Magnetic Resonance Spectroscopy in the Psychosis Risk Syndrome

描述(由申请人提供)：精神病的概念在最近几十年发生了变化，国际上为识别和治疗精神病高危青年所做的密集努力以及新出现的数据表明，普通人群中出现了亚临床精神病症状。患有“减弱型精神病综合症”(APS)的患者除了言语/行为混乱、主观苦恼和临床求助外，还存在较低程度的现实扭曲(异常思维内容、知觉异常、怀疑/偏执)。这种综合征是精神分裂症的典型持续表现，是研究APS和精神分裂症共同的病理生理机制的关键机会。抑制性GABA能和兴奋性谷氨酸能系统可能是一个重要的潜在机制。磁共振波谱(MRS)使得能够对GABA和谷氨酸/谷氨酰胺浓度进行区域性测量，从而能够在体内对这些神经递质进行分析。未经药物治疗的精神分裂症患者显示内侧前额叶皮质(MPFC)的GLX(谷氨酸/谷氨酰胺浓度)和GABA水平升高，这是大脑的一个区域，与精神分裂症和APS的功能和结构成像研究有关。我们发现，在慢性精神病患者中，mPFC对苯二氮卓类药物的挑战表现出更高的敏感性，这表明GABA能异常。一个关键的问题是，是否可以在APS状态下检测到这些异常，这项探索性的R21方案将通过测量APS患者的皮质GABA和GLX来解决这一问题，并与匹配的健康对照组和首发精神病(FEP)患者进行比较。在目标1中，我们将检测APS患者在mPFC和枕叶皮质中的GABA和GLX水平，测试相对于健康对照组和药物治疗的FEP患者，在mPFC中APS患者的GABA和GLX水平将升高的预测。相比之下，在APS和FEP受试者的枕叶皮质中，GABA和GLX预计都会减少。在目标2中，我们将评估APS个体的mPFC功能，并测试与同一区域的GABA能和GLX信号的相关性。我们预测，在APS患者(但不是药物治疗的FEP患者)中，GABA能信号和GLX信号将与mPFC BOLD信号呈负相关。这种R21的预期影响有三个方面：1)在R01级别的提案可以检查基线GABA和GLX作为结果预测因子(转化为精神病和临床改善)之前，必需的第一步；2)将检查GABA和Glu的变化及其与结果的关联的纵向研究的必要第一步；以及3)设计针对APS中GABA/GLX系统的治疗干预的机械原理。

DESCRIPTION (provided by applicant): The concept of psychosis has shifted in recent decades, as evidenced by an intensive international effort aimed at identifying and treating youth at high risk of psychosis and emerging data that subclinical psychotic symptoms appear in the general population. Individuals with an 'attenuated psychosis syndrome' (APS) present with low levels of reality distortion (unusual thought content, perceptual aberrations, suspiciousness/paranoia), in addition to disorganized speech/behavior, subjective distress and clinical help- seeking. The syndrome is phenotypically continuous with schizophrenia and a critical opportunity in which to study pathophysiological mechanisms that may be common to both APS and schizophrenia. One important potential mechanism may be found in inhibitory GABAergic and excitatory glutamatergic systems. Magnetic resonance spectroscopy (MRS) has enabled the regional measurement of GABA and glutamate/glutamine concentrations, permitting the in vivo assay of these neurotransmitters. Unmedicated patients with schizophrenia have shown elevations of Glx (glutamate/glutamine concentration) and GABA levels in the medial prefrontal cortex (mPFC), a region of the brain implicated in functional and structural imaging studies in schizophrenia and APS. We found the mPFC to exhibit greater sensitivity to benzodiazepine challenge in chronic psychotic patients, suggesting that GABAergic abnormalities. A critical question is whether these abnormalities may be detected in the APS state, which this exploratory R21 proposal will address by measuring cortical GABA and Glx in young persons with APS, compared to matched healthy control subjects and first episode psychosis (FEP) patients. In Aim 1, we will examine GABA and Glx levels in APS individuals in the mPFC and occipital cortex, testing the prediction that GABA and Glx levels will be elevated in APS subjects in the mPFC, relative to healthy controls and medicated FEP patients. In contrast, GABA and Glx are predicted to be reduced in the occipital cortex of both APS and FEP subjects. In Aim 2, we will assess mPFC function in APS individuals and test correlations with GABAergic and Glx signal from this same region. We predict that GABAergic and Glx signals will be inversely correlated with mPFC BOLD signal in the APS patients (but not medicated FEP patients). The anticipated impact of this R21 is three-fold: 1) An essential first step required before an R01-level proposal can examine baseline GABA and Glx as predictors of outcome (conversion to psychosis as well as clinical improvement), 2) An essential first step for a longitudinal study that will examine change in GABA and Glu and associations with outcome; and 3) A mechanistic rationale for designing therapeutic interventions that target GABA/Glx systems in APS.