Glutamate in OCD: a magnetic resonance spectroscopy study.

描述（由申请人提供）：强迫症影响2%的人口，并在世界范围内产生大量发病率。即使是最佳的心理治疗和药物治疗，它往往也没有反应。目前迫切需要对这种疾病的神经生物学以及它们可能导致的药理学策略有新的认识。 汇聚的证据表明，神经递质谷氨酸的失调可能有助于强迫症;谷氨酸调节药物可能因此在一些30%的情况下，难以标准治疗的好处。我们的小组和其他人已经报道了支持这一假设的遗传相关性和脑脊液（CSF）结果。磁共振波谱（MRS）允许非侵入性测量谷氨酸在定义的解剖区域，从而提供了独特的能力，以调查失调的神经递质在特定的电路与强迫症神经病学。磁共振波谱研究表明，谷氨酸异常的前扣带皮层（ACC），纹状体，眶额皮质。然而，这些研究是在低场强下进行的，无法将谷氨酸与谷氨酰胺解离（报告的是化合物测量Glx），并且通常无法相互复制。通过在更高场强下的最先进的谷氨酸测量可能的清晰度是迫切需要的，以完善我们对强迫症中谷氨酸失调的理解。 我们在这里报告了一个试点研究测量谷氨酸和谷氨酰胺在前扣带皮层。光谱拟合使用模拟的基础上收集的数据集从一个单一的中线体素在ACC在4 T MRS扫描仪显示减少谷氨酸，但正常的谷氨酰胺，只有在正常的胸腺强迫症患者。抑郁强迫症患者的谷氨酸水平正常。这种意外的影响表明这些经常合并疾病之间的病理生理相互作用。它也可能是导致Glx已发表报告中重复失败的变异性来源。我们建议复制和扩展这些发现。首先，我们将在一个更大的队列中重复我们的试点研究，这次也包括未服药的抑郁症患者作为对照组，以更好地阐明诊断之间的相互作用。其次，我们将在纹状体中进行谷氨酸和谷氨酰胺测量，这是另一种与强迫症有关的结构，其中Glx异常（在这种情况下升高）的报道不一致。然后，我们将研究这些脑神经化学测量结果预测药物治疗反应的能力;这种关联将确定谷氨酸测量作为潜在的临床有用的生物标志物，以帮助指导治疗选择。 这一系列最先进的光谱研究将阐明强迫症兴奋性神经传递的区域特异性失调，重要的是完善我们对这种疾病的神经化学的理解，同时探索一种新的和潜在的临床有用的生物标志物的潜在效用。

DESCRIPTION (provided by applicant): Obsessive-compulsive disorder affects 2% of the population and produces substantial morbidity worldwide. It is often unresponsive even to optimal psychotherapy and pharmacotherapy. New insights into the neurobiology of the disorder, and the pharmacological strategies to which they may lead, are urgently needed. Convergent evidence suggest that dysregulation of the neurotransmitter glutamate may contribute to OCD; glutamate-modulating medications may therefore be of benefit in some of the 30% of cases refractory to standard treatment. Genetic associations and cerebrospinal fluid (CSF) findings supporting this hypothesis have been reported, by our group and others. Magnetic resonance spectroscopy (MRS) allows noninvasive measurement of glutamate in defined anatomical regions and thus offers the unique capacity to investigate dysregulation of the neurotransmitter in the specific circuit associated with OCD symptomatology. MRS studies have suggested glutamate abnormalities in the anterior cingulate cortex (ACC), the striatum, and the orbitofrontal cortex. However, these studies have been performed at low field strength and have been unable to dissociate glutamate from glutamine (reporting instead a compound measure, Glx, and have not generally replicated one another. The clarity possible through state-of-the-art glutamate measures at higher field strength is badly needed to refine our understanding of glutamate dysregulation in OCD. We here report a pilot study measuring glutamate and glutamine in the anterior cingulate cortex. Spectral fitting using a simulated basis set on data collected from a single midline voxel over the ACC in a 4T MRS scanner revealed reduced glutamate, but normal glutamine, only in euthymic OCD patients. Depressed OCD patients had normal glutamate levels. This unexpected effect suggests a pathophysiological interaction between these frequently comorbid disorders. It also may be a source of variability contributing to the failures of replication among published reports of Glx. We propose to replicate and expand these findings. First, we will replicate our pilot study in a larger cohort, tis time also including unmedicated depressed patients as a comparison group to better elucidate the interaction between diagnoses. Second, we will perform glutamate and glutamine measures in the striatum, another structure implicated in OCD in which Glx abnormalities (elevations, in this case) have been inconsistently reported. We will then investigate the ability of these measurements of brain neurochemistry to predict the response to pharmacotherapy; such an association would identify glutamate measures as a potential clinically useful biomarker to help guide therapeutic choices. This series of state-of-the-art spectroscopic investigations will elucidate the region-specific dysregulation of excitatory neurotransmission in OCD, importantly refining our understanding of the neurochemistry of the disorder while probing the potential utility of a novel and potentially clinically useful biomarker.