Publications using TDT

Normal sensory perception requires the ability to detect and identify patterns of activity distributed across the receptor surface. In the visual system, the ability to perceive these patterns across the retina improves with training. This learning differs in magnitude for different trained stimuli and does not generalize to untrained spatial frequencies or retinal locations. Here, we asked whether training to detect patterns of activity across the cochlea yields learning with similar characteristics. Differences in learning between the visual and auditory systems would be inconsistent with the suggestion that the ability to detect these patterns is limited by similar constraints in these two systems. We trained three groups of normal-hearing listeners to detect spectral envelopes with a sinusoidal shape (spectral modulation) at 0.5, 1, or 2 cycles/octave and compared the performance of each group to that of a separate group that received no training. On average, as the trained spectral modulation frequency increased, the magnitude of training-induced improvement and the time to reach asymptotic performance decreased, while the tendency for performance to worsen within a training session increased. The training-induced improvements did not generalize to untrained spectral modulation frequencies or untrained carrier spectra. Thus, for both visual-spatial and auditory spectral modulation detection, learning depended upon and was specific to analogous features of the trained stimulus. Such similarities in learning could arise if, as has been suggested, similar constraints limit the ability to detect patterns across the receptor surface between the auditory and visual systems.

The production of graceful skeletal movements requires coordinated activation of multiple muscles that produce torques around multiple joints. The work described herein is focused on one such movement, stance, that requires coordinated activation of extensor muscles acting around the hip, knee and ankle joints. The forces evoked in these muscles by external stimulation all have a complex dependence on muscle length and shortening velocities, and some of these muscles are biarticular. In order to recreate sit-to-stand maneuvers in the anesthetized feline, we excited the hind limb musculature using intrafascicular multielectrode stimulation (IFMS) of the muscular branch of the sciatic nerve, the femoral nerve and the main branch of the sciatic nerve. Stimulation was achieved with either acutely or chronically implanted Utah Slanted Electrode Arrays (USEAs) via subsets of electrodes (1) that activated motor units in the extensor muscles of the hip, knee and ankle joints, (2) that were able to evoke large extension forces and (3) that manifested minimal coactivation of the targeted motor units. Three hind limb force-generation strategies were investigated, including sequential activation of independent motor units to increase force, and interleaved or simultaneous IFMS of three sets of six or more USEA electrodes that excited the hip, knee and ankle extensors. All force-generation strategies evoked stance, but the interleaved IFMS strategy also reduced muscle fatigue produced by repeated sit-to-stand maneuvers compared with fatigue produced by simultaneous activation of different motor neuron pools. These results demonstrate the use of interleaved IFMS as a means to recreate coordinated, fatigue-resistant multi-joint muscle forces in the unilateral hind limb. This muscle activation paradigm could provide a promising neuroprosthetic approach for the restoration of sit-to-stand transitions in individuals who are paralyzed by spinal cord injury, stroke or disease.

Excessive exposure to loud noise can damage the cochlea and create a hearing loss. These pathologies coincide with a range of CNS changes including reorganisation of frequency representation, alterations in the pattern of spontaneous activity and changed expression of excitatory and inhibitory neurotransmitters. Moreover, damage to the cochlea is often accompanied by acoustic disorders such as hyperacusis and tinnitus, suggesting that one or more of these neuronal changes may be involved in these disorders, although the mechanisms remain unknown. We tested the hypothesis that excessive noise exposure increases expression of markers of excitation and plasticity, and decreases expression of inhibitory markers over a 32-day recovery period. Adult rats (n = 25) were monaurally exposed to a loud noise (16 kHz, 1/10(th) octave band pass (115 dB SPL)) for 1-hour, or left as non-exposed controls (n = 5). Animals were euthanased at either 0, 4, 8, 16 or 32 days following acoustic trauma. We used Western Blots to quantify protein levels of GABA(A) receptor subunit α1 (GABA(A)α1), Glutamic-Acid Decarboxylase-67 (GAD-67), N-Methyl-D-Aspartate receptor subunit 2A (NR2A), Calbindin (Calb1) and Growth Associated Protein 43 (GAP-43) in the Auditory Cortex (AC), Inferior Colliculus (IC) and Dorsal Cochlear Nucleus (DCN). Compared to sham-exposed controls, noise-exposed animals had significantly (p<0.05): lower levels of GABA(A)α1 in the contralateral AC at day-16 and day-32, lower levels of GAD-67 in the ipsilateral DCN at day-4, lower levels of Calb1 in the ipsilateral DCN at day-0, lower levels of GABA(A)α1 in the ipsilateral AC at day-4 and day-32. GAP-43 was reduced in the ipsilateral AC for the duration of the experiment. These complex fluctuations in protein expression suggests that for at least a month following acoustic trauma the auditory system is adapting to a new pattern of sensory input.

Topographic maps are salient features of neuronal organization in sensory systems. Inhibitory components of neuronal circuitry are often embedded within this organization, making them difficult to isolate experimentally. The auditory system provides opportunities to study the topographic organization of inhibitory long‐range projection nuclei, such as the superior olivary nucleus (SON). We analyzed the topographic organization of response features of neurons in the SON of chickens. Quantitative methods were developed to assess and communicate this organization. These analyses led to three main conclusions: 1) sound frequency is linearly arranged from dorsal (low frequencies) to ventral (high frequencies) in SON; 2) this tonotopic organization is less precise than the organization of the excitatory nuclei in the chicken auditory brainstem; and 3) neurons with different response patterns to pure tone stimuli are interspersed throughout the SON and show similar tonotopic organizations. This work provides a predictive model to determine the optimal stimulus frequency for a neuron from its spatial location in the SON. J. Comp. Neurol. 520:1493–1508, 2012. © 2011 Wiley Periodicals, Inc.

The head bobber transgenic mouse line, produced by pronuclear integration, exhibits repetitive head tilting, circling behavior, and severe hearing loss. Transmitted as an autosomal recessive trait, the homozygote has vestibular and cochlea inner ear defects. The space between the semicircular canals is enclosed within the otic capsule creating a vacuous chamber with remnants of the semicircular canals, associated cristae, and vestibular organs. A poorly developed stria vascularis and endolymphatic duct is likely the cause for Reissner's membrane to collapse post-natally onto the organ of Corti in the cochlea. Molecular analyses identified a single integration of ~3 tandemly repeated copies of the transgene, a short duplicated segment of chromosome X and a 648 kb deletion of chromosome 7(F3). The three known genes (Gpr26, Cpxm2, and Chst15) in the deleted region are conserved in mammals and expressed in the wild-type inner ear during vestibular and cochlea development but are absent in homozygous mutant ears. We propose that genes critical for inner ear patterning and differentiation are lost at the head bobber locus and are candidate genes for human deafness and vestibular disorders.

Environmental enrichment induces powerful changes in the adult cerebral cortex. Studies in primary sensory cortex have observed that environmental enrichment modulates neuronal response strength, selectivity, speed of response, and synchronization to rapid sensory input. Other reports suggest that nonprimary sensory fields are more plastic than primary sensory cortex. The consequences of environmental enrichment on information processing in nonprimary sensory cortex have yet to be studied. Here we examine physiological effects of enrichment in the posterior auditory field (PAF), a field distinguished from primary auditory cortex (A1) by wider receptive fields, slower response times, and a greater preference for slowly modulated sounds. Environmental enrichment induced a significant increase in spectral and temporal selectivity in PAF. PAF neurons exhibited narrower receptive fields and responded significantly faster and for a briefer period to sounds after enrichment. Enrichment increased time-locking to rapidly successive sensory input in PAF neurons. Compared with previous enrichment studies in A1, we observe a greater magnitude of reorganization in PAF after environmental enrichment. Along with other reports observing greater reorganization in nonprimary sensory cortex, our results in PAF suggest that nonprimary fields might have a greater capacity for reorganization compared with primary fields.

The auditory and visual perception systems have developed special processing strategies for ecologically valid motion stimuli, utilizing some of the statistical properties of the real world. A well-known example is the perception of biological motion, for example, the perception of a human walker. The aim of the current study was to identify the cortical network involved in the integration of auditory and visual biological motion signals. We first determined the cortical regions of auditory and visual coactivation (Experiment 1); a conjunction analysis based on unimodal brain activations identified four regions: middle temporal area, inferior parietal lobule, ventral premotor cortex, and cerebellum. The brain activations arising from bimodal motion stimuli (Experiment 2) were then analyzed within these regions of coactivation. Auditory footsteps were presented concurrently with either an intact visual point-light walker (biological motion) or a scrambled point-light walker; auditory and visual motion in depth (walking direction) could either be congruent or incongruent. Our main finding is that motion incongruency (across modalities) increases the activity in the ventral premotor cortex, but only if the visual point-light walker is intact. Our results extend our current knowledge by providing new evidence consistent with the idea that the premotor area assimilates information across the auditory and visual modalities by comparing the incoming sensory input with an internal representation.

Two sounds with the same pitch may vary from each other based on saliency of their pitch sensation. This perceptual attribute is called “pitch strength.” The study of voice pitch strength may be important in quantifying of normal and pathological qualities. The present study investigated how pitch strength varies across normal and dysphonic voices. A set of voices (vowel /a/) selected from the Kay Elemetrics Disordered Voice Database served as the stimuli. These stimuli demonstrated a wide range of voice quality. Ten listeners judged the pitch strength of these stimuli in an anchored magnitude estimation task. On a given trial, listeners heard three different stimuli. The first stimulus represented very low pitch strength (wide-band noise), the second stimulus consisted of the target voice and the third stimulus represented very high pitch strength (pure tone). Listeners estimated pitch strength of the target voice by positioning a continuous slider labeled with values between 0 and 1, reflecting the two anchor stimuli. Results revealed that listeners can judge pitch strength reliably in dysphonic voices. Moderate to high correlations with perceptual judgments of voice quality suggest that pitch strength may contribute to voice quality judgments.

Objective: The purpose of this study was to determine the reliability of the electrophysiological binaural beat steady state response as a gauge of temporal fine structure coding, particularly as it relates to the aging auditory system. The hypothesis was that the response would be more robust in a lower, than in a higher, frequency region and in younger, than in older, adults. Design: Two experiments were undertaken. The first measured the 40 Hz binaural beat steady state response elicited by tone pairs in two frequency regions: lower (390 and 430 Hz tone pair) and higher (810 and 850 Hz tone pair). Frequency following responses (FFRs) evoked by the tones were also recorded. Ten young adults with normal hearing participated. The second experiment measured the binaural beat and FFRs in older adults but only in the lower frequency region. Fourteen older adults with relatively normal hearing participated. Response metrics in both experiments included response component signal-to-noise ratio (F statistic) and magnitude-squared coherence. Results: Experiment 1 showed that FFRs were elicited in both frequency regions but were more robust in the lower frequency region. Binaural beat responses elicited by the lower frequency pair of tones showed greater amplitude fluctuation within a participant than the respective FFRs. Experiment 2 showed that older adults exhibited similar FFRs to younger adults, but proportionally fewer older participants showed binaural beat responses. Age differences in onset responses were also observed. Conclusions: The lower prevalence of the binaural beat response in older adults, despite the presence of FFRs, provides tentative support for the sensitivity of this measure to age-related deficits in temporal processing. However, the lability of the binaural beat response advocates caution in its use as an objective measure of fine structure coding.

Many psychological and physiological studies with simple stimuli have suggested that perceptual learning specifically enhances the response of primary sensory cortex to task-relevant stimuli. The aim of this study was to determine whether auditory discrimination training on complex tasks enhances primary auditory cortex responses to a target sequence relative to non-target and novel sequences. We collected responses from more than 2000 sites in 31 rats trained on one of six discrimination tasks that differed primarily in the similarity of the target and distractor sequences. Unlike training with simple stimuli, long-term training with complex stimuli did not generate target-specific enhancement in any of the groups. Instead, cortical receptive field size decreased, latency decreased, and paired pulse depression decreased in rats trained on the tasks of intermediate difficulty, whereas tasks that were too easy or too difficult either did not alter or degraded cortical responses. These results suggest an inverted-U function relating neural plasticity and task difficulty.

Using rare intracranial recordings from the posterior interhemispheric region of the human brain, we explored the oscillatory properties of the posteromedial cortex (PMC) during rest. The PMC is a core structure of the default mode network, which is known for its higher activity during the resting state. We found that resting PMC spectral power peaked in the theta band range (4-7 Hz) and was clearly distinguishable from adjacent cortical sites in the occipital lobe displaying peaks in the alpha band range (8-12 Hz). Additionally, the phase of PMC theta oscillations modulated the amplitude of ongoing high gamma (70-180 Hz) activity during the resting state. The magnitude of this cross-frequency modulation was shown to fluctuate at time scales comparable to those observed in functional neuroimaging studies of intrinsic functional connectivity networks (~0.1 Hz). The difference of canonical oscillations in the PMC compared to its adjacent cortical sites conforms to functional specialization across anatomical boundaries. Such differences may reflect separate oscillatory preferences between networks that are functionally connected.

Recent evidence is reshaping the view of primary auditory cortex (A1) from a unisensory area to one more involved in dynamically integrating multisensory- and task-related information. We found A1 single- (SU) and multiple-unit (MU) activity correlated with macaques' choices in an amplitude modulation (AM) discrimination task. Animals were trained to discriminate AM noise from unmodulated noise by releasing a lever for AM noise and holding down the lever for unmodulated noise. Activity for identical stimuli was compared between trials where the animals reported AM and trials where they did not. We found 47.4% of MUs and 22.8% of SUs significantly increased firing shortly before the animal's behavioral response to report AM when compared to the equivalent time period on trials where AM was not reported. Activity was also linked to lever release in a different task context, suggesting A1 modulation by somatosensory, or efference copy, input. When spikes were counted only during the stimulus, 19.6% of MUs and 13.8% of SUs increased firing rate when animals reported AM compared to when they did not, suggesting an attentional effect, or that A1 activity can be used by higher decision areas, or that such areas provide feedback to A1. Activity associated with AM reporting was correlated with a unit's AM sensitivity, suggesting AM sensitive neurons' involvement in task performance. A1 neurons' phase locking to AM correlated more weakly (compared to firing rate) with the animals' report of AM, suggesting a preferential role for rate-codes in A1 for this AM discrimination task.

Cisplatin is an effective anti-cancer drug; however, one of its side effects is irreversible sensorineural hearing damage. Korean Red Ginseng (KRG) has been used clinically for the treatment of various diseases; however, the underlying mechanism of KRG treatment of ototoxicity has not been studied extensively. The present study aimed to further investigate the mechanism of KRG on cisplatin-induced toxicity in auditory HEI-OC1 cells in vitro, as well as in vivo. The pharmacological effects of KRG on cisplatin-induced changes in the hearing threshold of mice were determined, as well as the effect on the impairment of hair cell arrays. In addition, in order to elucidate the protective mechanisms of KRG, the regulatory effects of KRG on cisplatin-induced apoptosis-associated gene levels and nuclear factor-κB (NF-κB) activation were investigated in auditory cells. The results revealed that KRG prevented cisplatin-induced alterations in the hearing threshold of mice as well as the destruction of hair cell arrays in rat organ of Corti primary explants. In addition, KRG inhibited cisplatin-mediated cell toxicity, reactive oxygen species generation, interleukin-6 production, cytochrome c release and activation of caspases-3 in the HEI-OC1 auditory cell line. Furthermore, the results demonstrated that KRG inhibited the activation of NF-κB and caspase-1. In conclusion, these results provided a model for the pharmacological mechanism of KRG and provided evidence for potential therapies against ototoxicity.

Nicotinic acetylcholine receptors (nAChRs) in the brain are important for cognitive function; however, their specific role in relevant brain regions remains unclear. In this study, we used the novel compound 18 F‐nifene to examine the distribution of nAChRs in the rat forebrain, and for individual animals related the results to behavioral performance on an auditory‐cognitive task. We first show negligible binding of 18 F‐nifene in mice lacking the β2 nAChR subunit, consistent with previous findings that 18 F‐nifene binds to α4β2* nAChRs. We then examined the distribution of 18 F‐nifene in rat using three methods: in vivo PET, ex vivo PET and autoradiography. Generally, 18 F‐nifene labeled forebrain regions known to contain nAChRs, and the three methods produced similar relative binding among regions. Importantly, 18 F‐nifene also labeled some white matter (myelinated axon) tracts, most prominently in the temporal subcortical region that contains the auditory thalamocortical pathway. Finally, we related 18 F‐nifene binding in several forebrain regions to each animal's performance on an auditory‐cued, active avoidance task. The strongest correlations with performance after 14 days training were found for 18 F‐nifene binding in the temporal subcortical white matter, subiculum, and medial frontal cortex (correlation coefficients, r > 0.8); there was no correlation with binding in the auditory thalamus or auditory cortex. These findings suggest that individual performance is linked to nicotinic functions in specific brain regions, and further support a role for nAChRs in sensory‐cognitive function. Synapse, 2012. © 2011 Wiley Periodicals, Inc.

Down syndrome is one of the most common congenital disorders leading to a wide range of health problems in humans, including frequent otitis media. The Tc1 mouse carries a significant part of human chromosome 21 (Hsa21) in addition to the full set of mouse chromosomes and shares many phenotypes observed in humans affected by Down syndrome with trisomy of chromosome 21. However, it is unknown whether Tc1 mice exhibit a hearing phenotype and might thus represent a good model for understanding the hearing loss that is common in Down syndrome. In this study we carried out a structural and functional assessment of hearing in Tc1 mice. Auditory brainstem response (ABR) measurements in Tc1 mice showed normal thresholds compared to littermate controls and ABR waveform latencies and amplitudes were equivalent to controls. The gross anatomy of the middle and inner ears was also similar between Tc1 and control mice. The physiological properties of cochlear sensory receptors (inner and outer hair cells: IHCs and OHCs) were investigated using single-cell patch clamp recordings from the acutely dissected cochleae. Adult Tc1 IHCs exhibited normal resting membrane potentials and expressed all K(+) currents characteristic of control hair cells. However, the size of the large conductance (BK) Ca(2+) activated K(+) current (I(K,f)), which enables rapid voltage responses essential for accurate sound encoding, was increased in Tc1 IHCs. All physiological properties investigated in OHCs were indistinguishable between the two genotypes. The normal functional hearing and the gross structural anatomy of the middle and inner ears in the Tc1 mouse contrast to that observed in the Ts65Dn model of Down syndrome which shows otitis media. Genes that are trisomic in Ts65Dn but disomic in Tc1 may predispose to otitis media when an additional copy is active.

Natural auditory scenes such as frog choruses consist of multiple sound sources (i.e., individual vocalizing males) producing sounds that overlap extensively in time and spectrum, often in the presence of other biotic and abiotic background noise. Detection of a signal in such environments is challenging, but it is facilitated when the noise shares common amplitude modulations across a wide frequency range, due to a phenomenon called comodulation masking release (CMR). Here, we examined how properties of the background noise, such as its bandwidth and amplitude modulation, influence the detection threshold of a target sound (pulsed amplitude modulated tones) by single neurons in the frog auditory midbrain. We found that for both modulated and unmodulated masking noise, masking was generally stronger with increasing bandwidth, but it was weakened for the widest bandwidths. Masking was less for modulated noise than for unmodulated noise for all bandwidths. However, responses were heterogeneous, and only for a subpopulation of neurons the detection of the probe was facilitated when the bandwidth of the modulated masker was increased beyond a certain bandwidth - such neurons might contribute to CMR. We observed evidence that suggests that the dips in the noise amplitude are exploited by TS neurons, and observed strong responses to target signals occurring during such dips. However, the interactions between the probe and masker responses were nonlinear, and other mechanisms, e.g., selective suppression of the response to the noise, may also be involved in the masking release.

Within the last decade several genes have been identified as candidate risk genes for developmental dyslexia. Recent research using animal models and embryonic RNA interference (RNAi) has shown that a subset of the candidate dyslexia risk genes— DYX1C1, ROBO1, DCDC2, KIAA0319 —regulate critical parameters of neocortical development, such as neuronal migration. For example, embryonic disruption of the rodent homolog of DYX1C1 disrupts neuronal migration and produces deficits in rapid auditory processing (RAP) and working memory—phenotypes that have been reported to be associated with developmental dyslexia. In the current study we used a modified prepulse inhibition paradigm to assess acoustic discrimination abilities of male Wistar rats following in utero RNA interference targeting Kiaa0319 . We also assessed spatial learning and working memory using a Morris water maze (MWM) and a radial arm water maze. We found that embryonic interference with this gene resulted in disrupted migration of neocortical neurons leading to formation of heterotopia in white matter, and to formation of hippocampal dysplasia in a subset of animals. These animals displayed deficits in processing complex acoustic stimuli, and those with hippocampal malformations exhibited impaired spatial learning abilities. No significant impairment in working memory was detected in the Kiaa0319 RNAi treated animals. Taken together, these results suggest that Kiaa0319 plays a role in neuronal migration during embryonic development, and that early interference with this gene results in an array of behavioral deficits including impairments in rapid auditory processing and simple spatial learning.

The speech signal contains many acoustic properties that may contribute differently to spoken word recognition. Previous studies have demonstrated that the importance of properties present during consonants or vowels is dependent upon the linguistic context (i.e., words versus sentences). The current study investigated three potentially informative acoustic properties that are present during consonants and vowels for monosyllabic words and sentences. Natural variations in fundamental frequency were either flattened or removed. The speech envelope and temporal fine structure were also investigated by limiting the availability of these cues via noisy signal extraction. Thus, this study investigated the contribution of these acoustic properties, present during either consonants or vowels, to overall word and sentence intelligibility. Results demonstrated that all processing conditions displayed better performance for vowel-only sentences. Greater performance with vowel-only sentences remained, despite removing dynamic cues of the fundamental frequency. Word and sentence comparisons suggest that the speech envelope may be at least partially responsible for additional vowel contributions in sentences. Results suggest that speech information transmitted by the envelope is responsible, in part, for greater vowel contributions in sentences, but is not predictive for isolated words.

Mitochondrial dysfunction causes poorly understood tissue-specific pathology stemming from primary defects in respiration, coupled with altered reactive oxygen species (ROS), metabolic signaling, and apoptosis. The A1555G mtDNA mutation that causes maternally inherited deafness disrupts mitochondrial ribosome function, in part, via increased methylation of the mitochondrial 12S rRNA by the methyltransferase mtTFB1. In patient-derived A1555G cells, we show that 12S rRNA hypermethylation causes ROS-dependent activation of AMP kinase and the proapoptotic nuclear transcription factor E2F1. This retrograde mitochondrial-stress relay is operative in vivo, as transgenic-mtTFB1 mice exhibit enhanced 12S rRNA methylation in multiple tissues, increased E2F1 and apoptosis in the stria vascularis and spiral ganglion neurons of the inner ear, and progressive E2F1-dependent hearing loss. This mouse mitochondrial disease model provides a robust platform for deciphering the complex tissue specificity of human mitochondrial-based disorders, as well as the precise pathogenic mechanism of maternally inherited deafness and its exacerbation by environmental factors.

Understanding speech in noisy environments is often taken for granted; however, this task is particularly challenging for people with cochlear hearing loss, even with hearing aids or cochlear implants. A significant limitation to improving auditory prostheses is our lack of understanding of the neural basis for robust speech perception in noise. Perceptual studies suggest the slowly varying component of the acoustic waveform (envelope, ENV) is sufficient for understanding speech in quiet, but the rapidly varying temporal fine structure (TFS) is important in noise. These perceptual findings have important implications for cochlear implants, which currently only provide ENV; however, neural correlates have been difficult to evaluate due to cochlear transformations between acoustic TFS and recovered neural ENV. Here, we demonstrate the relative contributions of neural ENV and TFS by quantitatively linking neural coding, predicted from a computational auditory nerve model, with perception of vocoded speech in noise measured from normal hearing human listeners. Regression models with ENV and TFS coding as independent variables predicted speech identification and phonetic feature reception at both positive and negative signal-to-noise ratios. We found that: (1) neural ENV coding was a primary contributor to speech perception, even in noise; and (2) neural TFS contributed in noise mainly in the presence of neural ENV, but rarely as the primary cue itself. These results suggest that neural TFS has less perceptual salience than previously thought due to cochlear signal processing transformations between TFS and ENV. Because these transformations differ between normal and impaired ears, these findings have important translational implications for auditory prostheses.