Recovery from prior stimulation. II: Effects upon intensity discrimination.

We obtained just-noticeable differences (jnds) for the intensity of pure tones following a forward masker. The masker was a 100-ms burst of narrow-band noise centered at 1000 Hz presented at 90 dB SPL; the pure-tone signal was at 1000 Hz and was 25 ms in duration. The masker-signal delay was 100 ms. Under these conditions, there is no threshold shift for the detection of the pure-tone signal following the forward masker. In contrast with the absence of a forward-masker effect upon detection thresholds, unusually large midlevel (40-60 dB SPL) jnds were observed. These large midlevel jnds were measured as a function of signal delay, revealing that they are not completely recovered to the normal (unmasked) values by 400 ms. We interpret these data as a consequence of the slower recovery of low-spontaneous rate, high-threshold neurons following prior stimulation (Relkin and Doucet, 1990). These experiments may therefore provide psychophysical evidence that the low-spontaneous rate, high-threshold neurons are a necessary physiological component in the coding of the large dynamic range for intensity. In addition, the present data provide evidence that the assumption that the effect of forward masking is limited to 100-200 ms is inappropriate, as this recovery time does not necessarily apply to suprathreshold tasks.     

Stimulus induced and spontaneous rhythmic firing of single units in cat primary auditory cortex.

Recordings were made under ketamine anesthesia from 385 neurons in primary auditory cortex in adult cat and from 265 neurons in 10-55 day old kittens. The temporal Modulation Transfer Function for the response to repetitive click stimuli peaked at 8 Hz. After a click a suppression period of 130- 155 ms in duration, depending on click-rate, was observed. This suppression period limited the response to high click rates and thereby determined the 'resonance' in the click response. The suppression duration in kittens decreased in exponential fashion toward the adult value with a time constant of about 1 month. After the one second duration click-trains an oscillatory rebound with a mean period of 113 ms was observed in about 60% of the recordings in the adult cat. Spontaneous activity showed in about 30% of the neurons an oscillatory autocorrelogram with an average period of 126 ms in the adult cats and 170 ms in kittens.     

Relationship between tone burst discharge pattern and spontaneous firing rate of auditory nerve fibres in the guinea pig.

A detailed investigation was carried out of the response of single auditory nerve fibres in the guinea pig to tone bursts. Comparisons were made between the shapes of peri-stimulus-time histograms (PSTHs) of low and high characteristic frequency (CF) fibres grouped according to their spontaneous firing rates (SR). Both low and high CF fibres of high spontaneous rate (greater than 18 spikes/s) exhibited marked rapid adaptation in their PSTH's which became most pronounced at high stimulus intensities. The ratio of onset-to-adapted firing estimated from PSTH data in these fibres increased monotonically as a function of adapted firing rate. The behaviour of fibres with the lowest spontaneous rates (less than 0.5 spikes/s) was markedly different, particularly in fibres from low CF regions. In general, these low-SR fibres showed slower adaptation than high-SR fibres, and a less pronounced onset peak. This was most striking in low CF fibres. Furthermore, the ratio of onset-to-adapted firing rate tended to decrease with increasing stimulus intensity in both low and high CF fibres with low spontaneous firing rates. Low-SR fibres also showed the highest maximum discharge rates to tone burst stimuli. Fibres with medium spontaneous rates between 0.5 and 18 spikes/s displayed intermediate characteristics in their PSTH's. Recent data in the chinchilla (Relkin and Doucet, 1991), suggest that these differences may arise in part from differences in inter-stimulus recovery processes in the different spontaneous rate groups.     

Sensitivity of neurons in cat primary auditory cortex to tones and frequency-modulated stimuli. I: Effects of variation of stimulus parameters.

In the primary auditory cortex (AI) of barbiturate-anesthetized cats multi-unit responses to tones and to frequency-modulated (FM) tonal stimuli were analyzed. Characteristic frequency (CF), sharpness of tuning, minimum threshold, and dynamic range of spike count--intensity functions were determined. Minimum threshold and dynamic range were positively correlated. The response functions to unidirectional FM sweeps of varying linear rate of change of frequency (RCF) that traversed the excitatory frequency response areas (FRAs) displayed a variety of shapes. Preferences for fast RCFs (> 1000 kHz/s) were most common. Best RCF was not correlated with measures of sharpness of tuning. Directional preference and sensitivity were quantified by a DS index which varied with RCF. About two-thirds of the multi-unit responses showed a preference for downward sweeps. Directional sensitivity was independent of CF and independent of best RCF. Measurements of latencies of phasic responses to unidirectional FM sweeps of different RCF demonstrated that the discharges of a given multi-unit over its effective RCF range were initiated at the same instantaneous frequency (effective Fi), independent of RCF. Effective Fis fell within the excitatory FRA of a given multi-unit. The relationships of effective Fis to CF show that responses were evoked only when the frequency of the signal was modulated towards CF and not when modulated away from it, and that responses were initiated before the modulation reached CF. Changes in the range and depth of modulation had only minor, if any, effects on RCF response characteristics, FM directional sensitivity, and effective Fis, as long as the beginning and ending frequencies of FM sweeps fell outside a multi-unit's FRA. Stimulus intensity also had only moderate effects on RCF response characteristics and DS. However, effective Fis were influenced in systematic fashions; with increases in intensity, effective Fis to upward and downward sweeps decreased and increased, respectively. Thus, for higher intensities FM responses were initiated at instantaneous frequencies occurring earlier in the signal. The results are compared with previous data on tone and FM sensitivity of auditory neurons in cortical and subcortical structures, and mechanisms of FM rate and directional sensitivity are discussed. The topographic representations of these neuronal properties in AI are reported in the companion report.     

Changes in spontaneous firing rate and neural synchrony in cat primary auditory cortex after localized tone-induced hearing loss

Increase in spontaneous neural activity after noise-induced hearing loss has frequently been associated with the phenomenon of tinnitus. Eighteen juvenile and adult cats were exposed for 2 h to a 6 kHz tone with an intensity of 115 dB SPL at the cat’s head. Seven non-exposed littermates and seven other normal hearing cats were used as age-matched controls. The trauma cats showed localized hearing losses, as assessed by ABR, ranging from less than 20 to 60 dB. The frequency representation in primary auditory cortex was mapped using an eight-electrode array. Single-unit spontaneous activity was recorded for 15 min. Peak cross-correlation coefficients (R) for unit cluster activity recorded on separate electrodes were calculated. We found elevated spontaneous firing rates in regions with reorganization of the tonotopic map compared to the neurons in the non-reorganized cortical regions in the same animals. A second finding was that in these regions the peak cross-correlation coefficients were also increased relative to the non-reorganized parts. A third finding was that exposed animals showed higher spontaneous activity compared to controls regardless of the presence of cortical reorganization. This may be a correlate of tinnitus in the presence of only minor hearing losses.     

Multichannel electrical stimulation of the auditory nerve in man. I. Basic psychophysics

Basic psychophysical measurements were obtained from three patients implanted with multichannel cochlear implants. This paper presents measurements from stimulation of a single channel at a time (either monopolar or bipolar). The shape of the threshold vs. frequency curve can be partially related to the membrane biophysics of the remaining spiral ganglion and/or dendrites. Nerve survival in the region of the electrode may produce some increase in the dynamic range on that electrode. Loudness was related to the stimulus amplitude by a power law with exponents between 1.6 and 3.4, depending on frequency. Intensity discrimination was better than for normal auditory stimulation, but not enough to offset the small dynamic range for electrical stimulation. Measures of temporal integration were comparable to normals, indicating a central mechanism that is still intact in implant patients. No frequency analysis of the electrical signal was observed. Each electrode produced a unique pitch sensation, but they were not simply related to the tonotopic position of the stimulated electrode. Pitch increased over more than 4 octaves (for one patient) as the frequency was increased from 100 to 300 Hz, but above 300 Hz no pitch change was observed. Possibly the major limitation of single channel cochlear implants is the 1–2 ms integration time (probably due to the capacitative properties of the nerve membrane which acts as a low-pass filter at 100 Hz) Another limitation of electrical stimulation is that there is no spectral analysis of the electrical waveform so that temporal waveform alone determines the effective stimulus.     

Cochlear pathology following chronic electrical stimulation of the auditory nerve. I: Normal hearing kittens.

The present study examines the histopathological effects of long-term intracochlear electrical stimulation in young normal hearing animals. Eight-week old kittens were implanted with scala tympani electrode arrays and stimulated for periods of up to 1500 h using charge balanced biphasic current pulses at charge densities in the range 21-52 microC cm-2 geom. per phase. Both click and electrically evoked auditory brainstem responses were periodically recorded to monitor the status of the hair cell and spiral ganglion cell populations. In addition, the impedance of the stimulating electrodes was measured daily to monitor their electrical characteristics during chronic implantation. Histopathological examination of the cochleas showed no evidence of stimulus induced damage to cochlear structures when compared with implanted, unstimulated control cochleas. Indeed, there was no statistically significant difference in the ganglion cell density adjacent to the stimulating electrodes when compared with a similar population in implanted control cochleas. In addition, hair cell loss, which was restricted to regions adjacent to the electrode array, was not influenced by the degree of electrical stimulation. These histopathological findings were consistent with the evoked potential recordings. Finally, electrode impedance data correlated well with the degree of tissue growth observed within the scala tympani. The present findings indicate that the young mammalian cochlea is no more susceptible to cochlear pathology following chronic implantation and electrical stimulation than is the adult.     

雏鸡初级听神经元的原代培养方法

报告对出生后１０－１３ｄ龄鸡初级听神经细胞进行原代培养的方法，用倒置相差显微镜和扫描电镜，观察不同培养时间听神经元的发育过程与形态学特征。结果显示，培养ＰＡＮ数量和形态以了活时间，均可满足体外研究的要求，可作为多种体外研究的材料。表明ＰＡＮ原代培养方法，扩大了培养材料的来源，为开展内耳体我研究提供了一种新的实验手段。     

Selective activation of cat primary auditory cortex by way of direct intraneural auditory nerve stimulation

OBJECTIVES/HYPOTHESIS: Although cochlear implants have been successfully used by many individuals with profound hearing impairment, limitations still remain with this approach to hearing restoration, including poor stimulation selectivity because of cross-talk between electrodes and poor low-frequency percepts. These limitations may be mitigated by direct intraneural stimulation of the auditory nerve by way of an array of penetrating microelectrodes. Such an approach should provide focal stimulation and selective activation of the nerve fibers, thereby minimizing cross-talk among implanted stimulating electrodes and evoking narrow-band frequency percepts. STUDY DESIGN: We investigated the activation of primary auditory cortex evoked by such direct intraneural electrical stimulation of the auditory nerve. METHODS: We implanted 11 penetrating microelectrodes in the cat auditory nerve, simulated the nerve by way of these electrodes, and recorded the evoked neuronal activity patterns in cat primary auditory cortex. We compared these activation patterns with acoustically evoked cortical activity patterns obtained in a different animal. RESULTS: Our results showed that direct stimulation of the auditory nerve evoked localized activity patterns in primary auditory cortex similar in spatial extent to those evoked by acoustic stimulation and that the extent of cortical activation by both acoustic and electrical stimuli was graded with stimulus intensity. These results suggest that the implanted electrodes can excite independent and small populations of nerve fibers. CONCLUSION: This study demonstrates the functional feasibility of direct intraneural auditory nerve stimulation with an array of penetrating microelectrodes and that such an approach could form the foundation for an auditory prosthesis with improved frequency coding.     

Divergent response properties of layer-V neurons in rat primary auditory cortex

Layer-V pyramidal cells comprise a major output of primary auditory cortex (A1). At least two cell types displaying different morphology, projections and in vitro physiology have been previously identified in layer-V. The focus of the present study was to characterize extracellular receptive field properties of layer-V neurons to determine whether a similar breakdown of responses can be found in vivo. Recordings from 105 layer-V neurons revealed two predominant receptive field types. Thirty-two percent displayed strong excitatory V/U-shaped receptive field maps and spiking patterns with shorter stimulus-driven interspike intervals (ISIs), reminiscent of the bursting cells discussed in the in vitro literature. V/U-shaped maps remained relatively unchanged across the three sequential repetitions of the map run on each neuron. Neurons with V/U-shaped maps were also easily depolarized with extracellular current pulse stimulation. In contrast, 47% of the neurons displayed Complex receptive field maps characterized by weak and/or inconsistent excitatory regions and were difficult to depolarize with current pulses. These findings suggest that V/U-shaped receptive fields could correspond to previously described intrinsic bursting (IB) cells with corticotectal projections, and that neurons with Complex receptive fields might represent the regular spiking (RS) cells with their greater inhibitory input and corticocortical/corticostriatal projection pattern.     

Recovery of auditory function following meningitic deafness.

Two cases are presented that document improvement in hearing following Hemophilus influenzae meningitis. In both cases vestibular function was permanently lost. The possible anatomical and physiological sites of involvement are discussed. The two cases stress the importance of regularly scheduled audiometric reevaluations in cases of postmeningitic deafness.     

A device for patterned electrical stimulation of cultivated cells: preliminary tests with rat auditory neurons

The number of surviving spiral ganglion neurons (SGNs) is important for the function of cochlear implants. Electrical stimulation has been discussed controversially regarding its protective effects on SGNs both in vivo and in vitro. The aim of this study was to develop a device for electrical stimulation of cultured SGNs. The developed device was first evaluated with cultivated fibroblasts at voltages from 10 to 60 V using biphasic rectangular pulses (pulse width: 10 ms, frequency: 50 Hz, stimulus burst: 1 s, interburst interval: 19 s). Possible toxic effects of 48 h patterned electrical stimulation were evaluated by propidium-iodide flow cytometry of the harvested fibroblasts. Second, the effects of 48-h electrical stimulation at voltages of 6 and 30 V on survival of cultivated SGNs were investigated as a single treatment and in the presence of brain-derived neurotrophic factor (BDNF, 100 ngml) in the culture medium. The results demonstrated constant pH and temperature behavior during electrical stimulation. Furthermore, no toxic effects on fibroblasts up to 40 V were found. The electrical stimulation of cultured neurons did not alter the survival rate compared to unstimulated control conditions. While BDNF application alone showed a significant effect on SGN survival, combination with electrical stimulation resulted in a not significantly increased cell survival. As a limitation of the study, the sensitivity of the described experimental setup appears to be low and only one stimulation pattern has been tested. Thus, experiments using different patterns of electrical stimulation and a more sensitive cultivation setup have to be carried out to fully investigate the effects of electrical stimulation on cultured SGNs. In this context, the developed device can be of help as it provides controlled and reproducible electrical stimulation conditions.     

Sensitivity of neurons in cat primary auditory cortex to tones and frequency-modulated stimuli. II: Organization of response properties along the 'isofrequency' dimension.

The spatial distribution of neuronal responses to tones and frequency-modulated (FM) stimuli was mapped along the 'isofrequency' dimension of the primary auditory cortex (AI) of barbiturate-anesthetized cats. In each cat, electrode penetrations roughly orthogonal to the cortical surface were closely spaced (average separation approximately 130 microns) along the dorsoventral extent of a single 'isofrequency' strip in high frequency parts of AI (> 15 kHz). Characteristic frequency (CF), minimum threshold, sharpness of frequency tuning (Q10 and Q20), the dynamic range of the spike count-intensity function at CF, sensitivity to the rate of change of frequency (RCF) and to the direction of frequency-modulation (DS) were determined for contralaterally-presented tone and FM stimuli. Sharpness of tuning attained maximum values at central loci along the dorsoventral 'isofrequency' axis and values declined towards more dorsal and more ventral locations. Minimum threshold and dynamic range varied between high and low values in a similar and correlated periodic fashion. Their combined organization yielded an orderly spatial representation of response strength, relative to maximum, as a function of stimulus amplitude. The distributions of the most common forms of FM rate sensitivity (RCF response categories) and best RCF along 'isofrequency' strips were significantly non-random although there was a considerable degree of variability between cats. FM directional preference and sensitivity appeared to be randomly distributed. Sharpness of tuning may be related to the analysis of the spectral content of an acoustic stimulus, both minimum threshold and dynamic range are related to the encoding of stimulus intensity, and measures of FM rate and directional sensitivity assess the coding of temporal changes of stimulus spectra. The independent, or for minimum threshold and dynamic range dependent, topographic organizations of these neuronal parameters therefore suggest parallel and independent processing of these aspects of acoustic signals in AI.     

Sensitivity of neurons in the auditory midbrain of the grassfrog to temporal characteristics of sound. I. Stimulation with acoustic clicks

The coding of fine-temporal structure of sound, especially pulse repetition rate, was investigated on the single-unit level in the auditory midbrain of the grassfrog. As stimuli periodic click trains and Poisson distributed click ensembles have been used. The response to periodic click trains was studied in two aspects, focussing on two types of possible codes: a rate code and a synchrony code. From the iso-intensity rate histogram five basic average response rate characteristics as function of pulse repetition rate have been established: low-pass, band-pass, high-pass, bimodal and non-selective unit types. The synchronization capability, expressed in a synchronization index, was for a small majority of units non-significant and a low-pass function of pulse repetition rate for most of the other units. The rate code showed the largest diversity of response types and an enhanced selectivity to pulse repetition rate. The stimulus-response relation to Poisson distributed click ensembles was investigated by a non-linear system theoretical approach. On the basis of first- and second-order Poisson kernels possible neural mechanisms accounting for temporal selectivity were determined. A considerable fraction of units exhibited response characteristics that were invariant to changes in sound pressure level and average click rate. These units may function as feature detectors of fine-temporal structure of sound. The spectro-temporal sensitivity range of the auditory midbrain of the grassfrog appeared to be broad and not particularly tuned to the ensemble of conspecific cells.     

Sequential bilateral cochlear implantation in children: development of the primary auditory abilities of bilateral stimulation

The advantages of sequential bilateral cochlear implantation were assessed in 29 children with a severe to profound hearing loss. The effect of age at second implantation and the effect of duration of bilateral implant use on the outcomes in speech perception and directional hearing were investigated. The children received their second cochlear implant at an age ranging from 2.8 to 8.5 years. Measurements were carried out preoperatively and postoperatively after 6, 12 and 24 months of bilateral implant use. A matched control group of 9 children with a unilateral implant were also measured over time and were compared with the study group after 12 and 24 months. Speech reception in both quiet and in noise and lateralization were measured. After 24 months, a minimum audible angle task was carried out. Bilateral advantages with regard to speech reception in quiet and in noise were already present after 6 months of bilateral implant use and improved thereafter. After 24 months, speech reception in noise had significantly improved with bilateral implants compared to that of children with a unilateral implant. The percentage of children that could accurately lateralize increased from 57% after 6 months to 83% after 24 months. With regard to the minimum audible angle task, loudspeakers were placed on average at ±42°. Age at second implantation did not have an influence on all outcomes. From the results it can be concluded that the advantages of bilateral hearing occur after sequential bilateral implantation and that age at second implantation does not influence the amount of bilateral advantage. Furthermore, it can be concluded that longer periods of bilateral implant use lead to greater bilateral advantages.     

Reduction in excitability of the auditory nerve following electrical stimulation at high stimulus rates: V. Effects of electrode surface area

High rate intracochlear electrical stimulation at high intensities can induce significant reductions in the excitability of the auditory nerve as measured by a decrement in the amplitude of the electrically evoked auditory brainstem response (EABR). Such changes are primarily associated with stimulus induced neuronal activity, although direct current (DC) can also contribute. We examined the extent of stimulus induced change in auditory nerve excitability using large surface area platinum electrodes ('high-Q' electrodes). These electrodes have a surface area approximately 70 times greater than standard Pt electrodes of the same geometric area, resulting in lower DC and charge density (charge/electrode surface area) for a common stimulus. Guinea pigs were bilaterally implanted with either high-Q or standard Pt electrodes, and unilaterally stimulated for 2 h using stimulus intensities of 12 dB or 20-30 dB above EABR threshold (0.34 microC/phase) at stimulus rates of 200, 400, or 1000 pulses per second (pps). EABRs were recorded before and following the acute stimulation. While there were significant reductions in EABR amplitudes and elevated EABR thresholds following stimulation at 12 dB above threshold using 400 and 1000 pps delivered to standard Pt electrodes, there were fewer or no significant changes in the post-stimulus EABR amplitude and threshold using high-Q electrodes under equivalent stimulus conditions. At a higher stimulus intensity (20-30 dB above EABR threshold), no reduction in EABR amplitude was observed at 200 pps for both stimulating electrodes. However, EABRs were reduced significantly at 400 and 1000 pps. There was significantly greater EABR recovery following stimulation using high-Q electrodes compared with standard Pt electrodes at 400 (P<0.05) and 1000 pps (P<0.05). These data indicate that large surface area electrodes can significantly reduce stimulus induced changes in auditory nerve excitability, and may therefore have important clinical application.     

Cochlear nonlinearity and gain control as determinants of the response of primary auditory neurons to harmonic complexes

Earlier papers reported a calculational "model" (Greenwood, 1985, 1986a, b, c), composed of an initial compressive nonlinearity accompanied by a nonlinear gain control and "rectification", to demonstrate in principle certain "two-tone suppression" effects seen in primary fiber response. This paper presents simulations of primary fiber response to more complex stimuli. When harmonic stimuli of Horst et al. (1985a, b; 1986a, b) are used, the calculated spectra closely agree with the empirical spectra they report, from fibers with both low or high spontaneous activity. Thus, the simulated nonlinear motion of the cochlear partition reflects a sufficient degree of compressive distortion and an appropriate form to calculate spectra closely matching the empirical spectra in respect to the pattern of intermodulation products and the main "enhancement" and cancellation effects. Comparison of spectra of full and truncated waveforms assess added effects of "rectification". The gain control, as for simpler stimuli, leads to appropriate growth and saturation of Fourier coefficients and average firing rate. The implication that the measured transverse motion of the cochlear partition could provide sufficient distortion to account for the main features of the histograms has a two-part corollary: that the mechanism which produces severe overall saturation does not add much compressive distortion to the waveform passed radially to IHC and primary fibers, and that the IHC is kept operating chiefly in an approximately linear part of its range, by a prior gain control that is, perforce, cochlear and mechanical. Further consequences, for IHC synapses and fiber types, stem from the sufficiency of negatively biased waveform centerlines in generating simulated period histograms and spectra which match those of at least some primary fibers characterized by low spontaneous activity.     

Reduction in excitability of the auditory nerve following electrical stimulation at high stimulus rates. IV. Effects of stimulus intensity.

High rate intracochlear electrical stimulation using stimulus intensities well above clinical limits can induce a significant reduction in the excitability of the auditory nerve as measured by a reduction in the amplitude of the electrically evoked auditory brainstem response (EABR). The purpose of the present study was to assess the effect of stimulus intensity on these stimulus induced changes by comparing the effects of acute stimulation using stimulus intensities within normal clinical levels (6 dB and 12 dB above EABR threshold) and significantly above normal clinical levels (> 20 dB above EABR threshold; 0.34 microC/phase). Stimulus rates of 200, 400, or 1000 pulses/s (pps) were delivered to bipolar scala tympani electrodes. EABRs were recorded before and periodically following 2 h of continuous stimulation. No reduction in EABR amplitude was observed following stimulation at 6 dB above EABR threshold for the three stimulus rates examined. However, EABRs were reduced when stimulated at 12 dB above EABR threshold at 400 pps, and significantly reduced when stimulated at a rate of 1000 pps. Immediate post-stimulus response amplitudes of wave III were 63% and 35% of the pre-stimulus amplitude at 400 and 1000 pps respectively. More significant reductions in EABR amplitude were observed following stimulation at levels more than 20 dB above EABR threshold for both 400 and 1000 pps stimuli. Our findings indicate that stimulus induced changes in EABR amplitude are related to both stimulus rate and stimulus intensity. Moreover, stimulation using intensities within the normal clinical range show little evidence of prolonged reductions in auditory nerve excitability at stimulus rates of up to 1000 pps.