Spatiotemporal Imaging of Language in Schizophrenia

描述(申请人提供)：这个项目的长期目标是了解精神分裂症患者连贯的思维和意义的建立中断的机制。我们的实验将测试一个认知神经科学模型，该模型认为精神分裂症的特征是两种截然不同但相互作用的神经加工机制之间的活动不平衡：(1)基于联想的机制从属于颞叶和下额叶皮质，最大运行时间在300-500ms之间；(2)整合机制，由下顶叶和背侧前额叶皮质调节，当需要覆盖语义关联以建立整体意义时，在500-800ms之间运行。我们假设患者不能有效地参与整合过程，导致过度依赖基于语义联想的过程。我们进一步假设，思维障碍的症状来自于在300-400ms的颞叶皮质内叠加的自下而上的、纯粹自动的语义联想多动。这使得这两种加工机制进一步失衡，导致“联想松动”。为了测试这一模型，将使用互补的多通道技术。事件相关电位(ERPs)和脑磁图(MEG)将确定精神分裂症患者神经认知异常的时间进程。事件相关功能磁共振成像(FMRI)研究将描述这些机制的功能神经解剖学特征。提出了13个实验(1个MEG，7个事件相关电位和5个功能磁共振)。他们都使用严格控制的心理语言学设计，基于正常语义和语言加工的理论模型。目标1下的实验侧重于单个单词之间的语义联系。他们将使用一种潜意识启动范式，分离出颞叶皮质内的全自动语义联想活动。此外，他们将首次阐明自动联想活动直接影响精神分裂症患者语言产生的神经机制。目标2下的实验将确定语义联系是否能完全覆盖精神分裂症患者整个句子上下文的建立。目标3下的实验将首次确定过度依赖语义联想神经活动是否会导致精神分裂症患者无法建立句子之间的因果和参照连贯。总体而言，这种翻译认知神经科学方法利用了精神分裂症精神思维背后的神经机制，并可以解释其症状和功能障碍是如何由潜在大脑回路调制的特定异常引起的。在认知、临床、神经生理和神经解剖功能障碍之间建立这种直接联系，对于有针对性地开发有效的药物和神经认知补救策略来治疗这种破坏性疾病至关重要。 公共卫生相关性：精神分裂症是一种破坏性的神经精神障碍，影响1%的成年人口，可能导致连贯思维和沟通的建立中断。这个项目使用多模式神经成像技术来确定这种杂乱无章和不合逻辑的思维在大脑中出现的地点、时间和方式。这对于以关键的神经认知系统为目标，开发新的药理学和认知治疗方法至关重要。

DESCRIPTION (provided by applicant): The long-term goal of this project is to understand the mechanisms by which the build-up of coherent thought and meaning breaks down in schizophrenia. Our experiments will test a cognitive neuroscience model which proposes that schizophrenia is characterized by an imbalance in activity between two distinct but interactive neural mechanisms of processing: (1) Associative-based mechanisms subserved within temporal and inferior frontal cortices, and operating maximally between 300-500ms, and (2) Integrative mechanisms, mediated by inferior parietal and dorsal prefrontal cortices, and operating between 500-800ms when there are requirements to override semantic associations to build whole meaning. We hypothesize that patients fail to effectively engage integrative processes, leading to an over-reliance on semantic associative-based processes. We further hypothesize that the symptom of thought disorder arises from superimposed bottom-up, purely automatic semantic associative hyperactivity between 300-400ms, within the temporal cortex. This tips the two mechanisms of processing into further imbalance leading to 'loosening of associations'. To test this model, complementary multimodal techniques will be used. Event-related potentials (ERPs) and Magneto-encephalography (MEG) will determine the time course of neurocognitive abnormalities in schizophrenia. Event-related functional magnetic resonance imaging (fMRI) studies will characterize the functional neuroanatomy of these mechanisms. Thirteen experiments are proposed (1 MEG, 7 ERP and 5 fMRI). All use carefully controlled psycholinguistic designs, based on theoretical models of normal semantic and language processing. Experiments under Aim 1 focus on semantic associations between individual words. They will isolate fully automatic semantic associative activity within the temporal cortex using a subliminal priming paradigm. In addition, they will, for the first time, elucidate the neural mechanisms by which automatic associative activity directly impacts language production in schizophrenia. Experiments under Aim 2 will determine whether semantic associations can fully override the build-up of whole sentence context in schizophrenia. Experiments under Aim 3 will, for the first time, determine whether an over-reliance on semantic associative neural activity can lead to failures of establishing causal and referential coherence across sentences in schizophrenia. Overall, this translational cognitive neuroscience approach taps into the neural mechanisms underlying psychotic thought in schizophrenia, and can explain how its symptoms and functional impairment arise from specific abnormalities in the modulation of underlying brain circuitry. Establishing such direct links between cognitive, clinical, neurophysiological and neuroanatomical dysfunction is essential for the targeted development of effective pharmacological and neurocognitive remediation strategies to treat this devastating disorder. PUBLIC HEALTH RELEVANCE: Schizophrenia is a devastating neuropsychiatric disorder, affecting 1% of the adult population, that can lead to a breakdown in the build-up of coherent thought and communication. This project uses multimodal neuroimaging techniques to determine where, when and how such disorganized and illogical thinking arises in the brain. This is essential for targeting key neurocognitive systems for the development of new pharmacological and cognitive approaches for remediation.