Project Summary A large and increasing number of patients who have been infected with SARS-CoV-2, the virus that causes COVID-19, continue to experience a constellation of symptoms long past the time that they have recovered from the initial illness (long-COVID). The most frequently reported symptoms were fatigue, post exertional malaise and cognitive dysfunction, which are the main symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Clinically, many long-COVID patients fulfill the diagnostic criteria for ME/CFS. Post pandemic, we expect to see an increasing number of individuals with long-COVID ME/CFS. An important question is whether those with COVID ME/CFS are essentially the same as those with non-COVID ME/CFS and should be evaluated and treated similarly. If so, this group of COVID-related patients’ CFS could inform us about the features and mechanisms of ME/CFS in general. Although it was suggested that the brain is the organ responsible for both forms of ME/CFS, currently no specific neuroimaging biomarkers have been identified. In this project, we aim to conduct comprehensive neurological magnetic resonance imaging (MRI) to compare the similarities and differences between long-COVID and classic ME/CFS patients, as well as to individuals not affected by ME/CFS, in terms of brain anatomical and metabolic features. MRI exams at ultra-high field, such as 7 Tesla, offers exquisite resolution and can elucidate subtle abnormalities in the brain structure. We will apply advanced 7 Tesla MRI neuroimaging techniques to exam the cerebrum and brainstem. Beyond structural changes, limited studies have shown altered cerebral blood flow and increased cerebroventricular lactate in ME/CFS patients than sedentary controls suggesting perfusion and oxygen metabolic properties might be altered in ME/CFS. Another research focus of this project is to assess changes in oxygen metabolism of ME/CFS in vivo using MRI based methods. We will be measuring the oxygen level in the venous blood of sagittal sinus and the global cerebral blood flow using advanced MRI techniques. Using these parameters, we can calculate the global cerebral metabolic rate of oxygen in the brain which can inform us on whether energy failure is present in individuals with ME/CFS and long-COVID, as previously postulated. Finally, the structural volumetric and metabolic parameters measured by MRI will be correlated with patients’ self-reported symptom burden and multidimensional fatigue level. Completion of this timely study will provide comparison of COVID and non-COVID ME/CSF in terms of changes in brain anatomical features and oxygen metabolic properties, as well as how these imaging parameters are related to the disease burden. The knowledge learned from the structural and metabolic study will deepen our understanding the ME/CFS/long-COVID disease mechanisms, aid in ME/CFS diagnosis, inform treatment decisions and inspire new treatment targets.

Narrative Many long-COVID patients fulfill the clinical diagnostic criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). In this project, we aim to conduct comprehensive neurological magnetic resonance imaging (MRI) to compare the similarities and differences between long-COVID and classic ME/CFS patients, as well as to individuals not affected by ME/CFS, in terms of brain anatomical and metabolic features. Furthermore, the structural volumetric and metabolic parameters measured by MRI will be correlated with patients’ self-reported symptom burden and fatigue level.