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

GABA-谷氨酸相互作用作为抑郁症和精神分裂症脑静息态功能障碍的神经化学基础：7特斯拉多模态成像项目

• 批准号: 280244082
• 负责人: Professor Dr. Jürgen Gallinat
• 金额: --
• 依托单位: Fachbereich 8.1 - Biomedizinische Magnetresonanz
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/280244082?language=en
• 关键词: GABA; glutamate; interaction; neurochemical; basis

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.

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，以确定局部谷氨酸和GABA浓度的非侵入性，在人体内的大脑。由于难以可靠地定量Glu，特别是GABA，因此将投入大量精力来优化相应的MRS方法。为了克服低B0场（1.5和3特斯拉）的灵敏度限制，我们提出利用7特斯拉超高场强下的增强灵敏度用于MRS和功能磁共振成像（fMRI）。在30名未接受药物治疗的抑郁症患者、30名未接受药物治疗的精神分裂症患者和60名健康对照者中，将以7特斯拉的频率进行磁共振测量。在同一会议上，静息状态fMRI将针对这两种疾病的另一个病理生物学特征，即抑郁症的腹内侧前额叶皮层（vmPFC）过度激活和精神分裂症的低激活（k<s:1> hn & Gallinat 2013; schizophrenia Bull）。功能失调的vmPFC激活将在fMRI获取期间进一步以自我参照范式表征，以预测两种疾病的临床症状特征。该项目特别关注神经化学和功能性脑障碍作为两种主要精神疾病的核心病理机制的耦合。根据我们之前的工作，我们假设在感兴趣的区域，vmPFC：(1)与对照组相比，抑郁症患者谷氨酸升高，GABA浓度降低，静息状态高激活；(2)与健康对照相比，精神分裂症患者谷氨酸降低，GABA浓度升高，静息状态低激活；(3)谷氨酸浓度与静息状态活性呈正相关，GABA呈反比关系。(4)自我相关加工激活与重度抑郁症患者的反刍严重程度呈正相关，与精神分裂症患者的洞察力呈负相关。该项目将阐明两种关键神经递质系统在精神病和情感障碍及其功能后果中的病理生物学作用，允许在两种诊断实体中识别生物亚群，为未来的药物治疗建立除当前功能失调神经调节剂（如血清素）模型之外的知识，并将有助于开发7特斯拉的MRS方法，为超高B0的应用铺平道路。

项目成果

Assessment of measurement precision in single‐voxel spectroscopy at 7 T: Toward minimal detectable changes of metabolite concentrations in the human brain in vivo

7 T 下单体素光谱测量精度的评估：实现人脑体内代谢物浓度的最小可检测变化

• DOI: 10.1002/mrm.29034
• 发表时间: 2022
• 期刊: Magnetic Resonance in Medicine
• 影响因子: 3.3
• 作者: Layla Tabea Riemann;Christoph Stephan Aigner;Stephen L.R. Ellison;Rüdiger Brühl;Ralf Mekle;Sebastian Schmitter;Oliver Speck;Georg Rose;Bernd Ittermann;Ariane Fillmer
• 通讯作者: Ariane Fillmer