# Frontal stimulation to modulate threat sensitivity in anxious depression > **NIH NIH P20** · LAUREATE INSTITUTE FOR BRAIN RESEARCH · 2020 · $274,130 ## Abstract Over 50% of patients with major depressive disorder (MDD) do not respond to initial treatment and relapse is common [1]. In particular, comorbid depression and anxiety disorders are associated with more treatment resistance [2]. Thus, there is a great need for novel, more targeted treatments. Transcranial direct current stimulation (tDCS) is a novel intervention that can be used to causally target neural excitability and plasticity in brain regions/circuits implicated in regulating mood and anxiety and emerging evidence suggests that it reduces threat sensitivity. Here we propose to use tDCS to target threat sensitivity as a core symptom of anxious depression to determine if we can engage the neural circuits that are treatment targets. Following the administration of a single dose of anxiolytic or antidepressant treatment, early changes in emotional processing have been observed in healthy people and clinical groups. Among patients, acute cognitive effects – such as a reduction in threat sensitivity – have been shown to predict response to drug [3] and behavioral [4] treatments. Functional magnetic resonance imaging (fMRI) studies have confirmed hyperactive amygdala and/or hypoactive prefrontal activity in patients, indicating an imbalance of activity within this cortico-limbic circuit that sub-serves threat identification (amygdala) and top-down control (prefrontal). Specifically, treatments aiming to remediate prefrontal/ amygdala dysfunction could be a critical target in patients exhibiting these deficits. Several clinical trials have shown that administration of frontal cortex tDCS is a potentially effective treatment for MDD [5]. However, underlying mechanisms of action are unclear. To meet this gap, we propose an experimental medicine study (target identification and initial target engagement paths) where 120 volunteers with anxious MDD will be randomized to receive a single session of active or sham tDCS in a parallel design. Threat sensitivity will be measured using task and resting state fMRI and potentiated startle electrophysiology. Preliminary data suggest reductions in behavioral threat sensitivity from a single session of frontal tDCS [6]. This was followed up with an fMRI study which found that a single session of active vs sham frontal tDCS reduced amygdala response to fearful faces whilst simultaneously increasing frontal attentional control signals [7]. This provides evidence that modulating activity in the frontal cortex inhibits amygdala response to threat, highlighting a potential neural mechanism for the behavioral reduction in threat sensitivity. In addition, this offers initial mechanistic insights into the efficacy of tDCS in clinical trials for the treatment of MDD and anxiety disorders, suggesting that threat sensitivity may be a suitable cognitive target. The current proposal builds on this to establish acute effects of frontal tDCS on amygdala response to threat (primary aim), frontoparietal ... ## Key facts - **NIH application ID:** 10377706 - **Project number:** 5P20GM121312-04 - **Recipient organization:** LAUREATE INSTITUTE FOR BRAIN RESEARCH - **Principal Investigator:** Maria Ironside - **Activity code:** P20 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2020 - **Award amount:** $274,130 - **Award type:** 5 - **Project period:** 2021-03-24 → 2022-06-30 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10377706 ## Citation > US National Institutes of Health, RePORTER application 10377706, Frontal stimulation to modulate threat sensitivity in anxious depression (5P20GM121312-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10377706. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*