Multifield extended high-definition transcranial direct current stimulation in mild cognitive impairment: A proof-of-concept study on cognition and brain network connectivity

Background Treatment of mild cognitive impairment (MCI) could delay the progression of cognitive decline. Noninvasive neuromodulation might restore brain plasticity and lead to clinically meaningful cognitive improvements. Objective To investigate feasibility and tolerability of a multi-field (four regions) extended (80-min-long) intervention using high-definition transcranial direct current stimulation (HD-tDCS) combined with computerized cognitive training (CCT) in participants with MCI and to explore its effects on cognition and brain functional connectivity. Methods Double-blinded, randomized proof-of-concept trial of daily sham HD-tDCS + CCT (n = 4) or anodal HD-tDCS + CCT (n = 4) for 15 sessions over 3 months. Four cortical regions were targeted using neuronavigation, including putative frontal coordinates of cognitive reserve and lateral parietal coordinates hypothesized to have robust hippocampal connectivity. Neurocognitive outcomes were assessed at 3 and 6 months and resting-state functional connectivity changes were evaluated at 3 months. Statistical analysis included independent sample t-tests, Wilcoxon rank-sum tests, and Bonferroni correction for multiple comparisons. Results Eleven subjects were eligible and interviewed, and 8 consented (73% consent rate). All 8 completed the trial with only minor adverse events (100% completion rate). Blinding was successful. A large but non-significant increase in Alzheimer's Disease Cooperative Study-Preclinical Alzheimer's Cognitive Composite scores at 6 months was observed in the anodal group (59.8%) compared with sham (24.5%). Significant declines were seen in left parietal cortex–left caudal hippocampus connectivity (p = 0.004) and right intraparietal sulcus–right frontal eye fields connectivity (p = 0.039) in the anodal group. Conclusions The intervention was feasible and well tolerated. Findings suggest possible normalization of aberrant or compensatory hyperconnectivity in MCI. Larger studies are needed. Clinical Trial Number: NCT04246164