Study Revealed Brain Stimulation May Improve Attention but Also Heighten Threat Sensitivity in Individuals with Anxious Depression

Research investigating the effects of transcranial direct current stimulation (tDCS) on individuals with depression and comorbid anxiety reveals a dual impact of this noninvasive form of brain stimulation. Results showed enhanced task engagement and activation of brain regions associated with executive function, but also, unexpectedly, heightened sensitivity to threats. The findings from the study in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, published by Elsevier, suggest that tDCS could be considered as an adjunct (supporting) treatment for major depressive disorder (MDD) when used in combination with therapies that would benefit from higher attention/engagement.

Effectively treating MDD remains a significant public health challenge. Over half of patients with MDD fail to respond to initial treatment, relapse rates remain high, and treatment selection is underinformed. MDD is frequently accompanied by anxiety disorders, and this comorbidity is associated with worse clinical course trajectories and more treatment resistance than MDD alone. Although much recent work has focused on new treatment options for MDD, the need for more targeted, scalable treatments remains.

The noninvasive neuromodulation intervention tDCS can be used to target neural excitability and plasticity in specific neural circuits that are important for regulating mood and anxiety. Findings from previous clinical trials on the effectiveness of tDCS to treat MDD are mixed. A prior study by the investigators suggested that applying tDCS to frontal brain regions while anxious participants viewed fearful faces may increase frontal activation and simultaneously decrease activation of deeper brain regions (the amygdala) associated with threat processing.

“We were interested to see if this was the case in a larger sample of people with comorbid anxiety and depression, and to see if the effect on fear extended to eyeblink startle, which is another measure of threat processing,” explains lead investigator Maria Ironside, DPhil, Laureate Institute for Brain Research, and Oxley College of Health Sciences, The University of Tulsa.

In this study, 101 individuals with comorbid anxiety and depression were divided into two groups, one of which received a single 30 minute session of tDCS to the frontal cortex, and the other received sham (placebo) stimulation. Directly afterwards participants completed an attentional control task with fearful face distractors while in the MRI scanner. Following this, they completed an eyeblink startle task under threat of mild electrical shock.

Investigators found that tDCS enhanced task engagement, as evidenced by improved accuracy, reaction times, and frontal activation, suggesting a potential increase in executive function. However, it failed to reduce threat sensitivity as they had hypothesized.

Dr. Ironside says, “Compared to the sham stimulation, frontal tDCS increased the activation of the bilateral inferior frontal gyrus (a part of the brain thought to be associated with attention) when the task was more cognitively demanding and, unexpectedly, increased amygdala (a region which has been described as the brain's 'alarm system') response when the task was less cognitively demanding. We did not see expected effects (i.e., decreased amygdala) in the fearful face condition. We also observed that tDCS increased eyeblink startle response under conditions of unpredictable threat.”

Editor-in-Chief of Biological Psychiatry: Cognitive Neuroscience and Neuroimaging Cameron S. Carter, MD, University of California Irvine School of Medicine, comments, “Compared to other brain stimulation technologies, tDCS is more clinically feasible and scalable with the development of home-use devices, relying on remotely supervised protocols that support recent efforts to increase telehealth options, especially in rural areas and other situations where access to in-person mental healthcare is limited. However, tDCS is not yet an established treatment for more difficult-to-treat patients such as those with mixed anxiety and depression. This study helps shed light on the potential usefulness of this tool in this population.”

Dr. Ironside concludes. “The jury is still out on whether tDCS can be a helpful treatment for anxiety and depression, although the recent FDA approval of home tDCS for depression is promising. More research is needed to better understand how tDCS works and for whom it is most effective. Our study suggests that frontal tDCS may increase task engagement; this makes the case for further investigations pairing tDCS with therapies that would benefit from increased attention/engagement.”

Notes for editors

The article is "Frontal Cortex Stimulation Modulates Attentional Circuits and Increases Anxiety Potentiated Startle in Anxious Depression," by Tate Poplin, Rayus Kuplicki, Ebony A. Walker, Kyle Goldman, Cheldyn Ramsey, Nicholas Balderston, Robin L. Aupperle, Martin P. Paulus, and Maria Ironside (https://doi.org/10.1016/j.bpsc.2025.10.020). It appears online in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, published by Elsevier.

The article is openly available athttps://www.biologicalpsychiatrycnni.org/article/S2451-9022(25)00336-2/fulltext.

Copies of this paper are also available to credentialed journalists upon request; please contact Rhiannon Bugno at [email protected]. Journalists wishing to interview the study’s authors should contact Maria Ironside, DPhil, at [email protected].

The authors’ affiliations and disclosures of financial and conflicts of interest are available in the article.

Cameron S. Carter, MD, is Chair of the Department of Psychiatry & Human Behavior at the University of California Irvine School of Medicine. His disclosures of financial relationships and conflicts of interest are available here.

This study was funded by a Centers of Biomedical Research Excellence (CoBRE) award from the National Institute for General Medical Sciences (CoBRE; P20GM121312). This award supported the establishment of a scientific infrastructure in Tulsa, OK, to help young investigators develop research projects focused on identifying biological measures that predict how well individuals with anxiety and mood disorders will do after treatment and develop a critical mass of investigators competitive for peer-reviewed external research funding.

Clinical Trial: Frontal Stimulation to Modulate Threat Sensitivity in Anxious Depression https://clinicaltrials.gov/study/NCT04948944

About Biological Psychiatry: Cognitive Neuroscience and Neuroimaging

Biological Psychiatry: Cognitive Neuroscience and Neuroimaging is an official journal of the Society of Biological Psychiatry, whose purpose is to promote excellence in scientific research and education in fields that investigate the nature, causes, mechanisms and treatments of disorders of thought, emotion, or behavior. In accord with this mission, this peer-reviewed, rapid-publication, international journal focuses on studies using the tools and constructs of cognitive neuroscience, including the full range of noninvasive neuroimaging and human extra- and intracranial physiological recording methodologies. It publishes both basic and clinical studies, including those that incorporate genetic data, pharmacological challenges, and computational modeling approaches. The 2024 Journal Impact Factor^TM score, from Clarivate, for Biological Psychiatry: Cognitive Neuroscience and Neuroimaging is 4.8.www.sobp.org/bpcnni

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