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 characterised by dysautonomia, unrefreshing sleep, and post-exertional malaise (PEM). Adverse childhood experiences (ACEs) are epidemiologically associated with ME/CFS, but mechanistic links remain unclear. Hypothesis: Repeated corticotropin-releasing factor (CRF)-driven stress from ACEs induces a maladaptive 'high-tonic/low-phasic' firing mode in the locus coeruleus (LC). This leads to mitochondrial strain, adenosine triphosphate (ATP) shortfall, and vesicular norepinephrine (NE) depletion, producing a 'wired-but-tired' state. An acute trigger, often infection, overwhelms this vulnerable system, resulting in persistent neuroinflammation and impaired glymphatic clearance. Rationale: (i) ACE-related autonomic and inflammatory signatures persist into adulthood; (ii) preliminary pharmacological observations suggest substrate rather than receptor limitation; (iii) LC neurons are metabolically vulnerable to chronic activation; (iv) glymphatic function depends on LC quiescence during sleep. Testable Predictions: (1) Lower LC neuromelanin MRI signal correlates with ACE scores and ME/CFS severity (a priori anticipated: r < -0.5). (2) Reduced norepinephrine transporter (NET) positron emission tomography (PET) binding in LC correlates with hypervigilance. (3) Paradoxically low cerebrospinal fluid (CSF) 3-methoxy-4-hydroxyphenylglycol (MHPG) despite autonomic symptoms. (4) Heart rate variability (HRV) and pupillometry track functional capacity. (5) Pharmacological probe studies differentiate substrate-limited from receptor-limited states. Limitations: No direct vesicular NE measurements exist; ACE-ME/CFS association is cross-sectional; pharmacological observations are anecdotal. Prospective validation required.