Integrating music‐based interventions with gamma‐frequency stimulation for Subjective Cognitive Decline and Mild Cognitive Impairment

Background Alzheimer’s disease (AD) is characterized by disrupted, synchronous neural activity in the gamma‐band range (30‐100 Hz) and atypical cross‐frequency coupling between gamma and other bands of brain activity 1‐3 . In non‐human‐animal models, restoring aberrant gamma activity with non‐invasive gamma sensory stimulation remediates multiple pathophysiologies of AD (e.g., amyloid‐beta, tau tangles) and improves cognition 4,5 . While promising, gamma sensory stimulation may be difficult to use with human patients. We theorize that combining gamma sensory stimulation with natural music may increase the efficacy of gamma interventions for dementia, as music naturally drives gamma brain activity; engages multiple brain networks that are important for learning, memory, and reward processing; and music‐based interventions can reduce distress and agitation in older adults with dementia 6 . Method We developed a non‐invasive, gamma‐ and music‐based intervention for dementia, called SynchronyGamma (SynG). SynG delivers synchronized bursts of gamma‐frequency visual stimulation during natural music listening, cross‐frequency coupled to delta (0.5 – 4 Hz) and theta (4 – 8 Hz) visual rhythms, which adapt in real‐time to musical rhythms. In a preclinical experiment featuring older adults with and without Mild Cognitive Impairment (MCI) and Subjective Cognitive Decline (SCD) (N = 19 experimental group, 3 with MCI/SCD; N = 18 control group, 2 with MCI/SCD), we tested whether a single‐dose of music listening with SynG, relative to a control intervention, drives gamma neural activity; induces cross‐frequency coupling between delta, theta, and gamma brain activity; and improves cognition (e.g., delayed‐match‐to‐sample working‐memory task) Results SynG was found to drive scalp‐recorded gamma brain activity (p<0.05), and induce stronger cross‐frequency coupling, relative to the control condition (p<0.05). Additionally, enhanced gamma activity was observed during the working‐memory task that followed the intervention. Finally, SynG participants performed more accurately on a visual working memory task compared to their control counterparts, although this improvement fell short of statistical significance following a single dose (p>0.05). Conclusion Together, these findings suggest that combining self‐selected music with delta, theta, and gamma frequency visual stimulation is effective at driving gamma neural activity, inducing cross‐frequency coupling, and it may improve cognitive functioning. Future research will assess the effects of a longitudinal implementation of the intervention.