Key points
- Cognitive difficulties are one of the four key symptoms required for a diagnosis of ME/CFS under the 2021 NICE guidelines.
- Research suggests that physical exertion worsens cognitive dysfunction in people with ME/CFS but findings are inconsistent due to factors such as small sample size and varying measures of cognitive function.
- The authors of a paper, published in ‘Frontiers of Neuroscience’ in 2024, recognised the need to develop a method of accurately assessing cognitive function in people with ME/CFS both in the clinic and at home
- This tool also needed to be able to capture changes over time, and after exertion.
- The researchers took an existing tool used to assess cognitive function – the “CogState Brief Screening Battery” (CBSB) and assessed whether it was able to reliably distinguish between people with ME/CFS and healthy controls over time.
- Results suggest that the tool is sensitive to detect deficits in cognitive function in persons with ME/CFS when speed or performance – rather than accuracy, is used as an outcome measure.
- More research is needed to assess whether the CBSB is an effective tool to measure cognitive function in sub-groups of people with ME/CFS; for example those with different disease severity .
Background
Cognitive difficulties, often referred to as “brain fog”, are one of the four key symptoms required for a diagnosis of ME/CFS under the 2021 NICE guidelines. Cognitive difficulties can impact both on the wellbeing of a person with ME/CFS, and on their ability to work, and may include:
- Problems finding words or numbers
- Difficulty in speaking
- Slowed responsiveness
- Short-term memory problems
- Difficulty concentrating or multitasking
Importantly, research has shown that in people with ME/CFS, cognitive difficulties are not a reflection of poor effort or motivation, and are not linked to mood disorders.
Interestingly, a study, published in the journal ‘Frontiers of Neuroscience’ by Lange and colleagues, stated that although results are variable, generally studies show that:
- Those with ME/CFS take longer to complete tasks assessing cognitive function than healthy controls.
- Although those with ME/CFS take longer to complete tests assessing cognitive function, their responses are just as accurate as those from healthy controls.
Past research has also suggested that physical exertion worsens cognitive dysfunction in people with ME/CFS, but again the Lange and colleagues noted that findings have been inconsistent due to factors such as small sample size, and varying cognitive assessment measures. Additionally, cognitive difficulties may worsen over time, and after mental exertion.
Based on these findings – and the limitations of existing research, Lange and colleagues recognised that there was a need to develop a method of accurately assessing cognitive function in people with ME/CFS – both in clinic and at home – that can capture changes over time, and after exertion.
Therefore, the research team conducted a study which aimed to:
- Determine whether the computerised “CogState Brief Screening Battery” (CBSB) – a short series of questions relating to cognitive function, reliably distinguishes between people with the disease and healthy controls over time.
- Assess whether an all-day in clinic study visit had a detrimental effect on cognitive function.
- Determine whether a single short session of strenuous physical exercise would impact on cognitive function over and above that of the baseline clinical visit over 48 hours.
What did the research team do?
This research was a cognitive sub-study within the Multi-site clinical assessment of ME/CFS (MCAM) study – which was initiated and funded by the Centres for Disease Control and Prevention (CDC).
- The MCAM study aimed to enrol people with a diagnosis of ME/CFS from an “expert clinician” from 7 speciality clinics in the USA – it is important to note that “patients were not required to fit a specific case definition”.
- The MCAM study was initiated in 2012 and followed participants up over time. Notably, several sub-studies have now been published using data from MCAM – including a paper by Dr Elizabeth Unger and colleagues which investigated disease heterogeneity among people with ME/CFS. Each of the sub studies look at groups of participants who took part in the MCAM study.
The cognitive sub-study was conducted between November 2013 and February 2019. Participants were recruited from the MCAM study and provided informed consent – the process in which a prospective participant is informed about all aspects of the study which are important for the participant to decide whether or not they wish to take part.
Overall, 261 people with ME/CFS – 182 of whom completed an exercise test, and 165 healthy controls took part in the cognitive sub-study. Participants were predominantly white (78%), female (69%), educated to at least college level (73%), and insured (93%) – for those who had ME/CFS, 57% reported sudden onset of disease, and the average duration of illness was 15 years.
All participants completed several questionnaires evaluating illness and functioning status, and computerised cognitive assessments (the CBSB) – these assessments had been validated in “groups with similar cognitive symptom profiles documented in ME/CFS” such as those with mild traumatic brain injury.
Cognitive assessments were administered at 5 time points:
- At the beginning of the initial clinic visit (before the exercise testing if this was done).
- Immediately after the exercise testing if it was done, or at the end of the clinic visit.
- 6-12 hours after the clinic visit.
- 24 hours after the clinic visit.
- 48 hours after the clinic visit.
What did the results show?
Results were complex but in their discussion, the research team summarised their findings as follows:
“Our findings add to the growing realisation that persons with ME/CFS are compromised cognitively, they are reacting slower, attention is variable over time, and cognitive efficiency supporting executive function, learning and memory is significantly decreased to a clinically meaningful degree.”
Surprisingly, the study found that the exercise test did not result in further cognitive dysfunction beyond that of the clinical visit.
Limitations of the study
The authors acknowledge several limitations of the study:
- The study sample came from ME/CFS clinics in the US – while there was good geographical representation in the US, the participants were all recruited from a secondary care setting – a level of healthcare that involves specialized services, and may not represent those attending primary care – the first point of contact in the healthcare system.
- The study sample was not representative of all ethnic groups.
- The researchers state that the small numbers of participants in some ethnic groups – specifically “Black” and “Hispanic”, prevented more meaningful analysis being carried out.
- Two of the cognitive assessments relating to complex working memory and executive function/learning efficiency were not administered remotely.
- This meant that the researchers were unable to determine whether exercise would impact on performance speed in these areas after the clinic visit.
- The exercise testing was only completed by participants with ME/CFS and not healthy controls.
- This means that the impact of exercise on cognitive function for those with ME/CFS could not be compared to that of healthy controls.
Additional areas for consideration noted by ME Research UK are as follows:
- The participants with ME/CFS were not assessed against any diagnostic criteria – rather they received a diagnosis of ME/CFS from an “expert clinician” from one of 7 specialist clinics in the USA.
- The study did not comment on the ME/CFS severity of the participants.
- This may contribute to why there were no differences observed in cognitive function between those with ME/CFS who completed the maximal exercise test, and those who did not.
- The research team only considered the impact of the clinic visit and exercise test on cognitive function up to 48 hours after.
- The worsening of symptoms following exertion in ME/CFS – Post exertional malaise, can last for days, weeks or longer, it is possible that the 48-hour period in this study was not long enough to capture the full impact of the clinic visit and exercise test on those with the disease.
Conclusions
The results from this study suggest that the CBSB assessment tool is sensitive to detect deficits in cognitive function in people with ME/CFS both in clinic and remotely over time when speed or performance – rather than accuracy, is used as an outcome measure. Additionally, in this study, physical exertion did not appear to further exacerbate the magnitude of cognitive deficit over time in people with ME/CFS.
More research is needed to assess whether the CBSB works effectively to assess cognitive function in different sub-groups of people with ME/CFS, for example, those with different ME/CFS severity level, between males and females, by age, in different ethnic groups, by length of disease, and by delay in diagnosis. It is also essential to assess the accessibility of the CBSB for those with severe and very severe ME/CFS.
