Publications using TDT

Previous studies have shown that residual acoustic hearing supplements cochlear implant function to improve speech recognition in noise as well as perception of music. The current study had two primary objectives. First, we sought to determine how cochlear implantation and electrical stimulation over a time period of 14 to 21 months influence cochlear structures such as hair cells and spiral ganglion neurons. Second, we sought to investigate whether the structures that provide acoustic hearing also affect the perception of electrical stimulation. We compared psychophysical responses to cochlear implant stimulation in two groups of adult guinea pigs. Group I (11 animals) received a cochlear implant in a previously untreated ear, while group II (ten animals) received a cochlear implant in an ear that had been previously infused with neomycin to destroy hearing. Psychophysical thresholds were measured in response to pulse-train and sinusoidal stimuli. Histological analysis of all group I animals and a subset of group II animals was performed. Nine of the 11 group I animals showed survival of the organ of Corti and spiral ganglion neurons adjacent to the electrode array. All group I animals showed survival of these elements in regions apical to the electrode array. Group II animals that were examined histologically showed complete loss of the organ of Corti in regions adjacent and apical to the electrode array and severe spiral ganglion neuron loss, consistent with previous reports for neomycin-treated ears. Behaviorally, group II animals had significantly lower thresholds than group I animals in response to 100 Hz sinusoidal stimuli. However, group I animals had significantly lower thresholds than group II animals in response to pulse-train stimuli (0.02 ms/phase; 156 to 5,000 pps). Additionally, the two groups showed distinct threshold versus pulse rate functions. We hypothesize that the differences in detection thresholds between groups are caused by the electrical activation of the hair cells in group I animals and/or differences between groups in the condition of the spiral ganglion neurons.

Training-induced improvements on perceptual skills can be attributed to at least two learning types: learning of general aspects of the trained condition (conceptual learning) and learning of specific feature values of the stimulus used in training (stimulus learning). Here we asked whether conceptual and stimulus learning on interaural time difference (ITD) discrimination emerge along different time courses. Conceptual learning was clearly evident 10 h after training, when performance on a target ITD condition was equivalent following training on that condition or on a non-target condition differing only in the stimulus, and was better in both cases than immediately after training. In contrast, stimulus learning emerged 24 h after training. At that time, performance on the target ITD condition was better following target- than non-target training, due to a worsening in performance between 10 and 24 h after non-target training rather than from additional improvements over this time period after target training. Training amount influenced performance immediately, but not 10 or 24 h, after training. Thus, conceptual learning emerged before stimulus learning, and each manifested through different improvement trajectories many hours after training. These results suggest that on ITD discrimination, conceptual learning is consolidated earlier, and with different behavioral consequences, than stimulus learning.

Background: When sound arrives at the eardrum it has already been filtered by the body, head, and outer ear. This process is mathematically described by the head-related transfer functions (HRTFs), which are characteristic for the spatial position of a sound source and for the individual ear. HRTFs in the barn owl (Tyto alba) are also shaped by the facial ruff, a specialization that alters interaural time differences (ITD), interaural intensity differences (ILD), and the frequency spectrum of the incoming sound to improve sound localization. Here we created novel stimuli to simulate the removal of the barn owl's ruff in a virtual acoustic environment, thus creating a situation similar to passive listening in other animals, and used these stimuli in behavioral tests. Methodology/principal findings: HRTFs were recorded from an owl before and after removal of the ruff feathers. Normal and ruff-removed conditions were created by filtering broadband noise with the HRTFs. Under normal virtual conditions, no differences in azimuthal head-turning behavior between individualized and non-individualized HRTFs were observed. The owls were able to respond differently to stimuli from the back than to stimuli from the front having the same ITD. By contrast, such a discrimination was not possible after the virtual removal of the ruff. Elevational head-turn angles were (slightly) smaller with non-individualized than with individualized HRTFs. The removal of the ruff resulted in a large decrease in elevational head-turning amplitudes. Conclusions/significance: The facial ruff a) improves azimuthal sound localization by increasing the ITD range and b) improves elevational sound localization in the frontal field by introducing a shift of iso-ILD lines out of the midsagittal plane, which causes ILDs to increase with increasing stimulus elevation. The changes at the behavioral level could be related to the changes in the binaural physical parameters that occurred after the virtual removal of the ruff. These data provide new insights into the function of external hearing structures and open up the possibility to apply the results on autonomous agents, creation of virtual auditory environments for humans, or in hearing aids.

The inferior colliculus (IC) is unique, having both glutamatergic and GABAergic projections ascending to the thalamus. Although subpopulations of GABAergic neurons in the IC have been proposed, criteria to distinguish them have been elusive and specific types have not been associated with specific neural circuits. Recently, the largest IC neurons were found to be recipients of somatic terminals containing vesicular glutamate transporter 2 (VGLUT2). Here, we show with electron microscopy that VGLUT2-positive (VGLUT2 + ) axonal terminals make axosomatic synapses on IC neurons. These terminals contain only VGLUT2 even though others in the IC have VGLUT1 or both VGLUT1 and 2. We demonstrate that there are two types of GABAergic neurons: larger neurons with VGLUT2 + axosomatic endings and smaller neurons without such endings. Both types are present in all subdivisions of the IC, but larger GABAergic neurons with VGLUT2 + axosomatic terminals are most prevalent in the central nucleus. The GABAergic tectothalamic neurons consist almost entirely of the larger cells surrounded by VGLUT2 + axosomatic endings. Thus, two types of GABAergic neurons in the IC are defined by different synaptic organization and neuronal connections. Larger tectothalamic GABAergic neurons are covered with glutamatergic axosomatic synapses that could allow them to fire rapidly and overcome a slow membrane time constant; their axons may be the largest in the brachium of the IC. Thus, large GABAergic neurons could deliver IPSPs to the medial geniculate body before EPSPs from glutamatergic IC neurons firing simultaneously.

Changes in the sensory environment are good indicators for behaviorally relevant events and strong triggers for the reallocation of attention. In the auditory domain, violations of a pattern of repetitive stimuli precipitate in the event-related potentials as mismatch negativity (MMN). Stimulus-specific adaptation (SSA) of single neurons in the auditory cortex has been proposed to be the cellular substrate of MMN (Nelken and Ulanovsky, 2007). However, until now, the existence of SSA in the awake auditory cortex has not been shown. In the present study, we recorded single and multiunits in parallel with evoked local field potentials ( e LFPs) in the primary auditory cortex of the awake rat. Both neurons and e LFPs in the awake animal adapted in a stimulus-specific manner, and SSA was controlled by stimulus probability and frequency separation. SSA of isolated units was significant during the first stimulus-evoked “on” response but not in the following inhibition and rebound of activity. The e LFPs exhibited SSA in the first negative deflection and, to a lesser degree, in a slower positive deflection but no MMN. Spike adaptation correlated closely with adaptation of the fast negative deflection but not the positive deflection. Therefore, we conclude that single neurons in the auditory cortex of the awake rat adapt in a stimulus-specific manner and contribute to corresponding changes in e LFP but do not generate a late deviant response component directly equivalent to the human MMN. Nevertheless, the described effect may reflect a certain part of the process needed for sound discrimination.

Traditionally, the calyx of Held synapse is viewed as a highly reliable relay in the sound localization circuit of the auditory brainstem, with every presynaptic action potential triggering a postsynaptic action potential in vivo . However, this view is at odds with slice recordings that report large short-term depression (STD). To investigate the reliability and precision of this synapse, we compared slice and in vivo recordings from medial nucleus of the trapezoid body neurons of young adult mice. We show that the extracellularly recorded complex waveform can be used to estimate both presynaptic release and postsynaptic excitability. Whereas under standard slice conditions the synapse underwent large STD, both extracellular and whole-cell recordings indicated that in vivo the size of the EPSPs was independent of recent history. The estimated quantal content was typically <20 in vivo , much lower than in the resting synapse under standard slice conditions. However, due to the large quantal size and summation of EPSPs, the safety factor of this synapse was generally still sufficiently large and postsynaptic failures were observed only infrequently in vivo . When present, failures were typically due to stochastic fluctuations in EPSP size or postsynaptic spike depression. In vivo , the calyx of Held synapse thus functions as a tonic synapse. The price it pays for its low release probability is an increase in jitter and synaptic latency and occasional postsynaptic failures.

Spontaneous activity plays an important role in the function of neural circuits. Although many similarities between spontaneous and sensory-evoked neocortical activity have been reported, little is known about consistent differences between them. Here, using simultaneously recorded cortical populations and morphologically identified pyramidal cells, we compare the laminar structure of spontaneous and sensory-evoked population activity in rat auditory cortex. Spontaneous and evoked patterns both exhibited sparse, spatially localized activity in layer 2/3 pyramidal cells, with densely distributed activity in larger layer 5 pyramidal cells and putative interneurons. However, the propagation of spontaneous and evoked activity differed, with spontaneous activity spreading upward from deep layers and slowly across columns, but sensory responses initiating in presumptive thalamorecipient layers, spreading rapidly across columns. The similarity of sparseness patterns for both neural events and distinct spread of activity may reflect similarity of local processing and differences in the flow of information through cortical circuits, respectively.

Budgerigars and zebra finches were tested, using operant conditioning techniques, on their ability to identify a zebra finch song in the presence of a background masker emitted from either the same or a different location as the signal. Identification thresholds were obtained for three masker types differing in their spectrotemporal characteristics (noise, modulated noise, and a song chorus). Both bird species exhibited similar amounts of spatial unmasking across the three masker types. The amount of unmasking was greater when the masker was played continuously compared to when the target and masker were presented simultaneously. These results suggest that spatial factors are important for birds in the identification of natural signals in noisy environments.

Some past studies suggest that when sound elements are heard as one object, the spatial cues in the component elements are integrated to determine perceived location, and that this integration is reduced when the elements are perceived in separate objects. The current study explored how object localization depends on the spatial, spectral, and temporal configurations of sound elements in an auditory scene. Localization results are interpreted in light of results from a series of previous experiments studying perceptual grouping of the same stimuli, e.g., Shinn-Cunningham et al. [Proc. Natl. Acad. Sci. U.S.A. 104, 12223–12227 (2007)]. The current results suggest that the integration (pulling) of spatial information across spectrally interleaved elements is obligatory when these elements are simultaneous, even though past results show that these simultaneous sound elements are not grouped strongly into a single perceptual object. In contrast, perceptually distinct objects repel (push) each other spatially with a strength that decreases as the temporal separation between competing objects increases. These results show that the perceived location of an attended object is not easily predicted by knowledge of how sound elements contribute to the perceived spectro-temporal content of that object.

Neural representations of even temporally unstructured stimuli can show complex temporal dynamics. In many systems, neuronal population codes show ‘progressive differentiation’, whereby population responses to different stimuli grow further apart during a stimulus presentation. Here we analysed the response of auditory cortical populations in rats to extended tones. At onset (up to 300 ms), tone responses involved strong excitation of a large number of neurons; during sustained responses (after 500 ms) overall firing rate decreased, but most cells still showed statistically significant rate modulation. Population vector trajectories evoked by different tone frequencies expanded rapidly along an initially similar trajectory in the first tens of milliseconds after tone onset, later diverging to smaller amplitude fixed points corresponding to sustained responses. The angular difference between onset and sustained responses to the same tone was greater than between different tones in the same stimulus epoch. No clear orthogonalization of responses was found with time, and predictability of the stimulus from population activity also decreased during this period compared with onset. The question of whether population activity grew more or less sparse with time depended on the precise mathematical sense given to this term. We conclude that auditory cortical population responses to tones differ from those reported in many other systems, with progressive differentiation not seen for sustained stimuli. Sustained acoustic stimuli are typically not behaviorally salient: we hypothesize that the dynamics we observe may instead allow an animal to maintain a representation of such sounds, at low energetic cost.

Acoustic processing requires integration over time. We have used in vivo intracellular recording to measure neuronal integration times in anesthetized rats. Using natural sounds and other stimuli, we found that synaptic inputs to auditory cortical neurons showed a rather long context dependence, up to ≥4 s (τ ∼ 1 s), even though sound-evoked excitatory and inhibitory conductances per se rarely lasted ≳100 ms. Thalamic neurons showed only a much faster form of adaptation with a decay constant τ <100 ms, indicating that the long-lasting form originated from presynaptic mechanisms in the cortex, such as synaptic depression. Restricting knowledge of the stimulus history to only a few hundred milliseconds reduced the predictable response component to about half that of the optimal infinite-history model. Our results demonstrate the importance of long-range temporal effects in auditory cortex and suggest a potential neural substrate for auditory processing that requires integration over timescales of seconds or longer, such as stream segregation.

Consonant and dissonant pitch relationships in music provide the foundation of melody and harmony, the building blocks of Western tonal music. We hypothesized that phase-locked neural activity within the brainstem may preserve information relevant to these important perceptual attributes of music. To this end, we measured brainstem frequency-following responses (FFRs) from nonmusicians in response to the dichotic presentation of nine musical intervals that varied in their degree of consonance and dissonance. Neural pitch salience was computed for each response using temporally based autocorrelation and harmonic pitch sieve analyses. Brainstem responses to consonant intervals were more robust and yielded stronger pitch salience than those to dissonant intervals. In addition, the ordering of neural pitch salience across musical intervals followed the hierarchical arrangement of pitch stipulated by Western music theory. Finally, pitch salience derived from neural data showed high correspondence with behavioral consonance judgments ( r = 0.81). These results suggest that brainstem neural mechanisms mediating pitch processing show preferential encoding of consonant musical relationships and, furthermore, preserve the hierarchical pitch relationships found in music, even for individuals without formal musical training. We infer that the basic pitch relationships governing music may be rooted in low-level sensory processing and that an encoding scheme that favors consonant pitch relationships may be one reason why such intervals are preferred behaviorally.

A fundamental organizational principle of the primate motor system is cortical control of contralateral limb movements. Motor areas also appear to play a role in the control of ipsilateral limb movements. Several studies in monkeys have shown that individual neurons in primary motor cortex (M1) may represent, on average, the direction of movements of the ipsilateral arm. Given the increasing body of evidence demonstrating that neural ensembles can reliably represent information with a high temporal resolution, here we characterize the distributed neural representation of ipsilateral upper limb kinematics in both monkey and man. In two macaque monkeys trained to perform center-out reaching movements, we found that the ensemble spiking activity in M1 could continuously represent ipsilateral limb position. Interestingly, this representation was more correlated with joint angles than hand position. Using bilateral electromyography recordings, we excluded the possibility that postural or mirror movements could exclusively account for these findings. In addition, linear methods could decode limb position from cortical field potentials in both monkeys. We also found that M1 spiking activity could control a biomimetic brain–machine interface reflecting ipsilateral kinematics. Finally, we recorded cortical field potentials from three human subjects and also consistently found evidence of a neural representation for ipsilateral movement parameters. Together, our results demonstrate the presence of a high-fidelity neural representation for ipsilateral movement and illustrates that it can be successfully incorporated into a brain–machine interface.

Retinotopic mapping is a basic feature of visual system organization, but its role in processing visual information is unknown. Mutant mice lacking the β2 subunit of nicotinic acetylcholine receptor have imprecise maps in both visual cortex (V1) and the superior colliculus (SC) due to the disruption of spontaneous retinal activity during development. Here, we use behavioral and physiological approaches to study their visual functions. We find that β2−/− mice fail to track visual stimuli moving along the nasotemporal axis in a subcortical optomotor behavior, but track normally along the dorsoventral axis. In contrast, these mice display normal acuity along both axes in the visual water task, a behavioral test of cortical functions. Consistent with the behavioral results, we find that V1 neurons in β2−/− mice have normal response properties, while SC neurons have disrupted receptive fields, including enlarged structure and decreased direction and orientation selectivity along the nasotemporal axis. The subcortical-specific deficits indicate that retinotopic map disruption has different impacts on the development of functional properties in V1 and the SC.

Background: The giant synapses of Held play an important role in high-fidelity auditory processing and provide a model system for synaptic transmission at central synapses. Whether transmission of action potentials can fail at these synapses has been investigated in recent studies. At the endbulbs of Held in the anteroventral cochlear nucleus (AVCN) a consistent picture emerged, whereas at the calyx of Held in the medial nucleus of the trapezoid body (MNTB) results on the reliability of transmission remain inconsistent. In vivo this discrepancy could be due to the difficulty in identifying failures of transmission. Methods/findings: We introduce a novel method for detecting unreliable transmission in vivo. Based on the temporal relationship between a cells' waveform and other potentials in the recordings, a statistical test is developed that provides a balanced decision between the presence and the absence of failures. Its performance is quantified using simulated voltage recordings and found to exhibit a high level of accuracy. The method was applied to extracellular recordings from the synapses of Held in vivo. At the calyces of Held failures of transmission were found only rarely. By contrast, at the endbulbs of Held in the AVCN failures were found under spontaneous, excited, and suppressed conditions. In accordance with previous studies, failures occurred most abundantly in the suppressed condition, suggesting a role for inhibition. Conclusions/significance: Under the investigated activity conditions/anesthesia, transmission seems to remain largely unimpeded in the MNTB, whereas in the AVCN the occurrence of failures is related to inhibition and could be the basis/result of computational mechanisms for temporal processing. More generally, our approach provides a formal tool for studying the reliability of transmission with high statistical accuracy under typical in vivo recording conditions.

The 13-lined ground squirrel ( Ictidomys tridecemlineatus), a hibernating species, is a natural model of physiological adaption to an extreme environment. During torpor, body temperature drops to 0–4°C, and the cortex is electrically silent, yet the brain stem continues to regulate cardiorespiratory function. The mechanisms underlying selective inhibition in the brain during torpor are not known. To test whether altered GABAergic function is involved in regional and seasonal differences in neuronal activity, cortical and medullary slices from summer-active (SA) and interbout aroused (IBA) squirrels were placed in a standard in vitro recording chamber. Silicon multichannel electrodes were placed in cortex, ventral respiratory column (VRC), and nucleus tractus solitarius (NTS) to record spontaneous neuronal activity. In slices from IBA squirrels, bath-applied pentobarbital sodium (300 μM) nearly abolished cortical neuronal activity, but VRC and NTS neuronal activity was unaltered. In contrast, pentobarbital sodium (300 μM) nearly abolished all spontaneous cortical, VRC, and NTS neuronal activity in slices from SA squirrels. Muscimol (20 μM; GABA A receptor agonist) abolished all neuronal activity in cortical and medullary slices from both IBA and SA squirrels, thereby demonstrating the presence of functional GABA A receptors. Pretreatment of cortical slices from IBA squirrels with bicuculline (100 μM; GABA A receptor antagonist) blocked pentobarbital-dependent inhibition of spontaneous neuronal activity. We hypothesize that GABA A receptors undergo a seasonal modification in subunit composition, such that cardiorespiratory neurons are uniquely unaffected by surges of an endogenous positive allosteric modulator.

The capacity of auditory cortex on Heschl's gyrus (HG) to encode repetitive transients was studied in human patients undergoing surgical evaluation for medically intractable epilepsy. Multicontact depth electrodes were chronically implanted in gray matter of HG. Bilaterally presented stimuli were click trains varying in rate from 4 to 200 Hz. Averaged evoked potentials (AEPs) and event-related band power (ERBP), computed from responses at each of 14 recording sites, identified two auditory fields. A core field, which occupies posteromedial HG, was characterized by a robust polyphasic AEP on which could be superimposed a frequency following response (FFR). The FFR was prominent at click rates below ∼50 Hz, decreased rapidly as click rate was increased, but could reliably be detected at click rates as high as 200 Hz. These data are strikingly similar to those obtained by others in the monkey under essentially the same stimulus conditions, indicating that mechanisms underlying temporal processing in the auditory core may be highly conserved across primate species. ERBP, which reflects increases or decreases of both phase-locked and non–phase-locked power within given frequency bands, showed stimulus-related increases in gamma band frequencies as high as 250 Hz. The AEPs recorded in a belt field anterolateral to the core were typically of low amplitude, showing little or no evidence of short-latency waves or an FFR, even at the lowest click rates used. The non–phase-locked component of the response extracted from the ERBP showed a robust, long-latency response occurring here in response to the highest click rates in the series.

Understanding the mechanistic substrates of neural computations that lead to behavior remains a fundamental problem in neuroscience. In particular, the contributions of intrinsic neural properties such as burst firing and dendritic morphology to the processing of behaviorally relevant sensory input have received much interest recently. Pyramidal cells within the electrosensory lateral line lobe of weakly electric fish display an intrinsic bursting mechanism that relies on somato-dendritic interactions when recorded in vitro: backpropagating somatic action potentials trigger dendritic action potentials that lead to a depolarizing afterpotential (DAP) at the soma. We recorded intracellularly from these neurons in vivo and found firing patterns that were quite different from those seen in vitro: we found no evidence for DAPs as each somatic action potential was followed by a pronounced afterhyperpolarization (AHP). Calcium chelators injected in vivo reduced the AHP, thereby unmasking the DAP and inducing in vitro-like bursting in pyramidal cells. These bursting dynamics significantly reduced the cell's ability to encode the detailed time course of sensory input. We performed additional in vivo pharmacological manipulations and mathematical modeling to show that calcium influx through N-methyl-d-aspartate (NMDA) receptors activate dendritic small conductance (SK) calcium-activated potassium channels, which causes an AHP that counteracts the DAP and leads to early termination of the burst. Our results show that ion channels located in dendrites can have a profound influence on the processing of sensory input by neurons in vivo through the modulation of an intrinsic bursting mechanism.

Deafness is the most common sensory disorder in humans and the aetiology of genetic deafness is complex. Mouse mutants have been crucial in identifying genes involved in hearing. However, many deafness genes remain unidentified. Using N ‐ethyl N −nitrosourea (ENU) mutagenesis to generate new mouse models of deafness, we identified a novel semi‐dominant mouse mutant, Cloth‐ears ( Clth ). Cloth‐ears mice show reduced acoustic startle response and mild hearing loss from ∼30 days old. Auditory‐evoked brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) analyses indicate that the peripheral neural auditory pathway is impaired in Cloth‐ears mice, but that cochlear function is normal. In addition, both Clth/Clth and Clth/+ mice display paroxysmal tremor episodes with behavioural arrest. Clth/Clth mice also show a milder continuous tremor during movement and rest. Longitudinal phenotypic analysis showed that Clth/+ and Clth/Clth mice also have complex defects in behaviour, growth, neurological and motor function. Positional cloning of Cloth‐ears identified a point mutation in the neuronal voltage‐gated sodium channel α‐subunit gene, Scn8a , causing an aspartic acid to valine (D981V) change six amino acids downstream of the sixth transmembrane segment of the second domain (D2S6). Complementation testing with a known Scn8a mouse mutant confirmed that this mutation is responsible for the Cloth‐ears phenotype. Our findings suggest a novel role for Scn8a in peripheral neural hearing loss and paroxysmal motor dysfunction.