Evaluation of interventions for cognitive symptoms in Long COVID: A randomized clinical trial
Knopman, DS; Koltai, D; Laskowitz, D; et al., JAMA Neurology
Published
November 2025
Journal
JAMA Neurology
Abstract
Importance: Treatment for cognitive dysfunction due to postacute sequelae of Long COVID (i.e., 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.
Authors
David S. Knopman, Deborah Koltai, Daniel Laskowitz, Jacqueline Becker, Leigh Charvet, Juan Wisnivesky, Alex Federman, Adam Silverstein, Yuliya Lokhnygina, Giuseppina Pilloni, Michelle Haddad, Henry Mahncke, Tom Van Vleet, Rong Huang, Wendy Cox, Diana Terry, Jeannie Karwowski, Netia McCray, Jenny J. Lin, Grace A. McComsey, Upinder Singh, Linda N. Geng, Helen Y. Chu, Rebecca Reece, James Moy, Zoe Arvanitakis, Sairam Parthasarathy, Thomas F. Patterson, Aditi Gupta, Luis Ostrosky-Zeichner, Jeffrey Parsonnet, Elaine T. Kiriakopoulos, Tamara G. Fong, Janet Mullington, Sarah Jolley, Nirav S. Shah, Sarah Shizuko Morimoto, Joyce K. Lee-Iannotti, William D. S. Killgore, Brigid Dwyer, William Stringer, Carmen Isache, Jennifer A. Frontera, Jerry A. Krishnan, Ashley O’Steen, Melissa James, Barrie L. Harper, Kanecia O. Zimmerman, RECOVER-NEURO Clinical Trial Group
Keywords
Not available
Short Summary
The RECOVER-NEURO Cognitive Dysfunction (BrainHQ, PASC-CoRE, & tDCS) clinical trial tested three non-drug treatments to see if they improved thinking, focus, and memory for people with Long COVID. The three treatments included:
- An interactive online brain training program called BrainHQ.
- A virtually delivered, small group cognitive rehabilitation program called PASC-Cognitive Recovery or PASC-CoRE.
- A cap that provided a non-invasive form of brain stimulation via electrical current called transcranial direct current stimulation or tDCS.
A unique aspect of RECOVER-NEURO was its decentralized design, enabling 328 adults across 22 U.S. sites to participate in the this research, despite living with Long COVID symptoms. The participants completed most study activities remotely during a 10-week study period. Some participants were assigned to a treatment group and received one of the three active treatments (BrainHQ, PASC-CoRE plus BrainHQ, or tDCS-active plus BrainHQ). Other participants were assigned to a comparison group and received either the BrainHQ active comparator or tDCS-comparator plus BrainHQ. Researchers found that all of the treatment groups and comparison groups reported similar results in their improvement in thinking, focus, and memory. All participants reported some improvement over time and many said they felt better overall after they completed their assigned treatment, even though no one treatment outperformed other groups, including the comparison groups.