herein are consistent with experimental models using single auditory nerve fiber recordings in cats (Shepherd and Javel, 1997). However, the mechanism
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by which an increase in duration of the pulse acts to improve the thresholds is not perfectly understood. Theoretical studies modeling the mechanism of extra-cellular stimulation predict that nerve fibers are excited equally when increasing amplitude or duration of stimulation. This trend is captured by the so-called strength–duration curve which relates the response strength to the amount of injected charge Q = I × t. Strength–duration curves predict correctly that threshold is decreasing if stimulation pulse width increases. However, the assumptions behind the theory of strength duration (myelinated fibers of constant inter-node gap and simple stimulation geometry) are clearly not met in the clinical test where patients have variable nerve survival, peripheral process, and myelination degeneracy. In human studies, Davids et al. (2008b) suggest that longer duration pulses could activate multiple spikes in a single fiber and/ or induce more effective patterns of spikes across fibers. Some studies have suggested a relationship between the effects of pulse duration and neural survival, either in guinea pigs or in human (Miller et al., 1993; McKay and McDermott, 1999). Others hypothesized that neural demyelinization in consequence of prolonged deafness could result in increasing the time constant of the neural membrane causing longer time to reach the threshold potential for initiation of an action potential (Prado-Guitierrez et al., 2006). There is evidence that the maturational process of the auditory system relates to changes in eABR pattern (Thai-Van et al., 2007). For example, chronic electrical stimulation results in shortening the III–V interwave gap. Therefore, we aimed to compare at the scale of a population the latencies obtained for pre-lingually deafened patients in comparison to post-lingually deafened at a single time point. We choose to address this question by comparing the results obtained with identical parameters at the very first electrical stimulation of the pathway in both groups. Indeed, we describe significantly shorter latencies for waves V and III, and a shorter III–V gap at the apical level and for longer duration of T-pulse in the post-lingual deafened population. Further studies would be necessary to specifically address this point by gathering important information such as time of hearing deprivation and language skills before CI activation. Meanwhile our work is complementary to the literature, as a statistical model has been proposed to predict the maturational changes in wave V latency expected in CI users (Thai-Van et al., 2007). A new prospective study, with methodology based on this study but standardized, is warranted. Even though electrophysiological thresholds tend to be higher than behavioral comfort levels by 30–40 clinical current units (Pfingst, 1988; Smith et al.,
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1994; Hughes et al., 2001), a previous work found a significant correlation between eABR and perceptual thresholds, and demonstrated predictability of the loudness range in a population implanted with a DIGISONIC® CI (Gallego et al., 1999). Human studies suggest that eABR could be a powerful tool to predict speech recognition based on the wave III–V latency interval (Gallego et al., 1998). Indeed in the latter report, a small interval (1.44 ms) correlated with 100% speech recognition whereas 0% speech discrimination is obtained when the interval increased to 2.33 ms (Gallego et al., 1998). In conclusion, we can now provide normative values for intracochlear eABR registered during cochlear implantation under general anesthesia. These data will help in the fine assessment of implant function during CI surgery.
Disclaimer statements Contributors Nicolas-Xavier Bonne collected the data, did the statistical analysis, and wrote the article. Dorothée Douchement critically reviewed the manuscript. Grégory Hosana critically reviewed the manuscript. Julie Desruelles critically reviewed the manuscript. Pierre Fayoux critically reviewed the manuscript. Isabelle Ruzza and Christophe Vincent designed the study and reviewed the final manuscript. Funding This research has been funded by the University Hospital of Lille in full. Conflicts of interest None of the authors have conflicts of interest to disclose. Ethics approval Approval was felt to be unnecessary from the comity because it did not require specific experiments.
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