Training and brain stimulation in patients with cognitive impairment: a randomized controlled trial

Abstract

Background Repeated sessions of training and non-invasive brain stimulation have the potential to enhance cognition in patients with cognitive impairment. We hypothesized that combining cognitive training with anodal transcranial direct current stimulation (tDCS) will lead to performance improvement in the trained task and yield transfer to non-trained tasks. Methods In our randomized, sham-controlled, double-blind study, 46 patients with cognitive impairment (60–80 years) were randomly assigned to one of two interventional groups. We administered a 9-session cognitive training (consisting of a letter updating and a Markov decision-making task) over 3 weeks with concurrent 1-mA anodal tDCS over left dorsolateral prefrontal cortex (20 min in tDCS, 30 sec in sham group). Primary outcome was trained task performance (letter updating task) immediately after training. Secondary outcomes included performance in tasks testing working memory (N-back task), decision-making (Wiener Matrices test) and verbal memory (verbal learning and memory test), and resting-state functional connectivity (FC). Tasks were administered at baseline, at post-assessment, and at 1- and 7-month follow-ups (FU). MRI was conducted at baseline and 7-month FU. Thirty-nine participants (85%) successfully completed the intervention. Data analyses are reported on the intention-to-treat (ITT) and the per-protocol (PP) sample. Results For the primary outcome, no difference was observed in ITT or PP sample. However, the tDCS outperformed the sham group in the N-back working memory task. Frontoparietal network FC was increased from baseline to 7-month FU in the tDCS compared to the sham group. Exploratory analyses showed a correlation between individual memory improvements and higher electric field magnitudes induced by tDCS. Adverse events did not differ between groups, questionnaires indicated successful blinding. Conclusions In sum, cognitive training with concurrent brain stimulation induced transferred working memory benefits in patients with cognitive impairment who underwent the full 3-week intervention. MRI data pointed toward a potential intervention-induced modulation of neural network dynamics. A link between individual performance gains and electric fields suggested dosage-dependent effects of brain stimulation. Together, our findings show that the combined intervention might be a potential treatment option in patients with cognitive impairment. Future research needs to explore whether individualized protocols for both training and stimulation parameters might further enhance treatment gains. Trial registration The study is registered on ClinicalTrials.gov (NCT04265378). Registered on 7 February 2020. Retrospectively registered.