None listed
Conditions
Brief summary
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), is a debilitating illness affecting up to 24 million people worldwide but concerningly there is no known mechanism for ME/CFS and no objective test for diagnosis. A series of our neuroimaging findings in ME/CFS, including functional MRI (fMRI) signal characteristics and structural changes in brain regions particularly sensitive to hypoxia, has informed the hypothesis that abnormal neurovascular coupling (NVC) may be the neurobiological origin of ME/CFS. NVC is a critical process for normal brain function, in which glutamate from an active neuron stimulates Ca2+ influx in adjacent neurons and astrocytes. In turn, increased Ca2+ concentrations in both astrocytes and neurons trigger the synthesis of vascular dilator factors to increase local blood flow assuring activated neurons are supplied with their energy needs. This study will investigate NVC using multimodal MRIs: 1) hemodynamic response function (HRF) that represents regional brain blood flow changes in response to neural activities and will be modelled from a cognitive task fMRI; 2) respiration response function (RRF) that represents autoregulation of regional blood flow due to carbon dioxide and will be modelled from breath holding fMRI; 3) neural activity associated glutamate changes that will be modelled from a cognitive task functional magnetic resonance spectroscopy. We also aim to develop a neuromarker for ME/CFS diagnosis by integrating the multimodal MRIs with a deep machine learning framework. This cross-sectional study will recruit 288 participants (91 ME/CFS, 61 individuals with chronic fatigue, 91 healthy controls with sedentary lifestyles, 45 fibromyalgia). The ME/CFS will be diagnosed by an agreed diagnosis made by two clinicians using the Canadian Consensus Criteria. Symptoms, vital signs, and activity measures will be collected alongside multimodal MRI. The HRF, RRF, and glutamate changes will be compared among four groups using one-way analysis of covariance (ANCOVA). Equivalent non-parametric methods will be used for measures that do not exhibit a normal distribution. The activity measure, body mass index, age, depression, and anxiety will be included as covariates for all statistical analyses with the false discovery rate used to correct for multiple comparisons. The data will be randomly divided into a training (N = 188) and a validation (N = 100) group. Each MRI measure will be entered as input for a least absolute shrinkage and selection operator - regularized principal components regression to generate a brain pattern of distributed clusters that predict disease severity. The identified brain pattern will be integrated using multimodal deep Boltzmann machines as a neuromarker for predicting ME/CFS fatigue conditions. The receiver operating characteristic curve of the identified neuromarker will be determined using data from the validation group.
Interventions
Data collection includes (1) symptom questionnaires, (2) actigraphy, (3) clinical interviews, and (4) MRIs. Given the limited capabilities of ME/CFS patients, a participant may take over one month to complete all symptom questionnaires. The other data collection will start after the questionnaires and be completed over three weeks. Participants may visit the research site (Thompson Institute at University of the Sunshine Coast) one to three times, dependent on participants’ preferences and avail
Data collection includes (1) symptom questionnaires, (2) actigraphy, (3) clinical interviews, and (4) MRIs. Given the limited capabilities of ME/CFS patients, a participant may take over one month to complete all symptom questionnaires. The other data collection will start after the questionnaires and be completed over three weeks. Participants may visit the research site (Thompson Institute at University of the Sunshine Coast) one to three times, dependent on participants’ preferences and availabilities of clinicians and MRI scan times. (1) After informed consent has been obtained, the following assessments will be undertaken: 1) symptom information relevant to establishing CCC ME/CFS classification; 2) the 36-item Short-Form Health Survey; c) Hospital Anxiety and Depression Scale questionnaire; d) the Bell disability score; e) The Assessment of Quality of Life questionnaire; g) the Pittsburgh sleep quality index questionnaire. Symptom questionnaires will be undertaken only once at the start of participation. The questionnaires can be filled out online or mailed to participants upon their preferences. The total estimated time for the completed questionnaire is about 3 hours. (2) Actigraphy: Participants will be given a GT3X-BT device with a heart rate monitor to wear seven days before the MRI. The heart rate monitor is to be worn for 24 hours. After the MRI scan, participants will be given another GT3X-BT device to wear for seven days with a 24-hours heart rate monitor to be worn on the following morning of the MRI scan. The actigraphy will be posted to or picked up by participants at the first clinical interview. (3) Clinical interviews will only be undertaken by two clinicians independently with patients at a single time point. Each interview will happen at the research site and last about one hour. Before the clinical interviews, height, weight, BMI, blood pressure, pulse rate, oxygen saturation, and weighted standing time for evaluation of postural orthostatic tachycardia syndrome (POTS) for each participant will be collected and shared with the clinician. The Beighton scores (a measure of generalised joint hypermobility) for each participant will be collected during the second clinical interview. (4) Multimodal MRI will be undertaken only at a single time point. Brain images are acquired using a 3T MRI scanner with a 64-channel head coil (Skyra, Siemens) at the research site. The scan takes about 1.5 hours, including an MRI safety screen and preparation. A fatigue state questionnaire that measures current fatigue levels will be completed before and after the MRI for each participant.
Sponsors
University of the Sunshine Coast
Eligibility
Sex/Gender
All
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
The inclusion criteria include adult individuals who express an interest, meet each group definition, and are confirmed by clinicians. The ME/CFS group is patients who meet ME/CFS Canadian Consensus Criteria and have a consistent diagnosis by two clinicians. The two clinicians will discuss to reach a consistent diagnosis if different results are generated during the independent interviews. The chronic fatigue group is defined as (1) self-identified ME/CFS but not confirmed by the two clinicians (i.e., present with other conditions or lack core ME/CFS symptoms); (2) with other disorders (not ME/CFS or fibromyalgia) that fatigue is a significant symptom. The fibromyalgia group is defined as individuals who meet the 2016 American College of Rheumatology fibromyalgia criteria and confirmed by the clinic interview. The healthy controls are healthy individuals does not meet exclusion criteria and have a sedentary lifestyle. A sedentary lifestyle is defined as spending 4 or more hours/day (in addition to sleep) on activities that are less than 1.5 metabolic equivalents measured by the Actigraph GT3X-BT device.
Exclusion criteria
The exclusion criteria include individuals 1) out of the age range, 2) pregnant, 3) with severe intellectual or mental impairment preventing them from fully understanding the study to give consent, 4) with moderate or severe mental disorders who are taking medication as treatment, 5) with a known other neurological disorder, 6) who cannot read and communicate in English, 7) with an unequal relationship with the team unless there is the desire to be a volunteer with the right to withdraw at any time point, 8) with alcohol or substance related disorder, 9) with BMI >35, 10) smoking (including marijuana), 11) with diabetes, hypertension, or uncontrolled hyperlipidaemia, 12) currently on medication acting on the brain, 13) with a clinical diagnosis of hemochromatosis, 14) with a double copy of the Haemochromatosis gene, 15) who experienced migraines more than six times a year before the onset of their symptoms. Additional exclusion criteria for HCs include individuals 1) with a chronic disease and 2) who experience migraines more than six times a year, and 3) who do more than 60 minutes in moderate or high-intensity activity per week.
Outcome results
None listed