Neuroimaging and behavioral endophenotypes of response to DBS in OCD

强迫症的一个核心特征是高度焦虑，导致回避包括奖励在内的情况。 活动这表明工具性反应之间的异常平衡，以避免潜在的负面影响。 刺激和那些追求奖励。强迫症最有效的行为治疗（暴露和仪式 预防（ERP）教导患者消除对恐惧情况的回避和强迫反应。 然而，根据定义，ERP对于DBS候选人是不成功的。临床经验表明， 在DBS之前无法从ERP中获益，之后也是如此，描述了对强迫症触发的避免减少 以及对快乐活动的追求。出于这个原因，测量灭绝学习和 DBS患者的局部脑代谢是一种很有前途的途径，可以提高我们对神经系统疾病的认识。 参与ERP和DBS的电路。项目1将评估最佳DBS刺激 临床有效的腹侧囊/腹侧纹状体（VCA/S）靶点改变了眼眶内的活动， 内侧PFC-BG回路与奖赏和回避密切相关，使用FDG PET， 测量大脑代谢PET实验将根据初步结果检验这一假设 (P1)大鼠实验（P4）的结果表明，相对OFC和vmPFC活性将向有利于vmPFC的方向移动 在慢性DBS之后。我们将解释这些网络效应，并细化PET分析的区域，在 从P2、P3和P4提供的信息中推导出的回避-奖励网络的背景。后续 PI中的实验将检验慢性VCA/S DBS与增强的消退相关的假设， 这反过来又与强迫症的改善有关。此外，由于额纹状体的成分 与强迫症有关的神经回路也参与了物种间的回避和奖励，P1将 调整和测试一个新的范式，最初是作为灵长类动物模型开发的（见P3），以评估回避- 强迫症患者DBS前后的奖励竞争。最后，来自P5和P6的数据将提供关键的 关于PET代谢指标变化的潜在机制的假设的信息 在DBS之后他们还将建议刺激设备和范例的潜在改进， 有效地改变了所涉及的电路。 相关性（参见说明）： P1将促进DBS后脑回路变化的知识，以及消退学习/回忆的作用 和回避-奖励竞争作为发展和维持过程的内在表型 强迫症的症状更好地理解这些回路和行为内在表型的变化将有助于 为强迫症和相关疾病开发更有针对性和有效的治疗方法

A core feature of OCD is heightened anxiety resulting in avoidance of situations including rewarding activities. This suggests an abnormal balance between instrumental responses to avoid potentially negative stimuli and those to pursue reward. The most effective behavioral treatment for OCD (exposure and ritual prevention - ERP) teaches patients to extinguish avoidant and compulsive responses to feared situations. However, by definition ERP is unsuccessful for DBS candidates. Clinical experience indicates that patients unable to benefit from ERP before DBS did so afterwards, describing reduced avoidance of OCD triggers and increased pursuit of pleasurable activities. For this reason, measuring both extinction learning and regional brain metabolism in DBS patients is a promising route to improving our understanding of the neural circuitry involved in both ERP and DBS. Project 1 will assess how optimal DBS stimulation at the most clinically effective ventral capsule/ventral striatum (VCA/S) target changes activity within the orbital and medial PFC-BG circuits which have been strongly implicated in reward and avoidance, using FDG PET to measure brain metabolism. The PET experiments will test the hypothesis, informed by preliminary results (P1) and results from rat experiments (P4), that relative OFC and vmPFC activity will shift in favor of vmPFC after chronic DBS. We will interpret these network effects, and refine regions for PET analyses, in the context of the avoidance-reward network derived from information provided by P2, P3, & P4. Subsequent experiments in PI will test the hypothesis that chronic VCA/S DBS is associated with enhanced extinction, which in turn will correlate with improvement in OCD. Moreover, since the components of fronto-striatal circuitry that are implicated in OCD are also involved in both avoidance and reward across species, P1 will adapt and test a new paradigm, originally developed as a primate model (see P3), to assess avoidance- reward competition in OCD patients before and after DBS. Finally, data from P5 & P6 will provide critical information for developing hypotheses about mechanisms underlying changes in PET metabolic measures after DBS. They will also suggesting potential improvements in stimulation devices and paradigms to more effectively modify the circuits involved. RELEVANCE (See instructions): P1 will advance knowledge of brain circuit changes after DBS, and of the roles of extinction learning/recall and avoidance-reward competition as endophenotypes for processes in the development and maintenance of OCD symptoms. Better understanding changes in these circuits and behavioral endophenotypes will aid development of more targeted and effective treatments for OCD and related disorders