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In other words, didn’t work.
Evaluation of Interventions for Cognitive Symptoms in Long COVID, 2025, Knopman et al
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In other words, didn’t work.
Evaluation of Interventions for Cognitive Symptoms in Long COVID
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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.
Web | JAMA Neurology | Open Access
Knopman, David S.; Koltai, Deborah; Laskowitz, Daniel; Becker, Jacqueline; Charvet, Leigh; Wisnivesky, Juan; Federman, Alex; Silverstein, Adam; Lokhnygina, Yuliya; Pilloni, Giuseppina; Haddad, Michelle; Mahncke, Henry; Van Vleet, Tom; Huang, Rong; Cox, Wendy; Terry, Diana; Karwowski, Jeannie; McCray, Netia; Lin, Jenny J.; McComsey, Grace A.; Singh, Upinder; Geng, Linda N.; Chu, Helen Y.; Reece, Rebecca; Moy, James; Arvanitakis, Zoe; Parthasarathy, Sairam; Patterson, Thomas F.; Gupta, Aditi; Ostrosky-Zeichner, Luis; Parsonnet, Jeffrey; Kiriakopoulos, Elaine T.; Fong, Tamara G.; Mullington, Janet; Jolley, Sarah; Shah, Nirav S.; Morimoto, Sarah Shizuko; Lee-Iannotti, Joyce K.; Killgore, William D. S.; Dwyer, Brigid; Stringer, William; Isache, Carmen; Frontera, Jennifer A.; Krishnan, Jerry A.; O’Steen, Ashley; James, Melissa; Harper, Barrie L.; Zimmerman, Kanecia O.; Lawler, Andrew; Johnson, Brandon; Pitsch, Chloe; Feuerriegel, Elen; McKeehan, Jeff; Molden, Joie; Reid, Kayleigh; Erlandson, Kristine; Dowling, Sarah; Wodushek, Thomas; Canton, Diara; Turut, Dilara; Sheppard, Ethan; Scott-Sutherland, Jennifer; Hauser, Kristine; Shaughnessy, Lynn; Doyle, Michael; Beck, Michelle; Heisey, Sabrina; Katragadda, Vaishanvi; Yusuff, Amidat; Perlack, Amy; Tran, Anh; Dwyer, Brigid; Altaras, Caroline; Merisme, Christie; Krause, David; Schulte, Duncan; Dupre, Fabiola; Sanchez, Gina; Krengel, Maxine; Ly, Monica; Asupoto, Olanike; Simmons, Quinneil; Schroeder, Ryan; Timlin, Shannon; Devis, Ycar; Carter, Della; Caceres, Leomaris; Rodriguez, Miguel; Alvarez, Zariya; Yakubov, Amin; Engelson, Celia; Reyes, Michael; Youkhana, Alvin; Jennings, Cheryl; Gonzalez, David; Naquiallah, Dina; Behun, Dylan; Stephen, Ellen; Timm, Emily; Bilimoria, Farrah; Li, Grace; Stricker, Jakob; Torres, Jimena; Garcia, Maria; Thomas, Michelle; Kang, Minnie; Suarez, Rebeca; Carmona, Tania; Ramirez, Ana; Kadubek, Grace; Baker, Aileen; Romo-Serna, Andrea; Predki, Barbara; Leman, Cindy; Panhans, Cristina; Roth, Genevieve; Rudraraju, Gowrisree; Miller, Hannah; DeLisa, Julie; Williams, Kat; Woodson, Kimberly; Jennette, Kyle; Carrera, Laura; Villanueva, Laura; Norwick, Maria; Martinez, Mariam; Rowley, Matt; Rutherford, Melissa; Carrithers, Michael; Pliskin, Neil; Perez, Nicolas; Durkin, Nicole; Maniar, Nikita; Beety, Rachel; Daspgupta, Raktima; Ramchandran, Ramaswamy; Jaramillo, Ruthie; Hasek, Sharon; Macias, Susy; Schuh, Tina; Ialacci, Sarah; Bailey, Christopher; Labbato, Danielle; Hautmann, Amanda; Smith, Beth; Nath, Dia; Meyer, Jessica; DiFrancesco, Kathryn; Walkup, Kevin; Pettinato, Kimberly; Curtis, Lynette; Daher, Joviane; Scott, Sarah; Koberssy, Ziad; Mavar, Caleb; Andrefsky, John; Merheb, Alexander; Hernandez, Carla; Baissary, Jhony; Atieh, Ornina; Pereira, Carol; Carpenter, Deborah; Raynor, Jennifer; Brunton, Kristine; Podgoreanu, Andreea; Bunch, Pyper; Brown, Richard; O'Brien, Sean; Dickey, Sheila; McNulty, Steven; Gajjar, Varsha; Neale, Alec; Cohen, Cari; Escobar, Carolina; Geary, Elizabeth; Campanella, Franco; Anderson, Kirsten; Prestige, Laura; Guidotti-Breting, Leslie; Biewer, Megan; Morton, Melissa; Mathenia, Nicholas; Adeyemi, Oluwadamilola; Hengst, Samanike; Chi, Wei Ning; Vanderloo, Adam; Caplan, Amanda; Chen, July; Acree, Mary Ellen; Glickman, Michael; Nakhate, Mukund; Dan, Zaw Nu; Switzer, Phyliis; Aryal, Shambhu; Sanchez, Jessica; Sims, Luke; Ferdinand, Rebecca; Mammadova, Mehriban; Grimes, Carolyn; Vidales, Elizabeth; Pham, Hoai Phuang; Lopez, John; Nielsen, Laura; Keller, Maryjane; Uruba, Syeda; Hernandez, Maria; Patel, Bela; Lin, Matthew; Umana-Sanchez, Virginia; Pak, Chong; Gainer, Jeffery; Burr, Renae; Trapuzzano, Ashleigh; Celso, Brian; Bienkowski, Grace; Bowman, Jennifer; Verdecia, Jorge; Zerwekh, Kathryn; Serrano, Liliana; Marotz, Meghan; Propp, Piper; Sarig, Yonatan; Murphy, Annie; Comfort, Brandon; Brown, Gina; Torres, Iri; Klein, Jeffrey; Reed, Jessica; Walker, John; Moore, John; Tempest-Browning, Lisa; Arain, Mudassar; Kemp, Pamela; Sullivan, Samantha; Obrien, Sean; Way, Sonja; Chevalier, Jessica; Sykes, Carly; Kruck, Carrie; Kiriakopoulos, Elaine; Sackett, Lisa; Kaden, Sarah; Bang, Claire; Hynes, Mary; Gallagher, Torrey; Childers-Kakos, Margaret; Zia, Ahmad; South, Amy; Oravets, Anne; Ferreyra, Carolyn; Glaze, Chad; Villanueva, Daphne-Dominique; Blystone, Erica; Pritchard, Jane; Alyward, Laura; Cooper, Melissa; Chidester, Michelle; Alderson, Rachael; Clark, Renee; Hodder, Sally; Sarwari, Arif; Bardes, James; Juskowich, Joy; Welch, Shelly; Civil, Alyssa; Bendl, Ashley; Dicker, Elisa; Hanson, Hannah; Viola, Heather; Morinigo, Janice; Pantaleon, Karisma; Marcon, Kathryn; Stone, Kimberly; Stewart, Kiwan; Evo-Ortega, Lorraine; Loizos, Maria; McVeety, Megan; Guliyeva, Sabina; Watson, Eric; Pehel, Shayna; Ko, Tim; Caropolo, Leah; Kocas, Huriye Deniz; Fernandez, Luis; ODonnell, Andrew; Saperia, Corey; Thai, Daniel; Pathak, Divya; Keller, Jennifer; Olszewski, Kelly; Clinton, Kimberly; Cherian, Kirsten; Dutton, Layton; Elepano, Ma; Lin, Rebecca; Mohapatra, Sukanya; Chen, Ting; Wroolie, Tonita; Leang, Zenita; Shashidhar, Sumana; Nguyen, Tiffany; Ravisankar, Ashwath; Weiden, Brycie; Brown, Daniel; Bolliger, Dawn; Glesne, Heather; Dixon, Jennifer; Chebrolu, Praneeth; Gazali, Zarine; Hurst, Whitney; Fry, Avery; Murthy, Ganesh; Grischo, Garrett; Erickson, Heidi; Gomez, Isaias; Copeland, Jacquelynn; Galaz, Judy; Autry, Lynn; Dilise-Russo, Marjorie; James, Michelle; Kala, Mrinalini; Marshell, Nikki; Borwege, Sabine; Vadovicky, Sheila; Marsh, Stephanie; Hartley, William; Murtagh, Linda; Kennedy, Anna; Meltzer-Christensen, Annie; Stringham, Caitlyn; Gaskin, Ella; Judd, Melissa; Smith, Ryan; Cote, Sarah; Mahasenan, Shreya; Bjorklund, Todd; Farner, Cheryl; Taylor, Barbara; Soileau, Bridgette; Cote, Cyrena; Hromas, Gabrielle; Scholler, Irma; Longoria, Lisa; Heard, Patricia; Johnson, Hillary; Jones, Johnnie; Tragus, Robin; Harris, Maya; Pinones, Alexis; Anderson, Alyssa; Hastings, Gabrielyd; Courtright, jessica; Hernandez, Jessica; Jayakumar, Madhumita; Fischer, Melinda; Sullivan, Michael; Solis, Pamela; Harteloo, Alex; Elias-Warren, Anna; Nguyen, Daniel; McDonald, Dylan; Nguyen, Helen; Rau, Holly; Mernaugh, Jean; Logue, Jennifer; Pagulayan, Kathleen; Watanabe, Kino; Huden, Kristen; Peabody, Laurel; Mei, Tiffany; Ogunwuyi, Catherine; Cobbina, Esther; Sankar, Ian; Nguyen, Lisa; Fromm, Nicole; Arnold, Rowan; Ogu, Stephanie; Yuan, Ying; Ibrahim, Homam; Szum, Izabella; Patel, Jignesh; Sultan, Sonia; Jazayeri, Yasmin; Hatlen, Timothy; Anderson, Betty; Munoz, Isabel; Rhys, Logan; Wright, Matthew; Vane, Ryan; Kim, Jessica; Diaz, Leticia; Yee, Nathan; Gruhn, Robert; Browngoetz, Sarah; Decato, Thomas; Johnson, Elisha; Chand, Arista; Ortiz, Ernesto; Bottrill, Ken; Henderson, Kymberly; Hildebrand, Lindsey; Johnson, Marketta; DeArmond, Richard; Hughes, Trina
[Line breaks added]
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.
Web | JAMA Neurology | Open Access
The bar is set so low that I'm genuinely impressed with them for stating the lack of benefit, rather than digging out some vaguely positive speck of data and writing it up as their main finding.
Also they seem to have more authors than participants. Generally that might be a red flag for a study but in this case, wow.
Also they seem to have more authors than participants. Generally that might be a red flag for a study but in this case, wow.
Holy crap. Couldn’t fit all those people on the Titanic.
Yann04
Senior Member (Voting Rights)
Worth noting tDCS (what they used) is significantly different to taVNS (trans auricular Vagus Nerve Stimulation), which is what is sometimes proposed (without good evidence) for ME and Post COVID.
Agree on both points!
Kudos to the authors for stating the obvious. Because unfortunately that isn’t the standard.
Utsikt
Senior Member (Voting Rights)
Kudos for blunt reporting of null results, but..
29 is Nerli, and it did not show benefit (results below MCID), even though the authors claimed it was successful. It’s worrying that the RECOVER authors were unable to acknowledge that and keep putting forth what can only be described as propaganda.