Examining the mechanisms of anxiety regulation using a novel, sham-controlled, fMRI-guided rTMS protocol and a translational laboratory model of anxiety.

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Although extensive research has explored the involvement of subcortical structures in arousal, arousal symptoms are only one facet of the symptom profile shared across anxiety disorders. Much less is known about the cognitive symptoms (i.e. difficulty concentrating) experienced by anxiety patients. Accordingly, there is a critical need for mechanistic research into the CNS mechanisms that mediate the cognitive symptoms experienced by anxiety patients. Without such research, treatment development for these disorders will continue to make slow progress. The objective of this application is to determine the key neural mechanisms that mediate the cognitive symptoms of anxiety. My central hypothesis is that the right dorsolateral prefrontal cortex (dlPFC) regulates emotion through top-down inhibition of emotion-related regions. My approach will be to use repetitive transcranial magnetic stimulation (rTMS) to study the effect of right dlPFC activity on objective and subjective measures of induced anxiety, anxiety-related working memory deficits (WM), and TMS-evoked blood oxygenation-level dependent (BOLD) responses during simultaneous TMS/fMRI (i.e. target engagement). My rationale for this approach is that by experimentally manipulating right dlPFC activity using rTMS, I will be able to causally demonstrate involvement of this region in anxiety regulation, which could translate to future targeted rTMS treatments for anxiety. My first aim will be to determine the effect of a 1-week course of rTMS treatment (1 Hz vs. 10 Hz; right dlPFC target) on anxiety using the threat of unpredictable shock paradigm. My second aim will be to determine the effect of a 1-week course of rTMS treatment (1 Hz vs. 10 Hz; right dlPFC target) on anxiety-related WM-deficits using the Sternberg WM paradigm during threat of shock. My third aim will be to demonstrate target engagement by measuring BOLD responses evoked by TMS pulses to the right dlPFC during threat of shock. The work is innovative because it will combine advanced neuromodulatory techniques (fMRI guidance, electric-field modelling, neuronavigation, active-sham control) with a translational threat of shock paradigm.