Early Cortical Processing in Schizophrenia

精神分裂症的早期皮质处理

• 批准号: 8908263
• 负责人: DANIEL C. JAVITT
• 金额: $ 10.87万
• 依托单位: NATHAN S. KLINE INSTITUTE FOR PSYCH RES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-03 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8908263
• 关键词: Auditory; Auditory system; Behavioral; Brain; Brain region; Cognitive; Cognitive deficits; Cognitive remediation; Complex; Contrast Sensitivity; Coupling; Detection; Diffusion; Disease; Electroencephalography; Emotions; Evaluation; Event; Event-Related Potentials; Eye; Face; Facial Expression; Frequencies; Functional Magnetic Resonance Imaging; Functional disorder; Future; Generations; Glutamates; Grant; Health; Image; Impaired cognition; Impairment; Individual; Intervention; Lead; Magnetic Resonance Imaging; Measures; Modeling; Neurons; Patients; Pattern; Perceptual Closure; Phase; Population; Process; Reading; Rest; Schizophrenia; Sensory; Sensory Process; Social Functioning; Speech; Stimulus; Stress; Therapeutic; Transcranial magnetic stimulation; Visual; Visual Motion; Visual evoked cortical potential; Visual system structure; Voice; area striata; base; cognitive function; cohort; disability; functional outcomes; improved; indexing; insight; magnocellular; neuromechanism; neurophysiology; neuropsychiatry; novel; novel strategies; reading ability; response; sensory cortex; social cognition; therapy development; time use; tool; visual process; visual processing

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.

描述(由申请人提供)：精神分裂症(Sz)与认知功能缺陷有关，这是该疾病的核心特征。传统的多巴胺能模型强调高阶联想脑区的功能障碍。相比之下，较新的谷氨酸能模型预测了广泛的皮质区域功能障碍，包括初级和次级感觉皮质。在过去的项目期间，我们使用行为、事件相关电位(ERP)和基于MRI的方法记录了Sz区早期听觉和视觉处理的缺陷，支持Sz区皮质功能障碍的分布式模型。此外，我们还证明了早期感觉加工缺陷对高阶皮质损伤的重大贡献。这些研究使我们能够提出关于Sz感觉/认知功能障碍潜在神经机制的具体假设，以及潜在治疗开发的新方法。在听觉系统中，早期缺陷包括短暂延迟后的音调匹配能力受损，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，低级听觉加工的缺陷会导致高阶功能障碍，如韵律理解能力受损，导致听觉情感识别(AER)缺陷，进而导致社会功能受损。在视觉系统中，缺陷包括对比度降低，特别是对低对比度，低空间频率(LSF)刺激，优先参与大细胞视觉系统，以及稳态视觉诱发电位(SsVEP)和视觉P1的生成受损，以及初级视觉皮质大细胞受体区域的fMRI激活受损。低水平的缺陷会导致更高层次的损伤，包括知觉闭合和面孔情绪识别(FER)。听力和视觉缺陷都会导致阅读能力的进行性损害，这可能是Sz的早期标志。最后，根据扩散张量成像(DTI)和静息状态成像(RsfMRI)的评估，听觉和视觉缺陷都与低水平感觉区的结构和功能连接受损有关。到目前为止，神经生理学异常主要是用时间域方法来评估的。在接下来的一段时间里，我们还将结合先进的频域和振荡分层方法，提供神经元振荡的自发和事件相关动力学的单独指数。视觉ERP将与眼睛跟踪相结合，以允许对自然场景处理进行评估。我们还将使用在我们之前的赠款周期中验证的范例来探索前驱症状和首发(FE)队列中的功能障碍模式。最后，我们将结合新的脑刺激方法，包括经颅磁刺激(RTMS)，应用于感觉和额叶皮质区域，以扰乱健康对照组的局部处理，作为 和经颅直流电刺激(TDC)应用于感觉或额叶脑区，作为SZ基于可塑性的刺激干预的前奏。