Mismatch Negativity and Complex Second-Order Sensory Memory in Schizophrenia

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兴奋性谷氨酸和抑制性GABA之间的不平衡，以及随之而来的局部连贯电路功能和与神经元可塑性和学习相关的NMDA受体的问题。连贯的局部电路活动对于感觉皮层的真实联系模式分析和涉及额叶、颞叶和顶叶皮层的规则学习至关重要。失配负性（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对简单刺激变化（重复高音中的柔和音调，或重复低音中的高音）产生于初级和初级次级听觉皮层，并在慢性精神分裂症中减少。然而，单纯MMN在最初的精神病发作时是健康的，尽管它在疾病早期随着初级听觉皮层灰质丧失而下降，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/遗传研究或用于前期或前期鉴定。近年来，人们发现MMN是由更复杂的刺激模式和习得的规则引发的。这些高阶mmn尚未在精神分裂症中得到研究。由于这些规则的复杂性，抽象这些规则需要涉及跨越额叶和颞叶的第二皮质的复杂大脑回路。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，并提供更精确的指标，甚至在第一次发作时或之前，以及在亲属中。该项目的主要目的是检测在需要对刺激模式和学习规则进行二阶分析的任务中存在的复杂记忆MMN缺陷。作为第一步，这个项目的目的是在转移到有风险的人和亲属之前，在特征明确的精神分裂症参与者和首次破裂患者中确定复杂的MMN缺陷。九个实验将检验越来越复杂的二阶记忆。如果5个音调在它们之间的短暂延迟之后总是伴随着较长的延迟，格式塔接近使一个人形成5个音调的“单位”。违反这一“规则”，从5组中加减会产生一个复杂的MMN。违反增加音高、持续时间或响度趋势的二阶规则会产生MMN。语言经验是用来帮助感知音素的。（想想一个人需要听一段时间的外语，才能感觉到单词之间的间隔。）我们预测精神分裂症患者不会使用所学的音素分类规则，实际上他们对音节的声学差异比对照组更敏感。发现MMN对二级记忆的缺陷对于理解精神分裂症的基本病理生理具有重要意义，将为该疾病中Glu-GABA失衡提供新的和更敏感的指标，并增加MMN作为早期识别和治疗高危人群的工具的效用，在他们完全精神崩溃之前，以及家庭研究和发现该疾病的基本遗传危险因素。

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.