Magnetic Resonance Spectroscopy in the Psychosis Risk Syndrome

描述（由申请人提供）：近几十年来，精神病的概念已经发生了变化，这一点可以从旨在识别和治疗精神病高危青年的密集国际努力以及在一般人群中出现亚临床精神病症状的新数据中得到证明。患有“弱化精神病综合征”（APS）的个体除了言语/行为紊乱、主观痛苦和临床求助外，还表现出低水平的现实扭曲（不寻常的思想内容、知觉偏差、怀疑/偏执）。该综合征与精神分裂症在表型上是连续的，并且是研究APS和精神分裂症可能共同的病理生理机制的关键机会。一个重要的潜在机制可能存在于抑制性GABA能和兴奋性谷氨酸能系统中。磁共振波谱（MRS）已使GABA和谷氨酸/谷氨酰胺浓度的区域测量，允许这些神经递质的体内测定。未经药物治疗的精神分裂症患者显示内侧前额叶皮质（mPFC）中Glx（谷氨酸/谷氨酰胺浓度）和GABA水平升高，这是精神分裂症和APS功能和结构成像研究中涉及的大脑区域。我们发现慢性精神病患者的mPFC对苯二氮卓类药物激发表现出更大的敏感性，这表明GABA能异常。一个关键问题是这些异常是否可以在APS状态下检测到，这一探索性的R21建议将通过测量APS年轻人的皮质GABA和Glx来解决，与匹配的健康对照受试者和首发精神病（FEP）患者相比。在目标1中，我们将检查APS个体mPFC和枕叶皮质中的GABA和Glx水平，测试APS受试者mPFC中GABA和Glx水平相对于健康对照和药物治疗的FEP患者升高的预测。相比之下，GABA和Glx被预测为减少在APS和FEP受试者的枕叶皮质。在目标2中，我们将评估APS个体的mPFC功能，并测试与来自同一区域的GABA能和Glx信号的相关性。我们预测，GABA能和Glx信号将与APS患者的mPFC BOLD信号呈负相关（但不包括药物治疗的FEP患者）。该R21的预期影响有三个方面：1）在R 01级提案可以检查基线GABA和Glx作为结果预测因子之前，需要迈出重要的第一步（转化为精神病以及临床改善），2）纵向研究的重要第一步，该研究将检查GABA和Glu的变化以及与结果的关联;和3）设计针对APS中GABA/Glx系统的治疗干预的机制原理。

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.