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

• 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
• 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' 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

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.

感觉过敏是脆性 X 综合征的常见且令人痛苦的特征。这种临床症状被认为与新皮质神经元过度兴奋有关。正如项目 3 所追求的，我们高度新颖且综合的中心计划有三个主要目标。首先，我们的目标是利用临床神经生理学来表征脆性 X 患者听觉感觉过敏的神经基质。其次，我们将通过 P2 和 P3 中的平行“体内”听觉神经生理学研究建立小鼠与人类的同源性。第三，我们将使用与 P2 的 Fmr1 小鼠研究相同的范例，检查单剂量施用米诺环素、阿坎酸和洛伐他汀对 FXS 患者静息脑电图和听觉诱发反应的神经生理学影响。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，将通过检查早期感觉诱发反应幅度和对重复音调的习惯，从自下而上的局部电路角度进行分析。我们还将使用我们最近建立的说/听范例来分析听觉处理的自上而下的皮质控制。最后，我们将对调幅 (AM) 线性调频刺激的脑电图响应进行时频分解，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频率的伽马带活动，正如 P1 中测试的神经电路模型所预测的那样，我们在 Fragile X 的初步研究中发现其高度异常。将检查数据以了解 CGG 重复次数和基因甲基化之间的相关性以及与临床评级的相关性。结合 PI 和 P2 中的小鼠听觉回路研究、P1 和 P2 中的药理学研究以及“体内”小鼠听觉处理研究 (P2)，我们将对脆性 X 患者的听觉超敏反应形成机制理解，并更广泛地了解疾病机制和评估神经元的转化策略 过度兴奋及其临床影响。