Dissociating the Role of Dorsolateral Prefrontal Cortex and Ventrolateral Prefrontal Cortex in Cognitive Control in Depression: A Combined HD-tDCS and fNIRS Study

Abstract Major depressive disorder (MDD) is marked by cognitive and affective dysfunctions associated with altered prefrontal cortical activity. While high-definition transcranial direct current stimulation (HD-tDCS) shows promise in modulating these deficits, little is known about the differential effects of targeting specific prefrontal subregions. This study investigated whether HD-tDCS over the dorsolateral (DLPFC) or ventrolateral (VLPFC) prefrontal cortex produces distinct behavioural and neurophysiological effects in patients with MDD, focusing on cognitive control, mood, and functional brain connectivity. Twenty-six patients with MDD received ten sessions of HD-tDCS over the left DLPFC, left VLPFC, or sham stimulation. Assessments were performed pre-intervention, post-intervention, and at one-month follow-up. Measures included the Beck Depression Inventory (BDI), World Health Organization Quality of Life – BREF (WHOQOL-BREF), and performance on cognitive tasks. A subset underwent resting-state functional near-infrared spectroscopy (fNIRS) to assess changes in prefrontal connectivity. DLPFC stimulation led to early and sustained improvements in depressive symptoms, executive function (e.g., Trail Making Test, Wisconsin Card Sorting Task), and quality of life domains. VLPFC stimulation produced delayed improvements, particularly in inhibitory control (e.g., Attention Network Test). fNIRS revealed no significant within-group changes in global connectivity, but at follow-up, the DLPFC group showed greater prefrontal connectivity than both VLPFC and sham, suggesting lasting functional reorganization. VLPFC stimulation did not alter global connectivity, possibly reflecting more localized or subcortical effects. HD-tDCS can differentially modulate cognitive and affective processes in MDD. DLPFC stimulation promotes broader, earlier, and more durable effects, while VLPFC stimulation may exert more specific, delayed influences. Functional connectivity measures enhance interpretation of neuromodulatory outcomes in clinical research.