Investigating electromagnetic field-based neuromodulation of slow-wave brain activity and glymphatic system

Abstract The role of glymphatic system for brain health has been established in recent studies. Specifically, the removal of brain waste from the brain parenchyma through the cerebrospinal fluid (CSF) circulation is the key mechanism for maintaining brain health, and compromise of glymphatic activity is associated with

neuropathological conditions (e.g., Alzheimer’s disease, Parkinson’s disease, traumatic brain injury). It is of great interest to identify interventional approaches to enhance glymphatic activity, specifically the CSF circulation. The goal of this study is to modulate glymphatic activities through the use of oscillating

electromagnetic field, at the slow wave frequency (typically observed in non-REM sleep and anesthetized states) that enhances CSF movement and brain waste clearance. The proposed animal study in pigs, if successfully completed, is expected to create a new glymphatic modulation paradigm (translatable to humans)

with significant implications for brain health improvement and intervention of neurological disorders. In aim 1 of the study we plan to measure the global impact of slow wave entrainment on brain waste clearance. Sub-aim 1-1: We will use MRI-gradient-based neuromodulation (termed MRI-stim) to achieve slow-

wave entrainment in propofol-anesthetized pigs, and then assess glymphatic activity improvement through analyzing brain waste clearance in CSF samples (Aβ1-42, Aβ1-40, total tau, and phosphorylated tau). Sub-aim 1-2: We will use TMS-based slow-wave entrainment to modulate glymphatic activity, and assess changes of

brain waste clearance in CSF samples. Exploratory sub-aim: We will perform an exploratory study that compares brain waste levels (measured from CSF samples) before and after applying glymphatic modulation to pigs with pharmacologically induced elevation of amyloid beta level in the brains (specifically, with

intravenously injected amyloid beta entering brains through pharmacologically compromised blood-brain barrier). EEG signals will be concurrently measured to confirm brain wave entrainment. In aim 2 we will measure the regional impact of slow wave entrainment on brain and glymphatic physiology. Sub-aim 2-1: we will use unified MRI-stim and imaging pulse sequences, that are capable of

achieving slow-wave entrainment as well as acquiring multi-contrast MRI data, in pigs anesthetized with propofol. Multi-contrast MRI data (dynamic diffusion MRI; phase-contrast MRI and ferumoxytol-based T2*- weighted MRI) will be acquired at multiple time points before and after slow-wave entrainment, so that

neuromodulation induced dynamic changes in glymphatic activity (reflecting influx and clearance of CSF and ISF) can be quantified. EEG and ECG data will be concurrently obtained throughout the neuromodulation- neuroimaging sessions. Sub-aim 2-2: we will use our MRI-compatible TMS-based slow-wave entrainment to

enhance glymphatic activity in propofol-anesthetized pigs, and measure changes in glymphatic physiology with multi-contrast MRI.