Publications using TDT

This study examined the ability of listeners to utilize syntactic structure to extract a target stream of speech from among competing sounds. Target talkers were identified by voice or location, which was held constant throughout a test utterance, and paired with correct or incorrect (random word order) target sentence syntax. Both voice and location provided reliable cues for identifying target speech even when other features varied unpredictably. The target sentences were masked either by predominantly energetic maskers (noise bursts) or by predominantly informational maskers (similar speech in random word order). When the maskers were noise bursts, target sentence syntax had relatively minor effects on identification performance. However, when the maskers were other talkers, correct target sentence syntax resulted in significantly better speech identification performance than incorrect syntax. Furthermore, conformance to correct syntax alone was sufficient to accurately identify the target speech. The results were interpreted as supporting the idea that the predictability of the elements comprising streams of speech, as manifested by syntactic structure, is an important factor in binding words together into coherent streams. Furthermore, these findings suggest that predictability is particularly important for maintaining the coherence of an auditory stream over time under conditions high in informational masking.

Age-related hearing loss - presbycusis - is the number one communication disorder and most prevalent neurodegenerative condition of our aged population. Although speech understanding in background noise is quite difficult for those with presbycusis, there are currently no biomedical treatments to prevent, delay or reverse this condition. A better understanding of the cochlear mechanisms underlying presbycusis will help lead to future treatments. Objectives of the present study were to investigate GABAA receptor subunit α1, nicotinic acetylcholine (nACh) receptor subunit β2, and N-methyl-d-aspartate (NMDA) receptor subunit NR1 mRNA and protein expression changes in spiral ganglion neurons (SGN) of the CBA/CaJ mouse cochlea, that occur in age-related hearing loss, utilizing quantitative immunohistochemistry and semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) techniques. We found that auditory brainstem response (ABR) thresholds shifted over 40dB from 3 to 48kHz in old mice compared to young adults. DPOAE thresholds also shifted over 40dB from 6 to 49kHz in old mice, and their amplitudes were significantly decreased or absent in the same frequency range. SGN density decreased with age in basal, middle and apical turns, and SGN density of the basal turn declined the most. A positive correlation was observed between SGN density and ABR wave 1amplitude. mRNA and protein expression of GABAAR α1 and AChR β2 decreased with age in SGNs in the old mouse cochlea. mRNA and protein expression of NMDAR NR1 increased with age in SGNs of the old mice. These findings demonstrate that there are functionally-relevant age-related changes of GABAAR, nAChR, NMDAR expression in CBA mouse SGNs reflecting their degeneration, which may be related to functional changes in cochlear synaptic transmission with age, suggesting biological mechanisms for peripheral age-related hearing loss.

Brain-machine interface (BMI) systems give users direct neural control of robotic, communication, or functional electrical stimulation systems. As BMI systems begin transitioning from laboratory settings into activities of daily living, an important goal is to develop neural decoding algorithms that can be calibrated with a minimal burden on the user, provide stable control for long periods of time, and can be responsive to fluctuations in the decoder's neural input space (e.g. neurons appearing or being lost amongst electrode recordings). These are significant challenges for static neural decoding algorithms that assume stationary input/output relationships. Here we use an actor-critic reinforcement learning architecture to provide an adaptive BMI controller that can successfully adapt to dramatic neural reorganizations, can maintain its performance over long time periods, and which does not require the user to produce specific kinetic or kinematic activities to calibrate the BMI. Two marmoset monkeys used the Reinforcement Learning BMI (RLBMI) to successfully control a robotic arm during a two-target reaching task. The RLBMI was initialized using random initial conditions, and it quickly learned to control the robot from brain states using only a binary evaluative feedback regarding whether previously chosen robot actions were good or bad. The RLBMI was able to maintain control over the system throughout sessions spanning multiple weeks. Furthermore, the RLBMI was able to quickly adapt and maintain control of the robot despite dramatic perturbations to the neural inputs, including a series of tests in which the neuron input space was deliberately halved or doubled.

Temporopolar cortex plays a crucial role in the pathogenesis of temporal lobe epilepsy and subserves important cognitive functions. Because of its shape and position in the middle cranial fossa, complete electrode coverage of the temporal pole (TP) is difficult to achieve using existing devices. We designed a novel TP electrode array that conforms to the surface of temporopolar cortex and achieves dense electrode coverage of this important brain region. A multi-pronged electrode array was designed that can be placed over the surface of the TP using a straightforward insertion technique. Twelve patients with medically intractable epilepsy were implanted with the TP electrode array for purposes of seizure localization. Select patients underwent cognitive mapping by electrocorticographic (ECoG) recording from the TP during a naming task. Use of the array resulted in excellent TP electrode coverage in all patients. High quality ECoG data were consistently obtained for purposes of delineating seizure activity and functional mapping. During a naming task, significant increases in ECoG power were observed within localized subregions of the TP. One patient developed a transient neurological deficit thought to be related to the mass effect of multiple intracranial recording arrays, including the TP array. This deficit resolved following removal of all electrodes. The TP electrode array overcomes limitations of existing devices and enables clinicians and researchers to obtain optimal multi-site recordings from this important brain region.

Whisker-based object localization requires activation and plasticity of somatosensory and motor cortex. These parts of the cerebral cortex receive strong projections from the cerebellum via the thalamus, but it is unclear whether and to what extent cerebellar processing may contribute to such a sensorimotor task. Here, we subjected knock-out mice, which suffer from impaired intrinsic plasticity in their Purkinje cells and long-term potentiation at their parallel fiber-to-Purkinje cell synapses (L7-PP2B), to an object localization task with a time response window (RW). Water-deprived animals had to learn to localize an object with their whiskers, and based upon this location they were trained to lick within a particular period (“go” trial) or refrain from licking (“no-go” trial). L7-PP2B mice were not ataxic and showed proper basic motor performance during whisking and licking, but were severely impaired in learning this task compared with wild-type littermates. Significantly fewer L7-PP2B mice were able to learn the task at long RWs. Those L7-PP2B mice that eventually learned the task made unstable progress, were significantly slower in learning, and showed deficiencies in temporal tuning. These differences became greater as the RW became narrower. Trained wild-type mice, but not L7-PP2B mice, showed a net increase in simple spikes and complex spikes of their Purkinje cells during the task. We conclude that cerebellar processing, and potentiation in particular, can contribute to learning a whisker-based object localization task when timing is relevant. This study points toward a relevant role of cerebellum–cerebrum interaction in a sophisticated cognitive task requiring strict temporal processing.

Dysregulated endoplasmic reticulum (ER) calcium (Ca(2+)) signaling is reported to play an important role in Alzheimer disease (AD) pathogenesis. The role of ER Ca(2+) release channels, the ryanodine receptors (RyanRs), has been extensivelys tudied in AD models and RyanR expression and activity are upregulated in the brains of various familial AD (FAD) models.The objective of this study was to utilize a genetic approach to evaluate the importance of RyanR type 3 (RyanR3) in the context of AD pathology.The expression of RyanR3 was also elevated in hippocampus of APPPS1 mice (Thy1-APPKM670/671NL, Thy1-PS1L166P).In young (≤ 3 mo) APPPS1 mice, the deletion of RyanR3 increased hippocampal neuronal network excitability and accelerated AD pathology, leading to mushroom spine loss and increased amyloid accumulation. In contrast, deletion of RyanR3 in older APPPS1 mice (≥ 6 mo) rescued network excitability and mushroom spine loss, reduced amyloid plaque load and reduced spontaneous seizure occurrence.Our data suggests a dual role for RyanR3 in AD pathology. In young AD neurons, RyanR3 protects AD neurons from synaptic and network dysfunction. In older AD neurons, increased RyanR3 activity contributes to pathology. These results imply that blockade of RyanR3 may be beneficial for those in the later stages of the disease, but RyanR activators may be beneficial when used prior to disease onset or in its initial stages. Caffeine is an activator of RyanRs and our results may help to explain a complex epidemiological connection between coffee consumption in mid-life and risk of AD development in old age.

After severe hair cell loss, secondary degeneration of spiral ganglion cells (SGCs) is observed-a gradual process that spans years in humans but only takes weeks in guinea pigs. Being the target for cochlear implants (CIs), the physiological state of the SGCs is important for the effectiveness of a CI. For assessment of the nerve's state, focus has generally been on its response threshold. Our goal was to add a more detailed characterization of SGC functionality. To this end, the electrically evoked compound action potential (eCAP) was recorded in normal-hearing guinea pigs and guinea pigs that were deafened 2 or 6 weeks prior to the experiments. We evaluated changes in eCAP characteristics when the phase duration (PD) and inter-phase gap (IPG) of a biphasic current pulse were varied. We correlated the magnitude of these changes to quantified histological measures of neurodegeneration (SGC packing density and SGC size). The maximum eCAP amplitude, derived from the input-output function, decreased after deafening, and increased with both PD and IPG. The eCAP threshold did not change after deafening, and decreased with increasing PD and IPG. The dynamic range was wider for the 6-weeks-deaf animals than for the other two groups. Excitability increased with IPG (steeper slope of the input-output function and lower stimulation level at the half-maximum eCAP amplitude), but to a lesser extent for the deafened animals than for normal-hearing controls. The latency was shorter for the 6-weeks-deaf animals than for the other two groups. For several of these eCAP characteristics, the effect size of IPG correlated well with histological measures of degeneration, whereas effect size of PD did not. These correlations depend on the use of high current levels, which could limit clinical application. Nevertheless, their potential of these correlations towards assessment of the condition of the auditory nerve may be of great benefit to clinical diagnostics and prognosis in cochlear implant recipients.

Myosin light chain kinase (MLCK) phosphorylates myosin regulatory light chains to facilitate its interaction with actin filaments and produce contractile activity. The outer hair cells (OHCs) in the ear contain large amounts of actin and a variety myosins. The stereociliary and somatic motility of OHCs are closely related to hearing. It appears likely that MLCK may play an important role in acoustic trans-duction. In this study, we analyzed, both in vivo and in vitro, the OHCs of mice bearing a specific deletion of the MLCK gene and the OHCs of control mice. The phenotype was assessed by auditory function [acoustic brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs)], inner ear morphology and histology. MLCK-deficient mice aged 6-7 months showed impaired hearing, a 5- to 10-dB sound pressure level (SPL) increase in the ABR thresholds, when responding to clicks and tones of different frequencies (8 and 16 kHz) (P<0.05). The DPOAE amplitudes of 3-month-old MLCK-deficient mice decreased significantly (>10 dB SPL) at low frequencies (4, 5 and 6 kHz). The OHCs in the MLCK-deficient mice increased with abnormal stereocilia. The staining of F-actin and the phosphorylation of the regulatory light chain in MLCK-deficient OHCs was weak. Our results indicate that MLCK may regulate the structure and the motility of stereocilia through F-actin polymerization.

Aims: Pudendal afferent fibers can be excited using electrical stimulation to evoke reflex bladder activity. While this approach shows promise for restoring bladder function, stimulation of desired pathways, and integration of afferent signals for sensory feedback remains challenging. At sacral dorsal root ganglia (DRG), the convergence of pelvic and pudendal afferent fibers provides a unique location for access to lower urinary tract neurons. Our goal in this study was to demonstrate the potential of microstimulation in sacral DRG for evoking reflex bladder responses. Methods: Penetrating microelectrode arrays were inserted in the left S1 and S2 DRG of six anesthetized adult male cats. While the bladder volume was held at a level below the leak volume, single and multiple channel stimulation was performed using various stimulation patterns. Results: Reflex bladder excitation was observed in five cats, for stimulation in either S1 or S2 DRG at 1 Hz and 30-33 Hz with a pulse amplitude of 10-50 µA. Bladder relaxation was observed during a few trials. Adjacent electrodes frequently elicited very different responses. Conclusions: These results demonstrate the potential of low-current microstimulation to recruit reflexive bladder responses. An approach such as this could be integrated with DRG recordings of bladder afferents to provide a closed-loop bladder neuroprosthesis.

In epilepsy it has been challenging to detect early changes in brain activity that occurs prior to seizure onset and to map their origin and evolution for possible intervention. Here we demonstrate using a rat model of generalized epilepsy that diffuse optical tomography (DOT) provides a unique functional neuroimaging modality for noninvasively and continuously tracking such brain activities with high spatiotemporal resolution. We detected early hemodynamic responses with heterogeneous patterns, along with intracranial electroencephalogram gamma power changes, several minutes preceding the electroencephalographic seizure onset, supporting the presence of a "pre-seizure" state. We also observed the decoupling between local hemodynamic and neural activities. We found widespread hemodynamic changes evolving from local regions of the bilateral cortex and thalamus to the entire brain, indicating that the onset of generalized seizures may originate locally rather than diffusely. Together, these findings suggest DOT represents a powerful tool for mapping early seizure onset and propagation pathways.

Objective: Spatial localization of neural activity from within the brain with electrocorticography (ECoG) and electroencephalography remains a challenge in clinical and research settings, and while microfabricated ECoG (micro-ECoG) array technology continues to improve, complementary methods to simultaneously modulate cortical activity while recording are needed. Approach: We developed a neural interface utilizing optogenetics, cranial windowing, and micro-ECoG arrays fabricated on a transparent polymer. This approach enabled us to directly modulate neural activity at known locations around micro-ECoG arrays in mice expressing Channelrhodopsin-2. We applied photostimuli varying in time, space and frequency to the cortical surface, and we targeted multiple depths within the cortex using an optical fiber while recording micro-ECoG signals. Main results: Negative potentials of up to 1.5 mV were evoked by photostimuli applied to the entire cortical window, while focally applied photostimuli evoked spatially localized micro-ECoG potentials. Two simultaneously applied focal stimuli could be separated, depending on the distance between them. Photostimuli applied within the cortex with an optical fiber evoked more complex micro-ECoG potentials with multiple positive and negative peaks whose relative amplitudes depended on the depth of the fiber. Significance: Optogenetic ECoG has potential applications in the study of epilepsy, cortical dynamics, and neuroprostheses.

Endbulb of Held terminals of auditory nerve fibers (ANF) transmit auditory information at hundreds per second to bushy cells (BCs) in the anteroventral cochlear nucleus (AVCN). Here, we studied the structure and function of endbulb synapses in mice that lack the presynaptic scaffold bassoon and exhibit reduced ANF input into the AVCN. Endbulb terminals and active zones were normal in number and vesicle complement. Postsynaptic densities, quantal size and vesicular release probability were increased while vesicle replenishment and the standing pool of readily releasable vesicles were reduced. These opposing effects canceled each other out for the first evoked EPSC, which showed unaltered amplitude. We propose that ANF activity deprivation drives homeostatic plasticity in the AVCN involving synaptic upscaling and increased intrinsic BC excitability. In vivo recordings from individual mutant BCs demonstrated a slightly improved response at sound onset compared to ANF, likely reflecting the combined effects of ANF convergence and homeostatic plasticity. Further, we conclude that bassoon promotes vesicular replenishment and, consequently, a large standing pool of readily releasable synaptic vesicles at the endbulb synapse.

Our knowledge of the hearing abilities of frogs and toads is largely defined by work with a few well-studied species. One way to further advance comparative work on anuran hearing would be greater use of minimally invasive electrophysiological measures, such as the auditory brainstem response (ABR). This study used the ABR evoked by tones and clicks to investigate hearing in Cope's gray treefrog (Hyla chrysoscelis). The objectives were to characterize the effects of sound frequency, sound pressure level, and subject sex and body size on ABRs. The ABR in gray treefrogs bore striking resemblance to ABRs measured in other animals. As stimulus level increased, ABR amplitude increased and latency decreased, and for responses to tones, these effects depended on stimulus frequency. Frequency-dependent differences in ABRs were correlated with expected differences in the tuning of two sensory end organs in the anuran inner ear (the amphibian and basilar papillae). The ABR audiogram indicated two frequency regions of increased sensitivity corresponding to the expected tuning of the two papillae. Overall, there was no effect of subject size and only small effects related to subject sex. Together, these results indicate the ABR is an effective method to study audition in anurans.

Objective Identify cells supporting cochlear lateral wall regeneration. Study Design Prospective controlled trial. Setting Laboratory. Human presbyacusis occurs, in part, secondary to age‐related degeneration of cochlear lateral wall structures such as the stria vascularis and spiral ligament fibrocytes. This degeneration is likely linked to the diminished regenerative capacity of lateral wall cells with age. While lateral wall regeneration is known to occur after an acute insult, this process remains poorly understood and the cells capable of self‐replication unidentified. We hypothesized that spiral ligament fibrocytes constitute these proliferative cells. Subjects and Methods To test the hypothesis, an acute ototoxic insult was created in 65 normal‐hearing, young adult mice via cochlear exposure to heptanol. Sacrifice occurred at 1 to 60 days posttreatment. Auditory brainstem responses, 5‐ethynyl‐2′−deoxyuridine assay, and immunostaining were used to assess regeneration. Results Posttreatment hearing thresholds were elevated in nearly all treated mice. Selective fibrocyte apoptosis and strial injury were observed at the time of peak hearing loss around 1 to 7 days posttreatment. Cellular proliferation was detected in the region of type II fibrocytes during this time. Hearing thresholds plateaued at 7 days posttreatment followed by a significant recovery of both hearing and morphologic appearance. Permanent outer hair cell degeneration was observed. Conclusions Heptanol application to the round window of young adult mice is a rapid, selective, and reliable technique for investigating proliferation in the cochlear lateral wall. The data indirectly showed that spiral ligament fibrocytes may be the proliferative cells of the cochlear lateral wall. Further studies of this process are needed.

The systematic and topographic representation of frequency is a first principle of organization throughout the auditory system. The dorsal cochlear nucleus (DCN) receives direct tonotopic projections from the auditory nerve (AN) as well as secondary and descending projections from other sources. Among the recipients of AN input in the DCN are vertical cells (also called tuberculoventral cells), glycinergic interneurons thought to provide on‐ or near‐best‐frequency feed‐forward inhibition to principal cells in the DCN and various cells in the anteroventral cochlear nucleus (AVCN). Differing lines of physiological and anatomical evidence suggest that vertical cells and their projections are organized with respect to frequency, but this has not been conclusively demonstrated in the intact mammalian brain. To address this issue, we retrogradely labeled vertical cells via physiologically targeted injections in the AVCN of the CBA/J mouse. Results from multiple cases were merged with a normalized 3D template of the cochlear nucleus (Muniak et al. [ ] J. Comp. Neurol. 521:1510–1532) to demonstrate quantitatively that the arrangement of vertical cells is tonotopic and aligned to the innervation pattern of the AN. These results suggest that vertical cells are well positioned for providing immediate, frequency‐specific inhibition onto cells of the DCN and AVCN to facilitate spectral processing. J. Comp. Neurol. 522:937–949, 2014. © 2013 Wiley Periodicals, Inc.

Selective attention is the mechanism that allows focusing one's attention on a particular stimulus while filtering out a range of other stimuli, for instance, on a single conversation in a noisy room. Attending to one sound source rather than another changes activity in the human auditory cortex, but it is unclear whether attention to different acoustic features, such as voice pitch and speaker location, modulates subcortical activity. Studies using a dichotic listening paradigm indicated that auditory brainstem processing may be modulated by the direction of attention. We investigated whether endogenous selective attention to one of two speech signals affects amplitude and phase locking in auditory brainstem responses when the signals were either discriminable by frequency content alone, or by frequency content and spatial location. Frequency-following responses to the speech sounds were significantly modulated in both conditions. The modulation was specific to the task-relevant frequency band. The effect was stronger when both frequency and spatial information were available. Patterns of response were variable between participants, and were correlated with psychophysical discriminability of the stimuli, suggesting that the modulation was biologically relevant. Our results demonstrate that auditory brainstem responses are susceptible to efferent modulation related to behavioral goals. Furthermore they suggest that mechanisms of selective attention actively shape activity at early subcortical processing stages according to task relevance and based on frequency and spatial cues.

Cortical inhibitory circuits play important roles in shaping sensory processing. In auditory cortex, however, functional properties of genetically identified inhibitory neurons are poorly characterized. By two-photon imaging-guided recordings, we specifically targeted 2 major types of cortical inhibitory neuron, parvalbumin (PV) and somatostatin (SOM) expressing neurons, in superficial layers of mouse auditory cortex. We found that PV cells exhibited broader tonal receptive fields with lower intensity thresholds and stronger tone-evoked spike responses compared with SOM neurons. The latter exhibited similar frequency selectivity as excitatory neurons. The broader/weaker frequency tuning of PV neurons was attributed to a broader range of synaptic inputs and stronger subthreshold responses elicited, which resulted in a higher efficiency in the conversion of input to output. In addition, onsets of both the input and spike responses of SOM neurons were significantly delayed compared with PV and excitatory cells. Our results suggest that PV and SOM neurons engage in auditory cortical circuits in different manners: while PV neurons may provide broadly tuned feedforward inhibition for a rapid control of ascending inputs to excitatory neurons, the delayed and more selective inhibition from SOM neurons may provide a specific modulation of feedback inputs on their distal dendrites.

The function of ultrasonic vocalizations (USVs) produced by mice (Mus musculus) is a topic of broad interest to many researchers. These USVs differ widely in spectrotemporal characteristics, suggesting different categories of vocalizations, although this has never been behaviorally demonstrated. Although electrophysiological studies indicate that neurons can discriminate among vocalizations at the level of the auditory midbrain, perceptual acuity for vocalizations has yet to be determined. Here, we trained CBA/CaJ mice using operant conditioning to discriminate between different vocalizations and between a spectrotemporally modified vocalization and its original version. Mice were able to discriminate between vocalization types and between manipulated vocalizations, with performance negatively correlating with spectrotemporal similarity. That is, discrimination performance was higher for dissimilar vocalizations and much lower for similar vocalizations. The behavioral data match previous neurophysiological results in the inferior colliculus (IC), using the same stimuli. These findings suggest that the different vocalizations could carry different meanings for the mice. Furthermore, the finding that behavioral discrimination matched neural discrimination in the IC suggests that the IC plays an important role in the perceptual discrimination of vocalizations.

Temporal differences between the two ears are critical for spatial hearing. They can be described along axes of interaural time difference (ITD) and interaural correlation, and their processing starts in the brainstem with the convergence of monaural pathways which are tuned in frequency and which carry temporal information. In previous studies, we examined the bandwidth (BW) of frequency tuning at two stages: the auditory nerve (AN) and inferior colliculus (IC), and showed that BW depends on characteristic frequency (CF) but that there is no difference in the mean BW of these two structures when measured in a binaural, temporal framework. This suggested that there is little frequency convergence in the ITD pathway between AN and IC and that frequency selectivity determined by the cochlear filter is preserved up to the IC. Unexpectedly, we found that AN and IC neurons can be similar in CF and BW, yet responses to changes in interaural correlation in the IC were different than expected from coincidence patterns ("pseudo-binaural" responses) in the AN. To better understand this, we here examine the responses of bushy cells, which provide monaural inputs to binaural neurons. Using broadband noise, we measured BW and correlation sensitivity in the cat trapezoid body (TB), which contains the axons of bushy cells. This allowed us to compare these two metrics at three stages in the ITD pathway. We found that BWs in the TB are similar to those in the AN and IC. However, TB neurons were found to be more sensitive to changes in stimulus correlation than AN or IC neurons. This is consistent with findings that show that TB fibers are more temporally precise than AN fibers, but is surprising because it suggests that the temporal information available monaurally is not fully exploited binaurally.

The auxiliary subunit α 2 δ3 modulates the expression and function of voltage-gated calcium channels. Here we show that α 2 δ3 mRNA is expressed in spiral ganglion neurons and auditory brainstem nuclei and that the protein is required for normal acoustic responses. Genetic deletion of α 2 δ3 led to impaired auditory processing, with reduced acoustic startle and distorted auditory brainstem responses. α 2 δ3 −/− mice learned to discriminate pure tones, but they failed to discriminate temporally structured amplitude-modulated tones. Light and electron microscopy analyses revealed reduced levels of presynaptic Ca 2+ channels and smaller auditory nerve fiber terminals contacting cochlear nucleus bushy cells. Juxtacellular in vivo recordings of sound-evoked activity in α 2 δ3 −/− mice demonstrated impaired transmission at these synapses. Together, our results identify a novel role for the α 2 δ3 auxiliary subunit in the structure and function of specific synapses in the mammalian auditory pathway and in auditory processing disorders.