Background:

The way the brain processes rewards and punishments may play a role in some disorders of the nervous system. People with chronic overlapping pain conditions (such as myalgic encephalomyelitis/chronic fatigue syndrome [ME/CFS]) may have heightened responses to unpleasant, punishing sensations. Some of these conditions may also cause heightened responses to effort; this is an unpleasant sensation felt during physical and mental exertion.

Objective:

To learn more about how the brain processes different unpleasant sensations.

Eligibility:

People aged 18 to 50 years with ME/CFS. Healthy volunteers are also needed.

Design:

Participants will have 3 visits in 1 to 5 weeks.

Visit 1: Participants may have a neurologic exam. They will have a mock magnetic resonance imaging (MRI) scan. They will lie on a bed in a wooden tube while they practice 2 tasks:

Thermal pain rating: A device that creates mild to moderate heat will be placed on one leg.

Physical effort rating: Participants will squeeze a plastic bar with different levels of force.

Visit 2: Participants will have a real MRI scan. They will lie on a table that slides into a large tube.

Visit 3: Participants will have another MRI scan. They will repeat the thermal pain and physical effort tasks while in the scanner. Sensors will be placed on 1 arm to measure how the muscles function as they squeeze the bar.

Their heart rate will be tested: They will hold their finger against a camera lens for 1 minute. They will do 2 other tasks: 1 requires repeatedly pressing a key on a keyboard, and the other requires squeezing a bar.

Study Description:

This protocol will examine the associations between brain activation and the subjective unpleasantness associated with pain and physical effort in healthy individuals. We have developed two behavioral tasks for administration during neuroimaging: a Thermal Pain Rating task and a Physical Effort Rating task, which will allow us to identify brain regions in which activity is associated with the unpleasantness of these experiences. We hypothesize that the unpleasantness of the experiences will be associated with activity in a recently identified network of brain regions thought to be involved in computing subjective value, known as the subjective valuation network (SVN).

Objectives:

Primary Objectives:

1. Determine which regions of the SVN are specifically involved in the subjective experience of unpleasantness associated with sensations of pain.
2. Determine which regions of the SVN are specifically involved in the subjective experience of unpleasantness associated with sensations of physical effort.

Endpoints:

Primary Endpoints:

1. SVN regions in which activity is significantly associated with unpleasantness of pain.
2. SVN regions in which activity is significantly associated with unpleasantness of physical effort.

• INCLUSION CRITERIA:

Healthy Controls: In order to be eligible to participate in this study as a healthy control, an individual must meet all the following criteria:

1. Ability of subject to understand and the willingness to sign a written informed consent document.
2. Stated willingness to comply with all study procedures and availability for the duration of the study.
3. Male or female, aged 18-50 (inclusive).
4. Good general health as evidenced by medical history and/or physical examination.

ME/CFS Patients: In order to be eligible to participate in this study as an ME/CFS patient, an individual must meet all the following criteria:

1. Ability of subject to understand and the willingness to sign a written informed consent document.
2. Stated willingness to comply with all study procedures and availability for the duration of the study.
3. Male or female, aged 18-50 (inclusive).
4. Has a diagnosis of ME/CFS, meeting at least one of three ME/CFS criteria: the 1994 Fukuda Criteria, the 2003 Canadian Consensus Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, or the Institute of Medicine Diagnostic Criteria.

EXCLUSION CRITERIA:

Healthy Controls:

1. Any current major neurological or psychiatric disorder such as (but not limited to) stroke, Parkinson s disease, Alzheimer s disease, schizophrenia, or major depressive disorder.
2. Any other current major medical disorder, such as a kidney disease, liver disease, cardiovascular disease, chronic pain condition, or any other disorder which, in the opinion of the PI would make participation risky for the individual or negatively affect the individual s ability to cooperate with study procedures.
3. Current use of medications acting primarily on the central nervous system, such as antidepressants, stimulants, etc.
4. Use of opioid medications for more than two weeks within the last two years or any use in the last month.
5. Current or history of substance use disorder, binge drinking, illegal drug use, or excessive tobacco use (defined as more than 10 cigarettes of nicotine per week).
6. Any more than occasional use of cannabis, defined as a score >1 (indicating use on more than one or two days in the last two weeks) on the marijuana use item of the DSM-5 Level 2-Substance Use-Adult questionnaire.
7. Any use of other illicit drugs or misuse of prescription medications, defined as a score >0 on any of the other items of the DSM-5 Level 2-Substance Use-Adult questionnaire.
8. Condition or injury affecting grip.
9. Condition or injury affecting extremities that would alter peripheral sensitivity to painful thermal stimuli or would otherwise cause such stimuli to be contraindicated.
10. Contraindications to MRI, including ferromagnetic metal in the cranial cavity or eye, implanted neural stimulator, cochlear implant, or ocular foreign body, implanted cardiac pacemaker, auto-defibrillator, or pump, non-removable body piercing, claustrophobia, inability to lie supine for 90 minutes, known pregnancy, or plans to become pregnant during the study.
11. Members of the NINDS BNU and their family members.
12. Non-English speakers will be excluded from the study as several study instruments do not have validated translations.

ME/CFS Patients:

1. Any current major neurological or psychiatric disorder, other than ME/CFS, such as (but not limited to) stroke, Parkinson s disease, Alzheimer s disease, schizophrenia, or major depressive disorder.

2. Any other current major medical disorder, other than ME/CFS, such as a kidney disease, liver disease, cardiovascular disease, chronic pain condition, or any other disorder which, in the opinion of the PI would make participation risky for the individual or negatively

   affect the individual s ability to cooperate with study procedures.

3. Current use of psychomotor stimulants, antipsychotics, or benzodiazepines.

4. Use of opioid medications for more than two weeks within the last two years or any use in the last month.

5. Current or history of substance use disorder, binge drinking, illegal drug use, or excessive tobacco use (defined as more than 10 cigarettes of nicotine per week).

6. Any more than occasional use of cannabis, defined as a score >1 (indicating use on more than one or two days in the last two weeks) on the marijuana use item of the DSM-5 Level 2-Substance Use-Adult questionnaire.

7. Any use of other illicit drugs or misuse of prescription medications, defined as a score >0 on any of the other items of the DSM-5 Level 2-Substance Use-Adult questionnaire.

8. Condition or injury affecting grip.

9. Condition or injury affecting extremities that would alter peripheral sensitivity to painful thermal stimuli or would otherwise cause such stimuli to be contraindicated.

10. Contraindications to MRI, including ferromagnetic metal in the cranial cavity or eye, implanted neural stimulator, cochlear implant, or ocular foreign body, implanted cardiac pacemaker, auto-defibrillator, or pump, non-removable body piercing, claustrophobia, inability to lie supine for 90 minutes, known pregnancy, or plans to become pregnant during the study.

11. Members of the NINDS BNU and their family members.

12. Non-English speakers will be excluded from the study as several study instruments do not have validated translations.

It has not been determined if data analysis based on IPD is beneficial or feasible. This will be evaluated at a later time.