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）是美国大量健康相关和经济成本的原因。因此， 因此，迫切需要对ASD患者进行缓解症状的干预。目前没有治疗方法 经食品和药物管理局批准用于ASD。新型治疗干预措施的开发 将需要早期和可靠的生物标志物，并提高对潜在ASD病理生理学的理解。 到目前为止，大多数关于ASD的研究都集中在中枢神经系统特有的机制和回路上。 系统很少注意周围神经系统中异常信号的贡献， 脊髓与ASD的病理生理学和核心症状的关系。关键的是，大多数ASD患者表现出增强的 对感官刺激的反应，包括触觉刺激。此外，触觉过敏的程度是 与ASD中观察到的焦虑行为和社会行为缺陷增加密切相关。然而，在这方面， 目前还没有触觉超敏反应的神经生理学指标， 大脑网络 在40名ASD年轻人和40名神经典型年轻人的队列中，我们将比较配对的 ASD患者之间正中神经和初级运动皮层的联合刺激（PAS） 和对照组--这将作为对皮质骨持续影响的主要衡量标准， 异常的（病理性升高的）外周信号传导可能在ASD中具有。第二，我们将研究 ASD组PAS反应异常的程度与触觉损害程度的相关性 通过触觉前脉冲抑制（PPI）和机械检测阈值客观量化的超敏反应 用冯·弗雷纤维第三，我们将测试常见的Val 66 Met单核苷酸的贡献， 脑源性神经营养因子（BDNF）基因多态性（SNP）与PAS指标的关系。 每名参与者将接受4次访视，包括两次定量触觉评估访视和两次 PAS诱导的可塑性评估。所有参与者都将接受基线评估，包括详细的 筛查、身体/神经系统检查、神经心理学评估和唾液样本评估， BDNF SNP以探索PAS反应的预测因子。 拟议的研究将是第一个验证来自动物ASD研究的精心制定的假设， 触觉超敏反应的PAS测量。从拟议的实验的有利结果将验证 标准化的工具作为ASD触觉超敏反应的生物标志物，并将提供目标的测量 参与未来的治疗试验，旨在改善触觉过敏和相关的焦虑， ASD患者的社会行为缺陷。