. Bipolar Disorder (BD), defined by a history of hypo/mania, is common and debilitating. Yet, the neural mechanisms predisposing to hypo/mania, to guide new interventions for BD, are poorly understood. BD is characterized by abnormally elevated reward sensitivity, impulsivity and sensation seeking, response tendencies that predispose to hypo/mania in potentially rewarding contexts, e.g., uncertain reward expectancy (RE). In adults with BD, we reported abnormally elevated uncertain RE-related left ventrolateral prefrontal cortical (vlPFC) activity. Moreover, we showed a positive relationship between RE-related left vlPFC activity and an impulsivity component, negative urgency; and that negative urgency mediates a positive association between RE-related left vlPFC activity and the severity of lifetime predisposition to hypo/mania in young adults who have not yet developed BD. Abnormally elevated left vlPFC activity to RE is thus a potential neural mechanism underlying heightened negative urgency, which confers risk for development of/ worsening hypo/mania. Theta- burst stimulation (TBS) is a Repetitive Transcranial Magnetic Stimulation (rTMS) paradigm that can acutely, rapidly, and non-invasively modulate the left vlPFC. Examining if continuous (inhibitory) TBS (cTBS) over left vlPFC leads to acute changes in hypo/mania-related affect is thus a first step toward elucidating the neural mechanisms that predispose to hypo/mania. We will recruit 50 remitted/mild-moderate hypomanic adults with BD type I (in whom we reported the majority of RE-related neuroimaging data): 18-35 yrs (unmedicated/ on common BD medications), to avoid confounds of long psychiatric illness/ long medication history; and 50 age- and gender ratio-matched healthy/ non BD (history of anxiety/ non BD mood disorders) adults. We will examine activity in and functional connectivity (FC) among left vlPFC and reward regions: ventral striatum (VS), amygdala, orbitofrontal cortex (OFC) and dorsal/rostral anterior cingulate cortex (d/rACC). Each participant will have baseline assessments of negative urgency (and other BD-related response tendencies) and a baseline structural scan for neurotargeting and TBS dose thresholding. One week later, there will be 3 scan sessions over <2 weeks: each with 1 of 3 TBS conditions interleaved between pre and post cTBS scans, in randomized order: left vlPFC cTBS; left control region, somatosensory cortex, cTBS; and left vlPFC sham TBS. Positive and negative affect will be measured before each pre cTBS and after each post cTBS scan.
We aim to: 1. Determine the impact of acute cTBS over left vlPFC (vs. other cTBS conditions) on RE-related activity in and FC among left vlPFC, VS, amygdala, d/rACC, OFC; 2. Determine if cTBS-induced neural changes lead to acute changes in hypo/mania- related affect, and if negative urgency moderates these relationships; 3. Compare effects of cTBS over left vlPFC (vs. other conditions) on neural-affect measures in BD vs. healthy/ non BD adults. We will explore whether other BD-related response tendencies moderate cTBS-induced neural-affect changes. We will examine the acute impact of cTBS on reward circuitry and affect, to elucidate neural mechanisms that predispose to hypo/mania.

Public Health Relevance

. Bipolar Disorder (BD) is defined by a history of hypo/mania, and is common and highly debilitating; yet, the brain mechanisms predisposing to hypo/mania are poorly understood. Previously, we have shown that adults with BD have abnormally elevated left ventrolateral prefrontal cortex (vlPFC) activity during reward anticipation, and that elevated left vlPFC activity was associated with higher negative urgency, a response tendency that predisposes to future hypo/mania. Here, we will use theta burst stimulation (TBS) over the left vlPFC in adults with BD and a comparison group of healthy adults/ non BD adults with either present or previous anxiety and/or non BD mood disorders to: 1) determine the impact of TBS on left vlPFC and related brain circuitry activity and functional connectivity during reward anticipation; 2) assess whether TBS-induced brain changes lead to acute changes in hypo/mania-related affect, and how negative urgency influences these TBS-induced changes in brain and affect measures; and 3) compare the impact of TBS on these brain and affect measures in adults with BD and healthy/ non BD adults.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Adult Psychopathology and Disorders of Aging Study Section (APDA)
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Mcmullen, David
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University of Pittsburgh
Schools of Medicine
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