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。即使对最佳的心理治疗和药物治疗，它也常常没有反应。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。越来越多的证据表明，神经递质谷氨酸的失调可能导致强迫症；因此，在30%的标准治疗难治性病例中，谷氨酸调节药物可能是有益的。遗传关联和脑脊液（CSF）的发现支持这一假设已被报告，由我们的小组和其他人。磁共振波谱（MRS）允许在确定的解剖区域对谷氨酸进行无创测量，从而提供了独特的能力来研究与强迫症症状相关的特定回路中的神经递质失调。磁共振研究表明，谷氨酸异常在前扣带皮层（ACC），纹状体和眶额皮质。然而，这些研究是在低场强下进行的，并且无法将谷氨酸和谷氨酰胺分离（报告的是一种复合测量方法，Glx），并且通常不能相互复制。在更高场强下通过最先进的谷氨酸测量可能的清晰度，迫切需要完善我们对强迫症中谷氨酸失调的理解。我们在这里报告一个试点研究测量谷氨酸和谷氨酰胺在前扣带皮层。在4T MRS扫描仪中，对ACC上单个中线体素收集的数据进行模拟基础集的光谱拟合显示，只有在心境强迫症患者中，谷氨酸盐含量降低，但谷氨酸盐含量正常。抑郁症强迫症患者谷氨酸水平正常。这一意想不到的结果表明，这些常见的共病性疾病之间存在病理生理相互作用。这也可能是导致已发表的Glx报告中复制失败的变异性的来源。我们打算复制和扩展这些发现。首先，我们将在更大的队列中重复我们的试点研究，这次还包括未接受药物治疗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的测量，纹状体是另一个与强迫症有关的结构，在这种情况下，Glx异常（升高）的报道不一致。然后，我们将研究这些脑神经化学测量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一种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中兴奋性神经传递的区域特异性失调，重要的是完善我们对该疾病的神经化学的理解，同时探索一种新的、可能临床上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. PUBLIC HEALTH RELEVANCE: Obsessive-compulsive disorder (OCD) is common, is often severe, and is inadequately treated with available approaches; several lines of evidence suggest that the neurotransmitter glutamate may be disrupted in this disorder. We use magnetic resonance spectroscopy (MRS) to investigate levels of glutamate and related neurotransmitters in patients, in vivo, in brain regions known to be associated OCD, to better understand how disruption of glutamate-based neuronal signaling may contribute to the disorder. We then investigate how these abnormalities in glutamate may predict treatment response, with the ultimate aim of providing a new clinical tool to guide the selection of therapy.