Cochlear synaptopathy, characterized by damage to the synapses between inner hair cells (IHCs) and auditory nerve fibers, has emerged as a key contributor to auditory dysfunctions such as hidden hearing loss, tinnitus, and hyperacusis, often in the absence of elevated auditory thresholds. Despite the significant neurodegenerative consequences, conventional diagnostic methods lack sufficient sensitivity and specificity to detect synaptic dysfunction in living human subjects. Here, we introduce and validate the hypothesis that the I' potential—an early-latency component in the auditory brainstem response (ABR)—can serve as a sensitive, non-invasive biomarker for IHC ribbon synapse integrity.

The mammalian auditory system relies on the precise and rapid transmission of acoustic information, a process orchestrated by specialized ribbon synapses of the IHCs. These synapses convert graded receptor potentials, induced by hair bundle displacement, into neurotransmitter release, enabling the fine temporal coding required for accurate sound localization and speech perception. Given their unique ultrastructure, IHC ribbon synapses are particularly susceptible to insults such as acoustic overexposure, ototoxic drugs, and aging—factors implicated in cochlear synaptopathy. Notably, substantial synaptic loss can occur without detectable changes in the pure-tone audiogram, complicating early diagnosis.

To address the need for an accessible, reliable diagnostic tool, we explored the utility of the I' potential within the ABR using the paired-click paradigm. We first tested this hypothesis in a guinea pig model, correlating I' amplitude changes with histological assessments of ribbon synapse integrity following induced synaptopathy. Subsequently, the paradigm was applied to a cohort of young, normal-hearing adults. ABRs were recorded with standard clinical equipment, and mean I' amplitudes were quantified. Our animal model data revealed that reductions in the I' amplitude were strongly associated with synaptic ribbon loss, confirming that I' reflects synaptic integrity. In human participants, the I' potential was readily observable in ABRs elicited by the paired-click protocol, and its amplitude and presence were quantifiable across individuals with normal audiometric thresholds. These findings establish the practicality and feasibility of the I' potential as a cross-species measure of auditory synaptic function. The clinical implications of using the I' potential as a diagnostic biomarker are substantial. Unlike conventional ABR wave I amplitude or otoacoustic emissions—which may be affected by extraneous factors or lack specificity for synaptic dysfunction—the I' potential targets synaptic EPSPs, providing a more direct insight into ribbon synapse status. Clinically, diminished or absent I' amplitude may herald early cochlear synaptopathy in individuals reporting difficulty with speech-in-noise perception, even in the context of normal hearing thresholds.

Given its rapid, non-invasive, and cost-effective nature, the I' potential via the paired-click ABR could be integrated into routine clinical assessment, aiding in early detection, risk stratification, and selection of patients for targeted interventions or clinical trials. Moreover, establishing normative data on I' amplitude and latency across demographic variables will facilitate broader adoption and standardization. Our findings from both animal and human studies demonstrate that the I' potential, elicited by the paired-click ABR paradigm, is a promising biomarker for cochlear synaptopathy.