Neurophysiological and acute pharmacological studies in FXS patients

感觉过敏是脆性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质中的神经元过度兴奋有关。我们高度新颖和综合的中心计划有三个主要目标，如项目3所追求的。首先，我们的目标是用临床神经生理学来描述脆性X患者听觉感觉超敏反应的神经基础。第二，我们将建立小鼠-人的同源性，通过平行的“在体内”的听觉神经生理学研究在P2和P3。第三，我们将研究二甲胺四环素，阿坎酸，和洛伐他汀单剂量给药对静息脑电图和听觉诱发反应的FXS患者的神经生理作用，使用相同的范式在P2的Fmr 1小鼠研究。在Fmr 1小鼠模型和FXS患者中反复显示高度异常的听觉感觉反应，将通过检查早期感觉诱发反应幅度和对重复音调的习惯化，从自下而上的局部回路角度进行分析。我们还将分析自上而下的皮质控制的听觉处理使用我们最近建立的谈话/听范例。最后，我们将进行时频分解的EEG响应调幅（AM）啁啾刺激，以检查本地电路介导的神经振荡。对于啁啾范例，我们将特别关注更高频率的伽马带活动，我们已经发现，在脆性X的初步研究中，这是高度异常的，正如在P1中测试的神经回路模型所预测的那样。将检查CGG重复数与基因甲基化之间的相关性以及与临床评级之间的相关性。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进行机制性理解，并更广泛地了解疾病机制和评估神经元的翻译策略。 过度兴奋及其临床影响。

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.