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Frequency selectivity and neural phase-locking are two primary properties of the peripheral auditory system and are fundamental to hearing. These properties are reflected in neural signals as a place-rate and time code and are quantified by means of responses from single auditory nerve fibers (AN fibers). Because of practical issues, the limits of both properties are poorly characterized in humans and widely differing values are assumed in the interpretation of non-electrophysiological results. Recent otoacoustic and behavioral measurements suggest that frequency selectivity is higher in humans than in laboratory animals (Shera et al., 2002), but this is disputed based on comparisons of behavioral and electrophysiological measurements across species (Ruggero and Temchin, 2005). Neural phase-locking declines with frequency and becomes undetectable at an upper frequency limit which differs between species. Some studies suggest that phase-locking in human extends to much higher frequencies than that found in common laboratory animals such as cat. In this thesis we investigate the use of mass potentials to electrophysiologically quantify these properties in humans.A minimally invasive transtympanic protocol was developed to record stimulus-evoked mass-potentials from the cochlear promontory or from the niche of the round window in monkey (macaque) and human. This involved a custom made ear mold with openings for the transtympanic needle electrode and for acoustic stimulation (ER-2 earphone, in situ calibrated with an ER-7 microphone). To obtain frequency selectivity a notched-noise forward masking paradigm (Oxenham and Shera, 2003) was combined with the recording of compound action potentials (CAP). For neural phase-locking, we developed a method based on forward masking to disambiguate phase-locked contributions of receptor and neural origin (neurophonic). Both methods were first developed, assessed and validated at the round window in cat and thereafter applied in monkey and human.Frequency selectivity. We found that the empirical method that was first developed and assessed in cat was a suitable means to examine frequency tuning for a number of reasons. a) Masking of CAP responses behaved as expected from the physiology of single AN-fibers. b) Masking tuning curves were equivalent to tuning curve of single AN-fibers. c) The sharpness of masking tuning curves, quantified as a Q10-factor, closely followed the lower boundary of single AN-fibers and was only slightly higher at high frequencies. CAP-tuning was dependent on probe level consistent with cochlear physiology. The CAP responses behaved similar in human and monkey, but the responses and signal-to-noise ratios were much smaller and therefore higher stimulus levels (>30 dB) were needed in human and monkey. We found that CAP tuning in human was on average 1.6 times sharper than in cat and chinchilla and 1.35 times sharper than in monkey (macaque).Neural phase-locking. We found that potentials near the round window have a considerable neural phase-lockedcontribution that can be isolated and quantified with the present method. Moreover, the neural component was in many ways similar to that measured on the auditory nerve. The only noteworthy differences with the latter were a typically larger magnitude and a smaller time lag for the neural component at the round window. The frequency limit obtained in cat was 4.7 kHz, which is very similar to the limit reported for individual AN-fibers (~ 5 kHz). We found in many respects similarities between the measurements in human, monkey and those at the round window in cat, with similar temporal and spectral properties. The most notable difference in human and monkey compared to cat was a much smaller magnitude (-30 dB) and also signal-to-noise(floor) ratio (-20 dB) for the neurophonic. The upper detectable frequency limits of neural phase-locking obtained from stimulus evoked potentials was 3.3 kHz in human and 4.0 kHz in monkey (macaque).Frequency selectivity and neural phase-locking can be characterized from mass potentials with a minimally invasive technique from awake, normal hearing subjects. We found evidence that a) humans have sharper frequency tuning than commonly studied animals, consistent with previous reports (Shera et al., 2002; Oxenham and Shera, 2003) and; b) humans have an upper frequency limit of phase-locking that is not higher than in cat (5 kHz), and likely is somewhat lower. List of abbreviations xi Abstract xiii Chapter 1. General Introduction 1 Chapter 2. Auditory nerve frequency tuning measured with forward-masked compound action potentials 23 Chapter 3. Electrophysiological evidence for sharp cochlear tuning in humans 59 Chapter 4. Upper frequency limit of phase-locking in stimulus evoked potentials 73 Chapter 5. Upper frequency limit of phase-locking in human and monkey 121 Chapter 6. General Discussion 143 References 153 Summary/samenvatting 159 Bibliography 167 nrpages: 169 status: published

Frequency selectivity is one of the most fundamental cochlear properties (Robles and Ruggero, 2001). Recent behavioral and otoacoustic measurements suggest that it is sharper in humans than in laboratory animals (Shera et al., 2002), but this is disputed based on comparisons of behavioral and electrophysiological measurements across species (Ruggero and Temchin, 2005). There are no direct neural recordings from human single auditory nerve fibers, but gross potentials may enable tighter comparisons across species. We search a protocol that is minimally invasive and gives good correspondence with single fiber selectivity and can be applied to humans. Oxenham and Shera (2003) argued that forward masking of a brief signal probe is more suitable to study frequency selectivity than simultaneous masking, because it is less confounded by cochlear nonlinearities. We combined the forward masking paradigm of the latter study with compound action potential (CAP) recordings at the round window of chinchillas and cats - two species for which extensive single fiber data are available. Brief probe tones were presented at a level fixed at 10-15 dB above the unmasked CAP threshold, and the level of a notched noise masker causing a criterion reduction in CAP amplitude (typically 50%) was determined. By varying notch width, Q10 values (ratios of signal frequency to 10 dB notch bandwidth) were obtained. We found better agreement between Q10 values of forward-masked CAPs and single fibers than previous studies using simultaneous masking. Q10 values increased with probe frequency ; straddled the values for single fibers ; and were higher for cat than for chinchilla. These results suggest that forward-masked CAPs may enable electrophysiological assessment of human cochlear frequency selectivity. Supported by grants from FWO and BOF (Flanders, Belgium) and a BOF visiting professorship and FONDECYT to RL.