2f:I[703058,["/_next/static/immutable/chunks/3bhq_5eh1d760.js","/_next/static/immutable/chunks/1855-ogyi8eh4.js","/_next/static/immutable/chunks/2pfsjpn6k6zlg.js","/_next/static/immutable/chunks/26c7v3_3uwnwu.js","/_next/static/immutable/chunks/25a3ozcrvi1ff.js","/_next/static/immutable/chunks/2r4wx50nvjh_4.js","/_next/static/immutable/chunks/23fsw06hsi5b1.js","/_next/static/immutable/chunks/06_yt270h41rg.js","/_next/static/immutable/chunks/3ezsiz-7shkna.js","/_next/static/immutable/chunks/20x2y96ldu5wx.js","/_next/static/immutable/chunks/2lxntcm3pd1_h.js","/_next/static/immutable/chunks/00dgco8irq3jw.js","/_next/static/immutable/chunks/00nwe-kq0rboc.js","/_next/static/immutable/chunks/2051ffx3xzio9.js"],"PaperListPageClient"] 30:T701,SARS-CoV-2 infection has been implicated in hippocampal damage, contributing to the pathogenesis of dysexecutive syndrome observed in post-COVID-19 patients. Given the growing prevalence of long-COVID worldwide, understanding how SARS-CoV-2 affects hippocampal structure and function has become an urgent scientific and clinical priority. The hippocampus-crucial for memory, emotional regulation, and executive functioning-is especially susceptible to viral-driven neuroinflammatory cascades. SARS-CoV-2 triggers astrocyte and microglia activation, disrupts blood-brain barrier integrity, and induces cytokine-mediated neurotoxicity, ultimately impairing neuroplasticity and neurogenesis. These mechanisms converge to produce cognitive and affective disturbances-most notably fatigue, apathy, low mood, and executive dysfunction-that typify dysexecutive syndrome in long-COVID. This review synthesizes current evidence from clinical and experimental studies, integrating findings on viral neurotropism, hippocampal hypometabolism, and astrocyte-mediated neurodegeneration. Distinctions between depressive symptoms driven by neuroinflammation and classical depressive disorders are clarified to improve diagnostic accuracy and guide personalized treatment. Emerging data on the neuroprotective role of COVID-19 vaccination-particularly its capacity to modulate microglial activation and support hippocampal neurogenesis-are also examined. Overall, the findings underscore the need for targeted therapeutic strategies aimed at modulating neuroinflammation and supporting hippocampal plasticity, including cognitive rehabilitation approaches. Longitudinal studies are essential to elucidate the enduring impact of SARS-CoV-2 on hippocampal function and to inform effective clinical interventions.31:Tad9,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. To test evidence-based rehabilitation strategies for improving cognitive symptoms in persons with long COVID. 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. 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. 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. 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. 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. ClinicalTrials.gov Identifier: NCT05965739.32:T10c1, 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 . 25:[[["$","script","0",{"type":"application/ld+json","dangerouslySetInnerHTML":{"__html":"{\"@context\":\"https://schema.org\",\"@type\":\"CollectionPage\",\"name\":\"Cognitive Rehabilitation: modality Research & Clinical Takeaways\",\"description\":\"Explore peer-reviewed papers on Cognitive Rehabilitation (modality). Clinician-written summaries and actionable practice insights. 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The authors note a need for longitudinal studies, and vaccination data are described as emerging.","what_studied":"Narrative review evaluating how SARS‑CoV‑2 impacts hippocampal structure and function in long‑COVID dysexecutive syndrome. It integrates clinical and experimental evidence on astrocyte/microglial activation, blood–brain barrier disruption, cytokine‑mediated neurotoxicity, hippocampal hypometabolism, and early data on vaccination’s neuroprotective effects.","practice_takeaway":"In post‑COVID patients with fatigue, apathy, low mood, and executive dysfunction, consider neuroinflammatory hippocampal injury and use cognitive rehabilitation to support plasticity. Distinguish neuroinflammation‑driven depressive symptoms from classical depression; vaccination may be neuroprotective, but evidence is early."}},{"doi":"10.1001/jamaneurol.2025.4415","pmid":"41212544","title":"Evaluation of Interventions for Cognitive Symptoms in Long COVID","journal_title":"JAMA Neurology","journal_issn":"2168-6149","published_at":"2025-11-10T00:00:00.000Z","url":"https://doi.org/10.1001/jamaneurol.2025.4415","source_score":131,"is_retracted":false,"is_open_access":true,"raw_metadata":{"ooir":{"day":"2026-01-16","doi":"10.1001/jamaneurol.2025.4415","days":"7","issn":"2168-6149","rank":"6","field":"Clinical Medicine","score":"131","category":"Clinical Neurology","categories":["Clinical Neurology"],"_categories":["Clinical Neurology"]},"pubmed":{"doi":"10.1001/jamaneurol.2025.4415","title":"Evaluation of Interventions for Cognitive Symptoms in Long COVID: A Randomized Clinical Trial.","journal":"JAMA neurology","methods":"","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.","abstract":"$31","keywords":[],"pubmed_id":"41212544","conclusions":"","publication_date":"2025-11-10T00:00:00"},"crossref":{"DOI":"10.1001/jamaneurol.2025.4415","URL":"https://doi.org/10.1001/jamaneurol.2025.4415","ISSN":["2168-6149"],"link":[{"URL":"https://jamanetwork.com/journals/jamaneurology/articlepdf/2841155/jamaneurology_knopman_2025_oi_250076_1767644884.87942.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"page":"49","type":"journal-article","issue":"1","score":1,"title":["Evaluation of Interventions for Cognitive Symptoms in Long COVID"],"author":[{"given":"David S.","family":"Knopman","sequence":"first","affiliation":[{"name":"Department of Neurology, Mayo Clinic, Rochester, Minnesota"}]},{"given":"Deborah","family":"Koltai","sequence":"additional","affiliation":[{"name":"Department of Neurology, Duke University School of Medicine, Durham, North 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RECOVER clinical trials. 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Adults with cognitive long COVID (n=328) trained 5 days per week for 10 weeks; the primary outcome was change in self-reported modified Everyday Cognition Scale 2 (ECog2) at end of intervention versus baseline.","key_result":"No intervention outperformed its comparator on the primary outcome: adjusted mean change differences on ECog2 were 0.0 (95% CI, -0.2 to 0.2) for BrainHQ vs active comparator, 0.1 (-0.1 to 0.3) for PASC-CoRE + BrainHQ vs active comparator, 0.0 (-0.2 to 0.2) for active vs sham tDCS (both with BrainHQ), and 0.1 (-0.1 to 0.3) for PASC-CoRE + BrainHQ vs BrainHQ alone. Secondary patient-reported and neuropsychological outcomes also showed no differential benefit; all arms improved over time, and no serious adverse events occurred.","practice_takeaway":"For adults with cognitive long COVID, 10 weeks of online cognitive training, structured cognitive rehabilitation, or tDCS did not improve self-reported everyday cognition beyond active control or sham. Expect some improvement over time regardless of assignment; the tested approaches appeared safe without serious adverse events."}}],"initialOffset":3,"fetchConfig":{"kind":"tags","tags":[{"tag_type":"modality","value":"Cognitive Rehabilitation"}]},"breadcrumbItems":[{"name":"Home","href":"/"},{"name":"Research Hub","href":"/hub"},{"name":"Modalities","href":"/hub/tag/modality"},{"name":"Cognitive Rehabilitation"}],"hrefConfig":{"basePath":"/hub/papers","webViewQueryParams":{"hub_ctx":"tag","hub_tag_type":"modality","hub_tag_value":"Cognitive Rehabilitation"}}}]]

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