Spatiotemporal Imaging of Language in Schizophrenia

精神分裂症语言的时空成像

• 批准号: 8075526
• 负责人: GINA R KUPERBERG
• 金额: $ 62.9万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8075526
• 关键词: Adult; Affect; Area; Back; Brain; Clinical; Cognitive; Communication; Development; Disease; Dorsal; Equilibrium; Event; Event-Related Potentials; Failure; Functional Magnetic Resonance Imaging; Functional disorder; Funding; Goals; Hyperactive behavior; Image; Impairment; Individual; Inferior; Language; Lead; Light; Link; Mediating; Modeling; Names; Nature; Neuroanatomy; Neurocognitive; Parietal; Parietal Lobe; Patients; Pattern; Performance; Population; Prefrontal Cortex; Process; Production; Psycholinguistics; Relative (related person); Reliance; Rest; Schizophrenia; Semantic memory; Semantics; Short-Term Memory; Speech Disorders; Staging; Stream; Symptoms; System; Systems Development; Techniques; Temporal Lobe; Testing; Theoretical model; Thinking; Time; Visual; Work; base; behavioral impairment; cognitive neuroscience; design; encephalography; frontal lobe; functional disability; indexing; language processing; lexical; lexical processing; neural patterning; neuroimaging; neuromechanism; neurophysiology; neuropsychiatry; public health relevance; relating to nervous system; remediation; research study; response; semantic processing; spatiotemporal

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.

描述（由申请人提供）：这个项目的长期目标是了解精神分裂症患者建立连贯思维和意义的机制。我们的实验将测试一个认知神经科学模型，该模型提出精神分裂症的特征是两种不同但相互作用的神经处理机制之间的活动不平衡：(1)联想机制主要作用于颞叶和下额叶皮层，在300-500ms之间发挥最大作用；(2)整合机制由顶叶下皮层和前额叶背皮层介导，在500-800ms之间发挥最大作用，此时需要超越语义关联来构建整体意义。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颞叶皮层300-400ms之间自下而上的、纯粹自动的语义联想亢进。这使两种处理机制进一步失衡，导致“联想松动”。为了测试这个模型，将使用互补的多模态技术。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）研究将表征这些机制的功能神经解剖学。共设计了13个实验（1个MEG， 7个ERP， 5个fMRI）。所有这些都基于正常语义和语言处理的理论模型，使用精心控制的心理语言学设计。Aim 1下的实验侧重于单个单词之间的语义关联。他们将使用阈下启动范式在颞叶皮层中分离出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语言产生的神经机制。目的2的实验将确定精神分裂症患者的语义关联是否能够完全超越整个句子语境的构建。Aim 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在句子间建立因果和参照一致性的失败。总的来说，这种转化认知神经科学方法深入研究了精神分裂症精神病思维的神经机制，并可以解释其症状和功能损伤是如何从潜在脑回路调节的特定异常中产生的。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理和神经认知补救策略来治疗这种破坏性疾病至关重要。