ME/CFS Brain Fog: Cognitive Rehabilitation Trial

Brain Training for Chronic, Post-viral, Brain Fog: Study A

The purpose of this study is to compare two approaches to cognitive rehabilitation in adults with post-viral cognitive syndrome, which resulted in brain fog. All participants will be screened for eligibility prior to participation. Most of the procedures will take place over a phone call or secure telehealth platform (i.e., Zoom). However, participants will be asked to visit UAB on three occasions for blood sample collection and brain imaging (about 2 hours each). Online testing will happen one month before treatment, one day before treatment, one day afterwards, and 6 months afterwards. The study will utilize two different forms of rehabilitation training to improve participants' cognitive ability. Participants will be randomized to one of the two treatment groups. The first treatment approach, known as Constraint-Induced Cognitive Therapy (CICT), will feature (A) web-based computer "games" that trains how quickly individuals process information that they receive through their senses; (B) online training on everyday activities with important cognitive components, (C) procedures designed to transfer improvements in cognition from the treatment setting to everyday life, and (D) a non-invasive form of vagus nerve stimulation, also known as trans-auricular VNS (taVNS). The second approach, known as Brain Fitness Training (BFT), will include (A) web-based computer "games" that train reaction time and eye-hand coordination; (B) in-lab training on relaxation, breathing, healthy nutrition, and healthy sleep, (C) education about how relaxation, breathing, nutrition, and sleep are connected to thinking effectiveness, and (D) taVNS. Approximately 30 hours of training will be conducted over a secure telehealth platform (i.e., Zoom) in the span of two- to four- weeks. A typical CICT session will consist of one hour of gaming, with the bulk of the session being spent on cognitive training of the target behaviors and procedures designed to promote transfer of therapeutic gains to daily life. ta-VNS will be administered for 10 minutes before gaming and in-lab target behavior training. A typical BFT session will consist of one hour of gaming, training on healthy lifestyle behaviors (i.e., healthy sleep, nutrition, and relaxation habits), as well as procedures designed to promote transfer of behavior changes to daily life. Ta-VNS will be administered for 10 minutes before gaming and in-lab target behavior training. Training sessions in both conditions will be scheduled based on participants' availability, with the options for sessions scheduled to be as close as every weekday over 2 weeks or as loosely as every other weekday (i.e., over a 4-week span). If a caregiver is available, they will receive training on how to best support participants in their therapeutic program. After the training ends, both groups will receive 4 follow-up phone calls approximately one week apart to promote integration of the gained skills into everyday life. Outcomes measured will include cognitive processing speed, cognitive function on laboratory tests, and spontaneous performance of everyday activities with important cognitive components in daily life.

Study Overview

• Status: Not yet recruiting
• Conditions: Cognitive Impairment; Cognitive Dysfunction; Chronic Fatigue Syndrome (CFS); ME/CFS; Chronic Fatigue; Brain Fog; ME/CFS Following EBV-associated Infectious Mononucleosis; ME/CFS Following COVID-19
• Intervention / Treatment: Behavioral: Reaction Time Training; Procedure: Trans-auricular Vagus Nerve Stimulation: Low Intensity; Behavioral: Processing Speed Training; Behavioral: In-session Instrumental Activities of Daily Living Training; Behavioral: Transfer Package; Behavioral: Follow Up Phone Calls; Procedure: Trans-auricular Vagus Nerve Stimulation: High Intensity; Behavioral: In-session Brain Health Training

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Natalie Greig, BS; Phone Number: 205-934-9768; Email: nggreig@uab.edu
• Study Contact Backup: Name: Helen Bliss, BS; Phone Number: 205-934-0433; Email: stacemc@uab.edu

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
      • Principal Investigator: Gitendra Uswatte, PhD
      • Contact: Helen Bliss, BS; Phone Number: 205-934-0433; Email: hmbliss@uab.edu
      • Contact: Natalie Greig, BS; Phone Number: 205-934-9768; Email: nggreig@uab.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• diagnosis of ME/CFS that preceded cognitive complaints
• mild or greater cognitive impairment
• moderate or greater brain fog
• some impairment in the performance of daily activities
• ≥ 18 years, no upper limit if medically stable
• reside in the community (as opposed to a hospital or skilled nursing facility)
• able to travel to the laboratory on multiple occasions
• has Internet service
• has a personal computer, laptop, or tablet that can access the Internet
• sufficiently fit, from both a physical and mental health perspective, to take part in the study
• adequate sight and hearing to complete the UFOV test
• adequate thinking skills, e.g., ability to follow directions and retain information to complete UFOV and CTAL, as marked by the judgement of the screener that the candidate is able to adequately complete the UFOV and CTAL
• sufficient English proficiency (i.e., ability to speak, understand, read, and write to take part in study activities)

Exclusion Criteria:

• cognitive impairment due to a developmental disability, psychiatric disorder, or substance abuse, or due to another type of brain injury, such as traumatic brain injury, stroke, or a progressive brain disease, such as Alzheimer's Dementia
• current substance abuse disorder
• diagnosis of postural orthostatic tachycardia syndrome (POTS) by a healthcare provider
• prior cognitive processing speed training on DoubleDecision or a similar program
• cannot tolerate taVNS
• prior history of heart attack or other serious cardiac events
• implanted medical device of any type
• vasovagal syncope or history of fainting
• history of seizures or epilepsy
• temporomandibular Joint (TMJ) syndrome or other conditions that cause substantial jaw pain
• history of peripheral nerve injury to the head, neck, or face
• pregnant or breastfeeding
• not able or willing to get an MRI scan
• not able or willing to get a blood draw

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CICT + taVNS; Constraint-Induced Cognitive Therapy uses in-lab training on everyday activities with important cognitive components, along with the procedures designed to transfer improvements from the treatment setting to everyday life. This will be combined with computer-based processing speed training and non-invasive vagus nerve stimulation.	Behavioral: Processing Speed Training; Speed of processing training involves trainer-guided practice of computer-based video "games." The games require the "player" to rapidly distinguish targets from decoys, which trains the player to process information from their senses quickly.; Other Names: SOPT; Behavioral: In-session Instrumental Activities of Daily Living Training; Participants will receive shaping on IADLs. Participants will receive training on everyday tasks with important cognitive components, in which the difficulty is increased in small steps over the course of treatment.; Other Names: IADL Training; Behavioral: Transfer Package; The Transfer Package was designed to try to bridge the gap between what is trained in-session and what the participant does outside of treatment sessions. These components include negotiation of a behavioral contract with participants at the outset of treatment regarding the responsibilities of the participant, family caregivers, if available, and the treatment team, self-monitoring, assignment of "homework," review of homework by the trainer, and support of problem-solving by the participant.; Other Names: TP; Behavioral: Follow Up Phone Calls; After completing training, participants will receive four weekly follow-up phone calls in the first month of training. The focus of the calls will incorporate the lessons learnt during treatment into daily life.; Procedure: Trans-auricular Vagus Nerve Stimulation: High Intensity; The vagus nerve runs from the brain to the external ear, throat, chest, and abdomen and controls, among other functions, the rest and relax response, which supports learning and turns down inflammatory processes. The rest-and-relax response can be activated by electrically stimulating the vagus nerve. We will place electrodes on the external part of each ear and safely apply a microcurrent of at least 4 milliamps. Stimulation will be administered for 10 minutes near the start and midway point of each treatment session.; Other Names: taVNS
Active Comparator: BFT + taVNS; Brain Fitness Training involves in-lab training on relaxation, healthy nutrition, and healthy sleep with procedures designed to promote integration of these lifestyles into everyday life. This will be combined with computer-based reaction time training and non-invasive vagus nerve stimulation.	Behavioral: Reaction Time Training; Reaction time training involves trainer-guided practice of computer-based video "games." Several different games will be featured that train how rapidly "players" react to "threats" and train eye-hand coordination.; Procedure: Trans-auricular Vagus Nerve Stimulation: Low Intensity; The vagus nerve run from the brain to the external ear, throat, chest, and abdomen and controls, among other functions, the rest and relax response, which supports learning and turns down inflammatory processes. The rest and relax response can be turned on by electrically stimulating the vagus nerve. We will place electrodes on the external part of each ear and safely apply a microcurrent of less than 4 milliamps. Stimulation will administered for 10 minutes near the start and midway point of each treatment session.; Behavioral: Transfer Package; The Transfer Package was designed to try to bridge the gap between what is trained in-session and what the participant does outside of treatment sessions. These components include negotiation of a behavioral contract with participants at the outset of treatment regarding the responsibilities of the participant, family caregivers, if available, and the treatment team, self-monitoring, assignment of "homework," review of homework by the trainer, and support of problem-solving by the participant.; Other Names: TP; Behavioral: Follow Up Phone Calls; After completing training, participants will receive four weekly follow-up phone calls in the first month of training. The focus of the calls will incorporate the lessons learnt during treatment into daily life.; Behavioral: In-session Brain Health Training; Participants will receive training on healthy eating, sleeping, and relaxation techniques that have been shown to improve brain health.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Canadian Occupational Performance Measure (COPM)	The COPM is a standard, validated, trans-diagnostic, patient-centered structured interview commonly used to measure the real-world outcome of rehabilitation procedures that span both motor and cognitive functions after stroke. The Performance Scale assesses how well a participant performs five activities in their daily life, i.e., outside the lab, that are important to the participant. Activities, for this purpose, will be restricted to those with an important cognitive component ,i.e., IADL. The 10-point response scale ranges from 1 (not able to do the activity at all) to 10 (able to do the activity extremely well). Performance Scale scores from the participant will be the primary outcome.	Change from Day 30 to Day 60 (i.e., change from Pre- to Post-treatment)

Collaborators and Investigators

• Sponsor: University of Alabama at Birmingham
• Collaborators: Posit Science Corporation; UAB College of Arts and Sciences & Department of Psychology
• Investigators: Principal Investigator: Gitendra Uswatte, PhD, Professor of Psychology, University of Alabama at Birmingham

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2026
• Primary Completion (Estimated): April 1, 2026
• Study Completion (Estimated): April 1, 2028

Study Registration Dates

• First Submitted: April 4, 2026
• First Submitted That Met QC Criteria: April 4, 2026
• First Posted (Actual): April 13, 2026

Study Record Updates

• Last Update Posted (Actual): April 13, 2026
• Last Update Submitted That Met QC Criteria: April 4, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Cognitive Impairment; Cognitive Rehabilitation; Cognitive Dysfunction; Brain fog; ME/CFS; Chronic Fatigue; post-viral syndrome; CICT
• Additional Relevant MeSH Terms: Neuroinflammatory Diseases; Musculoskeletal Diseases; Nervous System Diseases; Muscular Diseases; Mental Disorders; Pathologic Processes; Encephalomyelitis; Neuromuscular Diseases; Chronic Disease; Disease Attributes; Behavioral Symptoms; Neurocognitive Disorders; Cognition Disorders; Fatigue; Pathological Conditions, Signs and Symptoms; Behavior; Signs and Symptoms; Fatigue Syndrome, Chronic; Cognitive Dysfunction; Mental Fatigue
• Other Study ID Numbers: IRB-300015629; UAB CAS (Other Identifier: UAB CAS)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: We will share baseline, post-treatment, and follow-up scores on the primary outcome on a de-identified basis.
• IPD Sharing Time Frame: The IPD will be published along with the primary outcome paper as a supplement. The primary outcome paper will describe the study protocol and the statistical analysis plan. We estimate this will take place within two years of the collection of the last data follow-up data point. The data will be available for as long the journal in which the paper appears exists.
• IPD Sharing Access Criteria: Anyone who can access the journal article will be able to access the supplemental data. As noted, we will post scores on the primary outcome on a de-identified basis. Interested parties will be able to access the data by going to the journal website, finding the article, and then downloading the supplement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

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