Mismatch Negativity and Complex Second-Order Sensory Memory in Schizophrenia

描述(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兴奋性谷氨酸和抑制性GABA之间的失衡，以及由此导致的连贯局部电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的真实领带模式分析和涉及额叶、颞叶和顶叶皮质的规则学习至关重要。失配负波(MMN)是一种对Glu-GABA失衡敏感的脑电波，可被阻断NMDA的药物消除。MMN对简单刺激的变化(重复的高音中的轻声，或重复的低音中的高音)出现在初级和最初的次级听觉皮质，并在慢性精神分裂症中减少。然而，简单的MMN在精神病发作时是健康的，尽管在疾病的早期病程中随着初级听觉皮质灰质的丧失而下降，在亲属中也是正常的。正因为如此，MMN不能用于家庭/遗传研究，也不能用于先证者或先证者的鉴定。最近发现，MMN是由更复杂的刺激模式和习得的规则引起的。这些更高阶的MMN在精神分裂症中还没有被研究过。由于它们的复杂性，这些规则的抽象需要复杂的大脑回路参与，这些回路跨越额叶和颞叶的次级皮质。复杂的MMN与NMDA调节的记忆形成密切相关，可能对精神分裂症患者的Glu-GABA失衡更敏感，并提供更准确的指标，即使在第一次发作时或之前，以及亲属中也是如此。这个项目的主要目的是在需要对刺激模式和学习规则进行二阶分析的任务中检测复杂记忆MMN缺陷的存在。作为第一步，这个项目的目的是在有良好特征的精神分裂症参与者和首次发作患者中识别复杂的MMN缺陷，然后转移到高危人群和亲属那里。九个实验将检验日益复杂的二阶记忆。如果播放的5个音调之间有一个短的延迟，然后总是有一个长的延迟，那么格式塔的接近使一个人形成一个由5个音调组成的“单位”。违反这一“规则”，从5国集团中增加或减去，就会产生复杂的MMN。违反增大音调、持续时间或响度趋势的二阶规则会产生MMN。使用语言的经验被用来帮助人们感知音素。(想一想，在感觉到单词之间的差距之前，一个人需要听一段时间的外语。)我们预测，精神分裂症患者将不会使用已学习的音素类别规则，而且实际上将比对照组对音节的声学差异更敏感。证明MMN的二级记忆缺陷对于了解精神分裂症的基本病理生理学具有重要意义，将为精神分裂症中Glu-GABA失衡提供新的和更敏感的指标，并增加MMN作为一种工具的实用性，在精神分裂症发作之前早期识别和治疗高危人群，以及家庭研究和发现疾病的基本遗传危险因素。 公共卫生相关性：精神分裂症涉及局部和远程皮质回路功能缺陷，以及与谷氨酸NMDA受体功能障碍有关的树突可塑性。失配负波(MMN)脑波是由NMDA介导的活动产生的。本研究将开发新的MMN神经生理学测试，依赖于颞叶和额叶次级皮质的NMDA功能，这将导致更好的方法来了解这种疾病的基本病理生理学，早期识别和预防性治疗精神分裂症的高危人群，并增加识别疾病的遗传危险因素的能力。

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.