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A Mechanical Basis: Brainstem Dysfunction as a Potential Etiology of ME/CFS and Long COVID The underlying pathologies driving post-acute infectious syndromes (e.g. myalgic encephalomyelitis / chronic fatigue syndrome, long COVID, etc) remain poorly understood. Given the extreme burden these illnesses impose on suffers, and the dramatic increase in cases following the COVID-19 pandemic, it is important to establish a deeper understanding of these pathologies. We propose a model of how ME/CFS (and related illnesses), might emerge following a viral insult. Central to this hypothesis is the recognition that the core diagnostic features of ME/CFS involve bodily systems known to be governed by the brainstem. This is consistent with the growing literature suggesting that spinal and craniocervical pathologies are over-represented in people with ME/CFS and other post-infectious disorders. We hypothesize that a non-trivial number of cases of ME/CFS and Long Covid (LC) may have a ``mechanical basis." We propose that an infectious insult may trigger an initial loss of connective tissue integrity in susceptible individuals (e.g. those with pre-existing hypermobility spectrum disorders), which in turn leads to instability at the craniocervical junction, and ultimately mechanical deformation of the brainstem. This ultimately causes widespread autonomic nervous system and immune system dysfunction due to aberrant signaling from the deformed nuclei. This causal chain may also lead to a vicious cycle: if the dysregulation produced by the initial brainstem deformation leads to a deranged immune response or state of chronic hyper-inflammation, further expression of connective tissue degrading and remodeling factors such as MMPs and mast cells may be triggered. This could further degrade the connective tissues of the craniocervical junction and, in turn, increase mechanical deformation of the brainstem, leading to symptom exacerbation over time and leading to the chronic, lifelong presentation typical of ME/CFS. https://www.preprints.org/manuscript/202506.0874/v1