Hypothesis The Locus Coeruleus Norepinephrine Depletion Hypothesis of ME/CFS: A Mechanistic Model, 2025, Hemmerich

John Mac

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.

 
On the author:
Dr. Fritz Helmut Hemmerich has moved and researched a great deal in his rich life and work. For decades, the 70-year-old doctor and philosopher devoted himself to the secrets of life and the human body.
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Trauma solutions and burnout were the focal points of his biographical development. His work as a senior and head physician in Germany led him to his own professional life's work, a salutogenesis center on Tenerife and in Andalusia, which he runs together with Annette Hemmerich.
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He is the author of several important books on burnout, mental recovery, creative feeling, emotional leadership, awakening meditation, guided sound and being born into death.
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Dozierende Person:: Dr. med Fritz Helmut Hemmerich

www.polarity.ch www.polarity.ch
 
John Mac said:
Testable Predictions:
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At least they make testable predictions. That's more than we can say about most of the hypotheses out there. Too bad it already fails at least one prediction it makes. People have been playing HRV and the evidence seems that there is no clear correlation between HRV and symptom severity.

But I'd reject this hypothesis on the basis that it does not explain PEM as I usually do. The effect of the depletion in LC shouldn't take a long delay, and the depletion does not explain PEM lasting days or weeks.
 
I first thought this paper was by the same NIH researcher featured in IACFS/ME conference. It is from Spain. I guess LC vesicle depletion theory is now fashionable?
 
Creekside said:
I was wondering whether their predictions are the type testable only by questionnaires, which can be tailored to give the desired results.
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Symptom severity is the only predictions that really matters. Since there is no objective measure for it, I guess they'll have to resort to questionnaires like everybody else till someone come up with objective measures.

Which brings us to my favorite topic: objective measure of exertion, fatigue and PEM. I think coming up with them would be one of the most productive things we can do to aid the research.
 
Trish said:
Is he equating ME/CFS with burnout?
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Sounds like he's equating burnout with vulnerability to CFS and trying to explain an established correlation between ACE and CFS.

An acute trigger, often infection, overwhelms this vulnerable system, resulting in persistent neuroinflammation and impaired glymphatic clearance.
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Moreover:
Important caveats: The ACE-ME/CFS association is derived from cross-sectional data;prospective confirmation is lacking. Confounders including socioeconomic status, comorbidities, andretrospective reporting bias must be acknowledged. The model proposed here applies to ahypothesised subgroup with ACE histories; ME/CFS heterogeneity means other pathways likelyexist.
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Pieces of this argument might make sense but still have to be proven. Adverse childhood experiences are a reach beyond sound evidence. However brain immune activation and other stressor signals during viral infection that crosses the blood brain barrier, or even just from chemical signals that cross, are much more plausible, and might impact NE synthesis. I want to see the paper from the recent conference that shows dopamine beta hydroxylase suppression. I still think it makes sense, but it is probably not the entire story. Choosing between vague and potentially highly biased brain hypotheses and specific biochemical testable predictions, I will choose the specific biochemical testing.

A primary symptom of inherited dopamine beta hydroxylase deficiency is orthostatic intolerance. This version of LC and NE hypothesis is worth pursuing, but without the woo, to see if its testable predictions are valid.
 
‘It is quite easy to evaluate if someone has had a childhood trauma that caused their CFS. If they have CFS then they had such a trauma.’

However seriously, such theories are totally unfalsifiable retrospectively and therefore are not science. It is impossible to objectively quantify trauma retrospectively, particularly if we are talking about it decades after the postulated event. If there was a serious attempt to evaluate such models, trauma needs to be defined objectively and then predict in advance who will and who will not subsequently develop ME/CFS. Even then if an association was demonstrated, you can not rule out that something else cooccurring with the trauma was the actual causal agent.
 
At least the author gives some ways to prove/disprove their beliefs one of those is by looking at metabolities in the CSF. I think there should be several ME/CFS studies looking at CSF metabolites. They certainly did so in the intramural study but I didn't find the metabolite listed here, namely MHPG. The only study I found by a quick google search is a "Plasma and cerebrospinal fluid monoamine metabolism in patients with chronic fatigue syndrome: Preliminary findings", with the results as claimed by the author, I assume the author knew this and that's why they included this measurement.
 
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