Mechanisms of Persistent Fatigue (MAP-FAT)

Mechanisms of Persistent Fatigue (MAP-FAT): A Prospective Observational Cohort Study of Persistent Fatigue Following Epstein-Barr Virus Infection in Adolescents and Young Adults

Persistent fatigue (PF) is a common symptom across countries and cultures, and an important cause of disability and reduced quality of life. Acute infection is a common trigger of PF, as exemplified by the 'Long COVID' phenomenon. Despite substantial burden for the suffering individuals as well as their next-of-kins, the healthcare systems and the economy, PF is an under-researched field, with scarce knowledge of disease mechanisms as well as treatment and preventive measures.

Existing knowledge on PF suggests complex interactions between functional brain processes (as opposed to permanent brain damage), aberrations of the immune system (that normally protects against infection) and the autonomic (or non-voluntary) part of the nervous system (that monitors the internal state of the body and adjusts the function of internal organs). Previous findings have been interpreted in light of two alternative models: A body-to-brain mechanism where disturbances of the immune system are thought to impact on brain functions, and a brain-to-body mechanism where functional brain alteration is regarded the central element whereas aberration of the immune system is seen as a consequence (rather than a cause) mediated through altered activity of the autonomic nervous system.

The multinational and collaborative Mechanism of Persistent Fatigue (MAP-FAT) project is determined to scrutinize both these potential brain-body interactions in PF. The main objectives are: a) To determine the relationship between PF, activities in certain brain areas, activity in a certain part of the autonomic nervous system (the sympathetic branch), and immunological alterations; b) To determine whether PF is primarily dependent upon the brain's automatic predictions rather than the continuous sensory information mediated to the brain. To achieve these objectives, MAP-FAT will exploit an existing health registry on post-infective fatigue (preparatory part) and conduct a new post-infective cohort study (main part) in which a total of 150 individuals with "kissing disease" and 150 healthy controls are followed for six months. Investigations include: a) Clinical and demographic assessment; b) Questionnaire charting; c) Functional and structural imaging of the brain (multimodal brain MRI); d) Assessment of autonomic nervous system activity; e) Deep immunological profiling; and f) Behavioral experiments. The latter are specifically designed to disentangle the relative contributions of the brain's automatic predictions and sensory input for the experience of PF. In addition, one of the experiments includes concurrent functional brain imaging, autonomic nervous system assessment, and immunological profiling during experimental injections of drugs that impact on autonomic activity; this experiment is key for addressing the causal association between brain functions, autonomic activity and immunological disturbance.

Study Overview

• Status: Recruiting
• Conditions: Fatigue Post Viral

• Study Type: Observational
• Enrollment (Estimated): 300

Contacts and Locations

• Study Contact: Name: Vegard Bruun Bratholm Wyller; Phone Number: +4791166681; Email: v.b.b.wyller@medisin.uio.no

Study Locations

• Norway
  • Lørenskog, Norway, N-1478
    • Recruiting
    • Akershus University Hospital
    • Contact: Director of Dept. of Paeditrics and Adolescent Medicine; Phone Number: 4767960000; Email: postmottak@ahus.no

Participation Criteria

Eligibility Criteria

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

• Sampling Method: Non-Probability Sample

Study Population

The population served by the South-Eastern Norway Regional Health Authority (approximately 3.1M)

Description

Inclusion Criteria (pertaining to EBV group only):

• EBV infection, laboratory confirmed.
• First symptoms > 3 and < 6 weeks away

Exclusion Criteria (pertaining to both groups)

• Co-morbidity, including mental illness (seasonal allergy/asthma is accepted if no signs/symptoms)
• Usage of pharmaceuticals (hormonal contraception and paracetamol/ibuprofen is accepted)
• Concurrent demanding life event causing fatigue.
• Disability impacting on daily living.
• Regular smoking
• Usage of illicit drugs
• Pregnancy

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
EBV; Individuals with acute Epstein-Barr virus infection
HC; Healthy control individuals (ie., no acute EBV infection)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ASP difference	The difference in symptom ratings between neutral and negative affect provoking pictures during the Affect and Symptom Paradigm (ASP)	At six months' follow-up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
VHBP regression ratio	Ratio between the regression coefficient for exerted power vs. fatigue (an index of interoceptive input) and the regression coefficient for virtual hill gradient vs. fatigue (an index of prior expectations) during the Virtual Hill Bicycling Paradigm (VHBP)	At six months' follow-up
INSULA connectivity	Functional connectivity characteristics of the Insula cortical brain region	At six months' follow-up
FATIGUE CFQ	Fatigue scores (sum score from the Chalder Fatigue Questionnaire (CFQ), where higher values means more fatigue).	At six months' follow-up

Collaborators and Investigators

• Sponsor: University Hospital, Akershus

Study record dates

Study Major Dates

• Study Start (Actual): April 28, 2026
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: January 31, 2026
• First Submitted That Met QC Criteria: January 31, 2026
• First Posted (Actual): February 6, 2026

Study Record Updates

• Last Update Posted (Actual): May 22, 2026
• Last Update Submitted That Met QC Criteria: May 19, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Other Study ID Numbers: AHUS p360 26/01004

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Anonymized IPD from all elements of MAP-FAT will be shared at a trusted, public repository such as ZENODO. We will adhere to the FAIR (findable, accessible, interoperable, reusable) principles:

• A unique and persistent Digital Object Identifier (DOI) will be assigned to each item in the public repository, thus making them easily findable.
• MAP-FAT (meta)data will be retrievable by its identifier; all beneficiaries will ensure open access to the deposited data, following the principle 'as open as possible as closed as necessary'.
• MAP-FAT (meta)data will use a formal, accessible, shared, and broadly applicable language for knowledge representation. Interoperability resources such as FAIRsharing will be applied.
• The conditions under which the data can be used will be made transparent through easy-to-use copyright licenses, such as Creative Commons (Creative Commons Attribution International Public License, CC BY) or Creative Commons Public Domain Dedication (CC 0).

• IPD Sharing Time Frame: Start date: six monhts after last patient to follow-up (anticipated Oct 2027) End date: After five years
• IPD Sharing Access Criteria: Cf. above. Anonymized data will be shared at a public repository. Data will be made available for scientific purposes upon request.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP