Publications using TDT

Sensory systems are known to adapt their coding strategies to the statistics of their environment, but little is still known about the perceptual implications of such adjustments. We investigated how auditory spatial processing adapts to stimulus statistics by presenting human listeners and anesthetized ferrets with noise sequences in which interaural level differences (ILD) rapidly fluctuated according to a Gaussian distribution. The mean of the distribution biased the perceived laterality of a subsequent stimulus, whereas the distribution's variance changed the listeners' spatial sensitivity. The responses of neurons in the inferior colliculus changed in line with these perceptual phenomena. Their ILD preference adjusted to match the stimulus distribution mean, resulting in large shifts in rate-ILD functions, while their gain adapted to the stimulus variance, producing pronounced changes in neural sensitivity. Our findings suggest that processing of auditory space is geared toward emphasizing relative spatial differences rather than the accurate representation of absolute position.

Age-related hearing loss is a highly prevalent sensory disorder, from both the clinical and animal model perspectives. Understanding of the neurophysiologic, structural, and molecular biologic bases of age-related hearing loss will facilitate development of biomedical therapeutic interventions to prevent, slow, or reverse its progression. Thus, increased understanding of relationships between aging of the cochlear (auditory portion of the inner ear) hair cell system and decline in overall hearing ability is necessary. The goal of the present investigation was to test the hypothesis that there would be correlations between physiologic measures of outer hair cell function (otoacoustic emission levels) and hearing sensitivity (auditory brainstem response thresholds), starting in middle age. For the CBA mouse, a useful animal model of age-related hearing loss, it was found that correlations between these two hearing measures occurred only for high sound frequencies in middle age. However, in old age, a correlation was observed across the entire mouse range of hearing. These findings have implications for improved early detection of progression of age-related hearing loss in middle-aged mammals, including mice and humans, and distinguishing peripheral etiologies from central auditory system decline.

The auditory sensory organ, the cochlea, not only detects but also generates sounds. Such sounds, otoacoustic emissions, are widely used for diagnosis of hearing disorders and to estimate cochlear nonlinearity. However, the fundamental question of how the otoacoustic emission exits the cochlea remains unanswered. In this study, emissions were provoked by two tones with a constant frequency ratio, and measured as vibrations at the basilar membrane and at the stapes, and as sound pressure in the ear canal. The propagation direction and delay of the emission were determined by measuring the phase difference between basilar membrane and stapes vibrations. These measurements show that cochlea-generated sound arrives at the stapes earlier than at the measured basilar membrane location. Data also show that basilar membrane vibration at the emission frequency is similar to that evoked by external tones. These results conflict with the backward-traveling-wave theory and suggest that at low and intermediate sound levels, the emission exits the cochlea predominantly through the cochlear fluids.

Extracellular adenosine triphosphate (ATP) has profound effects on the cochlea, including an effect on the regulation of the endocochlear potential (EP). Noise-induced release of ATP into the endolymph activates a shunt conductance mediated by P2X(2) receptors in tissues lining the endolymphatic compartment, which reduces the EP and, consequentially, hearing sensitivity. This may be a mechanism of adaptation or protection from high sound levels. As inaction of such a process could contribute to hearing loss, this study examined whether the action of ATP on EP changes with age and noise exposure in the mouse. The EP and the endolymphatic compartment resistance (CoPR) were measured in mice (CBA/CaJ) aged between 3 and 15 months. The EP and CoPR declined slightly with age with an associated small, but significant, reduction in auditory brainstem response thresholds. ATP (100-1,000 muM) microinjected into the endolymphatic compartment caused a dose-dependent decline in EP correlated to a similar decrease in CoPR. This was blocked by pyridoxal-phosphate-6-azophenyl-2',4'-disulfonate, consistent with a P2X(2) receptor-mediated shunt conductance. There was no substantial difference in the ATP response with age. Noise exposure (octave-band noise 80-100 decibels sound pressure level (dBSPL), 48 h) in young animals induced an upregulation of the P2X(2) receptor expression in the organ of Corti and spiral limbus, most noticeably with the 90-dB exposure. This did not occur in the aged animals except following exposure at 90 dBSPL. The EP response to ATP was muted in the noise-exposed aged animals except following the 90-dB exposure. These findings provide some evidence that the adaptive response of the cochlea to noise may be reduced in older animals, and it is speculated that this could increase their susceptibility to noise-induced injury.

Several studies have investigated the relationship between click-evoked auditory brainstem responses (ABRs) and loudness growth in human listeners. While some of these studies have reported promising results, showing a correlative relationship between click ABR and loudness growth as a function of level, additional studies are necessary to determine if similar results can be obtained with frequency-specific stimuli and more specific details of the loudness function can be derived from ABR recordings. The aims of this study, therefore, were to (1) develop a fully objective procedure that segments specific features of evoked, tone-burst ABR recordings, (2) investigate the feasibility of using information derived from these recordings for estimating frequency-specific loudness-growth functions, and (3) determine to what extent the loudness-growth estimation performance through ABR can be improved by controlling for residual noise levels and parametric fitting. Results from eight normal-hearing listeners using 1- and 4-kHz stimuli show that the average mean-square error of the loudness-growth estimation obtained through the procedure is comparable to that of standard psychoacoustical procedures used to estimate loudness growth. The data set has been made publicly available at www.physionet.org.

Responses of vestibular-only translation sensitive (VOTS) neurons in vestibular nuclei of two squirrel monkeys were studied at multiple frequencies to three-dimensional translations and rotations. A novel frequency-dependent spatiotemporal analysis examined in each neuron whether complex models, with unrestricted response dynamics in three-dimensional (3D) space, provided significantly better fits than restricted models following simple, cosine rule. Subsequently, the statistically selected optimal model was used to predict the maximum translation direction, expressed as a unitary vector, Vt max , and its associated sensitivity and phase across frequencies. Simple models were sufficient to quantify the 3D translational responses of 66% of neurons. Most VOTS neurons, complex or simple, exhibited flat-gain or low-pass response dynamics. The Vt max of simple neurons was fixed, whereas that of complex neurons changed with frequency. The spatial distribution of Vt max in simple neurons, which fell within 30° of either the horizontal plane or/and the sagittal plane, was closely aligned with Vt max of vestibular afferents. In contrast, the frequency-dependent Vt max of most complex neurons migrated from the dorsoventral axis at higher frequency toward the horizontal plane, especially the interaural axis, at lower frequency. When the maximum rotation direction was estimated from responses of the same VOTS neurons to 1.2 Hz yaw, pitch, and roll rotations, complex neurons were more likely to respond to rotations activating vertical canals. Responses to 0.15–0.3 Hz linear accelerations produced by inertial or gravitational forces were indistinguishable in most complex neurons but significantly different in most simple neurons. These observations suggest that simple and complex VOTS neurons constitute distinctive vestibular pathways where complex neurons, exhibiting a novel spatiotemporal filtering mechanism in processing otolith-related signals, are well suited to drive tilt-related responses, whereas simple neurons probably mediate pure translation related responses.

The study measured listener sensitivity to increments of a target inter-onset interval (IOI) embedded within isochronous tone sequences that featured a single accented tonal component. The sequences consisted of six 1000-Hz tone bursts separated by silent intervals to establish equal tonal IOIs of 200 ms within the sequence. Tone burst durations within the sequences were 50 ms, except one tone had a longer duration of 100 ms to produce a perception of accent. Duration DLs in ms for increments of a single sequence IOI were measured adaptively by adjusting the duration of the silent interval between two tones. Sequence position of the target IOI differed across conditions. Listeners included young normal-hearing adults and older adults with and without hearing loss. Discrimination performance of the two older listener groups was equivalent and significantly poorer than that of the younger listeners in each discrimination condition. The age-related discrimination deficits were independent of sequence locations of both the target interval and the accented tonal component. Comparative DLs collected for target intervals in unaccented tone sequences with equal tone durations revealed that the detrimental effects of accent on temporal discrimination were primarily restricted to the older listeners.

Psychophysical data on hearing sensitivity and various measures of supra-threshold auditory temporal processing are presented for large groups of young (18-35 y), middle-aged (40-55 y) and older (60-89 y) adults. Hearing thresholds were measured at 500, 1414 and 4000 Hz. Measures of temporal processing included gap-detection thresholds for bands of noise centered at 1000 and 3500 Hz, stimulus onset asynchronies for monaural and dichotic temporal-order identification for brief vowels, and stimulus onset/offset asynchronies for the monaural temporal masking of vowel identification. For all temporal-processing measures, the impact of high-frequency hearing loss in older adults was minimized by a combination of low-pass filtering the stimuli and use of high presentation levels. The performance of the older adults was worse than that of the young adults on all measures except gap-detection threshold at 1000 Hz. Middle-aged adults performed significantly worse than the young adults on measures of threshold sensitivity and three of the four measures of temporal-order identification, but not for any of the measures of temporal masking. Individual differences are also examined among a group of 124 older adults. Cognition and age were found to be significant predictors, although only 10-27% of the variance could be accounted for by these predictors.

Continuity of spatial location was recently shown to improve the ability to identify and recall a sequence of target digits presented in a mixture of confusable maskers [Best (2008). Proc. Natl. Acad. Sci. U.S.A.105, 13174–13178]. Three follow-up experiments were conducted to explore the basis of this improvement. The results suggest that the benefits of spatial continuity cannot be attributed to (a) the ability to plan where to direct attention in advance; (b) freedom from having to redirect attention across large distances; or (c) the challenge of filtering out signals that are confusable with the target.

The vasculature and neurons of the inner ear receive adrenergic innervation from the cervical sympathetic chain, and adrenergic receptors may be expressed by cells of the organ of Corti and stria vascularis, despite a lack of direct sympathetic innervation. To assess the functional role of adrenergic signaling in the auditory periphery, we studied mice with targeted deletion of the gene for dopamine beta-hydroxylase (DBH), which catalyzes the conversion of dopamine to noradrenaline; thus, these mutant mice have no measurable adrenaline or noradrenaline. Dbh (-/-) mice were more susceptible to spontaneous middle-ear infection than their control littermates, consistent with a role for sympathetics in systemic and/or local immune response. At 6-8 weeks of age, cochlear thresholds and suprathreshold responses assessed by auditory brainstem responses and distortion product otoacoustic emissions, as well as light-microscopic morphology, were indistinguishable from controls, if ears with conductive hearing loss were eliminated. Dbh (-/-) mice were no more susceptible to acoustic injury than controls, despite prior reports that sympathectomy reduces noise damage. Dbh (-/-) mice showed enhancement of shock-evoked olivocochlear suppression of cochlear responses, which may arise from the loss of adrenergic inputs to olivocochlear neurons in the brainstem. However, adrenergic modulation of olivocochlear efferents does not mediate the protective effect of contralateral cochlear destruction on ipsilateral response to acoustic overexposure.

Neural adaptation and visual auditory integration are two well studied and common phenomena in the brain, yet little is known about the interaction between them. In the present study, we investigated a visual forebrain area in barn owls, the entopallium (E), which has been shown recently to encompass auditory responses as well. Responses of neurons to sequences of visual, auditory, and bimodal (visual and auditory together) events were analyzed. Sequences comprised two stimuli, one with a low probability of occurrence and the other with a high probability. Neurons in the E tended to respond more strongly to low probability visual stimuli than to high probability stimuli. Such a phenomenon is known as stimulus-specific adaptation (SSA) and is considered to be a neural correlate of change detection. Responses to the corresponding auditory sequences did not reveal an equivalent tendency. Interestingly, however, SSA to bimodal events was stronger than to visual events alone. This enhancement was apparent when the visual and auditory stimuli were presented from matching locations in space (congruent) but not when the bimodal stimuli were spatially incongruent. These findings suggest that the ongoing task of detecting unexpected events can benefit from the integration of visual and auditory information.

Acetylcholine is the major neurotransmitter of the olivocochlear efferent system, which provides feedback to cochlear hair cells and sensory neurons. To study the role of cochlear muscarinic receptors, we studied receptor localization with immunohistochemistry and reverse transcription-PCR and measured olivocochlear function, cochlear responses, and histopathology in mice with targeted deletion of each of the five receptor subtypes. M 2 , M 4 , and M 5 were detected in microdissected immature (postnatal days 10–13) inner hair cells and spiral ganglion cells but not outer hair cells. In the adult (6 weeks), the same transcripts were found in microdissected organ of Corti and spiral ganglion samples. M 2 protein was found, by immunohistochemistry, in olivocochlear fibers in both outer and inner hair cell areas. M 3 mRNA was amplified only from whole cochleas, and M 1 message was never seen in wild-type ears. Auditory brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs) were unaffected by loss of G q -coupled receptors (M 1 , M 3 , or M 5 ), as were shock-evoked olivocochlear effects and vulnerability to acoustic injury. In contrast, loss of G i -coupled receptors (M 2 and/or M 4 ) decreased neural responses without affecting DPOAEs (at low frequencies). This phenotype and the expression pattern are consistent with excitatory muscarinic signaling in cochlear sensory neurons. At high frequencies, both ABRs and DPOAEs were attenuated by loss of M 2 and/or M 4 , and the vulnerability to acoustic injury was dramatically decreased. This aspect of the phenotype and the expression pattern are consistent with a presynaptic role for muscarinic autoreceptors in decreasing ACh release from olivocochlear terminals during high-level acoustic stimulation and suggest that muscarinic antagonists could enhance the resistance of the inner ear to noise-induced hearing loss.

Cortical sound representations are adapted to the acoustic environment. Early exposure to exponential frequency-modulated (FM) sweeps results in more neurons selective to the experienced sounds. Here we examined the influence of pulsed noise experience on the development of sound representations in the primary auditory cortex (AI) of the rat. In naïve animals, FM sweep direction selectivity depends on the characteristic frequency (CF) of the neuron—low CF neurons tend to select for upward sweeps and high CF neurons for downward sweeps. Such a CF dependence was not observed in animals that had received weeklong exposure to pulsed noise in periods from postnatal day 8 (P8) to P15 or from P24 to P39. In addition, AI tonotopicity, tuning bandwidth, intensity threshold, tone-responsiveness, and sweep response magnitude were differentially affected by the noise experience depending on the exposure time windows. These results are consistent with previous findings of feature-dependent multiple sensitive periods. The different effects induced here by pulsed noise and previously by FM sweeps further indicate that plasticity in cortical complex sound representations is specific to the sensory input.

Sanfilippo syndrome type B (MPS IIIB) is a lysosomal storage disease resulting from a deficiency of N-acetyl-glucosaminidase (NAGLU) activity. In an attempt to correct the disease in the murine model of MPS IIIB, neonatal mice were treated with intracranial AAV2/5-NAGLU (AAV), syngeneic bone marrow transplant (BMT), or both (AAV/BMT). All treatments resulted in some improvement in clinical phenotype. Adeno-associated viral (AAV) treatment resulted in improvements in lifespan, motor function, hearing, time to activity onset, and daytime activity level, but no reduction of lysosomal storage. BMT resulted in improved hearing by 9 months, and improved circadian measures, but had no effect on lifespan, motor function, or central nervous system (CNS) lysosomal storage. AAV/BMT treatment resulted in improvements in hearing, time to activity onset, motor function, and reduced CNS lysosomal storage, but had no effect on lifespan. Combination therapy compared to either therapy alone resulted in synergistic effects on hearing and CNS lysosomal inclusions but antagonistic effects on motor function and lifespan. AAV alone is more efficacious than BMT or AAV/BMT treatment for lifespan. BMT was the least efficacious treatment by all measures. CNS-directed AAV treatment alone appears to be the preferred treatment, combining the most efficacy with the least toxicity of the approaches assessed.

Sound-induced motion of the surface of the human tympanic membrane (TM) was studied by stroboscopic holographic interferometery, which measures the amplitude and phase of the displacement at each of about 40,000 points on the surface of the TM. Measurements were made with tonal stimuli of 0.5, 1, 4 and 8 kHz. The magnitude and phase of the sinusoidal displacement of the TM at each driven frequency were derived from the fundamental Fourier component of the raw displacement data computed from stroboscopic holograms of the TM recorded at eight stimulus phases. The correlation between the Fourier estimates and measured motion data was generally above 0.9 over the entire TM surface. We used three data presentations: (i) plots of the phasic displacements along a single chord across the surface of the TM, (ii) phasic surface maps of the displacement of the entire TM surface, and (iii) plots of the Fourier derived amplitude and phase-angle of the surface displacement along four diameter lines that define and bisect each of the four quadrants of the TM. These displays led to some common conclusions: at 0.5 and 1kHz, the entire TM moved roughly in-phase with some small phase delay apparent between local areas of maximal displacement in the posterior half of the TM. At 4 and 8 kHz, the motion of the TM became more complicated with multiple local displacement maxima arranged in rings around the manubrium. The displacements at most of these maxima were roughly in-phase, while some moved out-of-phase. Superposed on this in- and out-of-phase behavior were significant cyclic variations in-phase with location of less than 0.2 cycles or occasionally rapid half-cycle step-like changes in-phase. The high frequency displacement amplitude and phase maps discovered in this study can not be explained by any single wave motion, but are consistent with a combination of low and higher order modal motions plus some small traveling-wave-like components. The observations of the dynamics of TM surface motion from this study will help us better understand the sound-receiving function of the TM and how it couples sound to the ossicular chain and inner ear.

Stroboscopic holography was used to quantify dynamic deformations of the tympanic membrane (TM) of the entire surface of the TM before and after cartilage tympanoplasty of the posterior or posterior-superior part of the TM. Cartilage is widely used in tympanoplasties to provide mechanical stability for the TM. Three human cadaveric temporal bones were used. A 6 mm x 3 mm oval cartilage graft was placed through the widely opened facial recess onto the medial surface of the posterior or posterior-superior part of the TM. The graft was either in contact with the bony tympanic rim and manubrium or not. Graft thickness was either 0.5 or 1.0mm. Stroboscopic holography produced displacement amplitude and phase maps of the TM surface in response to stimulus sound. Sound stimuli were 0.5, 1, 4 and 7 (or 8)kHz tones. Middle-ear impedance was measured from the motion of the entire TM. Cartilage placement generally produced reductions in the motion of the TM apposed to the cartilage, especially at 4 kHz and 7 or 8 kHz. Some parts of the TM showed altered motion compared to the control in all three cases. In general, middle-ear impedance was either unchanged or increased somewhat after cartilage reconstruction both at low (0.5 and 1 kHz) and high (4 and 7 kHz) frequencies. At 4 kHz, with the 1.0mm thick graft that was in contact with the bony tympanic rim, the impedance slightly decreased. While our earlier work with time-averaged holography allowed us to observe differences in the pattern of TM motion caused by application of cartilage to the TM, stroboscopic holography is more sensitive to TM motions and allowed us to quantify the magnitude and phase of motion of each point on the TM surface. Nonetheless, our results are similar to those of our earlier work: The placement of cartilage on the medial surface of TM reduces the motion of the TM that apposes the cartilage. These obvious local changes occur even though the cartilage had little effect on the sound-induced motion of the stapes.

The saccule is known to play an important role in hearing in fishes. In this study we investigated spatial frequency selectivity of single saccular afferents in a teleost fish (the sleeper goby, Dormitator latifrons) to acoustic particle motion at 50–400 Hz. Saccular afferents have similar distributions of best sensitivity (−90.0 to −54.8 dB re. 1 g, mean ± s.d.=−81.1±8.0 dB) and characteristic frequencies (≤50–400 Hz, median=80 Hz) along the longitudinal, side-to-side and dorsoventral axes of fish. They were lowpass, bandpass or broadly tuned to low frequencies with Q50% at 15 dB above threshold in ranges from 0.28 to 3.30 (1.46±0.71), 0.18 to 2.54 (1.36±0.78), and 0.41 to 4.26 (2.25±0.1.12) along the three axes, showing slightly greater frequency tuning in the vertical axis than horizontal axes. At supra threshold we found tuning plasticity, i.e. best frequencies of saccular afferents shifted to high frequencies as stimulus level increased. Isolevel rate–frequency curves were asymmetrical with shallow slopes at the low-frequency edge and steep slopes at the high-frequency edge. Saccular afferents of the sleeper goby have similar capabilities of coding particle motion frequencies in the three orthogonal axes. Results from this and other studies suggest that (1) the saccule is the major hearing organ in this species, (2) the saccule of this species is capable of encoding sound frequencies in three dimensional space, and (3) saccular afferents in fishes without accessory auditory structures exhibit similar frequency selectivity in response to particle motion.

Listeners detected interaural differences of time (ITDs) or level (ILDs) carried by single 4000-Hz Gabor clicks (Gaussian-windowed tone bursts) and trains of 16 such clicks repeating at an interclick interval (ICI) of 2, 5, or 10 ms. In separate conditions, target interaural differences favored the right ear by a constant amount for all clicks (condition RR), attained their peak value at onset and diminished linearly to 0 at offset (condition R0), or grew linearly from 0 at onset to a peak value at offset (condition 0R). Threshold ITDs and ILDs were determined adaptively in separate experiments for each of these conditions and for single clicks. ITD thresholds were found to be lower for 16-click trains than for single clicks at 10-ms ICI, regardless of stimulus condition. At 2-ms ICI, thresholds in RR and R0 conditions were similar to single click thresholds at 2-ms ICI; thresholds in the 0R condition were significantly worse than for single clicks at 2-ms ICI, consistent with strong rate-dependent onset dominance in listeners’ temporal weighting of ITD. ILD thresholds, in contrast, were predominantly unaffected by ICI, suggesting little or no onset dominance for ILD of high-rate stimuli.

Acipenser fulvescens, the lake sturgeon, belongs to one of the few extant non-teleost ray-finned (bony) fishes. The sturgeons (family Acipenseridae) have a phylogenetic history that dates back about 250 million years. The study reported here is the first investigation of peripheral coding strategies for spectral analysis in the auditory system in a non-teleost bony fish. We used a shaker system to simulate the particle motion component of sound during electrophysiological recordings of isolated single units from the eighth nerve innervating the saccule and lagena. Background activity and response characteristics of saccular and lagenar afferents (such as thresholds, response–level functions and temporal firing) resembled the ones found in teleosts. The distribution of best frequencies also resembled data in teleosts (except for Carassius auratus, goldfish) tested with the same stimulation method. The saccule and lagena in A. fulvescens contain otoconia, in contrast to the solid otoliths found in teleosts, however, this difference in otolith structure did not appear to affect threshold, frequency tuning, intensity- or temporal responses of auditory afferents. In general, the physiological characteristics common to A. fulvescens, teleosts and land vertebrates reflect important functions of the auditory system that may have been conserved throughout the evolution of vertebrates.