TY - JOUR
T1 - Evaluation of Interventions for Cognitive Symptoms in Long COVID
T2 - A Randomized Clinical Trial
AU - RECOVER-NEURO Clinical Trial Group
AU - Knopman, David S
AU - Koltai, Deborah
AU - Laskowitz, Daniel T
AU - Becker, Jacqueline
AU - Charvet, Leigh
AU - Wisnivesky, Juan
AU - Federman, Alex
AU - Silverstein, Adam
AU - Lokhnygina, Yuliya
AU - Pilloni, Giuseppina
AU - Haddad, Michelle
AU - Mahncke, Henry
AU - Van Vleet, Tom
AU - Huang, Rong
AU - Cox, Wendy
AU - Terry, Diana
AU - Karwowski, Jeannie
AU - McCray, Netia
AU - Lin, Jenny J
AU - McComsey, Grace A
AU - Singh, Upinder
AU - Geng, Linda N
AU - Chu, Helen Y
AU - Reece, Rebecca
AU - Moy, James
AU - Arvanitakis, Zoe
AU - Parthasarathy, Sairam
AU - Patterson, Thomas F
AU - Gupta, Aditi
AU - Ostrosky-Zeichner, Luis
AU - Parsonnet, Jeffrey
AU - Kiriakopoulos, Elaine T
AU - Fong, Tamara G
AU - Mullington, Janet
AU - Jolley, Sarah
AU - Shah, Nirav S
AU - Morimoto, Sarah Shizuko
AU - Lee-Iannotti, Joyce K
AU - Killgore, William D S
AU - Dwyer, Brigid
AU - Stringer, William
AU - Isache, Carmen
AU - Frontera, Jennifer A
AU - Krishnan, Jerry A
AU - O'Steen, Ashley
AU - James, Melissa
AU - Harper, Barrie L
AU - Zimmerman, Kanecia O
PY - 2026/1/1
Y1 - 2026/1/1
N2 - 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.
AB - 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.
KW - Humans
KW - Female
KW - COVID-19/complications
KW - Male
KW - Middle Aged
KW - Cognitive Behavioral Therapy/methods
KW - Cognitive Dysfunction/etiology
KW - Adult
KW - Transcranial Direct Current Stimulation/methods
KW - Aged
KW - Treatment Outcome
U2 - 10.1001/jamaneurol.2025.4415
DO - 10.1001/jamaneurol.2025.4415
M3 - Article
C2 - 41212544
SN - 2168-6149
VL - 83
SP - 49
EP - 59
JO - JAMA Neurology
JF - JAMA Neurology
IS - 1
ER -