PEM, a Starting Point to Investigate ME/CFS (PEM_CFS)

PEM, a Starting Point to Investigate and Understand ME/CFS

Exercise is an important contributor to general health and is considered a potential remedy for chronic diseases. This is in strong contrast with the observation that in most myalgic encephalomyelitis (ME/CFS) patients exercise aggravates their symptoms. Recently, post-exertional malaise (PEM) is defined as the key symptom of ME/CFS. The etiology and pathophysiological mechanisms underlying ME/CFS are still unknown and objective diagnostic criteria are not available. Various hypotheses are postulated including disorders of several organ systems but the heterogenous presentation of symptoms in patients, and the multisystem deficits complicate reaching an all-encompassing hypothesis. It seems therefore reasonable to focus on the key symptom, i.e., PEM. PEM can be induced by minor cognitive or physical exertion and can be assessed with questionnaires. Acute physical activity triggers complex cardiovascular, metabolic, and molecular responses and for ME/CFS, hence it is important to understand the relation between these acute processes and the prolonged presentation of aggravated symptoms (PEM). We therefore want to measure metabolites, cardiovascular responses, cognitive performance, muscle force and fatigability in 50 patients and 50 controls matched on group level for sex, age, and activity. To follow changes in these parameters we perform time-series analysis, including data obtained before, during and after task performance. Besides understanding these interactions, it is also essential to understand how these acute and prolonged responses affect behaviour and perception.

Study Overview

• Status: Recruiting
• Conditions: Myalgic Encephalomyelitis / Chronic Fatigue Syndrome
• Intervention / Treatment: Other: No intervention is planned

• Study Type: Observational
• Enrollment (Estimated): 100

Contacts and Locations

• Study Contact: Name: Inge Zijdewind, Dr; Phone Number: 0625647190; Email: c.a.t.zijdewind@umcg.nl
• Study Contact Backup: Name: Leda Maffei; Phone Number: 0625647190; Email: l.b.maffei@umcg.nl

Study Locations

• Netherlands
  • Groningen, Netherlands, 9713VB
    • Recruiting
    • UMC Groningen
    • Contact: Inge Zijdewind; Email: c.a.t.zijdewind@umcg.nl
    • Contact: Leda Maffei; Phone Number: 0625647190; Email: l.b.maffei@umcg.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Patients with diagnosed ME/CFS according to the international consensus criteria or the canadian consensus criteria and 50 controls matched on group level for age, sex, and activity.

Description

Inclusion Criteria:

• Willing and be able to complete all study procedures
• Able to provide informed consent

Additional inclusion criteria for ME/CFS patients

• ME/CFS patients have to meet the criteria of the ICC OR CCC.
• A self-reported illness narrative of the development of persistent fatigue and post-exertional malaise according to the DSQ-2. The persistent fatigue may have an acute onset or become progressively worse over 6 months.

Exclusion Criteria:

• Use of immune-modulating drugs in the past 3 months.
• A serious medical condition that may explain symptoms similar to ME/CFS, such as cancer, coronary artery disease, uncontrolled diabetes, chronic infection (hepatitis B and C, tuberculosis, HIV), inflammatory diseases, autoimmune diseases (e.g. such as rheumatoid arthritis, lupus or polymyositis), severe COPD or other severe persistent respiratory disease, severe anemia, renal failure, Addison's or Cushing's disease or severe neurological disease (such as Parkinson's disease).
• History of head injury with loss of consciousness or amnesia lasting greater than a few seconds within last 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.
• Suspected, probable, or confirmed Lyme disease
• Current or substance use disorder within last 5 years
• A mood disorder or other psychiatric diagnosis prior to a diagnosis of ME/CFS.
• Pregnant, actively seeking to become or breastfeeding in the past 12 months.
• BMI >35.
• having cognitive or communication problems which reduces the capacity to understand instructions.
• planned a change in medication during the testing period.
• Use of medication that affects the blood pressure (e.g. Beta-blockers, fludrocortisone, vasoconstrictors).
• 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.
• Claustrophobia
• 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 visits. 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.
• Use of B12 high dosage injections
• Being colorblind

Additional exclusion criteria for control subjects:

• performing high intensity or moderate intensity activities more than 30 minutes per week
• substantial fatigue as determined using MFIS fatigue questionnaire >30

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
ME/CFS; 50 patients diagnosed with ME/CFS according to the International Consensus Criteria (ICC) and Canadian Consensus Criteria (CCC) will be included	Other: No intervention is planned; Investigation of the pathophysiology of PEM in ME/CFS patients and matched controls
Control; 50 sex, age and activity matched controls will be included	Other: No intervention is planned; Investigation of the pathophysiology of PEM in ME/CFS patients and matched controls

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cardiovascular parameters (Heart rate and blood pressure)	Heart rate (bpm) and blood pressure (mmHg) are measured with a continuous non-invasive monitoring system (Finapres Midi). The BP sensor is positioned around the middle finger on the second phalanx of the left hand and subjects must hold their arm at breast level. The recorded values during T1 and T2 will be compared between tasks, as well as between groups and sessions.	2023-2027
Short maximal voluntary contraction	Short isometric maximal voluntary contractions (MVC) of the right index finger abductor (FDI). The maximal index finger abduction force (newton) is measured with a force transducer which is held by the participant. The measurement is repeated 3 times per hand and the highest value is taken. On the second and third repetition, a superimposed twitch stimulation (SIT) will be induced to assess the voluntary activation during maximal contraction.	2023-2027
Submaximal voluntary contractions (20%,40%, 60% of the short MVC)	The participant is asked to produce force at different submaximal force targets (20%, 40%, 60%). The targets are presented on a monitor and subjects get online feedback of the target force and their produced force.	2023-2027
Sustained maximal voluntary contraction of the FDI	The participant performs a maximal contraction for 2 minutes. During the 2 minutes contraction 7 SIT stimulation are given to the subject to assess voluntary muscle activation during a fatiguing task.	2023-2027
Cognitive parameters (stroop task)	This test assesses the ability to inhibit cognitive interference, which occurs when the processing of a stimulus feature affects the simultaneous processing of another attribute of the same stimulus. Participants see a word describing a colour on a screen, the word is written in the same or different colour than the word they will read. They are asked to press a yes or no button to indicate whether the colour of the word and the meaning of the word matches (yes) or not (no). The number of correct answers and the reaction time will be assessed.	2023-2027
BOLD activation	Blood oxygenation level dependent (BOLD): changes both in oxy- and deoxyhemoglobin concentration. Brain activation in different tasks will be compared between groups and sessions.	2023-2027
Arterial Spin Labeling (ASL)	Is a non-invasive fMRI technique that uses arterial water as an endogenous tracer to measure cerebral blood flow. ASL provides reliable absolute quantification of cerebral blood flow with high spatial and temporal resolution. Perfusion data are used to identify patients suffering from impaired autoregulation of cerebral blood flow and to obtain associations with cardiovascular responses and muscle fatigue.	2023-2027
Cerebral oxygenation (near infrared spectroscopy)	Oxy- and deoxyhemoglobine concentrations are measured at the prefrontal cortex and leg muscle with a non-invasive near infrared spectroscopy device (NIRS), where small sensors are positioned on the forehead and the quadriceps muscle. For this measurement a standardized vascular occlusion test will be performed on the quadriceps muscle to assess the local tissue oxygen consumption and the microvascular reperfusion and reactivity. This measurement will be used as calibration to normalize per subject the oxy- and deoxyhemoglobin concentrations allowing for comparisons between subjects. The oxygenated and deoxygenated values for the prefrontal cortex and leg muscle will be compared across tasks, groups and sessions.	2023-2027

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
30 Chair to stand test	This test assesses functional lower extremity strength. Subjects sit on a chair and stand up repeatedly for 30 s. Arms of the subject are crossed and held against the chest. The number of cycles of standing up from sitting are counted.	2023-2027
Handgrip force (kg)	MVC of the handgrip is measured with a hydraulic hand dynamometer (JAMAR Hand Dynamometer). The measurement is repeated 3 times.	2023-2027
Activity monitor	To measure routine activities in daily life, participants will be asked to wear an activity device (Actigraph) on their dominant hip as well as a heart rate device (polar H10) around their chest. During the 7 days of wearing the devices participant will be asked to fill out an activity diary. The difference in activity level and heart rate variables will be compared across the groups.	2023-2027
Blood samples	The blood samples are used to analyse the short-lasting changes in metabolites before and after the performance of physical and cognitive tasks and long-lasting changes on the next day	2023-2027
Knee extension force	Maximal voluntary force (MVC) of the knee extensors is measured with a custom-built dynamometer. Subjects are seated in a chair with the knee and hip in 90° of flexion with their non-dominant lower leg strapped to the chair's lever arm (~ 10 cm up to lateral malleolus). Subjects are instructed to contract their knee extensors as rapidly and forcefully as possible and to maintain force generation for 5 s. MVC is determined as the peak force.	2023-2027
Chalder fatigue scale	Is a questionnaire used to measure the severity of tiredness in fatiguing illnesses. Scores per question range from 0 to 3. The higher the score the more fatigue experienced.	2023-2027
SF-36	It is a multipurpose, short-form health survey with 36 questions. It yields an eight-scale profile of scores as well as physical and mental health summary measures. It is useful in comparing general and specific populations and comparing the relative burden of diseases. Higher scores indicate a better health status.	2023-2027
DePaul Symptoms Questionnaire 2 (DSQ-2)	DSQ-2 is a questionnaire that assesses the key symptoms of ME/CFS. At each item, participants have to rate the frequency and severity of the symptom on a scale from 0 to 4. The higher the scores the worse the symptoms.	2023-2027
Bell disability scale	Bell scale is a scale that describes the levels of physical and mental activity health. The scores range from 0 to 100, the higher the score the better the health.	2023-2027
Pittsburgh sleep quality index	Is a questionnaire assessing sleep quality and disturbances. The higher the score the worse the sleep quality.	2023-2027
Hospital Anxiety and Depression Scale	Is a questionnaire to determine levels of anxiety and depression that a person is experiencing. Higher scores reflect a stronger impact.	2023-2027
Composite Autonomic Symptom Score 31	Is a questionnaire of 31 questions that assesses the autonomic nervous system symptoms. Higher score indicates greater autonomic symptom severity.	2023-2027
Modified Fatigue Impact Scale (MFIS)	Is a questionnaire related to sense of fatigue. The questionnaire consists of 21 questions providing assessment of the effect of fatigue in terms of physical, cognitive, and psychosocial function. Higher scores reflect a higher impact of fatigue.	2023-2027
DePaul Post-Exertional Malaise Questionnaire (DPEMQ)	Is a questionnaire that assesses the onset, triggers and recovery of PEM.	2023-2027
EQ-5D	Is a questionnaire that measures an individual's health status. It has five dimensions on mobility, usual activities, self-care, pain and discomfort and anxiety and depression. The higher the score the higher the impact on the quality of life.	2023-2027
Symptom severity score (SSS-12)	Is a questionnaire that assesses the severity of 12 main symptoms from o to 10, with 10 being the most severe.	2023-2027

Collaborators and Investigators

• Sponsor: University Medical Center Groningen

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2024
• Primary Completion (Estimated): October 31, 2026
• Study Completion (Estimated): July 31, 2027

Study Registration Dates

• First Submitted: March 29, 2024
• First Submitted That Met QC Criteria: July 14, 2026
• First Posted (Actual): July 21, 2026

Study Record Updates

• Last Update Posted (Actual): July 21, 2026
• Last Update Submitted That Met QC Criteria: July 14, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: Post exertional malaise
• Additional Relevant MeSH Terms: Neuroinflammatory Diseases; Musculoskeletal Diseases; Nervous System Diseases; Muscular Diseases; Pathologic Processes; Encephalomyelitis; Neuromuscular Diseases; Chronic Disease; Disease Attributes; Pathological Conditions, Signs and Symptoms; Fatigue Syndrome, Chronic
• Other Study ID Numbers: UMCG 17463

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No