Resting-state functional connectivity, cognition, and fatigue in response to cognitive exertion: a novel study in adolescents with chronic fatigue syndrome

  • Elisha K. JosevEmail author
  • Charles B. Malpas
  • Marc L. Seal
  • Adam Scheinberg
  • Lionel Lubitz
  • Kathy Rowe
  • Sarah J. Knight


Emerging evidence suggests that central nervous system dysfunction may underlie the core symptoms of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) in adults, such as cognitive disturbance, fatigue and post-exertional malaise. Research into brain dysfunction in the pediatric CFS/ME context, however, is severely lacking. It is unclear whether the adolescent CFS/ME brain functions differently compared with healthy peers, particularly in situations where significant mental effort is required. This study used resting-state functional MRI in a novel repeated-measures design to evaluate intrinsic connectivity, cognitive function, and subjective fatigue, before and after a period of cognitive exertion in 48 adolescents (25 CFS/ME, 23 healthy controls). Results revealed little evidence for a differential effect of cognitive exertion in CFS/ME compared with controls. Both groups demonstrated a similar rate of reduced intrinsic functional connectivity within the default mode network (DMN), reduced sustained attentional performance, slower processing speed, and increased subjective fatigue as a result of cognitive exertion. However, CFS/ME adolescents consistently displayed higher subjective fatigue, and controls outperformed the CFS/ME group overall on cognitive measures of processing speed, sustained attention and new learning. No brain-behavior relationships were observed between DMN connectivity, cognitive function, and fatigue over time. These findings suggest that effortful cognitive tasks may elicit similar levels of energy expenditure across all individuals in the form of reduced brain functioning and associated fatigue. However, CFS/ME may confer a lower starting threshold from which to access energy reserves and cognitive resources when cognitive effort is required.


Chronic fatigue syndrome Resting-state fMRI Cognitive function Fatigue Default mode network Adolescence 



This study was funded by ME Research UK (SCIO charity number SCO36942,, and supported by the Murdoch Children’s Research Institute, the Royal Children’s Hospital, Department of Paediatrics at The University of Melbourne, and the Victorian Government’s Operational Infrastructure Support Program. The authors have no conflicts of interest to declare. We sincerely thank Cathriona Clarke, Jian Chen, Sarah Arnup, Diana Zannino, the Royal Children’s Hospital CFS Rehabilitation Clinic, and Medical Imaging staff for their assistance with this study. We also thank the research participants and their families for generously donating their time to this study.

Compliance with ethical standards

Conflict of interest

The authors declare they have no conflicts of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.


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Authors and Affiliations

  1. 1.Neurodisability and RehabilitationMurdoch Children’s Research InstituteMelbourneAustralia
  2. 2.Department of PaediatricsUniversity of MelbourneMelbourneAustralia
  3. 3.Developmental ImagingMurdoch Children’s Research InstituteMelbourneAustralia
  4. 4.Clinical Outcomes Research Unit (CORe), Department of Medicine, Royal Melbourne HospitalThe University of MelbourneMelbourneAustralia
  5. 5.Department of PaediatricsMonash UniversityMelbourneAustralia
  6. 6.Victorian Paediatric Rehabilitation ServiceRoyal Children’s HospitalMelbourneAustralia
  7. 7.Department of General MedicineRoyal Children’s HospitalMelbourneAustralia

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