Optimization of tDCS brain network engagement in depression

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Project Summary/Abstract: Technological developments now make it possible to target specific, clinically relevant brain regions in patients using non-invasive neuromodulation. The effects of neuromodulation presumably propagate beyond the directly targeted brain regions through brain networks. To characterize this targeting of networks and thereby optimize neuromodulation, the proposed research aims to map the engagement of neural circuitry by a specific modality (transcranial direct current stimulation (tDCS)) in a specific clinical population (depression). Depression is characterized by dysfunction of the dorso-fronto-limbic network, with hypoactive left dorsolateral prefrontal cortex (DLPFC) and hyperactive right DLPFC. As investigational treatments for depression, these regions have been targeted using anodal and cathodal tDCS respectively, which are hypothesized to depolarize and hyperpolarize neurons (respectively), thereby counteracting pathological neural activity. K99 Aim 1 will use functional MRI (fMRI) during tDCS administration to investigate stimulation-specific activity and connectivity changes in the dorso-fronto-limbic network resulting from left DLPFC anodal tDCS. K99 Aim 2 will investigate whether tDCS induced activity changes are amplified in the same network when anodal left DLPFC tDCS is delivered concurrently with a salient cognitive task (2-back working memory). Work in model systems suggests that synaptic co-activation by a task during tDCS administration should enhance induced plasticity, and evidence of a super-additive two-way interaction of tDCS and task would provide presumptive evidence of target engagement to motivate future investigations of a tDCS-plus-task protocol. The R00 phase will follow up on the K99 phase's anodal tDCS research by focusing on cathodal tDCS. R00 Aim 1 will investigate stimulation-specific activity and connectivity changes in the dorso-fronto-limbic network induced by right DLPFC cathodal tDCS. R00 Aim 2 will investigate significant interactions between cathodal tDCS and the same DLPFC-coactivating cognitive task. For all aims, measurements will be carried out using a novel imaging approach employing spatially focal high- definition tDCS and concurrent blood oxygenation level dependent (BOLD) fMRI. This research is in line with the mission of NIMH/DNBBS, supporting interdisciplinary research into the modulation of clinically relevant neural circuits. My tDCS work to date has built upon my engineering background, using MRI to validate the precise delivery of tDCS in vivo. The proposed aims take the next logical step in this research, by using imaging to understand the response of brain circuits to such precisely delivered neuromodulation. To facilitate this work and help me achieve my long term goal of becoming an independent investigator in imaging-guided neuromodulation (applied to developing novel treatments for mental health disorders), training components to improve my expertise in pertinent areas of neuroscience (focusing on brain circuits and their pathology in neuropsychiatric disorders), clinical research and fMRI methodologies are proposed. The scientific aims address fundamental open questions in tDCS neuromodulation and are highly synergistic with the training objectives.