Publications using TDT

Duration-tuned neurons (DTNs) in the mammalian inferior colliculus (IC) arise from a combination of excitatory and inhibitory synaptic inputs. Previous research has shown that the inhibition responsible for creating DTNs has a shorter latency than that of excitation and lasts longer than the stimulus duration. We used monotic and dichotic paired tone stimulation and recorded responses of DTNs from the IC of the bat to assess the relative contributions of each ear in forming duration-tuned circuits. The stimulus consisted of a short best duration (BD) excitatory tone and a longer duration nonexcitatory (NE) tone. In the monotic condition, when the BD and NE tones were presented to the contralateral ear and were sufficiently close in time, the NE tone always suppressed spikes evoked by the BD tone. In the dichotic condition, when the BD tone was presented to the contralateral ear and the NE tone to the ipsilateral ear, half of DTNs no longer showed spike suppression to the NE tone. Of those DTNs with suppression in both conditions, the latency of the inhibition was shorter and the duration of the inhibition was longer in the monotic condition. Therefore, in the monotic condition, DTNs received a contralaterally evoked inhibitory input that preceded the excitatory input to the same neuron. In the dichotic condition, DTNs received an ipsilaterally evoked inhibitory input that was weaker, longer in latency, and shorter in duration than the inputs from the contralateral ear. These findings indicate that the neural mechanisms that create DTNs in the IC are monaural.

Absolute auditory threshold decreases with increasing sound duration, a phenomenon explainable by the assumptions that the sound evokes neural events whose probabilities of occurrence are proportional to the sound's amplitude raised to an exponent of about 3 and that a constant number of events are required for threshold (Heil and Neubauer, Proc Natl Acad Sci USA 100:6151-6156, 2003). Based on this probabilistic model and on the assumption of perfect binaural summation, an equation is derived here that provides an explicit expression of the binaural threshold as a function of the two monaural thresholds, irrespective of whether they are equal or unequal, and of the exponent in the model. For exponents >0, the predicted binaural advantage is largest when the two monaural thresholds are equal and decreases towards zero as the monaural threshold difference increases. This equation is tested and the exponent derived by comparing binaural thresholds with those predicted on the basis of the two monaural thresholds for different values of the exponent. The thresholds, measured in a large sample of human subjects with equal and unequal monaural thresholds and for stimuli with different temporal envelopes, are compatible only with an exponent close to 3. An exponent of 3 predicts a binaural advantage of 2 dB when the two ears are equally sensitive. Thus, listening with two (equally sensitive) ears rather than one has the same effect on absolute threshold as doubling duration. The data suggest that perfect binaural summation occurs at threshold and that peripheral neural signals are governed by an exponent close to 3. They might also shed new light on mechanisms underlying binaural summation of loudness.

Age-related hearing loss (AHL) is a multifactorial disorder characterized by a decline in peripheral and central auditory function. Here, we examined synaptic transmission in DBA/2 mice, which carry the AHL8 gene, at the identifiable glutamatergic synapse in the medial nucleus of the trapezoid body (MNTB), a nucleus in the superior olivary complex critical for acoustic timing. Mice exhibited raised auditory brainstem thresholds by P14, soon after hearing onset. Excitatory postsynaptic currents were prolonged; however, postsynaptic excitability was normal. By P18, high-frequency hearing loss was evident. Coincident with the onset of hearing loss, MNTB principal neurons displayed changes in intrinsic firing properties. These results suggest that changes in transmission in the superior olivary complex are associated with early onset hearing loss.

Delivery of therapeutic compounds to the inner ear via absorption through the round window membrane (RWM) has advantages over direct intracochlear infusions; specifically, minimizing impact upon functional hearing measures. However, previous reports show that significant basal-to-apical concentration gradients occur, with the potential to impact treatment efficacy. Here we present a new approach to inner ear drug delivery with induced advection aiding distribution of compounds throughout the inner ear in the murine cochlea. Polyimide microtubing was placed near the RWM niche through a bullaostomy into the middle ear cavity allowing directed delivery of compounds to the RWM. We hypothesized that a posterior semicircular canalostomy would induce apical flow from the patent cochlear aqueduct to the canalostomy due to influx of cerebral spinal fluid. To test this hypothesis, young adult CBA/CaJ mice were divided into two groups: bullaostomy approach only (BA) and bullaostomy+canalostomy (B+C). Cochlear function was evaluated by distortion product otoacoustic emission (DPOAE) and auditory brainstem response (ABR) thresholds during and after middle ear infusion of salicylate in artificial perilymph (AP), applied near the RWM. The mice recovered for 1week, and were re-tested. The results demonstrate there was no significant impact on auditory function utilizing the RWM surgical procedure with or without the canalostomy, and DPOAE thresholds were elevated reversibly during the salicylate infusion. Comparing the threshold shifts for both methods, the B+C approach had more of a physiological effect than the BA approach, including at lower frequencies representing more apical cochlear locations. Unlike mouse cochleostomies, there was no deleterious auditory functional impact after 1week recovery from surgery. The B+C approach had more drug efficacy at lower frequencies, underscoring potential benefits for more precise control of delivery of inner ear therapeutic compounds.

We have developed a classifier capable of locating and identifying speech sounds using activity from rat auditory cortex with an accuracy equivalent to behavioral performance and without the need to specify the onset time of the speech sounds. This classifier can identify speech sounds from a large speech set within 40 ms of stimulus presentation. To compare the temporal limits of the classifier to behavior, we developed a novel task that requires rats to identify individual consonant sounds from a stream of distracter consonants. The classifier successfully predicted the ability of rats to accurately identify speech sounds for syllable presentation rates up to 10 syllables per second (up to 17.9 ± 1.5 bits/s), which is comparable to human performance. Our results demonstrate that the spatiotemporal patterns generated in primary auditory cortex can be used to quickly and accurately identify consonant sounds from a continuous speech stream without prior knowledge of the stimulus onset times. Improved understanding of the neural mechanisms that support robust speech processing in difficult listening conditions could improve the identification and treatment of a variety of speech-processing disorders.

Rat fetal spinal cord (FSC) tissue, naturally enriched with interneuronal progenitors, was introduced into high cervical, hemi-resection (Hx) lesions. Electrophysiological analyses were conducted to determine if such grafts exhibit physiologically-patterned neuronal activity and if stimuli which increase respiratory motor output also alter donor neuron bursting. Three months following transplantation, the bursting activity of FSC neurons and the contralateral phrenic nerve were recorded in anesthetized rats during a normoxic baseline period and brief respiratory challenges. Spontaneous neuronal activity was detected in 80% of the FSC transplants, and autocorrelation of action potential spikes revealed distinct correlogram peaks in 87% of neurons. At baseline, the average discharge frequency of graft neurons was 13.0 ± 1.7 Hz, and discharge frequency increased during a hypoxic respiratory challenge (p<0.001). Parallel studies in unanesthetized rats showed that FSC tissue recipients had larger inspiratory tidal volumes during brief hypoxic exposures (p<0.05 vs. C2Hx rats). Anatomical connectivity was explored in additional graft recipients by injecting a transsynaptic retrograde viral tracer (pseudorabies virus, PRV) directly into matured transplants. Neuronal labeling occurred throughout graft tissues and also in the host spinal cord and brainstem nuclei, including those associated with respiratory control. These results underscore the neuroplastic potential of host-graft interactions and training approaches to enhance functional integration within targeted spinal circuitry.

Switching attention between different stimuli of interest based on particular task demands is important in many everyday settings. In audition in particular, switching attention between different speakers of interest that are talking concurrently is often necessary for effective communication. Recently, it has been shown by multiple studies that auditory selective attention suppresses the representation of unwanted streams in auditory cortical areas in favor of the target stream of interest. However, the neural processing that guides this selective attention process is not well understood. Here we investigated the cortical mechanisms involved in switching attention based on two different types of auditory features. By combining magneto- and electro-encephalography (M-EEG) with an anatomical MRI constraint, we examined the cortical dynamics involved in switching auditory attention based on either spatial or pitch features. We designed a paradigm where listeners were cued in the beginning of each trial to switch or maintain attention halfway through the presentation of concurrent target and masker streams. By allowing listeners time to switch during a gap in the continuous target and masker stimuli, we were able to isolate the mechanisms involved in endogenous, top-down attention switching. Our results show a double dissociation between the involvement of right temporoparietal junction (RTPJ) and the left inferior parietal supramarginal part (LIPSP) in tasks requiring listeners to switch attention based on space and pitch features, respectively, suggesting that switching attention based on these features involves at least partially separate processes or behavioral strategies.

The place of the posterolateral superior temporal (PLST) gyrus within the hierarchical organization of the human auditory cortex is unknown. Understanding how PLST processes spectral information is imperative for its functional characterization. Pure-tone stimuli were presented to subjects undergoing invasive monitoring for refractory epilepsy. Recordings were made using high-density subdural grid electrodes. Pure tones elicited robust high gamma event-related band power responses along a portion of PLST adjacent to the transverse temporal sulcus (TTS). Responses were frequency selective, though typically broadly tuned. In several subjects, mirror-image response patterns around a low-frequency center were observed, but typically, more complex and distributed patterns were seen. Frequency selectivity was greatest early in the response. Classification analysis using a sparse logistic regression algorithm yielded above-chance accuracy in all subjects. Classifier performance typically peaked at 100-150 ms after stimulus onset, was comparable for the left and right hemisphere cases, and was stable across stimulus intensities. Results demonstrate that representations of spectral information within PLST are temporally dynamic and contain sufficient information for accurate discrimination of tone frequencies. PLST adjacent to the TTS appears to be an early stage in the hierarchy of cortical auditory processing. Pure-tone response patterns may aid auditory field identification.

In auditory research, hearing function of mouse mutants is assessed in vivo by evoked potential recording. Evaluation of the response parameters should be performed with reference to the evoked responses recorded from wild-type mice. This study reports normative data calculated on auditory brainstem responses (ABRs) obtained from 20 wild-type C57 BL/6J mice at a postnatal age between 21 and 45 days. Acoustic stimuli consisted tone bursts at 8, 14, 20, 26, 32 kHz, and clicks. Each stimulus was delivered in free field at stimulation intensity starting from a maximum of 100 dB peak equivalent SPL (dB peSPL) at decreasing steps of 10 dB with a repetition rate of 13/sec. Evoked responses were recorded by needle electrodes inserted subcutaneously. At high intensity stimulation, five response waveforms, each consisting of a positive peak and a subsequent negative valley, were identified within 7 msec, and were labelled with sequential capital Roman numerals from I to V. Peak IV was the most robust and stable at low intensities for both tone burst and click stimuli, and was therefore utilized to estimate hearing thresholds. Both latencies and amplitudes of ABR peaks showed good reproducibility with acceptable standard deviations. Mean wave IV thresholds measured across all animals ranged from a maximum of 23 dB peSPL for clicks to a minimum of 7 dB peSPL for 20 kHz-tone burst stimuli. Statistical analysis of the distribution of latencies and amplitudes of peaks from I to V performed for each stimulus type yielded a normative data set which was utilised to obtain the most consistent fitting-curve model. This could serve as a reference for further studies on murine models of hearing loss.

Short-term tinnitus develops shortly after the administration of a high dose of salicylate. Since salicylate selectively potentiates N-methyl- D-aspartate (NMDA) currents in spiral ganglion neurons, it may play a vital role in tinnitus by amplifying NMDA-mediated neurotransmission. The aim of this study was to determine whether systemic treatment with a NMDA channel blocker, memantine, could prevent salicylate-induced tinnitus in animals. Additional experiments were performed to evaluate the effect of memantine on the auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE) to test for changes in hearing function. Thirty-six rats were divided into 3 groups and treated daily for four consecutive days. One group (n = 12) was injected with salicylate (300 mg/kg/d, IP), the second (n = 12) was treated with memantine (5 mg/kg/d, IP) and the third group (n = 12) was injected with salicylate and memantine. All rats were tested for tinnitus and hearing loss at 2, 24, 48 and 72 h after the first drug administration and 24 h post treatment; tinnituslike behaviour was assessed with gap prepulse inhibition of acoustic startle (GPIAS), and hearing function was measured with DPOAE, ABR and noise burst prepulse inhibition of acoustic startle (NBPIAS). Rats in the salicylate group showed impaired GPIAS indicative of transient tinnitus-like behaviour near 16 kHz that recovered 24 h after the last salicylate treatment. Memantine did not cause a significant change in GPIAS. Combined injection of salicylate and memantine significantly attenuated GPIAS tinnitus-like behaviour at 48 hours after the first injection. None of the treatments induced permanent threshold shifts in the ABR and DPOAE, which recovered completely within one day post treatment. Animals treated with salicylate plus memantine showed results comparable to animals treated with salicylate alone, confirming that there is no effect of memantine on DPOAE which reflects OHC function. The present study confirms the role of cochlear NMDA receptors in the induction of salicylate-induced tinnitus.

Diabetic encephalopathy is one of the complications of diabetes. Cognitive dysfunction is the main consequence. Previous findings from neuroanatomical and in vitro electrophysiological studies showed that the structure and function of the hippocampus is impaired in diabetes, which may underlie the cognitive dysfunction induced by diabetes. However the study of electrophysiological abnormality of hippocampal neurons in intact networks is sparse. In the current study, we recorded the spontaneous firing of neurons in hippocampal CA1 area in anesthetized streptozotozin (STZ)-diabetic and age-matched control rats. Profound reduction in burst activity was found in diabetic rats. Compared to control rats, the intra-burst inter-spike intervals were prolonged significantly in diabetic rats, while the burst ratio and the mean number of spikes within a burst decreased significantly. Treatment with APP 17-mer peptide retarded the effects of diabetes on these parameters. In addition, the average PLV of diabetic rats was lower than that of control rats. These findings provide in vivo electrophysiological evidence for the impairment of hippocampal function in STZ-diabetic rats, and may have some implications in the mechanisms associated with cognitive deficits in diabetes.

Age and hearing-level matched tinnitus and control groups were presented with a 40 Hz AM sound using a carrier frequency of either 5 kHz (in the tinnitus frequency region of the tinnitus subjects) or 500 Hz (below this region). On attended blocks subjects pressed a button after each sound indicating whether a single 40 Hz AM pulse of variable increased amplitude (target, probability 0.67) had or had not occurred. On passive blocks subjects rested and ignored the sounds. The amplitude of the 40 Hz auditory steady-state response (ASSR) localizing to primary auditory cortex (A1) increased with attention in control groups probed at 500 Hz and 5 kHz and in the tinnitus group probed at 500 Hz, but not in the tinnitus group probed at 5 kHz (128 channel EEG). N1 amplitude (this response localizing to nonprimary cortex, A2) increased with attention at both sound frequencies in controls but at neither frequency in tinnitus. We suggest that tinnitus-related neural activity occurring in the 5 kHz but not the 500 Hz region of tonotopic A1 disrupted attentional modulation of the 5 kHz ASSR in tinnitus subjects, while tinnitus-related activity in A1 distributing nontonotopically in A2 impaired modulation of N1 at both sound frequencies.

One of the most efficient mechanisms to optimize signal-to-noise ratios is the Lombard effect - an involuntary rise in call amplitude due to ambient noise. It is often accompanied by changes in the spectro-temporal composition of calls. We examined the effects of broadband-filtered noise on the spectro-temporal composition of horseshoe bat echolocation calls, which consist of a constant-frequency component and an initial and terminal frequency-modulated portion. We find that the frequency-modulated components became larger for almost all noise conditions, whereas the bandwidth of the constant-frequency component increased only when broadband-filtered noise was centered on or above the calls' dominant or fundamental frequency. This indicates that ambient noise modifies the associated acoustic parameters of the Lombard-effect, such as spectro-temporal features, independently and could significantly affect the bat's ability to detect and locate targets. Our findings may be of significance in evaluating the impact of environmental noise on echolocation behavior in bats.

Previous studies have shown that sodium salicylate (SS) activates not only central auditory structures, but also nonauditory regions associated with emotion and memory. To identify electrophysiological changes in the nonauditory regions, we recorded sound-evoked local field potentials and multiunit discharges from the striatum, amygdala, hippocampus, and cingulate cortex after SS-treatment. The SS-treatment produced behavioral evidence of tinnitus and hyperacusis. Physiologically, the treatment significantly enhanced sound-evoked neural activity in the striatum, amygdala, and hippocampus, but not in the cingulate. The enhanced sound evoked response could be linked to the hyperacusis-like behavior. Further analysis showed that the enhancement of sound-evoked activity occurred predominantly at the midfrequencies, likely reflecting shifts of neurons towards the midfrequency range after SS-treatment as observed in our previous studies in the auditory cortex and amygdala. The increased number of midfrequency neurons would lead to a relative higher number of total spontaneous discharges in the midfrequency region, even though the mean discharge rate of each neuron may not increase. The tonotopical overactivity in the midfrequency region in quiet may potentially lead to tonal sensation of midfrequency (the tinnitus). The neural changes in the amygdala and hippocampus may also contribute to the negative effect that patients associate with their tinnitus.

Brain machine interfaces (BMIs) have attracted intense attention as a promising technology for directly interfacing computers or prostheses with the brain’s motor and sensory areas, thereby bypassing the body. The availability of multiscale neural recordings including spike trains and local field potentials (LFPs) brings potential opportunities to enhance computational modeling by enriching the characterization of the neural system state. However, heterogeneity on data type (spike timing versus continuous amplitude signals) and spatiotemporal scale complicates the model integration of multiscale neural activity. In this paper, we propose a tensor-product-kernel-based framework to integrate the multiscale activity and exploit the complementary information available in multiscale neural activity. This provides a common mathematical framework for incorporating signals from different domains. The approach is applied to the problem of neural decoding and control. For neural decoding, the framework is able to identify the nonlinear functional relationship between the multiscale neural responses and the stimuli using general purpose kernel adaptive filtering. In a sensory stimulation experiment, the tensor-product-kernel decoder outperforms decoders that use only a single neural data type. In addition, an adaptive inverse controller for delivering electrical microstimulation patterns that utilizes the tensor-product kernel achieves promising results in emulating the responses to natural stimulation.

Canavan disease is a leukodystrophy caused by mutations in the ASPA gene. This gene encodes the enzyme that converts N-acetylaspartate into acetate and aspartic acid. In Canavan disease spongiform encephalopathy of the brain causes progressive mental retardation, motor deficit and death. We have isolated a mouse with a novel ethylnitrosourea-induced mutation in Aspa. This mutant, named deaf14, carries a c.516T>A mutation that is predicted to cause a p.Y172X protein truncation. No full-length ASPA protein is produced in deaf14 brain and there is extensive spongy degeneration. Interestingly, we found that deaf14 mice have an attenuated startle in response to loud noise. The first auditory brainstem response peak has normal latency and amplitude but peaks II, III, IV and V have increased latency and decreased amplitude in deaf14 mice. Our work reveals a hitherto unappreciated pathology in a mouse model of Canavan disease, implying that auditory brainstem response testing could be used in diagnosis and to monitor the progression of this disease.

Human listeners, and other animals too, use interaural time differences (ITD) to localize sounds. If the sounds are pure tones, a simple frequency factor relates the ITD to the interaural phase difference (IPD), for which there are known iso-IPD boundaries, 90°, 180°… defining regions of spatial perception. In this article, iso-IPD boundaries for humans are translated into azimuths using a spherical head model (SHM), and the calculations are checked by free-field measurements. The translated boundaries provide quantitative tests of an ecological interpretation for the dramatic onset of ITD insensitivity at high frequencies. According to this interpretation, the insensitivity serves as a defense against misinformation and can be attributed to limits on binaural processing in the brainstem. Calculations show that the ecological explanation passes the tests only if the binaural brainstem properties evolved or developed consistent with heads that are 50% smaller than current adult heads. Measurements on more realistic head shapes relax that requirement only slightly. The problem posed by the discrepancy between the current head size and a smaller, ideal head size was apparently solved by the evolution or development of central processes that discount large IPDs in favor of interaural level differences. The latter become more important with increasing head size.

States of consciousness have been associated with information integration in the brain as modulated by anesthesia and the ascending arousal system. The present study was designed to test the hypothesis that electrical stimulation of the oral part of the pontine reticular nucleus (PnO) can augment information integration in the cerebral cortex of anesthetized rats. Extracellular unit activity and local field potentials were recorded in freely moving animals from parietal association (PtA) and secondary visual (V2) cortices via chronically implanted microwire arrays at three levels of anesthesia produced by desflurane: 3.5, 4.5, and 6.0% (where 4.5% corresponds to that critical for the loss of consciousness). Information integration was characterized by integration (multiinformation) and interaction entropy, estimated from the statistical distribution of coincident spike patterns. PnO stimulation elicited electrocortical activation as indicated by the reductions in δ- and θ-band powers at the intermediate level of anesthesia. PnO stimulation augmented integration from 1.13 ± 0.03 to 6.12 ± 1.98 × 10(3) bits and interaction entropy from 0.44 ± 0.11 to 2.18 ± 0.72 × 10(3) bits; these changes were most consistent in the PtA at all desflurane concentrations. Stimulation of the retina with discrete light flashes after PnO stimulation elicited an additional 166 ± 25 and 92 ± 12% increase in interaction entropy in V2 during light and intermediate levels. The results suggest that the PnO may modulate spontaneous ongoing and sensory stimulus-related cortical information integration under anesthesia.

Here we propose a methodology to analyze volumetric electrical activity of neuronal masses in the somatosensory barrel field of Wistar rats. The key elements of the proposed methodology are a three-dimensional microelectrode array, which was customized by our group to observe extracellular recordings from an extended area of the barrel field, and a novel method for the current source density analysis. By means of this methodology, we were able to localize single barrels from their event-related responses to single whisker deflection. It was also possible to assess the spatiotemporal dynamics of neuronal aggregates in several barrels at the same time with the resolution of single neurons. We used simulations to study the robustness of our methodology to unavoidable physiological noise and electrode configuration. We compared the accuracy to reconstruct neocortical current sources with that obtained with a previous method. This constitutes a type of electrophysiological microscopy with high spatial and temporal resolution, which could change the way we analyze the activity of cortical neurons in the future.

Frequency tagging of sensory inputs (presenting stimuli that fluctuate periodically at rates to which the cortex can phase lock) has been used to study attentional modulation of neural responses to inputs in different sensory modalities. For visual inputs, the visual steady-state response (VSSR) at the frequency modulating an attended object is enhanced, while the VSSR to a distracting object is suppressed. In contrast, the effect of attention on the auditory steady-state response (ASSR) is inconsistent across studies. However, most auditory studies analyzed results at the sensor level or used only a small number of equivalent current dipoles to fit cortical responses. In addition, most studies of auditory spatial attention used dichotic stimuli (independent signals at the ears) rather than more natural, binaural stimuli. Here, we asked whether these methodological choices help explain discrepant results. Listeners attended to one of two competing speech streams, one simulated from the left and one from the right, that were modulated at different frequencies. Using distributed source modeling of magnetoencephalography results, we estimate how spatially directed attention modulates the ASSR in neural regions across the whole brain. Attention enhances the ASSR power at the frequency of the attended stream in contralateral auditory cortex. The attended-stream modulation frequency also drives phase-locked responses in the left (but not right) precentral sulcus (lPCS), a region implicated in control of eye gaze and visual spatial attention. Importantly, this region shows no phase locking to the distracting stream. Results suggest that the lPCS in engaged in an attention-specific manner. Modeling results that take account of the geometry and phases of the cortical sources phase locked to the two streams (including hemispheric asymmetry of lPCS activity) help to explain why past ASSR studies of auditory spatial attention yield seemingly contradictory results.