Frontal Stimulation to Modulate Threat Sensitivity in Anxious Depression
Condition: Depression; Anxiety and Fear
MeSH terms: Hypersensitivity; Depression; Depressive Disorder
Study type: Interventional

Summary: 
      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 141 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) and approach-avoidance-conflict (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.
    

Detailed description: 
      141 participants with anxious MDD were 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). 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 behavioral data (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 in prefrontal cortical
      areas and subcortical-limbic areas (fearful>neutral) 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. For additional exploratory analyses relating to blood based
      markers of neuroplasticity (Kynurenine), a blood sample will be taken.
    

Intervention name(s): transcranial direct current stimulation
Intervention type(s): Device
Intervention description(s): the tDCS stimulator delivers very low (2mAmp) current with surface electrodes to the skull
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: double blind randomized controlled trial
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Basic Science
Keywords: depression; anxiety; transcranial direct current stimulation; fMRI; startle reflex; threat sensitivity