Spatiotemporal Imaging of Language in Schizophrenia

描述（由申请人提供）：本项目的长期目标是了解精神分裂症患者连贯思维和意义的建立机制。我们的实验将测试认知神经科学模型，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）颞叶和下额叶皮层内的联想机制，最大运作时间为300- 500 ms;（2）整合机制，由下顶叶和背侧前额叶皮层介导，并且当需要覆盖语义关联以构建整体含义时，在500- 800 ms之间操作。我们假设，患者未能有效地参与整合过程，导致过度依赖语义联想为基础的过程。我们进一步假设，思维障碍的症状是由颞叶皮层内300- 400毫秒之间的自下而上的纯自动语义联想过度活跃引起的。这使得两种处理机制进一步失衡，导致“关联松动”。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（ERP）和脑磁图（MEG）将确定精神分裂症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。提出了13个实验（1 MEG，7 ERP和5 fMRI）。所有这些都使用了基于正常语义和语言处理理论模型的精心控制的心理语言学设计。目标1下的实验侧重于单个词之间的语义关联。他们将使用阈下启动范式在颞叶皮层内分离出完全自动的语义联想活动。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。目标2下的实验将确定语义关联是否可以完全覆盖精神分裂症患者的整句语境的建立。目标3下的实验将首次确定是否过度依赖语义联想神经活动会导致精神分裂症患者在句子之间建立因果和参照连贯性的失败。总的来说，这种转化认知神经科学方法挖掘了精神分裂症中精神病性思维的神经机制，并可以解释其症状和功能障碍是如何从潜在脑回路调制的特定异常中产生的。在认知、临床、神经生理学和神经解剖学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学和神经认知补救策略来治疗这种破坏性疾病至关重要。

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.