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.