Evidence of clinical and brain recovery in post-COVID-19 condition: a three-year follow-up study

Abstract:

Fatigue and cognitive dysfunction linked to persistent brain changes have been reported for up to two years after COVID-19. In this study, we followed the clinical, neuroimaging and fluid biomarker trajectories over three years post SARS-CoV-2 infection to evaluate potential signs and underlying factors of brain recovery.

We conducted a monocentric, longitudinal study using resting-state functional and structural T1-weighted magnetic resonance imaging data from 51 patients with Post-COVID-19 Condition (mean age 50 years, 33 female) collected at a mean time of 6, 23 and 38 months after COVID-19 infection. The trajectory of brain changes was compared to 23 age- and sex-matched healthy controls (mean age 37 years, 13 female) with similar time intervals between brain scans and analysed in relation to clinical, neuropsychological and fluid biomarkers including interleukins and neurodestruction markers at all timepoints. In addition, hand grip strength to evaluate muscular fatigue, was assessed at the final follow-up visit.

Self-reported fatigue improved over time but was still moderate on average three years after COVID-19 infection, while measures of hand grip strength and cognitive performance were largely unaffected. We found a significant increase of both lateral ventricles (∼8%) and the third (∼6%) ventricle accompanied by a structural volume reduction in adjacent areas including the thalamus, pallidum, caudate nucleus and putamen. An increased neuronal activation pattern was widespread and pronounced in these areas. The brainstem no longer exhibited volume loss as reported in our pervious study, but enhanced functional connectivity. Laboratory markers including interleukins and neuronal injury markers remained within the normal reference ranges across all study timepoints.

Our study revealed an overall slow but evident clinical improvement, including improved fatigue, regular muscular strength and recovery as well as normal cognitive function without signs of systemic inflammation three years after COVID-19. Clinical improvement is reflected by a pattern of brain recovery along periventricular regions. This pattern is characterized by structural stabilization and increased connectivity starting in the brainstem as well as efficient neuronal recruitment and increased activation in the basal ganglia, with no evidence of neuronal injury. These results highlight the positive long-term recovery trajectory in post-COVID patients.

Source: Ravi Dadsena, Sophie Wetz, Anna Hofmann, Ana Sofia Costa, Sandro Romanzetti, Stella Andrea Lischewski, Christina Krockauer, Carolin Balloff, Ferdinand Binkofski, Jörg B Schulz, Kathrin Reetz, Julia Walders, Evidence of clinical and brain recovery in post-COVID-19 condition: a three-year follow-up study, Brain Communications, 2025;, fcaf366, https://doi.org/10.1093/braincomms/fcaf366 https://academic.oup.com/braincomms/advance-article/doi/10.1093/braincomms/fcaf366/8262587 (Full study available as PDF file)

Gulf War Illness, Fibromyalgia, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID Overlap in Common Symptoms and Underlying Biological Mechanisms: Implications for Future Therapeutic Strategies

Abstract:

Although Gulf War Illness (GWI), fibromyalgia (FM), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID have distinct origins, in this article we have reviewed evidence that these disorders comprise a group of so-called low-energy associated disorders with overlapping common symptoms underlying pathology.

In particular, evidence for mitochondrial dysfunction, oxidative stress, inflammation, immune dysregulation, neuroendocrine dysfunction, disrupted brain-gut-microbiome axis, apoptosis/ferroptosis and telomere shortening as common features in the pathogenesis of these disorders has been identified.

Given the role of coenzyme Q10 (CoQ10) in promoting normal mitochondrial function, as an antioxidant, antiinflammatory and antiapoptotic and antiferroptotic agent, there is a rationale for supplementary CoQ10 in the management of these disorders. The reported benefits of supplementary CoQ10 administration in GWI, FM, ME/CFS and long COVID have been reviewed; the potential benefit of supplementary CoQ10 in reducing telomere shortening and improving the efficiency of stem cell transfer relevant has also been identified as promising therapeutic strategies in these disorders.

This review advances beyond previous systematic reviews and consensus statements on overlapping similar symptoms and underlying biological pathomechanisms in these complex disorders.

Source: Mantle D, Domingo JC, Golomb BA, Castro-Marrero J. Gulf War Illness, Fibromyalgia, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID Overlap in Common Symptoms and Underlying Biological Mechanisms: Implications for Future Therapeutic Strategies. Int J Mol Sci. 2025 Sep 17;26(18):9044. doi: 10.3390/ijms26189044. PMID: 41009608. https://www.mdpi.com/1422-0067/26/18/9044 (Full text)

Endometriosis and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Systematic Review and Meta-Analysis

Abstract:

Background/Objectives: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and endometriosis are debilitating conditions that share overlapping features of chronic inflammation and immune dysregulation, yet their epidemiological relationship remains poorly characterized. The objective of this study was to investigate the association between ME/CFS and endometriosis, examining shared risk factors, clinical correlates, and epidemiological patterns.

Methods: We conducted a systematic review and meta-analysis. Two independent reviewers screened 236 records after duplicate removal, with seventeen studies undergoing full-text review and thirteen meeting inclusion criteria for meta-analysis. Data were extracted using standardized forms and analyzed using random-effects models in R, with heterogeneity assessed using I2 statistics and the risk of bias evaluated using the JBI critical appraisal tool.

Results: Our meta-analysis of five studies (n = 2261 participants) revealed that women with endometriosis had 2.79-fold higher odds (95% CI: 2.00-3.89) of developing ME/CFS compared to controls. Similarly, our fixed-effects meta-analysis of two studies assessing the association of ME/CFS and endometriosis yielded a pooled OR of 2.52 (95% CI: 2.45-2.60, p < 0.001). There was minimal statistical heterogeneity (I2 = 0.0%, p > 0.7969) for both meta-analyses.

Conclusions: This study demonstrates a significant bidirectional association between endometriosis and ME/CFS, driven by shared mechanisms of immune dysregulation and chronic inflammation. Despite high heterogeneity, the consistent effect sizes support clinical vigilance for comorbidity. Future research should prioritize standardized diagnostic criteria to elucidate causal pathways. These findings underscore the need for integrated care approaches to address overlapping symptomatology in affected patients.

Source: Compton S, Alkabalan R, Cadet J, Mastali A, Ramdass PVAK. Endometriosis and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Systematic Review and Meta-Analysis. Diagnostics (Basel). 2025 Sep 15;15(18):2332. doi: 10.3390/diagnostics15182332. PMID: 41008704. https://www.mdpi.com/2075-4418/15/18/2332 (Full text)

The genetic architecture of fibromyalgia across 2.5 million individuals

Abstract:

Fibromyalgia is a common and debilitating chronic pain syndrome of poorly understood etiology. Here, we conduct a multi-ancestry genome-wide association study meta-analysis across 2,563,755 individuals (54,629 cases and 2,509,126 controls) from 11 cohorts, identifying the first 26 risk loci for fibromyalgia.

The strongest association was with a coding variant in HTT , the causal gene for Huntington’s disease. Gene prioritization implicated the HTT regulator GPR52 , as well as diverse genes with neural roles, including CAMKV ,  DCC ,  DRD2 / NCAM1 ,   MDGA2 , and CELF4 . Fibromyalgia heritability was exclusively enriched within brain tissues and neural cell types.

Fibromyalgia showed strong, positive genetic correlation with a wide range of chronic pain, psychiatric, and somatic disorders, including genetic correlations above 0.7 with low back pain, post-traumatic stress disorder and irritable bowel syndrome. Despite large sex differences in fibromyalgia prevalence, the genetic architecture of fibromyalgia was nearly identical between males and females.

This work provides the first robust genetic evidence defining fibromyalgia as a central nervous system disorder, thereby establishing a biological framework for its complex pathophysiology and extensive clinical comorbidities.

Source: Kerrebijn I, Bjornsdottir G, Arbabi K, Urpa L, Haapaniemi H, Thorleifsson G, Stefansdottir L, Frangakis S, Valliere J, Kunorozva L, Abner E, Ji C, Aagaard B, Bliddal H, Brunak S, Bruun MT, Didriksen M, Erikstrup C, Geirsson AJ, Gudbjartsson DF, Hansen TF, Jonsdottir I, Knight S, Knowlton KU, Mikkelsen C, Nadauld LD, Olafsdottir TA, Ostrowski SR, Pedersen OB, Saevarsdottir S, Skuladottir AT, Sørensen E, Stefansson H, Sulem P, Sveinsson OA, Thorlacius GE, Thorsteinsdottir U, Ullum H, Vikingsson A, Werge TM; Chronic Pain Genomics Consortium; FinnGen; DBDS Genomic Consortium; Estonian Biobank Research Team; Genes & Health Research Team; Saxena R, Stefansson K, Brummett CM, Glintborg B, Clauw DJ, Thorgeirsson TE, Williams FM, Sinnott-Armstrong N, Ollila HM, Wainberg M. The genetic architecture of fibromyalgia across 2.5 million individuals. medRxiv [Preprint]. 2025 Sep 19:2025.09.18.25335914. doi: 10.1101/2025.09.18.25335914. PMID: 41001472; PMCID: PMC12458511. https://pmc.ncbi.nlm.nih.gov/articles/PMC12458511/ (Full text available as PDF file)

The health and economic burden on family caregivers of persons with me/cfs diagnosis: a register data study from Norway

Abstract:

Background: Myalgic encephalomyelitis is an illness that affects the labor capability and need for services among those affected. Interventions and services for comparable illnesses are either inaccessible or ineffective for this group. Partners and parents may take on the caregiver burden, affecting their labor capability and health.

Objective: This study tested how limited treatment and support options available to persons with myalgic encephalomyelitis is associated to work participation, health, and use of public transfers among partners and parents of those affected.

Methods: We used administrative data from Norwegian patient registries from 2009 to 2018 on the diagnostic code G93.3, matched with population register income and health data from Statistics Norway. The dataset made it possible to identify a sample of partners and parents of persons with the diagnosis. The data included a control group drawn from the general population. We used optimal pair matching to construct separate datasets for pairs of matched individuals from the control group and the group of G93.3 cases, their mothers, fathers, and male and female partners.

Results: Having a partner or child with the G93.3 diagnosis contributes to strengthening traditional gender roles. Female family members worked less, and male family members worked more. Whereas female family members more often ended up depending on public transfers, male family members did so less often. All caregiver groups experienced increased personal health problems.

Conclusions: When tailoring support for the patient group, welfare services should consider how especially female family caregivers may be adversely affected by insufficient or inadequate support.

Source: Kielland, A., Liu, J. & Anthun, K.S. The health and economic burden on family caregivers of persons with me/cfs diagnosis: a register data study from Norway. Discov Public Health 22, 567 (2025). https://doi.org/10.1186/s12982-025-00936-5 https://link.springer.com/article/10.1186/s12982-025-00936-5 (Full text)

Burden of Disease in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Scoping Review

Abstract:

Objective: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious chronic and complex multi-system disease characterised by symptoms such as post-exertional malaise, fatigue, cognitive impairment and pain. Diagnosis is based on international consensus criteria, and no curative treatment is available. In the USA, its prevalence is estimated at 0.42% among adults, with women affected three times as often as men. Prevalence is expected to increase due to the COVID-19 pandemic. In addition to its severe symptoms, ME/CFS has a substantial economic impact. This scoping review aimed to systematically examine the global health, social and economic burden of ME/CFS.

Methods: We conducted a systematic literature search following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis extension for Scoping Reviews (PRISMA-ScR) guidelines in six databases and supplemented it with a citation search. We assessed study quality using a modified version of the Mixed Methods Appraisal Tool.

Results: We included 20 studies that assessed costs (n = 16), disability-adjusted life years (DALYs) (n = 3), employment rates (n = 1), and school attendance (n = 1) as indicators of disease burden. Reported costs per patient ranged from USD 2,916 to USD 119,611, with indirect costs accounting for the largest proportion. DALYs reported for the USA ranged from 0.714 million in 2016 to 5.77 million in 2022.

Conclusion: ME/CFS imposes a substantial health, social and economic burden of disease. Discrepancies in estimates are probably due to differences in study samples, methodologies, cost components, and healthcare systems. Because ME/CFS is assumed to be underdiagnosed, its true burden may be even higher.

Source: Vester P, Boudouroglou-Walter S, Schreyögg J, Wieting C, Blome C. Burden of Disease in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Scoping Review. Appl Health Econ Health Policy. 2025 Sep 23. doi: 10.1007/s40258-025-01006-2. Epub ahead of print. PMID: 40986167. https://link.springer.com/article/10.1007/s40258-025-01006-2 (Full text)

Advancing Digital Precision Medicine for Chronic Fatigue Syndrome through Longitudinal Large-Scale Multi-Modal Biological Omics Modeling with Machine Learning and Artificial Intelligence

Abstract:

We studied a generalized question: chronic diseases like ME/CFS and long COVID exhibit high heterogeneity with multifactorial etiology and progression, complicating diagnosis and treatment. To address this, we developed BioMapAI, an explainable Deep Learning framework using the richest longitudinal multi-omics dataset for ME/CFS to date.

This dataset includes gut metagenomics, plasma metabolome, immune profiling, blood labs, and clinical symptoms. By connecting multi-omics to a symptom matrix, BioMapAI identified both disease- and symptom-specific biomarkers, reconstructed symptoms, and achieved state-of-the-art precision in disease classification.

We also created the first connectivity map of these omics in both healthy and disease states and revealed how microbiome-immune-metabolome crosstalk shifted from healthy to ME/CFS.

Source: Xiong R. Advancing Digital Precision Medicine for Chronic Fatigue Syndrome through Longitudinal Large-Scale Multi-Modal Biological Omics Modeling with Machine Learning and Artificial Intelligence. ArXiv [Preprint]. 2025 Jun 18:arXiv:2506.15761v1. PMID: 40980765; PMCID: PMC12447721. https://pmc.ncbi.nlm.nih.gov/articles/PMC12447721/ (Full text available as PDF file)

Improvement in Upper Limb and Systemic Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Symptoms After Surgical Treatment of Neurogenic Thoracic Outlet Syndrome

Abstract:

Thoracic outlet syndrome (TOS) is characterized by compression of nerves or blood vessels as they pass through the scalene triangle and the costoclavicular space, and under the pectoralis minor. Common symptoms include arm fatigue and heaviness, paresthesias, and neck and upper back pain, provoked by arm extension or elevation.

We have recently reported that some myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients report symptoms suggestive of TOS, specifically with respect to overhead activity, but there is uncertainty whether this overlap in symptoms is more related to ME/CFS itself or a direct contribution by TOS. This case report describes an ME/CFS patient diagnosed with TOS, who experienced major decreases in many expected and unexpected symptoms after bilateral TOS surgery.

A 19-year-old female patient with ME/CFS and the hypermobile Ehlers-Danlos syndrome (hEDS) developed progressive symptoms of numbness and tingling in the upper limbs, which did not improve after two months of physical therapy. The patient elected to undergo the rib resection with neurolysis and scalenectomy surgery on her left side. Due to the success in the reduction of symptoms, she elected to undergo the same procedure on the right side three months later.

By eight weeks after the second surgery, the patient had experienced an expected complete resolution of upper limb numbness and tingling. She also reported a complete resolution of migraines, occipital neuralgia, vertigo, and visual disturbances, along with a marked improvement in cognitive fogginess and lightheadedness.

This case report highlights the potential for marked improvements in clinical function after recognition and surgical treatment of TOS in a patient with comorbid hEDS and ME/CFS. In addition to expected improvement in upper limb symptoms and the resolution of occipital headaches, our patient noted improvement in systemic symptoms of lightheadedness, cognitive dysfunction, and visual disturbances.

This experience suggests that those with hEDS and ME/CFS should be more carefully screened for brachial plexus dysfunction. Conversely, ascertainment of systemic symptoms may enhance the diagnosis of TOS and the items assessed in surgical treatment outcome studies.

Source: Christoforou ME, Lum YW, Sroge SC, Azola AM, Rowe PC. Improvement in Upper Limb and Systemic Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Symptoms After Surgical Treatment of Neurogenic Thoracic Outlet Syndrome. Cureus. 2025 Aug 19;17(8):e90494. doi: 10.7759/cureus.90494. PMID: 40978926; PMCID: PMC12445393. https://pmc.ncbi.nlm.nih.gov/articles/PMC12445393/ (Full text)

Exploration of Intersections and Divergences of Long COVID and Chronic Fatigue Syndrome

Abstract:

Background: Fatigue is the most common symptom of Long COVID (LC), defined by persistent or newly emerging symptoms that develop at least three months after an initial SARS-CoV-2 infection, in the absence of other identifiable cause. This study investigates the prevalence of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) as a potential comorbidity of LC.

Methods: The study enrolled 37 adult controls with no documented SARS-CoV-2 infection and 32 individuals with a history of infection, categorized as LC-yes (with LC symptoms) and LC-no (without LC symptoms). ME/CFS diagnosis was based on the International Consensus Criteria (ICC).

Results: Among LC-yes cases, the most frequently reported symptoms included post-exertional malaise (PEM); neurosensory, perceptual, or motor disturbances; cognitive impairment; sleep disturbances; pain; impaired thermoregulation; and flu-like symptoms, all occurring significantly more than in the LC-no or control groups. All individuals in the LC-yes group reported PEM. ME/CFS was diagnosed in three LC-yes cases (18.8%), one LC-no case (6.7%), and four control subjects (10.8%), with no statistically significant differences observed among groups. Experiencing more than six symptoms during acute infection, such as fatigue, loss of taste or smell, headache, fever, cough, myalgia, sore throat, shortness of breath, rhinorrhea, and diarrhea, was associated with a twofold higher risk of developing LC.

Conclusion: A substantial proportion of LC-yes individuals experienced PEM; neurosensory, perceptual, or motor disturbances; cognitive impairment; and sleep disturbances, with rates significantly exceeding those in the LC-no and control groups. Nevertheless, only a minority of LC-yes cases (18.8%) satisfied criteria for the ME/CFS, and the prevalence did not significantly differ from LC-no and controls. These findings suggest that while many symptoms of LC overlap with those of ME/CFS, only a subset of LC cases meet established ME/CFS diagnostic criteria.

Source: Kouyoumdjian JA, Yamamoto LA, Graca CR. Exploration of Intersections and Divergences of Long COVID and Chronic Fatigue Syndrome. Cureus. 2025 Aug 20;17(8):e90607. doi: 10.7759/cureus.90607. PMID: 40978825; PMCID: PMC12448662. https://pmc.ncbi.nlm.nih.gov/articles/PMC12448662/ (Full text)

Abnormal Brain Activation Patterns in Patients With Post-Acute Sequelae of COVID-19 (PASC) During Recovery: A fNIRS Study

Abstract:

COVID-19 has increased the likelihood of cognitive impairment in patients with post-acute sequelae of COVID-19 (PASC). There is a lack of direct evidence regarding the working memory performance of mild patients during the recovery period. This study employed functional near-infrared spectroscopy (fNIRS) to construct a mixed effects model for PASC patients performing the N-back task, assessing brain activation levels and brain connectivity.

PASC patients exhibited abnormally low activation in the parietal lobe (β = −0.21) and abnormally high activation in the occipital lobe (β = 0.40). There was a significant reduction in brain connectivity within the frontal–parietal and frontal–occipital networks.

These findings suggest that PASC patients experience impaired fronto-parietal network connectivity, rely more on the visual cortex to compensate for executive function deficits, and use this as a compensatory mechanism to reduce overall cerebral blood oxygenation. This study provides evidence of altered brain activation patterns in PASC patients during the recovery period due to cognitive impairment.

Source: Y. Ran, S. Wu, S. Liu, et al., “ Abnormal Brain Activation Patterns in Patients With Post-Acute Sequelae of COVID-19 (PASC) During Recovery: A fNIRS Study,” Journal of Biophotonics (2025): e202500206, https://doi.org/10.1002/jbio.202500206. https://onlinelibrary.wiley.com/doi/epdf/10.1002/jbio.202500206