The Locus Coeruleus Norepinephrine Depletion Hypothesis of ME/CFS: A Mechanistic Model with Testable Predictions and Multimodal Study Plans (Protocol Framework)

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is character-ised by dysautonomia, unrefreshing sleep, and post-exertional malaise. Epidemiologicalstudies have identified an association between adverse childhood experiences (ACEs) andME/CFS risk, but the mechanistic links underlying this relationship remain unclear. Hypothesis: We propose that repeated corticotropin-releasing factor-driven stress arisingfrom ACEs induces a maladaptive 'high-tonic/low-phasic' firing mode in the locus co-eruleus. Over time, this leads to mitochondrial strain, adenosine triphosphate shortfall,and vesicular norepinephrine depletion—producing a 'wired-but-tired' state in which neu-rons fire continuously but release inadequate neurotransmitter. An acute trigger, oftenviral infection, then overwhelms this vulnerable system, resulting in persistent neuroin-flammation and impaired glymphatic clearance. Rationale: Four lines of evidence support this hypothesis. First, ACE-related autonomicand inflammatory signatures persist into adulthood and are well documented. Second,preliminary pharmacological observations suggest substrate limitation rather than recep-tor dysfunction. Third, LC neurons are known to be metabolically vulnerable to chronicactivation. Fourth, recent research has established that glymphatic function depends crit-ically on LC quiescence during sleep. Testable Predictions: The hypothesis generates five specific, falsifiable predictions. First,LC neuromelanin MRI signal should be reduced and correlate inversely with ACE scoresand ME/CFS severity. Second, norepinephrine transporter PET binding in the LC regionshould be reduced and correlate with hypervigilance symptoms. Third, cerebrospinal fluidlevels of 3-methoxy-4-hydroxyphenylglycol should be paradoxically low despite autonomicsymptoms suggesting high sympathetic activity. Fourth, heart rate variability and pupil-lometry measures should correlate with functional capacity. Fifth, pharmacological probestudies should differentiate substrate-limited from receptor-limited states. Limitations: Several important limitations must be acknowledged. No direct measure-ments of vesicular norepinephrine content in human LC neurons currently exist. TheACE-ME/CFS association derives from cross-sectional data, and prospective confirmationis lacking. The pharmacological observations that inform this hypothesis are anecdotal ra-ther than derived from controlled studies. Prospective validation is therefore essential.