Intermittent Theta Burst Stimulation (iTBS) for Emotion Regulation in Bipolar Disorder

The specific goal of this mechanistic study is to test whether targeted engagement of the inferior parietal lobule (IPL) using a rapid and robust form of transcranial magnetic stimulation, accelerated intermittent theta burst stimulation (aiTBS), will increase emotion regulation (ER) in patients with bipolar disorder (BD). Specifically, the Investigators will experimentally test whether stimulation the IPL with aiTBS can strengthen functional neurocircuitry supporting healthy ER, as indexed by increased IPL and anterior insula (AI) functional connectivity and improved performance on ER-related behavioral tasks. The Investigators will use computer tasks that measure ER and functional magnetic resonance imaging (fMRI) to examine changes in brain function and behavior following real versus sham aiTBS in individuals with BD. Patients will be randomized to either active or sham aiTBS and will receive 6 sessions of high dose (1800 pulses) iTBS per day over a course of 4 days (24 sessions total). Patients will be scanned at baseline and 3 days after Day 4 of aiTBS in order to examine ER-related neuroplastic effects of IPL stimulation. To increase the potential clinical utility of findings from this study, the Investigators will examine the effects of aiTBS to the IPL in a sample of BD patients who are currently depressed, the most common and chronic mood state in this population. Following informed consent, all participants will complete a battery of self-report questionnaires assessing ER and will complete a computer-based ER task (Balloon Analog Risk Task; BART). Participants will then complete a functional magnetic resonance imaging (fMRI) scanning session consisting of (1) structural, (2) resting state, and (3) task-based (Affective Multisource Interference Task; MSIT-IAPS) scans. Participants will then be randomized to either Active (n=60, 30 per site) or Sham (N=60, 30 per site) aiTBS conditions in a double-blind design. Both Active and Sham procedures will consist of 4 days of iTBS (6 sessions/day). Participants will repeat the BART computer-based task and fMRI scanning procedures (structural, resting state, MSIT-IAPS in scanner task) within 3 days after Day 4 stimulation to measure the neuroplastic effects of aiTBS. The Investigators propose to recruit 136 individuals with a diagnosis of BD and a current depressed episode. The study will have 68 per each of the two groups (Active, Sham) at baseline and anticipate approximately 10% loss to attrition by post aiTBS. As the study has a single primary outcome (aiTBS-induced changes in IPL-AI functional connectivity), the Investigators use an alpha-level (Type 1 error rate) of 0.05. In preliminary data (n=8), the Investigators observed an increase in IPL-AI functional connectivity from 0.04 (SD=0.17) to 0.15 (SD=0.22), with correlation of 0.80 after a single day of 10 sessions active iTBS, corresponding to an effect size of Cohen's d=0.57. The Investigators anticipate a small "placebo" effect in the TBS group, of about d=0.10, and conservatively assume a correlation of 0.65, rather than the 0.80 seen in the pilot study. With these assumptions, the study has 80% power for an active aiTBS effect of 0.45, relative to sham aiTBS. The Investigators note that these effect size estimates are based on a much smaller dose of iTBS than the dose to be administered in the proposed study (18,000 pulses versus 43,200 pulses) - thus, it is plausible that the effect sizes seen in the study will be larger than those in the pilot data. See "Statistical Design and Power" for full details of data analysis plan.