Publications using TDT

Although it is known that neural selectivity for species-specific vocalizations changes during development, the mechanisms underlying such changes are not known. This study followed the development of mechanisms underlying selectivity for the direction and rate of frequency-modulated (FM) sweeps in the auditory cortex of the pallid bat, a species that uses downward FM sweeps to echolocate. In the adult cortex, direction and rate selectivity arise as a result of different spectral and temporal properties of low-frequency inhibition (LFI) and high-frequency inhibition (HFI). A narrow band of delayed HFI shapes rate selectivity for downward FM sweeps. A broader band of early LFI shapes direction selectivity. Here we asked whether these differences in LFI and HFI are present at the onset of hearing in the echolocation range or whether the differences develop slowly. We also studied how the development of properties of inhibitory frequencies influences FM rate and direction selectivity. We found that adult-like FM rate selectivity is present at 2 weeks after birth, whereas direction selectivity matures 12 weeks after birth. The different developmental time course for direction and rate selectivity is attributable to the differences in the development of LFI and HFI. Arrival time and bandwidth of HFI are adult-like at 2 weeks. Average arrival time of LFI gradually becomes faster and bandwidth becomes broader between 2 and 12 weeks. Thus, two properties of FM sweeps that are important for vocalization selectivity follow different developmental time courses attributable to the differences in the development of underlying inhibitory mechanisms.

Deficits in parsing concurrent auditory events are believed to contribute to older adults' difficulties in understanding speech in adverse listening conditions (e.g., cocktail party). To explore the level at which aging impairs sound segregation, we measured auditory evoked fields (AEFs) using magnetoencephalography while young, middle-aged, and older adults were presented with complex sounds that either had all of their harmonics in tune or had the third harmonic mistuned by 4 or 16% of its original value. During the recording, participants were asked to ignore the stimuli and watch a muted subtitled movie of their choice. For each participant, the AEFs were modeled with a pair of dipoles in the superior temporal plane, and the effects of age and mistuning were examined on the amplitude and latency of the resulting source waveforms. Mistuned stimuli generated an early positivity (60–100 ms), an object-related negativity (ORN) (140–180 ms) that overlapped the N1 and P2 waves, and a positive displacement that peaked at ∼230 ms (P230) after sound onset. The early mistuning-related enhancement was similar in all three age groups, whereas the subsequent modulations (ORN and P230) were reduced in older adults. These age differences in auditory cortical activity were associated with a reduced likelihood of hearing two sounds as a function of mistuning. The results reveal that inharmonicity is rapidly and automatically registered in all three age groups but that the perception of concurrent sounds declines with age.

Since its introduction in the early 1980s, the concept of a “preferred direction” for neuronal discharge has proven to be a powerful means of studying motor areas of the brain. In the current paper, we introduce the concept of a “muscle-space”–preferred direction (PD M ) that is analogous to the familiar hand-space–preferred direction (PD H ). PD M reflects the similarity between the discharge of a given neuron and the activity of each muscle in much the way that PD H reflects the similarity of discharge with motion along each of the three Cartesian coordinate axes. We used PD M to analyze the data recorded from neurons in the primary motor cortex (M1) of three different monkeys. The monkeys performed center-out movements within two different cubical workspaces centered either to the left or right of the monkey's shoulder while we simultaneously recorded neuronal discharge, muscle activity, and limb orientation. We calculated preferred directions in both hand space and muscle space, and computed the angles between these vectors under a variety of conditions. PDs for different neurons were broadly distributed throughout both hand space and muscle space, but the muscle-space vectors appeared to form clusters of functionally similar neurons. In general, repeated estimates of PD M were more stable over time than were similar estimates of PD H . Likewise, there was less change in PD M than in PD H for data recorded from the two different workspaces. However, although a majority of neurons had this muscle-like property, a significant minority was more stable in Cartesian hand space, reflecting a heterogeneity of function within M1.

Based on in vitro studies, it is hypothesized that neurotrophic factor deprivation following deafferentation elicits an oxidative state change in the deafferented neuron and the formation of free radicals that then signal cell death pathways. This pathway to cell death was tested in vivo by assessing the efficacy of antioxidants (AOs) to prevent degeneration of deafferented CNVIII spiral ganglion cells (SGCs) in deafened guinea pigs. Following destruction of sensory cells, guinea pigs were treated immediately with Trolox (a water soluble vitamin E analogue)+ascorbic acid (vitamin C) administered either locally, directly in the inner ear, or systemically. Electrical auditory brainstem response (EABR) thresholds were recorded to assess nerve function and showed a large increase following deafness. In treated animals EABR thresholds decreased and surviving SGCs were increased significantly compared to untreated animals. These results indicate that a change in oxidative state following deafferentation plays a role in nerve cell death and antioxidant therapy may rescue SGCs from deafferentation-induced degeneration.

Cochlear sensory cells and neurons receive efferent feedback from the olivocochlear (OC) system. The myelinated medial component of the OC system and its effects on outer hair cells (OHCs) have been implicated in protection from acoustic injury. The unmyelinated lateral (L)OC fibers target ipsilateral cochlear nerve dendrites and pharmacological studies suggest the LOC's dopaminergic component may protect these dendrites from excitotoxic effects of acoustic overexposure. Here, we explore LOC function in vivo by selective stereotaxic destruction of LOC cell bodies in mouse. Lesion success in removing the LOC, and sparing the medial (M)OC, was assessed by histological analysis of brain stem sections and cochlear whole mounts. Auditory brain stem responses (ABRs), a neural-based metric, and distortion product otoacoustic emissions (DPOAEs), an OHC-based metric, were measured in control and surgical mice. In cases where the LOC was at least partially destroyed, there were increases in suprathreshold neural responses that were frequency- and level-independent and not attributable to OHC-based effects. These interaural response asymmetries were not found in controls or in cases where the lesion missed the LOC. In LOC-lesion cases, after exposure to a traumatic stimulus, temporary threshold shifts were greater in the ipsilateral ear, but only when measured in the neural response; OHC-based measurements were always bilaterally symmetric, suggesting OHC vulnerability was unaffected. Interaural asymmetries in threshold shift were not found in either unlesioned controls or in cases that missed the LOC. These findings suggest that the LOC modulates cochlear nerve excitability and protects the cochlea from neural damage in acute acoustic injury.

Contemporary auditory prostheses ("cochlear implants") employ arrays of stimulating electrodes implanted in the scala tympani of the cochlea. Such arrays have been implanted in some 100,000 profoundly or severely deaf people worldwide and arguably are the most successful of present-day neural prostheses. Nevertheless, most implant users show poor understanding of speech in noisy backgrounds, poor pitch recognition, and poor spatial hearing, even when using bilateral implants. Many of these limitations can be attributed to the remote location of stimulating electrodes relative to excitable cochlear neural elements. That is, a scala tympani electrode array lies within a bony compartment filled with electrically conductive fluid. Moreover, scala tympani arrays typically do not extend to the apical turn of the cochlea in which low frequencies are represented. In the present study, we have tested in an animal model an alternative to the conventional cochlear implant: a multielectrode array implanted directly into the auditory nerve. We monitored the specificity of stimulation of the auditory pathway by recording extracellular unit activity at 32 sites along the tonotopic axis of the inferior colliculus. The results demonstrate the activation of specific auditory nerve populations throughout essentially the entire frequency range that is represented by characteristic frequencies in the inferior colliculus. Compared to conventional scala tympani stimulation, thresholds for neural excitation are as much as 50-fold lower and interference between electrodes stimulated simultaneously is markedly reduced. The results suggest that if an intraneural stimulating array were incorporated into an auditory prosthesis system for humans, it could offer substantial improvement in hearing replacement compared to contemporary cochlear implants.

Sensory development can be dependent on input from multiple modalities. During metamorphic development, ranid frogs exhibit rapid reorganization of pathways mediating auditory, vestibular, and lateral line modalities as the animal transforms from an aquatic to an amphibious form. Here we show that neural sensitivity to the underwater particle motion component of sound follows a different developmental trajectory than that of the pressure component. Throughout larval stages, cells in the medial vestibular nucleus show best frequencies to particle motion in the range from 15 to 65 Hz, with displacement thresholds of <10 μm. During metamorphic climax, best frequencies significantly increase, and sensitivity to lower-frequency (<25 Hz) stimuli tends to decline. These findings suggest that continued sensitivity to particle motion may compensate for the considerable loss of sensitivity to pressure waves observed during the developmental deaf period. Transport of a lipophilic dye from peripheral end organs to the dorsal medulla shows that fibers from the saccule in the inner ear and from the anterior lateral line both terminate in the medial vestibular nucleus. Saccular projections remain stable across larval development, whereas lateral line projections degenerate during metamorphic climax. Sensitivity to particle motion may be based on multimodal input early in development and on saccular input alone during the transition to amphibious life.

Mutations in genes coding for connexin26 (Cx26) and/or Cx30 are linked to approximately half of all cases of human autosomal nonsyndromic prelingual deafness. Cx26 and Cx30 are the two major Cx isoforms found in the cochlea, and they coassemble to form hybrid (heteromeric and heterotypic) gap junctions (GJs). This molecular arrangement implies that homomeric GJs would remain in the cochlea if one of the coassembly partners were mutated resulting in null expression. We generated mice in which extra copies of the Cx26 gene were transgenically expressed from a modified bacterial artificial chromosome in a Cx30 −/− background. In the absence of the Cx30 gene, Cx26 expressed from extra alleles completely restored hearing sensitivity and prevented hair cell death in deaf Cx30 −/− mice. The results indicated that hybrid GJs consisting of Cx26 and Cx30 were not essential for normal hearing in mice and suggested that up-regulation of Cx26 or slowing down its protein degradation might be a therapeutic strategy to prevent and treat deafness caused by Cx30 mutations.

After a yeast two-hybrid screen identified prosaposin as a potential interacting protein with the nicotinic acetylcholine receptor (nAChR) subunit α10, studies were performed to characterize prosaposin in the normal rodent inner ear. Prosaposin demonstrates diffuse organ of Corti expression at birth, with gradual localization to the inner hair cells (IHCs) and its supporting cells, inner pillar cells, and synaptic region of the outer hair cells (OHCs) and Deiters' cells (DCs) by postnatal day 21 (P21). Microdissected OHC and DC quantitative reverse transcriptase-PCR and immunohistology localizes prosaposin mRNA to DCs and OHCs, and protein predominantly to the apex of the DCs. Subsequent studies in a prosaposin knock-out (KO) (−/−) mouse showed intact but slightly reduced hearing through P19, but deafness by P25 and reduced distortion product otoacoustic emissions from P15 onward. Beginning at P12, the prosaposin KO mice showed histologic organ of Corti changes including cellular hypertrophy in the region of the IHC and greater epithelial ridge, a loss of OHCs from cochlear apex, and vacuolization of OHCs. Immunofluorescence revealed exuberant overgrowth of auditory afferent neurites in the region of the IHCs and proliferation of auditory efferent neurites in the region of the tunnel of Corti. IHC recordings from these KO mice showed normal I – V curves and responses to applied acetylcholine. Together, these results suggest that prosaposin helps maintain normal innervation patterns to the organ of Corti. Furthermore, prosaposin's overlapping developmental expression pattern and binding capacity toward the nAChR α10 suggest that α10 may also play a role in this function.

Normal perception depends, in part, on accurate judgments of the temporal relationships between sensory events. Two such relative-timing skills are the ability to detect stimulus asynchrony and to discriminate stimulus order. Here we investigated the neural processes contributing to the performance of auditory asynchrony and order tasks in humans, using a perceptual-learning paradigm. In each of two parallel experiments, we tested listeners on a pretest and a posttest consisting of auditory relative-timing conditions. Between these two tests, we trained a subset of listeners ∼1 h/d for 6–8 d on a single relative-timing condition. The trained listeners practiced asynchrony detection in one experiment and order discrimination in the other. Both groups were trained at sound onset with tones at 0.25 and 4.0 kHz. The remaining listeners in each experiment, who served as controls, did not receive multihour training during the 8–10 d between the pretest and posttest. These controls improved even without intervening training, adding to evidence that a single session of exposure to perceptual tasks can yield learning. Most importantly, each of the two groups of trained listeners learned more on their respective trained conditions than controls, but this learning occurred only on the two trained conditions. Neither group of trained listeners generalized their learning to the other task (order or asynchrony), an untrained temporal position (sound offset), or untrained frequency pairs. Thus, it appears that multihour training on relative-timing skills affects task-specific neural circuits that are tuned to a given temporal position and combination of stimulus components.

The nucleus isthmi pars parvocellularis (Ipc) is a midbrain cholinergic nucleus that shares reciprocal, topographic connections with the optic tectum (OT). Ipc neurons project to spatially restricted columns in the OT, contacting essentially all OT layers in a given column. Previous research characterizes the Ipc as a visual processor. We found that, in the barn owl, the Ipc responds to auditory as well as to visual stimuli. Auditory responses were tuned broadly for frequency, but sharply for spatial cues. We measured the tuning of Ipc units to binaural sound localization cues, including interaural timing differences (ITDs) and interaural level differences (ILDs). Units in the Ipc were tuned to specific values of both ITD and ILD and were organized systematically according to their ITD and ILD tuning, forming a map of space. The auditory space map aligned with the visual space map in the Ipc. These results demonstrate that the Ipc encodes the spatial location of objects, independent of stimulus modality. These findings, combined with the precise pattern of projections from the Ipc to the OT, suggest that the role of the Ipc is to regulate the sensitivity of OT neurons in a space-specific manner.

Recent studies, conducted almost exclusively in primates, have shown that several cortical areas usually associated with modality-specific sensory processing are subject to influences from other senses. Here we demonstrate using single-unit recordings and estimates of mutual information that visual stimuli can influence the activity of units in the auditory cortex of anesthetized ferrets. In many cases, these units were also acoustically responsive and frequently transmitted more information in their spike discharge patterns in response to paired visual-auditory stimulation than when either modality was presented by itself. For each stimulus, this information was conveyed by a combination of spike count and spike timing. Even in primary auditory areas (primary auditory cortex [A1] and anterior auditory field [AAF]), approximately 15% of recorded units were found to have nonauditory input. This proportion increased in the higher level fields that lie ventral to A1/AAF and was highest in the anterior ventral field, where nearly 50% of the units were found to be responsive to visual stimuli only and a further quarter to both visual and auditory stimuli. Within each field, the pure-tone response properties of neurons sensitive to visual stimuli did not differ in any systematic way from those of visually unresponsive neurons. Neural tracer injections revealed direct inputs from visual cortex into auditory cortex, indicating a potential source of origin for the visual responses. Primary visual cortex projects sparsely to A1, whereas higher visual areas innervate auditory areas in a field-specific manner. These data indicate that multisensory convergence and integration are features common to all auditory cortical areas but are especially prevalent in higher areas.

Many models of cortical dynamics have focused on the high-firing regime, in which neurons are driven near their maximal rate. Here we consider the responses of neurons in auditory cortex under typical low-firing rate conditions, when stimuli have not been optimized to drive neurons maximally. We used whole-cell patch-clamp recording in vivo to measure subthreshold membrane potential fluctuations in rat primary auditory cortex in both the anesthetized and awake preparations. By analyzing the subthreshold membrane potential dynamics on single trials, we made inferences about the underlying population activity. We found that, during both spontaneous and evoked responses, membrane potential was highly non-Gaussian, with dynamics consisting of occasional large excursions (sometimes tens of millivolts), much larger than the small fluctuations predicted by most random walk models that predict a Gaussian distribution of membrane potential. Thus, presynaptic inputs under these conditions are organized into quiescent periods punctuated by brief highly synchronous volleys, or “bumps.” These bumps were typically so brief that they could not be well characterized as “up states” or “down states.” We estimate that hundreds, perhaps thousands, of presynaptic neurons participate in the largest volleys. These dynamics suggest a computational scheme in which spike timing is controlled by concerted firing among input neurons rather than by small fluctuations in a sea of background activity.

Parallel ON and OFF pathways conduct visual signals from bipolar cells in the retina to higher centers in the brain. ON responses are thought to originate by exclusive use of metabotropic glutamate receptor 6 (mGluR6) expressed in retinal ON bipolar cells. Paradoxically, we find ON responses in retinal ganglion cells of mGluR6-null mice, but they occur at long latency. The long-latency ON responses are not blocked by metabotropic glutamate or cholinergic receptor antagonists and are not produced by activation of receptive field surrounds. We show that these longer-latency ON responses are initiated in the OFF pathways. Our results expose a previously unrecognized intrinsic property of OFF retinal pathways that generates responses to light onset. In mGluR6-null mice, long-latency ON responses are observed in the visual cortex, indicating that they can be conducted reliably to higher visual areas. In wild-type (WT) mice, APB ( dl -2-amino-4-phosphonobutyric acid), an mGluR6 agonist, blocks normal, short-latency ON responses but unmasks longer-latency ones. We find that these potentially confusing ON responses in the OFF pathway are actively suppressed in WT mice via two pharmacologically separable retinal circuits that are activated by the ON system in the retina. Consequently, we propose that a major function of the signaling of the ON pathway to the OFF pathway is suppression of these mistimed, and therefore inappropriate, light-evoked responses.

Our understanding of cochlear mechanics is impeded by the lack of truly panoramic data. Sensitive mechanical measurements cover only a narrow cochlear region, mostly in the base. The global spatiotemporal pattern of vibrations along the cochlea cannot be inferred from such local measurements but is often extrapolated beyond the measurement spot under the assumption of scaling invariance. Auditory nerve responses give an alternative window on the entire cochlea, but traditional techniques do not allow recovery of the effective vibration pattern. We developed a new analysis technique to measure cochlear amplitude and phase transfer of fibers with characteristic frequencies <5 kHz. Data from six cats yielded panoramic phase profiles along the apex of the cochlea for an ∼5 octave range of stimulus frequencies. All profiles accumulated systematic phase lags from base to apex. Phase accumulation was not gradual but showed a two-segment character: a steep segment (slow propagation) around the characteristic position of the stimulus, and a shallow segment (fast propagation) basal to it. The transition between the segments occurred in a narrow region and was smooth. Wavelength near characteristic position decreased from ∼3.5 to ∼1 mm for frequencies from 200 to 4000 Hz, corresponding to phase velocities of ∼0.5 to ∼5 m/s. The accumulated phase lag between the eardrum and characteristic position varied from ∼1 cycle at 200 Hz to ∼2.5 cycle at 4 kHz, invalidating scaling invariance. The generic character of our analysis technique and its success in solving the difficult problem of reconstructing the effective sensory input from neural recordings suggest its wider application as a powerful alternative to customary system analysis techniques.

Adjacent speech, and even nonspeech, contexts influence phonetic categorization. Four experiments investigated how preceding sequences of sine-wave tones influence phonetic categorization. This experimental paradigm provides a means of investigating the statistical regularities of acoustic events that influence online speech categorization and, reciprocally, reveals regularities of the sound environment tracked by auditory processing. The tones comprising the sequences were drawn from distributions sampling different acoustic frequencies. Results indicate that whereas the mean of the distributions predicts contrastive shifts in speech categorization, variability of the distributions has little effect. Moreover, speech categorization is influenced by the global mean of the tone sequence, without significant influence of local statistical regularities within the tone sequence. Further arguing that the effect is strongly related to the average spectrum of the sequence, notched noise spectral complements of the tone sequences produce a complementary effect on speech categorization. Lastly, these effects are modulated by the number of tones in the acoustic history and the overall duration of the sequence, but not by the density with which the distribution defining the sequence is sampled. Results are discussed in light of stimulus-specific adaptation to statistical regularity in the acoustic input and a speculative link to talker normalization is postulated.

Gonadectomized and surgically intact adult C57BL/6J (B6) mice of both sexes were exposed for 12h nightly to a high-frequency augmented acoustic environment (AAE): repetitive bursts of a half-octave noise band centered at 20 kHz, 70 dB SPL. The effects of sex, gonadectomy, and AAE treatment on genetic progressive hearing loss (exhibited by B6 mice) were evaluated by obtaining auditory brainstem response thresholds at ages 3-, 6-, and 9-months; hair cell counts (cytocochleograms) were obtained at 9 months. A sex difference in the rate of genetic progressive hearing loss in B6 mice (observed by earlier studies) was confirmed, with females exhibiting a faster rate of threshold elevations and more severe loss of hair cells at age 9 months. Gonadectomy had no consistent effects on the rate or severity of hearing loss in non-exposed mice of either sex. An unexpected finding was that the high-frequency AAE treatment caused additional ABR threshold elevations and hair cell loss. In an earlier study, the same high-frequency AAE treatment on DBA/2J mice ameliorated hearing loss. The most severe AAE-induced losses occurred in surgically intact females, suggesting a potentiating effect of ovarian hormone(s).

Responses to acoustic input were recorded from human temporal cortex using subdural electrodes in order to investigate in greater anatomical detail how attentional load modulates exogenous auditory responses. Four patient-volunteers performed a dichotic listening task in which they listened for rare frequency deviants in a series of tones presented to both ears at interstimulus intervals (ISIs) of 400, 800, and 2000 ms. Across all ISIs, stimuli presented contralateral to electrode location produced the strongest deflections in the averaged ERP at approximately 90 and 170 ms post-stimulus on average (labeled N90stg and P170stg). Maximal recording sites for these peaks most often occurred over the Sylvian fissure or the upper bank of the posterior superior temporal gyrus. Neither ISI nor selective attention exhibited substantial effects on peak latencies. However, as presentation rates increased (decreasing ISI), overall averaged event-related potential (ERP) amplitudes declined significantly, while attending to the contralateral stimulus significantly increased both the N90stg and P170stg peaks for most patients. This effect of attention increased with decreasing ISI for both components most clearly in the difference between the grand-average ERPs for attending to vs. ignoring the contralateral stimulus, and even more dramatically in the percentage ratio of that difference over the mean peak amplitude. This amplifying effect of attention with increasing load, along with its anatomical location, suggests that attention can enhance exogenous sources in auditory cortex.

To examine possible neural strategies for the detection of tones in broadband noise, single-neuron extracellular recordings were obtained from the anteroventral cochlear nucleus (AVCN) in anesthetized gerbils. Detection thresholds determined by average discharge rate and several temporal metrics were compared with previously reported psychophysical detection thresholds in cats ( Costalupes 1985 ). Because of their limited dynamic range, the average discharge rates of single neurons failed to predict psychophysical detection thresholds for relatively high-level noise at all measured characteristic frequencies (CFs). However, temporal responses changed significantly when a tone was added to a noise, even for neurons with flat masked rate-level functions. Three specific temporal analyses were applied to neural responses to tones in noise. First, temporal reliability, a measure of discharge time consistency across stimulus repetitions, decreased with increasing tone level for most AVCN neurons at all measured CFs. Second, synchronization to the tone frequency, a measure of phase-locking to the tone, increased with tone level for low-CF neurons. Third, rapid fluctuations in the poststimulus time histograms (PSTHs) decreased with tone level for a number of neurons at all CFs. For each of the three temporal measures, some neurons had detection thresholds at or below psychophysical thresholds. A physiological model of a higher-stage auditory neuron that received simple excitatory and inhibitory inputs from AVCN neurons was able to extract the PSTH fluctuation information in a form of decreased rate with tone level.