Brain white matter changes not found in adolescents newly diagnosed with ME/CFS


Elisha Josev, Sarah Knight and colleagues, Murdoch Children’s Research Institute, Melbourne, Australia


Journal of Neuroscience Research, 2023 October; 101(10):1572–85

Key points

  • While changes in the white matter of the brain (the part containing nerves) have been observed in adults with ME/CFS, they have not yet been investigated in children and adolescents with the disease.
  • In this study, researchers used magnetic resonance imaging (MRI) to explore potential abnormalities in the structure of white matter in 25 adolescents with ME/CFS, compared with 23 healthy adolescents (controls).
  • Adolescents with ME/CFS had higher levels of pain and fatigue than controls, as well as poorer sleep quality and quality of life, and a lower performance on tasks assessing the ability of the brain to process, retain and recall information. Despite this, there were no significant differences in the structure of white matter.
  • These findings suggest that the white matter changes found in adults with ME/CFS are not yet present in adolescents with the disease, and may be related to older age and/or a longer duration of illness.

Why was this study carried out?

Dr Elisha Josev

Existing research suggests that there is dysfunction of the central nervous system in adults with ME/CFS. This includes changes in part of the brain and spinal cord containing nerves, called the white matter, which may lead to disrupted cognitive function. One theory relating to the progression of ME/CFS, based on evidence including preliminary findings from the UK ME/CFS Biobank, has suggested that these changes in the central nervous system may be due to a prolonged state of low-grade inflammation in ME/CFS.

However, no research has previously considered whether changes in white matter are also present in adolescents with ME/CFS.

As cognitive function enables us to gather and process information, disruption of this leads to symptoms such as difficulty thinking, and issues with memory and processing information, often collectively referred to as ‘brain fog’, and one of the NICE diagnostic criteria for ME/CFS.

In a previous ME Research UK-funded study, Drs Josev, Knight and colleagues showed that the majority of adolescents with ME/CFS still met diagnostic criteria for ME/CFS two years after their initial diagnosis, with persistence of symptoms such as fatigue, pain and reduced quality of life. The authors highlighted that the impact of these symptoms on the academic, social and emotional development of adolescents whose brains are still developing is a cause for concern.

This new study is the third in a series supported by funding from ME Research UK, investigating neurological changesprognosis, health and wellbeing in those aged 13 to 18 years (adolescents) with ME/CFS.

Dr Sarah Knight

The first study, published in 2020, found that that while adolescents with ME/CFS had higher levels of fatigue and reduced cognitive function compared with controls, there was little difference in the brain in the response to mental effort between the two groups. The authors suggested that while there was no observable difference in the brain’s response, those with ME/CFS may have lower energy reserves and cognitive resources to draw upon when needed to make mental exertion.

The second study, published in 2021, showed that, while adolescents with ME/CFS had good general health and psychological wellbeing, most still met diagnostic criteria for ME/CFS two years after diagnosis, and levels of pain and health-related quality of life remained poorer than in healthy controls.

This new study builds on the findings of the previous two, specifically highlighting three questions of interest that emerged:

  1. Did the findings in the first study represent a genuine lack of a difference in neural connectivity between adolescents with ME/CFS and healthy controls? 
  2. Did the duration of the illness of participants in the first study affect the findings of ongoing inflammation on neural connectivity?
  3. Was the type of MRI used in first study precise enough to detect more subtle changes in white matter, and could a more detailed type of MRI analysis be more useful?

What was the aim of the study?

These three questions led the team to investigate in detail the structure of the brain and spinal cord white matter in adolescents newly diagnosed with ME/CFS, compared with healthy adolescent controls.

They looked at:

  1. The overall structure of white matter (macrostructure);
  2. The fine detail of the structure of white matter (microstructure);
  3. Clinical factors including cognitive functioning, general intellectual functioning, fatigue, mood (anxiety and depression), sleep quality, pain, and fatigue-related quality of life; and
  4. Whether these clinical factors were associated with any identified changes in white matter structure.

What methods were used?

This exploratory case-control study used participants from the first study, including 25 adolescents newly diagnosed with ME/CFS and 23 healthy adolescents (controls). Participants were asked to complete a number of questionnaires relating to clinical factors including mood (anxiety and depression), sleep quality and habits, pain, and fatigue-related quality of life, as well as other illness characteristics including school attendance, time since symptom onset at diagnosis, and illness trigger.

Following this, participants attended a study visit which comprised a brain MRI scan, as well as clinical assessments of fatigue, general intellectual functioning, cognitive ability and academic ability.

All participants underwent a standard MRI to look at the overall structure of white matter. A more detailed MRI analysis technique was also carried out to consider the microstructure of white matter for 24 adolescents with ME/CFS and 21 healthy controls. Three participants were excluded from this analysis due to issues with MRI signals caused by things such as metal dental implants.

What were the key findings?

In both groups, most of the participants were female, and the average age was 16 years. Those with ME/CFS were newly diagnosed, and the majority had been experiencing symptoms of ME/CFS for fewer than 2 years prior to diagnosis.

In summary, compared with the healthy controls, adolescents with ME/CFS had:

No difference in:

  • Brain structure.


  • Performance on tasks that assessed ability of the brain to process, retain and recall information (cognitive performance);
  • Sleep quality; and
  • Quality of life relating to fatigue.


  • Levels of pain;
  • Levels of fatigue.


This study found that while there were differences in clinical factors – such as higher levels of pain and fatigue, and lower sleep quality – in adolescents newly diagnosed with ME/CFS compared with healthy controls, both the overall microstructure and the more detailed microstructure of white matter were comparable between the two groups.

The researchers suggest that the changes in white matter sometimes seen in adults with ME/CFS are not yet present in adolescents recently diagnosed with the disease. Rather, these changes may be related to older age, a longer duration of illness, or a combination of both.

This was the first case–control study to look at the microstructure of white matter in adolescents with ME/CFS, providing evidence in an area where previously there was very little research. The study used healthy controls which allowed the researchers to account for the impact of adolescent brain development on chronic illness.

In addition, the ME/CFS diagnosis was made by paediatricians specialising in ME/CFS using the Canadian Consensus Criteria for children and adolescents. The study also found consistent findings across the different methods they used, which adds to the reliability of the findings.

The researchers acknowledge the limitations of the study. These include the small sample size, which may mean that the study did not have the ability to detect a significant difference using statistical tests when there actually was one. This highlights the need for replication of this study using larger groups of participants. It was also mentioned that while this study did include healthy controls, it did not include a comparison group of adults with ME/CFS. Inclusion of an adult comparison group may enable researchers to assess whether they are able to predict changes in white matter microstructure. In addition, more research is needed to look at whether these white matter changes develop in children and adolescents who have had ME/CFS for a longer period of time.

Verified by MonsterInsights