ABSTRACT. 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.