Transcranial direct current stimulation-augmented cognitive training for post-COVID-19 cognition: A phase IIb randomized controlled trial

BackgroundCognitive dysfunction is a prevalent and debilitating symptom of post-COVID-19 condition with limited evidence-based interventions. Here, we assessed the efficacy of cognitive training (CT) alone and combined with transcranial direct current stimulation (tDCS) for cognitive enhancement in post-COVID-19 patients. MethodsNeuromod-COV was a phase IIb, prospective, randomized, open-label, blinded-endpoint trial conducted at University Medicine Greifswald, Germany. The tDCS intervention was evaluated through a double-blind, sham-controlled design. Adults aged 18-60 with confirmed SARS-CoV-2 infection [≥] 6 weeks prior and post-infection cognitive complaints were eligible. Participants were randomly assigned (1:1:1) to CT with active tDCS (CT+AtDCS), CT with sham tDCS (CT+StDCS), or progressive muscle relaxation (PMR, non-cognitive control intervention) with sham tDCS. Intervention consisted of nine 20-minute sessions over three weeks of CT (letter updating task) or PMR with 2 mA tDCS (active/sham) applied over the left dorsolateral prefrontal cortex. The primary outcome was untrained working memory (WM; measured by N-back task accuracy) comparing CT with PMR at post-intervention. Secondary outcomes included trained and untrained WM, visuospatial memory, and self-report measures at post-intervention and 1-month follow-up comparing CT vs. PMR and CT+AtDCS vs. CT+StDCS. The trial was registered at ClinicalTrials.gov (NCT04944147). ResultsBetween October 1, 2021, and August 7, 2024, 60 participants were randomized (76.7% female) to CT+AtDCS (n = 20), CT+StDCS (n = 20), or PMR (n = 20). CT did not improve untrained WM at post-intervention compared with PMR (primary outcome: {beta} = 1.59, 95% CI - 1.30 to 4.48, p = 0.278; 1-back: {beta} = 2.52, 95% CI -1.27 to 6.31, p = 0.191; 2-back: {beta} = 0.66, 95% CI -3.12 to 4.44, p = 0.732). However, CT+AtDCS enhanced untrained WM at post-intervention and follow-up, and visuospatial memory at post-intervention compared with CT+StDCS (secondary outcomes). No intervention improved self-report outcomes. No serious adverse events occurred and incidence rate ratios were similar between groups. ConclusionCT alone did not improve untrained WM performance. However, CT with tDCS enhanced untrained WM and visuospatial memory, suggesting potential benefits of combined neuromodulation approaches for cognitive enhancement in post-COVID-19 patients.