Dissociating the Role of the DLPFC and VLPFC in Cognitive Control in Depression: A Combined HD-tDCS and fNIRS Study

Purpose Major depressive disorder (MDD) is characterized by cognitive and affective dysfunctions linked to altered prefrontal cortical activity. While high-definition transcranial direct current stimulation (HD-tDCS) has shown promise in modulating these deficits, little is known about the differential impact of targeting distinct prefrontal subregions. This study examined whether HD-tDCS over the dorsolateral (DLPFC) or ventrolateral (VLPFC) prefrontal cortex produces distinct behavioural and neurophysiological effects in patients with MDD, particularly regarding cognitive control, mood, and functional brain connectivity. Methods Twenty-six patients with MDD were randomized to receive ten consecutive sessions of HD-tDCS over the left DLPFC, left VLPFC, or sham. Assessments were conducted pre-intervention, post-intervention, and at one-month follow-up. The outcome measures included depressive symptoms (BDI), quality of life (WHOQOL-BREF), and performance on six cognitive tasks. A subset of participants underwent resting-state functional near-infrared spectroscopy (fNIRS) to assess changes in prefrontal functional connectivity. Results DLPFC stimulation led to early and sustained improvements in depressive symptoms, executive function (e.g., TMT, WCST), and the psychological and physical domains of quality of life. The VLPFC group showed delayed improvements, particularly in conflict resolution tasks (ANT), which is consistent with its role in inhibitory control. Sham stimulation resulted in limited changes. The fNIRS results revealed no significant within-group changes in the overall connectivity degree. However, one month after the intervention, the DLPFC group exhibited significantly greater prefrontal connectivity than the sham and VLPFC groups did, suggesting a lasting reorganization of functional networks. In contrast, VLPFC stimulation did not lead to measurable changes in global connectivity, possibly due to its more localized or subcortical projection patterns. Conclusions This study provides preliminary evidence that HD-tDCS can differentially modulate cognitive and affective processes in depression depending on the prefrontal target. DLPFC stimulation appears to promote broader and earlier improvements across mood, cognition, and functional network organization, whereas VLPFC stimulation may facilitate more selective, delayed effects on inhibitory control. Importantly, increased resting-state connectivity following DLPFC stimulation suggests that HD-tDCS may induce durable changes in large-scale prefrontal networks, potentially supporting long-term cognitive resilience. These findings support a functional dissociation between prefrontal subregions and highlight the importance of incorporating functional connectivity metrics when evaluating neuromodulatory interventions in clinical populations. Longitudinal and larger-scale studies are needed to validate these findings and optimize clinical applications.