Publications using TDT

Interaural time differences (ITDs) are the primary cue for the localization of low-frequency sound sources in the azimuthal plane. For decades, it was assumed that the coding of ITDs in the mammalian brain was similar to that in the avian brain, where information is sparsely distributed across individual neurons, but recent studies have suggested otherwise. In this study, we characterized the representation of ITDs in adult male and female gerbils. First, we performed behavioral experiments to determine the acuity with which gerbils can use ITDs to localize sounds. Next, we used different decoders to infer ITDs from the activity of a population of neurons in central nucleus of the inferior colliculus. These results show that ITDs are not represented in a distributed manner, but rather in the summed activity of the entire population. To contrast these results with those from a population where the representation of ITDs is known to be sparsely distributed, we performed the same analysis on activity from the external nucleus of the inferior colliculus of adult male and female barn owls. Together, our results support the idea that, unlike the avian brain, the mammalian brain represents ITDs in the overall activity of a homogenous population of neurons within each hemisphere.

The generalization of learning from trained to untrained conditions is of great potential value because it markedly increases the efficacy of practice. In principle, generalization and the learning itself could arise from either the same or distinct neural changes. Here, we assessed these two possibilities in the realm of human perceptual learning by comparing the time course of improvement on a trained condition (learning) to that on an untrained condition (generalization) for an auditory temporal-interval discrimination task. While significant improvement on the trained condition occurred within 2 d, generalization to the untrained condition lagged behind, only emerging after 4 d. The different time courses for learning and generalization suggest that these two types of perceptual improvement can arise from at least partially distinct neural changes. The notably longer time course for generalization than learning demonstrates that increasing the duration of training can be an effective means to increase the number of conditions to which learning generalizes on perceptual tasks.

Primary sensory cortex integrates sensory information from afferent feedforward thalamocortical projection systems and convergent intracortical microcircuits. Both input systems have been demonstrated to provide different aspects of sensory information. Here we have used high-density recordings of laminar current source density (CSD) distributions in primary auditory cortex of Mongolian gerbils in combination with pharmacological silencing of cortical activity and analysis of the residual CSD, to dissociate the feedforward thalamocortical contribution and the intracortical contribution to spectral integration. We found a temporally highly precise integration of both types of inputs when the stimulation frequency was in close spectral neighborhood of the best frequency of the measurement site, in which the overlap between both inputs is maximal. Local intracortical connections provide both directly feedforward excitatory and modulatory input from adjacent cortical sites, which determine how concurrent afferent inputs are integrated. Through separate excitatory horizontal projections, terminating in cortical layers II/III, information about stimulus energy in greater spectral distance is provided even over long cortical distances. These projections effectively broaden spectral tuning width. Based on these data, we suggest a mechanism of spectral integration in primary auditory cortex that is based on temporally precise interactions of afferent thalamocortical inputs and different short- and long-range intracortical networks. The proposed conceptual framework allows integration of different and partly controversial anatomical and physiological models of spectral integration in the literature.

Spatial attention mediates the selection of information from different parts of space. When a brief cue is presented shortly before a target [cue to target onset asynchrony (CTOA)] in the same location, behavioral responses are facilitated, a process called attention capture. At longer CTOAs, responses to targets presented in the same location are inhibited; this is called inhibition of return (IOR). In the visual modality, these processes have been demonstrated in both humans and non‐human primates, the latter allowing for the study of the underlying neural mechanisms. In audition, the effects of attention have only been shown in humans when the experimental task requires sound localization. Studies in monkeys with the use of similar cues but without a sound localization requirement have produced negative results. We have studied the effects of predictive acoustic cues on the latency of gaze shifts to visual and auditory targets in monkeys experienced in localizing sound sources in the laboratory with the head unrestrained. Both attention capture and IOR were demonstrated with acoustic cues, although with a faster time course than with visual cues. Additionally, the effect was observed across sensory modalities (acoustic cue to visual target), suggesting that the underlying neural mechanisms of these effects may be mediated within the superior colliculus, a center where inputs from both vision and audition converge.

Young normal-hearing (YNH) and older normal-hearing (ONH) listeners identified vowels in naturally produced /bVb/ syllables and in modified syllables that consisted of variable portions of the vowel edges (silent-center [SC] stimuli) or vowel center (center-only [CO] stimuli). Listeners achieved high levels of performance for all but the shortest stimuli, indicating that they were able to access vowel cues throughout the syllable. ONH listeners performed similarly to YNH listeners for most stimuli, but performed more poorly for the shortest CO stimuli. SC and CO stimuli were equally effective in supporting vowel identification except when acoustic information was limited to 20 ms.

Dynamin-1 (Dnm1) encodes a large multimeric GTPase necessary for activity-dependent membrane recycling in neurons, including synaptic vesicle endocytosis. Mice heterozygous for a novel spontaneous Dnm1 mutation--fitful--experience recurrent seizures, and homozygotes have more debilitating, often lethal seizures in addition to severe ataxia and neurosensory deficits. Fitful is a missense mutation in an exon that defines the DNM1a isoform, leaving intact the alternatively spliced exon that encodes DNM1b. The expression of the corresponding alternate transcripts is developmentally regulated, with DNM1b expression highest during early neuronal development and DNM1a expression increasing postnatally with synaptic maturation. Mutant DNM1a does not efficiently self-assemble into higher order complexes known to be necessary for proper dynamin function, and it also interferes with endocytic recycling in cell culture. In mice, the mutation results in defective synaptic transmission characterized by a slower recovery from depression after trains of stimulation. The DNM1a and DNM1b isoform pair is highly conserved in vertebrate evolution, whereas invertebrates have only one isoform. We speculate that the emergence of more specialized forms of DNM1 may be important in organisms with complex neuronal function.

Adult rats were trained to detect the occurrence of a two-element sound sequence in a background of nine other nontarget sound pairs. Training resulted in a modest, enduring, static expansion of the cortical areas of representation of both target stimulus sounds. More importantly, once the initial stimulus A in the target A-B sequence was presented, the cortical “map” changed dynamically, specifically to exaggerate further the representation of the “anticipated” stimulus B. If B occurred, it was represented over a larger cortical area by more strongly excited, more coordinated, and more selectively responding neurons. This biasing peaked at the expected time of B onset with respect to A onset. No dynamic biasing of responses was recorded for any sound presented in a nontarget pair. Responses to nontarget frequencies flanking the representation of B were reduced in area and in response strength only after the presentation of A at the expected time of B onset. This study shows that cortical areas are not representationally static but, to the contrary, can be biased moment by moment in time as a function of behavioral context.

Objective: High incidence of poor neurologic sequelae after resuscitation from cardiac arrest underscores the need for objective electrophysiological markers for assessment and prognosis. This study aims to develop a novel marker based on somatosensory evoked potentials (SSEPs). Normal SSEPs involve thalamocortical circuits suggested to play a role in arousal. Due to the vulnerability of these circuits to hypoxic-ischemic insults, we hypothesize that quantitative SSEP markers may indicate future neurologic status. Design: Laboratory investigation. Setting: University Medical School and Animal Research Facility. Subjects: : Sixteen adult male Wistar rats. Interventions: None. Measurements and main results: SSEPs were recorded during baseline, during the first 4 hrs, and at 24, 48, and 72 hrs postasphyxia from animals subjected to asphyxia-induced cardiac arrest for 7 or 9 mins (n = 8/group). Functional evaluation was performed using the Neurologic Deficit Score (NDS). For quantitative analysis, the phase space representation of the SSEPs-a plot of the signal vs. its slope-was used to compute the phase space area bounded by the waveforms recorded after injury and recovery. Phase space areas during the first 85-190 mins postasphyxia were significantly different between rats with good (72 hr NDS >or=50) and poor (72 hr NDS <50) outcomes (p = .02). Phase space area not only had a high outcome prediction accuracy (80-93%, p < .05) during 85-190 mins postasphyxia but also offered 78% sensitivity to good outcomes without compromising specificity (83-100%). A very early peak of SSEPs that precedes the primary somatosensory response was found to have a modest correlation with the 72 hr NDS subscores for thalamic and brainstem function (p = .066) and not with sensory-motor function (p = .30). Conclusions: Phase space area, a quantitative measure of the entire SSEP morphology, was shown to robustly track neurologic recovery after cardiac arrest. SSEPs are among the most reliable predictors of poor outcome after cardiac arrest; however, phase space area values early after resuscitation can enhance the ability to prognosticate not only poor but also good long-term neurologic outcomes.

Objective: To further examine the reliability of categorical loudness scaling (CLS) for individual loudness categories and for the slope of the CLS functions. And, to evaluate the relationship between CLS and audiometric threshold. Design: CLS functions were obtained in 74 subjects, 58 with hearing loss and 16 with normal hearing. CLS functions were measured at three frequencies (1, 2, and 4 kHz) in two separate sessions separated by as little as 1 wk and as much as 6 mo. Reliability of mean and median levels within each loudness category was assessed using SDs and correlation coefficients. Lines were fit to the CLS functions, and slopes of the lines were used to assess reliability and the relation between CLS and audiometric threshold. Results: Similar reliability for CLS measurements was observed in both normal-hearing and hearing-impaired subjects at all frequencies. Across both groups of subjects, correlations describing the reliability of mean stimulus level within category exceeded 0.92 at all frequencies. In addition, SDs of the mean stimulus-level difference between visits ranged from 6.6 to 7.8 dB, depending on frequency. The correlation between the slope of a straight line fitted to the entire CLS function and audiometric threshold collapsed across frequencies was 0.72. Two line segments were then fit to the CLS function: one segment was fit to the soft portion of the CLS function (categorical units < or =20) and the other segment to the loud portion (categorical unit >20). Slopes of the line fit to the entire CLS function and of the line fit to the soft portion of the CLS function were both reliable across sessions. The slope of the line fit to the soft portion increased as audiometric threshold increased, with the correlations greater than 0.86 at all frequencies. No relationship was observed between slope of the line fit to the loud portion of the CLS function and audiometric threshold. Iso-loudness contours were constructed from the CLS data and used to determine the gain that would be needed to produce "normal" loudness percepts for hearing-impaired individuals. Conclusions: Within-subject CLS measurements were reliable across sessions both for individual loudness categories and for slope of the CLS functions. In addition, the slope of the low-level portion of the CLS function varied in a predictable manner with audiometric threshold, with slope increasing as audiometric threshold increased. Finally, gain as a function of input level needed to provide loudness percepts for individuals with hearing loss equal to the loudness percepts of normal-hearing individuals can be estimated from audiometric threshold. This finding supports the assumption that audiometric threshold and response growth (loudness) are both determined by the same underlying cochlear mechanisms.

In the intermediate nucleus of the lateral lemniscus (INLL), some neurons display a form of spectral integration in which excitatory responses to sounds at their best frequency are inhibited by sounds within a frequency band at least one octave lower. Previous work showed that this response property depends on low-frequency-tuned glycinergic input. To identify all sources of inputs to these INLL neurons, and in particular the low-frequency glycinergic input, we combined retrograde tracing with immunohistochemistry for the neurotransmitter glycine. We deposited a retrograde tracer at recording sites displaying either high best frequencies (>75 kHz) in conjunction with combination-sensitive inhibition, or at sites displaying low best frequencies (23-30 kHz). Most retrogradely labeled cells were located in the ipsilateral medial nucleus of the trapezoid body (MNTB) and contralateral anteroventral cochlear nucleus. Consistent labeling, but in fewer numbers, was observed in the ipsilateral lateral nucleus of the trapezoid body (LNTB), contralateral posteroventral cochlear nucleus, and a few other brainstem nuclei. When tracer deposits were combined with glycine immunohistochemistry, most double-labeled cells were observed in the ipsilateral MNTB (84%), with fewer in LNTB (13%). After tracer deposits at combination-sensitive recording sites, a striking result was that MNTB labeling occurred in both medial and lateral regions. This labeling appeared to overlap the MNTB labeling that resulted from tracer deposits in low-frequency recording sites of INLL. These findings suggest that MNTB is the most likely source of low-frequency glycinergic input to INLL neurons with high best frequencies and combination-sensitive inhibition. This work establishes an anatomical basis for frequency integration in the auditory brainstem.

The monoclonal antibody SMI-32 was used to characterize and distinguish individual areas of cat auditory cortex. SMI-32 labels non-phosphorylated epitopes on the high- and medium-molecular weight subunits of neurofilament proteins in cortical pyramidal cells and dendritic trees with the most robust immunoreactivity in layers III and V. Auditory areas with unique patterns of immunoreactivity included: primary auditory cortex (AI), second auditory cortex (AII), dorsal zone (DZ), posterior auditory field (PAF), ventral posterior auditory field (VPAF), ventral auditory field (VAF), temporal cortex (T), insular cortex (IN), anterior auditory field (AAF), and the auditory field of the anterior ectosylvian sulcus (fAES). Unique patterns of labeling intensity, soma shape, soma size, layers of immunoreactivity, laminar distribution of dendritic arbors, and labeled cell density were identified. Features that were consistent in all areas included: layers I and IV neurons are immunonegative; nearly all immunoreactive cells are pyramidal; and immunoreactive neurons are always present in layer V. To quantify the results, the numbers of labeled cells and dendrites, as well as cell diameter, were collected and used as tools for identifying and differentiating areas. Quantification of the labeling patterns also established profiles for ten auditory areas/layers and their degree of immunoreactivity. Areal borders delineated by SMI-32 were highly correlated with tonotopically-defined areal boundaries. Overall, SMI-32 immunoreactivity can delineate ten areas of cat auditory cortex and demarcate topographic borders. The ability to distinguish auditory areas with SMI-32 is valuable for the identification of auditory cerebral areas in electrophysiological, anatomical, and/or behavioral investigations.

Cave fish have rarely been investigated with regard to their inner ear morphology, hearing abilities, and acoustic communication. Based on a previous study that revealed morphological differences in the saccular otolith between a cave and two surface populations of Poecilia mexicana, we checked for additional differences in utricular and lagenar otoliths and tested whether different populations have similar hearing sensitivities. We found pronounced differences in the shape of all three otoliths. Otoliths of the saccule and lagena from cave fish differed from those of surface fish in the features of the face oriented towards the sensory epithelium. In addition, otoliths of the utricle and lagena were significantly heavier in cave fish. Auditory sensitivities were measured between 100 and 1500Hz, utilizing the auditory evoked potential recording technique. We found similar hearing abilities in cave and surface fish, with greatest sensitivity between 200 and 300Hz. An acoustic survey revealed that neither ecotype produced species-specific sounds. Our data indicate that cave dwelling altered the otolith morphology in Atlantic mollies, probably due to metabolic differences. Different otolith morphology, however, did not affect general auditory sensitivity or acoustic behavior.

Linear measures of auditory receptive fields do not always fully account for a neuron's response to spectrotemporally-complex signals such as frequency-modulated sweeps (FM) and communication sounds. A possible source of this discrepancy is cross-frequency interactions, common response properties which may be missed by linear receptive fields but captured using two-tone masking. Using a patterned tonal sequence that included a balanced set of all possible tone-to-tone transitions, we have here combined the spectrotemporal receptive field with two-tone masking to measure spectrotemporal response maps (STRM). Recording from single units in the mustached bat inferior colliculus, we found significant non-linear interactions between sequential tones in all sampled units. In particular, tone-pair STRMs revealed three common features not visible in linear single-tone STRMs: 1) two-tone facilitative interactions, 2) frequency-specific suppression, and 3) post-stimulatory suppression in the absence of spiking. We also found a correlative relationship between these nonlinear receptive field features and sensitivity for different rates and directions of FM sweeps, dynamic features found in many vocalizations, including speech. The overwhelming prevalence of cross-frequency interactions revealed by this technique provides further evidence of the central auditory system's role as a pattern-detector, and underscores the need to include nonlinearity in measures of the receptive field.

Plasticity is a crucial component of normal brain function and a critical mechanism for recovery from injury. In vitro, associative pairing of presynaptic spiking and stimulus-induced postsynaptic depolarization causes changes in the synaptic efficacy of the presynaptic neuron, when activated by extrinsic stimulation. In vivo, such paradigms can alter the responses of whole groups of neurons to stimulation. Here, we used in vivo spike-triggered stimulation to drive plastic changes in rat forelimb sensorimotor cortex, which we monitored using a statistical measure of functional connectivity inferred from the spiking statistics of the neurons during normal, spontaneous behavior. These induced plastic changes in inferred functional connectivity depended on the latency between trigger spike and stimulation, and appear to reflect a robust reorganization of the network. Such targeted connectivity changes might provide a tool for rerouting the flow of information through a network, with implications for both rehabilitation and brain-machine interface applications.

In the precedence effect, sounds emanating directly from the source are localized preferentially over their reflections. Although most studies have focused on the delay between the onset of a sound and its echo, humans still experience the precedence effect when this onset delay is removed. We tested in barn owls the hypothesis that an ongoing delay, equivalent to the onset delay, is discernible from the envelope features of amplitude-modulated stimuli and may be sufficient to evoke this effect. With sound pairs having only envelope cues, owls localized direct sounds preferentially, and neurons in their auditory space-maps discharged more vigorously to them, but only if the sounds were amplitude modulated. Under conditions that yielded the precedence effect, acoustical features known to evoke neuronal discharges were more abundant in the envelopes of the direct sounds than of the echoes, suggesting that specialized neural mechanisms for echo suppression were unnecessary.

Although lizards have highly sensitive ears, it is difficult to condition them to sound, making standard psychophysical assays of hearing sensitivity impractical. This paper describes non-invasive measurements of the auditory brainstem response (ABR) in both Tokay geckos (Gekko gecko; nocturnal animals, known for their loud vocalizations) and the green anole (Anolis carolinensis, diurnal, non-vocal animals). Hearing sensitivity was measured in 5 geckos and 7 anoles. The lizards were sedated with isoflurane, and ABRs were measured at levels of 1 and 3% isoflurane. The typical ABR waveform in response to click stimulation showed one prominent and several smaller peaks occurring within 10 ms of the stimulus onset. ABRs to brief tone bursts revealed that geckos and anoles were most sensitive between 1.6–2 kHz and had similar hearing sensitivity up to about 5 kHz (thresholds typically 20–50 dB SPL). Above 5 kHz, however, anoles were more than 20 dB more sensitive than geckos and showed a wider range of sensitivity (1–7 kHz). Generally, thresholds from ABR audiograms were comparable to those of small birds. Best hearing sensitivity, however, extended over a larger frequency range in lizards than in most bird species.

Vestibular evoked myogenic potentials (VEMPs) were measured in 22 unilateral Menière patients with monaural and binaural stimulation with 250 and 500 Hz tone bursts. For all measurement situations significantly lower VEMP amplitudes were on average measured at the affected side compared to the unaffected side. Unilateral Menière patients have, in contrast to normal subjects, asymmetric VEMPs, indicating a permanently affected vestibular (most likely otolith) system at the side of hearing loss. The diagnostic value of VEMP amplitude asymmetry measurement in individual patients is low, because of the large overlap of the VEMP amplitude asymmetry range for unilateral Menière patients with that for normal subjects.

The auditory system has two parallel streams in the brain that have been implicated in auditory fear learning. The lemniscal stream has selective neurons that are tonotopically organized and is thought to be important for sound discrimination. The nonlemniscal stream has less selective neurons, which are not tonotopically organized, and is thought to be important for multimodal processing and for several forms of learning. Therefore, it has been hypothesized that the lemniscal, but not the nonlemniscal, pathway supports discriminative fear to auditory cues. To test this hypothesis we assessed the effect of electrolytic lesions to the ventral, or medial, division of the medial geniculate nucleus (MGv or MGm, which correspond, respectively, to the lemniscal and the nonlemniscal auditory pathway to amygdala) on the acquisition, expression and extinction of fear responses in discriminative auditory fear conditioning, where one tone is followed by shock (conditioned stimulus, CS(+)), and another is not (CS(-)). Here we show that with single-trial conditioning control, MGv- and MGm-lesioned male rats acquire nondiscriminative fear of both the CS(+) and the CS(-). However, after multiple-trial conditioning, control rats discriminate between the CS(+) and CS(-), whereas MGv- and MGm-lesioned do not. Furthermore, post-training lesions of MGm, but not MGv, lead to impaired expression of discriminative fear. Finally, MGm-lesioned rats display high levels of freezing to both the CS(+) and CS(-) even after an extinction session to the CS(+). In summary, our findings suggest that the lemniscal pathway is important for discriminative learning, whereas the nonlemniscal is important for negatively regulating fear responses.

A complex of proteins scaffolded by the PDZ protein, whirlin, reside at the stereocilia tip and are critical for stereocilia development and elongation. We have shown that in outer hair cells (OHCs) whirlin is part of a larger complex involving the MAGUK protein, p55, and protein 4.1R. Whirlin interacts with p55 which is expressed exclusively in outer hair cells (OHC) in both the long stereocilia that make up the stereocilia bundle proper as well as surrounding shorter microvilli that will eventually regress. In erythrocytes, p55 forms a tripartite complex with protein 4.1R and glycophorin C promoting the assembly of actin filaments and the interaction of whirlin with p55 indicates that it plays a similar role in OHC stereocilia. However, the components directly involved in actin filament regulation in stereocilia are unknown. We have investigated additional components of the whirlin interactome by identifying interacting partners to p55. We show that the actin capping and severing protein, gelsolin, is a part of the whirlin complex. Gelsolin is detected in OHC where it localizes to the tips of the shorter rows but not to the longest row of stereocilia and the pattern of localisation at the apical hair cell surface is strikingly similar to p55. Like p55, gelsolin is ablated in the whirler and shaker2 mutants. Moreover, in a gelsolin mutant, stereocilia in the apex of the cochlea become long and straggly indicating defects in the regulation of stereocilia elongation. The identification of gelsolin provides for the first time a link between the whirlin scaffolding protein complex involved in stereocilia elongation and a known actin regulatory molecule.

Adenosine signalling has an important role in cochlear protection from oxidative stress. In most tissues, intracellular adenosine kinase (ADK) is the primary route of adenosine metabolism and the key regulator of intracellular and extracellular adenosine levels. The present study provides the first evidence for ADK distribution in the adult and developing rat cochlea. In the adult cochlea, ADK was localized to the nuclear or perinuclear region of spiral ganglion neurons, lateral wall tissues, and epithelial cells lining scala media. In the developing cochlea, ADK was strongly expressed in multiple cell types at birth and reached its peak level of expression at postnatal day 21 (P21). Ontogenetic changes in ADK expression were evident in the spiral ganglion, organ of Corti, and stria vascularis. In the spiral ganglion, ADK showed a shift from predominantly satellite cell immunolabelling at P1 to neuronal expression from P14 onward. In contrast to the role of ADK in various aspects of cochlear development, the ADK contribution to the cochlear response to noise stress was less obvious. Transcript and protein levels of ADK were unaltered in the cochlea exposed to broadband noise (90–110 dBSPL, 24 hr), and the selective inhibition of ADK in the cochlea with ABT‐702 failed to restore hearing thresholds after exposure to traumatic noise. This study indicates that ADK is involved in purine salvage pathways for nucleotide synthesis in the adult cochlea, but its role in the regulation of adenosine signalling under physiological and pathological conditions has yet to be established. © 2010 Wiley‐Liss, Inc.