Linking persistent avoidance with abnormalities in the OCD neural network

摘要。项目3（P3）的目标是描述强迫症患者的白色物质（WM）束和功能 在假定的强迫症神经网络中，与持续性强迫症相关的区域之间的神经异常 回避是强迫症的典型特征我们首要的中心更新假设，建立在我们现在的基础上， 强迫症患者的持续回避是特定神经元之间功能障碍性联系的表现， 集线器，即，整合和分配来自多个区域的信息的子区域，位于腹外侧前额叶 皮层（vlPFC）和喙前扣带皮层（rACC），以及OCD网络中的其他区域，包括 背侧ACC（dACC），眶额皮质（OFC）和吻侧纹状体。这些不正常的连接 导致响应于变化的上下文线索的行为灵活性受损，特别是在 不确定的令人厌恶的结果。在P3中，我们将招募并检查50例未用药/血清素再摄取 抑制剂/氯丙咪嗪药物治疗的OCD参与者和50名健康参与者（18-35岁;以最小化 长期病史和药物对神经测量的影响）。我们会用最先进的扩散成像技术 （dMRI），使用纤维束成像，分割和束轮廓-纤维束测量-检查WM束在 网络我们将使用功能性磁共振成像（fMRI）来检查活动，功能和有效 在新的概率接近回避任务（PAAT）期间网络区域之间的连通性（FC，EC）， 我们研究了不确定的奖励和厌恶结果对选择行为的影响， 神经活动，FC和EC在评估和预期这些结果。我们将研究 强迫症参与者的WM、活动、FC和EC异常与强迫症的严重程度 与持续回避相关的症状维度，例如，避免伤害性别将是协变量， 分析。目的（A）1将比较连接vlPFC、rACC、VACC、dACC的WM束的微观结构， 强迫症与健康受试者的OFC和头侧纹状体，使用纤维束描记术的新组合， 分割和纤维束测量。A2将比较这些OCD网络区域中FC和EC内的活动 在PAAT期间，OCD与健康参与者，以确定PAAT表现和fMRI之间的关系 强迫症与健康参与者之间的差异。A3将检查强迫症症状维度之间的关系 与持续回避有关的问题：例如，避免伤害、污染/清洗、责任 伤害/检查症状，以及：A1-2中的WM和fMRI异常。P3将受益于以下方面的专业知识： P1，2（A2）中的神经解剖学和生理学; P1，核心B（A1）中的dMRI数据分析;临床评估和 在P4，5（A3）中治疗强迫症;在核心C（A2-3）中研究神经解剖学的个体差异; 核心D中跨项目分析的整合。通过与其他项目和核心的密切合作，P3将 这是第一项阐明特定WM束和功能性强迫症网络异常的研究， 与持续性回避相关，以告知以这种行为为特征的疾病的干预措施。

ABSTRACT. The goal of Project 3 (P3) is to characterize, in OCD, white matter (WM) bundle and functional neural abnormalities among regions in a putative OCD neural network that are associated with persistent avoidance, a characteristic feature of OCD. Our overarching Center renewal hypothesis, building on our present findings, is that persistent avoidance in OCD is a manifestation of dysfunctional connections among specific hubs, i.e., subregions that integrate and distribute information from multiple regions, in the ventrolateral prefrontal cortex (vlPFC) and rostral anterior cingulate cortex (rACC), and other regions in the OCD network, including the insula, dorsal ACC (dACC), orbitofrontal cortex (OFC) and rostral striatum. These dysfunctional connections lead to impaired behavioral flexibility in response to changing contextual cues, specifically in situations with uncertain aversive outcomes. In P3, we will recruit and examine 50 unmedicated/ serotonin reuptake inhibitor/clomipramine medicated participants with OCD, and 50 healthy participants (18-35 yrs; to minimize effects of long illness history and medication on neural measures). We will use state-of-the-art diffusion imaging (dMRI), using tractography, segmentation and tract profiling - tractometry - to examine WM bundles in the network. We will use functional Magnetic Resonance Imaging (fMRI) to examine activity, functional and effective connectivity (FC, EC) among network regions during a novel probabilistic approach avoidance task (PAAT) that we developed to examine the influence of uncertain rewarding and aversive outcomes on choice behavior, and neural activity, FC and EC during evaluation and anticipation of these outcomes. We will examine relationships among WM, activity, FC and EC abnormalities in the OCD network in OCD participants and the severity of OCD symptom dimensions associated with persistent avoidance, e.g., harm avoidance. Gender will be a covariate in analyses. Aim (A)1 will compare the microstructure of WM bundles that connect vlPFC, rACC, insula, dACC, OFC and rostral striatum in OCD vs. healthy participants, using a novel combination of tractography, segmentation and tractometry. A2 will compare activity within and FC and EC among these OCD network regions in OCD vs. healthy participants during the PAAT, to determine relationships among PAAT performance and fMRI abnormalities in OCD vs. healthy participants. A3 will examine relationships among OCD symptom dimensions that are relevant to persistent avoidance: e.g., harm avoidance, contamination/ washing, responsibility for harm/checking symptoms, and: WM and fMRI abnormalities in A1-2. P3 will benefit from expertise in: NHP neuroanatomy and physiology in P1, 2 (A2); dMRI data analysis in P1, Core B (A1); clinical assessment and treatment of OCD in P4, 5 (A3); the study of individual differences in neuroanatomy in Core C (A2-3); and integration of analyses across projects in Core D. In close collaboration with other projects and cores, P3 will be the first study to elucidate the specific WM bundle, and functional, OCD network abnormalities that are associated with persistent avoidance, to inform interventions for disorders characterized by this behavior.