Maturation of the mismatch negativity: effects of profound deafness and cochlear implant use.

The use of cochlear implants to restore auditory sensation in deaf children is increasing, with a trend toward earlier implantation. However, little is known about how auditory deprivation and subsequent cochlear implant use affect the maturing human central auditory system. Our previous studies have demonstrated that the obligatory auditory evoked potentials (AEPs) of implanted children are very different from those of normal-hearing children. Unlike the obligatory potentials, which primarily reflect neural responses to stimulus onset, the mismatch negativity (MMN) provides a neurophysiological measure of auditory short-term memory and discrimination processes. The purpose of this investigation is to review our studies of the effects of auditory deprivation due to profound deafness and cochlear implant use on the maturation of the MMN in children, placed in the context of overall age-related changes in the AEPs. The development and application of a statistical technique to assess the MMN in individuals is also reviewed. Results show that although the morphology of the obligatory AEPs is substantially altered by the absence of a normal N(1) peak, the MMN is robustly present in a group of implanted children who have good spoken language perception through their device. Differences exist in the scalp distribution of the MMN between implanted and normal-hearing children. Specifically, the MMN appears to be more symmetrical in amplitude over both hemispheres, whereas it is initially much larger over the contralateral hemisphere in normal-hearing children. These findings suggest that, compared to N(1), the MMN is a better measure of basic auditory processes necessary for the development of spoken language perception skills in profoundly deaf children and adults who use a cochlear implant.

Cochlear implantation of auditory neuropathy.

Auditory neuropathy (AN) is a hearing disorder that presents with a grossly abnormal or absent neural response as measured by evoked potentials in the presence of normal outer hair cell function evidenced by present otoacoustic emissions or cochlear microphonics. Rehabilitation for patients with AN is challenging due to abnormal temporal encoding at the auditory nerve leading to severely impaired speech perception. Although patients with AN may demonstrate improvement in thresholds with amplification, temporal encoding dysfunction, and consequently speech perception degradation, is not alleviated by amplification. Another issue is the heterogeneity of the AN population in terms of audiologic and neurologic findings, in addition to uncertain etiology and pathophysiology. For children with prelingual onset of AN, development of auditory and oral communication skills is particularly compromised. All children with hearing loss in the severe-to-profound range who do not benefit from conventional amplification can be considered candidates for a cochlear implant (CI). This paper presents a case study of a child with AN who received a CI. Whereas no synchronous neural response auditory brainstem response could be elicited to acoustic stimuli, an electrically evoked auditory nerve action potential was evident following implantation, suggesting restoration to some degree of neural synchrony. Significant improvement in speech perception was found post-CI. Recommendation to implant all patients with AN would be premature, but these findings suggest that electrical stimulation in some cases of auditory neuropathy can be a viable option.

Regenerated hair cells become functional during continuous administration of kanamycin.

The compound action potential (CAP) was used to assess the functional status of regenerated hair cells in the chick cochlea during prolonged administration of kanamycin (KM). Immediately after 10 days of KM treatment, the CAP thresholds were elevated by 6-54 dB above those from age-matched control animals. The frequencies with the greatest threshold shifts (> 1 kHz) corresponded to the hair cell lesion in the basal 40% of the basilar papilla. After 20 days of KM, the CAP thresholds at 3 and 4 kHz were significantly lower than those after 10 days of KM treatment, but virtually the same as those after 10 days of KM plus 10 days of recovery. Similarly, the CAP amplitudes at frequencies higher than 1.5 kHz were significantly greater in animals that received KM for 20 days than in animals that received KM for 10 days. The threshold as well as amplitude improvement between 10 days and 20 days of KM treatment was associated with the morphological maturation of the regenerated hair cells in the basal 25% of the cochlea. In addition, the rapid functional recovery seen at high frequencies coincided with the base-to-apex gradient of morphological recovery in the basilar papilla. These results suggest that the process of hair cell maturation is not suppressed by the presence of aminoglycosides in the extracellular environment.

Hair cell regeneration and recovery of function in the avian auditory system.

Chickens were exposed to an intense pure tone that destroyed the hair cells and tectorial membrane in a crescent shaped patch along the abneural edge of the basilar papilla. During the following weeks, when the hair cells and tectorial membrane were regenerating, psychophysical and electrophysiological measures were obtained to assess the time course and degree of recovery. Immediately after the exposure, the behavioral thresholds were elevated 30-40 dB and auditory temporal integration was greatly reduced; however, both measures fully recovered by 28 days post-exposure. In addition, tone-on-tone masking patterns recovered to normal. Immediately after the exposure, the thresholds of single cochlear ganglion neurons were elevated more than 30 dB, tuning curves were broader than normal, two-tone rate suppression (TTRS) boundary slopes were shallower than normal and spontaneous activity was reduced. Threshold and spontaneous discharge rate fully recovered after the exposure. Tuning and TTRS also recovered significantly in most neurons; however, some units with characteristic frequencies (CFs) near the exposure frequency showed abnormal tuning and TTRS suppression. The regeneration of the hair cells and lower honeycomb layer of the tectorial membrane is associated with considerable recovery of function; however, the incomplete recovery of tuning and TTRS in some neurons may be linked to the incomplete regeneration of the tectorial membrane.

Steady state EP is not responsible for hearing loss in adult chickens following acoustic trauma.

The steady state DC endocochlear potential (EP) in young chicks shows a large decrease after acoustic overstimulation followed by a rapid recovery that parallels the recovery of threshold (Poje et al., Hear. Res. 82 (1995) 197-204). These results raise a question as to whether or not the EP could account for the hearing loss and make a significant contribution to the recovery of the threshold. In contrast to results in young chicks, we show that acoustic overstimulation, which causes extensive hair cell damage, does not cause a decrease in the steady state EP in adult chickens. However, there is a significant reduction in the negative EP seen during anoxia which persists even after 4 weeks of recovery. Thus, our results indicate that the steady state EP cannot account for the hearing loss observed in adult chickens.

Effects of selective inner hair cell loss on auditory nerve fiber threshold, tuning and spontaneous and driven discharge rate.

Current theories assume that the outer hair cells (OHC) are responsible for the sharp tuning and exquisite sensitivity of the ear whereas inner hair cells (IHC) are mainly responsible for transmitting acoustic information to the central nervous system. To further evaluate this model, we used a single (38 mg/kg) or double dose (38 mg/kg, 2 times) of carboplatin to produce a moderate (20-28%) or severe (60-95%) IHC loss while sparing a large proportion of the OHCs. The surviving OHCs were functionally intact as indicated by normal cochlear microphonic (CM) potentials and distortion product otoacoustic emissions (DPOAE). Single-unit responses were recorded from auditory nerve fibers to determine the effects of the moderate or severe IHC loss on the output of the surviving IHCs. Most neurons that responded to sound in the single-dose group had normal or near-normal thresholds and normal tuning. Relatively few neurons in the double-dose group responded to sound because of the severe IHC loss. The neurons that did respond to sound had narrow tuning curves. Some neurons in the double-dose group also had thresholds that were within the normal range, but most had thresholds that were elevated a mild-to-moderate degree. These results indicate that intact IHCs can retain relatively normal sensitivity and tuning despite massive IHC loss in surrounding regions of the cochlea. However, the spontaneous and driven discharge rates of neurons in the carboplatin-treated animals were significantly lower than normal. These changes could conceivably be due to sublethal damage to surviving IHCs or to postsynaptic dysfunction in the auditory nerve.

Two-tone rate suppression boundaries of cochlear ganglion neurons in chickens following acoustic trauma.

The purpose of the present study was to examine the effects of acoustic trauma and hair cell loss and regeneration on the two-tone rate suppression (TTRS) boundaries of cochlear ganglion neurons in chickens. Chickens were exposed for 48 hours to a 525-Hz, 120-dB SPL tone which destroyed the hair cells and tectorial membrane in a crescent-shaped patch along the abneural side of the basilar papilla. Afterwards, TTRS boundaries were recorded from cochlear ganglion neurons at 0-1, 5, 14, and 28 days postexposure. Acoustic trauma reduced the percentage of neurons with TTRS boundaries below CF (TTRSb) (52.6% to 8.2%) and above CF (TTRSa) (88.4% to 46.6%). In addition, the exposure reduced TTRS boundary slopes, elevated best suppression threshold (BST), and increased the frequency separation between the tips of the TTRS boundaries and CF. All the TTRS measures started to recover by 5 days postexposure and by 14 days and 28 days postexposure, most measures had recovered to normal levels. However, the BST, TTRS slopes, and the frequency separation of TTRSb boundaries from CF were still slightly abnormal near the exposure frequency. In addition, the percentage of neurons with TTRS below CF was reduced significantly. The partial recovery of TTRS boundaries is presumably due to the regeneration of hair cells and the lower honeycomb layer of the tectorial membrane. The residual TTRS deficits observed 28 days postexposure were most closely associated with the missing upper fibrous layer of the tectorial membrane.

The effects of click level, click rate, and level of background masking noise on the inferior colliculus potential (ICP) in the normal and carboplatin-treated chinchilla.

Carboplatin produces a selective loss of inner hair cells in chinchilla, substantially reducing the amplitude of the compound action potential. A key question that arises from these experiments is: What effect does a reduction in IHC-eighth-nerve fiber input have on the central auditory nervous system? This investigation evaluated the inferior colliculus potential (ICP) in chinchillas treated with carboplatin. The left ear was surgically destroyed and a recording electrode was placed in the left inferior colliculus. Following thirteen days of recovery time, the ICP was recorded in the awake animal. Click level was varied from 10-20 to 80 dB pSPL. Click rate was varied from 10 to 1000 Hz using both conventional averaging and a cross-correlation procedure. Broadband masking noise was varied from 30 to 70 dB SPL with click level held constant at 80 dB pSPL. The dependent variables were the positive peak latency and peak-to-following trough amplitude of the evoked potential. Following baseline studies, the animals were administered carboplatin (50 mg/kg IP) and retested two weeks later. Prior to carboplatin administration, there was an increase in ICP latency and a decrease in ICP amplitude with decreasing stimulus level, increasing rate and increasing noise level. Mean ICP threshold was 30 dB pSPL. Following carboplatin administration, there was little change in threshold or peak latencies. In contrast, the amplitude of the ICP was reduced on average by one-third, although this effect varied considerably across animals. The magnitude of this amplitude decrement was not strongly dependent on click level, click rate, or the level of background noise.

Tuning, spontaneous activity and tonotopic map in chicken cochlear ganglion neurons following sound-induced hair cell loss and regeneration.

Adult chickens were exposed for 48 h to a 525 Hz, 120 dB SPL tone that destroyed the hair cells and tectorial membrane in a crescent-shaped patch along the abneural edge of the basilar papilla. Single-unit recordings were obtained from cochlear ganglion neurons 0-1, 5, 14 and 28 days post-exposure to determine what effect the cochlear lesion had on neural discharge patterns and if the discharge patterns fully recovered. Immediately after exposure, the tuning curves were extremely broad and CF thresholds were elevated by 30-40 dB. In addition, the average spontaneous rate and percentage of neurons with interspike interval histograms with preferred intervals were greatly reduced. Tuning curves and spontaneous activity started to recover by 5 days post-exposure; however, some W-shaped tuning curves with two distinct tips and a hypersensitive tail were observed at this time. W-shaped tuning curves disappeared and spontaneous activity recovered to normal levels 14-28 days post-exposure. However, the CF thresholds of the most sensitive neurons were still slightly elevated, tuning curve slopes below CF were shallower than normal, and thresholds in the low-frequency tail of the tuning curves were often hypersensitive. These functional deficits were most closely associated with residual damage to the upper fibrous layer of the tectorial membrane. To determine if the cochlear frequency-place map was altered by the cochlear lesion, four physiologically characterized neurons were labeled with biocytin at 5 days post-exposure. The CFs of the labeled neurons were consistent with the normal frequency-place map (Chen et al. (1994) Hearing Research 81, 130-136) indicating that the tonotopic map was not altered.

Two-tone rate suppression boundaries of cochlear ganglion neurons in normal chickens.

The purpose of the present study was to provide a quantitative description of two-tone rate suppression boundaries in normal chickens. The boundaries were measured in 249 cochlear ganglion neurons using a tone 20 dB above threshold at the characteristic frequency (CF). The boundaries were present in 90.4% of neurons either on both sides or only one side of CF but more frequently above CF than below CF. The best suppression thresholds were positively correlated with and, on the average, 19-25 dB higher than CF thresholds. The boundary was farther from CF and shallower below CF than above CF. The boundary slope varied slightly with CF threshold and the tuning curve slope. These results are generally consistent with previous reports from mammals except that: (1) the boundary below CF did not follow and lie above the tuning curve flank; (2) the average best suppression threshold was slightly lower below CF than above CF; (3) the boundaries below and above CF were not particularly asymmetrical.

Selective inner hair cell loss does not alter distortion product otoacoustic emissions.

Outer hair cells (OHC) are believed to be the dominant source of distortion product otoacoustic emissions (DPOAE) in mammals; however, some studies in genetic mutants suggest that inner hair cell (IHC) loss may lead to a significant reduction of DPOAE amplitude. In the present study, we determined the extent to which IHC loss altered DPOAE amplitude by using carboplatin to destroy selectively the IHCs in the chinchilla while sparing virtually all of the OHCs. IHC losses of 80-100% with normal retention of OHCs did not reduce the amplitude of the DPOAEs or the cochlear microphonic potential (CM); however, it completely abolished the compound action potential (CAP). The only time that the amplitude of the DPOAEs and CM were reduced was in cases where both the IHCs and OHCs were destroyed in the base of the cochlea. We conclude that the total loss of IHCs does not lead to a significant change in DPOAE amplitude. DPOAE amplitude was only reduced when there was a significant loss of OHCs.

Incomplete recovery of chicken distortion product otoacoustic emissions following acoustic overstimulation.

Distortion product otoacoustic emissions (DPOAEs) were measured in chickens before and after exposure to a 525-Hz pure tone (120 dB SPL, 48 h). The exposure caused extensive hair cell loss and destroyed the tectorial membrane along the abneural edge of the basilar papilla in the low-to-mid-frequency region of the cochlea. Although the lesion was restricted, DPOAEs were greatly depressed at all frequencies immediately after the exposure. The high-frequency DPOAEs gradually recovered to preexposure values after the exposure; however, there was little or no improvement in DPOAEs at test frequencies equal to or slightly above the exposure frequency even after 16 weeks of recovery. By 28 days of recovery, the previously damaged region of the basilar papilla had been repopulated by hair cells and the lower honeycomb layer of the tectorial membrane had regenerated, but not the upper fibrous layer. The upper fibrous layer of the tectorial membrane was still missing after 16 weeks of recovery and the region of damage corresponded closely to the frequency regions where the DPOAEs were depressed.

Effects of kanamycin ototoxicity and hair cell regeneration on the DC endocochlear potential in adult chickens.

High doses of aminoglycoside antibiotics cause massive damage to the avian basilar papilla. The resulting functional loss could conceivably arise from the reduction in the DC endocochlear potential (EP) due to impairment of the tegmentum vasculosum (TV) or to shunting of current through the damaged sensory epithelium. To test this hypothesis, the EP was measured in adult chickens after destroying hair cells in the basal half of the cochlea with a high dose (400 mg/kg per day for 10 days) of kanamycin (KM). KM treatment caused an increase in the steady-state EP from +18.1 to +23.3 mV and a decrease in the magnitude of the negative EP from -42.0 to -19.2 mV. The EP showed almost no change between 1 and 2 days and 1 week post-KM treatment. After 4 weeks of recovery, most hair cells had regenerated; however, the steady-state EP was still elevated by 13% and the negative EP was depressed by 37%. These results suggest that functional loss as shown by the large reduction in cochlear microphonic (CM) and the elevated thresholds of compound action potential (CAP) following KM treatment is not due to a reduction in the EP but may arise from functional deficits in the hair cells and/or the auditory nerve.