Category: Neurology

Distinct functional connectivity patterns in myalgic encephalomyelitis and long COVID patients during cognitive fatigue: a 7 Tesla task-fMRI study

Abstract:

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and long COVID are chronic debilitating illnesses featuring fatigue, post-exertional malaise (PEM) and neurocognitive deficits. Temporal correlation of neural activity between distinct brain regions, also referred to as functional connectivity (FC), can provide insights into how brain networks coordinate, at rest or during task. Therefore, we explored intrinsic FC correlates of cognitive fatigue in ME/CFS and long COVID patients during two Stroop-colour-word paradigms on 7 Tesla fMRI.

Methods: 450 sagittal volumes were acquired from seventy-eight participants: 32 patients with MECFS (pwME/CFS); 19 long COVID (pwLC) and 27 healthy controls (HC) during performance of baseline or Pre (before/during fatigue build-up) and repeat Post (fatigue set-in) Stroop tasks. Structural and functional data were analysed using the CONN toolbox.

Results: Regions of interest (ROI-to-ROI) analysis revealed significantly increased FC in subcortical regions in HC for Pre vs Post. Relative to HC, pwLC showed significantly reduced FC between nucleus accumbens and vermis 3 (p = 0.02) in Pre and increased FC in the prefrontal cortex and hippocampus (p = 0.02) in Post. pwME/CFS showed a significantly increased FC between the left cuneiform nucleus and right medulla (p = 0.03). Compared to HC, reduced FC was significant in pwLC during Pre, and between medulla and hippocampus (p = 0.04) and between nucleus accumbens and vermis (p = 0.001) during Post. Aberrant FC was significant for pwME/CFS in core networks during Pre. Core network FC to the cerebellum, amygdala, caudate and red nucleus correlated with symptom scores for cognition in both pwME/CFS and pwLC. Hippocampus and cerebellar FC correlated with duration of illness in pwME/CFS.

Conclusions: Our findings of reduced dopaminergic hippocampal-nucleus-accumbens connectivity imply blunted motivation and cognition. Extensive FC differences in subcortical and core networks in patient cohorts were detected relative to an increased FC in HC. High regional communication indicative of greater task engagement by HC was distinctive while FC differences in ME/CFS and long COVID patients indicated reduced and dysregulated regional coordination that may serve as candidate biomarkers of symptomatology in long COVID and ME/CFS.

Source: Inderyas M, Thapaliya K, Marshall-Gradisnik S, Barnden L. Distinct functional connectivity patterns in myalgic encephalomyelitis and long COVID patients during cognitive fatigue: a 7 Tesla task-fMRI study. J Transl Med. 2026 Jan 20. doi: 10.1186/s12967-026-07708-y. Epub ahead of print. PMID: 41559785. https://link.springer.com/article/10.1186/s12967-026-07708-y (Full text)

Evaluating working memory functioning in individuals with myalgic encephalomyelitis/chronic fatigue syndrome: a systematic review and meta-analysis

Abstract:

Individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) frequently report pronounced cognitive difficulties, yet the empirical literature has not fully characterised how discrete components of working memory are affected. Given that working memory serves as a foundational system supporting complex cognitive processes, differentiating performance across verbal and visual modalities provides critical insight into which higher-order functions may be most vulnerable. This systematic review/meta-analysis aimed to synthesise current research to investigate how ME/CFS impacts working memory systems.

Using PRISMA guidelines, a systematic search of 6 databases was undertaken (MEDLINE, CINAHL, Web of Science Core Collection, PubMed, EMBASE and PsycINFO). Initially, 10 574 papers were imported and following screening 34 studies of good to strong quality met the inclusion criteria. A series of random effects models were utilised to analyse working memory.

Results indicated a significant difference and large effect size between ME/CFS individuals and controls on verbal working memory tasks; however, no significant difference in visual working memory performance was found between the groups. Following the breakdown of these subsystems into span/attentional control tasks and object/spatial tasks, these results remained consistent.

These findings contribute to the body of ME/CFS research by articulating where specific working memory deficits lie. Specifically, they show that individuals with ME/CFS have impaired verbal memory performance. This knowledge can guide future research targeting higher-order verbal cognition and underscores the importance of recognising cognitive manifestations within ME/CFS clinical care.

Source: Penson M, Kelly K. Evaluating working memory functioning in individuals with myalgic encephalomyelitis/chronic fatigue syndrome: a systematic review and meta-analysis. Psychol Health Med. 2026 Jan 8:1-30. doi: 10.1080/13548506.2025.2606183. Epub ahead of print. PMID: 41504224. https://pubmed.ncbi.nlm.nih.gov/41504224/

Metabolic neuroimaging of myalgic encephalomyelitis/chronic fatigue syndrome and Long-COVID

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long-COVID are complex, disabling conditions that have emerged as significant public health challenges, affecting millions worldwide. Despite their growing prevalence, effective diagnostics and treatments remain limited, largely due to an incomplete understanding of their underlying pathophysiology. Both conditions share hallmark symptoms of chronic fatigue, cognitive dysfunction, and postexertional malaise, but their biological underpinnings remain to be elucidated. Neuroimaging offers a promising, noninvasive window into the brain’s metabolic landscape and has the potential to uncover objective biomarkers for these conditions.

In this mini review, we highlight recent advancements in metabolic neuroimaging, particularly positron emission tomography and magnetic resonance imaging/magnetic resonance spectroscopy, that reveal alterations in glucose and oxygen metabolism, neurotransmitter balance, and oxidative stress. These insights point toward shared disruptions in brain energy metabolism and neuroinflammatory processes, which may underlie the persistent symptoms in both ME/CFS and Long-COVID.

Importantly, while some findings overlap, inconsistencies in metabolite profiles between ME/CFS and Long-COVID underscore the need for further stratification and longitudinal research. Standardizing definitions, such as identifying Long-COVID patients who meet ME/CFS diagnostic criteria, could help improve study comparability.

By summarizing current imaging evidence, this review underscores the potential of neuroimaging to identify imaging biomarkers to advance the clinical diagnosis of Long-COVID and identify therapeutic targets for treatment development. As we continue to face the growing burden of Long-COVID and ME/CFS, metabolic imaging may serve as a powerful tool to bridge gaps in knowledge and accelerate progress toward effective care.

Source: Zhu Y, Quan P, Yamazaki T, Norweg A, Natelson B, Xu X. Metabolic neuroimaging of myalgic encephalomyelitis/chronic fatigue syndrome and Long-COVID. Immunometabolism (Cobham). 2025 Sep 12;7(4):e00068. doi: 10.1097/IN9.0000000000000068. PMID: 40958852; PMCID: PMC12435251. https://pmc.ncbi.nlm.nih.gov/articles/PMC12435251/ (Full text)

Distinct white matter alteration patterns in post-infectious and gradual onset chronic fatigue syndrome revealed by diffusion MRI

Abstract:

While post-infectious (PI-ME/CFS) and gradual onset (GO-ME/CFS) myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) manifest similar symptoms, it has long been suspected that different disease processes underlie them. However, the lack of biological evidence has left this question unanswered. In this study, how white matter microstructural changes in PI-ME/CFS and GO-ME/CFS patients were investigated.

PI-ME/CFS and GO-ME/CFS patients were recruited based on consensus diagnoses made by two experienced clinicians and compared their diffusion MRI features with those of rigorously matched healthy controls (HCs) with sedentary lifestyles. PI-ME/CFS participants showed significantly higher axial diffusivity (AD) in several association and projection fibres compared to HCs. Higher AD in PI-ME/CFS was significantly related to worse physical health.

In contrast, GO-ME/CFS participants exhibited significantly decreased AD in the corpus callosum. Lower AD in GO-ME/CFS was significantly associated with worse mental health in commissural and projection fibres. No significant group differences were found for fractional anisotropy, mean diffusivity, or radial diffusivity. Distinct patterns of AD alterations in PI-ME/CFS and GO-ME/CFS provide neurophysiological evidence of different disease processes and highlight the heterogeneities of ME/CFS.

Source: Yu Q, Kwiatek RA, Del Fante P, Bonner A, Calhoun VD, Bateman GA, Yamamura T, Shan ZY. Distinct white matter alteration patterns in post-infectious and gradual onset chronic fatigue syndrome revealed by diffusion MRI. Sci Rep. 2025 Jul 7;15(1):24256. doi: 10.1038/s41598-025-09379-z. PMID: 40624094; PMCID: PMC12234658. https://pmc.ncbi.nlm.nih.gov/articles/PMC12234658/ (Full text)

Neurodevelopment Genes Encoding Olduvai Domains Link Myalgic Encephalomyelitis to Neuropsychiatric Disorders

Abstract:

Background/Objectives: The aetiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a chronic and severe debilitating disease with a complex phenotype, remains elusive. Associations with infectious diseases and autoimmune and neuropsychiatric disorders have been observed, without the identification of mechanisms. Previous studies suggest that genetic predisposition plays a role, but results are difficult to replicate, with Genome-Wide Association Studies of ME/CFS being challenging due to the relative rareness and heterogeneity of the disorder.
Methods: We studied a well-defined Australian patient cohort diagnosed via the International Consensus Criteria, recruited by a specialist ME/CFS clinic. The whole-exome sequences of 77 patients were contrasted against genome variation in the 1000 Genome Project’s genome-matched population.
Results: Significant associations with ME/CFS were harboured in genes that belong to the Neuroblastoma Breakpoint Family encoding Olduvai (DUF1220) domains, namely NBPF1 (rs3897177, p-value = 3.15 × 10−8), NBPF10 (rs1553120233, p-value = 9.262 × 10−13), and NBPF16 (rs200632836, p-value = 1.04 × 10−6). Other significantly associated variants were detected in the ATR, RSPH10B, ADGRE5-CD97, and NTRK2 genes, among others. Replication of these results was attempted via a GWAS on raw data from a US cohort, which confirmed shared significant associations with variation identified in the PTPRD, CSMD3, RAPGEF5, DCC, ALDH18A1, GALNT16, UNC79, and NCOA3 genes.
Conclusions: These genes are involved in cortical neurogenesis, brain evolution, and neuroblastoma, and have been implicated by several studies in schizophrenia and autism. The sharing of these associations by the two cohorts supports their validity and grants the necessity of future studies to evaluate the implications for ME/CFS aetiology.
Source: Arcos-Burgos, M., Arcos-Holzinger, M., Mastronardi, C., Isaza-Ruget, M. A., Vélez, J. I., Lewis, D. P., Patel, H., & Lidbury, B. A. (2025). Neurodevelopment Genes Encoding Olduvai Domains Link Myalgic Encephalomyelitis to Neuropsychiatric Disorders. Diagnostics, 15(12), 1542. https://doi.org/10.3390/diagnostics15121542 https://www.mdpi.com/2075-4418/15/12/1542 (Full text)

Review of Neuroimaging Methods in ME/CFS

Abstract:

The brain is the most complex organ in the human body, and is involved in memory, speech, and movement, as well as regulating the functions of many other organs within the body. Various imaging techniques have detected subtle brain changes in vivo in ME/CFS. This chapter explores different neuroimaging studies used to investigate structural, functional, neurochemical, and tissue microstructural alterations in ME/CFS. These include magnetic resonance imaging (MRI), positron emission tomography (PET), and single photon emission computed tomography (SPECT).

Source: Thapaliya K, Inderyas M, Barnden L. Review of Neuroimaging Methods in ME/CFS. Methods Mol Biol. 2025;2920:257-277. doi: 10.1007/978-1-0716-4498-0_15. PMID: 40372688.  https://link.springer.com/protocol/10.1007/978-1-0716-4498-0_15

Small fiber neuropathy in the post-COVID condition and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Clinical significance and diagnostic challenges

Abstract:

Background: Patients with post-COVID condition (PCC) and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) experience symptoms potentially associated with small fiber neuropathy (SFN).

Methods: A sample of 90 participants, comprising 30 PCC patients, 30 ME/CFS patients, and 30 healthy controls (HC), matched by sex and age, was assessed. Neuropathic, autonomic, and fatigue symptoms were measured with TaskForce Monitor, the Sudoscan, heat and cold evoked potentials, In Vivo Corneal Confocal Microscopy (IVCCM), and specialized questionaries.

Results: PCC and ME/CFS patients demonstrated significantly higher levels of autonomic symptoms (H = 39.89, p < 0.001), neuropathic symptoms (H = 48.94, p < 0.001), and fatigue (H = 49.29, p < 0.001) compared to HC. Quantitative sensory testing revealed significant differences in heat detection thresholds between PCC patients and HC (F = 4.82; p < 0.01). Regarding corneal small fiber tortuosity, there were statistically significant differences between patients and HC (F = 6.80; p < 0.01), indicating pathological responses in patients. Small fiber tortuosity in IVCCM was identified as the main discriminator between patients and HC (AUC = 0.720; p < 0.01).

Conclusion: PCC and ME/CFS patients demonstrated sensory SFN, as evidenced by impaired heat detection and increased tortuosity of small fibers in the central corneal subbasal plexus. The findings underscore the importance of a multimodal approach to comprehensively detect and characterize SFN. This study provides valuable scientific insights into the neuropathic manifestations associated with these conditions.

Source: Azcue N, Teijeira-Portas S, Tijero-Merino B, Acera M, Fernández-Valle T, Ayala U, Barrenechea M, Murueta-Goyena A, Lafuente JV, de Munain AL, Ruiz-Irastorza G, Martín-Iglesias D, Gabilondo I, Gómez-Esteban JC, Del Pino R. Small fiber neuropathy in the post-COVID condition and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Clinical significance and diagnostic challenges. Eur J Neurol. 2025 Feb;32(2):e70016. doi: 10.1111/ene.70016. PMID: 39888240. https://onlinelibrary.wiley.com/doi/10.1111/ene.70016 (Full text)

Hippocampal subfield volume alterations and associations with severity measures in long COVID and ME/CFS: A 7T MRI study

Abstract:

Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patients share similar symptoms including post-exertional malaise, neurocognitive impairment, and memory loss. The neurocognitive impairment in both conditions might be linked to alterations in the hippocampal subfields. Therefore, this study compared alterations in hippocampal subfields of 17 long COVID, 29 ME/CFS patients, and 15 healthy controls (HC).

Structural MRI data was acquired with sub-millimeter isotropic resolution on a 7 Telsa MRI scanner and hippocampal subfield volumes were then estimated for each participant using FreeSurfer software. Our study found significantly larger volumes in the left hippocampal subfields of both long COVID and ME/CFS patients compared to HC.

These included the left subiculum head (long COVID; p = 0.01, ME/CFS; p = 0.002,), presubiculum head (long COVID; p = 0.004, ME/CFS; p = 0.005), molecular layer hippocampus head (long COVID; p = 0.014, ME/CFS; p = 0.011), and whole hippocampal head (long COVID; p = 0.01, ME/CFS; p = 0.01). Notably, hippocampal subfield volumes were similar between long COVID and ME/CFS patients.

Additionally, we found significant associations between hippocampal subfield volumes and severity measures of ‘Pain’, ‘Duration of illness’, ‘Severity of fatigue’, ‘Impaired concentration’, ‘Unrefreshing sleep’, and ‘Physical function’ in both conditions. These findings suggest that hippocampal alterations may contribute to the neurocognitive impairment experienced by long COVID and ME/CFS patients. Furthermore, our study highlights similarities between these two conditions.

Source: Thapaliya K, Marshall-Gradisnik S, Eaton-Fitch N, Barth M, Inderyas M, Barnden L. Hippocampal subfield volume alterations and associations with severity measures in long COVID and ME/CFS: A 7T MRI study. PLoS One. 2025 Jan 13;20(1):e0316625. doi: 10.1371/journal.pone.0316625. PMID: 39804864; PMCID: PMC11729965. https://pmc.ncbi.nlm.nih.gov/articles/PMC11729965/ (Full text)

Inactivation of ATG13 stimulates chronic demyelinating pathologies in muscle-serving nerves and spinal cord

Abstract:

Chronic muscle fatigue is a condition characterized by debilitating muscle weakness and pain. Based on our recent finding to study the potential effect of mTOR on ATG13 inactivation in chronic muscle fatigue, we report that biweekly oral administration with MHY1485, a potent inducer of mTOR, develops chronic illness in mice resulting in severe muscle weakness. As a mechanism, we observed that MHY1485 feeding impaired ATG13-dependent autophagy, caused the infiltration of inflammatory M1 macrophages (Mφ), upregulated IL6 and RANTES by STAT3 activation, and augmented demyelination in muscle-serving nerve fibers. Interestingly, these mice displayed worsened muscle fatigue during 2-day post-treadmill exercise, suggesting the critical role of chronic mTOR activation in potential PEM pathogenesis. Interestingly, ATG13-repressor mice exhibited enhanced infiltration of M1Mφ cells, STAT3 activation, demyelination of nerve fibers, and PEM-like symptoms, suggesting the potential role of ATG13 impairment in post-exertional fatigue.

HIGHLIGHTS: The potential role of mTOR activation in post-exertional fatigue is highlighted. As a molecular mechanism, mTOR activation augments autophagy impairment via ATG13 inactivation. Autophagy impairment induces IL-6 and RANTES via STAT3, demyelinates nerves in the muscle and spinal cord. ATG13 repressor mice (Tg-ATG13) displayed inflammatory demyelination and post-treadmill fatigue.

Source: Drosen ME, Bulbule S, Gottschalk G, Peterson D, Allen LA, Arnold LA, Roy A. Inactivation of ATG13 stimulates chronic demyelinating pathologies in muscle-serving nerves and spinal cord. Immunol Res. 2025 Jan 7;73(1):27. doi: 10.1007/s12026-024-09557-7. PMID: 39777574. https://link.springer.com/article/10.1007/s12026-024-09557-7 (Full text)

Expanded autonomic testing helps to pinpoint cases of orthostatic intolerance

News:

Using expanded, state-of-the-art capabilities in autonomic testing, Peter Novak, MD, PhD, Chief of the Division of Autonomic Neurology in the Department of Neurology, is driving better understanding of hard-to-diagnose patients with orthostatic intolerance.

The debilitating condition is among the most common neurological conditions affecting women in the United States ages 35 or younger. While knowledge of orthostatic intolerance has become more nuanced in recent years, diagnosing some patients’ symptoms when changing from lying to standing (dizziness, weakness and shortness of breath, with or without rapid heartbeat) has remained elusive.

The identification of postural orthostatic tachycardia syndrome (POTS) in the early 1990s led to clearer diagnosis of many patients. But the syndrome, by definition, excludes those who do not experience tachycardia. To address their symptoms, these patients sometimes are prescribed antianxiety or antidepressant medications.

To better understand these patients, Dr. Novak turned to continuous monitoring of end tidal CO2 and CBFv (cerebral blood flow velocity). As the technologies became available for clinical use, Novak added them to routine testing. The results led him to identify two new syndromes relating to orthostatic dizziness.

“We can now diagnose people who were previously thought to have psychiatric illness or had no diagnosis at all,” says Dr. Novak, of the Department of Neurology, one of only a few departments in the United States that has a Division of Autonomic Neurology.

In addition to continuous monitoring of heart rate and blood pressure that is standard for Valsalva maneuver and tilt-table tests, Dr. Novak’s Autonomic Testing Lab, located at Brigham and Women’s Faulkner Hospital, also measures and interprets end tidal CO2 and CBFv during these tests. Through testing, he has characterized two new syndromes:

  • Hypocapnic cerebral hypoperfusion (HYCH) is a novel syndrome of low CBFv that Novak described in late 2018 in PLoS ONE, as a biomarker of orthostatic intolerance. HYCH can be detected during a tilt test, in patients without orthostatic tachycardia, hypotension, arrhythmia, vascular abnormalities or other causes of abnormal orthostatic CBFv. “This is POTS without the T,” explains Dr. Novak. “These people have normal BP and normal heart rate. But they have the same low blood flow as in POTS due to vasoconstrictive effect of hypocapnia (low end tidal CO2). This is the main reason to monitor blood flow. Otherwise you can miss what is going on with this the patient, and the patient could be misdiagnosed as having a psychiatric illness.” The Autonomic Testing Lab currently sees at last two patients each month who meet the criteria of HYCH. Treatment is similar to that of patients with POTS (combination of exercise, diet and medication for more severe cases), since HYCH and POTS are probably on a spectrum of the same disorder.
  • Orthostatic Cerebral Hypoperfusion Syndrome (OCHOS) is a syndrome of orthostatic intolerance associated with low CBFv that Dr. Novak first described in 2016. In this syndrome, the orthostatic cerebral blood flow is reduced while all other variables are normal. OCHOS can be disabling. Many patients respond to volume expansion or cerebral vasodilators, but the optimal therapy has yet to be found.

Both OCHOS and HYCH are described among the 100 case studies in Dr. Novak’s recently published book Autonomic Testing, (Oxford University Press, April 2019), intended as a practical manual for performing and interpreting autonomic testing. Each case study includes the testing evaluation, results (with visual images to guide test interpretations) and recommendations for treatment and follow-up. Nearly all cases show results of the newer techniques of continuous CBFv and CO2 monitoring concurrent with traditional heart rate and blood pressure testing. “Together, they are more valuable than separately,” Dr. Novak explains.

The combination of classic autonomic tests (Valsalva maneuver, deep breathing and tilt test) enhanced by using of continuous CBFv and CO2 monitoring together make up “the Brigham Protocol.” In addition, the protocol includes non-invasive skin biopsies, now routinely performed in the lab to assess direct small fiber damage, which may indicate inflammation that is treatable. “We call it autonomic testing, but it is more than that at our institution,” says Dr. Novak.

Since 2015, the Autonomic Testing Lab has performed autonomic testing on approximately 1,300 people, about half of them for orthostatic symptoms, says Dr. Novak.

For questions about autonomic testing or if you have a patient who would benefit from autonomic testing, learn more here.