Neurophysiologic investigation of somatosensory dysfunction in Autism Spectrum Disorders

自闭症谱系障碍体感功能障碍的神经生理学研究

• 批准号: 10057023
• 负责人: Alexander Rotenberg
• 金额: $ 50.25万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-11 至 2023-05-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10057023
• 关键词: Address; Age; Animals; Anxiety; Area; Attention; Behavior; Behavioral; Biological Markers; Brain region; Brain-Derived Neurotrophic Factor; Budgets; Cerebrum; Congenital neurologic anomalies; Contralateral; Control Groups; Coupled; Coupling; Data; Detection; Development; Diagnosis; Diffuse; Disease model; Electromyography; Electrophysiology (science); Exhibits; Fiber; Functional disorder; Future; Genes; Genetic Variation; Health; Human; Hypersensitivity; Impairment; Individual; Intervention; Investigation; Knowledge; Measurement; Measures; Mechanics; Mediating; Motor; Motor Cortex; Motor Evoked Potentials; Motor output; Mus; Neuraxis; Neurologic; Neuropsychology; Outcome; Participant; Pathologic; Pathway interactions; Patients; Peripheral; Peripheral Nerves; Peripheral Nervous System; Pharmacology; Physiologic pulse; Physiological; Population; Protocols documentation; Publishing; Reporting; Research; Risk; Saliva; Sampling; Sensory; Series; Signal Pathway; Signal Transduction; Single Nucleotide Polymorphism; Skin; Social Behavior; Socialization; Somatosensory Disorders; Spinal Cord; Spinal Ganglia; Standardization; Stimulus; Surface; Symptoms; Synaptic plasticity; Tactile; Testing; Therapeutic; Therapeutic Trials; Transcranial magnetic stimulation; United States Food and Drug Administration; Visit; Work; autism spectrum disorder; autistic; base; behavioral phenotyping; brain dysfunction; cognitive ability; cohort; cost; experience; experimental study; improved; indexing; insight; median nerve; neurophysiology; novel; novel therapeutic intervention; pre-clinical; predicting response; prepulse inhibition; reduce symptoms; response; restoration; screening; sensory integration; sensory stimulus; somatosensory; tool; young adult

Project Summary Autism spectrum disorders (ASD) are the cause of large health-related and economical costs in the U.S. Thus, interventions that relieve symptoms for ASD patients are urgently needed. There are currently no treatments approved by the Food and Drug Administration for ASD. The development of novel therapeutic interventions will require early and reliable biomarkers and improved understanding of the underlying ASD pathophysiology. Most of the research on ASD so far has focused on mechanisms and circuits specific to the central nervous system with little attention to the contributions of abnormal signaling in the peripheral nervous system and spinal cord to the pathophysiology and core symptoms of ASD. Critically, most ASD patients exhibit enhanced responses to sensory stimuli, including tactile stimuli. Moreover, the degree of tactile hypersensitivity is strongly correlated with increased anxiety behaviors and social-behavior deficits observed in ASD. However, there are currently no neurophysiologic indices of tactile hypersensitivity and its contribution to dysfunction of brain networks. In cohorts of 40 ASD young adults, and 40 neurotypical young adults, we will compare the responses to paired associative stimulation (PAS) of the median nerve and the primary motor cortex between individuals with ASD and the control group – this will serve as a primary measure of the lasting effects on cortical cuntion that aberrant (pathologically heightened) peripheral signaling may have in ASD. Second, we will examine the correlation between the extent of abnormal PAS response in the ASD group and the degree of tactile hypersensitivity as objectively quantified by tactile prepulse inhibition (PPI) and mechanical detection threshold with von Frey fibers. Third, we will test the contribution of the common Val66Met single-nucleotide polymorphism (SNP) in the brain-derived neurotrophic factor (BDNF) gene to PAS measures. Each participant will undergo 4 visits, including two visits for quantitative tactile assessments and two visits for assessment of PAS-induced plasticity. All participants will undergo baseline assessment, including detailed screening, physical/neurological exam, neuropsychological assessment, and assessment of saliva samples for the BDNF SNP to explore predictors of PAS response. The proposed studies will be the first to validate well-formulated hypotheses from animal ASD research with PAS measures of tactile hypersensitivity. Favorable results from proposed experiments will validate standardized tools as biomarkers of tactile hypersensitivity in ASD and will provide measures of target engagement in future therapeutic trials aimed at improving tactile hypersensitivity and associated anxiety and social behavior deficits among ASD patients.

项目摘要 自闭症谱系障碍（ASD）是美国与健康相关和经济成本庞大的原因， 迫切需要为ASD患者挽救症状的干预措施。目前没有治疗 获得食品和药物管理局的ASD批准。新型治疗干预措施的发展 将需要早期可靠的生物标志物，并提高对基础ASD病理生理学的理解。 到目前为止，关于ASD的大多数研究都集中在中枢神经特定的机制和电路上 系统很少关注周围神经系统中异常信号传导的贡献 ASD的病理生理学和核心症状的脊髓。至关重要的是，大多数ASD患者暴露了增强 对感觉刺激的反应，包括触觉刺激。此外，触觉超敏反应的程度是 与焦虑行为的增加密切相关，社交行为定义在ASD中观察到的。然而， 目前尚无触觉超敏反应的神经生理指标及其对功能障碍的贡献 大脑网络。 在40名ASD年轻人和40名神经型年轻人的队列中，我们将比较对配对的反应 ASD患者之间正中神经和主要运动皮层的联想刺激（PA） 对照组 - 这将是对皮质c的持久影响的主要衡量， 异常（病理增强）外周信号传导可能在ASD中。第二，我们将检查 ASD组异常PAS响应的程度与触觉程度之间的相关性 高敏性通过触觉预硫化（PPI）和机械检测阈值进行客观量化 与冯·弗雷纤维。第三，我们将测试公共Val66met单核苷酸的贡献 脑衍生的神经营养因子（BDNF）基因的多态性（SNP）至PAS测量。 每个参与者将进行4次访问，包括两次定量触觉评估的访问和两次访问 评估PAS诱导的可塑性。所有参与者将接受基线评估，包括详细 筛查，身体/神经检查，神经心理学评估和唾液样本评估 BDNF SNP探索PAS响应的预测指标。 拟议的研究将是第一个从动物ASD研究中验证良好成熟的假设的研究 PAS的触觉超敏反应。提议的实验的有利结果将验证 标准化工具作为ASD触觉超敏反应的生物标志物，将提供目标的测量 参与未来的治疗试验，旨在改善触觉超敏反应和相关动画和 社会行为定义了ASD患者。