Traditional cochlear implant systems depend on external devices and face challenges related to convenience, esthetics, and auditory performance in complex soundscapes. Recently, research has shifted from “functional substitution” to “functional enhancement” and “biological fusion.” However, most emerging approaches remain in the preclinical, prototype verification, or early clinical stages, lacking substantial evidence of clinical benefits. This narrative review examines research progress across five key dimensions of cochlear implants: The electrode interface has advanced from passive implants to dynamic, adaptive, and biologically active intelligent interfaces. Signal processing strategies are moving toward intelligence and physiological adaptation, with deep learning primarily used for noise suppression and coding optimization; however, clinical application is limited by real-time performance and individual variability. Bionic sensing aims to replicate the energy conversion mechanism between hair cells and the basement membrane at the signal source, currently focusing on laboratory prototypes. Optogenetics-driven optical regulation offers high spatial selectivity but remains in the early preclinical stage. The development of fully implanted systems emphasizes internal energy supply, ultra-low power consumption processing, and system integration, marking a significant engineering direction for making devices “invisible.” Each section of this article critically evaluates evidence maturity and transformation barriers, highlighting common challenges such as long-term biological stability, safety, energy consumption, and regulatory verification that must be addressed before large-scale clinical application. Future advancements will require collaboration among materials science, neuroscience, microelectronics, and artificial intelligence to create a two-way high-fidelity interface. The ultimate goal is not only to restore hearing but also to reconstruct a more natural auditory perception.
A reduction in brain-derived neurotrophic factor (BDNF) protein levels has been reported in post-stroke depression (PSD). However, whether transcript abundance and translation efficiency change in parallel or become uncoupled in PSD remains to be determined. In addition to classical transcriptional regulation by histone deacetylase (HDAC) inhibitors, pathological processes may affect BDNF translation independently of transcription, but the relevant epitranscriptomic pathways remain unresolved. Drawing on reports that butyrate can influence m6A-related processes in peripheral tissues and that YTHDF1-dependent translation operates in adult hippocampus and cellular systems, this article proposes the “butyrate–m6A–BDNF” axis as a testable hypothesis. The hypothesis predicts that post-stroke changes in butyrate availability could alter central m6A regulation and thereby affect translation of a biologically motivated candidate transcript such as BDNF. The framework separates established mechanisms, cross-model evidence, and predictions that require direct measurement. The validation plan includes future exposure-resolved, genetic, and cell-type-specific studies; no validation experiments are presented here.
Transcutaneous auricular vagus nerve stimulation (taVNS) is typically delivered electrically, while alternative stimulation modalities and their potential for personalization remain underexplored. We present TEMPO-taVNS (Thermal, Electrical, and Mechanical Parameter Optimization for taVNS), a human-centered methodology for multimodal auricular neuromodulation designed to explore and optimize stimulation of sensory pathways associated with the auricular branch of the vagus nerve (ABVN). The platform integrates custom hardware capable of delivering thermal, vibrotactile, and electrical stimulation with software that enables systematic parameter sweeps. Responses are characterized through high-resolution physiological monitoring including heart rate, heart rate variability, gastric slow-wave activity, pupil diameter, beat-to-beat blood pressure, brain response activity, and electrodermal activity, together with participant-reported perception and comfort. To address interindividual variability, a Pareto-front Gaussian-process optimization framework identifies personalized stimulation parameters by balancing physiological response with user comfort. We further describe experimental protocols for evaluating this multimodal parameter space in humans. Together, the hardware, software, physiological sensing, and optimization framework provide a scalable foundation for individualized, non-invasive and nonpharmacological auricular neuromodulation, and for investigating non-electrical approaches to vagal stimulation for wearable neuromodulation systems.
Microglia show substantial functional heterogeneity during neuroinflammatory responses, yet the upstream mechanisms through which they interpret extracellular perturbation-associated signals and transition between functional states remain incompletely understood. Purinergic signaling is well positioned to serve as such an environmental sensing system because ATP is released rapidly from stressed or damaged cells and is subsequently metabolized to adenosine, generating an extracellular purine landscape that changes with the magnitude and persistence of tissue stress. We propose a Purinergic Receptor Dominance Model for microglial state transitions during neuroinflammation. Microglial responses are shaped by the changing balance among ATP- and adenosine-sensitive receptor systems. P2Y12-associated signaling supports physiological surveillance; P2X4 contributes to early injury responses; and A1 and A2A receptors provide temporally layered adenosine-linked regulation. Persistent or severe stress may recruit P2X7-associated inflammatory amplification. Under the high-adenosine conditions that can accompany prolonged stress or hypoxia, A2B-linked signaling may also become relevant. The model focuses on the upstream receptor systems through which microglia may gauge the intensity, duration, and metabolic context of tissue stress. It is presented as a testable organizing hypothesis that can be evaluated, refined, or rejected experimentally.
