Elucidating neural mechanisms of hypo/mania using theta burst stimulation

摘要。双相情感障碍（BD），定义为低/躁狂病史，是常见的和衰弱的。然而 神经机制诱发低/躁狂，以指导新的干预BD，是知之甚少。BD 其特征是异常升高的奖励敏感性，冲动性和感觉寻求，反应 在潜在的有益环境中倾向于轻度/躁狂的倾向，例如，不确定报酬期望 （RE）。在成人BD患者中，我们报告了不确定RE相关的左腹外侧前额叶皮质异常升高， （vlPFC）活性。此外，我们发现RE相关的左vlPFC活性与 冲动成分，消极紧迫感;消极紧迫感介导了 患有抑郁症的年轻人中RE相关的左侧vlPFC活动和终生低/躁狂倾向的严重程度 尚未开发BD。因此，RE引起的左侧vlPFC活性异常升高是一种潜在的神经机制 潜在的负面紧迫感增强，这会导致低血糖/躁狂发展/恶化的风险。θ- 脉冲串刺激（TBS）是重复经颅磁刺激（rTMS）范例， 快速且非侵入性地调节左侧vlPFC。检查连续（抑制性）TBS（cTBS）是否超过左侧 因此，vlPFC导致轻躁狂相关情感的急性变化是阐明神经功能障碍的第一步。 易患轻躁狂症的机制。我们将招募50名缓解/轻中度轻躁狂成年人， BD I型（我们报告了其中大部分RE相关神经影像学数据）：18-35岁（未用药/用药 常见的BD药物），以避免长期精神疾病/长期用药史的混淆; 50岁- 和性别比例匹配的健康/非BD（焦虑/非BD情绪障碍史）成年人。我们将研究 左vlPFC和奖赏区的活动和功能连接（FC）：腹侧纹状体（VS），杏仁核， 眶额皮质（OFC）和背侧/喙侧前扣带回皮质（d/rACC）。每个参与者将有 消极紧迫性（和其他与BD相关的响应趋势）的基线评估和基线结构 扫描神经靶向和TBS剂量阈值。一周后，将在<2周内进行3次扫描： 每种情况在cTBS扫描前和扫描后交错出现3种TBS状况之一，按随机顺序：左侧vlPFC cTBS;左侧对照区，体感皮层，cTBS;和左侧vlPFC假TBS。正性负性情绪 将在每次cTBS扫描前和每次cTBS扫描后测量。我们的目标是：1.确定影响 左vlPFC急性cTBS（与其他cTBS条件相比）对左vlPFC中RE相关活性和FC的影响，VS， 杏仁核、d/rACC、OFC; 2.确定cTBS诱导的神经变化是否导致轻度/躁狂的急性变化- 相关的影响，如果消极的紧迫性缓和这些关系; 3。比较cTBS对左侧vlPFC的影响 (vs.其他条件）对BD与健康/非BD成人神经影响测量的影响。我们将探讨其他 BD相关的反应倾向中度cTBS诱导的神经影响的变化。我们将检查急性 cTBS对奖赏回路和情感的影响，以阐明易患轻躁狂的神经机制。

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.