GABA-glutamate interaction as neurochemical basis of cerebral resting-state dysfunction in depression and schizophrenia: A 7 tesla multimodal imaging project

在抑郁症和精神分裂症中，谷氨酸（Glu）和γ-氨基丁酸（GABA）系统的功能障碍被认为是这些疾病的重要神经化学特征。质子磁共振波谱（MRS）提供了独特的可能性，以确定当地的谷氨酸和GABA浓度非侵入性，在体内人脑。由于仍然难以可靠地量化Glu，特别是GABA，因此将投入大量精力来优化相应的MRS方法。为了克服较低的B 0场（1.5和3特斯拉）的灵敏度限制，我们建议利用增强的灵敏度在7特斯拉的磁共振波谱和功能性磁共振成像（fMRI）的磁场强度。在30名未用药的抑郁症患者、30名未用药的精神分裂症患者和60名健康对照者中，将在7特斯拉下进行MRS测量。在同一阶段，静息态fMRI将针对这两种疾病的另一个病理生物学特征，即抑郁症中的腹内侧前额叶皮层（vmPFC）过度激活和精神分裂症中的低激活（Kühn & Gallinat 2013; Schizophr Bull）。功能障碍的vmPFC激活将进一步表征与fMRI采集过程中的自我参照范式，以预测这两种疾病的临床症状。该项目特别关注神经化学和功能性脑障碍的耦合，作为两种主要精神疾病的核心病理机制。基于我们之前的工作，我们假设在感兴趣的区域中，vmPFC：（1）与对照组相比，抑郁症患者显示出谷氨酸盐增加和GABA浓度降低以及静息状态超活化，（2）与健康对照组相比，精神分裂症患者具有谷氨酸盐减少和GABA浓度增加以及静息状态低活化，谷氨酸浓度与静息态活动呈正相关，GABA浓度与静息态活动呈负相关。(4)抑郁症患者自我相关加工的激活与沉思的严重程度呈正相关，而精神分裂症患者自我相关加工的激活与自知力呈负相关。该项目将阐明精神病和情感障碍的两个关键神经递质系统的病理生物学作用及其功能后果，允许在两个诊断实体中识别生物亚组，建立未来药物治疗的知识，除了目前功能失调的神经调节剂模型。（例如血清素），并将有助于开发7特斯拉的MRS方法，为在TIB 0的应用铺平道路。

In depression and schizophrenia, dysfunctions in the glutamate (Glu) and gamma-amino-butyric acid (GABA) systems have been postulated as important neurochemical characteristics of the disorders. Proton magnetic resonance spectroscopy (MRS) offers the unique possibility to determine local glutamate and GABA concentrations non-invasively, in vivo in the human brain. Since it remains difficult to reliably quantify Glu and, especially GABA, significant efforts will be invested to optimize the corresponding MRS methodology. To overcome the sensitivity constraints of lower B0 fields (1.5 and 3 tesla) we propose to take advantage of the enhanced sensitivity at the ultrahigh field strength of 7 tesla for MRS and functional magnetic resonance imaging (fMRI). In 30 unmedicated depressive patients, 30 unmedicated schizophrenic patients and 60 healthy controls, MRS measurements will be carried out at 7 tesla. In the same session, resting-state fMRI will target another pathobiological characteristic of both diseases, namely ventromedial prefrontal cortex (vmPFC) hyperactivations in depression and hypoactivations in schizophrenia (Kühn & Gallinat 2013; Schizophr Bull). Dysfunctional vmPFC activation will be further characterized with a self-referential paradigm during fMRI acquisition to predict clinical symptom profil of both diseases. The project focuses particularly the proposed coupling of neurochemical and functional cerebral disturbance as a core pathomechanism of two major psychiatric diseases. Based on our previous work we hypothesize that in the region of interest, the vmPFC: (1) depressed patients show increased glutamate and decreased GABA concentrations together with resting-state hyperactivation compared to controls, (2) schizophrenic patients have decreased glutamate and increased GABA concentrations together with resting state hypoactivation compared to healthy controls, and (3) the concentration of glutamate is positively correlated with resting-state activity while GABA shows an inverse relationship. (4) the activation during self-related processing is positively correlated with severity of ruminations in major depression and negatively associated with insight in schizophrenic patients. The project will clarify the pathobiological role of two crucial neurotransmitter systems for psychotic and affective disorders and their functional consequences, allows the identification of biological subgroups within the two diagnostic entities, establishes the knowledge for future pharmacotherapy apart from current models of dysfunctional neuromodulators (e.g. serotonin), and will help to develop MRS methodology at 7 tesla to pave the way for applications at ultrahigh B0.