Huib Versnel

Involvement of monkey inferior colliculus in spatial hearing.

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.

Time course of cochlear electrophysiology and morphology after combined administration of kanamycin and furosemide.

In animal models of deafness, administration of an aminoglycoside in combination with a loop diuretic is often applied to produce a rapid loss of cochlear hair cells. However, the extent to which surviving hair cells remain functional after such a deafening procedure varies. In a longitudinal electrocochleographical study, we investigated the variability of cochlear function between and within guinea pigs after combined administration of kanamycin and furosemide. Concurrently, histological data were obtained at 1, 2, 4 and 8 weeks after deafening treatment. The main measures in our study were compound action potential (CAP) thresholds, percentage of surviving hair cells and packing density of spiral ganglion cells (SGCs). One day after deafening treatment, we found threshold shifts widely varying among animals from 0 to 100dB. The variability decreased after 2 days, and in 18 out of 20 animals threshold shifts greater than 55dB were found 4-7 days after deafening. Remarkably, in the majority of animals, thresholds decreased by up to 25dB after 7 days indicating functional recovery. As expected, final thresholds were negatively correlated to the percentage of surviving hair cells. Notably, the percentage of surviving hair cells might be predicted on the basis of thresholds observed one day after deafening. SGC packing density, which rapidly decreased with the period after deafening treatment and correlated to the percentage of surviving inner hair cells, was not a determining factor for the CAP thresholds.

Morphological changes in spiral ganglion cells after intracochlear application of brain-derived neurotrophic factor in deafened guinea pigs.

When guinea pigs are deafened with ototoxic drugs spiral ganglion cells (SGCs) degenerate progressively. Application of neurotrophins can prevent this process. Morphological changes of rescued SGCs have not been quantitatively determined yet. It might be that SGCs treated with neurotrophins are more vulnerable than SGCs in cochleae of normal-hearing guinea pigs. Therefore, the mitochondria and myelinisation of type-I SGCs were studied and the perikaryal area, cell circularity and electron density were determined. Guinea pigs were deafened with a subcutaneous injection of kanamycin followed by intravenous infusion of furosemide. Brain-derived neurotrophic factor (BDNF) delivery was started two weeks after the deafening procedure and continued for four weeks. Four cohorts of cochleae were studied: (1) cochleae of normal-hearing guinea pigs; (2) of guinea pigs two weeks after deafening; (3) six weeks after deafening; (4) cochleae treated with BDNF after deafening. The deafening procedure resulted in a progressive loss of SGCs. Six weeks after deafening the size of mitochondria, perikaryal area and cell circularity of the remaining untreated SGCs were decreased and the number of layers of the myelin sheath was reduced. In the basal part of the cochlea BDNF treatment rescued SGCs from degeneration. SGCs treated with BDNF were larger than SGCs in normal-hearing guinea pigs, whereas circularity had normal values and electron density was unchanged. The number of layers in the myelin sheath of BDNF-treated SGCs was reduced as compared to the number of layers in the myelin sheath of SGCs in normal-hearing guinea pigs. The morphological changes of SGCs might be related to the rapid loss of SGCs that has been reported to occur after cessation of BDNF treatment.

Neurotrophins and their role in the cochlea

Spiral ganglion cell (SGC) degeneration following hair cell loss can be prevented by administration of exogenous neurotrophic factors. Many of these neurotrophic factors, in particular the neurotrophins brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), have been described to be involved in the development of the rodent cochlea. While expression of most of the neurotrophins has decreased to below detectable levels during adulthood (only NT-3 remains highly expressed), their respective receptors remain present in SGCs. Indeed much less is known about the function of neurotrophins in the mature cochlea. Such knowledge is crucial in the search for tools to improve SGC survival following cochlear implantation. In this review, we will critically regard the current experimental findings of neurotrophic treatment of the SGCs in the perspective of fundamental cellular mechanisms underlying neurotrophin signaling. We conclude that, in order to fully apprehend the effects of neurotrophic treatment of degenerating SGCs and in order to consider clinical application of neurotrophins, future research should focus (a) on characterizing the expression pattern of neurotrophins in the cochlea after deafening, (b) on more detailed characterization of functional and morphological changes of SGCs associated with both deafening and neurotrophic treatment and (c) on the possible self-supporting state of SGCs after cessation of short-term neurotrophic treatment.

Auditory-Nerve Responses to Varied Inter-Phase Gap and Phase Duration of the Electric Pulse Stimulus as Predictors for Neuronal Degeneration

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.

Development of contralateral and ipsilateral frequency representations in ferret primary auditory cortex.

Little is known about the maturation of functional maps in the primary auditory cortex (A1) after the onset of sensory experience. We used intrinsic signal imaging to examine the development of the tonotopic organization of ferret A1 with respect to contralateral and ipsilateral tone stimulation. Sound‐evoked responses were recorded as early as postnatal day (P) 33, a few days after hearing onset. From P36 onwards, pure tone stimuli evoked restricted, tonotopically organized patches of activity. There was an age‐dependent increase in the cortical area representing each octave, with a disproportionate expansion of cortical territory representing frequencies > 4 kHz after P60. Similar tonotopic maps were observed following stimulation of the contralateral and ipsilateral ears. During the first few weeks following hearing onset, no differences were found in the area of cortical activation or in the magnitude of the optical responses evoked by stimulation of each ear. In older animals, however, contralateral stimuli evoked stronger responses and activated a larger A1 area than ipsilateral stimuli. Our findings indicate that neither the tonotopic organization nor the representation of inputs from each ear reach maturity until approximately 1 month after hearing onset. These results have important implications for cortical signal processing in juvenile animals.

Single-fibre and whole-nerve responses to clicks as a function of sound intensity in the guinea pig

This paper describes a study of the intensity dependence of click-evoked responses of auditory-nerve fibres in relation to the simultaneously recorded compound action potential (CAP). Condensation and rarefaction clicks were presented to normal hearing guinea pigs over an intensity range of 60 dB. The recorded poststimulus time histograms (PSTHs) were characterized by the latency (tp), amplitude (Ap) and synchronization (Sp) of their dominant peak, parameters that are particularly important for the understanding of the CAP. For all fibres tp decreased monotonically with increasing intensity, in a continuous way for fibres with high characteristic frequency (CF greater than 3 kHz), and in discrete steps of one CF-cycle for low-CF (CF less than or equal to 3 kHz) fibres. An additional analysis of PSTH envelopes revealed that average latency shifts with intensity are similar for all CFs above 2 kHz. For all fibres Ap increased monotonically with intensity; the increase was stronger and maximum values were larger for low-CF than for high-CF fibres. A schematic model PSTH was then formulated on the basis of the experimental data. A sum of these model PSTHs from a hypothesized fibre population was convolved with an elemental unit response (Versnel et al., 1992) in order to simulate the compound action potential. Synthesized CAPs agreed with experimental CAPs in their main aspects.

Spectrotemporal Response Properties of Inferior Colliculus Neurons in Alert Monkey

Because of its central position in the ascending auditory pathway, its large number of converging auditory brainstem inputs, and its fundamental role as a relay to auditory cortex and midbrain superior colliculus, the mammalian inferior colliculus (IC) is regarded pivotal for the integration of acoustic spectral–temporal cues to mediate sound-evoked behavior. However, detailed quantitative analyses of spectrotemporal neural responses are scarce. Moreover, most studies have been performed in anesthetized preparations, and it is unclear how to extrapolate findings to awake and behaving animals. Here, we characterize spectrotemporal receptive fields (STRFs) of single units in alert monkey IC by using a variety of broadband sounds with rippled amplitude spectra. We measured the response sensitivity to the ripple parameters density, Ω (cycles/octave), velocity, w (hertz), and direction selectivity, D. We observed a variety of dynamic STRFs, with a strong preference for low ripple densities, and a generally weak direction selectivity. Most cells preferred dynamic rippled stimuli above pure amplitude modulated noise (i.e., Ω = 0). Half of the cells could be characterized by good spectral–temporal separability, in which the ripple transfer function can be written as T(w, Ω) = F(w) × G(Ω). Inseparability could be attributed to a difference in responses to up and downward direction with respect to both amplitude and temporal phase. We tested linearity of IC neurons by using the STRF to predict neural responses to natural stimuli and broadband noise and discuss our results in the light of findings obtained from auditory cortex.

Bilateral Low-Frequency Repetitive Transcranial Magnetic Stimulation of the Auditory Cortex in Tinnitus Patients Is Not Effective: A Randomised Controlled Trial

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.

Chronic electrical stimulation does not prevent spiral ganglion cell degeneration in deafened guinea pigs

Several studies have demonstrated that treatment with intracochlear chronic electrical stimulation (CES) protects spiral ganglion cells (SGCs) from degeneration in deafened animals. Other studies could not confirm this effect of CES. The present study examined whether CES in a mode as presented in cochlear implant users (amplitude modulated, high pulse rate) affects survival, morphology and functionality of SGCs in deafened guinea pigs. Eleven guinea pigs were implanted in the right cochlea with an electrode array to monitor the electrically evoked auditory brainstem responses (eABRs). The guinea pigs were deafened four weeks later. Two days after deafening, monopolar CES was started in five animals through three electrodes in the basal cochlear turn. CES lasted 4 hours per day, five days per week, for six weeks. SGC packing densities, perikaryal area, cell circularity, amplitudes of suprathreshold eABRs and eABR thresholds were not affected by CES. SGCs of all implanted cochleae were larger and more circular than SGCs in unimplanted cochleae, but this did not depend on CES treatment. Interestingly, an increase in eABR latencies observed after deafening, occurred faster in CES-treated than in untreated animals. In conclusion, amplitude-modulated chronic electrical stimulation with a high pulse rate does not affect survival, morphology and functionality of spiral ganglion cells with the exception of eABR latencies.