RECOVER-NEURO clinical trial shares results of three non-drug treatments for cognitive symptoms of Long COVID

The clinical trial—RECOVER-NEURO Cognitive Dysfunction (BrainHQ, PASC-CoRE, and tDCS)—focused on symptoms of cognitive dysfunction associated with Long COVID, which may include trouble remembering things (brain fog), focusing, and thinking clearly. The study included 328 adult patients at 22 sites across the United States that conducted the research from August 2023 to December 2024. Results from RECOVER-NEURO were published today in JAMA Neurology.

“None of our rehabilitation approaches to treatment for cognitive Long COVID proved to be effective. Detecting a benefit for one of the interventions was made more difficult because participants in all 5 treatment arms showed modest improvements,” said David Knopman, MD, of the Mayo Clinic and lead author of the study. “RECOVER-NEURO is an important contribution to the evolving science of Long COVID. This was one of the first NIH-funded trials to study any treatments for people who have cognitive symptoms from a SARS-CoV-2 infection, and the outcomes of RECOVER-NEURO will inform future clinical trials.”

A unique aspect of RECOVER-NEURO was its decentralized design, enabling participants to complete most study activities at home during the 10-week study period. Trial participants were assigned to one of five groups, including three active treatment groups and two comparison groups.

• Participants in the active treatment group were split into three groups:
  • Group 1 received only Brain HQ, an interactive online brain training program (developed by Posit Science, Inc.) with activities designed to improve memory, attention and the time it takes to understand and respond to information.
  • Group 2 received BrainHQ and PASC-Cognitive Recovery (PASC-CoRE), a virtually delivered, small group cognitive rehabilitation program designed to help participants learn skills and strategies for working through distractions and mental tiredness.
  • Group 3 received BrainHQ and active transcranial direct current simulation (tDCS), a cap that provided a non-invasive form of brain stimulation via an electrical current.
• Participants in the comparison group were split into two groups:
  • Group 4 completed a computer puzzle and game program that looked the same as BrainHQ but did not include the same interactive features.
  • Group 5 received BrainHQ plus a device that looked like the tDCS cap but did not deliver the same electrical current. 

New York University (NYU) coordinated the BrainHQ and tDCS groups, and Mount Sinai and Emory University administered the PASC-CoRE group.

Study results were collected through surveys and brain function tests to track any changes in symptoms throughout the clinical trial. RECOVER-NEURO researchers relied on patient-reported outcomes, or participants rating their symptoms, to measure the effectiveness of the treatments. 

NYU researchers provided video visits for participants during the 50 at-home brain training sessions, ensuring they received the necessary guidance to complete their assigned activities remotely to reduce the need for in-person clinic visits. This feature was especially important for people with Long COVID, who may experience challenges visiting a clinic regularly or whose brain fog and other symptoms may lead to exhaustion after leaving home. 

“People living with Long COVID often experience profound fatigue and other disabling symptoms that can make attending in-person appointments challenging. To address this, we deliberately structured the trial to support remote participation whenever possible,” said Jacqueline Becker, PhD, of Icahn School of Medicine at Mount Sinai and a multiple principal investigator of the study. “Our approach allowed people who might otherwise not have been able to participate to contribute to this emerging science.”

In addition to Dr. Knopman and Dr. Becker, the RECOVER-NEURO principal investigators include Deborah Koltai, PhD, Duke University Medical Center; Daniel Laskowitz, MD, MHS, Duke Clinical Research Institute; Leigh E. Charvet, PhD, NYU Langone Health; and Juan Wisnivesky, MD, DrPH, and Alex Federman, MD, both from Icahn School of Medicine at Mount Sinai.  The team also included a group of Patient, Caregiver, and Community Representatives who helped design the study protocol as well as provided feedback throughout the trial. The study teams at each of the 22 sites also helped to advise on the project to enhance participants’ experiences. The full site list is available on ClinicalTrials.gov.