Cognitive Rehabilitation for Long COVID Brain Fog

Overseen By Gitendra Uswatte, PhD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: University of Alabama at Birmingham

Disqualifiers: Developmental disability, Psychiatric disorder, Substance abuse, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 17

Duration: 2-4 weeks

40 Participants Needed

Trial Summary

What is the purpose of this trial?

This study will compare two approaches to cognitive rehabilitation in adults with long COVID with persistent, mild to moderate, cognitive impairment. One approach will feature (A) web-based computer "games" that trains how quickly individuals process information that they receive through their senses; (B) in-lab 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 (VNS), i.e., trans-auricular VNS (taVNS). Component B will include work-related tasks. This approach is termed Constraint-Induced Cognitive Therapy (CICT). The other approach will feature (A) web-based computer "games" that train reaction time and eye-hand coordination; (B) in-lab training on relaxation, healthy nutrition, and healthy sleep, (C) procedures designed to promote integration of these lifestyle changes into everyday life, and (D) taVNS. This approach is termed Brain Fitness Training (BFT). A subset of participants, who qualify for and and desire vocational rehabilitation (VR), will receive VR from the Alabama Department of Rehabilitation Services (ADRS) in addition to CICT or BFT. ADRS VR will include career counseling, prescription of on-the-job accommodations, and guidance on return-to-work. Those in the CICT + VR group will also receive on-the-job coaching from a peer mentor for a month after completing training. CICT, with or without VR, will involve 30 hours of training. Ten 3-hour in-lab, face-to-face, therapist-directed sessions will be scheduled. These sessions will feature one hour of gaming; the remainder will be committed to in-lab training on the target behaviors and the procedures designed to promote transfer of therapeutic gains to daily life and improving skills essential to work; the set of the latter procedures is termed the Transfer Package. ta-VNS will administered for 10 minutes before gaming and in-lab target behavior training. To accommodate the demands of participants' other activities, training sessions will be permitted to be scheduled as tightly as every weekday over 2 weeks or as loosely as every other weekday or so over 4 weeks. If a family caregiver is available, they will receive training on how to best support participants in their therapeutic program. After training ends, four follow-up phone calls will be scheduled approximately one-week apart with participants to promote integration of the skills gained during training into everyday life. BFT, with or without VR, will involve 30 hours of training following the same schedule as for CICT. Ten 3-hour in-lab, face-to-face, therapist-directed sessions will be scheduled. These sessions will feature one hour of gaming; the remainder will be committed to in-lab training on the target behaviors (healthy sleep, nutrition and relaxation habits) and the procedures designed to promote transfer of behavior change to daily life. ta-VNS will be administered for 10 minutes before gaming and in-lab target behavior training. If a family caregiver is available, they will receive training on how to best support participants in their therapeutic program. After training ends, four follow-up phone calls will be scheduled approximately one-week apart with participants to promote integration of the skills gained during training into everyday life. Participants will be randomly assigned to the interventions. Randomization will be stratified by whether participants qualify for and desire VR from ADRS or not. If yes, participants will be randomized in equal numbers to CICT + VR or BFT + VR. If no, participants will be randomized in equal numbers to CICT or BFT. Testing will happen one month before treatment, one day before treatment, one day afterwards, and 6- and 12-months afterwards. 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. Another important outcome measure will be whether or not participants were able to return back to work or had significant improvements in their work activities.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It is best to discuss this with the trial coordinators or your healthcare provider.

What data supports the effectiveness of the treatment for Long COVID brain fog?

Research suggests that cognitive training, like Speed of Processing Training, can improve cognitive function in conditions such as multiple sclerosis, and similar approaches have shown promise in improving cognitive function in COVID-19 survivors. Additionally, personalized computerized cognitive training has been found to significantly enhance cognitive abilities in people with post-COVID-19 cognitive dysfunction. ^{1 2 3 4 5}

Is cognitive rehabilitation for Long COVID brain fog safe for humans?

The studies reviewed do not report any specific safety concerns related to cognitive rehabilitation or training for brain fog or cognitive impairment, suggesting it is generally safe for humans. ^{1 5 6 7 8}

How is the Processing Speed Training and Reaction Time Training treatment unique for Long COVID brain fog?

This treatment is unique because it focuses on improving cognitive functions like processing speed and reaction time through specific cognitive exercises, which is different from other treatments that may not target these specific cognitive skills. Additionally, there are currently no standard treatments for cognitive impairment in Long COVID, making this approach novel. ^{1 4 9 10 11}

Research Team

Gitendra Uswatte, PhD

Principal Investigator

Professor of Psychology, University of Alabama at Birmingham

Eligibility Criteria

Adults with long COVID experiencing mild to moderate cognitive issues, such as brain fog and trouble with daily activities. They must be over 3 months post-COVID, able to travel to the lab, mentally and physically fit enough for participation, have good vision and hearing, follow instructions well, and speak English. Excluded are those with a history of stroke before COVID-19 or current substance abuse.

Inclusion Criteria

I struggle with daily activities due to my condition.

I can follow directions and remember information.

I had COVID-19 over 3 months ago.

Exclusion Criteria

Current substance abuse disorder

I had a stroke before getting COVID.

I have previously completed a cognitive speed training program like DoubleDecision.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

4 weeks

1 visit (in-person)

Treatment

Participants undergo 30 hours of training over 2 to 4 weeks, including web-based games, in-lab training, and vagus nerve stimulation

2-4 weeks

10 visits (in-person)

Follow-up

Participants receive four follow-up phone calls to promote integration of skills gained during training into everyday life

4 weeks

4 calls (virtual)

Long-term Follow-up

Participants are monitored for cognitive processing speed and performance in everyday activities at 6 and 12 months post-treatment

12 months

2 visits (in-person)

Treatment Details

Interventions

• Processing Speed Training
• Reaction Time Training
• Trans-auricular Vagus Nerve Stimulation: High Intensity
• Trans-auricular Vagus Nerve Stimulation: Low Intensity

Trial Overview The trial compares two cognitive rehabilitation methods: Constraint-Induced Cognitive Therapy (CICT) focuses on processing speed training and practical tasks including work-related ones; Brain Fitness Training (BFT) emphasizes reaction time training along with lifestyle habits like relaxation. Both use non-invasive vagus nerve stimulation (taVNS) and may include vocational rehab for eligible participants.

Participant Groups

Group I: CICT + VR Experimental Treatment 7 Interventions

Constraint-Induced Cognitive Therapy plus Vocational Rehabilitation uses in-lab training on everyday activities with important cognitive components and procedures designed to transfer improvements from the treatment setting to every day life. This will be combined with computer-based processing speed training and non-invasive vagus nerve stimulation. This group will also receive vocational rehabilitation from the Alabama Department of Rehabilitation Services, such as career counseling and building important career skills.

Group II: CICT Experimental Treatment 5 Interventions

Constraint-Induced Cognitive Therapy uses in-lab training on everyday activities with important cognitive components and procedures designed to transfer improvements from the treatment setting to every day life. This will be combined with computer-based processing speed training and non-invasive vagus nerve stimulation.

Group III: BFT Active Control 5 Interventions

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.

Group IV: BFT + VR Active Control 6 Interventions

Brain Fitness Training plus Vocational Rehabilitation 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. This group will also receive vocational rehabilitation from the Alabama Department of Rehabilitation Services, such as career counseling and building important career skills.

Processing Speed Training is already approved in United States, Canada for the following indications:

Approved in United States as Speed of Processing Training for:

• Cognitive impairment in older adults
• Long COVID brain fog

Approved in Canada as Speed of Processing Training for:

• Cognitive impairment in older adults
• Long COVID brain fog

Who Is Running the Clinical Trial?

University of Alabama at Birmingham

Lead Sponsor

Trials

1,677

Recruited

2,458,000+

Posit Science

Collaborator

Trials

2

Recruited

120+

National Institute on Disability, Independent Living, and Rehabilitation Research

Collaborator

Trials

83

Recruited

10,500+

Findings from Research

This study will investigate the effects of cognitive training, with and without transcranial direct current stimulation (tDCS), on cognitive performance and quality of life in patients experiencing cognitive impairments after COVID-19, involving a 3-week intervention period.

The primary outcome will focus on improvements in working memory, assessed through an n-back task, with secondary outcomes including overall cognitive performance and health-related quality of life measured at post-intervention and one month later.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neuromodulation through brain stimulation-assisted cognitive training in patients with post-COVID-19 cognitive impairment (Neuromod-COV): study protocol for a PROBE phase IIb trial. Thams, F., Antonenko, D., Fleischmann, R., et al.[2022]

COVID-19 survivors are experiencing cognitive problems, often referred to as 'brain fog', which can significantly impact their daily activities and ability to return to work.

There is a need for further research into the nature and prevalence of these cognitive issues, as well as the potential application of brain injury recovery treatments to help improve cognitive function in these individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A proposal to apply brain injury recovery treatments for cognitive impairment in COVID-19 survivors. Nouraeinejad, A.[2022]

In a randomized controlled trial with 60 participants with multiple sclerosis, Speed of Processing Training (SOPT) led to significant improvements in everyday functional outcomes, specifically in the Timed Instrumental Activities of Daily Living (TIADL) scores compared to an active control group.

While SOPT improved cognitive performance in some participants, it did not result in overall changes in quality of life or self-reported functional status, indicating that while cognitive training can enhance certain skills, it may not fully translate to broader functional improvements.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Efficacy of the Speed of Processing Training Program in Improving Functional Outcome: From Restoration to Generalization. Goverover, Y., Costa, S., DeLuca, J., et al.[2023]

This study will evaluate the effectiveness of Goal Management Training (GMT) in improving attention and executive functions in 240 adults who have persistent cognitive deficits after COVID-19, with results expected at six months post-treatment.

Participants will be randomly assigned to either the GMT group or a waitlist control, allowing for a comparison of cognitive improvements, which could lead to evidence-based treatment options for common post-COVID-19 cognitive issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cognitive rehabilitation in post-COVID-19 condition: A study protocol for a randomized controlled trial. Hagen, BI., Lerdal, A., Søraas, A., et al.[2023]

A pilot study involving 73 adults with cognitive dysfunction post-COVID-19 showed that an 8-week personalized computerized cognitive training (CCT) significantly improved cognitive function across multiple domains, including attention, memory, and reasoning.

Participants reported higher cognitive scores after the training compared to their baseline assessments, indicating that self-administered CCT could be an effective intervention for alleviating cognitive issues in individuals suffering from post-acute sequelae of COVID-19.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Personalized Computerized Training for Cognitive Dysfunction after COVID-19: A Before-and-After Feasibility Pilot Study. Duñabeitia, JA., Mera, F., Baro, Ó., et al.[2023]

A pilot study involving six patients with mild traumatic brain injury (TBI) or non-traumatic acquired brain injury (ABI) showed significant cognitive improvements after 60 hours of a cognitive training program called Brain Booster, with notable increases in long-term memory, processing speed, reasoning, and a mean IQ score increase of 20 points.

MRI results indicated significant changes in brain connectivity, particularly in the cerebellum, and correlations between cognitive improvements and white matter integrity, suggesting that cognitive training can enhance both cognitive function and underlying neural structures in individuals with mild brain injuries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neuroimaging and Neuropsychological Outcomes Following Clinician-Delivered Cognitive Training for Six Patients With Mild Brain Injury: A Multiple Case Study. Moore, AL., Carpenter, DM., James, RL., et al.[2020]

In a study involving 681 participants aged 50 and older, cognitive speed of processing training (SOPT) did not significantly enhance overall cognitive abilities compared to an attention-control group that engaged in crossword puzzles.

Despite the training showing a statistically significant time effect on cognitive processing, there was no notable difference in improvement across different treatment groups or age bands after 10-14 hours of SOPT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of cognitive speed of processing training on a composite neuropsychological outcome: results at one-year from the IHAMS randomized controlled trial. Wolinsky, FD., Vander Weg, MW., Howren, MB., et al.[2022]

In a randomized trial involving older adults (ages 57-71), cognitive training over 12 weeks significantly improved processing speed compared to wait-listed and exercise control groups, indicating its efficacy in enhancing cognitive function.

The cognitive training led to a notable change in neural activity, where faster reaction times were linked to reduced activation in the left prefrontal cortex, suggesting a more efficient neural processing mechanism in the CT group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Higher-order cognitive training effects on processing speed-related neural activity: a randomized trial. Motes, MA., Yezhuvath, US., Aslan, S., et al.[2022]

A 4-week interactive cognitive-motor training (CMT) program significantly improved cognitive health components, including depression, anxiety, and overall mental health scores, in 42 elderly men who had recovered from COVID-19.

Participants showed lasting improvements in cognitive functions such as attention, recall, and language skills, indicating that CMT is an effective intervention for enhancing cognitive health in older adults post-COVID-19.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effectiveness of cognitive-motor training on reconstructing cognitive health components in older male adults, recovered from the COVID-19. Amini, A., Vaezmousavi, M., Shirvani, H.[2022]

Computerized cognitive training (CCT) significantly improved overall cognitive function, attention, and memory in older adults with traumatic brain injury compared to usual care over a 6-month period.

Tai chi (TC) also enhanced cognitive scores and showed lasting benefits, particularly in conceptualization and initiation/preservation, with effects observed up to 12 months, while also improving physical strength and mobility.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of Computerized Cognitive Training and Tai Chi on Cognitive Performance in Older Adults With Traumatic Brain Injury. Hwang, HF., Chen, CY., Wei, L., et al.[2021]

A study of Veterans with traumatic brain injury (TBI) showed that both those with cognitive difficulties and those with normal cognition improved in executive functioning and memory after participating in a group-format EF training, with significant improvements observed at least six months post-training.

Veterans with cognitive difficulties experienced greater improvements in learning and memory compared to those with normal cognition, suggesting that cognitive rehabilitation can be particularly beneficial for individuals with more severe cognitive impairments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Effect of Cognitive Rehabilitation Regardless of Prerehabilitation Cognitive Status for Veterans with TBI. Kornblith, E., Posecion, L., Abrams, G., et al.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

Neuromodulation through brain stimulation-assisted cognitive training in patients with post-COVID-19 cognitive impairment (Neuromod-COV): study protocol for a PROBE phase IIb trial. [2022]

2. England pubmed.ncbi.nlm.nih.gov

A proposal to apply brain injury recovery treatments for cognitive impairment in COVID-19 survivors. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

The Efficacy of the Speed of Processing Training Program in Improving Functional Outcome: From Restoration to Generalization. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Cognitive rehabilitation in post-COVID-19 condition: A study protocol for a randomized controlled trial. [2023]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Personalized Computerized Training for Cognitive Dysfunction after COVID-19: A Before-and-After Feasibility Pilot Study. [2023]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Neuroimaging and Neuropsychological Outcomes Following Clinician-Delivered Cognitive Training for Six Patients With Mild Brain Injury: A Multiple Case Study. [2020]

7. England pubmed.ncbi.nlm.nih.gov

Effects of cognitive speed of processing training on a composite neuropsychological outcome: results at one-year from the IHAMS randomized controlled trial. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Higher-order cognitive training effects on processing speed-related neural activity: a randomized trial. [2022]

9. Italy pubmed.ncbi.nlm.nih.gov

The effectiveness of cognitive-motor training on reconstructing cognitive health components in older male adults, recovered from the COVID-19. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Effects of Computerized Cognitive Training and Tai Chi on Cognitive Performance in Older Adults With Traumatic Brain Injury. [2021]

11. United States pubmed.ncbi.nlm.nih.gov

Long-Term Effect of Cognitive Rehabilitation Regardless of Prerehabilitation Cognitive Status for Veterans with TBI. [2021]