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

精神分裂症和临床精神病高危状态中受干扰网络的药理学和电调节 â 精神分裂症氯胺酮模型中注意力网络的药理学调节结合多模态 EEG/fMRI

• 批准号: 522570761
• 负责人: Moritz Nils Haaf, Ph.D.
• 金额: --
• 依托单位: Klinik und Poliklinik für Psychiatrie und Psychotherapie
• 依托单位国家: 德国
• 项目类别: WBP Fellowship
• 财政年份: 2023
• 资助国家: 德国
• 起止时间: 2022-12-31 至 无数据
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/522570761?language=en
• 关键词: Pharmacological; electrical; modulation; disturbed; networks

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.

N-甲基-D-天冬氨酸受体（NMDAR）的功能似乎有助于显着精神分裂症的病理生理。这种多巴胺能受体的功能减退与兴奋性/抑制性（E/I）不平衡有关，该不平衡阿利亚表现为γ频率范围（30-100 Hz）内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，并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的NMDAR功能减退，伴有短暂的精神分裂症样症状。此外，健康受试者也显示出与精神分裂症患者相当的γ活性变化。这提供了用NMDAR共激动剂（例如，甘氨酸）在精神分裂症的氯胺酮模型中的作用。迄今为止，NMDAR调制对听觉信息处理网络的功能连接性和潜在通路的微结构完整性的影响尚未被研究。因此，拟议的研究项目的主要目标是调查NMDA受体调制的影响：（一）功能（γ波段）连接（EEG和功能磁共振成像）在听觉信息处理的额颞网络和（二）白色物质微结构的完整性（测量为分数各向异性）之间的组件的网络和（三）这些变化之间可能的相互作用。为此目的，同时EEG/fMRI获得的听觉选择反应任务的性能和随后的DTI记录从28名健康男性受试者进行分析。在基线阶段，每个参与者将接受安慰剂输注作为治疗前和任务执行期间。在随访时，EEG/fMRI数据收集与NMDAR神经传递的药理学调节相结合，随后立即进行第二次DTI记录。在药理学调节期间，一半受试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），两种预处理后在选择反应任务处理期间连续亚麻醉氯胺酮输注。这个项目的结果可能会扩大知识的作用，NMDAR功能减退的信息处理和其潜在的治疗调制受体共激动剂。