Neural Mechanisms of Fatigue in Post-Acute Sequela of SARS-CoV-2

Motivated Decision-Making and Performance

This proposal aims to understand the neurobiological mechanisms of fatigue in individuals with Post-Acute Sequelae of SARS-CoV-2 Infection (PASC). This knowledge will eventually provide candidate mechanisms to target with pharmacological intervention and inform rehabilitative care for those individuals suffering from symptoms of fatigue in PASC.

Study Overview

• Status: Recruiting
• Conditions: Fatigue; PASC Post Acute Sequelae of COVID 19
• Intervention / Treatment: Behavioral: Physical Fatigue

• Study Type: Interventional
• Enrollment (Estimated): 200
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Anthony Gonzalez; Phone Number: 443-923-2716; Email: gonzalezan@kennedykrieger.org
• Study Contact Backup: Name: Vikram Chib, PhD

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Recruiting
      • Kennedy Krieger Institute
      • Contact: Anthony Gonzalez; Phone Number: 443-923-2716; Email: gonzalezan@kennedykrieger.org

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Age 18 to 75 years old.
• Have received a clinical diagnosis of post-acute sequelae of SARS-CoV-2 (PASC)/long COVID syndrome using the criteria specified by Thaweethai, et al., 2023 (JAMA). This symptom checklist provides a score based on the number and severity of symptoms. An individual with a score >12 is classified as having PASC.
• Currently experiencing Fatigue/Brain Fog as assessed with the Post-COVID symptom checklist and the PedsQL questionnaire.

Exclusion Criteria:

• Neurological disorders including, but not limited to, stroke, head injury, epilepsy, seizures, brain tumors, brain surgery, Parkinson's Disease, or any other neuromuscular disease (self-report).
• Diagnosed history of severe psychiatric diseases such as depression and schizophrenia (self-report).
• Congestive heart failure.
• Peripheral artery disease with claudication.
• Cancer.
• Pulmonary or renal failure.
• Unstable angina.
• Uncontrolled hypertension (more than 190/110 mmHg).
• Severe aphasia.
• Orthopedic or pain conditions.
• Have had exposure to metal or metal implants, due to the hazardous effects of the magnetic field.
• If on immunomodulatory therapy, they must have been on that therapy for at least 6 months before the start of the study.

Healthy age- and sex-matched controls for PASC - Exclusion criteria: Participants with a history of any of the following will be excluded from the study:

• Hospitalization due to SARS-CoV-2 infection.
• Neurological disorders including, but not limited to, stroke, head injury, epilepsy, seizures, brain tumors, brain surgery, Parkinson's Disease, or any other neuromuscular disease (self-report).
• Diagnosed history of severe psychiatric diseases such as depression and schizophrenia (self-report).
• Congestive heart failure.
• Peripheral artery disease with claudication.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PASC Participants - Physical Fatigue Task; Participants will perform a physically demanding task (grip force exertion task) repeatedly to induce physical fatigue.	Behavioral: Physical Fatigue; Participants will perform a physically demanding task (grip force exertion task) repeatedly to induce physical fatigue.
Experimental: Control Participants - Physical Fatigue Task; Participants will perform a physically demanding task (grip force exertion task) repeatedly to induce physical fatigue.	Behavioral: Physical Fatigue; Participants will perform a physically demanding task (grip force exertion task) repeatedly to induce physical fatigue.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison between PASC and HC - difference in mean Assessment Error	The difference between the level of effort rated by participants, and their average grip force exerted on a grip force dynamometer. Compared between PASC and HC.	Baseline, during experimental protocol.
Comparing between PASC and HC - difference in BBB permeability	Collected from and MRI sequence designed to measure BBB permeability.	Baseline, during MRI acquisition.
Comparing between PASC and HC - Regions of the brain that are sensitive to Assessment error as a function of disease state	We will examine an fMRI contrast, at the time of effort assessment, between HC and PASC groups. This contrast will examine percent signal change in brain activity.	Baseline, during experimental protocol.
The modulatory effect of BBB permeability on the relationship between Neural Activity and Effort Assessment	We will create a structural equation model that includes BBB permeability, fMRI activity, effort assessment behavior, and disease state (PASC/HC).	Baseline, during experimental protocol and MRI aquisition.
Comparing between PASC and HC - Difference in momentary subjective fatigue ratings	Measures of subjective fatigue will be collected on self report scale that ranges from 'not fatigued at all' to 'very fatigued'.	Baseline and during fatiguing exertions in the experimental protocol.
Comparing between PASC and HC - Difference in Mean Acceptance Rate of Risky Effort Options between rested/baseline and fatigue choices	Proportion of decisions in which inviduals choice to accept a risky effort opitions over a sure effort option.	Baseline and during fatiguing exertions in the experimental protocol.
Comparing between PASC and HC - Regions of the brain encoding a difference in effort cost between rested/baseline and fatigue choices	We will examine a contrast between chosen effort value pre versus post fatigue, between the HC and PASC groups. This contrast will examine percent signal change in brain activity.	Baseline and during fatiguing exertions in the experimental protocol.
The modulatory effect of BBB permeability on the relationship between Neural Activity and change effort-based decision-making	We will create a structural equation model that includes BBB permeability, fMRI activity, change in effort-based decision-making, and disease state (PASC/HC).	Baseline, fatigueing exertion, and during experimental protocol and MRI aquisition
Comparing between PASC and HC - Difference in mean assessment error as a function of time	The difference between the level of effort rated by participants, and their average grip force exerted on a grip force dynamometer. Compared between PASC and HC.	Data collections at months 0, 3, 6, 12
Comparing between PASC and HC - Difference in momentary subjective fatigue ratings as a function of time	Measures of subjective fatigue will be collected on self report scale that ranges from 'not fatigued at all' to 'very fatigued'.	Data collections at months 0, 3, 6, 12
Comparing between PASC and HC - difference in BBB permeability as a function of time	Collected from and MRI sequence designed to measure BBB permeability.	Data collections at months 0, 3, 6, 12
Comparing between PASC and HC - Regions of the brain that are sensitive to Assessment error as a function of disease state and time	We will examine a contrast, at the time of effort assessment, between HC and PASC groups, and use time as a covariate. This contrast will examine percent signal change in brain activity.	Data collections at months 0, 3, 6, 12

Collaborators and Investigators

• Sponsor: Hugo W. Moser Research Institute at Kennedy Krieger, Inc.
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS)
• Investigators: Principal Investigator: Vikram Chib, PhD, Johns Hopkins University; Kennedy Krieger Institute

Study record dates

Study Major Dates

• Study Start (Actual): July 16, 2025
• Primary Completion (Estimated): December 31, 2029
• Study Completion (Estimated): December 31, 2029

Study Registration Dates

• First Submitted: November 19, 2025
• First Submitted That Met QC Criteria: December 1, 2025
• First Posted (Actual): December 12, 2025

Study Record Updates

• Last Update Posted (Actual): December 12, 2025
• Last Update Submitted That Met QC Criteria: December 1, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Post-Infectious Disorders; COVID-19; Pathologic Processes; Chronic Disease; Disease Attributes; Respiratory Tract Infections; Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Diseases; Lung Diseases; Pneumonia, Viral; Pneumonia; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Post-Acute COVID-19 Syndrome; Fatigue
• Other Study ID Numbers: IRB00283000_1; R01NS140610 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

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

Drug and device information, study documents

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