THE PSYCHOLBIOLOGY AND TREATMENT OF OBESSIVE COMPULSIVE DISORDER IN ADULTS

本项目涉及强迫症（OCD）的临床研究，旨在（1）提高我们对OCD发病机制的理解，（2）研究这种主要神经精神障碍的潜在新治疗方法。 我们的研究使用神经影像学和成对脉冲经颅磁刺激来研究强迫症的病理生理学及其药物治疗的机制。其他研究评估了神经传递相关的候选基因与强迫症的相关性，以及与疾病潜在相关的人格维度的相关性。利用最早建立的GABA/谷氨酸介导的大脑皮层生理学探针--“成对脉冲”经颅磁刺激（TMS）技术，我们发现TMS阈值异常。 这一发现是有趣的，因为临床前数据表明大脑GABA能和多巴胺能回路之间存在重要的相互作用，我们的初步证据表明，GABA调节剂加巴喷丁可改善强迫症患者对5-羟色胺再摄取抑制抗抑郁药的反应。一项加巴喷丁增强的对照研究即将完成，该研究包括TMS测量，以确定加巴喷丁治疗后皮质醇兴奋性是否发生变化。我们使用磁共振弛豫测量法对强迫症患者基底神经节结构异常的初步发现与强迫症患者纹状体病理学的理论一致。在MRI容积研究中，我们还通过对强迫症患者的基底神经节和其他脑区进行容积研究，来验证基底神经节异常与强迫症相关的假设。我们最近的神经解剖学方法是一个合作项目，使用扩散张量MRI来评估伽玛刀囊切开术后白色物质解剖结构变化的治疗相关性，我们的同事在布朗大学进行治疗难治性患者。最后，我们正在积极探索影响中枢神经传递和强迫症的候选基因之间的关联。在我们正在进行的焦虑和抑郁相关人格维度的遗传学研究中，已经确定了一些潜在的候选基因，如影响单胺能神经传递的基因启动子区的功能性遗传变异。在一个这样的维度表型研究中，我们最近发现，5-羟色胺转运蛋白启动子区的功能等位基因变异与抑郁和焦虑相关的遗传性人格特质之间的关联，我们以前在一个大的，主要是男性队列中看到的，在一个大的，主要是女性人口样本中复制。此外，最近的一项研究发现5-羟色胺转运蛋白启动子区多态性的等位基因变异与强迫症之间存在关联，这是5-羟色胺系统遗传差异可能易患强迫症的第一个和最近重复的证据。

This project involves clinical research in obsessive-compulsive disorder (OCD) directed towards (1) enhancement of our understanding of OCD pathogenesis, and (2) investigating potential new treatments for this major neuropsychiatric disorder. Our studies use neuroimaging and paired pulse transcranial magnetic stimulation to investigate pathophysiology in OCD and mechanisms underlying its pharmacological treatment. Other studies assess the relevance of neurotransmission-related candidate genes to OCD and to personality dimensions which are potentially relevant to the illness. Using the "paired-pulse" transcranial magnetic stimulation (TMS) technique first established as a probe of GABA/glutamate-mediated cortical physiology, we found that TMS threshold was abnormal. This finding was interesting in view of preclinical data indicating important interactions between brain GABAergic and serotonergic circuits and our preliminary evidence that gabapentin, a GABA-modulator, improves the response to serotonin reuptake inhibiting antidepressants in OCD. A controlled study of gabapentin augmentation, which includes TMS measures to determine if corticol excitability changes after gabapentin treatment, is nearing completion. Our preliminary finding of structural abnormalities in the basal ganglia of OCD patients using magnetic resonance relaxometry is consistent with theories of striatal pathology in OCD. In an MRI volumetric study we are also testing the hypothesis that basal ganglia abnormalities are associated with OCD by performing volumetric studies of the basal ganglia and other brain regions in OCD. Our most recent neuroanatomical approach to OCD is a collaborative project using diffusion tensor MRI to assess the therapeutic relevance of changes in white matter anatomy after gamma-knife capsulotomy in treatment-refractory patients performed by our colleagues at Brown University. Finally, we are actively pursuing associations between candidate genes affecting central neurotransmission and OCD. Some candidate genes of potential interest, such as functional genetic variants in the promoter regions of genes affecting monoaminergic neurotransmission, have been identified in our ongoing studies of the genetics of anxiety- and depression-related personality dimensions. In one such dimensional phenotype study, we have recently found that the association between functional allelic variation in the serotonin transporter promoter region and heritable personality traits related to depression and anxiety that we had seen previously in a large, mainly male cohort was replicated in a large primarily female population sample. In addition, a recent study found an association between allelic variation at the serotonin transporter promoter region polymorphism and OCD, some of the first and recently replicated evidence that genetic differences in serotonin systems may predispose to OCD.