Neurophysiological and acute pharmacological studies in FXS patients

感觉超敏是脆性X综合征的常见和令人痛苦的特征。这种临床症状被认为与新皮层神经元的高兴奋性有关。我们在项目3中追求的高度新颖和综合的中心项目有三个主要目标。首先，我们的目的是利用临床神经生理学表征脆性X患者听觉超敏反应的神经基质。其次，我们将通过P2和P3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小鼠研究相同的范式，研究单剂量给药米诺环素、阿坎普罗酸和洛伐他汀对FXS患者静息脑电图和听觉诱发反应的神经生理影响。在Fmr1小鼠模型和FXS患者中反复显示高度异常的听觉感觉反应将从自下而上的局部电路角度进行分析，通过检查早期感觉诱发反应幅度和对重复音调的习惯。我们还将使用我们最近建立的说话/听范式分析自上而下的皮层-皮层控制听觉处理。最后，我们将对脑电图对调幅（AM）啁啾刺激的响应进行时频分解，以检查局部电路介导的神经振荡。对于啁啾范式，我们将特别关注更高频率的伽马带活动，我们在脆性X的初步研究中发现，正如在P1中测试的神经回路模型所预测的那样，这是高度异常的。数据将检查CGG重复数和基因甲基化以及临床评分之间的相关性。结合PI和P2的小鼠听觉回路研究，P1和P2的药理学研究，以及“体内”小鼠听觉加工研究（P2），我们将对脆性X患者听觉超敏反应的机制进行了解，并更广泛地了解疾病机制和评估神经元的翻译策略

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.