Pharmacological and electrical modulation of disturbed networks in schizophrenia and the clinical high-risk state for psychosis – Pharmacological modulation of an attentional network in the ketamine model of schizophrenia combined with multimodal EEG/fMRI

n -甲基- d -天冬氨酸受体（NMDAR）的功能似乎在精神分裂症的病理生理中起着重要作用。这种谷氨酸能受体功能低下与兴奋性/抑制性（E/I）失衡有关，这种失衡特别表现为伽马频率范围（30-100 Hz）振荡神经元活动的变化。同步诱发伽马活动在注意力和感知等认知功能中起着核心作用，在精神分裂症患者的听觉信息处理网络中表现出活动减少。氯胺酮诱导健康受试者NMDAR功能减退，并伴有短暂的精神分裂症样症状。此外，健康受试者也表现出与精神分裂症患者相似的伽马活动变化。这提供了一个独特的机会来调节精神分裂症氯胺酮模型中NMDAR共激动剂（如甘氨酸）的E/I失衡。迄今为止，尚未研究NMDAR调制对听觉信息处理网络的功能连通性和潜在通路的微观结构完整性的影响。因此，拟议研究项目的主要目标是研究NMDA受体调节对以下方面的影响：(I)额颞叶网络听觉信息处理过程中的功能（伽马波段）连通性（EEG和fMRI）； （II）网络组成部分之间的白质微结构完整性（以分数各向异性测量）；（III）这些变化之间可能的相互作用。为此，我们将分析28名健康男性受试者在执行听觉选择反应任务期间同时获得的EEG/fMRI和随后的DTI记录。在基线阶段，参与者将接受安慰剂输注作为预处理和任务执行期间。在随访中，EEG/fMRI数据收集与NMDAR神经传递的药理调节相结合，随后立即进行第二次DTI记录。在药理学调节期间，一半的参与者将接受甘氨酸预处理（n = 14），另一半将接受匹配的安慰剂（n = 14），在处理选择反应任务期间，两种预处理之后都持续注射亚麻醉氯胺酮。本项目的结果可能会扩展关于NMDAR功能障碍在信息处理中的作用及其受体协同激动剂的潜在治疗调节的知识。

N-methyl-D-aspartate receptor (NMDAR) function appears to contribute significantly to the pathophysiology of schizophrenia. Hypofunction of this glutamatergic receptor is associated with an excitatory/inhibitory (E/I) imbalance that is manifested inter alia in changes in oscillatory neuronal activity in the gamma frequency range (30-100 Hz). Synchronized evoked gamma activity plays a central role in cognitive functions such as attention and perception and exhibits reduced activity in an auditory information processing network in people with schizophrenia. Ketamine induces NMDAR hypofunction in healthy subjects, which is accompanied by transient schizophrenia-like symptoms. In addition, the healthy subjects also show changes in gamma activity comparable to patients with schizophrenia. This provides a unique opportunity to modulate E/I imbalance with NMDAR co-agonists (e.g., glycine) in the ketamine model of schizophrenia. To date, the effects of NMDAR modulation on the functional connectivity of the auditory information processing network and the microstructural integrity of the underlying pathways have not been investigated. Accordingly, the main goal of the proposed research project is to investigate the effects of NMDA receptor modulation on: (I) functional (gamma band) connectivity (EEG and fMRI) during auditory information processing in a fronto-temporal network and (II) white matter microstructural integrity (measured as fractional anisotropy) between components of the network and (III) a possible interplay between these changes. For this purpose, simultaneous EEG/fMRI acquired during performance of an auditory choice reaction task and subsequent DTI recordings from 28 healthy male subjects will be analyzed. In a baseline session, participants will each receive placebo infusions as pretreatment and during task performance. At a follow-up visit, EEG/fMRI data collection is combined with pharmacological modulation of NMDAR neurotransmission, which is immediately followed by a second DTI recording. During the pharmacological modulation, half of the participants will receive glycine pretreatment (n = 14) and the other half will receive matching placebo (n = 14), with both pretreatments followed by a continuous subanesthetic ketamine infusion during the processing of the choice response task. The results of this project may expand knowledge regarding the role of NMDAR hypofunction in information processing and its potential therapeutic modulation by receptor co-agonists.