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Original Investigation
January 2019

Effect of Prefrontal Cortex Stimulation on Regulation of Amygdala Response to Threat in Individuals With Trait Anxiety: A Randomized Clinical Trial

Author Affiliations
  • 1Department of Psychiatry, University of Oxford, Oxford, England
  • 2Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, England
  • 3Center for Depression, Anxiety and Stress Research, McLean Hospital, Harvard Medical School, Belmont, Massachusetts
  • 4Oxford Health National Health Service Trust, Oxford, England
  • 5University of California, Berkeley, Berkeley
JAMA Psychiatry. 2019;76(1):71-78. doi:10.1001/jamapsychiatry.2018.2172
Key Points

Question  Does stimulation of prefrontal cortex reduce amygdala threat reactivity in individuals with human trait anxiety?

Findings  In this randomized clinical trial of 16 women, placebo-controlled stimulation of the prefrontal cortex vs sham procedure reduced amygdala fear signaling and increased frontoparietal attentional control, reducing attentional capture by threat.

Meaning  Single-session stimulation can improve prefrontal control of limbic threat reactivity, indicating a candidate mechanism underlying treatment effects of noninvasive brain stimulation in affective disorders.


Importance  Transcranial direct current stimulation (tDCS) of the dorsolateral prefrontal cortex (DLPFC) is under clinical investigation as a treatment for major depressive disorder. However, the mechanisms of action are unclear, and there is a lack of neuroimaging evidence, particularly among individuals with affective dysfunction. Furthermore, there is no direct causal evidence among humans that the prefrontal-amygdala circuit functions as described in animal models (ie, that increasing activity in prefrontal cortical control regions inhibits amygdala response to threat).

Objective  To determine whether stimulation of the prefrontal cortex reduces amygdala threat reactivity in individuals with trait anxiety.

Design, Setting, and Participants  This community-based randomized clinical trial used a double-blind, within-participants design (2 imaging sessions per participant). Eighteen women with high trait anxiety (age range, 18-42 years) who scored greater than 45 on the trait measure of State-Trait Anxiety Inventory were randomized to receive active or sham tDCS of the DLPFC during the first session and the other intervention during the next session. Each intervention was followed immediately by a functional imaging scan during which participants performed an attentional task requiring them to ignore threatening face distractors. Data were collected from May 7 to October 6, 2015.

Main Outcomes and Measures  Amygdala threat response, measured with functional magnetic resonance imaging.

Results  Data from 16 female participants (mean age, 23 years; range, 18-42 years), with 8 in each group, were analyzed. Compared with sham stimulation, active DLPFC stimulation significantly reduced bilateral amygdala threat reactivity (z = 3.30, P = .04) and simultaneously increased activity in cortical regions associated with attentional control (z = 3.28, P < .001). In confirmatory behavioral analyses, there was a mean improvement in task accuracy of 12.2% (95% CI, 0.30%-24.0%; mean [SD] difference in number of correct answers, 2.2 [4.5]; t15 = 1.94, P = .04) after active DLPFC stimulation.

Conclusions and Relevance  These results reveal a causal role for prefrontal regulation of amygdala function in attentional capture by threat in individuals with high trait anxiety. The finding that prefrontal stimulation acutely increases attentional control signals and reduces amygdala threat reactivity may indicate a neurocognitive mechanism that could contribute to tDCS treatment effects in affective disorders.

Trial Registration  isrctn.org Identifier: ISRCTN78638425