Manca, Riccardo, Khan, Katija, Mitolo, Micaela et al. · Journal of the neurological sciences · 2021 · DOI
This study looked at how the brain responds to mental effort in women with ME/CFS compared to healthy women. Researchers used brain imaging to examine specific networks involved in attention and awareness before and after a cognitive task. Women with ME/CFS experienced increased fatigue and pain after the mental exertion, while a particular brain region (the insula) showed stronger connections to areas controlling reward and decision-making—changes that matched worsening symptoms.
Post-exertional malaise (PEM) is a hallmark and debilitating feature of ME/CFS with poorly understood neurobiological mechanisms. This study provides preliminary evidence that cognitive exertion triggers specific brain network abnormalities linked to symptom worsening, potentially opening new avenues for understanding the neurobiology of PEM and identifying therapeutic targets.
This pilot study does not prove that insula hyperconnectivity causes PEM or that it is specific to ME/CFS—the small sample size (6 patients) and observational design prevent causal claims. It does not establish whether these brain changes occur before, during, or after symptom worsening, nor does it confirm whether similar patterns would be found in men or across diverse ME/CFS presentations. Correlation between FC changes and symptom reports does not establish mechanism.
About the PEM badge: “PEM required” means post-exertional malaise was an explicit required diagnostic criterion for participant inclusion in this study — not that PEM was studied, observed, or discussed. Studies using criteria that do not require PEM (e.g. Fukuda, Oxford) are tagged “PEM not required”. How the atlas works →
The first block is for the primary paper and is the citation you should use in research work. The atlas-snapshot line only applies if you are specifically referring to this atlas’s reading of the paper on the date shown.
Primary citation
Manca, Riccardo, Khan, Katija, Mitolo, Micaela, De Marco, Matteo, Grieveson, Lynsey, Varley, Rosemary, et al. (2021). Modulatory effects of cognitive exertion on regional functional connectivity of the salience network in women with ME/CFS: A pilot study.. Journal of the neurological sciences. https://doi.org/10.1016/j.jns.2021.117326
BibTeX
@article{mecfsatlas-manca-2021-modulatory-effects,
author = {Manca, Riccardo and Khan, Katija and Mitolo, Micaela and De Marco, Matteo and Grieveson, Lynsey and Varley, Rosemary and Wilkinson, Iain D and Venneri, Annalena},
title = {Modulatory effects of cognitive exertion on regional functional connectivity of the salience network in women with ME/CFS: A pilot study.},
journal = {Journal of the neurological sciences},
year = {2021},
doi = {10.1016/j.jns.2021.117326},
note = {PubMed: 33556867},
url = {https://www.mecfsatlas.com/evidence/manca-2021-modulatory-effects},
}Atlas snapshot reference
ME/CFS Atlas. Generator v1 / Scanner v1.4 / policy v0.1. Accessed 2026-05-28. https://www.mecfsatlas.com/evidence/manca-2021-modulatory-effects
Contribute
Private, reviewed by a human. Not a public comment thread.