Neurophysiology of Receptive Speech in Rett Syndrome

雷特综合征接受言语的神经生理学

• 批准号: 8299879
• 负责人: Aleksandra Djukic
• 金额: $ 24.99万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-10 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8299879
• 关键词: Acoustics; Address; Affect; Age-Months; Ally; Area; Auditory; Behavioral Assay; Biological Assay; Body part; Brain; Breathing; Caregivers; Cerebellum; Child; Clinic; Clinical; Clinical Research; Clinical Trials; Communication; Communication Aids for Disabled; Data; Development; Diagnostic; Disease; Dyslexia; Electrodes; Electroencephalography; Environment; Event-Related Potentials; Exhibits; Female; Functional Magnetic Resonance Imaging; Functional disorder; Future; Gait abnormality; Generations; Genes; Genetic; Genotype; Goals; Hand; Impairment; Individual; Investigation; Knowledge; Language; Lead; Leg; Life; Link; Magnetic Resonance Imaging; Maps; Measures; Methodology; Methods; Methyl-CpG-Binding Protein 2; Motor; Motor Cortex; Motor Skills; Movement; Mutation; Outcome Measure; Parents; Patients; Phase; Phenotype; Phonetics; Physicians; Procedures; Process; Reading; Relative (related person); Reporting; Research; Residual state; Resolution; Rett Syndrome; Sedation procedure; Self-Help Devices; Semantics; Sensory; Signal Transduction; Source; Spectrum Analysis; Speech; Speech Perception; Symptoms; Syndrome; System; Techniques; Testing; Theft; Training; Ursidae Family; Word Processing; arm; auditory stimulus; base; child neglect; density; design; developmental disease; deviant; foot; impression; innovation; language processing; motor impairment; nervous system disorder; neuroimaging; neurophysiology; new technology; novel; relating to nervous system; research study; response; semantic processing; skills; speech processing; speech recognition; treatment trial

DESCRIPTION (provided by applicant): The loss of acquired language and motor skills are two main diagnostic criteria for Rett Syndrome (RTT), a devastating developmental disorder caused by known mutations in the MECP2 gene. RTT is characterized by apparently normal development until 6 to 18 months of age followed by a ruinous regression phase that robs RTT children of their ability to speak, as well as leading to major motor dysfunction, breathing irregularities, digestive problems, gait abnormalities and other symptoms. While the genetic basis of the syndrome is understood, much less is known about the cortical alterations associated with it and what skills and abilities may yet be preserved. From clinical observations, we and others contend that these mostly non-verbal children have much greater abilities to understand speech than might at first be apparent. But anecdotal evidence and behavioral assays are inadequate for assessing potentially preserved speech-language function and there is a clear need to bring modern neurophysiological techniques to bear on this issue. In this project, high-density electrophysiological recordings allied with novel systems-identification data-analytic approaches will allow for a direct assessment of the extent of preserved speech reception abilities in RTT. The overarching goal of this project is to develop a thorough neurophysiological quantification of receptive auditory speech capabilities in RTT to deepen our understanding of this disorder. The proposed methods are likely the only feasible way to obtain functional brain measures in RTT, since magnetic resonance imaging has only been obtained under sedation in these children. The project takes a systematic approach to assaying speech-reception, moving from measures of basic phonemic processing, to measures of semantic processing, and in turn to measures that assay the processing of the highly dynamic speech envelope itself during natural speaking conditions. In this way, we can assess the fundamental building blocks of speech processing. The second major clinical symptom of RTT, loss of motor abilities affecting hands, arms, and legs, will also be examined using a novel electrophysiological approach. The processing of semantic auditory information involving action words that involve body parts (e.g. "leg" and "kick") elicits activity in the corresponding parts o motor cortex. If motor impairments in RTT are primarily due to motor cortex dysfunction, then semantic processing for action words should be impaired relative to non-action words. As such, this paradigm represents a potentially powerful functional examination of motor cortical function in RTT. Taken together, the proposed project will examine two fundamental aspects of RTT in a quantitative way using a combination of well-established and cutting-edge methodologies. The derived knowledge could greatly impact ongoing development of assistive technologies to support more effective communication by these individuals with their caregivers and environment. In addition, a thorough quantitative description of two main symptoms of the disorder should lead to an enhancement in determining phenotype-genotype relations as well as an outcome measure for pharmacological clinical trials. PUBLIC HEALTH RELEVANCE: Rett Syndrome, a devastating neuro-developmental disorder that affects about 1 in 10,000 females, is characterized by a regressive loss of acquired spoken language and motor capabilities during the first two years of life. In patients who do not produce speech and lack motor abilities to respond to spoken words in a controlled manner, it is all too common to assume a more general lack of speech capabilities, but recent evidence suggests that this is likely not a valid assumption. There are now several reports indicating altogether greater receptive language processing skills in RETT children. This project therefore aims at developing widely applicable quantitative tests of the most important aspects of receptive speech processing using objective neurophysiological methods allied with novel systems identification data-analytic approaches. The goal is to determine just how intact the receptive speech system is in RETT, with important implications for the development of assistive communication devices for these oft-neglected children.

描述（由申请人提供）：获得的语言和运动技能的丧失是RETT综合征（RTT）的两个主要诊断标准，这是MECP2基因中已知突变引起的毁灭性发育障碍。 RTT的特征是显然是正常的发展，直到6至18个月大，然后是毁灭性的回归阶段，该阶段使RTT儿童说话能力，并导致重大运动功能障碍，呼吸不规则，消化问题，步态异常和其他症状。尽管了解了综合征的遗传基础，但对与之相关的皮质改变以及可以保留哪些技能和能力的皮质改变知之甚少。从临床观察中，我们和其他人认为，这些大多数非语言儿童的理解能力比最初显而易见的能力要大得多。但是，轶事证据和行为分析不足以评估潜在的语音语言功能，并且显然需要带来现代神经生理技术来解决这个问题。在这个项目中，与新型系统识别数据分析方法相关的高密度电生理记录将可以直接评估RTT中保留的语音接收能力的程度。该项目的总体目标是开发RTT中接受听觉语音能力的彻底神经生理量化，以加深我们对这种疾病的理解。所提出的方法可能是获得RTT功能性脑测量的唯一可行方法，因为磁共振成像仅在这些儿童的镇静下才获得。该项目采用一种系统的方法来分析语音受到的态度，从基本音素处理的度量转变为语义处理的度量，进而转变为测定在自然语言条件下高度动态语音信封的处理的措施。通过这种方式，我们可以评估语音处理的基本构件。 RTT的第二个主要临床症状，影响手，手臂和腿部运动能力的丧失也将使用新型的电生理方法检查。涉及身体部位（例如“腿”和“踢”）的动作词的语义听觉信息的处理引起了相应的部分运动皮层的活动。如果RTT中的运动障碍主要是由于运动皮层功能障碍引起的，则相对于非动作单词，动作词的语义处理应受到损害。因此，该范式代表了RTT中运动皮质功能的潜在强大功能检查。综上所述，拟议的项目将使用建立良好和尖端的方法组合以定量方式检查RTT的两个基本方面。派生的知识可能会极大地影响辅助技术的持续发展，以支持这些人与照料者和环境的更有效的沟通。此外，对该疾病的两个主要症状的彻底定量描述应导致确定表型基因型关系以及药理学临床试验的结果指标。 公共卫生相关性：RETT综合征是一种毁灭性的神经发展疾病，影响了10,000名女性中约1个，其特征是在生命的头两年中丧失了获得的口语和运动能力。在不产生言语和缺乏运动能力无法以受控方式反应口语的患者中，这太常见了，以至于无法普遍缺乏语音能力，但是最近的证据表明，这可能不是一个有效的假设。现在有几份报告表明，Rett儿童中完全具有更高的接受语言处理能力。因此，该项目旨在使用与新型系统识别数据分析方法相关的客观神经生理学方法来开发广泛适用于接受语音处理的最重要方面的定量测试。目的是确定RETT中接受语音系统的完整程度，对这些经常被忽视的儿童的辅助通信设备的开发具有重要意义。