Effect of Donepezil on Speech Recognition in Adult Cochlear Implant Users: A Pilot Randomized Clinical Trial

Speech recognition outcomes following cochlear implantation vary widely among users, potentially due to differences in neuroplasticity. The cholinergic system plays a critical role in cortical reorganization and sensory learning; yet, its potential to enhance auditory plasticity in cochlear implant (CI) users has not been explored. The aim of this study is to investigate the effects of donepezil, a cholinergic agonist, on speech perception and cortical plasticity in adults with CIs.

This pilot randomized clinical trial was conducted at a single tertiary academic center from April 2023 to December 2024. Adult CI recipients with a postlingual onset of deafness and at least 6 months of device experience were eligible for inclusion. Participants were randomized to oral donepezil 5 mg (DPZ) or placebo (PL) daily for 90 days. Both groups were encouraged to increase their daily device use during the study. The primary outcome measure was the change in consonant-nucleus-consonant word recognition scores for the implanted ear. Secondary outcomes included binaural word recognition, sentence recognition in quiet, signal to noise ratio loss for sentence recognition in noise, and questionnaires related to hearing satisfaction, listening fatigue, and quality of life. The questionnaires included the Speech, Spatial, and Quality of Hearing Scale, Vanderbilt Fatigue Scale, and CI Quality of Life Profile. Cortical plasticity was assessed using functional near-infrared spectroscopy.

Thirteen experienced CI users were enrolled in this pilot study, with nine completing the 90-day protocol and included in the group descriptive analyses (DPZ: n = 4, PL: n = 5). Four participants (45%) were female, and the median age was 68 years. All study participants increased their device use, with a mean increase of 3.1 hr per day in both groups. Donepezil treatment was associated with a 14.5-point increase in mean CI-only consonant-nucleus-consonant word recognition, surpassing the 10-point threshold for clinical significance, whereas the placebo group decreased by 0.8 points (d = 0.88). Binaural word recognition, sentence recognition, and speech-in-noise performance also improved in the DPZ group relative to PL. Subjective measures showed greater improvements in speech perception (Speech, Spatial, and Quality of Hearing Scale) and reduced listening fatigue (Vanderbilt Fatigue Scale) in the DPZ group, while CI-related quality of life was similar between groups. Neuroimaging analyses revealed significant Group × Time interaction effects, with DPZ increasing left frontal cortex activation during a speech-in-noise task (β = 3.721, p < 0.001).

These findings provide preliminary evidence that cholinergic enhancement with donepezil may improve speech perception and facilitate neuroplasticity in multisensory and cognitive brain regions in CI users. In addition, the neuroimaging analyses support cholinergic-induced neuroplasticity with DPZ treatment. While this pilot study was underpowered to determine the clinical efficacy of donepezil, pharmacological interventions like donepezil represent a promising novel approach to optimizing CI outcomes, and we offer recommendations for future clinical trials in this population.