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Randomized Controlled Trial
. 2026 Jan 1;83(1):49-59.
doi: 10.1001/jamaneurol.2025.4415.

Evaluation of Interventions for Cognitive Symptoms in Long COVID: A Randomized Clinical Trial

David S Knopman  1 , Deborah Koltai  2 , Daniel T Laskowitz  2 , Jacqueline Becker  3 , Leigh Charvet  4 , Juan Wisnivesky  3 , Alex Federman  3 , Adam Silverstein  5 , Yuliya Lokhnygina  5   6 , Giuseppina Pilloni  4 , Michelle Haddad  7 , Henry Mahncke  8 , Tom Van Vleet  8 , Rong Huang  5 , Wendy Cox  9 , Diana Terry  9 , Jeannie Karwowski  9 , Netia McCray  9 , Jenny J Lin  10 , Grace A McComsey  11 , Upinder Singh  12 , Linda N Geng  13 , Helen Y Chu  14 , Rebecca Reece  15 , James Moy  16 , Zoe Arvanitakis  17 , Sairam Parthasarathy  18 , Thomas F Patterson  19 , Aditi Gupta  20 , Luis Ostrosky-Zeichner  21 , Jeffrey Parsonnet  22 , Elaine T Kiriakopoulos  23 , Tamara G Fong  24 , Janet Mullington  24 , Sarah Jolley  25 , Nirav S Shah  26 , Sarah Shizuko Morimoto  27 , Joyce K Lee-Iannotti  28 , William D S Killgore  29 , Brigid Dwyer  30 , William Stringer  31 , Carmen Isache  32 , Jennifer A Frontera  4 , Jerry A Krishnan  33 , Ashley O'Steen  5 , Melissa James  5 , Barrie L Harper  5 , Kanecia O Zimmerman  5   34 ; RECOVER-NEURO Clinical Trial Group
Collaborators, Affiliations
Randomized Controlled Trial

Evaluation of Interventions for Cognitive Symptoms in Long COVID: A Randomized Clinical Trial

David S Knopman et al. JAMA Neurol. .

Abstract

Importance: Treatment 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.

Objective: To test evidence-based rehabilitation strategies for improving cognitive symptoms in persons with long COVID.

Design, setting, and participants: This 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.

Interventions: Participants 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 measures: Cognitive 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.

Results: A 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 relevance: This 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 registration: ClinicalTrials.gov Identifier: NCT05965739.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Knopman reported serving on a data safety monitoring board (DSMB) for the Dominantly Inherited Alzheimer Network Treatment Unit study sponsored by Washington University St Louis, and for the SMART-HS clinical trial (Univ of Kentucky); being an investigator in Alzheimer disease clinical trials sponsored by Biogen, Lilly Pharmaceuticals, and the University of Southern California, both of which have ended; currently serving as an investigator in a trial in frontotemporal degeneration with Alector; and serving as a consultant for Roche, AriBio, BioVie, and Alzeca Biosciences but receiving no personal compensation. Dr Charvet reported receiving consultant fees from Neuroelectrics; being a former employee of Johnson & Johnson, holding stock in that company, and receiving consultant fees from Ceragem, Neuroelectrics, and Syntropic. Dr Wisnivesky reported receiving honoraria from Banook, PPD, BioNTech, the American Medical Association, and Sanofi, and research grants from Regeneron, Sanofi, and Axella. Dr Pilloni reported receiving speaker fees from Soterix Medical Inc and consultant fees from Ceragem. Drs Mahncke and Van Vleet reported being employees of and hold equity in Posit Science, the developer of BrainHQ. Dr McComsey reported serving as a research consultant for Merck and Gilead, and on a DSMB for GlaxoSmithKline, neither related to this study or to long COVID. Dr Singh reported receiving funding from Pfizer for studies on long COVID. Dr Geng reported receiving research funding (paid to her institution) from Pfizer outside the submitted work. Dr Chu reported receiving consulting fees from Vir and Roche. Dr Arvanitakis reported receiving funding from the Illinois Department of Public Health and Amylyx Inc, and consulting fees from Novo Nordisk, Eisai, the California Institute for Regenerative Medicine, Summus, Spire Learning; performing expert witness work (medical-legal cases) and serving in journal editorial roles (Frontiers in Dementia); and receiving honoraria from not-for-profit organizations such as local Alzheimer’s Association chapters, universities, and the American College of Physicians Internal Medicine (for speaking at a conference). Dr Parthasarathy reported receiving grants from Sergey-Brin Foundation, Philips Inc, and Regeneron Inc and personal fees from Jazz Pharmaceuticals and AbbVie Inc, all outside the submitted work. Dr Morimoto reported receiving grant support from the Utah State Legislature, the Huntsman Mental Health Institute, and the Marriot Family Foundation, as well as serving on the senior scientific advisory committee for Otsuka Pharmaceuticals’ Digital Medicine/Digital Therapeutics Division. Dr Krishnan reported receiving fees from AstraZeneca, Medimmune, BioVie, ResporAI, and Verona for consulting, as well as research grants from the American Lung Association and COPD Foundation. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Study Design
PASC indicates postacute sequelae of SARS-CoV-2 infection; PASC-CoRE, PASC-Cognitive Recovery; tDCS, transcranial direct current stimulation.
Figure 2.
Figure 2.. Patient Flow in A Platform Protocol for Evaluation of Interventions for Cognitive Dysfunction in Postacute Sequelae of SARS-CoV-2 Infection (RECOVER-NEURO) Trial
PASC indicates postacute sequelae of SARS-CoV-2 infection; PASC-CoRE, PASC-Cognitive Recovery; PROMIS, Patient-Reported Outcomes Measurement Information System; tDCS, transcranial direct current stimulation.
See this image and copyright information in PMC

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