Magnetic Resonance Analysis of Neural Inflammatory Factors and External Stimulation (MANIFEST)

Background: Chronic symptoms from infection with SARS-CoV-19 can have debilitating effects on return to service, functional independence and quality of life. Unfortunately, evidence-based therapies for post-acute sequelae of COVID-19 (PASC) have not been established, and therapies borrowed from other neuroinflammatory disease models have only modest effects. To improve the availability of treatments for neurological symptoms of PASC ("neuro-PASC"), our collaborative team has used a novel magnetic resonance imaging (MRI) sequence, called diffusion magnetic resonance spectroscopy (dMRS) to demonstrate that neuro-PASC symptoms such as impaired attention are associated with increased inflammation in the thalamus. We have also demonstrated that repetitive transcranial magnetic stimulation can modulate inflammatory changes in the thalamus using a stimulation paradigm called intermittent theta burst stimulation (iTBS) with an accelerated schedule (multiple treatments/day) and functional MRI guidance. Additionally, these treatments lead to robust improvements in depression and anxiety within nine days, even in treatment-resistant patients. Therefore, the MANIFEST study team will apply this paradigm to improve chronic neuro-PASC symptoms in patients following COVID-19 infection (fiscal year 2023 Peer Reviewed Medical Research Program Clinical Trial Award Neuroscience topic area of "Neuroinflammatory Responses to Emerging Viral Diseases," strategic goal of "Treatment: develop and evaluate novel treatments, strategies, or therapeutic targets for associated neurological diseases and psychological conditions"). We will use advanced fiber tract imaging techniques and finite element modeling of the induced electric field in the brain to predict response to stimulation. Objective/Hypothesis: The objective of this application is to conduct a prospective, randomized, sham-controlled trial of accelerated, fMRI-guided iTBS to improve neuro-PASC symptoms. Aim 1: Demonstrate that accelerated iTBS is effective and feasible for reducing neuro-PASC symptoms. Hypothesis 1: Participants undergoing active iTBS in MANIFEST will demonstrate a significantly greater reduction in neuro-PASC symptoms, depression, and anxiety with active stimulation compared to sham stimulation (Visit #1-#2). These benefits will also be observed in the open-label phase following the sham-controlled phase (Visit #2-#3). Aim 2: Identify neurometabolic and structural features associated with outcomes in MANIFEST. Hypothesis 1: Patients with neuro-PASC undergoing active iTBS in MANIFEST will demonstrate a significant change in dMRS-based ADCcho in the thalamus from Visit #1 to #2 compared to sham iTBS, and this will correlate with improvement in clinical symptoms. Integrity of white matter projections and electric field magnitude in the DLPFC from Visit #1 will also predict response. Study Design: Sixty patients with neuro-PASC will undergo demographic, clinical and cognitive assessment at baseline after consenting. They will undergo resting-state fMRI to analyze functional network connectivity, as well as dMRS and diffusion tensor imaging to characterize metabolic activity and white matter integrity of the dlPFC, respectively. Functional data will be processed to determine the target in the dlPFC most anticorrelated with the subgenual cingulate cortex. They will then be randomized to 25 sessions (5 sessions/day, 5 days) of active (n=30) or sham (n=30) accelerated fMRI-guided iTBS delivered to the left dlPFC during the blinded phase. Testing and MRI are repeated, then all 60 participants will receive 25 sessions of active iTBS in the open-label phase. After the final session, they will repeat all assessments and MRI. At 1, 3, and 6 months, participants will be called to report on neuro-PASC symptoms to establish longevity and stability of clinical benefit. Clinical Impact: If successful, in the near-term future MANIFEST will provide critical information about effect size, tolerability and clinical and imaging predictors of efficacy that will inform a phase 3 multi-site study. In the long-term future, Long COVID clinical programs will be able to adopt MANIFEST as a treatment option for neuro-PASC, as many medical centers in the civilian and VA spheres already have the equipment necessary to perform accelerated iTBS. Our data will also inform a common best target that can be used generically. As a result, patients will experience faster recovery, increased levels of functioning, improved quality of life and diminished morbidity from ineffective treatments. Relevance to Military Health: PASC is a common and significant health problem for civilians, Veterans and active-duty Service Members and is associated with significant disability and reduced quality of life. Substantial resources are currently devoted to the definition, characterization, and pathophysiology or PASC, and yet there are still no established mechanisms of disease nor evidence-based treatments available. MANIFEST seeks to study and validate accelerated fMRI-guided iTBS as a rapid-acting, personalized treatment option for patients and clinicians that mitigates thalamic neuroinflammation. Less