Brainstem dysfunction as a potential etiology of ME/CFS and long COVID: A mechanical basis

The underlying mechanism of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) remains poorly understood. Given the dramatic increase in cases following the COVID-19 pandemic, it is important to establish a deeper understanding of the disease. We propose a model of how ME/CFS, and post-infectious syndromes such as long Covid (LC), might emerge following a viral insult. Central to this hypothesis is the recognition that the core diagnostic features of ME/CFS involve physiological systems known to be governed by the brainstem. With emerging literature suggesting that spinal and craniocervical pathologies may be over-represented in people with ME/CFS, we hypothesize that a non-trivial number of cases of ME/CFS and LC may have a “mechanical basis”: In vulnerable individuals, an infection may damage the connective tissue structures responsible for maintaining the physical integrity of the brainstem. This can lead to neuromechanical pathologies such as craniocervical instability (CCI) and intracranial pressure dysregulation that cause mechanical deformation or displacement of the brainstem. The resulting brainstem deformative stress causes autonomic nervous system, immune system, and metabolic dysfunction due to aberrant signaling from deformed brainstem nuclei, leading to the chronic and often lifelong presentation typical of ME/CFS. • The multi-systemic presentation of ME/CFS suggests dysfunction in the brainstem. • In some cases, connective tissue remodeling during infection may become pathological. • Damaged connective tissue results in mechanical forces exerted on the brainstem. • Illness will not abate as long as brainstem deformative stress is present. • This model suggests a number of research avenues, diagnostics, and interventions.