Epigenetics of Post-exertional Malaise in Patients With ME/CFS

Study Overview
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Brief Summary
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Exploring epigenetic mechanisms of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) is crucial to understand the mechanisms underlying its pathophysiology. Three potential candidates have been selected (BDNF, COMT, and HDAC genes). DNA methylation in the promoter regions of those genes will be explored. The investigators designed a randomised controlled trial and will enrol 70 patients with ME/CFS and 35 age-, sex-, and BMI-matched healthy controls. Both groups will be randomised in 2 groups and receive either one session of aerobic exercise or a validated test designed to trigger mental stress and mental fatigue. The primary aim is to assess genetic and epigenetic mechanisms of BDNF, COMT and HDAC genes in response to exercise and the stress task.

Detailed Description
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The only way to improve the diagnosis and treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) is to better understand the mechanisms underlying its pathophysiology. Central nervous system dysfunctions play a major role in ME/CFS and help explaining patients' symptoms, such as general malaise occurring after physical activity (i.e. post-exertional malaise). Therefore, post-exertional malaise in relation to three major candidates involved in central nervous system functioning - brain-derived neurotrophic factor (BDNF), catechol-O-methyltransferase (COMT) and histone de-acetylases (HDAC) - will be explored. BDNF is a protein involved in crucial functions such as nerve growth, memory and learning, and plays a role in neuronal sensitisation and pain. However, no study has explored the role of BDNF in ME/CFS. Our research group performed a preliminary study which focussed on BDNF in ME/CFS. In a previous study, the investigators assessed DNA methylation (an epigenetic mechanism that contribute to gene expression silencing), and protein expression in serum of the BDNF in patients with ME/CFS and healthy controls. Patients showed significantly less DNA methylation and significantly more BDNF protein. Given these exciting findings, further study is warranted. COMT is an enzyme encoded by its homonymous gene. The enzyme degrades catecholamines like dopamine, epinephrine and norepinephrine. Catecholamines have been repeatedly associated with pain, stress, and depression. Lower COMT activity increases catecholamines level, causes hyperalgesia, and has been associated with depressive symptoms. Similarly, research on histone acetylation shows that another group of enzymes (Histone de-acetylases, HDACs) are increased during neural sensitisation and pain. However, no research has been done on HDACs in patients with ME/CFS. Interestingly, aerobic exercise has been shown to increase BDNF release and decrease COMT and HDACs activity. Given the detrimental acute effects that exercise can have on patients with ME/CFS, investigators hypothesised that understanding the role of BDNF, COMT, and HDACs following exercise would help elucidating both mechanisms of post-exertional malaise and ME/CFS pathophysiology. A randomised controlled trial has been designed including 70 patients with ME/CFS and 35 age-, sex-, and BMI-matched healthy controls. Both groups will be randomised in 2 groups. One group will undergo one session of aerobic exercise, and the other group undergoes a validated test designed to trigger mental stress and mental fatigue. All participants will undergo clinical assessments, measurements of pain thresholds, and blood withdrawal before and after the exercise/mental stress exposure. The aims are to assess genetic and epigenetic mechanisms of BDNF, COMT and HDAC genes, as well as the expression of these factors in blood and serum in patients with ME/CFS.

Official Title
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The Influence of Epigenetic Modifications and Post-Exertional Malaise in People With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Conditions
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Fatigue Syndrome, Chronic

Intervention / Treatment
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* Behavioral: Exercise
* Other: Mental Stress Test


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: diagnosis of ME/CFS established by a MD experienced in the field of internal medicine and ME/CFS - according to the published international criteria developed by the Canadian Consensus Criteria (CCC); age between 18 and 70 years old; body mass index (BMI) below 30 (no obesity). Exclusion Criteria: presence of other neurological disorders (Parkinson's disease, Multiple Sclerosis, etc); presence of systemic disorders (lupus erythematosus, rheumatoid arthritis, etc.); presence or history of cardiac disorders (coronary heart disease, history of heart failure, etc); presence or history of cancer; presence or history of neuropathic pain (e.g. pain related to herpes zoster virus); pregnancy;

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomised Controlled Trial
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ME/CFS Exercise<br>Patients undergoing the physical stress test (aerobic power index) | Behavioral: Exercise<br>* Sub-maximal exercise test<br>* Other names: Aerobic Power Index;Other: Mental Stress Test<br>* Computerised mental arithmetic challenges and social evaluative threat tasks<br>* Other names: Montreal Imaging Stress Task;|
| Experimental: Patients Stress<br>Patients undergoing the mental stress task (MIST) | Behavioral: Exercise<br>* Sub-maximal exercise test<br>* Other names: Aerobic Power Index;Other: Mental Stress Test<br>* Computerised mental arithmetic challenges and social evaluative threat tasks<br>* Other names: Montreal Imaging Stress Task;|
| Active Comparator: Healthy Exercise<br>Healthy controls undergoing the physical stress test (aerobic power index) | Behavioral: Exercise<br>* Sub-maximal exercise test<br>* Other names: Aerobic Power Index;Other: Mental Stress Test<br>* Computerised mental arithmetic challenges and social evaluative threat tasks<br>* Other names: Montreal Imaging Stress Task;|
| Active Comparator: Healthy Stress<br>Healthy controls undergoing the mental stress task (MIST) | Behavioral: Exercise<br>* Sub-maximal exercise test<br>* Other names: Aerobic Power Index;Other: Mental Stress Test<br>* Computerised mental arithmetic challenges and social evaluative threat tasks<br>* Other names: Montreal Imaging Stress Task;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DNA methylation | DNA methylation measured at several CpGs of the genes' promoter regions using pyrosequencing technology | Baseline through 1 week post intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Symptoms | Symptoms reported by the patients using the DePaul Symptoms Questionniare | Baseline through 1 week post intervention | 
| Pain sensitivity | Sensitivity to mechanical stimuli using a digital algometer (FPXTM, Fisher, Wagner Instruments, Greenwich) as well as heat and cold stimuli using the TSA-II device (Medoc, CA, USA). The devices will be placed, in random order to prevent test order effects, at three different body sites: the skin web between thumb and index finger, trapezius muscle, and proximal third of tibialis anterior muscle, in order to test pain thresholds on non-specific locations both on the extremities and the trunk. | Baseline through 1 week post intervention | 
| Serum BDNF | BDNF protein expression in serum using Enzyme-Linked Immunosorbent Assay (ELISA) kit for human BDNF | Baseline through 1 week post intervention | 
| Cortisol response | Cortisol will be measured in saliva and used as a measure of stress responses using LC/MS-MS method. | Baseline through 1 week post intervention | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Exercise, Chronic Fatigue Syndrome, Epigenetics, DNA methylation