Miscellaneous Research Thread

It looks as if CRH very much does have other functions and ones of direct relevance to ME/CFS, fibromyalgia and dorsal root ganglia (and maybe CA10):

CRH is expressed in peripheral tissues outside of the central nervous system (CNS) and directly exerts extensive effects on cardiovascular, reproductive, digestive, and immune systems (15). Gastrointestinal CRH delays the motility of the gastrointestinal tract response to stress and even enhances visceral pain, a predominant feature of irritable bowel syndrome (IBS). Immunostaining has revealed CRH-positive neurons in the DRG and TG, as well as CRH-positive fibers in the superficial layer of the spinal cord and trigeminal complex in the medulla, where the central terminals of primary nociceptive neurons end (16). Under the neuropathic state, CRH expression is increased in damaged DRG neurons; however, whether and how CRH tunes pain signals at the DRG and spinal cord level remains unclear (17).
CRH receptors (CRHR1 and CRHR2) belong to the G protein–coupled receptor (GPCR) superfamily, members of which are widely distributed in nervous and peripheral tissues and integrate the responses of these tissues to various internal and external stimuli. Peripheral CRHR1 and CRHR2 mediate diverse functions in different organs. Pharmacologic data have shown that CRHR1 and CRHR2 play a counteracting role in the occurrence of visceral pain induced by colorectal distention (18). Multiple experimental studies have showed that CRH receptors (CRHR1 and CRHR2) are expressed in primary sensory neurons, the spinal cord, and the trigeminal complex in the medulla under normal and neuropathic pain conditions (16, 19–21). Thus, CRH might act on its receptors to tune the pain signals in the DRG and spinal cord after peripheral nerve injury.
Here, we investigated the function of DRG-localized CRH in persistent and chronic neuropathic pain. Through analysis of public datasets and a mouse model, we found that CRH expression in small- and medium-sized neurons of the DRG is induced in a transcription-dependent manner after peripheral nerve injury and mediates a persistent neuropathic pain state through activation of its receptor CRHR2 on dorsal spinal neurons. The findings reveal potential targets for alleviating neuropathic pain caused by peripheral nerve injury.
 
Interesting to see Iwasaki giving credence to the idea that Covid escaped from the Wuhan lab, even if she is diplomatically non-committal. The pity is that she does not spell out the madness of labs continuing to play around with gene editing of viruses with never any guarantee that safety procedures are up to scratch.
 
Short letter in a Canadian journal. I think it's in response to: Exercise and pharmacologic management of fibromyalgia (2026, Canadian Family Physician)

Exercise May Cause Harm in a Subset of Fibromyalgia Patients
  • Farah Tabassum, Focused Practice Family Physician at the Environmental Health Clinic, Women’s College Hospital, Women's College Hospital; Part-time Clinical Lecturer, Department of Family and Community Medicine, University of Toronto
  • Other Contributors:
    • Kathleen Walsh, Family Physician, NOSM University
    • Kathleen Kerr, Focused Practice Family Physician at the Environmental Health Clinic, Women’s College Hospital, Women's College Hospital; Clinical Lecturer, Department of Family and Community Medicine, University of Toronto
    • Moira Sarah A. Selke, Focused Practice Family Physician at the Environmental Health Clinic, Women’s College Hospital, Women's College Hospital

Snippets:
Thank you for this informative article on the management of fibromyalgia. The authors provide a clear and concise summary of current Canadian guidelines, including the emphasis on encouraging patients to engage in a graduated exercise program.
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An important consideration that is not addressed in the article or the Canadian fibromyalgia guidelines is the impact of exercise recommendations on fibromyalgia patients with comorbid myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), hereafter referred to as ME.
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In patients with fibromyalgia alone, exercise may indeed be appropriate and beneficial. In contrast, for those fibromyalgia patients with coexisting ME, physical exertion may precipitate post-exertional malaise (PEM), which is a defining feature of ME.
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Web | Canadian Family Physician | Letter | 2026
 
Grabbing most of that abstract.

193 | Advanced Diffusion MRI Reveals Distinct White Matter Pathophysiology in Myalgic Encephalomyelitis and Fibromyalgia (2026)

AIMS
[…] to: (i) identify in vivo white matter (WM) neuroinflammatory changes in ME/CFS and FMS, and (ii) clarify whether the two conditions share common or distinct WM pathophysiology.

METHODS
[…]

RESULTS
Compared with HCs, ME/CFS patients demonstrated widespread white matter abnormalities across association, commissural, and projection fibres, characterised by significantly lower NII-HR and NII-RF, alongside higher NII-FF, NII-AD, NII-MD, NII-FA and DTI-AD, with regional reductions in NII-AD and NII-MD also observed. In contrast, FMS patients only showed evidence of significantly higher NII-AD, NII-FA, DTI-AD and DTI-FA in several major white matter tracts.

CONCLUSION
These findings provide important confirmatory evidence of WM neuroinflammation in ME/CFS, consistent with cerebral oedema (reduced NII-HR), cellular infiltration (reduced NII-RF), and axonal reorganisation (increased NII-FF), supporting the investigation of anti-neuroinflammatory therapies. FMS, while lacking unequivocal NII evidence of WM neuroinflammation, is associated with altered tissue composition, underscoring its legitimacy as a significant neurological condition. Together, the results suggest that ME/CFS and FMS are biologically distinct entities rather than manifestations of a single pathogenetic continuum.

Authors of Evidence of White Matter Neuroinflammation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Diffusion-Based Neuroinflammation Imaging Study (2026)
 
O15 Is there more to understand about circadian rhythm sleep wake disorders (CRSWDs) in young adults with autistic spectrum conditions (ASC) referred to myalgic encephalopathy/Chronic fatigue syndrome (ME/CFS) services? A case report
Catchpool, Nicola; Hill, Elizabeth
Introduction
The Bath Centre for Fatigue Services (BCFS) is a national Consultant Allied Health Professional-lead service, providing evidence-based treatments for a range of long-term health conditions predominantly ME/CFS, where longstanding fatigue impacts on daytime function and engagement in meaningful occupations.

Presentations of fatigue vary and can be complex and multifactorial, involving multi-morbidities, anxiety, mental health conditions and neurodiversity. It can be challenging to understand where and how sleep features in the midst of such presentations. ME/CFS is a condition that is often considered as an explanation. However, is there enough awareness of CRSWDs to ensure individuals receive appropriate support and treatment?

Method
This case report presents a general practitioner (GP) referral to BCFS for a young autistic adult with suspected ME/CFS and the subsequent steps to identify an underlying sleep-related cause for their symptoms, drawing on current diagnostic criteria and published guidelines.

Results
The patient’s demographic and clinical/sleep history is shown in table 1. Sleep diary data demonstrated a non-24hr sleep/wake rhythm/disorder (N24SWD), with a step-wise delaying sleep phase (table 1). Delayed sleep-onset is present when trying to maintain a consistent bedtime. Sleep duration averages 8.6 hours over four weeks.

Discussion
The prevalence of N24SWD in the sighted population is uncommon (Malkani etal 2018). Carmassi etal (2019) suggest the prevalence may be higher in individuals with ASC due to reduced melatonin production and the role that melatonin is thought to play in circadian rhythm maintenance.

There may be overlap between ME/CFS and CRSWDs (Jackson & Bruck 2012). Education in sleep medicine may help accurately identify causes of disrupted circadian rhythm, providing opportunity for appropriate diagnosis. Collaborative working across fatigue and sleep services, could optimise skills and resources to improve individual’s ability to engage in meaningful occupations and positively influence quality of life.
Web | DOI | PDF | BMJ Open Respiratory Research | 2026 | Abstract
 
forestglip said:
O15 Is there more to understand about circadian rhythm sleep wake disorders (CRSWDs) in young adults with autistic spectrum conditions (ASC) referred to myalgic encephalopathy/Chronic fatigue syndrome (ME/CFS) services? A case report
Catchpool, Nicola; Hill, Elizabeth
Introduction
The Bath Centre for Fatigue Services (BCFS) is a national Consultant Allied Health Professional-lead service, providing evidence-based treatments for a range of long-term health conditions predominantly ME/CFS, where longstanding fatigue impacts on daytime function and engagement in meaningful occupations.

Presentations of fatigue vary and can be complex and multifactorial, involving multi-morbidities, anxiety, mental health conditions and neurodiversity. It can be challenging to understand where and how sleep features in the midst of such presentations. ME/CFS is a condition that is often considered as an explanation. However, is there enough awareness of CRSWDs to ensure individuals receive appropriate support and treatment?

Method
This case report presents a general practitioner (GP) referral to BCFS for a young autistic adult with suspected ME/CFS and the subsequent steps to identify an underlying sleep-related cause for their symptoms, drawing on current diagnostic criteria and published guidelines.

Results
The patient’s demographic and clinical/sleep history is shown in table 1. Sleep diary data demonstrated a non-24hr sleep/wake rhythm/disorder (N24SWD), with a step-wise delaying sleep phase (table 1). Delayed sleep-onset is present when trying to maintain a consistent bedtime. Sleep duration averages 8.6 hours over four weeks.

Discussion
The prevalence of N24SWD in the sighted population is uncommon (Malkani etal 2018). Carmassi etal (2019) suggest the prevalence may be higher in individuals with ASC due to reduced melatonin production and the role that melatonin is thought to play in circadian rhythm maintenance.

There may be overlap between ME/CFS and CRSWDs (Jackson & Bruck 2012). Education in sleep medicine may help accurately identify causes of disrupted circadian rhythm, providing opportunity for appropriate diagnosis. Collaborative working across fatigue and sleep services, could optimise skills and resources to improve individual’s ability to engage in meaningful occupations and positively influence quality of life.
Web | DOI | PDF | BMJ Open Respiratory Research | 2026 | Abstract
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Could have been about me! Lots of folks with sighted N24 are diagnosed with ME/CFS as well, but most I spoke to don't consider ME to be a misdiagnosis. You wouldn't expect N24 to cause such a wide range of symptoms that arranges so well to ME/CFS, but who knows, as the level of sleep deprivation can get pretty extreme.
 
Chronic Fatigue Syndrome in MS: an endogenous response pattern to an immunological challenge mediated by orexin/hypocretin? (Brain Disorders, May 2026, open access)
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.

The role of sphingolipids in major depressive disorder and associated cognitive impairment: interactions with monoaminergic signaling, neuroinflammation, and neurogenesis (Molecular Psychiatry, May 2026, open access)
Major depressive disorder (MDD) represents a leading cause of disability. Despite decades of research focused on monoaminergic dysregulation, the exact pathophysiological mechanisms underlying MDD remain incompletely understood. This gap in knowledge has contributed to suboptimal therapeutic outcomes, with approximately one-third of MDD patients showing resistance to conventional treatments. Recent advances in lipidomics support that sphingolipids—including ceramides, sphingomyelins, and their metabolites—could play important roles in depression pathophysiology. This review examines the role of sphingolipid dysregulation in MDD and associated cognitive impairment, with a particular focus on interactions with neurogenesis and apoptosis, monoaminergic signaling, neuroinflammation, mitochondrial dysfunction and oxidative stress, glutamatergic signaling, and synaptic plasticity. Several clinical studies demonstrate altered sphingolipid profiles in MDD patients, with elevated ceramide levels correlating with depression severity. Preclinical evidence supports potential causal relationships between sphingolipid alterations and depressive behaviors through effects on neurotransmission, neuroplasticity, neurogenesis, mitochondrial function, and inflammatory processes. Many established antidepressants influence sphingolipid metabolism through distinct mechanisms—acting directly as functional inhibitors of acid sphingomyelinase (ASM) or modulating this pathway indirectly. This mechanistic convergence positions sphingolipid dysregulation as a potential central mediating node across major pathophysiological pathways in MDD and as a common pathway through which key risk factors may converge, potentially explaining its biological heterogeneity. Sphingolipid metabolism also offers a potential mechanistic explanation for the frequently observed cognitive deficits in MDD. This review synthesizes current evidence regarding sphingolipid involvement in depression pathophysiology and outlines promising avenues for personalized medicine through biomarker development and sphingolipid-targeted therapeutics.
 
Alinda said:
Could have been about me! Lots of folks with sighted N24 are diagnosed with ME/CFS as well, but most I spoke to don't consider ME to be a misdiagnosis. You wouldn't expect N24 to cause such a wide range of symptoms that arranges so well to ME/CFS, but who knows, as the level of sleep deprivation can get pretty extreme.
Click to expand...
Some form of non-24 was central to what I think of as the prodromal phase of my MECFS.
 
494 IgG-mediated mast cell dysregulation drives chronic pain in post-acute sequelae of SARS-CoV-2 (PASC)
Limerick, Gerard; Sanchez, Karla; Dong, Xinzhong
Objectives/Goals
PASC affects 6% of individuals recovering from SARS-CoV-2 infection. The primary objective of this study was to explore the underlying neuroimmune changes which are responsible for the chronic widespread pain and fatigue that these patients often experience.

Methods/Study Population
We recruited eight post-acute sequelae of SARS-CoV-2 (PASC) patients from the PASC and physical medicine and rehabilitation clinics. Patients were included if they had daily, chronic pain, rated at least 5/10 intensity on the numeric rating scale. Patients were excluded if they had pre-existing pain or autoimmune conditions. Healthy age-matched controls were also recruited.

We obtained blood samples from both groups of patients and purified IgG from the plasma. The IgG was reconstituted and transferred to 48 mice via intraperitoneal injection. After IgG transfer, we completed behavioral, flow cytometry, immunofluorescence, and degranulation assays to quantify the effects of the IgG on the animal’s behavior and mast cell activity.

Results/Anticipated Results
IgG from PASC patients selectively binds mast cells and induces greater mast cell activation and degranulation than IgG from healthy control patients (p<0.001). This increase in mast cell activation is dependent on mas-related G-protein coupled receptor member X2 signaling.

Transferring IgG from PASC patients to mice produces increased sensitivity to cold (p<0.001) in the animals and also decreases their locomotor activity (p<0.01). IgG from healthy patients did not induce any changes cold sensitivity in the animals, nor did it affect their locomotor activity (p<0.001).

Lastly, transferring IgG from PASC patients to mice increases the mast cell population in the animals’ hindpaws (p<0.05).

Discussion/Significance of Impact:
This work elucidates a pathophysiological mechanism involved in the development of PASC-associated chronic pain. It also provides insights that may be useful in understanding the pain that is often associated with other autoimmune conditions.
Web | DOI | PDF | Journal of Clinical and Translational Science | Abstract
 
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