Myalgic Encephalomyelitis Chronic Fatigue at the National Institutes of Health

* INCLUSION CRITERIA: * Inclusion criteria for all participants 1. Adult participants aged 18-60 years at the time of enrollment. 2. Self-reported completion of at least the 7th grade of school. 3. Ability to speak, read, and understand English. 4. Willing and able to complete all study procedures 5. Participant has a primary care physician at the time of enrollment. 6. Able to provide informed consent. * Additional inclusion criteria for participants with PI-ME/CFS for the phenotyping visit: 1. A self-reported illness narrative of the development of persistent fatigue and post-exertional malaise as the consequence of an acute infection. The persistent fatigue may have an acute onset or become progressively worse over 6 months. 2. Licensed Independent Practitioner documentation of ME/CFS onset: * Medical documentation of absence of symptoms within one year of ME/CFS onset. This may include medical records, letters, or information gathered from telephone calls with study personnel. * Documentation of a medical evaluation for symptoms of an acute infection or documentation of a medical evaluation of persistent symptoms within 2 months following an assumed infection. 3. Persistent fatigue and PEM onset less than 5 years prior to enrollment. * Additional inclusion criteria for participants with PI-ME/CFS for the exercise stress visit: 1. Be unanimously considered to be a case of PI-ME/CFS by the protocol s adjudication committee. 2. Meet the 1994 Fukuda Criteria or the 2003 Canadian Consensus Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome or the Institute of Medicine Diagnostic Criteria.. 3. Have moderate to severe clinical symptom severity: * Severe fatigue as determined using the Multidimensional Fatigue Inventory (MFI): score of greater than or equal to 13 on the general fatigue subscale or greater than or equal to 10 on the reduced activity subscale. * Functional impairment as determined using the Short-Form 36 (SF-36): score of less than or equal to 70 physical function subscale, or less than or equal to 50 on role physical subscale, or less than or equal to 75 on social function subscale * Additional inclusion criteria for healthy volunteer group: None * Additional inclusion criteria for COVID-19 Healthy Volunteers: documented prior COVID19 infection as evidenced by: 1. A history of clinical manifestations compatible with COVID-19 2. Laboratory evidence of Covid-19 infection: * Detectionof SARS-CoV-2RNA or antigen in nasopharyngeal swab, sputum, other sample source with Emergency Use Authorization/approval from the FDA; OR * A positive antibody test using an assay that has received Emergency Use Authorization/approval from the FDA 3. Has been recovered from the COVID-19 infection for at least six months and no more than five years. EXCLUSION CRITERIA: * Exclusion criteria for all participants: 1. Current or past psychotic disorder including depression with psychosis, bipolar disorder, and schizophrenia 2. Current DSM-5-defined major depression disorder, generalized anxiety disorder, post-traumatic stress disorder, panic disorder, or obsessive-compulsive disorder unless managed for more than six months with a stable treatment regimen 3. Current or prior substance use disorder as diagnosed on the Structured Clinical Interview for DSM-5 (SCID-5). 4. Current suicidal ideation 5. History of head injury with loss of consciousness or amnesia lasting greater than a few seconds within lasta five years or lasting greater than 5 minutes at any point during their lifetime. Persons with medical record evidence of post-concussive symptoms lasting more than six months are also excluded. Persons with medical record evidence of post-concussive symptoms lasting more than six months are also excluded. 6. Women who are pregnant, actively seeking to become pregnant, or have been pregnant in the year prior to study enrollment. 7. Current or previous malignancy. Certain dermatologic malignancies (e.g. basal cell carcinoma) will be allowed. A history of malignancy that have fully resolved with surgical resection only (i.e. no chemotherapy, radiation therapy, or immunotherapy) will be allowed. 8. Current systemic immunologic disorder (e.g. Type 1 diabetes, rheumatoid arthritis) will be excluded. Allergies requiring anti-histamines may not be an exclusion, but allergies requiring immunosuppressants may be an exclusion. 9. Current or previous long term immune suppressive or immunomodulatory therapy. Systemic steroid use, even short-term, must not have been used within the month prior to enrollment 10. Any medical condition (eg, congestive heart failure, coronary artery disease, chronic obstructive pulmonary disease, severe osteoarthritis, poorly controlled asthma) that would make the study procedures risky for the participant (e.g. exercise-induced angina and asthma) or that may confound the study results (e.g. untreated obstructive sleep apnea, severe osteoarthritis). 11. Participation in a clinical protocol (e.g. anti-inflammatory drug intervention study) which includes an intervention that may affect the results of the current study. 12. Inability to perform the bicycling exercise task. 13. Clinically significant claustrophobia 14. Not willing to allow for research samples to be shared with other researchers. 15. Employees or staff at NIH that are directly supervised by the primary investigator or associate investigators. * Additional exclusion criteria for participants with PI-ME/CFS for phenotyping visit: 1. Significant neurological disorder (e.g. neurodegenerative disorder, stroke, epilepsy). 2. PI-ME/CFS disease severity that makes it impossible for the volunteer to leave the home or requires inpatient treatment. 3. Suspected, probable, or confirmed Lyme disease per 2011 CDC Lyme Disease National Surveillance Case Definitions. 4. Underlying illness that may cause fatigue such as thyroid dysfunction, hepatitis, or other systemic diseases. * Additional exclusion criteria for participants with PI-ME/CFS for exercise stress visit: 1\. Current (within 1 week) use of prescription or over-the-counter medications, herbal supplements, or nutraceuticals that may influence brain excitability that the potential participant is either unwilling or clinically unable to safely wean off for the duration of the period of the exercise stress visit. The possibility for a potential participant to be weaned off medication will be cooperatively determined by both the clinical investigative team and personal physicians. Examples of medications that influence brain excitability include tricyclic antidepressants, hypnotic, antiepileptic, antipsychotic medication, stimulants, antihistamines, muscle relaxants, dopaminergic medications, and sleep medications. * Additional exclusion criteria for healthy volunteer group: 1. Substantial daily fatigue as determined using PROMIS-SF Fatigue: score of \> 17. 2. Significant neurological disorder (e.g. neurodegenerative disorder, stroke, epilepsy). 3. Current (within 1 week) use of prescription or over-the-counter medications, herbal supplements, or nutraceuticals that may influence brain excitability * Additional exclusion criteria for COVID-19 healthy volunteer group: 1. Substantial daily fatigue as determined using PROMIS-SF Fatigue: score of \>17. 2. Significant neurological disorder (e.g. neurodegenerative disorder, stroke, epilepsy). 3. Current (within 1 week) use of prescription or over-the-counter medications, herbal supplements, or nutraceuticals that may influence brain excitability