After severe hair cell loss, secondary degeneration of spiral ganglion cells (SGCs) is observed-a gradual process that spans years in humans but only takes weeks in guinea pigs. Being the target for cochlear implants (CIs), the physiological state of the SGCs is important for the effectiveness of a CI. For assessment of the nerve's state, focus has generally been on its response threshold. Our goal was to add a more detailed characterization of SGC functionality. To this end, the electrically evoked compound action potential (eCAP) was recorded in normal-hearing guinea pigs and guinea pigs that were deafened 2 or 6 weeks prior to the experiments. We evaluated changes in eCAP characteristics when the phase duration (PD) and inter-phase gap (IPG) of a biphasic current pulse were varied. We correlated the magnitude of these changes to quantified histological measures of neurodegeneration (SGC packing density and SGC size). The maximum eCAP amplitude, derived from the input-output function, decreased after deafening, and increased with both PD and IPG. The eCAP threshold did not change after deafening, and decreased with increasing PD and IPG. The dynamic range was wider for the 6-weeks-deaf animals than for the other two groups. Excitability increased with IPG (steeper slope of the input-output function and lower stimulation level at the half-maximum eCAP amplitude), but to a lesser extent for the deafened animals than for normal-hearing controls. The latency was shorter for the 6-weeks-deaf animals than for the other two groups. For several of these eCAP characteristics, the effect size of IPG correlated well with histological measures of degeneration, whereas effect size of PD did not. These correlations depend on the use of high current levels, which could limit clinical application. Nevertheless, their potential of these correlations towards assessment of the condition of the auditory nerve may be of great benefit to clinical diagnostics and prognosis in cochlear implant recipients.

1. We studied the topographic organization of the response areas obtained from single- and multiunit recordings along the isofrequency planes of the primary auditory cortex in the barbiturate-anesthetized ferret. 2. Using a two-tone stimulus, we determined the excitatory and inhibitory portions of the response areas and then parameterized them in terms of an asymmetry index. The index measures the balance of excitatory and inhibitory influences around the best frequency (BF). 3. The sensitivity of responses to the direction of a frequency-modulated (FM) tone was tested and found to correlate strongly with the asymmetry index of the response areas. Specifically, cells with strong inhibition from frequencies above the BF preferred upward sweeps, and those from frequencies below the BF preferred downward sweeps. 4. Responses to spectrally shaped noise were also consistent with the asymmetry of the response areas. For instance, cells that were strongly inhibited by frequencies higher than the BF responded best to stimuli that contained least spectral energy above the BF, i.e., stimuli with the opposite asymmetry. 5. Columnar organization of the response area types was demonstrated in 66 single units from 16 penetrations. Consistent with this finding, it was also shown that response area asymmetry measured from recordings of a cluster of cells corresponded closely with those measured from its single-unit constituents. Thus, in a local region, most cells exhibited similar response area types and other response features, e.g., FM directional sensitivity. 6. The distribution of the asymmetry index values along the isofrequency planes revealed systematic changes in the symmetry of the response areas. At the center, response areas with narrow and symmetric inhibitory sidebands predominated. These gave way to asymmetric inhibition, with high-frequency inhibition (relative to the BF) becoming more effective caudally and low-frequency inhibition more effective rostrally. These response types tended to cluster along repeated bands that paralleled the tonotopic axis. 7. Response features that correlated with the response area types were also mapped along the isofrequency planes. Thus, in four animals, a map of FM directional sensitivity was shown to be superimposed on the response area map. Similarly, it was demonstrated in six animals that the spectral gradient of the most effective noise stimulus varied systematically along the isofrequency planes. 8. One functional implication of the response area organization is that cortical responses encode the locally averaged gradient of the acoustic spectrum by their differential distribution along the isofrequency planes. This enhances the representation of such features as the symmetry of spectral peaks and edges and the spectral envelope.(ABSTRACT TRUNCATED AT 400 WORDS)

Multi-unit responses to frequency-modulated (FM) sweeps were studied in the primary auditory cortex of ferrets using six different stimulation paradigms. In particular, the differences between the responses to linear FM sweeps (where frequency changes linearly with time) and logarithmic FM sweeps (where frequency changes exponentially with time) were emphasized. Some general features of the responses to FM sweeps are independent of the exact details of the frequency trajectory. Both for linear and for logarithmic FM sweeps, a short burst of spikes occurred when the sweep reached a triggering frequency close to the best frequency of the cluster. The neuronal preference for FM velocity was also independent of frequency trajectory. Thus, clusters that responded best to slow logarithmic FM also preferred slow linear FM and vice versa. Consequently, topographic distributions of velocity preference were roughly independent of the stimulation paradigm. Other characteristics of the responses, however, depended on the exact details of the frequency trajectory. A significant number of clusters showed large differences in directional sensitivity between linear and logarithmic FM sweeps; these differences depended on the velocity preference of the clusters in some paradigms but not in others. Consequently, topographic distributions of directional sensitivity differed between linear and logarithmic paradigms. In conclusion, some characteristics of cluster responses to FM sweeps depend on the exact details of the stimulation paradigm and are not 'invariants' of the cluster.

The midbrain inferior colliculus (IC) is implicated in coding sound location, but evidence from behaving primates is scarce. Here we report single-unit responses to broadband sounds that were systematically varied within the two-dimensional (2D) frontal hemifield, as well as in sound level, while monkeys fixated a central visual target.Results show that IC neurons are broadly tuned to both sound-source azimuth and level in a way that can be approximated by multiplicative, planar modulation of the firing rate of the cell. In addition, a fraction of neurons also responded to elevation. This tuning, however, was more varied: some neurons were sensitive to a specific elevation; others responded to elevation in a monotonic way. Multiple-linear regression parameters varied from cell to cell, but the only topography encountered was a dorsoventral tonotopy.In a second experiment, we presented sounds from straight ahead while monkeys fixated visual targets at different positions. We found that auditory responses in a fraction of IC cells were weakly, but systematically, modulated by 2D eye position. This modulation was absent in the spontaneous firing rates, again suggesting a multiplicative interaction of acoustic and eye-position inputs. Tuning parameters to sound frequency, location, intensity, and eye position were uncorrelated. On the basis of simulations with a simple neural network model, we suggest that the population of IC cells could encode the head-centered 2D sound location and enable a direct transformation of this signal into the eye-centered topographic motor map of the superior colliculus. Both signals are required to generate rapid eye-head orienting movements toward sounds.

Exogenous delivery of neurotrophic factors into the cochlea of deafened animals rescues spiral ganglion cells (SGCs) from degeneration. To be clinically relevant for human cochlear implant candidates, the protective effect of neurotrophins should persist after cessation of treatment and the treated SGCs should remain functional. In this study, the survival and functionality of SGCs were investigated after temporary treatment with brain-derived neurotrophic factor (BDNF). Guinea pigs in the experimental group were deafened, and 2 weeks later, the right cochleae were implanted with an electrode array and drug delivery cannula. BDNF was administered to the implanted cochleae during a 4-week period via a mini-osmotic pump. After completion of the treatment, the osmotic pumps were removed. Two weeks later, the animals were killed and the survival of SGCs was analyzed. To monitor the functionality of the auditory nerve, electrically evoked auditory brainstem responses (eABRs) were recorded in awake animals throughout the experiment. BDNF treatment resulted in enhanced survival of SGCs 2 weeks after cessation of the treatment and prevented the decreases in size and circularity that are seen in the untreated contralateral cochleae. The amplitude of the suprathreshold eABR response in BDNF-treated animals was significantly larger than in deafened control animals and comparable to that in normal-hearing control animals. The amplitude in the BDNF-treated group did not decrease significantly after cessation of treatment. The eABR latency in BDNF-treated animals was longer than normal and comparable to that in deafened control animals. These morphological and functional findings demonstrate that neurotrophic intervention had a lasting effect, which is promising for future clinical application of neurotrophic factors in implanted human cochleae.

After substantial loss of cochlear hair cells, exogenous neurotrophins prevent degeneration of the auditory nerve. Because cochlear implantation, the current therapy for profound sensorineural hearing loss, depends on a functional nerve, application of neurotrophins is being investigated. We addressed two questions important for fundamental insight into the effects of exogenous neurotrophins on a degenerating neural system, and for translation to the clinic. First, does temporary treatment with brain-derived neurotrophic factor (BDNF) prevent nerve degeneration on the long term? Second, how does a BDNF-treated nerve respond to electrical stimulation? Deafened guinea pigs received a cochlear implant, and their cochleas were infused with BDNF for 4 weeks. Up to 8 weeks after treatment, their cochleas were analyzed histologically. Electrically evoked compound action potentials (eCAPs) were recorded using stimulation paradigms that are informative of neural survival. Spiral ganglion cell (SGC) degeneration was prevented during BDNF treatment, resulting in 1.9 times more SGCs than in deafened untreated cochleas. Importantly, SGC survival was almost complete 8 weeks after treatment cessation, when 2.6 times more SGCs were observed. In four eCAP characteristics (three involving alteration of the interphase gap of the biphasic current pulse and one involving pulse trains), we found large and statistically significant differences between normal-hearing and deaf controls. Importantly, for BDNF-treated animals, these eCAP characteristics were near normal, suggesting healthy responsiveness of BDNF-treated SGCs. In conclusion, clinically practicable short-term neurotrophin treatment is sufficient for long-term survival of SGCs, and it can restore or preserve SGC function well beyond the treatment period.

Background: Although some therapies may be beneficial for some patients in reducing tinnitus, there is no curative therapy. Repetitive transcranial magnetic stimulation (rTMS) has been applied as a treatment for chronic tinnitus, but the effect remains controversial. Material and Methods: Fifty patients were treated with rTMS or placebo. Treatment consisted of 2,000 TMS pulses on each auditory cortex, at a rate of 1 Hz and an intensity of 110% of the individual motor threshold, on 5 consecutive days. rTMS and placebo effects were evaluated directly after treatment, after 1 week, and after 1, 3 and 6 months. Primary outcome was the Tinnitus Questionnaire (TQ). Secondary outcomes were the Tinnitus Handicap Inventory (THI) and a visual analogue scale. Results: At none of the follow-up evaluation moments a significant difference between rTMS and placebo was observed with respect to changes in TQ or THI scores relative to pretreatment scores. Multilevel modelling (MLM) analyses did not show a global treatment effect either. Patients with a higher degree of burden showed slightly greater improvement after rTMS (only significant on the THI with MLM analyses). Conclusion: Bilateral low-frequency rTMS of the auditory cortex was not effective in treating tinnitus.

1. Characteristics of an anterior auditory field (AAF) in the ferret auditory cortex are described in terms of its electrophysiological responses to tonal stimuli and compared with those of primary auditory cortex (AI). Ferrets were barbiturate-anesthetized and tungsten microelectrodes were used to record single-unit responses from both AI and AAF fields. Units in both areas were presented with the same stimulus paradigms and their responses analyzed in the same manner so that a direct comparison of responses was possible. 2. The AAF is located dorsal and rostral to AI on the ectosylvian gyrus and extends into the suprasylvian sulcus rostral to AI. The tonotopicity is organized with high frequencies at the top of the sulcus bordering the high-frequency area of AI, then reversing with lower BFs extending down into the sulcus. AAF contained single units that responded to a frequency range of 0.3-30 kHz. 3. Stimuli consisted of single-tone bursts, two-tone bursts and frequency-modulated (FM) stimuli swept in both directions at various rates. Best frequency (BF) range, rate-level functions at BF, FM directional sensitivity, and variation in asymmetries of response areas were all comparable characteristics between AAF and AI. Responses in both areas were primarily phasic. 4. The characteristics that were different between the two cortical areas were: latency to tone onset, excitatory bandwidth 20 dB above threshold (BW20), and preferred FM rate as parameterized with the centroid (a weighted average of spike counts). The mean latency of AAF units was shorter than in AI (AAF: 16.8 ms, AI: 19.4 ms). BW20 measurements in AAF were typically twice as large as those found in AI (AAF: 2.5 octaves, AI 1.3 octaves). The AI centroid population had a significantly larger standard deviation than the AAF centroid population. 5. We examined the relationship between centroid and BW20 to see whether wider bandwidths were a factor in a unit's ability to detect fast sweeps. There was significant (P < 0.05) linear correlation in AAF but not in AI. In both fields the variance of the centroid population decreased with increasing BW20. BW20 decreased as BF increased for units in both auditory fields.