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Evaluation of Interventions for Cognitive Symptoms in Long COVID
Journal article   Open access   Peer reviewed

Evaluation of Interventions for Cognitive Symptoms in Long COVID

David S. Knopman, Deborah Koltai, Daniel Laskowitz, Jacqueline Becker, Leigh Charvet, Juan Wisnivesky, Alex Federman, Adam Silverstein, Yuliya Lokhnygina, Giuseppina Pilloni, …
JAMA neurology, Vol.83(1), pp.49-59
01/01/2026
DOI: 10.1001/jamaneurol.2025.4415
PMID: 41212544
url
https://doi.org/10.1001/jamaneurol.2025.4415View
Published (Version of record) Open Access

Abstract

This randomized clinical trial investigates if evidence-based rehabilitation strategies improve cognitive symptoms in persons with long COVID. QuestionDo evidence-based rehabilitation strategies improve cognitive symptoms in persons with long COVID (ie, symptoms of fatigue, malaise, weakness, confusion that persist beyond 12 weeks after an initial COVID infection)?FindingsThis randomized clinical trial included 328 participants randomly assigned to 3 active interventions over 10 weeks at 22 clinical sites. None of the interventions demonstrated benefits on the modified Everyday Cognition Scale 2 in the intention-to-treat population by the end of the intervention period.MeaningThe trial failed to demonstrate differential benefits from online cognitive training, a structured cognitive rehabilitation program, or transcranial direct current stimulation in participants with cognitive long COVID. ImportanceTreatment for cognitive dysfunction due to postacute sequelae of long COVID (ie, symptoms of fatigue, malaise, weakness, confusion that persist beyond 12 weeks after an initial COVID infection) remains a significant unmet need.ObjectiveTo test evidence-based rehabilitation strategies for improving cognitive symptoms in persons with long COVID.Design, Setting, and ParticipantsThis was a 5-arm, multicenter, randomized clinical trial of 3 remotely delivered interventions conducted between August 17, 2023, and June 10, 2024. The study took place at 22 trial sites and included the screening of individuals with cognitive long COVID.InterventionsParticipants were randomized to 1 of 5 arms: adaptive computerized cognitive training (BrainHQ [Posit Science]), cognitive-behavioral rehabilitation involving both group and individual counseling sessions (PASC-Cognitive Recovery [PASC-CoRE]) paired with BrainHQ, and transcranial direct current stimulation (tDCS) paired with BrainHQ. Two comparator arms were included as follows: unstructured computer puzzles and games (active comparator) and sham tDCS paired with BrainHQ. The interventions occurred 5 times per week over 10 weeks.Main Outcomes and MeasuresCognitive and behavioral in-person assessments were performed at baseline, midintervention, at the end of intervention, and 3 months after the end of the intervention. The primary outcome measure was the modified Everyday Cognition Scale 2 (ECog2) completed at the end of the intervention compared to the baseline visit based on participant self-report looking back over the prior 7 days.ResultsA total of 378 individuals were screened, from which there were 328 participants (median [IQR] age, 48.0 [37.0-58.0] years; 241 female [73.5%]; race: 15 Asian [4.6%], 47 Black [14.3%], and 235 White [71.6%]; ethnicity: 52 Hispanic [15.9%]). None of the 3 active interventions demonstrated benefits on the modified ECog2 in the intention-to-treat population by the end of the intervention period. The adjusted differences in mean change were 0.0 (95% CI, -0.2 to 0.2) for BrainHQ vs active comparator, 0.1 (95% CI, -0.1 to 0.3) for PASC-CoRE + BrainHQ vs active comparator, 0.0 (95% CI, -0.2 to 0.2) for tDCS-active + BrainHQ vs tDCS-sham + BrainHQ, and 0.1 (95% CI, -0.1 to 0.3) for PASC-CoRE + BrainHQ vs BrainHQ alone. Secondary participant-reported outcomes and neuropsychological tests showed no differential benefits for any treatment arm. All 5 arms demonstrated some improvements over time on the modified ECog2 and on secondary outcomes. There were no serious adverse events attributable to the interventions.Conclusions and RelevanceThis phase 2 randomized clinical trial failed to demonstrate differential benefits for online cognitive training, a structured cognitive rehabilitation program, and tDCS for cognitive long COVID.Trial RegistrationClinicalTrials.gov Identifier: NCT05965739.
 Clinical Neurology Life Sciences & Biomedicine Neurosciences & Neurology Science & Technology

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