Patient-Centered Neurological Evaluation of Functional MRI Outcomes in Multiple Sclerosis

Abstract: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease with over 1 million individuals affected in the US; early diagnosis and effective treatment are thus critical to protect quality of life. MS diagnosis follows from lesions disseminated in time and space, including lesions in the spinal cord (SC). While SC lesions are associated with a higher rate of relapse, the association between neurological symptoms and progression with SC damage has been underexplored due to the challenges of imaging the SC. Functional MRI (fMRI) can uniquely probe SC function in the resting-state and relies on blood oxygenation level-dependent contrast to link neuronal activity with hemodynamic processes which, when spatially correlated, is a measure of functional connectivity (FC). Prior SC resting-state fMRI (rs-fMRI) showed ventral-ventral (motor) and dorsal-dorsal (sensory) gray matter FC at 7T using seed-based analyses, and that lesions can influence FC in patients with relapsing-remitting MS (pwRRMS). At 3T, diffusion-derived indices of microstructural damage were associated with FC, suggesting structural-functional interdependence. However, clinically relevant data-driven rs-fMRI FC signatures have not been explored in depth at 3T, nor their relationship with neurologic deficits. Evaluating data- driven rs-fMRI FC in the SC of pwRRMS and identifying associations with sensorimotor impairment may provide an objective evaluator of pathology in the MS SC, beyond what can be explained by structural (clinical) MRI or neurological evaluation alone. We hypothesize rs-fMRI SC FC is an objective surrogate for neurologic symptomatology, and that alterations in FC can be related to macrostructural (lesions), microstructural (diffusion), and/or vascular hallmarks (susceptibility). Unique to this proposal, we will apply rs-fMRI SC FC as a quantifiable measure to assess motor and sensory integrity of the cervical SC and investigate the complex interactions between disease deficits and SC rs-fMRI using ROI- and data-driven analyses (Aim 1). We will then evaluate how microstructural integrity influences observed FC using novel approaches such as tractography and lesionometry (Aim 2). Finally, vascular hallmarks, such as the central vein sign and paramagnetic rim lesions, have been identified in the MS cord by our group. We will utilize SC susceptibility imaging at 7T in the same cohorts to investigate whether these vascular hallmarks are related to altered FC measured at lower field (Aim 3). The clinical impact of this proposal is to evaluate rs-fMRI as a marker of neurologic impairment, in the same manner that fMRI has been utilized to predict surgical (non)responders in refractory temporal lobe epilepsy. From this proposal, we may better understand the impact of a devastating neurologic disease and empower patients with MS. This proposed fellowship will provide research training in a collaborative research atmosphere, with expert mentors in neuroimaging at a top-tier academic medical center and imaging institute uniquely suited to all aspects of this work. My training will further develop my resources and knowledge to become a physician- scientist focused on clinical investigation of cutting-edge imaging methods.