Publications using TDT

Background Plasticity from auditory experience shapes the brain’s encoding and perception of sound. Though prior research demonstrates that neural entrainment (i.e., brain-to-acoustic synchronization) aids speech perception, how long- and short-term plasticity influence entrainment to concurrent speech has not been investigated. Here, we explored neural entrainment mechanisms and the interplay between short- and long-term neuroplasticity for rapid auditory perceptual learning of concurrent speech sounds in young, normal-hearing musicians and nonmusicians. Method Participants learned to identify double-vowel mixtures during ∼45 min training sessions with concurrent high-density EEG recordings. We examined the degree to which brain responses entrained to the speech-stimulus train (∼9 Hz) to investigate whether entrainment to speech prior to behavioral decision predicted task performance. Source and directed functional connectivity analyses of the EEG probed whether behavior was driven by group differences auditory-motor coupling. Results Both musicians and nonmusicians showed rapid perceptual learning in accuracy with training. Interestingly, listeners’ neural entrainment strength prior to target speech mixtures predicted behavioral identification performance; stronger neural synchronization was observed preceding incorrect compared to correct trial responses. We also found stark hemispheric biases in auditory-motor coupling during speech entrainment, with greater auditory-motor connectivity in the right compared to left hemisphere for musicians (R>L) but not in nonmusicians (R=L). Conclusions Our findings confirm stronger neuroacoustic synchronization and auditory-motor coupling during speech processing in musicians. Stronger neural entrainment to rapid stimulus trains preceding incorrect behavioral responses supports the notion that alpha-band (∼10 Hz) arousal/suppression in brain activity is an important modulator of trial-by-trial success in perceptual processing.

The Inferior Colliculus (IC) has traditionally been regarded as an important relay in the auditory pathway, primarily involved in relaying auditory information from the brainstem to the thalamus. However, this study uncovers the multifaceted role of the IC in bridging auditory processing, sensory prediction, and reward prediction. Through extracellular recordings in monkeys engaged in a sound duration-based deviation detection task, we observed a “climbing effect” in neuronal firing rates, indicative of an enhanced response over sound sequences linked to sensory prediction rather than reward anticipation. Moreover, our findings demonstrate reward prediction errors within the IC, highlighting its complex integration in auditory and reward processing. Further analysis revealed a direct correlation between IC neuronal activity and behavioral choices, suggesting its involvement in decision-making processes. This research highlights a more complex role for the IC than traditionally understood, showcasing its integral role in cognitive and sensory processing and emphasizing its importance in integrated brain functions.

GABAergic interneurons, including somatostatin (SST) and vasoactive intestinal peptide (VIP) positive cells, play a crucial role in cortical circuit processing. Cre recombinase-mediated manipulation of these interneurons is facilitated by commercially available knock-in mouse strains such as Sst-IRES-Cre (Sst-Cre) and Vip-IRES-Cre (Vip-Cre). However, these strains are troublesome for hearing research because they are only available on the C57BL/6 genetic background, which suffer from early onset age-related hearing loss (AHL) due to a mutation of the Cdh23 gene. To overcome this limitation, we backcrossed Sst-Cre and Vip-Cre mice to CBA mice to create normal-hearing offspring with the desired Cre transgenes. We confirmed that in these “CBA Cre” lines, Cre drives appropriate expression of Cre-dependent genes, by crossing CBA Cre mice to Ai14 reporter mice. To assess the hearing capabilities of the CBA Cre mice, we measured auditory brainstem responses (ABRs) using clicks and tones. CBA Cre mice showed significantly lower ABR thresholds compared to C57 control mice at 3, 6, 9, and 12 months. In conclusion, our study successfully generated Sst-Cre and Vip-Cre mouse lines on the CBA background that will be valuable tools for investigating the roles of SST and VIP positive interneurons without the confounding effects of age-related hearing loss.

Background Spinal cord stimulation (SCS) has demonstrated multiple benefits in treating chronic pain and other clinical disorders related to sensorimotor dysfunctions. However, the underlying mechanisms are still not fully understood, including how electrode placement in relation to the spinal cord neuroanatomy influences epidural spinal recordings (ESRs). To characterize this relationship, this study utilized stimulation applied at various anatomical sections of the spinal column, including at levels of the intervertebral disc and regions correlating to the dorsal root entry zone. Method Two electrode arrays were surgically implanted into the dorsal epidural space of the swine. The stimulation leads were positioned such that the caudal-most electrode contact was at the level of a thoracic intervertebral segment. Intraoperative cone beam computed tomography (CBCT) images were utilized to precisely determine the location of the epidural leads relative to the spinal column. High-resolution microCT imaging and 3D-model reconstructions of the explanted spinal cord illustrated precise positioning and dimensions of the epidural leads in relation to the surrounding neuroanatomy, including the spinal rootlets of the dorsal and ventral columns of the spinal cord. In a separate swine cohort, implanted epidural leads were used for SCS and recording evoked ESRs. Results Reconstructed 3D-models of the swine spinal cord with epidural lead implants demonstrated considerable distinctions in the dimensions of a single electrode contact on a standard industry epidural stimulation lead compared to dorsal rootlets at the dorsal root entry zone (DREZ). At the intervertebral segment, it was observed that a single electrode contact may cover 20-25% of the DREZ if positioned laterally. Electrode contacts were estimated to be ~0.75 mm from the margins of the DREZ when placed at the midline. Furthermore, ventral rootlets were observed to travel in proximity and parallel to dorsal rootlets at this level prior to separation into their respective sides of the spinal cord. Cathodic stimulation at the level of the intervertebral disc, compared to an ‘off-disc’ stimulation (7 mm rostral), demonstrated considerable variations in the features of recorded ESRs, such as amplitude and shape, and evoked unintended motor activation at lower stimulation thresholds. This substantial change may be due to the influence of nearby ventral roots. To further illustrate the influence of rootlet activation vs. dorsal column activation, the stimulation lead was displaced laterally at ~2.88 mm from the midline, resulting in variances in both evoked compound action potential (ECAP) components and electromyography (EMG) components in ESRs at lower stimulation thresholds. Conclusion The results of this study suggest that the ECAP and EMG components of recorded ESRs can vary depending on small differences in the location of the stimulating electrodes within the spinal anatomy, such as at the level of the intervertebral segment. Furthermore, the effects of sub-centimeter lateral displacement of the stimulation lead from the midline, leading to significant changes in electrophysiological metrics. The results of this pilot study reveal the importance of the small displacement of the electrodes that can cause significant changes to evoked responses SCS. These results may provide further valuable insights into the underlying mechanisms and assist in optimizing future SCS-related applications.

Neuronal responses during behavior are diverse, ranging from highly reliable ‘classical’ responses to irregular ‘non-classically responsive’ firing. While a continuum of response properties is observed across neural systems, little is known about the synaptic origins and contributions of diverse responses to network function, perception, and behavior. To capture the heterogeneous responses measured from auditory cortex of rodents performing a frequency recognition task, we use a novel task-performing spiking recurrent neural network incorporating spike-timing-dependent plasticity. Reliable and irregular units contribute differentially to task performance via output and recurrent connections, respectively. Excitatory plasticity shifts the response distribution while inhibition constrains its diversity. Together both improve task performance with full network engagement. The same local patterns of synaptic inputs predict spiking response properties of network units and auditory cortical neurons from in vivo whole-cell recordings during behavior. Thus, diverse neural responses contribute to network function and emerge from synaptic plasticity rules.

Objective. Measures of functional connectivity (FC) can elucidate which cortical regions work together in order to complete a variety of behavioral tasks. This study’s primary objective was to expand a previously published model of measuring FC to include multiple subjects and several regions of interest. While FC has been more extensively investigated in vision and other sensorimotor tasks, it is not as well understood in audition. The secondary objective of this study was to investigate how auditory regions are functionally connected to other cortical regions when attention is directed to different distinct auditory stimuli. Approach. This study implements a linear dynamic system (LDS) to measure the structured time-lagged dependence across several cortical regions in order to estimate their FC during a dual-stream auditory attention task. Results. The model’s output shows consistent functionally connected regions across different listening conditions, indicative of an auditory attention network that engages regardless of endogenous switching of attention or different auditory cues being attended. Significance. The LDS implemented in this study implements a multivariate autoregression to infer FC across cortical regions during an auditory attention task. This study shows how a first-order autoregressive function can reliably measure functional connectivity from M/EEG data. Additionally, the study shows how auditory regions engage with the supramodal attention network outlined in the visual attention literature.

Existing studies have indicated that noise induces apoptosis and necroptosis in cochlear outer hair cells (OHCs). However, the role of the extrinsic cell death pathway, initiated by death ligands in the cochlea, remains unknown. In this study, we hypothesized that noise could induce the NFAT3/FasL axis-mediated extrinsic death pathway in the cochlea. We found that NFAT3/FasL signaling was silent in normal OHCs. Noise exposure induced apoptosis and necroptosis in OHCs with specifically high FasL expression. Multiplex immunofluorescence staining revealed that NFAT3 nuclear translocation and FasL upregulation were colocalized in the apoptotic and necroptotic OHCs following noise trauma. Administration of FK506 or 11R-vivit (an specific NFAT inhibitor) blocked NFAT3 nuclear translocation, inhibited FasL expression, mitigated apoptosis and necroptosis, and protected against noise-induced hearing loss (NIHL). Finally, FasL knockdown by delivering siRNA intratympanically attenuated apoptosis and necroptosis in OHCs and alleviated NIHL, confirming the role of FasL in OHC death. Collectively, our study demonstrates that the NFAT3/FasL axis mediates noise-induced extrinsic death pathway in OHCs, leading to their apoptosis and necroptosis.

The overall focus of this research program is to investigate the viability and safety of microelectrode arrays (MEAs) and ultramicroelectrode arrays (UMEAs) for microstimulation (µStim) in the brain. We aim to assess their potential to deliver adequate electrical stimulation for neural activation without causing electrode or tissue damage. To this end, here we conducted galvanostatic Electrochemical Impedance Spectroscopy (EIS) to assess the behavior of electrodes of various diameters both pre- and post-stimulation in a rat model. Our first-generation electrode arrays (G1) were designed with electrode diameters spanning 3 orders of magnitude and including subcellular dimensions. Using these devices, we delivered 0.4 nC/phase stimulation in vivo. We conducted in vitro EIS measurements before and after the current pulsing. Our findings show that these electrode arrays, including UMEAs, exhibit stable electrochemical behavior following a 0.4 nC/phase current pulse. To validate the EIS frequency range used for the G1 measurements, we designed a second-generation electrode array (G2) that included a terminating lead and a looping lead. This array provided the ability to assess the accuracy contour plot of our EIS system and electrode array platform. This exploratory research contributes to the ongoing knowledge of UMEAs in µStim applications. These developments may result in high-fidelity, non-damaging multichannel µStim, and improved neuromodulation technology for the treatment of neural diseases and injuries.

Objectives: Electro-acoustic stimulation (EAS) combines electric stimulation via a cochlear implant (CI) with residual low-frequency acoustic hearing, with benefits for music appreciation and speech perception in noise. However, many EAS CI users lose residual acoustic hearing, reducing this benefit. The main objectives of this study were to determine whether chronic EAS leads to more hearing loss compared with CI surgery alone in an aged guinea pig model, and to assess the relationship of any hearing loss to histology measures. Conversely, it is also important to understand factors impacting efficacy of electric stimulation. If one contributor to CI-induced hearing loss is damage to the auditory nerve, both acoustic and electric thresholds will be affected. Excitotoxicity from EAS may also affect electric thresholds, while electric stimulation is osteogenic and may increase electrode impedances. Hence, secondary objectives were to assess how electric thresholds are related to the amount of residual hearing loss after CI surgery, and how EAS affects electric thresholds and impedances over time. Design: Two groups of guinea pigs, aged 9 to 21 months, were implanted with a CI in the left ear. Preoperatively, the animals had a range of hearing losses, as expected for an aged cohort. At 4 weeks after surgery, the EAS group (n = 5) received chronic EAS for 8 hours a day, 5 days a week, for 20 weeks via a tether system that allowed for free movement during stimulation. The nonstimulated group (NS; n = 6) received no EAS over the same timeframe. Auditory brainstem responses (ABRs) and electrically evoked ABRs (EABRs) were recorded at 3 to 4 week intervals to assess changes in acoustic and electric thresholds over time. At 24 weeks after surgery, cochlear tissue was harvested for histological evaluation, only analyzing animals without electrode extrusions (n = 4 per ear). Results: Cochlear implantation led to an immediate worsening of ABR thresholds peaking between 3 and 5 weeks after surgery and then recovering and stabilizing by 5 and 8 weeks. Significantly greater ABR threshold shifts were seen in the implanted ears compared with contralateral, non-implanted control ears after surgery. After EAS and termination, no significant additional ABR threshold shifts were seen in the EAS group compared with the NS group. A surprising finding was that NS animals had significantly greater recovery in EABR thresholds over time, with decreases (improvements) of −51.8 ± 33.0 and −39.0 ± 37.3 c.u. at 12 and 24 weeks, respectively, compared with EAS animals with EABR threshold increases (worsening) of +1.0 ± 25.6 and 12.8 ± 44.3 c.u. at 12 and 24 weeks. Impedance changes over time did not differ significantly between groups. After exclusion of cases with electrode extrusion or significant trauma, no significant correlations were seen between ABR and EABR thresholds, or between ABR thresholds with histology measures of inner/outer hair cell counts, synaptic ribbon counts, stria vascularis capillary diameters, or spiral ganglion cell density. Conclusions: The findings do not indicate that EAS significantly disrupts acoustic hearing, although the small sample size limits this interpretation. No evidence of associations between hair cell, synaptic ribbon, spiral ganglion cell, or stria vascularis with hearing loss after cochlear implantation was seen when surgical trauma is minimized. In cases of major trauma, both acoustic thresholds and electric thresholds were elevated, which may explain why CI-only outcomes are often better when trauma and hearing loss are minimized. Surprisingly, chronic EAS (or electric stimulation alone) may negatively impact electric thresholds, possibly by prevention of recovery of the auditory nerve after CI surgery. More research is needed to confirm the potentially negative impact of chronic EAS on electric threshold recovery.

In autism spectrum disorder (ASD), atypical sensory experiences are often associated with irregularities in predictive coding, which proposes that the brain creates hierarchical sensory models via a bidirectional process of predictions and prediction errors. However, it remains unclear how these irregularities manifest across different functional hierarchies in the brain. To address this, we study a marmoset model of ASD induced by valproic acid (VPA) treatment. We record high-density electrocorticography (ECoG) during an auditory task with two layers of temporal control, and applied a quantitative model to quantify the integrity of predictive coding across two distinct hierarchies. Our results demonstrate a persistent pattern of sensory hypersensitivity and unstable predictions across two brain hierarchies in VPA-treated animals, and reveal the associated spatio-spectro-temporal neural signatures. Despite the regular occurrence of imprecise predictions in VPA-treated animals, we observe diverse configurations of underestimation or overestimation of sensory regularities within the hierarchies. Our results demonstrate the coexistence of the two primary Bayesian accounts of ASD: overly-precise sensory observations and weak prior beliefs, and offer a potential multi-layered biomarker for ASD, which could enhance our understanding of its diverse symptoms.

3D printing has been widely used for on-demand prototyping of complex three-dimensional structures. In biomedical applications, PEDOT:PSS has emerged as a promising material in versatile bioelectronics due to its tissue-like mechanical properties and suitable electrical properties. However, previously developed PEDOT:PSS inks have not been able to fully utilize the advantages of commercial 3D printing due to its long post treatment times, difficulty in high aspect ratio printing, and low conductivity. We propose a one-shot strategy for the fabrication of PEDOT:PSS ink that is able to simultaneously achieve on-demand biocompatibility (no post treatment), structural integrity during 3D printing for tall three-dimensional structures, and high conductivity for rapid-prototyping. By using ionic liquid-facilitated PEDOT:PSS colloidal stacking induced by a centrifugal protocol, a viscoplastic PEDOT:PSS-ionic liquid colloidal (PILC) ink was developed. PILC inks exhibit high-aspect ratio vertical stacking, omnidirectional printability for generating suspended architectures, high conductivity (~286 S/cm), and high-resolution printing (~50 µm). We demonstrate the on-demand and versatile applicability of PILC inks through the fabrication of 3D circuit boards, on-skin physiological signal monitoring e-tattoos, and implantable bioelectronics (opto-electrocorticography recording, low voltage sciatic nerve stimulation and recording from deeper brain layers via 3D vertical spike arrays).

Reactive astrocytes are associated with neuroinflammation and cognitive decline in diverse neuropathologies; however, the underlying mechanisms are unclear. We used optogenetic and chemogenetic tools to identify the crucial roles of the hippocampal CA1 astrocytes in cognitive decline. Our results showed that repeated optogenetic stimulation of the hippocampal CA1 astrocytes induced cognitive impairment in mice and decreased synaptic long-term potentiation (LTP), which was accompanied by the appearance of inflammatory astrocytes. Mechanistic studies conducted using knockout animal models and hippocampal neuronal cultures showed that lipocalin-2 (LCN2), derived from reactive astrocytes, mediated neuroinflammation and induced cognitive impairment by decreasing the LTP through the reduction of neuronal NMDA receptors. Sustained chemogenetic stimulation of hippocampal astrocytes provided similar results. Conversely, these phenomena were attenuated by a metabolic inhibitor of astrocytes. Fiber photometry using GCaMP revealed a high level of hippocampal astrocyte activation in the neuroinflammation model. Our findings suggest that reactive astrocytes in the hippocampus are sufficient and required to induce cognitive decline through LCN2 release and synaptic modulation. This abnormal glial–neuron interaction may contribute to the pathogenesis of cognitive disturbances in neuroinflammation-associated brain conditions.

Losing either type of cochlear sensory hair cells leads to hearing impairment. Inner hair cells act as primary mechanoelectrical transducers, while outer hair cells enhance sound-induced vibrations within the organ of Corti. Established inner ear damage models, such as systemic administration of ototoxic aminoglycosides, yield inconsistent and variable hair cell death in mice. Overcoming this limitation, we developed a method involving surgical delivery of a hyperosmotic sisomicin solution into the posterior semicircular canal of adult mice. This procedure induced rapid and synchronous apoptotic demise of outer hair cells within 14 h, leading to irreversible hearing loss. The combination of sisomicin and hyperosmotic stress caused consistent and synergistic ototoxic damage. Inner hair cells remained until three days post-treatment, after which deterioration in structure and number was observed, culminating in a complete hair cell loss by day seven. This robust animal model provides a valuable tool for otoregenerative research, facilitating single-cell and omics-based studies toward exploring preclinical therapeutic strategies.

The synaptojanin-1 ( SYNJ1 ) gene is known to be important for dopamine-related disorders. Recent evidence has demonstrated that Synj1 deficient mice ( Synj1 +/− ) have impairments in dopaminergic synaptic vesicular recycling. However, less is known about how Synj1 deficits affect the mesolimbic system, reward processing, and motivated behavior. To examine the role of the Synj1 gene in motivated behavior, we subjected male and female Synj1 +/− and Synj1 +/+ mice to a battery of behavioral tests evaluating hedonic responses, effortful responding, and responses to psychomotor stimulants. We observed that Synj1 +/− mice exhibit few differences in reward processing and motivated behavior, with normal hedonic responses and motivated responding for sucrose. However, male but not female Synj1 +/− demonstrated an attenuated conditioned place preference for cocaine that could not be attributed to deficits in spatial memory. To further understand the dopamine signaling underlying the attenuated response to cocaine in these mutant mice, we recorded nucleus accumbens dopamine in response to cocaine and observed that Synj1 +/− male and female mice took longer to reach peak dopamine release following experimenter-administered cocaine. However, female mice also showed slower decay in accumbens dopamine that appear to be linked to differences in cocaine-induced DAT responses. These findings demonstrate that SYNJ1 deficiencies result in abnormal mesolimbic DA signaling which has not previously been demonstrated. Our work also highlights the need to develop targeted therapeutics capable of restoring deficits in DAT function, which may be effective for reversing the pathologies associated with Synj1 mutations.

Visual object memory is a fundamental element of various cognitive abilities, and the underlying neural mechanisms have been extensively examined especially in the anterior temporal cortex of primates. However, both macroscopic large-scale functional network in which this region is embedded and microscopic neuron-level dynamics of top-down regulation it receives for object memory remains elusive. Here, we identified the orbitofrontal node as a critical partner of the anterior temporal node for object memory by combining whole-brain functional imaging during rest and a short-term object memory task in male macaques. Focal chemogenetic silencing of the identified orbitofrontal node downregulated both the local orbitofrontal and remote anterior temporal nodes during the task, in association with deteriorated mnemonic, but not perceptual, performance. Furthermore, imaging-guided neuronal recordings in the same monkeys during the same task causally revealed that orbitofrontal top-down modulation enhanced stimulus-selective mnemonic signal in individual anterior temporal neurons while leaving bottom-up perceptual signal unchanged. Furthermore, similar activity difference was also observed between correct and mnemonic error trials before silencing, suggesting its behavioral relevance. These multifaceted but convergent results provide a multiscale causal understanding of dynamic top-down regulation of the anterior temporal cortex along the ventral fronto-temporal network underpinning short-term object memory in primates.

Although epidural spinal cord and muscle stimulation have each been separately used for restoration of movement after spinal cord injury, their combined use has not been widely explored. Using both approaches in combination could provide more flexible control compared to using either approach alone, but whether responses evoked from such combined stimulation can be easily predicted is unknown. We evaluate whether responses evoked by combined spinal and muscle stimulation can be predicted simply, as the linear summation of responses produced by each type of stimulation individually. Should this be true, it would simplify the prediction of co-stimulation responses and the development of control schemes for spinal cord injury rehabilitation. In healthy anesthetized rats, we measured hindlimb isometric forces in response to spinal and muscle stimulation. Force prediction errors were calculated as the difference between predicted and observed co-stimulation forces. We found that spinal and muscle co-stimulation could be closely predicted as the linear summation of the individual spinal and muscle responses and that the errors were relatively low. We discuss the implications of these results to the use of combined muscle and spinal stimulation for the restoration of movement following spinal cord injury.

Background Implantable vagus nerve stimulation is a promising approach for restoring autonomic cardiovascular functions after heart transplantation. For successful treatment a system should have multiple electrodes to deliver precise stimulation and complex neuromodulation patterns. Methods This paper presents an implantable multi-channel stimulation system for vagal-cardiac neuromodulation studies in swine species. The system comprises an active electrode array implant percutaneously connected to an external wearable controller. The active electrode array implant has an integrated stimulator ASIC mounted on a ceramic substrate connected to an intraneural electrode array via micro-rivet bonding. The implant is silicone encapsulated for biocompatibility and implanted lifetime. The stimulation parameters are remotely transmitted via a Bluetooth telemetry link. Results The size of the encapsulated active electrode array implant is 8 mm × 10 mm × 3 mm. The stimulator ASIC has 10-bit current amplitude resolution and 16 independent output channels, each capable of delivering up to 550 µA stimulus current and a maximum voltage of 20 V. The active electrode array implant was subjected to in vitro accelerated lifetime testing at 70 °C for 7 days with no degradation in performance. After over 2 h continuous stimulation, the surface temperature change of the implant was less than 0.5 °C. In addition, in vivo testing on the sciatic nerve of a male Göttingen minipig demonstrated that the implant could effectively elicit an EMG response that grew progressively stronger on increasing the amplitude of the stimulation. Conclusions The multi-channel stimulator is suitable for long term implantation. It shows potential as a useful tool in vagal-cardiac neuromodulation studies in animal models for restoring autonomic cardiovascular functions after heart transplantation.

Sleep is indispensable for health and wellbeing, but its basic function remains elusive. The locus coeruleus (LC) powerfully promotes arousal by releasing noradrenaline. We found that noradrenaline transmission is reduced by prolonged wakefulness and restored during sleep. Fiber-photometry imaging of noradrenaline using its biosensor showed that its release evoked by optogenetic LC neuron activation was strongly attenuated by three hours of sleep deprivation and restored during subsequent sleep. This is accompanied by the reduction and recovery of the wake-promoting effect of the LC neurons. The reduction of both LC evoked noradrenaline release and wake-inducing potency is activity dependent, and the rate of noradrenaline transmission recovery depends on mammalian target of rapamycin (mTOR) signaling. The decline and recovery of noradrenaline transmission also occur in spontaneous sleep-wake cycles on a timescale of minutes. Together, these results reveal an essential role of sleep in restoring transmission of a key arousal-promoting neuromodulator.

Background Presbycusis, also referred to as age-related hearing loss (ARHL), is a condition that results from the cumulative effects of aging on an individual's auditory capabilities. Given the limited understanding of epigenetic mechanisms in ARHL, our research focuses on alterations in chromatin-accessible regions. Methods We employed assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) in conjunction with unique identifier (UID) mRNA-seq between young and aging cochleae, and conducted integrated analysis as well as motif/TF-gene prediction. Additionally, the essential role of super-enhancers (SEs) in the development of ARHL was identified by comparative analysis to previous research. Meanwhile, an ARHL mouse model and an aging mimic hair cell (HC) model were established with a comprehensive identification of senescence phenotypes to access the role of SEs in ARHL progression. Results The control cochlear tissue exhibited greater chromatin accessibility than cochlear tissue affected by ARHL. Furthermore, the levels of histone 3 lysine 27 acetylation were significantly depressed in both aging cochlea and aging mimic HEI-OC1 cells, highlighting the essential role of SEs in the development of ARHL. The potential senescence-associated super-enhancers (SASEs) of ARHL were identified, most of which exhibited decreased chromatin accessibility. The majority of genes related to the SASEs showed obvious decreases in mRNA expression level in aging HCs and was noticeably altered following treatment with JQ1 (a commonly used SE inhibitor). Conclusion The chromatin accessibility in control cochlear tissue was higher than that in cochlear tissue affected by ARHL. Potential SEs involved in ARHL were identified, which might provide a basis for future therapeutics targeting SASEs related to ARHL.

Little is known about the electrophysiologic activity of the intact human spinal cord during volitional movement. We analyzed epidural spinal recordings from a total of five human subjects of both sexes during a variety of upper extremity movements and found that these spinal epidural electrograms contain spectral information distinguishing periods of movement, rest, and sensation. Cervical epidural electrograms also contained spectral changes time-locked with movement. We found that these changes were primarily associated with increased power in the theta (4–8 Hz) band and feature increased theta phase to gamma amplitude coupling, and this increase in theta power can be used to topographically map distinct upper extremity movements onto the cervical spinal cord in accordance with established myotome maps of the upper extremity. Our findings have implications for the development of neurostimulation protocols and devices focused on motor rehabilitation for the upper extremity, and the approach presented here may facilitate spatiotemporal mapping of naturalistic movements.