Early Cortical Processing in Schizophrenia

描述（由申请人提供）：精神分裂症（Sz）与认知功能缺陷相关，这是该疾病的核心特征。传统的多巴胺能模型强调高级关联脑区域内的功能障碍。相比之下，最近的神经元模型预测广泛的功能障碍，包括初级和次级感觉皮层。在过去的项目期间，我们已经记录了赤字的早期听觉和视觉处理的SZ使用行为，事件相关电位（ERP）和MRI为基础的方法，支持分布式模型的皮质功能障碍的SZ。此外，我们已经证明了早期感觉处理缺陷的显着贡献高阶皮层损伤。这些研究使我们能够制定具体的假设，神经机制的感觉/认知功能障碍的SZ，以及新的方法，潜在的治疗发展。在听觉系统中，早期缺陷包括短暂延迟后匹配音调的能力受损，以及失配负波（MMN）、听觉N1和听觉稳态（ASSR）反应的产生受损。此外，低水平听觉处理的缺陷导致高阶功能障碍，例如解释韵律的能力受损，导致听觉情感识别（AER）的缺陷，这反过来又导致社会功能受损。在视觉系统中，缺陷包括对比敏感度降低，特别是对优先参与大细胞视觉系统的低对比度、低空间频率（LSF）刺激的对比敏感度降低，以及稳态视觉诱发电位（ssVEP）、视觉P1的产生受损，以及初级视觉皮层的大细胞受体区域的fMRI激活受损。低水平的缺陷有助于高阶损伤，包括知觉闭合和面部情绪识别（FER）。听觉和视觉缺陷均导致阅读能力的进行性损害，这可能是Sz的早期标志。最后，听觉和视觉缺陷与低水平感觉区域内的结构和功能连接受损相关，如使用扩散张量（DTI）和静息状态（rsfMRI）成像所评估的。迄今为止，神经生理学异常主要使用时域方法进行评估。在接下来的一段时间里，我们将结合先进的频域和振荡层次的方法，以及，提供单独的指数的自发和事件相关的动态神经元振荡。视觉ERP将与眼动追踪相结合，以评估自然场景处理。我们还将探索功能障碍的模式，前驱期和首次发作（FE）队列使用范式验证在我们以前的资助周期。最后，我们将结合新的脑刺激方法，包括经颅磁刺激（rTMS），应用于感觉与额叶皮层区域，以破坏健康对照的局部处理，作为模型， Sz;和经颅直流电刺激（tDCS）应用于感觉或额叶脑区作为Sz的可塑性为基础的刺激干预的前奏。

DESCRIPTION (provided by applicant): Schizophrenia (Sz) is associated with deficits in cognitive function that represent a core feature of the disorder. Traditional dopaminergic models stress dysfunction within higher order associational brain regions. In contrast, more recent glutamatergic models predict widespread dysfunction across cortical regions, including primary and secondary sensory cortices. Over the past project period, we have documented deficits in early auditory and visual processing in Sz using behavioral-, event-related potential (ERP) and MRI-based approaches, supporting distributed models of cortical dysfunction in Sz. In addition, we have demonstrated significant contributions of early sensory processing deficits to higher order cortical impairments. These studies have permitted us to formulate specific hypotheses concerning neural mechanisms underlying sensory/cognitive dysfunction in Sz, as well as novel approaches to potential treatment development. In the auditory system, early deficits include impaired ability to match tones following brief delay, as well as impaired generation of mismatch negativity (MMN), auditory N1 and auditory steady-state (ASSR) responses. Furthermore, deficits in low level auditory processing contribute to higher order dysfunction, such as impaired ability to interpret prosody, leading to deficits in auditory emotion recognition (AER), which, in turn, contributes to impaired social function. In the visual system, deficits include reduced contrast sensitivity particularly to low contrast, low spatial frequency (LSF) stimuli that preferentially engage the magnocellular visual system, as well as impaired generation of steady state visual evoked potentials (ssVEP), visual P1, and impaired fMRI activation of magnocellular-recipient regions of primary visual cortex. Low level deficits contribute to higher order impairments including in perceptual closure and face emotion recognition (FER). Both auditory and visual deficits contribute to progressive impairment in reading ability, which may be an early marker of Sz. Finally, both auditory and visual deficits correlate with impaired structura and functional connectivity within low level sensory regions, as assessed using diffusion tensor (DTI) and resting state (rsfMRI) imaging. To date, neurophysiological abnormalities have been assessed mainly using time-domain approaches. Over the upcoming period, we will incorporate advanced frequency-domain and oscillatory hierarchical approaches as well, which provide separate indices of spontaneous and event-related dynamics of neuronal oscillations. Visual ERP will be combined with eye tracking to permit evaluation of naturalistic scene processing. We will also explore patterns of dysfunction within both prodromal and first episode (FE) cohorts using paradigms validated during our prior grant cycle. Finally, we will incorporate novel brain stimulation approaches including Transcranial Magnetic Stimulation (rTMS) applied over sensory vs. frontal cortical regions to disrupt local processing in healthy controls as a model for Sz; and transcranial Direct Current Stimulation (tDCS) applied over sensory or frontal brain regions as a prelude to plasticity-based stimulatory intervention in Sz.