Prediction of treatment response and course of disease in schizophrenia using EEG high frequency oscillations as a correlate of glutamatergic neurotransmission

最近，兴奋和抑制(E/I平衡)之间的失衡导致兴奋性升高，这与精神分裂症的病理生理学有关。E/I平衡被认为关键依赖于一种电路机制，该机制涉及抑制性GABA能和兴奋性谷氨酸能信号。支持这一假设的关键证据来自动物模型、基因工作、尸检研究、患者的神经成像研究、谷氨酸能治疗效应和精神分裂症的药物模型。申请人之前关于精神分裂症不同阶段高频振荡活动(听觉诱发伽马频段反应减少)的脑电图(EEG)工作也有助于这一证据，因为涉及小白蛋白阳性GABA能中间神经元和谷氨酸能锥体细胞的微电路对伽马振荡的产生起着关键作用。伽玛振荡改变的逆转已被证明是抗精神病活性的预测，氯氮平在动物工作中有独特的特征。然而，到目前为止，还没有研究通过结合使用7-特斯拉的高MR场强对GABA/谷氨酸浓度的磁共振波谱(MRS)测量、任务诱发的EEG测量以及持续的静息状态伽马振荡以及氯氮平的药物调节对这些测量的影响来全面解决精神分裂症患者单一队列中这些发现之间的关系。因此，本提案旨在整合关于谷氨酸和GABA浓度的MRS研究、来自EEG关于高频伽马振荡的研究以及关于氯氮平治疗精神分裂症患者的谷氨酸能效应的研究结果。与以前的研究相比，墨尔本脑中心使用7-特斯拉的MR磁场强度将提高MRS在检测代谢物谷氨酸、GABA和谷胱甘肽方面的准确性。该提案希望有助于更好地了解精神分裂症病理生理学中E/I失衡的变化。例如，将相同受试者的脑电伽马测量与体内谷氨酸和GABA测量联系起来，被认为可以进一步揭示精神分裂症患者静息状态增加和任务诱发伽马振荡活动减少之间明显矛盾的本质。此外，该提案希望有助于开发新的生物标记物，用于预测谷氨酸能治疗策略的治疗反应。如果与体内谷氨酸和GABA的测量直接相关，脑电高频振荡作为神经传递的相关指标，在未来的临床常规中可能是一种与MRS相比廉价且易于应用的替代方案。最后，建议的研究旨在检验静息状态伽马网络改变在预测精神病病程中的适用性。

Recently, an imbalance between excitation and inhibition (E/I-balance) towards elevated excitability has been implicated in the pathophysiology of schizophrenia. The E/I-balance is thought to be crucially dependent on a circuit mechanism involving inhibitory GABAergic and excitatory glutamatergic signaling. Critical evidence supporting this assumption comes from animal models, genetic work, postmortem studies, neuroimaging studies in patients, glutamatergic treatment effects and pharmacological models of schizophrenia. The applicant’s previous electroencephalography (EEG) work on altered high-frequency oscillatory activity (reduction of the auditory evoked gamma-band response) in different stages of schizophrenia also contributes to this evidence, as the microcircuit involving parvalbumin-positive GABAergic interneurons and glutamatergic pyramidal cells plays a crucial role for the generation of gamma oscillations. The reversal of gamma oscillation alterations has been shown to be predictive of antipsychotic activity with a unique profile for clozapine in animal work. However, to date, no study has comprehensively addressed the relationship between these findings in a single cohort of schizophrenia patients by combining magnetic resonance spectroscopy (MRS) measurements of GABA/glutamate concentrations utilizing a high MR field strength of 7-Tesla, EEG measurements of task evoked as well as ongoing resting state gamma oscillations and effects of pharmacological modulation with clozapine on these measures. Thus, the present proposal aims to integrate findings from MRS studies on glutamate and GABA concentrations, from EEG studies on high frequency gamma oscillations and about glutamatergic effects of clozapine treatment in schizophrenia patients. Using MR field strength of 7-Tesla at the Melbourne Brain Centre will improve the accuracy of MRS in examining the metabolites glutamate, GABA and glutathione compared to previous studies. The proposal wants to contribute to a better understanding of alterations of the E/I-imbalance in the pathophysiology of schizophrenia. For instance, linking EEG gamma measures and in vivo measures of glutamate and GABA of identical subjects is supposed to further reveal the nature of the apparent contradiction between increased resting state and diminished task evoked gamma oscillatory activity in schizophrenia. Furthermore, the proposal wants to contribute to the development of new biological markers for the prediction of treatment response to glutamatergic treatment strategies. If directly related to in vivo measures of glutamate and GABA, EEG high frequency oscillations as a correlate of neurotransmission might be a cheap and easily applicable alternative compared to MRS in future clinical routine. Finally, the proposed research aims to examine the applicability of resting state gamma network alterations in the prediction of the course of psychosis.