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

Research output: Contribution to journalResearch articleContributedpeer-review


  • Daria Antonenko - , University of Greifswald (Author)
  • Anna Elisabeth Fromm - , University of Greifswald (Author)
  • Friederike Thams - , University of Greifswald (Author)
  • Anna Kuzmina - , University of Greifswald (Author)
  • Malte Backhaus - , University of Greifswald (Author)
  • Elena Knochenhauer - , University of Greifswald (Author)
  • Shu Chen Li - , Chair of Lifespan Developmental Neuroscience, Clusters of Excellence CeTI: Centre for Tactile Internet (Author)
  • Ulrike Grittner - , Berlin Institute of Health at Charité (Author)
  • Agnes Flöel - , University of Greifswald, German Center for Neurodegenerative Diseases (DZNE) (Author)


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 the left dorsolateral prefrontal cortex (20 min in tDCS, 30 s 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 the ITT (β = 0.1, 95%-CI [− 1.2, 1.3, p = 0.93] or PP sample (β = − 0.2, 95%-CI [− 1.6, 1.2], p = 0.77). However, secondary analyses in the N-back working memory task showed that, only in the PP sample, the tDCS outperformed the sham group (PP: % correct, β = 5.0, 95%-CI [− 0.1, 10.2], p = 0.06, d-prime β = 0.2, 95%-CI [0.0, 0.4], p = 0.02; ITT: % correct, β = 3.0, 95%-CI [− 3.9, 9.9], p = 0.39, d-prime β = 0.1, 95%-CI [− 0.1, 0.3], p = 0.5). Frontoparietal network FC was increased from baseline to 7-month FU in the tDCS compared to the sham group (p FDR < 0.05). Exploratory analyses showed a correlation between individual memory improvements and higher electric field magnitudes induced by tDCS (ρ tDCS = 0.59, p = 0.02). Adverse events did not differ between groups, questionnaires indicated successful blinding (incidence rate ratio, 1.1, 95%-CI [0.5, 2.2]). Conclusions: In sum, cognitive training with concurrent brain stimulation, compared to cognitive training with sham stimulation, did not lead to superior performance enhancements in patients with cognitive impairment. However, we observed transferred working memory benefits in patients 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 do not support the immediate benefit of the combined intervention on the trained function, but provide exploratory evidence for transfer effects on working memory 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 (NCT04265378). Registered on 7 February 2020. Retrospectively registered.


Original languageEnglish
Article number6
JournalAlzheimer's Research and Therapy
Issue number1
Publication statusPublished - Dec 2024

External IDs

PubMed 38212815
ORCID /0000-0001-8409-5390/work/159608530



  • Electric field simulation, Mild cognitive impairment, Resting-state functional connectivity, Subjective cognitive decline, Transcranial direct current stimulation, Brain, Double-Blind Method, Transcranial Direct Current Stimulation/methods, Humans, Memory, Short-Term/physiology, Prefrontal Cortex, Cognitive Dysfunction/therapy, Cognitive Training

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