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


Elisha K Josev, Charles B Malpas, Marc L Seal, Adam Scheinberg, Lionel Lubitz, Kathy Rowe, Sarah J Knight


Neurodisability and Rehabilitation, Murdoch Children’s Research Institute, Melbourne, Australia


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.


Josef et al, Brain Imaging Behave, 2020 October; 14(5):1815–30


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.

Comment by ME Research UK

Cognitive symptoms are very common in ME/CFS, and can be some of the most frustrating problems affecting the daily lives of people with the illness. Since cognitive function is what enables us gather and process information, abnormalities will have a significant impact on our ability to function at home, work, or school.

Often collectively referred to as ‘brain fog’, cognitive symptoms include difficulties with memory, concentration, and the sorting of information. These elements have been measured objectively in ME/CFS patients, including in studies supported by ME Research UK, such as the work of Prof. Jo Nijs and his group in Belgium.

But can cognitive problems in ME/CFS be traced back to abnormalities in the structure or function of the brain? Evidence from a few studies suggests that it can, but there is still little information about this aspect of the illness – particularly in young people, whose brains are still developing.

These are some of the questions being tackled by Dr Sarah Knight, Dr Elisha Josev, and colleagues from the Murdoch Children’s Research Institute in Melbourne, Australia. ME Research UK awarded funding to the group to look at brain function in adolescents with ME/CFS, and the first results from the study were recently published in the journal, Brain Imaging and Behavior.

The researchers aimed to look at the impact of mental effort on the cognitive function of adolescents with ME/CFS, as well as changes in functional connectivity in the brain.

Simply put, functional connectivity describes the links that exist between different regions of the brain, and which allow information to be processed. Activity occurring in two particular regions of the brain at the same time suggests a connection between those regions – either in the form of a direct pathway, or a more indirect cause-and-effect. For example, one specific connectivity network may indicate the processing of visual stimuli.

Forty-eight adolescents – including 25 with ME/CFS (defined using the Canadian criteria) and 23 healthy control subjects – were asked to undergo a 90-minute period of mental exertion, which included a number of tests of things such as literacy, mathematics, and general intellectual ability.

Various aspects of cognitive function were measured before and after this exertion, and magnetic resonance imaging (MRI) was used to acquire images of the brain which were analysed to determine the presence of functional connectivity networks. Levels of fatigue were also assessed in all participants.

Both before and after the period of mental exertion, the adolescents with ME/CFS performed worse than the healthy controls on the tests of cognitive function – including measures of processing speed (time taken to do a mental task), sustained attention (ability to focus on an activity), working memory (temporary storage of information), and visual new learning. They also had a higher level of fatigue.

However, the impact of mental exertion on cognitive function and fatigue was similar in ME/CFS patients and control subjects. Fatigue increased, and processing speed and sustained attention decreased after exertion, but to a similar extent in both groups.

Similarly, functional connectivity decreased following mental exertion in the adolescents with ME/CFS and in the healthy control subjects, and this reduction was of a similar magnitude in both groups.

So what do these results mean? Mental exertion did reduce functional connectivity in the brains of these adolescents, but by a similar amount in both ME/CFS and control groups. So the energy expenditure caused by the exertion appears to be comparable in adolescents with and those without ME/CFS.

However, the adolescents with ME/CFS already had higher fatigue and reduced cognitive function, and the mental exertion resulted in a decrease to even lower levels. The authors suggest that they will have had lower energy reserves and cognitive resources from which to draw when required to make a mental exertion, so compounding their problems.

Although abnormalities in brain functional connectivity have been demonstrated in other chronic conditions such as fibromyalgia and chronic pain, and in some adults with ME/CFS, there is little indication – from this study, at least – that this aspect of brain function will provide useful biomarkers for adolescents.

The Melbourne team are not stopping here. The MRI images collected in this study provide a whole host of other information about brain function, which the researchers have now started analysing. They have also been following up this group of adolescents over a longer period of time, and we look forward to seeing what’s uncovered.

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