Frontal Stimulation to Modulate Threat Sensitivity in Anxious Depression

  • End date
    Mar 31, 2024
  • participants needed
  • sponsor
    Laureate Institute for Brain Research, Inc.
Updated on 15 July 2022
behavior therapy
depressive disorder
depressed mood
depressive episode


Over 50% of patients with major depressive disorder (MDD) do not respond to initial treatment and relapse is common. In particular, comorbid depression and anxiety disorders are associated with more treatment resistance. 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 the investigators propose to use tDCS to target threat sensitivity as a core symptom of anxious depression to determine if the investigators 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 and behavioral 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. However, underlying mechanisms of action are unclear. To meet this gap, the investigators 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. 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. 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 response to threat (secondary aim), startle response under threat (secondary aim), approach-avoidance-conflict (exploratory aim) and model-based learning (exploratory aim). The ultimate aim is to apply these multi-level acute findings to mechanistic clinical trials of tDCS, to test their prediction of treatment response (full model path) and improve patient outcomes.


120 participants with anxious MDD will be recruited from the community. Participants will undergo screening and baseline assessments using self-report and clinical assessments. Eligible participants will be invited for an additional screening session where they will allocated to either active or sham stimulation arms (50% in each arm, balanced for biological sex). Participants in the active arm will receive 30 minutes tDCS over bilateral prefrontal cortex using an optimized lateral electrode (OLE) placement montage. This montage is selected as it is commonly used in clinical trials of tDCS for MDD and is designed to target the lateral DLPFC. Moreover, hypoactive frontal activation and related impaired top-down control is associated with MDD and anxiety disorders. Resting state (rs) fMRI data will be collected immediately before, during and after active or sham tDCS. After tDCS, task-based fMRI data (attentional control task with fearful distractors and approach avoidance task) will be acquired. Mood will be assessed with a single item 0-100 visual analogue scale (VAS) question and Positive and Negative Affective schedule (PANAS) at multiple time points before and after imaging and tDCS. Subjective and neural responses to fearful faces and approach/avoidance decisions in prefrontal cortical areas and subcortical-limbic areas (fearful>neutral and avoid>approach activations) and their connectivity during resting state will be assessed with contrasts made between active and sham stimulation. Anxiety (unpredictable shock > neutral) and fear (predictable shock > neutral) potentiated startle will be measured using EMG. Reinforcement learning will be assessed using a behavioral task. For additional exploratory analyses relating to blood based markers of neuroplasticity (Kynurenine), a blood sample will be taken.

Condition Depression, Anxiety and Fear
Treatment Transcranial Direct Current Stimulation
Clinical Study IdentifierNCT04948944
SponsorLaureate Institute for Brain Research, Inc.
Last Modified on15 July 2022


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Inclusion Criteria

Current major depressive episode assessed by clinician administered MINI
Minimum score of 8 on OASIS anxiety scale
Normal or corrected to normal vision/hearing, as protocol elements may not be valid otherwise
Fluent English speaker, capable of providing written informed consent

Exclusion Criteria

Has uncontrolled, clinically significant neurologic (including seizure disorders): cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, urologic, immunologic, endocrine disease, or psychiatric disorder, or other abnormality, which may impact the ability of the participant to participate or potentially confound the study results
History of moderate or severe traumatic brain injury, as assessed by a TBI questionnaire
Family history of psychotic or bipolar disorder, because of low risk of inducing a manic episode with tDCS
Current diagnosis of eating disorder or obsessive-compulsive disorder
Current use of medications with major effects on brain function or the fMRI hemodynamic response (e.g., methylphenidate, acetazolamide, excessive caffeine intake > 1000 mg/day) following an initial list compiled by the Aupperle lab at LIBR but also assessed on a case by case basis)
Moderate to severe current substance use disorder, defined as 5 or more symptoms of the criteria for Substance Use Disorder according to DSM 5
Drug or alcohol intoxication (based on positive UTOX or breathalyzer test at screen or baseline) or reported alcohol/drug withdrawal
Has a risk of suicide according to the Investigator's clinical judgement or per Columbia-Suicide Severity Rating Scale (C-SSRS), the subject scores "yes" on items 4 or 5 in the Suicidal Ideation section with referent to a 30-day period prior to Screening/Baseline or the subject has had one or more suicidal attempts with reference to a 2-year period prior to Screening/Baseline
MRI or tDCS contraindications
Is pregnant or lactating or intending to become pregnant before, during, or within 12 weeks after participating in this study; or intending to donate ova during this time-period
History of highly irritable skin and/or contact dermatitis that affects skin integrity of the scalp
Any participant judged by the Investigator to be inappropriate for the study
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