Cerebellar metabolism, neural circuits, and symptoms in bipolar disorder

摘要 双相情感障碍（BD）是一种经常具有破坏性的精神疾病，具有挑战性的诊断和治疗。 确定这种疾病的潜在机制可能为更好的循证医学提供基础。 诊断和治疗技术。在精神疾病的背景下，我们最近首次 探索了磁共振成像（MRI）策略的效用，称为T1弛豫在旋转框架中 (T1ρ），这是高度敏感的大脑pH值。我们测试了患者与BD在正常的胸腺状态，发现 与匹配对照相比，T1ρ差异显著。最近，我们还拍摄了参与者与BD 在抑郁和狂躁的状态下。这些研究表明，T1ρ最突出的大脑区域 在双相情感障碍的变化是小脑，结构已被先前建议，以促进BD 但与前脑结构相比，受到的关注相对较少。BD的神经解剖模型 尽管有令人信服的证据表明小脑与人类的神经系统 大脑区域与情绪控制网络有关，而情绪控制网络被认为是这种疾病的模型。 我们假设小脑活动在调节BD的情绪中起着关键作用，这将在本研究中进行测试。 建议使用横截面设计和招募跨情绪谱的BD受试者，以及 匹配的控制。参与者将接受精神症状评估和脑成像。精神病 症状评估将包括蒙哥马利-艾斯伯格抑郁评定量表（MADRS）和Young 躁狂评定量表（YMRS）。脑成像将包括定量全脑T1ρ标测、31 P-和1H- 小脑蚓部的MRS，以及弥散成像（DWI）和静息状态fMRI。用药将 评估并用作分析中的协变量。这些数据将用于评估以下目标：目标1） 小脑活动在BD患者情绪调节中起重要作用？我们假设小脑扮演了一个 在维持正常情绪状态中的重要作用（即，起补偿作用）。我们推断如果 小脑活动使情绪正常化，那么当BD参与者情绪正常时， 随着情绪症状严重程度的增加而减少。或者，如果小脑活动导致异常情绪， 那么在躁狂或抑郁的患者中可能最大。目标2）是否连接的 小脑蚓部的情绪控制网络与BD的情绪症状不同？我们假设 情绪控制网络的蚓部和节点之间的功能连接会随着情绪而变化 在正常情绪状态下连接性增加，而在夸张情绪状态下连接性减少 抑郁症/躁狂症（Depression/Mania）我们还预计，在正常状态下的BD参与者将表现出增加的 相对于健康对照的连通性。这些结果将进一步证明小脑是 起着维持情绪的补偿作用。此外，这将支持神经网络的精细模型。 BD的病理生理学基础电路。

Abstract Bipolar disorder (BD) is a frequently devastating psychiatric illness that is challenging to diagnose and treat. Identifying the underlying mechanisms of this illness may provide a foundation for better evidence-based diagnostic and therapeutic techniques. For the first time in the context of psychiatric illness, we recently explored the utility of a magnetic resonance imaging (MRI) strategy called T1 relaxation in the rotating frame (T1ρ), which is highly sensitive to brain pH. We tested patients with BD in the euthymic state and found prominent T1ρ differences compared to matched controls. More recently, we also imaged participants with BD in depressed and manic states. These studies suggest that the brain area with the most prominent T1ρ changes in bipolar disorder is the cerebellum, a structure has been previously suggested to contribute to BD but has received relatively little attention compared to forebrain structures. Neuroanatomical models of BD have largely overlooked the cerebellum despite compelling evidence that the cerebellum is strongly connected to brain regions involved in the emotional control network that has been put forth as a model of the disorder. We hypothesize that cerebellar activity plays a critical role in regulating mood in BD, which will be tested in this proposal using a cross-sectional design and recruiting BD subjects across the mood spectrum as well as matched controls. Participants will undergo psychiatric symptom assessment and brain imaging. Psychiatric symptom assessments will include, the Montgomery-Asberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS). Brain imaging will include quantitative whole-brain T1ρ mapping, 31P- and 1H- MRS of the cerebellar vermis, as well as diffusion imaging (DWI) and resting state fMRI. Medications will be assessed and used as covariates in analyses. This data will be used to assess the following aims: Aim 1) Does cerebellar activity play a significant role in mood regulation in BD? We hypothesize that the cerebellum plays a significant role in maintaining a euthymic mood state (i.e., plays a compensatory role). We reason that if cerebellar activity normalizes mood, then its activity should be greatest when BD participants are euthymic and decrease with increasing mood symptom severity. Alternatively, if cerebellar activity drives abnormal moods, then it is likely to be greatest in patients who are manic or depressed. Aim 2) Does connectivity of the cerebellar vermis with the emotional control network differ with mood symptoms in BD? We hypothesize that functional connectivity between the vermis and nodes of the emotional control network will vary with mood state with increased connectivity in the euthymic state and decreased connectivity during exaggerated mood states (depression/mania). We also expect that BD participants in the euthymic state will exhibit increased connectivity relative to healthy controls. These results would provide further evidence that the cerebellum is playing a compensatory role to maintain mood. In addition, this would support a refined model of the neural circuits underlying the pathophysiology of BD.