DEPARTMENT OF PSYCHIATRY Dr Beata Godlewska beata.godlewska@psych.ox.ac.uk PARTICIPANT INFORMATION SHEET (People with ME/CFS) Central University Research Ethics Committee Approval Reference: Version 1.0 Date: 16.08.2024 Lactate response to light stimulation in people with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) (OxLac) We would like to invite you to take part in a research study. Before you decide, it is important for you to understand why the research is being done and what it will involve. Please take time to read the following information carefully and discuss it with friends, family or your GP if you wish. If there is anything that you do not understand, or if you would like more information, please ask us. Please take time to consider whether you wish to take part. 1. What is the purpose of the research? Previous research has shown problems with energy production in the cells of people with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). ME/CFS is a serious and often chronic biological condition characterised by severe tiredness (fatigue) which does not get better with rest, can worsen after simple physical or mental activities, and can continue for days or weeks (so called ‘post exertional malaise’). People with ME/CFS commonly have problems with thinking, concentration and memory (‘brain fog’), sleep, as well as experience many other symptoms, such as pain or dizziness. Lactate is a chemical in the brain that is involved in the production of energy. Its higher levels indicate that the brain is not able to perform the processes leading to energy production. To better understand the role of lactate in ME/CFS, we would like to measure lactate concentrations using brain imaging when people are at rest and when their brain is active during a brief period of exposure to a flashing light. 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. 2. Why have I been invited to take part? You have been invited to take part because you have a diagnosis of ME/CFS and you are ≥ 18 years of age . We believe you have either expressed an interest in hearing more about this study, or have previously expressed an interest in participating in our studies (please do let us know if this is no longer the case). In total, we will be recruiting 20 participants with ME/CFS and 20 healthy individuals who will be a comparison group. Participant Information Sheet Version 1 CUREC reference: R93723/RE001 16.08.2024 Page 1 of 9 Our inclusion criteria for the study are as follows: ● ≥ 18 years of age ● You are willing and able to give informed consent for participation in the study ● You meet the Canadian Consensus Criteria for ME/CFS (this will be checked during the screening) ● You have had your symptoms for at least 6 months ● Your symptoms started at some point of your life (ie. they are not lifelong) ● Your symptoms cannot be clearly linked to COVID-19 You are not eligible for the study if you have at least one of the following conditions: ● Current or previous significant psychiatric disorder, for example mood or anxiety disorder, post-traumatic stress disorder, obsessive compulsive disorder, psychosis (past depressive symptoms will be assessed during the screening as they might be, for example, a reaction to change in your life situation rather than independent mood condition.) ● Any general medical conditions known to influence energy processing and/or to be linked to fatigue (for example, problems with thyroid or post-COVID fatigue) ● Current treatment with any medication/supplementation if deemed relevant by the medically trained investigator (for example, if you are taking treatments likely to interfere with energy metabolism, such as creatine; this will be discussed during the screening). The contraceptive pill, the Depo-Provera injection or the progesterone implant will not result in exclusion. ● High consumption of legal substances (like alcohol, caffeine, nicotine) to an extent that would make complying with study protocol challenging ● Past history of dependence to illicit substances, and any consumption of illicit substances in the three months prior to the study ● Current or past epilepsy or photosensitive migraines ● If you are currently pregnant, breastfeeding or trying to get pregnant ● If you have metallic implants or other devices in your body that make it unsafe for you to go into the scanner. 3. Do I have to take part? No. It is up to you to decide whether to take part. Even after you have signed the consent form, you are free to withdraw from the study at any time without giving any reason by advising us of this decision (more information about how your personal data will be stored and destroyed is in Section 9) . This will have no impact on your medical and support care. If you are a student, there would be no academic penalty if you do not want to take part, or if you decide to stop at any point. 4. What will happen to me if I take part? In brief, if you decide to go ahead after reading this participant information sheet, we will invite you to a screening visit. This will either take place at the Neurosciences building at the Warneford Hospital for an in-person screening, or over the telephone or via a Microsoft Teams video call for a remote screening. We will be able to accommodate your preference. During the screening we will discuss the main inclusion and exclusion criteria. If any of the information you have provided is within the exclusion criteria, we will exclude you and not continue with the rest of the screening session. If you are deemed eligible after the Participant Information Sheet Version 1 CUREC reference: R93723/RE001 16.08.2024 Page 2 of 9 screening is complete, and you are still happy to take part, we will proceed with the scanning visit. The scanning visit will be conducted at the Oxford Centre for Functional MRI of the Brain (FMRIB), John Radcliffe Hospital in Oxford. Below is a description of what you should expect at each visit. ● Screening Visit You will be invited for a screening visit to check whether you meet the criteria for participation in our study, to make sure that taking part in the study is safe and appropriate for you, and to ensure that you have a clear understanding of the study procedures. The screening process will take up to one hour (usually less than that). The screening visit will be as follows. First, we will take your consent to take part in the study. This will be done once we have explained the study and answered all your questions. After that we will ask for some details, including your age (we look for people ≥ 18 years of age), biological sex, weight and height, general and mental health, main ME/CFS symptoms necessary for the diagnosis, whether you have the chance of being pregnant and we will review your medical history. As depressive symptoms are common, and we need to exclude depression, we will ask you to fill out a brief questionnaire on depression. It will be done using a paper form if you attend the screening in person, or the questions will be read by the researcher, if the screening is online. To get a full picture of your ME/CFS symptoms, we would like to ask you to fill out DuPaul Questionnaire. As this questionnaire takes time, you will have a choice of doing it during the screening or to have it sent to you by email or post and to bring it to the scanning visit. This will allow you to do it in your own time. This questionnaire will be done only if you can be included in the study. If you meet the study criteria and want to continue, we will agree the dates of the scanning visit. ● Scanning visit There will be one scanning visit. This will take place at the Oxford Centre for Functional MRI of the Brain (FMRIB), John Radcliffe Hospital in Oxford and will last around 1.5 - 2 hours. You will be met by the researcher at the FMRIB reception and they will take you to the screening preparation room. First, you will be asked to fill out some pen and paper questionnaires (this can be done after the scan if you prefer). Then, you will be invited to change into FMRIB-provided scrubs in the private changing room facility and asked to remove any metallic accessories. Your belongings can be safely locked away in one of the available lockers. After this is complete, you will be asked to fill out the WIN Scanner Safety Form, which will be checked by the operating radiographer at FMRIB. You will be taken into the scanner suite and given earplugs to be fitted and checked by the radiographer for adequate ear protection during the scan session. You will then be asked to lie down on the scanner bed where you will be attached to physiological monitors (i.e. pulse oximeter and respiration belt). You will be instructed about the use of the “call button” – a hand-held Participant Information Sheet Version 1 CUREC reference: R93723/RE001 16.08.2024 Page 3 of 9 squeeze bulb that allows you to communicate directly with the researcher and radiographer at any time for any reason. Once you are comfortable, the scan will commence. First, structural MRI images will be acquired which lasts approximately 5 minutes. Once structural scans are completed, we will start measuring lactate in your brain. First, we will take a measurement at rest. This will last about 10min. After that, there will be three blocks with MRS scans measuring lactate during each block. The blocks will consist of a ~12 minute rest block, followed by a ~6 minute flickering checkerboard block and a ~12 minute rest block. There will then be a 6 -7 minute scan to measure resting activity of the brain. You will be asked to close your eyes during rest periods and have them open for the visual stimulus. These instructions will be relayed through the radiographer intercom. The flickering checkerboard will be displayed on a small monitor screen visible from where you are lying down in the scanner. It will consist of a quick succession of alternating black and white squares that create the effect of flickering lights. Once the MRS acquisition is completed, you will be brought back to the screening preparation room to retrieve any belongings and change back into the clothes that you came with. The researcher will answer any queries or concerns you have after the scan and also provide you with any follow up information. You will be reimbursed according to section 8 of this document, Expenses and payments . Once you are ready, you will be able to leave the hospital and the scanning visit will have concluded. 5. What is MRI/MRS? MRI and MRS scanning works by using powerful magnetic fields to examine the tissues of the body. It is used widely in medicine to provide images inside many different parts of the body to help doctors detect diseases or to guide treatments. Both MRI & MRS are routine procedures that are safe, painless, and involves no ionising radiation (i.e. ‘X-rays’). Having a scan involves simply lying still inside the scanner. During this time, you will be made comfortable and you will be able to contact researchers at all times. You will not feel anything, although you will hear some quite loud noises. As some of the scans are noisy, we would give you earplugs to make this quieter for you. It is important that these are fitted correctly as they are designed to protect your hearing. We will use MRI scans to obtain an image of your brain for research purposes only. MRS is used to collect information about the presence of brain chemicals in specific brain regions. These types of scans are safe, and thousands of people have such scans every year. However, because of the magnetic fields involved, some people are not suitable for MRI/MRS scanning (refer to section 6, Are there any possible disadvantages or risks from taking part? ). The scanning will take around 60 minutes altogether. In the scanner, you will be asked to lie on your back and be as still as possible. MRI-compatible pads and cushions may be used to improve your comfort. 6. Are there any possible disadvantages or risks from taking part? ● Clinical Interview Sometimes, clinical interviews during the screening session can ask for information that might be potentially upsetting (for example, information about your mood). All clinical assessments will be performed by a trained researcher who can provide adequate information and treat any sensitive Participant Information Sheet Version 1 CUREC reference: R93723/RE001 16.08.2024 Page 4 of 9 issues with care. You are under no obligation to answer the questions if they make you uncomfortable. We will also do our best to make you feel as comfortable as possible throughout the whole study. ● 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. You would be asked to answer some safety questions to determine if you can take part. Normally, we would need more information before you take part in the research MRI scan if you have a heart pacemaker or stent, mechanical heart valve, mechanical implants such as an aneurysm clip, joint replacement (e.g. hip/knee), or if you carry other pieces of metal that have accidentally entered your body. 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. We do not test for pregnancy as routine so if you think you may be pregnant you should not take part in this research. While very rare, tattoos can occasionally warm up in the scanner. Please inform the person operating the scanner immediately if you feel any heating. If you have a new tattoo, you should not take part in a scan until 48 hours after receiving the tattoo. If you think you might be claustrophobic, please talk to the researcher in advance, or let the person operating the scanner know before you start. Some of the scans are noisy, so we will give you earplugs to make this quieter for you. It is important that these are fitted correctly, as they are designed to protect your hearing. In preparation for your scan and for your comfort and safety we may ask you to change into scrubs ("pyjama-style" top and trousers), available in a range of sizes. You may keep your underwear and socks on, but you will need to remove underwired bras. If you have a suitable non-wired bra, you may wear this instead. Do not wear any fabrics that contain metallic threads or are silver impregnated (often marketed as anti-microbial/bacterial or anti-odour/stink). Metal jewellery, including body piercing, must also be removed. If you wish to wear eye makeup to your scan, we will give you makeup removal wipes because you should not wear eye shadow or mascara in the scanner. Please bring your own makeup to reapply. Lockers are provided to secure your personal belongings and clothing. Some people scanned in MRI scanners, especially 7 Tesla scanners, may experience a mild dizzy feeling as they are moved into the scanner. This is normal and the feeling starts to go away as soon as you are in the scanner. You will be introduced carefully to the scanner and allowed to leave at any stage. Whilst in the scanner you will have a call button, which you can press if you need to stop the scan or speak with the person operating the scanner. It is important to note that we do not carry out scans for diagnostic purposes, only for research. Our scans are not routinely looked at by a doctor and are therefore not a substitute for a doctor’s Participant Information Sheet Version 1 CUREC reference: R93723/RE001 16.08.2024 Page 5 of 9 appointment. Occasionally, however, a possible abnormality may be detected. In this case, we would have the scan checked by a doctor. If the doctor felt that the abnormality was medically important, you would be contacted directly and recommended to have a hospital (NHS) diagnostic scan arranged. You would not be informed unless the doctor considers the finding has clear implications for your current or future health. All information about you is 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 from 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 you are given the option to stop the flickering checkerboard at any moment during the scan by squeezing the call button. For this reason, we will also be excluding individuals who suffer with photosensitive migraines. 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. 7. Are there any benefits in taking part? While there are no immediate benefits for people participating in the project, it is hoped that this research will lead to a better understanding of problems with energy production in the brain. Ideally, this will lead to future studies exploring the potential of lactate as a diagnostic biomarker for ME/CFS, and facilitate the studies on pharmacological treatments targeting energy metabolism. 8. Expenses and payments Upon completion of all your visits, you will receive £50 for your participation in the research which will be paid through bank transfer. In case you are screened but do not fulfil the study criteria, you will still be reimbursed £10 for your time. Reasonable travel expenses will also be reimbursed on production of receipts, or a mileage allowance will be provided as appropriate. 9. What information will be collected and why is the collection of this information relevant for achieving the research objectives? We will be collecting data such as screening records, written consent forms, contact details for the purpose of this research only (and for future use if you have given us consent), bank details for payment, and MRI data. We will securely store and keep identifiable information about you for several years after the study has finished, depending on the types of documents and data, as outlined below. Paper Based Documents: Research paper-based documents with personal information, such as screening records, consent forms and contact details, will be held securely in a locked filling cabinet in a secure University of Oxford building for 5 years after the end of the study. They will be securely destroyed after this period of time. Participant Information Sheet Version 1 CUREC reference: R93723/RE001 16.08.2024 Page 6 of 9 We will also collect questionnaires and clinical interview notes in the paper form, however, they will be assigned a number and will not have any personal information on them. MRI Safety screening forms collected on the day of the scan may be kept for up to 5 years in a secure location by the centre. As part of those 5 years, the forms can be scanned and stored digitally on protected university computers and the paper copies shredded. Electronic Data: The only electronic identifiable data that will be collected are your bank details, we will input this into a password protected excel spreadsheet that is located within a two-step verified folder accessed by a password locked device. Also, relevant personal details will be shared with the financial unit of the Department of Psychiatry for payment purposes. The electronic expense form shared with the financial unit will be encrypted. The personal details information for payment purposes will be instantly deleted from our electronic database once they have been received by the financial unit. Your details will be kept by the finance team for seven years before they are securely destroyed. The electronic forms of non-identifiable data will be kept securely on the University of Oxford Servers, this includes data such as results of statistical spreadsheets and statistical analysis. As this is non-identifiable, it will be retained indefinitely for potential further analysis. MRI data are another form of electronic data that will be collected during this study. Authorised scanning centre personnel and the research team will have access to the MRI imaging data. MRI imaging data is assigned a unique ID as it is collected, and stored in a secure database within the scanning system. Due to the nature of these images, they remain potentially identifiable, even after we destroy your personal details. Imaging data will be stored on archive tapes indefinitely, even if you withdraw from this research. Data Security: Individuals from the University of Oxford may look at your research records to check the accuracy of the research study. The only people in the University of Oxford who will have access to information that identifies you will be the researchers and the people who need to contact you to for safety reasons or audit/monitor the research. Research data may be transferred to, and stored at, a destination outside the UK and the European Economic Area. Details that directly identify you will be removed and any data transfer will be done securely and with a similar level of data protection as required under UK law. With your consent, we will keep your contact details for 5 years after the end of the study on a secure database in order to let you know about future studies. We will keep a copy of your consent form with this database, as your consent is our legal basis for re-contacting you under UK data protection law. If you are contacted about a future study, you do not have to agree to participate. You can have your details removed from the database at any time by contacting the researchers. If you do not consent for your contact details to be kept, they will be deleted as soon as no longer needed for this study. Participant Information Sheet Version 1 CUREC reference: R93723/RE001 16.08.2024 Page 7 of 9 Study Withdrawal: You are able to withdraw yourself from participating in the study at any point. Once you are withdrawn from the study the research team will no longer contact you for further participation in the study. If you would like to withdraw your data, you will be able to do it until the point the data are pooled into the analysis. If you would like to withdraw before this data pooling occurs, we will ask for permission to keep the research data that we have already obtained. The data will be then safeguarded in the same way as data from participants who did not withdraw (as described above). However, if you do not want any data retained we will proceed to remove your data by deleting electronic data and destroying paper-based documents (other than the consent and MRI screening form) immediately. In this case, we will only keep the consent form. You will be unable to withdraw your data once data are pooled for analysis. 10. Will the research be published? Could I be identified from any publications or other research outputs? The findings from the research may be written up in a thesis, dissertation, academic publications, conference presentations, a report commissioned by an external organisation, and/or websites. However, you will not be identified in the publication or any other source of dissemination. A copy of the thesis will be deposited both in print and online in the Oxford University Research Archive where it will be publicly available to facilitate its use in future research. 11. Data Protection The University of Oxford is the data controller with respect to your personal data and, as such, will determine how your personal data are used in the study. The University will process your personal data for the purpose of the research outlined above. Research is a task that we perform in the public interest. Further information about your rights with respect to your personal data is available from the University’s Information Compliance web site at https://compliance.admin.ox.ac.uk/individual-rights. 12. Who has reviewed this research? This study has received ethics approval from a subcommittee of the University of Oxford Central University Research Ethics Committee. (Ethics reference: ) 13. Who is organising and funding the research? The study is organised by Dr Beata Godlewska and the Department of Psychiatry at the University of Oxford. The study is funded by grants from the Medical Research Council. The researchers are not being paid specifically for including you in this study. 14. Who do I contact if I have a concern about the research or I wish to complain? Participant Information Sheet Version 1 CUREC reference: R93723/RE001 16.08.2024 Page 8 of 9 If a participant in research is ever considered to have suffered harm through their participation, the University has arrangements in place to provide for compensation. If you have a concern about any aspect of this study, please contact Dr Beata Godlewska, 01865618309, beata.godlewska@psych.ox.ac.uk, or Prof. Phil Cowen, 01865618311, phil.cowen@psych.ox.ac.uk, and we will do our best to answer your query. We will acknowledge your concern within 10 working days and give you an indication of how it will be dealt with. If you remain unhappy or wish to make a formal complaint, please contact the University of Oxford Research Governance, Ethics & Assurance (RGEA) team at rgea.complaints@admin.ox.ac.uk or on 01865 616480 15. Further Information and Contact Details If you would like to discuss the research with someone beforehand (or if you have questions afterwards), please contact: Dr Beata Godlewska Department of Psychiatry Warneford Hospital, OX3 7JX University tel: 01865 618309 University email: beata.godlewska@psych.ox.ac.uk Participant Information Sheet Version 1 CUREC reference: R93723/RE001 16.08.2024 Page 9 of 9