Frontal Cortex Stimulation Modulates Attentional Circuits and Increases Anxiety-Potentiated Startle in Anxious...

Major depressive disorder (MDD) with comorbid anxiety presents significant treatment challenges, with high relapse rates and suboptimal outcomes. Transcranial direct current stimulation (tDCS) offers a scalable, noninvasive intervention targeting neural dysfunction in the frontoparietal-amygdala circuitry implicated in anxious depression. In this study, we investigated the acute effects of tDCS on multilevel (neural, behavioral, and physiological) measures of threat sensitivity in individuals with anxious depression.

A double-blinded, parallel, randomized trial enrolled 141 participants (78% female, mean age 36.2 years) who met MDD criteria and had elevated anxiety (Overall Anxiety Severity and Impairment Scale ≥ 7). Participants received a 30-minute session of active (2 mA) or sham tDCS targeting the bilateral dorsolateral prefrontal cortex during functional magnetic resonance imaging. Neural responses to emotional face distractors were assessed using an attentional load paradigm. Fear-potentiated startle and anxiety-potentiated startle (APS) were measured via electromyography during the None, Predictable, Unpredictable threat task.

Active tDCS increased activation in the bilateral inferior frontal gyrus and mid-cingulate and parietal cortex (η_p² = 0.44-0.78) under high attentional load and improved task accuracy (Cohen's d = 0.52) and reaction times (Cohen's d = 0.58). Unexpectedly, active tDCS heightened amygdala response under low attentional load (η² = 0.02), APS responses (partial η² = 0.07), and increased anxiety ratings (partial η_p² = 0.001).

tDCS enhanced executive function and task engagement, as evidenced by improved accuracy, reaction times, and frontal activation. However, it failed to reduce threat sensitivity as hypothesized. Contextual interventions engaging target circuits during stimulation may optimize tDCS efficacy as an adjunctive treatment for anxious depression. Future studies should explore synergistic therapeutic approaches.