Fan-Gang Zeng

Cognitive decline in Alzheimers disease and related dementias (AD/ADRD) frequently cooccurs with motor and sensory processing impairments. While auditory abnormalities were reported in beta-amyloid-based models before cognitive decline, the effects of tau pathology on auditory circuit function remain poorly understood. The PS19 mouse model expressing the P301S tau mutation exhibits tau pathology associated with frontotemporal dementia. When combined with the humanized ApoE ?4 allele, these mice show accelerated tau accumulation and neurodegeneration. We investigated the temporal progression of auditory and behavioral deficits in PS19 and ApoE4/PS19 mice of either sex at 3 and 7 months. Auditory processing was assessed using auditory brainstem response (ABR) recordings, while anxiety-like and motor behaviors were evaluated using the elevated plus maze and rotarod assays. PS19 mice exhibited auditory pathway dysfunction at 3 months, characterized by reduced and delayed neural responses to acoustic stimuli. These auditory deficits occurred without detectable behavioral changes in anxiety- or motor-related measures. By 7 months, cochlear nucleus-derived ABR activity shifted from an initial reduction to elevation relative to controls, suggesting compensatory hyperexcitability. In contrast, ApoE4/PS19 mice showed reduced ABR amplitudes and shortened response latencies that persisted with age, accompanied by altered anxiety-like behavior and motor performance. Together, these results demonstrate that auditory pathway dysfunction may represent an early marker of tau pathology preceding behavioral impairment. The divergent temporal patterns of ABR alterations across genotypes suggest that genetic context, particularly ApoE4, modulates the progression of tau-driven circuit dysfunction, highlighting ABR as a potential noninvasive biomarker for early tau-related neurodegenerative disease.

Age-related cognitive decline is a growing global concern, motivating the search for non-invasive, accessible biomarkers to support early detection and monitoring. Click-evoked auditory brainstem responses (ABRs), collected in routine clinical settings, offer a promising signal source. Building on prior evidence that ABRs relate to cognitive function, this study investigates whether raw human ABR waveforms can predict cognitive performance using deep learning without manual peak measurements. We used a dataset from 118 adults spanning a broad range of cognitive abilities, pairing each click-evoked ABR with a cognitive score. A one-dimensional convolutional neural network (CNN) was trained to learn time-series patterns directly from the raw signal. Model performance was evaluated using two, five, and ten-fold cross-validation and compared against traditional wave V metrics and a randomized-input baseline. After adjusting scores for age, the CNN achieved a mean area under the receiver operating characteristic curve of 0.77 ± 0.06, outperforming all benchmarks. To interpret model decisions, Gradient-weighted Class Activation Mapping (Grad-CAM) was applied. Three key latency windows were identified: 1.8 to 2.3 ms, 3.2 to 4.0 ms, and 4.9 to 6.5 ms. These correspond to canonical ABR waves I, III, and V, supporting the physiological relevance of the learned features and highlighting Wave III as a previously underutilized marker. Although limited to click stimuli from a single recording system, this work demonstrates that a CNN can extract meaningful features from raw ABRs collected using only three electrodes and predict cognitive status more accurately than traditional methods using the same dataset.

Gene therapy has recently restored natural audibility in humans with OTOF‐gene mutations. This biological restoration of hearing is different from cochlear implantation (CI) that produces artificial hearing via electric stimulation of the auditory nerve. In three published trials, 21 DFNB9 patients show 244 grade I/II adverse events (AEs), 2 grade III AEs and no serious AEs. The average gene therapy effect is substantial (52.4‐dB improvement from baseline complete deafness), rapid (0.74‐month time constant), and stable over the initial six months. However, individual outcomes vary from restored normal audibility (≤20 dB HL) to severe hearing loss (≥80 dB HL). Here critical knowledge gaps in gene therapy are identified such as understanding the individual variability, assessing temporal processing, and comparing efficacy with cochlear implantation. It is predicted that gene therapy will include patients with less than complete hearing loss and target other monogenic forms of congenital deafness. Advanced technologies in minimally invasive drug delivery and gene editing will further increase the safety, efficacy and applicability of gene therapy for hearing loss. Cochlear implantation likely remains the standard intervention for severe‐to‐profound hearing loss, but gene therapy will emerge as a viable alternative in treating monogenic forms of deafness.

Gene therapy for congenital deafness has shown promising results in children but lacks data in older populations. We conducted a single-arm trial of adeno-associated virus (AAV)-OTOF gene therapy using the Anc80L65 capsid in ten participants with autosomal recessive deafness 9 aged 1.5 to 23.9 years at five sites in China. The primary endpoints were safety and tolerability within 5 years, and secondary endpoints assessed auditory function. Initial findings from the ten patients with 6–12 months of follow-up, including one patient who received two injections, revealed that the therapy was well tolerated, with 162 grade I/II adverse events. Decreased neutrophil percentage was the most common event (16 of 162). All ten participants had at least 6 months of follow-up and improved their pure-tone-average hearing level from baseline 106 ± 9 (mean ± s.d.) to 52 ± 30 decibels (dB). Other secondary endpoints showed similar improvements, including the average click auditory brainstem response (ABR) threshold, the tone-burst ABR threshold and the auditory steady-state response (101 ± 1 to 48 ± 26 dB, 91 ± 4 to 57 ± 19 dB and 80 ± 14 to 64 ± 21 dB, respectively). Post hoc analyses were conducted to evaluate the timecourse and factors contributing to the hearing improvement. Therapeutic effect was rapid, taking 1 month to achieve most of the overall hearing improvement. On an individual level, click and tone-burst ABR thresholds, but not the auditory steady-state response, reliably predicted the behavioral pure-tone-average thresholds after 4 months (R² = 0.68, 0.73 and 0.17, respectively). An age-dependent therapeutic effect was observed, with optimal outcomes in 5- to 8-year-olds. These preliminary results show that AAV-OTOF was safe and well tolerated in patients ranging from toddlerhood to adulthood. The trial remains ongoing and requires extended follow-up to confirm the long-term safety and efficacy. ClinicalTrials.gov registration: NCT05901480.

Humans can modify their speech to improve intelligibility in noisy environments. With the advancement of speech synthesis technology, machines may also synthesize voices that remain highly intelligible in noise condition. This study evaluates both the subjective and objective intelligibility of synthesized speech in speech-shaped noise from three major speech synthesis platforms. It was found that synthesized voices have a similar intelligibility range to human voices, and some synthesized voices were more intelligible than human voices. It was also found that two modern automatic speech recognition systems recognized 10% more words than human listeners.

Cochlear implants restore functional hearing but may cause side effects like facial nerve stimulation, sound sensitivity or reactive tinnitus. The present study aimed to establish a general framework for optimizing stimulation parameters to manage these side effects while maximizing speech perception performance. A second objective was to understand how side effect origins impact treatment outcomes. Eight adult cochlear implant subjects had intolerable side effects that rendered device usage difficult or even impossible. New maps were created by reducing stimulation levels, increasing pulse duration, reducing stimulation rate, altering channel gains and frequency maps, deactivating problematic electrodes, or a combination of the above. Outcomes were measured in terms of side effect reduction and changes in speech performance. Facial nerve stimulation was reduced or eliminated in five of five subjects. Sound hypersensitivity was eliminated in two of two subjects. Tinnitus was alleviated in three of four subjects, while the remaining one with cerebellar malformation experienced no change. Speech performance was either maintained or improved in all subjects. Except for the subject with cerebellar malformation who chose to explant the device, all subjects were able to use the implant effectively without bothersome side effects. Facial nerve stimulation is usually related to electric current spread on the same side, which can be effectively managed by customized strategies. In contrast, the origins of sound sensitivity and reactive tinnitus are more variable and likely more difficult to manage. Customized mapping can alleviate cochlear implant side effects without compromising speech performance.

A non-invasive, accessible and effective biomarker is critical to the diagnosis, monitoring and treatment of age-related cognitive decline. Recent work has suggested a strong association between auditory brainstem responses (ABR) and cognitive function in aging macaques. Here we show in 118 human participants (66 females; age range=18-92 years; hearing loss = -5 to 70 dB HL) that cognition is associated with both age and hearing level, but this triad relationship is mainly driven by the age factor. After adjusting for age, cognition is still significantly associated with both the ABR wave V amplitude (B, 0.110, 95% CI, 0.018– 0.202; p = 0.020) and latency (B, -0.101, 95% CI, -0.186– -0.016; p = 0.021). Importantly, this age-adjusted ABR-cognition association is primarily driven by older individuals and language-dependent cognitive functions. We also perform the area under the curve (AUC) of the receiver-operating-characteristic analysis and find that the ABR wave V amplitude is best for detecting good cognitive performers (AUC = 0.96) whereas the wave V latency is best for detecting poor ones (AUC = 0.86). The present result not only confirms the previous animal work in humans but also shows the clinical potential of using auditory brainstem responses to improve diagnosis and treatment of age-related cognitive decline.

Background: Cochlear implants have helped over one million individuals restore functional hearing globally, but their clinical utility in suppressing tinnitus has not been firmly established. Methods: In a decade-long study, we examined longitudinal effects of cochlear implants on tinnitus in 323 post-lingually deafened individuals including 211 with pre-existing tinnitus and 112 without tinnitus. The primary endpoints were tinnitus loudness and tinnitus handicap inventory. The secondary endpoints were speech recognition, anxiety and sleep quality. Results: Here we show that after 24 month implant usage, the tinnitus cohort experience 58% reduction in tinnitus loudness (on a 0–10 scale from 4.3 baseline to 1.8 = −2.5, 95% CI: −2.7 to −2.2, p = 3 x 10⁻⁶; effect size d’ = −1.4,) and 44% in tinnitus handicap inventory (=−21.2, 95% CI: −24.5 to −17.9, p = 1 x 10⁻¹⁵; d’=−1.0). Conversely, only 3.6% of those without pre-existing tinnitus develop it post-implantation. Prior to implantation, the tinnitus cohort have lower speech recognition, higher anxiety and poorer sleep quality than the non-tinnitus cohort, measured by Mandarin monosyllabic words, Zung Self-rating Anxiety Scale and Pittsburgh Sleep Quality Index, respectively. Although the 24 month implant usage eliminate the group difference in speech and anxiety measures, the tinnitus cohort still face significant sleep difficulties likely due to the tinnitus coming back when the device was inactive at night. Conclusions: The present result shows that cochlear implantation can offer an alternative effective treatment for tinnitus. The present result also identifies a critical need in developing always-on and atraumatic devices for tinnitus patients, including potentially those with normal hearing.