Neurophysiological and acute pharmacological studies in FXS patients

FXS 患者的神经生理学和急性药理学研究

基本信息

批准号：
9360824
负责人：
KIMBERLY M. HUBER
金额：
$ 2.44万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9360824
关键词：
Acute Animal Model Area Auditory Auditory Evoked Potentials Auditory area Automobile Driving Behavior Biological Markers Broca&apos s area CGG repeat Clinical Clinical Research Clinical Trials Complement Data Distress Dose Drug Targeting Electroencephalography Fragile X Syndrome Frequencies Genes Goals Hour Human Hypersensitivity Individual Interneurons Knockout Mice Knowledge Lovastatin Mediating Methods Methylation Minocycline Modeling Mus Neocortex Neurons Outcome Parvalbumins Patients Persons Pharmaceutical Preparations Pharmacology Phase Population Preparation Procedures Process Psychopharmacology Recovery Recovery of Function Refractory Rest Sensory Sensory Physiology Slice Speech Speech Sound Speed Stimulus Study models Symptoms System Testing Time acamprosate auditory stimulus biomarker development density disability drug development frontal lobe habituation improved in vivo interest mouse model neocortical neural circuit neuromechanism neurophysiology novel patient oriented research personalized medicine potential biomarker preclinical study programs relating to nervous system response sensory input sensory system sound sound frequency time use translational approach

项目摘要

Sensory hypersensitivities are common and distressing feature of the Fragile X Syndrome. This clinical symptom is believed to be associated with neuronal hyperexcitability in neocortex. There are three primary goals of our highly novel and integrated Center program as pursued in Project 3. First, we aim to characterize the neural substrate of auditory sensory hypersensitivities in Fragile X patients using clinical neurophysiology. Second, we will establish mouse-human homologies via parallel 'in vivo' auditory neurophysiology studies in P2 and P3. Third, we will examine neurophysiological effects of single dose administration of minocycline, acamprosate, and lovastatin on resting EEG and auditory evoked responses in patients with FXS, using the same paradigms as in the Fmr1 mouse studies of P2. Auditory sensory responses, repeatedly shown to be highly abnormal in the Fmr1 mouse model and FXS patients, will be analyzed from a bottom-up, local circuit perspective by examining early sensory evoked response amplitudes and habituation to repeated tones. We will also analyze top-down corticocortical control of auditory processing using our recently established talk/listen paradigm. Last, we will perform a time-frequency decomposition of the EEG response to amplitude modulated (AM) chirp stimuli in order to examine local circuit-mediated neural oscillations. For the chirp paradigm, we will focus particularly on higher frequency gamma band activity, which we have found to be highly abnormal in Preliminary Studies in Fragile X as predicted by the neural circuitry model being tested in P1. Data will be examined for correlations between CGG repeat number and gene methylation, and with clinical ratings. Together with the mouse auditory circuit studies in PI & P2, pharmacological studies in P1 & P2, and 'in vivo' mouse auditory processing studies (P2), we will develop a mechanistic understanding of auditory hypersensitivity in Fragile X patients, and more broadly about illness mechanisms and translational strategies for evaluating neuronal hyperexcitability and its clinical impact.

感觉超敏反应是脆弱X综合征的常见和令人沮丧的特征。据信这种临床症状与新皮层的神经元过度兴奋性有关。我们在项目3中提出的高度新颖和综合中心计划的三个主要目标。首先，我们旨在使用临床神经生理学来表征脆弱X患者听觉感觉超敏反应的神经底物。其次，我们将通过P2和P3中的“体内”听觉神经生理学研究来建立小鼠人类同源性。第三，我们将使用与FMR1小鼠P2的FMR1小鼠研究相同的范例，研究米诺环素，丙糖酸和洛伐他汀单剂量施用对静止的脑电图和听觉诱发反应的神经生理作用。在FMR1小鼠模型和FXS患者中反复显示出高度异常的听觉感觉反应，将通过检查早期的感觉引起的响应幅度和重复音调的习惯，从自下而上的局部电路角度分析。我们还将使用我们最近建立的Talk/Listen范式分析听觉处理的自上而下的皮质皮质控制。最后，我们将对脑电图对振幅调节（AM）CHIRP刺激的脑电图反应进行时间频率分解，以检查局部电路介导的神经振荡。对于Chirp范式，我们将特别关注较高的频率伽马频带活性，我们发现在脆弱X的初步研究中，这是由P1中测试的神经回路模型所预测的。将检查数据是否与CGG重复数和基因甲基化以及临床评级之间的相关性。与PI＆P2中的小鼠听觉电路研究，P1和P2中的药理学研究以及“体内”小鼠听觉加工研究（P2），我们将对脆弱X患者的听觉性超敏反应以及更广泛的疾病机制和用于评估神经元的疾病机制和转化策略发展一种机械理解过度兴奋性及其临床影响。