Cognitive 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 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 ClinicalTrials.gov (NCT04265378). Registered on 7 February 2020. Retrospectively registered.

Keywords: Electric field simulation; Mild cognitive impairment; Resting-state functional connectivity; Subjective cognitive decline; Transcranial direct current stimulation.

Fig. 1

Consolidated Standards of Reporting Trials (CONSORT) diagram. Intention-to-treat analysis (ITT) was performed for the primary outcome at post-assessment (N = 46). Seven participants did not receive the complete intervention and were therefore not included in the per-protocol analysis (PP, n = 39)

Fig. 2

Forest plot for performance outcomes (per-protocol set). Per-protocol analyses of training and transfer effects at post and follow-ups. Abbreviations and units: Letter Updating # correct. Markov %, optimal actions. Nback % correct and d-prime. WMT % correct. VLMT (German version of the AVLT) # words recalled. Separate linear mixed model analyses were conducted for post-assessment and follow-up time points, for each task (i.e., 1/7mFU values are derived from the same models as for the corresponding overall FU scores). In the case of missing data, the results are based on multiple imputation. For separate time points: n = 39 if not indicated otherwise. ^§n = 34. °n = 33. AVLT, auditory verbal learning test; CI, confidence interval; FU, follow-up; WMT, Wiener Matrices Test

Fig. 3

Training and transfer task performance (per-protocol set). A Training improvement in the letter updating task. B Training improvement in the Markov decision-making task. No enhanced training gains were observed after anodal stimulation compared to sham stimulation. C Enhanced performance in the N-back task after anodal stimulation compared to sham stimulation. D Transfer task performance in the WMT. E Transfer task performance in the VLMT. There were no differences in WMT or VLMT between anodal and sham groups. Pre, pre-assessment. T3, T6, T9, training days 3, 6, 9. Dots represent mean values and shaded areas indicate 95% confidence intervals. tDCS, transcranial direct current stimulation. FU, 1-month follow-up. FUII, 7-months follow-up. WMT, Wiener Matrices Test. VLMT, verbal learning and memory test

Fig. 4

A Functional connectivity. Resultant cluster (P_FDR < 0.05; P_unc < 0.001 in yellow, p_unc < 0.005 in red) from seed-to-voxel resting-state FC analysis with seed in stimulation target (lMFG). Cluster location in the right supramarginal/angular gyrus (x = 44, y =  − 40, z = 50) and in the right superior/middle frontal gyrus (x = 22, y =  − 4, z = 60): increase in FC to the stimulation target in the anodal group compared to the sham group. Means (black diamonds for anodal and white diamonds for sham) and individual datapoints (single circles in orange/red for anodal and light blue/dark blue for sham). Box plots indicate median (middle line), 25th, 75th (box), and 5th and 95th percentile (whiskers). N = 27 independent participants. sbFC, seed-based functional connectivity. lMFG, left middle frontal gyrus. tDCS, transcranial direct current stimulation. RH, right hemisphere. B Computational modeling of electric fields. Group average of electric fields induced by anodal tDCS (in V/m), projected in “fsaverage” space. Scatterplots display the correlation between electric field magnitudes and change in N-back task performance (Post minus Pre of d-prime values), anodal: ρ_tDCS = 0.6, P = 0.02; sham: ρ_sham =  − 0.24, P = 0.31. Note that sensitivity analysis for the anodal group without the outlier yielded similar Spearman’s correlation coefficient (ρ_tDCS = 0.5, P = 0.05)