Temporal dynamics of neurophysiological patterns as treatment targets in Sz

作为 Sz 治疗目标的神经生理模式的时间动态

• 批准号: 9055968
• 负责人: DANIEL C. JAVITT
• 金额: $ 80.45万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9055968
• 关键词: Address; Affect; Animal Model; Anodes; Attention; Auditory; Auditory Hallucination; Behavioral; Brain; Brain Diseases; Brain region; Cathodes; Clinical; Clinical Treatment; Cognition; Cognitive; Cognitive deficits; Computer Simulation; Coupling; Data; Detection; Effectiveness; Electrical Stimulation of the Brain; Electrodes; Electroencephalography; Etiology; Event-Related Potentials; Frequencies; Functional disorder; Future; Generations; Glutamate Receptor; Grant; Head; Human; Impaired cognition; Impairment; Individual; Injection of therapeutic agent; Intervention; Intervention Studies; Investigation; Ketamine; Lead; Maps; Mental disorders; Methods; Modality; Modeling; Molecular Abnormality; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurocognition; Neurocognitive; Neurocognitive Deficit; Neuronal Dysfunction; Neurons; Pattern; Phase; Pilot Projects; Play; Population Dynamics; Process; Psychotic Disorders; Regulation; Risk; Role; Schizophrenia; Sensory; Stimulus; Stream; Structure; Surface; System; Testing; Thalamic structure; Translating; Visual attention; attentional control; base; behavior measurement; cognitive function; cognitive process; effective intervention; functional outcomes; improved; information processing; neural patterning; neurophysiology; neuropsychiatric disorder; neuropsychiatry; nonhuman primate; novel; novel strategies; phonology; primary outcome; receptor; relating to nervous system; segregation; social cognition; stimulus processing; therapeutic development

This project responds to PAR 14-153, Temporal Dynamics of Neurophysiological Patterns as Potential Targets for Treating Cognitive Deficits in Brain Disorders.  As described in the RFA, a rich body of evidence suggests that cognitive processes are associated with particular patterns of neural activity. These data indicate that oscillatory rhythms, their co-modulation across frequency bands, spike-phase correlations, spike population dynamics, and other patterns might be useful drivers of therapeutic development for cognitive improvement in neuropsychiatric disorders. This project uses parallel human and non-human primate (NHP) investigations to evaluate effects of transcranial direct current stimulation (tDCS)/transcranial alternating current stimulation (tACS) on neural oscillatory patterns underlying auditory cognitive impairments in schizophrenia (Sz), with particular emphasis on impairments in theta and delta phase reset mechanisms and delta/gamma phase amplitude coupling. In addition it evaluates the role of N- methyl-D-aspartate receptors (NMDAR) in the etiology of oscillatory dysfunction in Sz, as well as the ability of tDCS/tACS to reverse NMDAR antagonist-induced impairments in NHP as a model for future therapeutic development. The project addresses Topic 1 of the RFA by mapping neuro-oscillatory patterns underlying impaired auditory information processing in Sz using parallel human and NHP studies; Topic 2 by investigating mechanisms underlying NMDAR antagonist-induced effects; Topic 3 by evaluating tDCS/tACS effects on neuro-oscillatory function in both NHP and Sz; and Topic 4 by evaluating relative effects of high definition (HD-tDCS) and conventional tDCS using neurocomputational mapping approaches. The project includes active manipulations in both humans and NHP, and tests specific hypotheses regarding low frequency (delta, theta) oscillation and cross-frequency (e.g. delta/gamma) phase-amplitude coupling impairments as a basic mechanism of neurocognitive impairment in Sz. The recording methods detect neural activity directly using multichannel surface/intracranial electrodes in humans and NHP, respectively, and employ spectral analyses of EEG data along with quantitative behavioral measures as the primary outcome variables. Auditory dysfunction, as reflected both behaviorally and by impaired generation of mismatch negativity (MMN) and other auditory potentials is a prominent and severe feature of Sz and contributes directly to global functional outcome via direct impact on processes such as auditory hallucinations, phonological processing impairments and social cognition. Deficits in MMN generation, moreover, predict conversion to psychosis among at risk individuals. The proposed stimulation approaches including HD- tDCS and delta frequency tACS are highly novel and will have direct, real-world impact not only on neurocognitive dysfunction in Sz, but also on related forms of neurocognitive impairments across relevant associated neuropsychiatric disorders.

本项目响应PAR 14-153，神经生理模式的时间动力学作为潜力 治疗脑疾病认知缺陷的靶点。正如RFA所描述的， 表明认知过程与特定的神经活动模式有关。这些数据 表明振荡节律、它们跨频带的共同调制、尖峰相位相关性 尖峰群体动态和其他模式可能是治疗发展的有用驱动力， 神经精神障碍的认知改善。这个项目使用平行的人类和非人类 评价经颅直流电刺激效果的灵长类动物（NHP）研究 （tDCS）/经颅交流电刺激（tACS）对听觉神经振荡模式的影响 精神分裂症（Sz）的认知障碍，特别强调θ和δ的障碍 相位复位机制和δ/γ相位幅度耦合。此外，它还评估了N- 甲基-D-天冬氨酸受体（NMDAR）在Sz振荡功能障碍病因学中的作用，以及 tDCS/tACS逆转NMDAR拮抗剂诱导的NHP损伤作为未来治疗的模型 发展该项目通过映射神经振荡模式来解决RFA的主题1， Sz的听觉信息处理受损，使用平行的人类和NHP研究;主题2， 研究NMDAR拮抗剂诱导效应的潜在机制;主题3通过评估 tDCS/tACS对NHP和Sz的神经振荡功能的影响;以及通过评估相对 使用神经计算映射的高清（HD-tDCS）和传统tDCS的影响 接近。该项目包括在人类和NHP中的主动操作，并测试特定的 关于低频（δ，θ）振荡和交叉频率（例如δ/γ）的假设 相位振幅耦合损伤作为神经认知功能障碍的基本机制。的 记录方法直接使用多通道表面/颅内电极检测神经活动， 人类和NHP，分别采用EEG数据的频谱分析沿着定量 行为测量作为主要结果变量。听觉功能障碍，反映了 行为和不匹配负波（MMN）和其他听觉电位的产生受损是一种 Sz的突出和严重特征，并通过直接影响直接影响全球功能结局 对幻听、语音处理障碍和社会认知的影响。 此外，MMN生成的缺陷可以预测高危个体向精神病的转化。的 包括HD-tDCS和Δ频率tACS的建议刺激方法是非常新颖的， 不仅对Sz的神经认知功能障碍有直接的，现实世界的影响，而且对相关形式的 相关的神经精神障碍中的神经认知障碍。