Publications using TDT

During conversation, people take turns speaking by rapidly responding to their partners while simultaneously avoiding interruption1,2. Such interactions display a remarkable degree of coordination, as gaps between turns are typically about 200 milliseconds3-approximately the duration of an eyeblink4. These latencies are considerably shorter than those observed in simple word-production tasks, which indicates that speakers often plan their responses while listening to their partners2. Although a distributed network of brain regions has been implicated in speech planning5-9, the neural dynamics underlying the specific preparatory processes that enable rapid turn-taking are poorly understood. Here we use intracranial electrocorticography to precisely measure neural activity as participants perform interactive tasks, and we observe a functionally and anatomically distinct class of planning-related cortical dynamics. We localize these responses to a frontotemporal circuit centred on the language-critical caudal inferior frontal cortex10 (Broca's region) and the caudal middle frontal gyrus-a region not normally implicated in speech planning11-13. Using a series of motor tasks, we then show that this planning network is more active when preparing speech as opposed to non-linguistic actions. Finally, we delineate planning-related circuitry during natural conversation that is nearly identical to the network mapped with our interactive tasks, and we find this circuit to be most active before participant speech during unconstrained turn-taking. Therefore, we have identified a speech planning network that is central to natural language generation during social interaction.

Objectives: Listening effort is needed to understand speech that is degraded by hearing loss, a noisy environment, or both. This in turn reduces cognitive spare capacity, the amount of cognitive resources available for allocation to concurrent tasks. Predictive sentence context enables older listeners to perceive speech more accurately, but how does contextual information affect older adults’ listening effort? The current study examines the impacts of sentence context and cognitive (memory) load on sequential dual-task behavioral performance in older adults. To assess whether effects of context and memory load differ as a function of older listeners’ hearing status, baseline working memory capacity, or both, effects were compared across separate groups of participants with and without hearing loss and with high and low working memory capacity. Design: Participants were older adults (age 60–84 years; n = 63) who passed a screen for cognitive impairment. A median split classified participants into groups with high and low working memory capacity. On each trial, participants listened to spoken sentences in noise and reported sentence-final words that were either predictable or unpredictable based on sentence context, and also recalled short (low-load) or long (high-load) sequences of digits that were presented visually before each spoken sentence. Speech intelligibility was quantified as word identification accuracy, and measures of listening effort included digit recall accuracy, and response time to words and digits. Correlations of context benefit in each dependent measure with working memory and vocabulary were also examined. Results: Across all participant groups, accuracy and response time for both word identification and digit recall were facilitated by predictive context, indicating that in addition to an improvement in intelligibility, listening effort was also reduced when sentence-final words were predictable. Effects of predictability on all listening effort measures were observed whether or not trials with an incorrect word identification response were excluded, indicating that the effects of predictability on listening effort did not depend on speech intelligibility. In addition, although cognitive load did not affect word identification accuracy, response time for word identification and digit recall, as well as accuracy for digit recall, were impaired under the high-load condition, indicating that cognitive load reduced the amount of cognitive resources available for speech processing. Context benefit in speech intelligibility was positively correlated with vocabulary. However, context benefit was not related to working memory capacity. Conclusions: Predictive sentence context reduces listening effort in cognitively healthy older adults resulting in greater cognitive spare capacity available for other mental tasks, irrespective of the presence or absence of hearing loss and baseline working memory capacity.

Listeners with sensorineural hearing loss (SNHL) struggle to understand speech, especially in noise, despite audibility compensation. These real-world suprathreshold deficits are hypothesized to arise from degraded frequency tuning and reduced temporal-coding precision; however, peripheral neurophysiological studies testing these hypotheses have been largely limited to in-quiet artificial vowels. Here, we measured single auditory-nerve-fiber responses to a connected speech sentence in noise from anesthetized male chinchillas with normal hearing (NH) or noise-induced hearing loss (NIHL). Our results demonstrated that temporal precision was not degraded following acoustic trauma, and furthermore that sharpness of cochlear frequency tuning was not the major factor affecting impaired peripheral coding of connected speech in noise. Rather, the loss of cochlear tonotopy, a hallmark of NH, contributed the most to both consonant-coding and vowel-coding degradations. Because distorted tonotopy varies in degree across etiologies (e.g., noise exposure, age), these results have important implications for understanding and treating individual differences in speech perception for people suffering from SNHL. SIGNIFICANCE STATEMENT Difficulty understanding speech in noise is the primary complaint in audiology clinics and can leave people with sensorineural hearing loss (SNHL) suffering from communication difficulties that affect their professional, social, and family lives, as well as their mental health. We measured single-neuron responses from a preclinical SNHL animal model to characterize salient neural-coding deficits for naturally spoken speech in noise. We found the major mechanism affecting neural coding was not a commonly assumed factor, but rather a disruption of tonotopicity, the systematic mapping of acoustic frequency to cochlear place that is a hallmark of normal hearing. Because the degree of distorted tonotopy varies across hearing-loss etiologies, these results have important implications for precision audiology approaches to diagnosis and treatment of SNHL.

Goal-directed behavior requires identifying objects in the environment that can satisfy internal needs and executing actions to obtain those objects. The current study examines ventral and dorsal corticostriatal circuits that support complementary aspects of goal-directed behavior. We analyze activity from the amygdala, ventral striatum, orbitofrontal cortex, and lateral prefrontal cortex (LPFC) while monkeys perform a three-armed bandit task. Information about chosen stimuli and their value is primarily encoded in the amygdala, ventral striatum, and orbitofrontal cortex, while the spatial information is primarily encoded in the LPFC. Before the options are presented, information about the to-be-chosen stimulus is represented in the amygdala, ventral striatum, and orbitofrontal cortex; at the time of choice, the information is passed to the LPFC to direct a saccade. Thus, learned value information specifying behavioral goals is maintained throughout the ventral corticostriatal circuit, and it is routed through the dorsal circuit at the time actions are selected.

Dopamine degeneration in Parkinson's disease (PD) dysregulates the striatal neural network and causes motor deficits. However, it is unclear how altered striatal circuits relate to dopamine-acetylcholine chemical imbalance and abnormal local field potential (LFP) oscillations observed in PD. We perform a multimodal analysis of the dorsal striatum using cell-type-specific calcium imaging and LFP recording. We reveal that dopamine depletion selectively enhances LFP beta oscillations during impaired locomotion, supporting beta oscillations as a biomarker for PD. We further demonstrate that dynamic cholinergic interneuron activity during locomotion remains unaltered, even though cholinergic tone is implicated in PD. Instead, dysfunctional striatal output arises from elevated coordination within striatal output neurons, which is accompanied by reduced locomotor encoding of parvalbumin interneurons and transient pathological LFP high-gamma oscillations. These results identify a pathological striatal circuit state following dopamine depletion where distinct striatal neuron subtypes are selectively coordinated with LFP oscillations during locomotion.

The cochlear efferent system provides a negative feedback to control hair cell activity and hearing sensitivity and plays a critical role in noise protection. We reveal a new efferent control pathway in which medial olivocochlear efferent fibers have innervations with cochlear supporting cells to control their gap junctions, therefore regulating outer hair cell electromotility and hearing sensitivity. This supporting cell gap junction-mediated efferent control pathway is required for the protection of hearing from noise.

We report on the ensemble organization of interneuronal activity in the spinal cord during locomotor movements and show that lumbar intermediate zone interneurons organize in two groups related to the two major phases of walking: stance and swing. Ensemble organization is also shown to better correlate with muscular output than single-cell activity, although ensemble membership does not appear to be somatotopically organized within the spinal cord.

Myosin VI（MYO6） is an unconventional myosin that is vital for auditory and vestibular function. Pathogenic variants in the human MYO6 gene cause autosomal-dominant or -recessive forms of hearing loss. Effective treatments for Myo6 mutation causing hearing loss are limited. We studied whether adeno-associated virus (AAV)-PHP.eB vector-mediated in vivo delivery of Staphylococcus aureus Cas9 (SaCas9-KKH)-single-guide RNA (sgRNA) complexes could ameliorate hearing loss in a Myo6WT/C442Y mouse model that recapitulated the phenotypes of human patients. The in vivo editing efficiency of the AAV-SaCas9-KKH-Myo6-g2 system on Myo6C442Y is 4.05% on average in Myo6WT/C442Y mice, which was ∼17-fold greater than editing efficiency of Myo6WT alleles. Rescue of auditory function was observed up to 5 months post AAV-SaCas9-KKH-Myo6-g2 injection in Myo6WT/C442Y mice. Meanwhile, shorter latencies of auditory brainstem response (ABR) wave I, lower distortion product otoacoustic emission (DPOAE) thresholds, increased cell survival rates, more regular hair bundle morphology, and recovery of inward calcium levels were also observed in the AAV-SaCas9-KKH-Myo6-g2-treated ears compared to untreated ears. These findings provide further reference for in vivo genome editing as a therapeutic treatment for various semi-dominant forms of hearing loss and other semi-dominant diseases.

Listening to speech in noisy environments is challenging and effortful. Factors like the signal-to-noise ratio (SNR), the spatial separation between target speech and noise interferer(s), and possibly also the listener's age might influence perceived listening effort (LE). This study measured and modeled the effect of the spatial separation of target speech and interfering stationary speech-shaped noise on the perceived LE and its relation to the age of the listeners. Reference ranges for the relationship between subjectively perceived LE and SNR for different noise azimuths were established. For this purpose, 70 listeners with normal hearing and from three age groups rated the perceived LE using the Adaptive Categorical Listening Effort Scaling method (ACALES, Krueger et al., 2017a) with speech from the front and noise from 0°, 90°, 135°, or 180° azimuth. Based on these data, the spatial release from listening effort (SRLE) was calculated. The noise azimuth had a strong effect on SRLE, with the highest release for 135°. The binaural speech intelligibility model (BSIM2020, Hauth et al., 2020) predicted SRLE very well at negative SNRs, but overestimated for positive SNRs. No significant effect of age was found on the respective subjective ratings. Therefore, the reference ranges were determined independently of age. These reference ranges can be used for the classification of LE measurements. However, when the increase of the perceived LE with SNR was analyzed, a significant age difference was found between the listeners of the youngest and oldest group when considering the upper range of the LE function.

Alpha synuclein (α-Syn) is a small synaptic protein expressed within the central nervous system (CNS). α-Syn has been implicated in the pathogenesis of Parkinson’s disease (PD), and current theory suggests that α-Syn over-expression may lead to some of the CNS changes seen in PD, but the precise function of α-Syn remains elusive. α-Syn has also been identified in the auditory system and it is predominantly localized to the efferent auditory synapses below outer hair cells. In these studies, we studied a transgenic mouse model over-expressing α-Syn to investigate whether over-expression of α-Syn leads to pathologic changes within the cochlea. In the cochleae of wild-type (WT) mice, immunofluorescence using an anti-α-Syn antibody revealed strong labeling only in the base of outer hair cells. In contrast, in mice over-expressing α-Syn, there was robust staining in cells throughout the organ of Corti. Auditory brainstem responses (ABR) showed significant threshold elevations and a significant decrease of the ABR wave I amplitude in the transgenic mice as compared to WT mice. No significant differences were seen between WT and transgenic mice in hair cell counts, morphology or distortion product otoacoustic emissions. Following noise exposure, WT mice demonstrated an ABR threshold shift of 10-20dB whereas transgenic mice showed no significant threshold shift, suggesting a protective effect of α-Syn over-expression against noise-induced hearing loss. Together, these studies demonstrate that α-Syn over-expression causes a mild hearing loss and a protective effect against noise damage with no apparent damage to the cochlear hair cells. These findings suggest that the hearing loss seen with α-Syn over-expression occurs more centrally, while the mechanism of noise protection with over-expression remains unknown.

The human hand is unique in the animal kingdom for unparalleled dexterity, ranging from complex prehension to fine finger individuation. How does the brain represent such a diverse repertoire of movements? We evaluated mesoscale neural dynamics across the human "grasp network," using electrocorticography and dimensionality reduction methods, for a repertoire of hand movements. Strikingly, we found that the grasp network represented both finger and grasping movements alike. Specifically, the manifold characterizing the multi-areal neural covariance structure was preserved during all movements across this distributed network. In contrast, latent neural dynamics within this manifold were surprisingly specific to movement type. Aligning latent activity to kinematics further uncovered distinct submanifolds despite similarities in synergistic coupling of joints between movements. We thus find that despite preserved neural covariance at the distributed network level, mesoscale dynamics are compartmentalized into movement-specific submanifolds; this mesoscale organization may allow flexible switching between a repertoire of hand movements.

Thermoregulatory behavior is a basic motivated behavior for body temperature homeostasis. Despite its fundamental importance, a forebrain region or defined neural population required for this process has yet to be established. Here, we show that Vgat-expressing neurons in the lateral hypothalamus (LHVgat neurons) are required for diverse thermoregulatory behaviors. The population activity of LHVgat neurons is increased during thermoregulatory behavior and bidirectionally encodes thermal punishment and reward (P&R). Although this population also regulates feeding and caloric reward, inhibition of parabrachial inputs selectively impaired thermoregulatory behaviors and encoding of thermal stimulus by LHVgat neurons. Furthermore, two-photon calcium imaging revealed a subpopulation of LHVgat neurons bidirectionally encoding thermal P&R, which is engaged during thermoregulatory behavior, but is largely distinct from caloric reward-encoding LHVgat neurons. Our data establish LHVgat neurons as a required neural substrate for behavioral thermoregulation and point to the key role of the thermal P&R-encoding LHVgat subpopulation in thermoregulatory behavior.

Hair cell death induced by excessive reactive oxygen species (ROS) has been identified as the major pathogenesis of noise‐induced hearing loss (NIHL). Recent studies have demonstrated that cisplatin‐ and neomycin‐induced ototoxicity can be alleviated by ferroptosis inhibitors. However, whether ferroptosis inhibitors have a protective effect against NIHL remains unknown. We investigated the protective effect of the ferroptosis inhibitor ferrostatin‐1 (Fer‐1) on NIHL in vivo in CBA/J mice and investigated the protective effect of Fer‐1 on tert‐butyl hydroperoxide (TBHP)‐induced hair cell damage in vitro in cochlear explants and HEI‐OC1 cells. We observed ROS overload and lipid peroxidation, which led to outer hair cell (OHC) apoptosis and ferroptosis, in the mouse cochlea after noise exposure. The expression level of apoptosis‐inducing factor mitochondria‐associated 2 (AIFM2) was substantially increased following elevation of the expression of its upstream protein P53 after noise exposure. The ferroptosis inhibitor Fer‐1was demonstrated to enter the inner ear after the systemic administration. Administration of Fer‐1 significantly alleviated noise‐induced auditory threshold elevation and reduced the loss of OHCs, inner hair cell (IHC) ribbon synapses, and auditory nerve fibers (ANFs) caused by noise. Mechanistically, Fer‐1 significantly reduced noise‐ and TBHP‐induced lipid peroxidation and iron accumulation in hair cells, alleviating ferroptosis in cochlear cells consequently. Furthermore, Fer‐1 treatment decreased the levels of TfR1, P53, and AIFM2. These results suggest that Fer‐1 exerted its protective effects by scavenging of ROS and inhibition of TfR1‐mediated ferroptosis and P53‐AIFM2 signaling pathway‐mediated apoptosis. Our findings suggest that Fer‐1 is a promising drug for treating NIHL because of its ability to inhibit noise‐induced hair cell apoptosis and ferroptosis, opening new avenues for the treatment of NIHL.

The inflammasome is a multiprotein oligomer in the cell cytoplasm and is part of the innate immune system. It plays a crucial role in the pathological process of noise-induced hearing loss (NIHL). However, the mechanisms of NLR family pyrin domain containing 3 (NLRP3) inflammasome activation in NIHL have not been clearly demonstrated. In this study, miniature pigs were exposed to white noise at 120 dB(A) and auditory brainstem response measurements were used to measure their hearing function. Immunofluorescence staining, confocal laser scanning microscopy, western blot assay, and quantitative reverse transcription-polymerase chain reaction were used to analyze inflammasome-related protein distribution and expression. NLRP3, interleukin-1β, interleukin-18, and cleaved-caspase-1 were highly expressed in the cochlea after 120 dB(A) white noise exposure. Our findings suggest that NLRP3-inflammasomes in the cochlea may be activated after acoustic trauma, which may be an important mechanism of noise-induced hearing loss.

Novelty detection is a primitive subcomponent of cognitive control that can be deficient in Parkinson's disease (PD) patients. Here, we studied the corticostriatal mechanisms underlying novelty-response deficits. In participants with PD, we recorded from cortical circuits with scalp-based electroencephalography (EEG) and from subcortical circuits using intraoperative neurophysiology during surgeries for implantation of deep brain stimulation (DBS) electrodes. We report three major results. First, novel auditory stimuli triggered midfrontal low-frequency rhythms; of these, 1-4 Hz "delta" rhythms were linked to novelty-associated slowing, whereas 4-7 Hz "theta" rhythms were specifically attenuated in PD. Second, 32% of subthalamic nucleus (STN) neurons were response-modulated; nearly all (94%) of these were also modulated by novel stimuli. Third, response-modulated STN neurons were coherent with midfrontal 1-4 Hz activity. These findings link scalp-based measurements of neural activity with neuronal activity in the STN. Our results provide insight into midfrontal cognitive control mechanisms and how purported hyperdirect frontobasal ganglia circuits evaluate new information.

Recent studies have established significant anatomical and functional connections between visual areas and primary auditory cortex (A1), which may be important for cognitive processes such as communication and spatial perception. These studies have raised two important questions: First, which cell populations in A1 respond to visual input and/or are influenced by visual context? Second, which aspects of sound encoding are affected by visual context? To address these questions, we recorded single-unit activity across cortical layers in awake mice during exposure to auditory and visual stimuli. Neurons responsive to visual stimuli were most prevalent in the deep cortical layers and included both excitatory and inhibitory cells. The overwhelming majority of these neurons also responded to sound, indicating unimodal visual neurons are rare in A1. Other neurons for which sound-evoked responses were modulated by visual context were similarly excitatory or inhibitory but more evenly distributed across cortical layers. These modulatory influences almost exclusively affected sustained sound-evoked firing rate (FR) responses or spectrotemporal receptive fields (STRFs); transient FR changes at stimulus onset were rarely modified by visual context. Neuron populations with visually modulated STRFs and sustained FR responses were mostly non-overlapping, suggesting spectrotemporal feature selectivity and overall excitability may be differentially sensitive to visual context. The effects of visual modulation were heterogeneous, increasing and decreasing STRF gain in roughly equal proportions of neurons. Our results indicate visual influences are surprisingly common and diversely expressed throughout layers and cell types in A1, affecting nearly one in five neurons overall.

Noise‐induced hearing loss (NIHL) has always been an important occupational hazard, but the exact etiopathogenesis underlying NIHL remains unclear. Herein, we aimed to find metabolic biomarkers involved in the development of NIHL based on a mouse model using a gas chromatography coupled with mass spectrometry (GC‐MS) metabolomics technique. We showed that the auditory brainstem response (ABR) thresholds at the frequencies of 4, 8, 12, 16, 24, and 32 kHz were all significantly elevated in the noise‐exposed mice. Noise could cause outer hair cell (OHC) loss in the base of the cochlea. A total of 17 differential metabolites and 9 metabolic pathways were significantly affected following noise exposure. Spermidine acting as an autophagy modulator was found to be 2.85‐fold higher in the noise‐exposed group than in the control group and involved in β ‐alanine metabolism and arginine and proline metabolism pathways. Additionally, we demonstrated that LC3B and Beclin1 were expressed in the spiral ganglion neurons (SGNs), and their mRNA levels were increased after noise. We showed that SOD activity was significantly decreased in the cochlea of noise‐exposed mice. Further experiments suggested that SOD1 and SOD2 proteins in the SGNs were all decreased following noise exposure. The upregulation of spermidine may induce LC3B‐ and Beclin1‐mediated autophagy in the cochlear hair cells (HCs) through β ‐alanine metabolism and arginine and proline metabolism and be involved in the NIHL. ROS‐mediated oxidative damage may be a pivotal molecular mechanism of NIHL. Taken together, spermidine can be regarded as an important metabolic marker for the diagnosis of NIHL.

Outer hair cell (OHC) degeneration is a major cause of progressive hearing loss and presbycusis. Despite the high prevalence of these disorders, targeted therapy is currently not available. Methods: We generated a mouse model harboring Kcnq4W276S/+ to recapitulate DFNA2, a common genetic form of progressive hearing loss accompanied by OHC degeneration. After comprehensive optimization of guide RNAs, Cas9s, vehicles, and delivery routes, we applied in vivo gene editing strategy to disrupt the dominant-negative allele in Kcnq4 and prevent progressive hearing loss. Results:In vivo gene editing using a dual adeno-associated virus package targeting OHCs significantly improved auditory thresholds in auditory brainstem response and distortion-product otoacoustic emission. In addition, we developed a new live-cell imaging technique using thallium ions to investigate the membrane potential of OHCs and successfully demonstrated that mutant allele disruption resulted in more hyperpolarized OHCs, indicating elevated KCNQ4 channel activity. Conclusion: These findings can facilitate the development of targeted therapies for DFNA2 and support the use of CRISPR-based gene therapy to rectify defects in OHCs.

Speech recognition in rooms requires the temporal integration of reflections which arrive with a certain delay after the direct sound. It is commonly assumed that there is a certain temporal window of about 50–100 ms, during which reflections can be integrated with the direct sound, while later reflections are detrimental to speech intelligibility. This concept was challenged in a recent study by employing binaural room impulse responses (RIRs) with systematically varied interaural phase differences (IPDs) and amplitude of the direct sound and a variable number of reflections delayed by up to 200 ms. When amplitude or IPD favored late RIR components, normal-hearing (NH) listeners appeared to be capable of focusing on these components rather than on the precedent direct sound, which contrasted with the common concept of considering early RIR components as useful and late components as detrimental. The present study investigated speech intelligibility in the same conditions in hearing-impaired (HI) listeners. The data indicate that HI listeners were generally less able to “ignore” the direct sound than NH listeners, when the most useful information was confined to late RIR components. Some HI listeners showed a remarkable inability to integrate across multiple reflections and to optimally “shift” their temporal integration window, which was quite dissimilar to NH listeners. This effect was most pronounced in conditions requiring spatial and temporal integration and could provide new challenges for individual prediction models of binaural speech intelligibility.

Dysregulated homeostasis of neural activity has been hypothesized to drive Alzheimer's disease (AD) pathogenesis. AD begins with a decades-long presymptomatic phase, but whether homeostatic mechanisms already begin failing during this silent phase is unknown. We show that before the onset of memory decline and sleep disturbances, familial AD (fAD) model mice display no deficits in CA1 mean firing rate (MFR) during active wakefulness. However, homeostatic down-regulation of CA1 MFR is disrupted during non-rapid eye movement (NREM) sleep and general anesthesia in fAD mouse models. The resultant hyperexcitability is attenuated by the mitochondrial dihydroorotate dehydrogenase (DHODH) enzyme inhibitor, which tunes MFR toward lower set-point values. Ex vivo fAD mutations impair downward MFR homeostasis, resulting in pathological MFR set points in response to anesthetic drug and inhibition blockade. Thus, firing rate dyshomeostasis of hippocampal circuits is masked during active wakefulness but surfaces during low-arousal brain states, representing an early failure of the silent disease stage.