Glutamate in OCD: a magnetic resonance spectroscopy study.
强迫症中的谷氨酸:磁共振波谱研究。
基本信息
- 批准号:8370654
- 负责人:
- 金额:$ 35.48万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-07-20 至 2017-05-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAnteriorBasal GangliaBiological MarkersBrainBrain PartBrain regionCaringCerebrospinal FluidCharacteristicsClinicalControl GroupsCorpus striatum structureDataData AnalysesDepressed moodDiagnosisDiseaseEtiologyFailureFluoxetineFunctional ImagingFunctional disorderGeneticGlutamatesGlutamineHeadHeterogeneityHumanImageInvestigationInvestigational TherapiesLeadLifeLiteratureMagnetic Resonance SpectroscopyMajor Depressive DisorderMeasurementMeasuresMental DepressionMental disordersMorbidity - disease rateNatureNeurobiologyNeuronsNeurotransmittersObsessive-Compulsive DisorderPatientsPharmaceutical PreparationsPharmacotherapyPilot ProjectsPopulationPredictive ValueProtonsPsychotherapyPublishingRefractoryRefractory DiseaseReportingRiluzoleSelection for TreatmentsSelective Serotonin Reuptake InhibitorSeriesSerotoninSignal TransductionSimulateSourceStructureSymptomsTechniquesTherapeuticTimebasecaudate nucleuscingulate cortexcohortcomparison groupdata acquisitiondisorder controlevidence basegenetic associationin vivoinsightmonoamineneurochemistryneurotransmissionnovelputamenresponsesmall moleculestandard caretooltreatment response
项目摘要
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.
描述(申请人提供):强迫症影响2%的人口,并在世界范围内产生相当大的发病率。即使对最佳的心理治疗和药物治疗也常常没有反应。迫切需要对这种疾病的神经生物学及其可能导致的药理学策略有新的见解。一致的证据表明,神经递质谷氨酸的失调可能导致强迫症;因此,在标准治疗无效的30%的病例中,谷氨酸调节药物可能是有益的。我们小组和其他人已经报道了支持这一假说的遗传关联和脑脊液(CSF)发现。磁共振波谱(MRS)允许在定义的解剖区域对谷氨酸进行非侵入性测量,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神经递质的调节失调。MRS研究表明,前扣带回皮质(ACC)、纹状体和眶前叶皮质存在谷氨酸异常。然而,这些研究是在低场强下进行的,无法将谷氨酸从谷氨酰胺中分离出来(相反,报告了一种复合测量,GLX,并且通常没有相互复制)。在更高的场强下,通过最先进的谷氨酸测量可能实现的清晰度是迫切需要的,以完善我们对强迫症谷氨酸失调的理解。我们在此报告一项初步研究,测量前扣带回皮质中的谷氨酸和谷氨酰胺。在4TMRS扫描仪中,对从ACC上的单个中线体素收集的数据进行模拟基组的光谱拟合,结果显示谷氨酸减少,但谷氨酰胺正常,仅在心境良好的强迫症患者中。抑郁的强迫症患者谷氨酸水平正常。这一意想不到的效果表明,这些经常并存的疾病之间存在着病理生理上的相互作用。它也可能是导致GLX已发表报告复制失败的一个变异性来源。我们建议复制和扩大这些发现。首先,我们将在更大的队列中重复我们的先导性研究,这段时间也包括未用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,我们将在纹状体进行谷氨酸和谷氨酰胺的测量,纹状体是与强迫症有关的另一个结构,在这种情况下,GLX异常(在这种情况下是升高的)被不一致地报告。然后,我们将调查这些脑神经化学测量方法预测药物治疗反应的能力;这样的关联将确定谷氨酸测量方法为一种潜在的临床有用的生物标记物,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患者兴奋性神经传递的区域特异性失调,重要的是加深我们对该疾病的神经化学的理解,同时探索一种新的、具有潜在临床实用价值的生物标志物的潜在用途。
公共卫生相关性:强迫症(OCD)很常见,通常很严重,现有的治疗方法不够充分;几条证据表明,这种疾病的神经递质谷氨酸可能受到干扰。我们使用磁共振波谱(MRS)来研究患者体内已知与强迫症相关的大脑区域的谷氨酸和相关神经递质的水平,以更好地了解基于谷氨酸的神经元信号的中断如何导致这种疾病。然后我们研究谷氨酸的这些异常如何预测治疗反应,最终目的是提供一种新的临床工具来指导治疗的选择。
项目成果
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Christopher John Pittenger其他文献
Christopher John Pittenger的其他文献
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{{ truncateString('Christopher John Pittenger', 18)}}的其他基金
Examining individual differences in large scale brain networks in individuals with OCD and their relations to heterogeneity of obsessive compulsive symptoms.
检查强迫症患者大规模大脑网络的个体差异及其与强迫症状异质性的关系。
- 批准号:
10624934 - 财政年份:2022
- 资助金额:
$ 35.48万 - 项目类别:
Anti-interneuron antibodies in rapid-onset pediatric OCD: clinical generalization and target identification
快速发作的儿科强迫症中的抗中间神经元抗体:临床概括和靶标识别
- 批准号:
10530955 - 财政年份:2022
- 资助金额:
$ 35.48万 - 项目类别:
Dysregulation of dopamine receptors in the basal ganglia in OCD and tic disorders: Positron Emission Tomography with [11C]-PHNO
强迫症和抽动障碍中基底神经节多巴胺受体的失调:[11C]-PHNO 正电子发射断层扫描
- 批准号:
10672999 - 财政年份:2022
- 资助金额:
$ 35.48万 - 项目类别:
Examining individual differences in large scale brain networks in individuals with OCD and their relations to heterogeneity of obsessive compulsive symptoms.
检查强迫症患者大规模大脑网络的个体差异及其与强迫症状异质性的关系。
- 批准号:
10527692 - 财政年份:2022
- 资助金额:
$ 35.48万 - 项目类别:
Dysregulation of dopamine receptors in the basal ganglia in OCD and tic disorders: Positron Emission Tomography with [11C]-PHNO
强迫症和抽动障碍中基底神经节多巴胺受体的失调:[11C]-PHNO 正电子发射断层扫描
- 批准号:
10501537 - 财政年份:2022
- 资助金额:
$ 35.48万 - 项目类别:
Patient Oriented Research and Mentorship and Training in Functional Neuroimaging of Obsessive-Compulsive Disorder
强迫症功能神经影像以患者为导向的研究、指导和培训
- 批准号:
10314023 - 财政年份:2020
- 资助金额:
$ 35.48万 - 项目类别:
Patient Oriented Research and Mentorship and Training in Functional Neuroimaging of Obsessive-Compulsive Disorder
强迫症功能神经影像以患者为导向的研究、指导和培训
- 批准号:
10535440 - 财政年份:2020
- 资助金额:
$ 35.48万 - 项目类别:
Anti-interneuron antibodies in abrupt-onset pediatric obsessive-compulsive disorder
突发性小儿强迫症中的抗中间神经元抗体
- 批准号:
9916831 - 财政年份:2019
- 资助金额:
$ 35.48万 - 项目类别:
Evidence accumulation in obsessive-compulsive disorder during perceptual and value-based decisions
在基于知觉和价值的决策过程中强迫症的证据积累
- 批准号:
9755518 - 财政年份:2018
- 资助金额:
$ 35.48万 - 项目类别:
Histamine Regulation of the Basal Ganglia and the Pathophysiology of Tics
基底神经节的组胺调节和抽动的病理生理学
- 批准号:
9288634 - 财政年份:2017
- 资助金额:
$ 35.48万 - 项目类别:
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