Temporal dynamics of neurophysiological patterns as treatment targets in Sz

本项目响应PAR 14-153，作为潜在的神经生理模式的时间动力学 治疗大脑疾病认知缺陷的目标。正如RFA中所描述的，丰富的证据 这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、它们在频带上的共调制、尖峰-相位相关性 尖峰种群动态和其他模式可能是治疗发展的有用驱动因素 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 经颅直流电刺激效果的灵长类(NHP)研究 (Tdcs)/经颅交流电刺激(Tacs)对听觉神经振荡模式的影响 精神分裂症的认知障碍(Sz)，特别强调theta和delta区的障碍 相位重置机制和增量/伽马相位幅度耦合。此外，它还评估了N-的作用 甲基-D-天冬氨酸受体(NMDAR)在Sz振荡功能障碍发病机制中的作用 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。该项目通过映射潜在的神经振荡模式来解决RFA的主题1 使用平行的人类和NHP研究的SZ听觉信息处理受损；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神经振荡功能的影响；主题4，通过评估相对 应用神经计算地形图研究高清晰度(HD-tDC)和常规tDC的影响 接近了。该项目包括在人类和NHP中进行主动操作，并进行特定的测试 关于低频(Delta，theta)振荡和交叉频率(例如，Delta/Gamma)的假设 相位-幅度耦合损害是Sz患者神经认知损害的基本机制。这个 记录方法使用多通道表面/颅内电极直接检测脑组织的神经活动 分别是人类和NHP，并使用脑电数据的频谱分析以及定量 作为主要结果变量的行为测量。听觉功能障碍，反映在 行为和失配负波(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对全球功能结果做出贡献 对幻听、语音处理障碍和社会认知等过程的研究。 此外，MMN代缺陷预示着高危个体会转化为精神病。这个 建议的刺激方法包括HD-TDC和Delta频率TAC，非常新颖，将 不仅对Sz的神经认知功能障碍有直接的、真实的影响，而且对相关形式的 相关相关神经精神障碍的神经认知障碍。

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.