Brain response to light stimulation in people with myalgic encephalomyelitis/chronic fatigue syndrome

Plain English summary of protocol

Background and study aims
Literature suggests that impairments in cellular energy processes involving mitochondria may play an important role in the pathophysiology of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). A marker for this is the accumulation of a biochemical called lactate, resulting from the mitochondria not being able to use lactate as the energy source, or cellular respiration switching from normal oxidative mechanisms to another process, glycolysis, whose waste product is lactate.
Using magnetic resonance spectroscopy (MRS), it is possible to measure lactate in the brain. Our pilot MRS study showed an overall increase in lactate in the anterior cingulate cortex (ACC) in people with ME/CFS compared with healthy controls. Studies in people with ME/CFS, however, lack replication; also, the results usually show much overlap between the lactate levels in ME/CFS patients and healthy controls.

One possible explanation for this overlap is that neural systems compensate at rest, while the capacity for compensation is exceeded during physiological challenge; thus, during physiological challenge, the differences between ME/CFS patients and healthy controls may become much more pronounced. This would mirror clinical changes in patients with ME/CFS, who may feel comfortable at rest but even simple physical/cognitive challenges (such as reading) may rapidly lead to exhaustion.

The research team recently developed a functional MRS (fMRS) approach, where MRS is used to measure lactate concentrations in the visual cortex during rest and stimulation with flashing light. This method is safe and requires minimal active effort as participants are simply asked to look at the flashing checkerboard for a few minutes; hence, this can be easily applied in patient populations. This study aims to 1) replicate those findings of increased lactate concentration in the ACC of ME/CFS patients compared to healthy controls, and to 2) apply the above-described fMRS method to explore differences between ME/CFS patients and healthy controls during activation with flashing lights. It is expected that the difference during activation will be more pronounced than at rest.

Who can participate?
Adult patients with ME/CFS and healthy control volunteers.

What does the study involve?
The study involves a screening assessment that can be done either in person or remotely through a video or telephone call, and one in-person visit at the John Radcliffe Hospital in Oxford. During this visit, participants will have an MRI scan (about 1.5 hours) and will be asked to fill out questionnaires asking about their symptoms. Testing will take about 2 hours.

What are the possible benefits and risks of participating?
While there are no individual benefits from participating in the study, if there is a difference between people with ME/CFS and healthy participants, this could guide the search for biomarkers for ME/CFS and facilitate thinking about therapeutic approaches.

Possible risks of participating:
• Clinical Interview
Sometimes, clinical interviews during the screening session can ask for information that might be potentially upsetting (for example, information about mood). All clinical assessments will be performed by a trained researcher who can provide adequate information and treat any sensitive issues with care. Participants will be under no obligation to answer the questions if they make them uncomfortable.

• MRI/MRS
MRI is safe and does not involve any ionising radiation (x-rays). However, because it uses a large magnet to work, MRI scans are not suitable for everybody. Participants will be asked to answer some safety questions to determine if they can take part. For example, people with a heart pacemaker or stent, a mechanical heart valve, mechanical implants such as an aneurysm clip, joint replacement (e.g. hip/knee), or with other pieces of metal that have accidentally entered the body, cannot be scanned.

While there is no evidence that MRI is harmful to unborn babies, as a precaution, the Department of Health advises against scanning pregnant women unless there is a clinical benefit. The study does not routinely test for pregnancy, so if a participant thinks they may be pregnant, they should not take part in this research.

While very rare, tattoos can occasionally warm up in the scanner. As a safety measure, people with tattoos above their shoulders will be excluded, as this is too close to the head. People should not take part in a scan until 48 hours after receiving the new tattoo.

The enclosed space of the scanner can induce feelings of claustrophobia. People who declare they suffer from claustrophobia will be excluded. All operators and radiographers are accustomed to dealing with participants who may be claustrophobic and have a variety of strategies to employ with people who exhibit feelings of claustrophobia but who still wish to participate in the study.

Comfort: As certain MRI sequences can be very noisy so participants will be given earplugs. Lying on the scanner table for prolonged periods can induce lower back pain. This will be minimised by means of comfortable padding and positioning.

Participants will be introduced carefully to the scanner and allowed to leave at any stage. Whilst in the scanner, they will have a call button, which they can press if they need to stop the scan or speak with the person operating the scanner.

It is important to note that the scans will not be carried out for diagnostic purposes, only for research. The scans are not routinely looked at by a doctor and are therefore not a substitute for a doctor’s appointment. Occasionally, however, a possible abnormality may be detected. In this case, the study team would have the scan checked by a doctor. If the doctor felt that the abnormality was medically important, participants would be contacted directly and recommended to have a hospital (NHS) diagnostic scan arranged. All information will be kept strictly confidential.

• Flickering Checkerboard Stimulation
This visual stimulation is a succession of alternating black and white squares on a small monitor in the scanner; the black and white checkerboard creates the effect of flickering lights. It is not a harmful or painful stimulus. However, it is important to exclude participants who have a history of epilepsy as the flickering produced by the checkerboard may be intense enough to induce an epileptic seizure. There is a small possibility that the visual stimulation could also evoke a mild headache, and as such, participants are given the option to stop the flickering checkerboard at any moment during the scan by squeezing the call button. For this reason, individuals who suffer from photosensitive migraines will also be excluded. Any effect would be temporary and should rapidly fade once the monitor is turned off. This flickering checkerboard stimulation has been used in many previous research studies and has not been harmful to the participant.

Where is the study run from?
Department of Psychiatry, University of Oxford, UK.

When is the study starting and how long is it expected to run for?
September 2024 to December 2025

Who is funding the study?
Medical Research Council, UK

Who is the main contact?
Dr Beata Godlewska, beata.godlewska@psych.ox.ac.uk

Contact information

Dr Beata Godlewska
Public, Scientific, Principal investigator

Department of Psychiatry, University of Oxford, Warneford Lane
Oxford
OX3 7JX
United Kingdom

ORCID ID	0000-0002-5973-3765
Phone	+44 1865 618309
Email	beata.godlewska@psych.ox.ac.uk

Prof Philip Cowen
Public, Scientific

Department of Psychiatry, University of Oxford, Warneford Lane
Oxford
OX3 7JX
United Kingdom

ORCID ID	0000-0001-5518-6138
Phone	0044 1865 618311
Email	phil.cowen@psych.ox.ac.uk

Study information

Eligibility

Locations

Countries of recruitment

• United Kingdom
• England

Study participating centre

Results and Publications

Editorial Notes

13/11/2025: Study’s existence confirmed by the Medical Sciences Interdivisional Research Ethics Committee, University of Oxford, UK.