Sensory hypersensitivities are common and distressing features of Fragile X Syndrome (FXS). While there are many drug interventions that reduce behavioral deficits in Fmr1 mice and efforts to translate these preclinical breakthroughs into clinical trials for FXS, evidence-based clinical interventions are almost non-existent potentially due to lack of valid neural biomarkers. Local circuit function in sensory networks is dependent on the dynamic balance of activity in inhibitory/excitatory synapses. Studies are needed to examine the association of electrophysiological alterations in neural systems with sensory and other clinical features of FXS to establish their clinical relevance. Adolescents and adults with FXS (n = 38, Mean age = 25.5, std = 10.1; 13 females) and age matched typically developing controls (n = 40, Mean age = 27.7, std = 12.1; 17 females) completed auditory chirp and auditory habituation tasks while undergoing dense array electroencephalography (EEG). Amplitude, latency, and percent change (habituation) in N1 and P2 event-related potential (ERP) components were characterized for the habituation task; time-frequency calculations using Morlet wavelets characterized phase-locking and single trial power for the habituation and chirp tasks. FXS patients showed increased amplitude but some evidence for reduced habituation of the N1 ERP, and reduced phase-locking in the low and high gamma frequency range and increased low gamma power to the chirp stimulus. FXS showed increased theta power in both tasks. While the habituation finding was weaker than previously found, the remaining findings replicate our previous work in a new sample of patients with FXS. Females showed less deficit in the chirp task but not the habituation task. Abnormal increases in gamma power were related to more severe behavioral and psychiatric features as well as reductions in neurocognitive abilities. Replicating electrophysiological deficits in a new group of patients using different EEG equipment at a new data collection site with differing levels of environmental noise that were robust to data processing techniques utilizing multiple researchers, indicates a potential for scalability to multi-site clinical trials. Given the robust replicability, relevance to clinical measures, and preclinical evidence for sensitivity of these EEG measures to pharmacological intervention, the observed abnormalities may provide novel translational markers of target engagement and potentially outcome measures in large-scale studies evaluating new treatments targeting neural hyperexcitability in FXS.

中文翻译：

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易碎X综合征的听觉EEG生物标志物：临床相关性。

感觉超敏反应是脆性X综合征（FXS）的常见和困扰特征。尽管有许多药物干预措施可减少Fmr1小鼠的行为缺陷，并努力将这些临床前突破转化为FXS的临床试验，但由于缺乏有效的神经生物标记物，基于证据的临床干预措施几乎不存在。感觉网络中的局部回路功能取决于抑制性/兴奋性突触中活性的动态平衡。需要进行研究以检查神经系统中电生理变化与FXS的感觉和其他临床特征之间的联系，以建立其临床相关性。拥有FXS的青少年和成年人（n = 38，平均年龄= 25.5，std = 10.1； 13位女性），年龄相匹配，通常与发展中的对照组（n = 40，平均年龄= 27.7，std = 12.1；17名女性）在接受密集阵列脑电图（EEG）的同时完成了听觉chi声和听觉习惯化任务。N1和P2事件相关电位（ERP）组件的振幅，潜伏期和百分比变化（适应性）用于适应性任务。使用Morlet小波进行时频计算，表征了惯性和and任务的锁相和单次尝试功率。FXS患者表现出幅度增加，但一些证据表明N1 ERP的适应性降低，低和高伽马频率范围内的锁相减少，并且to刺激的低伽马功率增加。FXS在两项任务中均显示出增加的theta力量。虽然习惯发现比以前发现的要弱，但其余发现在新的FXS患者样本中重复了我们以前的工作。女性在the任务中表现出较少的赤字，但在习惯性任务中则没有。γ功率异常增加与更严重的行为和精神病学特征以及神经认知能力下降有关。在新的数据收集地点使用不同的EEG设备在具有不同环境噪声水平的新患者中复制电生理缺陷，这对于利用多名研究人员进行数据处理的技术很可靠，这表明可扩展到多地点临床试验的潜力。鉴于其强大的可复制性，与临床措施的相关性以及这些脑电图措施对药理干预敏感性的临床前证据，