Hypothesis Chronic fatigue syndrome in MS: an endogenous response pattern to an immunological challenge mediated by orexin/hypocretin?, 2026, Hildebrandt et al

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Chronic fatigue syndrome in MS: an endogenous response pattern to an immunological challenge mediated by orexin/hypocretin?

Hildebrandt, Helmut; Stuke, Heiner

Abstract
Fatigue is a common and disabling symptom in patients with inflammatory or autoimmune diseases like Multiple Sclerosis, Rheumatoid Arthritis, and post-COVID syndrome. The biological basis of chronic fatigue remains unclear.

In this review, we argue that chronic fatigue should be conceptualized as a syndrome defined by an organismic state (changes in the autonomous nervous system, lower set points for executing movements), a behavioral response (loss of activity), and a mental state (the feeling of fatigue and a loss of drive).

We discuss empirical findings showing that fatigue is a functional consequence of an activated immune system, which modulates activity in posterior hypothalamic areas. Subsequently, we introduce orexin/hypocretin, a neurotransmitter expressed by neurons of the posterior hypothalamus, as a major target of the neuroinflammatory reflex, and we argue that the dysregulated modulation of circadian orexinergic release might offer a biological explanation of many aspects of the chronic fatigue syndrome.

We then analyze the functions of orexin/hypocretin in different domains of behavior (energy and motivation, sleep, autonomous nervous system activation, pain, and anxiety), and try to show that the ensemble of disturbances in these functions constitute the fatigue syndrome. In the last part of the paper, we briefly discuss potential implications of this explanation for the treatment of chronic fatigue syndrome.

Web | DOI | PDF | Brain Disorders | Open Access
 
This is a psychology group and they end up recommending psychotherapy as well as pills - on the grounds that you can 'unlearn' chronic fatigue.

The paper is long and rather one-sided. Orexin does everything so it probably does chronic fatigue syndrome (which they seem to equate to chronic fatigue in all diseases including MS).
Orexin is interesting but I did not pick up anything very special here that changed my view on it.
 
The paper said:
In this review, we argue that chronic fatigue should be conceptualized as a syndrome defined by an organismic state (changes in the autonomous nervous system, lower set points for executing movements), a behavioral response (loss of activity), and a mental state (the feeling of fatigue and a loss of drive).
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This is where the whole concept falls apart. No matter how many times they hear from most patients telling them that we badly want to do things but we can't, they will always twist fatigue to include, to be mainly about, loss of motivation. It doesn't matter how many times it's disproved, it's been decided to be true, presumably at some secret society bunker meeting with powerful medical wizards, or whatever, somewhere in the 14th century, presumably, and that's just what it is. The "feeling of fatigue" is also not a mental state, and the resulting loss of activity is not behavior. What a bunch of useless crap.

Every single time the direct voice of patients is available to speak on this it's one of the dominant, if not the primary, theme. And it doesn't matter one bit. It doesn't matter who votes, how many votes were cast, or who the voters voted for. The only thing that matters is who counts the votes. It's the only thing that counts, it's the only thing that's actually counted.

Every bit of inconvenient, conflicting data on this is dutifully ignored. Every single made-up interpretation of those things is amplified to excess, forcing a narrative whose outcomes no one actually wants, but the egocracy must save face and maintain that it was always, and will always be, forever right, simply because it can't be wrong, is all-knowing and all-powerful, except when it conveniently isn't.
 
In a recent paper [122], we argued that associative learning, over-generalization of environmental consequences, and avoidance behavior are also core features of the chronic fatigue syndrome and that these consequences need to be treated by variants of psychotherapeutic interventions entailing exposition, extinction, and regaining a sense of self-efficacy.
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For these interventions, an additional pharmacological intervention might be helpful, tackling set point definition and energy ranges related directly to the activity of orexinergic neurons.
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However, this will not replace the task of extinction and successive recovery of deconditioning. It also will not have any impact on the status of the adaptive immunological system.
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Therefore, pharmacological and psychological interventions both have their strengths and weaknesses (for example, in the case of the treatment of depressive episodes).
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From their other paper:

Highlights​

  • We propose that fatigue in MS involves a sensory component reflecting the state of the immune system.
  • The predetermined consequence of this feeling is a reduction of behavior.
  • The main treatment goal is to learn a strategy to distract attention from the feeling of fatigue.
  • The second step therefore includes graded exposition by executing the fatigue-reducing strategy.
  • A central element of the treatment should be a systematic reconditioning program to enhance fitness.
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Psychobabble is characterised nothing so much as its stubborn failure to learn from its obvious mistakes. If anything it wilfully repeats them and endlessly compounds the whole disaster.

All it is proving is the danger of theory led medicine.

The psychopathology is in their minds, not patients'.
 
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