Electrophysiological Neuroimmunology in ME/CFS: Validating rTMS Target Engagement of Oscillatory and Neuroinflammatory Biosignatures

The proposed research addresses the critical need for mechanistically informed treatments for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a debilitating and unremitting condition currently lacking FDA-approved therapies. Our approach is grounded in the conceptualization of ME/CFS as a neuroimmune dysfunction characterized by brain network dysregulation driven by glial-neuronal coupling. Recent findings highlight a shared pathophysiological basis between ME/CFS and specific Long COVID subtypes, suggesting that breakthroughs in this area will have broad public health implications. This study utilizes a novel "electrophysiological neuroimmunology" framework to define neural targets and validate a therapeutic breakthrough using dual-target repetitive Transcranial Magnetic Stimulation (rTMS). We build upon our strong pilot data demonstrating that a 30-session protocol targeting the left dorsolateral prefrontal cortex (DLPFC) and primary motor cortex (M1) is both feasible and clinically beneficial. Preliminary evidence shows that high baseline delta/theta power and low alpha power serve as objective proxies for illness severity and predict treatment response. Simultaneously, collaborative whole-brain 3D Magnetic Resonance Spectroscopic Imaging (MRSI) has identified metabolic markers of neuroinflammation, including elevated lactate (LAC), choline (CHO) and myo-inositol (MI) in the cingulate and insula. We will recruit 30 ME/CFS patients, 30 Long COVID patients and 30 healthy controls. The project will integrate simultaneous rTMS-EEG with MRSI to confirm these pathophysiological signatures in ME/CFS and Long COVID patients compared to healthy controls. Half of the participants will receive sham rTMS. Aim 1 will establish objective biosignatures by comparing source-localized EEG oscillations and neuroinflammatory metabolite levels across cohorts. Aim 2 focuses on validating EEG-based target engagement by demonstrating that active rTMS normalizes pathological power spectra. Exploratory Aim 3 will quantify acute changes in a the neuroinflammatory markers (LAC, CHO, MI) can be achieved with rTMS. We anticipate that active rTMS will induce transient, normalizing reductions in neuroinflammation while restoring healthy cortical rhythms. This innovative study integrates TMS-EEG and wb-MRSI for the first time in this population. The results will provide a rigorous foundation for large-scale clinical implementation of dual-target rTMS. This work offers a biological blueprint for treating the neuroimmune causes of chronic fatigue by validating "electrophysiological neuroinflammation" as a modifiable target. By defining neural targets, the research moves the field toward precision care, transforming the standard from symptom management to a restorative approach. These outcomes will advance our understanding of how neuromodulation affects the neuroimmune-network axis. We expect these findings to pave the way for future biomarker-guided trials in multiple post-viral conditions.