The functioning of overlapping frontostriatal circuits in children with OCD

描述(由申请人提供)：强迫症(OCD)是一种致残性疾病，通常从童年开始，一直持续到成年。神经影像研究提示强迫症患者额纹状体环路的解剖和功能障碍，但很少有研究评估儿童(儿童起病)强迫症的这些环路的功能，这可能是一种独特的强迫症亚型，与前额叶皮质功能和结构的发育变化相吻合。我们假设，重叠的额纹状体回路的功能障碍通过削弱对侵入性思维(强迫症)和重复行为(强迫症)的控制以及降低处理奖励的能力而导致强迫症。过度依赖较早发育的纹状体，就会让强迫性行为成为习惯。在这项R21中，我们将使用功能磁共振成像来评估30名未服用药物的强迫症儿童(6-12岁)的这些回路的功能，并与30名年龄匹配的健康对照组进行比较。背侧额纹状体控制系统的功能将使用经过充分验证的Simon任务进行评估。支持习惯学习和奖励处理的背侧纹状体和前额纹状体腹侧回路的功能 使用一种新的功能磁共振成像范式进行评估，该范式直接类似于定义啮齿动物基于奖励的学习系统的神经基础的任务，该任务是为磁共振扫描仪内的虚拟现实环境量身定做的。这一范式为研究强迫症的脑功能提供了一种翻译神经科学方法。我们还将评估同一儿童额纹状体背侧和腹侧环路的功能连接，并确定这些重叠环路的干扰是否与强迫症症状的严重程度有关。在强迫症中识别这两个回路中的任何一个的功能障碍将支持未来对其在强迫症中的神经发育轨迹的纵向研究。我们的长期目标是确定强迫症背后的大脑异常的独特模式，并开发直接针对这些异常的新疗法。通过验证使用特定的功能磁共振成像范例来检查强迫症潜在的大脑机制，R21的应用是朝着这个方向迈出的第一步，并与NIMH促进大脑发现的战略计划相一致。

DESCRIPTION (provided by applicant): Obsessive-Compulsive Disorder (OCD) is a disabling illness that typically begins in childhood and persists into adulthood. Neuroimaging studies suggest anatomical and functional disturbances of frontostriatal circuits in OCD but few studies have assessed the functioning of these circuits in pediatric (child-onset) OCD which is likely a distinct OCD subtype, coinciding with developmental changes in the function and structure of the prefrontal cortex. We hypothesize that dysfunction in overlapping frontostriatal circuits contributes to OCD by impairing control over intrusive thoughts (obsessions) and repetitive behaviors (compulsions) and diminishing the capacity to process rewards. An over-reliance on the earlier developing striatum then allows compulsions to become habits. In this R21, we will use fMRI to assess the functioning of these circuits in 30 unmedicated children with OCD (ages 6-12) compared to 30 age-matched healthy controls. The functioning of dorsal frontostriatal control systems will be assessed using the well-validated Simon task. Functioning of the dorsal striatum and ventral frontostriatal circuits that support habit learning and reward processing will be assessed using a novel fMRI paradigm directly analogous to tasks used to define the neural bases of reward-based learning systems in rodents, tailored to a virtual reality environment within the MRI scanner. This paradigm provides a translational neuroscience approach to the study of brain function in OCD. We will also assess functional connectivity in dorsal and ventral frontostriatal circuits in the same children, and determine whether disturbances in these overlapping circuits are associated with OCD symptom severity. Identification of dysfunction in either of these circuits in OCD will support future longitudinal study of their neurodevelopmental trajectories in OCD. Our long-term goal is to identify a distinct pattern of brain abnormalities tht underlies OCD and to develop novel treatments that target these abnormalities directly. By validating the use of specific fMRI paradigms to examine potential brain mechanisms underlying OCD, this R21 application is a first step in this direction and consistent with the NIMH strategic plan to promote brain discovery.