Electrophysiology publications

Classic theories propose opponent functions for striatal dopamine (DA) and serotonin (5-hydroxytryptamine; 5HT), with DA promoting approach and 5HT promoting patience or avoidance. How these neuromodulators regulate downstream circuits to achieve such antagonistic effects remains mysterious. Here, we mapped striatal 5HT receptor expression in mice to reveal preferential enrichment of putatively excitatory, Gq-coupled 5HT receptors on medium spiny neurons expressing inhibitory D2 DA receptors (D2-MSNs). Acute slice recordings from genetically identified striatal neurons showed that DA and 5HT inversely regulate D2-MSN firing and confirmed that 5HT's excitatory effect on these cells is blocked by 5HT2a and 5HT2c receptor antagonists. Pharmacologically upregulating striatal 5HT release preferentially induced cfos expression in D2-MSNs, validating that 5HT's excitatory effect on these cells also occurs in vivo. Finally, 5HT2c receptor loss-of-function in D2-MSNs, but not D1-MSNs, enhanced animals' sensitivity to the behavioral effects of cocaine - a potent releaser of DA and 5HT - showing that 5HTergic excitation of D2-MSNs counteracts the reinforcing effects of striatal DA release. Altogether these results demonstrate that DA and 5HT inversely modulate D2-MSN activity to regulate cocaine reward, identifying a key circuit mechanism underlying the opponent behavioral effects of these important neuromodulators.

The unique gyral patterns of the human brain demand patient‐specific neural interfaces to achieve precise neuromodulation, mitigate adverse tissue responses, and optimize therapeutic efficacy and safety. One‐size‐fits‐all, conventional rigid electrocorticography (ECoG) electrodes, standardized for mass production through lithographic techniques, exhibit limited conformability to the brain's heterogeneous cortical topography. This mechanical mismatch results in poor electrode‐tissue contact, signal loss, and foreign body responses. To address these limitations, we present an integrated novel platform, synergizing MRI‐based anatomical mapping, finite element analysis (FEA)—optimized mechanical design, and direct ink writing (DIW) 3D printing to fabricate electrodes customized to individual gyral patterns. The resulting honeycomb‐inspired printable gel electrode (HiPGE) employs a bioinspired honeycomb architecture with ultra‐soft hydrogels, engineered to match the bending stiffness of brain tissue (0.1–10 kPa) while maintaining cost‐efficiency and long‐term durability. This mechanical congruence ensures exceptional cortical conformability and adaptive interfacing, circumventing the geometric and material limitations of traditional rigid electrodes. By combining patient‐specific design with scalable fabrication, our platform establishes a transformative framework for neural interface engineering, enhancing precision, biocompatibility, and functional performance in neuromodulation therapies and neuroprosthetic applications.

In the auditory cortex, neural responses to stimuli inside receptive fields (RFs) can be further facilitated by behavioral demands, such as attending to a spatial location. It is less clear how off-RF stimuli modulate neural responses and contribute to behavioral tasks. Our recent study revealed a particular form of location-specific facilitation evoked by repeated stimulation from an off-RF location, suggesting behavioral modulation of spatial RFs. To further explore this question, we trained marmosets to attend to sound locations that were either inside or outside the RFs of auditory cortical neurons. The majority of neurons showed increased firing rates at target locations inside their RFs. Interestingly, this increase also occurred outside the RFs, sometimes exceeding the responses at the RF center during passive listening. This task-related off-RF facilitation was much more common in the caudal area than in the rostral area and the primary auditory cortex. A normalization model reproduced the off-RF facilitation using widespread suppression. The model’s prediction was confirmed by experimental observations of widespread reductions in firing rate and hyperpolarized membrane potentials for off-RF stimuli. These results suggest that behavioral task demands recruit a broader range of neurons than those that are responsive to a target sound in the passive state.

The acoustic flutter is processed through complementary monotonic rate coding and cannot be modulated by other acoustic parameters in the auditory cortex (AC). However, it remains unclear how the inferior colliculus (IC) encodes acoustic flutter, especially when changing other acoustic parameters. Here, we recorded IC neural activity in response to acoustic flutter and determined the existence of conjunctive processing between repetition rate and other acoustic parameters. We found that most IC neurons also encode the repetition rate at the flutter range through complementary monotonic rate coding. In addition, although the acoustic parameters did not change their monotonicity, most IC neurons encode both repetition rate and other acoustic parameters, different from the flutter processing in AC. Thus, complementary monotonic rate coding for acoustic flutter was widespread in the auditory system; however, coding specificity for repetition rate increased from IC to AC, and the capacity for conjunctive coding with other acoustic parameters decreased.

Humans localise sounds in the horizontal plane by processing level and timing differences between the ears. This neurocomputational process is continuously and adaptively calibrated using visual input, as seen in the ventriloquism aftereffect: a shift in sound perception toward a previously seen light. It is unknown from where in the brain this aftereffect originates; adaptation could occur at an early level in the auditory system where neurons are narrowly tuned to frequency, at a later level in the auditory system where localisation cues are extracted, or outside the auditory system at a higher-level spatial map. To investigate this, we examined how the ventriloquism aftereffect generalises across sound frequencies. Participants localised seven narrowband sounds (0.5–8 kHz), targeting different localisation cues. We found that sound localisation accuracy in darkness varied slightly with frequency. When sounds were paired with a visual stimulus that was offset by 10 deg, participants exhibited a pronounced bias toward the light of about ~ 63%, corresponding to the well-known ventriloquism effect. The bias was stronger for narrowband compared to broadband sounds. After exposure to a block of these audiovisual stimuli, a ventriloquism aftereffect in the form of a spatial bias of ~ 12% was observed across all tested frequencies, largely independent of the frequency of the exposure sound. Together with earlier reports of both frequency-specific and frequency-general recalibration, our results indicate that under conditions of a fixed and consistent audiovisual spatial offset, the ventriloquism aftereffect generalises across sound frequencies, consistent with adaptation at a frequency-independent multisensory spatial stage.

Evolutionary shifts in diel activity patterns shape sensory remodeling across mammals, yet the genetic basis remains poorly understood. Tapirs represent a unique natural experiment, having reverted from a cathemeral ancestor to a nocturnal niche characterized by reduced vision but enhanced hearing and olfaction. Here, we investigate the genetic basis of this phenomenon by generating high-quality chromosome-level genomes for Tapirus terrestris and Tapirus indicus . Comparative analyses revealed extensive lineage-specific remodeling of genes and cis-regulatory elements linked to sensory pathways. Notably, functional validation via CRISPR-Cas9 editing of a tapir-specific conserved noncoding element (CNE74) upstream of the FLT1 gene in mice revealed coordinated sensory effects, including retinal degeneration and reduced visual acuity, yet enhanced auditory sensitivity. These findings suggest that regulatory element evolution may induce pleiotropic effects on competing sensory modalities, offering genetic insights into sensory evolution during temporal niche adaptation and potential relevance to human retinal vascular diseases.

Reconstructing speech from neural recordings is crucial for understanding human speech coding and developing brain-computer interfaces (BCIs). However, existing methods trade off acoustic richness (pitch, prosody) for linguistic intelligibility (words, phonemes). To overcome this limitation, we propose a dual-path framework to concurrently decode acoustic and linguistic representations. The acoustic pathway uses a long-short term memory (LSTM) decoder and a high-fidelity generative adversarial network (HiFi-GAN) to reconstruct spectrotemporal features. The linguistic pathway employs a transformer adaptor and text-to-speech (TTS) generator for word tokens. These two pathways merge via voice cloning to combine both acoustic and linguistic validity. Using only 20 min of electrocorticography (ECoG) data per human subject, our approach achieves highly intelligible synthesized speech (mean opinion score = 4.0/5.0, word error rate = 18.9%). Our dual-path framework reconstructs natural and intelligible speech from ECoG, resolving the acoustic-linguistic trade-off.

Neural interfaces for monitoring and modulating spinal nerve activity are increasingly being designed to be flexible and stretchable to enhance their biomechanical compatibility and integration. However, excessive flexibility introduces practical limitations such as difficulty in insertion into narrow spinal spaces and long-term electrical instability, hindering real-world applications. In this study, we developed a spinal nerve interface by incorporating a liquid-metal conductor and dynamic stiffness-based variable-compliance structure, which can address the challenges of current flexible neural interface technologies. During insertion, the dynamic stiffness enhancer minimizes unintended buckling and ensures minimally invasive implantation into the intended target. The proximity of the proposed device to the spinal cord increases as it flexes automatically and rapidly in a humid environment. The liquid-metal conductor maintained stable electrical properties in freely moving rats, ensuring reliable and sustained functionality. This study lays the foundation for practical, fully implantable spinal bioelectronics designed with a focus on ease of implantation and long-term functionality.

The clinical manifestations of mood and psychotic disorders encompass phasic and transdiagnostic features. The complexity of these symptoms may hamper the development of biomarkers for these diagnostic categories. In the present study, machine learning was employed to cluster their transdiagnostic clinical manifestations as a means of developing state-dependent biomarkers with electroencephalography (EEG). This data-driven clustering classified the items of multiple symptom scales into three symptom domains, which subsequently stratified patients with major depressive, bipolar, and schizophrenia spectrum disorders into distinct symptom state groups. The specific brain activity profiles of each stratum were then characterized by resting-state and auditory steady-state EEG paradigms. The resting-state readings of patients in manic states revealed significantly increased gamma and beta oscillations, whereas 40-Hz and 20-Hz auditory steady-state responses (ASSRs) showed no significant differences. These findings suggest that manic states are associated with heightened high-frequency oscillatory activity, represented by gamma and beta oscillations, without a concomitant increase in sensory-evoked information processing precision. Further investigations of excessive gamma and beta oscillations may facilitate the development of state-dependent biomarkers for the assessment, diagnosis, and treatment of manic state symptomatology in clinical psychiatry.

Auditory areas on the superior temporal plane and lateral convexity are key initial stages of speech processing in the human cortex, representing acoustic and phonetic attributes in a temporally precise manner. More complex representations in auditory-related cortex along the ventral and dorsal processing streams and prefrontal cortex are associated with perception and action. In this study, we used intracranial electroencephalography (iEEG) to clarify where and how activity leading to perceptually driven behavioral events emerges. Participants were patients undergoing iEEG monitoring for medically intractable epilepsy. Stimuli were monosyllabic words, and participants pressed a button in response to a semantic target category. Significant high gamma activity after stimulus onset and immediately prior to motor response defined stimulus- and behavior-related activity patterns, respectively. The stimulus-related pattern was more common than behavior-related throughout the cortical auditory hierarchy as well as sensorimotor cortex. Behavior-related activity was sparsely represented, with the highest prevalence in the prefrontal cortex and a more limited representation in anterior temporal and parieto-occipital cortex. Hemispheric asymmetries included a higher prevalence of stimulus-related activity in the right sensorimotor cortex and a higher prevalence of the behavior-related pattern in the left prefrontal cortex. Faster behavioral responses were associated with greater stimulus-locked high gamma power in non-core auditory, prefrontal, and premotor cortex. Results reveal the cortical distribution of sensory stimulus-driven responses and activity time-locked to behavior and provide insights into neural substrates of speech perception.

Background: In Parkinson's disease, motor network electrophysiology frequently exhibits excessive beta oscillations. The cornerstone of therapeutic efficacy lies in the ability to modulate these pathological oscillations. Transcranial alternating current stimulation (tACS), a non-invasive method that applies oscillating electric fields to modulate ongoing brain activity, offers a promising approach. Objective: The objective of the manuscript is to investigate the dose-dependent effects of tACS on motor network cortical neurons in a Parkinson's disease model. Methods: We recorded neuronal spike activity in the motor cortex in parkinsonian non-human primates during tACS to determine how stimulation-induced electric fields affect spike timing. Results: Strong electric fields entrained neural activity at the stimulation frequency but altered the preferred spiking phase. Conversely, weak fields disrupted beta-band synchronization by modulating spike timing and phase preference. Frequency-matched stimulation significantly enhanced entrainment when aligned with endogenous oscillatory activity. Conclusion: Thus, with appropriately chosen stimulation parameters, tACS exhibits significant potential for controlling and modulating pathological oscillatory patterns that are characteristic of many neurological disorders.

Electromotility in mammalian outer hair cells (OHC) is the mechanism underlying cochlear amplification. It is brought about by the piezoelectric-like property of the membrane protein prestin (Slc26a5) that lies in the OHCs lateral plasma membrane. Prestin connects to an underlying cytoskeletal network of circumferential actin filaments that bridge longitudinal spectrin filaments. This network, in turn, lies between the plasma membrane and a closely apposed ER-like tubular array of subsurface cisternae (SSC). Two previous papers examining spectrin knockouts in embryonic hair cells were confined to analyzing the effects on the apical cuticular plate and overlying stereocilia. In this paper, we examine the effects of conditional knockouts of alpha2 spectrin in postnatal OHCs. We find a significant auditory phenotype likely due to the novel disassociation of prestin's gating charge movement from OHC electromotility. In addition, OHCs show enlargement in their SSC and plasma membrane-SSC space with preserved cuticular plates and overlying stereocilia, the latter contrasts with the findings in embryonic knockouts.

Stimulation of sensory vagal pathways is typically delivered via invasive, cervical vagus nerve stimulation (cVNS) or noninvasive, trans-auricular nerve stimulation (taNS). While both methods are investigated therapeutically, their effects on brain physiology remain poorly understood, hindering mechanistic insights and stimulus optimization. In 6 awake nonhuman primates, we recorded cortical vagal-evoked potentials (VEPs) from subdural electrodes placed in prefrontal, sensorimotor and parietal cortical areas, in response to cVNS or taNS. Across 478 different taNS and cVNS protocols, we varied stimulation side, intensity, frequency, pulse count, and pulse width and assessed independent effects on amplitude and latency of early (EC; 30-100 ms), intermediate (IC; 101-200 ms) and late components (LC; 201-500 ms) of VEPs. Fixed and random effects of stimulation parameters and subjects, respectively, on VEPs were assessed using a linear mixed-effects model. Overall, cVNS elicits more robust VEPs than taNS, with larger EC, IC and LC amplitudes, in both hemispheres. cVNS-elicited ECs and LCs are largest in PFC and PC areas, whereas ICs are largest in SM areas. On the other hand, taNS generally does not elicit area-specific responses. cVNS-elicited ECs have slower latency than ta-NS elicited ECs. Higher stimulation frequencies and intensities and a longer pulse width elicit larger ECs and ICs for cVNS, and to some extent for taNS. Both short and long cVNS trains elicit stronger ECs, and long trains elicit slower ICs. Earlobe stimulation elicits VEPs that partially overlap with those from taNS. In conclusion, cVNS and taNS elicit cortical VEPs in a manner consistent with distinct engagement of ascending vagal pathways, with both similarities and differences in the effects of stimulation parameters on evoked responses.

Alzheimer's disease (AD) is a brain condition with heterogeneity in disease progression due to genetic and environmental variables. There is a critical need to better understand the relationship of AD pathologies and potential modifiable factors like hearing loss. Auditory processing measurements in AD mouse models have been reported, but the results are mixed. Most were conducted using evoked potential recordings measured under anesthesia, unlike typical hearing assessments on aging adult humans. Here, we used operant conditioning and signal detection theory to measure daily pure tone behavioral detection throughout the lifespan of trained mutant and wild-type (WT) control APP/PS1 (on a C57BL/6J background) and 5xFAD (on a C57/SJL background) mice. At the conclusion of operant testing, auditory brainstem response (ABR) measures were taken on the same subjects to determine if evoked potentials provided accurate estimates of perceptual abilities. Behavioral detection worsened significantly across the lifespan in APP/PS1 mice, but there were no differences between mutant and WT mice. For 5xFAD mice, behavioral thresholds generally worsened over the lifespan but with substantial variability, which may be explained by genetic heterogeneity among the background strain. There were no differences between 5xFAD mutant and WT mice. ABR hearing threshold estimates generally matched behavioral findings, with APP/PS1 having significantly worse thresholds than 5xFAD mice but no within-model differences between mutants and WTs. The within-subject differences between behavioral and ABR thresholds ranged from <1 dB to over 40 dB across subjects, suggesting physiological measurements of auditory function are not necessarily reflective of an animal's acoustic perception.

Harmonicity is a property of complex sounds such as vocalizations or music, but it remains unclear how harmonicity is processed in the auditory cortex (ACtx). Subregions of ACtx are thought to process harmonic stimuli differently. Selective responses to sound features in ACtx emerge hierarchically from primary ACtx (A1) L4 and secondary ACtx (A2) layer (L)2/3, which is believed to be the most responsive to harmonic sounds. Since harmonic stacks can range from 2 to >10 components, being more similar to naturalistic vocalizations, harmonic sensitivity might also arise hierarchically across layers and areas. We studied responses to harmonic stacks of 2–10 frequencies across A1 L4, A1 L2/3, and A2 L2/3 in adult male and female mice using in vivo two-photon microscopy. We found harmonic-sensitive neurons (HNs) responding only to harmonic stacks but not to individual frequencies in all areas at similar proportions. HNs showed highly nonlinear spectral integration of harmonic frequencies that decreased as the harmonic stacks became more complex. Specifically, onset-biased HNs showed greater nonlinearity than offset-biased HNs only in A1 L4. Moreover, HNs in A1 L4 exhibited higher signal correlation than A2 L2/3. Sound-responsive neurons in A1 L4 have the weakest noise correlation compared with A1 L2/3 and A2 L2/3. Together, harmonic sensitivity is not a unique feature of A2 L2/3 but is already established in A1 L4, where neurons robustly encode harmonic sounds through sparse connections.

Habituation is a crucial sensory filtering mechanism whose dysregulation can lead to a continuously intense world in disorders with hypersensitivity. Although habituation is often termed the simplest form of learning, its circuit mechanisms remain elusive. Conventional peripheral explanations fail to fully account for long-term habituation in complex sensory environments, leading to theories proposing top-down regulation. Here we evaluated two competing top-down mechanistic explanations for habituation in mice (growth in predictive filtering and waning of novelty-driven amplification) and identified an unexpected role for the orbitofrontal cortex (OFC) in predictive filtering. After daily sound exposure, neural habituation in the primary auditory cortex (A1) was reversed by inactivating the OFC. Top-down projections from the OFC, but not other frontal areas, carried predictive signals that grew with daily sound experience and suppressed A1 via somatostatin-expressing inhibitory neurons. Thus, prediction signals from the OFC cancel out anticipated stimuli by generating their 'negative images' in sensory cortices.

Hearing loss is a pervasive global health challenge with profound impacts on communication, cognitive function, and quality of life. Recent studies have established age-related hearing loss as a significant risk factor for dementia, highlighting the importance of hearing loss research. Auditory brainstem responses (ABRs), which are electrophysiological recordings of acoustically evoked synchronized neural activity from the auditory nerve and brainstem, serve as in vivo correlates for sensory hair cell and synaptic function, hearing sensitivity, and other critical readouts of auditory pathway physiology, making them highly valuable for both basic neuroscience and clinical research. Despite the utility of the ABR, traditional ABR analyses rely heavily on subjective manual interpretation, which may introduce variability and pose challenges for reproducibility across studies. Here, we introduce Auditory Brainstem Response Analyzer (ABRA), a novel suite of open-source ABR analysis tools powered by deep learning, which automates and standardizes ABR waveform analysis. ABRA employs convolutional neural networks trained on diverse datasets collected from multiple experimental settings, achieving rapid and unbiased extraction of key ABR metrics, including peak amplitude, latency, and auditory threshold estimates. We demonstrate that ABRA’s deep learning models provide performance comparable to expert human annotators while dramatically reducing analysis time and enhancing reproducibility across datasets from different laboratories. By bridging hearing research, sensory neuroscience, and advanced computational techniques, ABRA facilitates broader interdisciplinary insights into auditory function. An online version of the tool is available for use at no cost at https://abra.ucsd.edu .

Spinal cord injury (SCI) remains a debilitating neurological disorder with limited therapeutic options, as existing treatments primarily address symptoms rather than address the complex interplay of cellular and molecular barriers to regeneration. These barriers collectively hinder functional recovery, including inhibitory glial scarring, chronic neuroinflammation, intrinsic neuronal regenerative deficits, and disruption of the blood-spinal cord barrier (BSCB). To address these limitations, we developed NanoScript-PTEN (NS-PTEN), a nonviral nanoparticle platform that delivers synthetic transcription factors to transiently suppress phosphatase and tensin homolog (PTEN) expression. PTEN negatively regulates the PI3K/AKT/mTOR signaling axis, which is a critical determinant of neuronal survival and axonal growth. By reducing PTEN levels, NS-PTEN derepresses this pro-survival pathway, promoting neuronal regeneration in the injured spinal cord. By integrating a DNA-binding domain targeting the PTEN promoter, a transcriptional repression module, and a nuclear localization signal onto a gold nanoparticle (AuNP) scaffold, NS-PTEN achieves transient control over PTEN repression, reactivating pro-regenerative signaling while minimizing the risks of tumorigenesis associated with permanent gene silencing. In a clinically relevant contusion SCI rat model, NS-PTEN induced a coordinated series of structural and microenvironmental improvements that collectively support spinal cord repair. Histologically, NS-PTEN enhanced axonal continuity and remyelination, as evidenced by denser NF-positive fibers and substantially greater MBP preservation than in both the injury and AuNP groups. Concurrently, NS-PTEN markedly attenuated astroglial and microglial reactivity, reducing GFAP+ border formation and diminishing Iba1+ inflammatory cell accumulation. At the vascular interface, NS-PTEN upregulated CD31 and occludin expression, indicating restored endothelial integrity and the reconstruction of tight junctions, which are critical for BSCB repair. In parallel, the inflammatory milieu shifted toward a regenerative phenotype, characterized by suppressed pro-inflammatory cytokine expression (IL-6, TNF-α, and iNOS) and elevated anti-inflammatory/neurotrophic factors (IL-10 and BDNF). These improvements are consistent with secondary, microenvironment-level benefits arising from acute neuronal PTEN repression rather than direct modification of non-neuronal cell types. Importantly, PTEN expression partially rebounded by DPI-28, aligning with the intended transient activity window of the nanoscript system and supporting its translational safety. Through this combination of precise, nonintegrative gene modulation and broad downstream remodeling, NS-PTEN addresses both intrinsic neuronal limitations and extrinsic inhibitory features of the SCI microenvironment.

In the mammalian cochlea upon acoustic stimulation, outer hair cells (OHCs) push and pull the basilar membrane, amplifying its vibration and therefore expanding the dynamic range of hearing. As a result, spiking patterns in auditory nerve fibers (ANFs) are believed to be significantly different, but how the central nervous system adapts to this substantial change is poorly understood. In this study, we took advantage of Prestin −/− mice of either sex where prestin, the motor protein in OHCs, was genetically knocked out, therefore removing cochlear amplification completely without changing the cellular structure of the cochlea significantly. While exocytosis from inner hair cells in the cochlea was largely intact, transmission at the endbulb of Held synapse between ANFs and bushy cells in the cochlear nucleus was significantly changed in Prestin −/− mice. Specifically, excitability of bushy cells was significantly increased, due to combination of slightly more depolarized resting membrane potential, increased membrane input resistance, and smaller and briefer afterhyperpolarization. Furthermore, synaptic strength was greatly reduced, caused by substantial decrease in the readily releasable pool (RRP) of synaptic vesicles. Significantly, paired-pulse plasticity at this synapse was reversed from depression in WT mice to facilitation in Prestin −/− mice, likely caused by quicker refilling of RRP observed in Prestin −/− mice. In conclusion, we found that transmission at the endbulb of Held synapse is significantly altered in absence of cochlear amplification, revealing interplay between the peripheral and central processing of auditory signals that contributes to expanded dynamic range of hearing seen in mammals and humans.

Mutations in SLC26A4 are the second most common cause of hereditary hearing loss (HL) in many Asian countries, leading to DFNB4, a condition characterized by progressive HL and inner ear malformations. While gene therapy holds great potential, its postnatal application has remained unexplored because of the lack of suitable animal models and the challenges of prenatal intervention. To our knowledge, this study represents the first preclinical investigation of postnatal gene therapy for DFNB4 using a clinically relevant Slc26a4 -mutant mouse model that closely replicates human auditory phenotypes. Utilizing the synthetic AAV.Anc80L65 vector, we achieved robust SLC26A4 delivery to critical cochlear regions, including the endolymphatic sac and cochlear lateral wall. Comprehensive phenotypic analyses revealed a critical therapeutic window spanning the neonatal and juvenile stages, within which AAV.Anc80L65-mediated SLC26A4 delivery significantly improved hearing, as evidenced by lower auditory brainstem response thresholds. Moreover, the therapy preserved hair cells, reduced endolymphatic sac enlargement, partially restored the endocochlear potential, and mitigated inner ear structural degeneration. These therapeutic effects persisted into adulthood, highlighting the long-term efficacy of postnatal gene therapy. Together, these findings establish a critical therapeutic window for DFNB4 and demonstrate the feasibility of targeting the endolymphatic sac and cochlear lateral wall for effective intervention.