A 11C-UCB-J PET Study of Synaptic Density in Binge Eating Disorder (BED)

摘要 暴饮暴食障碍(Bed)是一种常见的、使人衰弱的饮食障碍[1-6]。更好地理解 Bed的神经生物学将有助于治疗开发工作。关于床的神经生物学的多方面研究 将前额叶皮质(PFC)-岛状-纹状体结构确定为主要区域和 电路[7-24]。然而，当涉及到对神经生物学基础的理解时，存在着显著的差距。 在微结构水平(即突触可塑性或突触密度)对PFC-岛-纹状体改变的研究。 尽管目前存在差距，但临床前和临床文献表明， 物质使用障碍(SODS)和卧床之间的重叠，例如相似区域的改变[25，26]，相似 临床特征(例如，强迫性食物或药物摄入)[27-29]，以及潜在的常见药理学 干预措施(例如，针对可卡因使用障碍和床的利地非他明、托吡酯和芬太尼)[30-38]。 临床前研究表明，包括兴奋剂在内的某些药理制剂有能力产生微量的 额岛纹状体结构的构筑变化以及突触之间的联系 前额叶锥体细胞的密度/树突状分支与工作记忆、反向学习和行为 灵活性[39-54]。在临床水平上，我们小组开发了一种用于成像的新型放射性示踪剂11C-UCB-J 活体人脑中突触密度的正电子发射断层扫描(PET)[55-58]。因此，当前的 探索性/发育性(PA-21-235)R21旨在首次测量PFC内的突触密度， 未用药卧床受试者(N=18)的岛叶皮质和腹侧纹状体 对照组(HCS；N=18)，使用11C-UCB-J PET。卧床参与者将接受单次11C-UCB-J PET扫描， 门诊患者和HC数据将从先前和正在进行的研究中获得。床上参与者也将完成 基于研究领域标准(RDoC)的认知和行为评估 认知系统，以及床上严重程度的评估和进食问卷。我们假设 突触密度将在四个先验的PFC区域(即前扣带皮质，腹内侧PFC， 背外侧PFC和外侧眶前叶皮质)，在岛叶皮质，在床上腹侧纹状体 与HC受试者相比。我们还假设半卵圆中心等白质区域没有变化。 在探索性目标中，我们还将探索：1)11C-UCB-J PET结果与卧床严重程度之间的相关性 以及行为/认知功能的测量，2)床和床之间突触密度的差异 2a)CUD和2b)来自先前和正在进行的研究的肥胖(OB)和瘦肉组以及3)全脑差异 应用一般线性模型(GLM)和独立成分分析(ICA)对BED组和HC组之间的差异进行分析。如果 这将是第一个检测卧床成年人体内突触密度的转译研究。正性 这些结果可能会为未来对生物标记物的发展以及阐明其机制的研究提供指导。 治疗的作用和突触密度变化的纵向性质。

Abstract Binge eating disorder (BED) is a common and debilitating eating disorder [1-6]. An improved understanding of the neurobiology of BED will aid treatment development efforts. Multiple studies on the neurobiology of BED converge on the identification of the prefrontal cortex (PFC)-insular-striatal structures as prime regions and circuits [7-24]. However, there is a significant gap when it comes to understanding neurobiological underpinnings of PFC-insular-striatal alterations at a micro-architectural level (i.e., synaptic plasticity or synaptic density). Notwithstanding current gaps, preclinical and clinical literature suggests there is significant neurobiological overlap between substance use disorders (SUDs) and BED, such as alterations in similar areas [25, 26], similar clinical features (e.g., compulsive food or drug intake) [27-29], and potential common pharmacological interventions (e.g., lisdexamfetamine, topiramate, and phentermine for cocaine use disorder and BED) [30-38]. Preclinical studies show the capacity of certain pharmacological agents, including stimulants, to produce micro- architectural changes in fronto-insular-striatal structures as well as an association between synaptic density/dendritic branching in pyramidal cells of the PFC and working memory, reversal learning, and behavioral flexibility [39-54]. At a clinical level, our group has developed a novel radiotracer, 11C-UCB-J, for imaging synaptic density in the living human brain using positron-emission tomography (PET) [55-58]. Thus, the current exploratory/developmental (PA-21-235) R21 aims to measure for the first time synaptic density in the PFC, insular cortex, and ventral striatum of unmedicated BED subjects (N =18), as compared to Healthy Controls (HCs; N =18), using 11C-UCB-J PET. BED participants will undergo single 11C-UCB-J PET scans as outpatients and HC data will be obtained from previous and ongoing studies. BED participants will also complete cognitive and behavioral assessments based on Research Domain Criteria (RDoC) positive valence and cognitive systems as well as assessments of BED severity and eating questionnaires. We hypothesize that synaptic density will be decreased in four a priori PFC areas (i.e., anterior cingulate cortex, ventromedial PFC, dorsolateral PFC, and lateral orbitofrontal cortex), in the insular cortex, and in the ventral striatum in BED as compared to HC subjects. We also hypothesize no changes in white matter regions such as centrum semiovale. In exploratory aims, we also will explore: 1) correlations between 11C-UCB-J PET outcomes and BED severity as well as measures of behavioral/cognitive functioning, 2) differences in synaptic density between BED and 2a) CUD and 2b) obese (OB) and lean groups from previous and ongoing studies and 3) whole-brain differences between BED and HC groups using general linear model (GLM) and independent component analysis (ICA). If funded, this will be the first translational study examining synaptic density in vivo in adults with BED. Positive results could inform future studies on biomarker’s development as well as studies elucidating mechanisms of action of treatments and longitudinal natures of changes in synaptic density.