Mismatch Negativity and Complex Second-Order Sensory Memory in Schizophrenia

精神分裂症的失配消极性和复杂的二阶感觉记忆

• 批准号: 8292569
• 负责人: Dean F Salisbury
• 金额: $ 38.13万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-22 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8292569
• 关键词: Acoustics; Area; Attention; Auditory area; Brain; Butyric Acids; Categories; Chronic; Chronic Schizophrenia; Cognitive; Complex; Cues; Defect; Disease; Early identification; Early treatment; Equilibrium; Event-Related Potentials; Failure; Family Study; Functional disorder; Generations; Glutamate Receptor; Glutamates; Hearing; Language; Lead; Learning; Left; Location; Loudness; Mediating; Memory; Methods; Metric; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Nature; Neuronal Plasticity; Occupational; P300 Event-Related Potentials; Parietal Lobe; Participant; Patients; Pattern; Perception; Perceptual learning; Persons; Pharmaceutical Preparations; Plant Roots; Play; Process; Prophylactic treatment; Relative (related person); Research; Risk; Role; Schizophrenia; Sensory; Series; Stimulus; Stream; Temporal Lobe; Testing; Time; Visual; Voice; Work; comparative; deviant; experience; family genetics; flexibility; foreign language; frontal lobe; genetic risk factor; gray matter; indexing; information processing; memory process; neurochemistry; neurophysiology; novel; research study; sensory cortex; social; theories; tool; trend

DESCRIPTION (provided by applicant): A major component of the pathophysiology in schizophrenia involves an imbalance between excitatory glutamate and inhibitory GABA in the cortex, and consequent problems in coherent local circuit function and at the NMDA receptor related to neuronal plasticity and learning. Coherent local circuit activity is crucial for real tie pattern analysis in sensory cortex and for rule learning involving frontal, temporal, and parietal cortices. Mismatch negativity (MMN) is a brainwave that is sensitive to Glu-GABA imbalance, and is abolished by drugs that block NMDA. MMN to simple stimulus changes (a soft tone among repetitive loud tones, or a high note among repetitive low notes) arises in primary and initial secondary auditory cortices, and is reduced in chronic schizophrenia. Yet the simple MMN is healthy at first psychotic break, though it declines during the early disease course in conjunction with primary auditory cortex gray matter loss, and is also normal in relatives. Because of this simple MMN cannot be used for family/genetic studies or for pre- or pro-dromal identification. Recently it has been discovered that MMN is elicited by more complex stimulus patterns and learned rules. These higher-order MMNs have not been studied in schizophrenia. Because of their complexity, abstraction of these rules requires involvement of sophisticated brain circuits spanning secondary cortices across frontal and temporal lobes. Complex MMN, intimately tied to NMDA-modulated memory formation, is likely to be more sensitive to and provide a more precise index of Glu-GABA imbalance in schizophrenia, even at or before first break, and in relatives. The main aim of this project is to detect the presence of complex memory MMN deficits in tasks that require second-order analysis of stimulus patterns and learned rules. As a first step, this project aims to identify complex MMN deficits in well characterized schizophrenia participants and first break patients before moving to at risk persons and relatives. Nine experiments will examine increasingly more complex second-order memory. If 5 tones played with a short delay between them are always followed by a long delay, gestalt proximity makes one form a "unit" of 5 tones. Violating that "rule" by adding or subtracting from the group of 5 elicits a complex MMN. Violations of second order rules of increasing pitch, duration, or loudness trends generate a MMN. Experience with language is used to aid perception of phonemes. (Consider how one needs to hear a foreign language for some time before perceiving the gap between words.) We predict that schizophrenics will not use learned rules for phoneme categories and will actually be more sensitive to acoustic differences in syllables than will controls. Demonstrating defects in MMN to second order memory is important for understanding the basic pathophysiology in schizophrenia, will provide novel and more sensitive indices of Glu-GABA imbalance in the disorder, and increase the utility of MMN as a tool for early identification and treatment of at risk persons before they have a full blown psychotic break, and for family studies and discovery of the basic genetic risk factors for the disease. PUBLIC HEALTH RELEVANCE: Schizophrenia involves deficits in local and long-range cortical circuit function and dendritic plasticity related to glutamate NMDA-receptor dysfunction. The mismatch negativity (MMN) brainwave is generated by NMDA-mediated activity. The present study will develop new neurophysiological tests of MMN depending on NMDA function in secondary cortex in temporal and frontal lobes that will lead to better methods for understanding the basic pathophysiology of the disorder, earlier identification and prophylactic treatment of persons at risk for schizophrenia, and increased power for identifying genetic risk factors for the disease.

描述（由申请人提供）：精神分裂症病理生理学的一个主要组成部分涉及皮质中兴奋性谷氨酸和抑制性GABA之间的不平衡，以及随之而来的相干局部回路功能和与神经元可塑性和学习相关的NMDA受体的问题。连贯的局部回路活动对于感觉皮层中的真实的领带模式分析以及涉及额叶、颞叶和顶叶皮层的规则学习至关重要。错配负波（MMN）是一种对Glu-GABA失衡敏感的脑波，可被阻断NMDA的药物消除。MMN到简单刺激的变化（在重复的高音中出现柔和的音调，或在重复的低音中出现高音）出现在初级和初级次级听觉皮层中，并在慢性精神分裂症中减少。然而，简单的MMN在第一次精神病发作时是健康的，尽管它在疾病的早期过程中随着初级听觉皮层灰质的丧失而下降，并且在亲属中也是正常的。由于这种简单的MMN不能用于家庭/遗传研究或用于前驱或前驱鉴定。最近，它已被发现，MMN引起的更复杂的刺激模式和学习规则。这些高阶MMN尚未在精神分裂症中进行过研究。由于其复杂性，这些规则的抽象需要复杂的大脑回路的参与，这些回路跨越额叶和颞叶的次级皮层。复杂的MMN，密切相关的NMDA调制的记忆形成，可能是更敏感的，并提供了一个更精确的指标谷氨酸-GABA不平衡的精神分裂症，甚至在或之前的第一次休息，并在亲属。这个项目的主要目的是检测存在的复杂的记忆MMN赤字的任务，需要二阶分析的刺激模式和学习的规则。作为第一步，该项目的目的是确定复杂的MMN赤字在充分表征精神分裂症的参与者和第一次打破患者转移到危险的人和亲属。九个实验将研究越来越复杂的二阶记忆。如果5个音调之间有一个短暂的延迟，之后总是有一个很长的延迟，完形接近使一个形成一个5个音调的“单位”。违反这一“规则”，从5个元素中增加或减少一个复杂的MMN。违反增加音高、持续时间或响度趋势的二阶规则会生成MMN。语言经验是用来帮助感知音素的。（想想看，一个人需要听一段时间的外语，才能感知单词之间的差距。）我们预测，精神分裂症患者将不会使用学习规则的音素类别，实际上会更敏感的音节声学差异比将控制。证明MMN到二级记忆的缺陷对于理解精神分裂症的基本病理生理学是重要的，将提供新的和更敏感的Glu-GABA失衡的指标，并增加MMN作为早期识别和治疗风险人群的工具的效用，在他们完全爆发精神病发作之前，以及用于家族研究和发现疾病的基本遗传风险因素。 公共卫生关系：精神分裂症涉及与谷氨酸NMDA受体功能障碍相关的局部和长程皮层回路功能和树突可塑性的缺陷。错配负波（MMN）脑电波由NMDA介导的活动产生。本研究将开发新的神经生理学测试MMN依赖于NMDA功能在颞叶和额叶的次级皮层，这将导致更好的方法来了解疾病的基本病理生理学，早期识别和预防性治疗的人在精神分裂症的风险，并增加电力识别疾病的遗传危险因素。