THE PSYCHOLBIOLOGY AND TREATMENT OF OBESSIVE COMPULSIVE DISORDER IN ADULTS

该项目涉及强迫症(OCD)的临床研究，旨在(1)加强我们对强迫症发病机制的了解，(2)探索这种主要神经精神障碍的潜在新疗法。我们的研究使用神经成像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。其他研究评估了与神经传递相关的候选基因与强迫症以及与疾病潜在相关的人格维度的相关性。利用首次建立的双脉冲经颅磁刺激(TMS)技术作为GABA/谷氨酸介导的皮质生理学的探针，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5-羟色胺能回路之间存在重要的相互作用，并且我们的初步证据表明，GABA调节剂加巴喷丁可以改善强迫症患者对5-羟色胺再摄取抑制抗抑郁药的反应。一项关于加巴喷丁增强的对照研究即将完成，其中包括TMS措施，以确定加巴喷丁治疗后皮质醇兴奋性是否发生变化。我们用磁共振松弛计量术初步发现强迫症患者基底节结构异常，这与强迫症的纹状体病理学理论一致。在一项MRI体积研究中，我们还通过对强迫症患者的基底节和其他脑区进行体积研究，验证了基底节异常与强迫症相关的假设。我们最近对强迫症的神经解剖学方法是一个合作项目，使用扩散张量MRI来评估伽玛刀截囊后脑白质解剖变化与治疗的相关性，这是我们在布朗大学的同事进行的。最后，我们正在积极寻求影响中枢神经传递的候选基因与强迫症之间的联系。一些可能感兴趣的候选基因，例如影响单胺类神经传递的基因启动子区域的功能性遗传变异，已经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被发现。在一项这样的维度表型研究中，我们最近发现，5-羟色胺转运体启动子区的功能等位基因变异与与抑郁和焦虑相关的可遗传个性特征之间的关联，我们以前在大量的、主要是男性的队列中看到的，在以女性为主的大量人群样本中重复出现。此外，最近的一项研究发现，5-羟色胺转运体启动子区域的等位基因变异与强迫症之间存在关联，这是一些最早和最近复制的证据，表明5-羟色胺系统的遗传差异可能是强迫症的易感因素。

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.