Project Summary Neuromodulation strategies can alter the neuronal activity patterns, and many recent studies report on beneficial effects of neuromodulation on cognitive performance. The focus of the current proposal is on characterizing the effects of the transcranial electric current stimulation (tACS), a type of neuromodulation, on the phase amplitude coupling between neuronal oscillatory bands, neurotransmission, and working memory in an experimental model of Alzheimer’s disease (AD). tACS is non-invasive, well tolerated, easily implementable, and temporally adaptable over long periods of time, making it well suited to application in slowly evolving diseases such as AD. Recent evidence in both healthy elderly and AD patients suggests that tACS may improve working memory. At the same time, however, these data indicate a great heterogeneity in tACS effects across individuals, underscoring the importance of deepening our understanding of tACS effects on the AD brain and identifying sensitive biomarkers of the brain's response to tACS. Using advanced multi-modal and multi-scale imaging techniques in a transgenic rat model of AD, we will characterize the effects of varying tACS frequency on the theta-gamma phase amplitude coupling of the neuronal oscillations that are thought to underlie working memory and get attenuated in the early stage of AD. We will inject the brains of TgAD rats with viruses carrying voltage indicators that incorporate into the neuronal membrane to elucidate tACS effects on excitatory vs. inhibitory neurons because excitation-to-inhibition disbalance gives rise to phase amplitude coupling disturbances. Having established the tACS stimulation frequency that achieves greatest normalization of neuronal activity patterns, we will undertake multimodal, multiscale studies to evaluate the effectiveness of our tACS protocol, when combined with anti- tau immunotherapy, on rescuing phase amplitude coupling and cognition in the TgAD rats vs. their non-transgenic littermates. To this end, we will map the effects of tACS in these animals both at the microscopic scale using two-photon fluorescence microscopy and electrophysiology and at the mesoscopic scale using MRI-based assays of functional/structural connectivity, neurotransmission and neurometabolism; as well as establish its effects on working memory using behavioral testing. Finally, we will train machine learning models using these neuroimaging data to predict whether a tACS intervention is likely to elicit memory benefits in the presence of early AD-like pathology. Our work will lay the foundation for the use of tACS as an adjuvant therapy in AD patients.

Project Narrative: Despite the availability and promise of transcranial alternating current stimulation, its effectiveness at arresting memory decline has hitherto been limited and highly variable across Alzheimer’s Disease (AD) patients. Our experimental AD model studies will leverage novel approaches to cellular-level interrogation of neuronal function and relate the cellular scale changes in brain activity elicited by tACS to mesoscopic scale changes in neurotransmitter levels and flux, and working memory. We will establish multi-scale machine learning models for predicting the effects of transcranial alternating current stimulation on neuronal activity and working memory using clinic-ready neuroimaging protocols, so as to lay the foundation for development of personalized neuromodulation interventions for treating memory deficits in the early stage of AD pathology.