John Mac
Senior Member (Voting Rights)
Full title: The Locus Coeruleus Norepinephrine Depletion Hypothesis of ME/CFS: A Mechanistic Model with Testable Predictions and Multimodal Study Plans(Protocol Framework)
Highlights
• ACEs programme the locus coeruleus into a maladaptive high-tonic/low-phasic firing mode
• Chronic LC overactivation depletes vesicular norepinephrine via ATP-dependent mechanisms
• Glymphatic clearance requires LC quiescence; persistent LC activation impairs waste removal
• The model explains ME/CFS core phenomena: PEM, unrefreshing sleep, orthostatic intolerance
• Testable predictions include LC neuromelanin MRI, NET-PET, CSF MHPG, and HRV correlates
Abstract
Background:
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterised bydysautonomia, unrefreshing sleep, and post-exertional malaise (PEM). Adverse childhoodexperiences (ACEs) are epidemiologically associated with ME/CFS, but mechanistic links remainunclear.
Hypothesis:
Repeated corticotropin-releasing factor (CRF)-driven stress from ACEs inducesa maladaptive ‘high-tonic/low-phasic’ firing mode in the locus coeruleus (LC). This leads tomitochondrial 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) LCneurons are metabolically vulnerable to chronic activation;
(iv) glymphatic function depends on LCquiescence during sleep.
Testable Predictions:
(1) Lower LC neuromelanin MRI signal correlateswith ACE scores and ME/CFS severity (a priori anticipated: r < −0.5).
(2) Reduced norepinephrinetransporter (NET) positron emission tomography (PET) binding in LC correlates with hypervigilance.
(3) Paradoxically low cerebrospinal fluid (CSF) 3-methoxy-4-hydroxyphenylglycol (MHPG) despiteautonomic 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.
Highlights
• ACEs programme the locus coeruleus into a maladaptive high-tonic/low-phasic firing mode
• Chronic LC overactivation depletes vesicular norepinephrine via ATP-dependent mechanisms
• Glymphatic clearance requires LC quiescence; persistent LC activation impairs waste removal
• The model explains ME/CFS core phenomena: PEM, unrefreshing sleep, orthostatic intolerance
• Testable predictions include LC neuromelanin MRI, NET-PET, CSF MHPG, and HRV correlates
Abstract
Background:
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterised bydysautonomia, unrefreshing sleep, and post-exertional malaise (PEM). Adverse childhoodexperiences (ACEs) are epidemiologically associated with ME/CFS, but mechanistic links remainunclear.
Hypothesis:
Repeated corticotropin-releasing factor (CRF)-driven stress from ACEs inducesa maladaptive ‘high-tonic/low-phasic’ firing mode in the locus coeruleus (LC). This leads tomitochondrial 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) LCneurons are metabolically vulnerable to chronic activation;
(iv) glymphatic function depends on LCquiescence during sleep.
Testable Predictions:
(1) Lower LC neuromelanin MRI signal correlateswith ACE scores and ME/CFS severity (a priori anticipated: r < −0.5).
(2) Reduced norepinephrinetransporter (NET) positron emission tomography (PET) binding in LC correlates with hypervigilance.
(3) Paradoxically low cerebrospinal fluid (CSF) 3-methoxy-4-hydroxyphenylglycol (MHPG) despiteautonomic 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.
