Biomarkers of Response to Treatment With Frontal Cortex Stimulation for Anxious Depression

BACKGROUND Importance: Over 50% of patients with major depressive disorder (MDD) do not respond to initial treatment and relapse is common. Poor treatment response is likely due to limited treatment options, the heterogeneous nature of MDD, its high comorbidity with other psychiatric conditions (particularly anxiety disorders) and the lack of data to support a targeted treatment approach. In addition, existing treatments can have negative side effects. Thus, there is a great need for novel, more targeted treatments. Transcranial direct current stimulation (tDCS) is a novel intervention that targets neural excitability and plasticity in regions implicated in the cognitive features of MDD and anxiety disorders. This proposal applies cognitive neuroscience approaches in a tDCS treatment study to establish biomarkers of response to inform treatment selection and improve patient outcomes.

Cognitive neuropsychological features of mood and anxiety disorders: Depressed and anxious patients typically show negative biases in emotional perception and memory, and such biases are believed to play a fundamental role in the maintenance of emotional disorders. In terms of neural correlates, functional magnetic resonance imaging (fMRI) studies have confirmed hyperactive amygdala and/or hypoactive prefrontal activity in patients with MDD and anxiety disorders, indicating an imbalance of activity within this cortico-limbic circuit. There is evidence that treatment with antidepressant drugs (Paulus et al. 2005) can reduce amygdala hyperactivity and cognitive behavioral therapy can increase frontal activation (Ritchey et al. 2011). In addition, emerging fMRI findings indicate that pre-treatment neural markers can be used to predict whether patients will respond to behavioral or drug treatments (McGrath et al. 2014). 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, in the absence of acute mood improvements. Critically, among patients, acute cognitive effects - such as a reduction in vigilance to threat (e.g. fearful faces) - have been shown to predict response to drug and behavioral treatments (Tranter et al. 2009; Reinecke et al. 2013). Thus, baseline and acute behavioral and neural markers could be leveraged to identify characteristics of likely responders to different treatments. Specifically, treatments aiming to remediate prefrontal and amygdala dysfunction (underlying negative biases) could be a critical target in patients with MDD and anxiety disorders exhibiting these deficits.

Transcranial direct current stimulation: Mounting evidence from clinical trials indicates that repeated administration (10-15 sessions over 2-4 weeks) of tDCS to the dorsolateral prefrontal cortex (DLPFC) is a potentially effective treatment for MDD (Brunoni et al. 2015). However, underlying mechanisms of action are unclear, although spectroscopy imaging suggests that tDCS causes alterations in inhibitory neurotransmitter GABA (Stagg & Nitsche 2011), and a recent review (Ironside & Perlo 2018) implicated protective effects on cognition as a potential mechanism of action for DLPFC tDCS. An initial investigation in healthy volunteers by the applicant revealed an anxiolytic-like effect (reduced threat vigilance) from a single session of DLPFC tDCS vs sham tDCS on a behavioral test of proven clinical relevance (Ironside et al. 2016). To investigate the neural correlates of this effect, the applicant followed up with an fMRI study which found that, in a sample of trait anxious females, a single session of DLPFC vs. sham tDCS reduced amygdala response to fearful faces (p < 0.05) whilst simultaneously increasing frontal attentional control signals (p < 0.001) (Ironside et al. 2019). This provides causal evidence that modulating activity directly in the DLPFC inhibits amygdala response to threat in humans, highlighting a potential neural mechanism for the prior behavioral reduction in vigilance. In addition, this offers initial mechanistic insights into the efficacy tDCS in the treatment of MDD and anxiety disorders.

Candidate mechanisms of action for tDCS: These acute cognitive neuropsychological effects of tDCS can mirror acute effects of antidepressant and anxiolytic treatment. This provides a rationale for patient investigations of tDCS to characterize these as potential markers of treatment response. The current proposal seeks to apply - the investigators believe for the first time - these findings to patients receiving tDCS treatment for MDD, using behavioral, neural and molecular measures to test the predictive validity of acute effects of tDCS on behavioral threat vigilance (Aim 1), amygdala response to fear (Aim 2) and resting brain activation (Aim 3) as markers of future treatment response. Additionally, evidence from magnetic resonance spectroscopy (MRS) indicates that a change in the inhibitory neurotransmitter GABA is implicated in the effects of tDCS (Stagg et al. 2009) and thus exploratory analyses will probe the role of baseline GABA in treatment response.

SPECIFIC AIMS