High-definition Transcranial Direct Current Stimulation Improves Cognitive Function in Patients with Cerebral Small Vessel Disease: An Open-label Pilot Study Informed by Cross-sectional Analysis

INTRODUCTION: Cerebral Small Vessel Disease (CSVD) is one of the most common causes of vascular cognitive impairment and dementia, and there is still a lack of effective treatment options. High-Definition Transcranial Direct Current Stimulation (HD-tDCS) is a non-invasive neural regulation method with promising prospects in the treatment of cognitive impairment. Therefore, we explore whether HD-tDCS can improve cognitive function and potential mechanisms in patients with CSVD. METHODS: This study was divided into two complementary parts. Part 1 involved 104 patients with CSVD and 36 matched Healthy Controls (HCs) to establish the optimal HD-tDCS stimulation target. Part 2 enrolled an additional 20 patients with CSVD who received a 2-week HD-tDCS intervention targeting the stimulation site identified in Part 1. Cognitive assessments and multimodal magnetic resonance imaging data were collected from all participants at both baseline and follow-up. RESULTS: In part 1 of the study, the patients with CSVD showed significant differences in Montreal Cognitive Assessment (MoCA), Auditory Verbal Learning Test (AVLT)-study, AVLT-immediate, AVLT-delay, AVLT-recognition, Trail Making Test (TMT)-A, TMT-B, and Verbal Fluency Test -fruits/vegetables compared with HCs. Meanwhile, left hippocampal subregions to whole-brain resting state-functional connectivity (rs-FC) analysis showed that the rs-FC strength between the hippocampal cognitive subregion (HIPc) and both the left dorsolateral superior frontal gyrus and the right medial superior frontal gyrus significantly altered in patients with CSVD compared with HCs, suggesting that the prefrontal cortex is a stimulation target of HD-tDCS. In part 2 of the study, performance on the MoCA, AVLT-study, AVLT-delay, SDMT, and digit span test improved in 20 patients with CSVD after 14 days of HD-tDCS targeting the left dorsolateral prefrontal cortex. At the same time, the rs-FC strength between HIPc and the alteration cluster found in the first part of the study, located in the left dorsolateral superior frontal gyrus, was decreased after treatment. DISCUSSION: HD-tDCS may help normalize brain network function and improve cognitive function in patients with CSVD by reducing rs-FC between the hippocampus and the left dorsolateral prefrontal cortex. Further research is needed to refine treatment plans and evaluate the long-term effects of HD-tDCS on cognitive function in patients with CSVD. CONCLUSION: The patients with CSVD exhibited altered rs-FC in the hippocampal-prefrontal circuit. HD-tDCS could modulate this circuit and improve cognitive function in patients with CSVD.