Division of Child and Adolescent Psychiatry, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Commun Biol. 2022 May 11;5(1):442. doi: 10.1038/s42003-022-03395-9.
Fragile X Syndrome (FXS) is a monogenetic form of intellectual disability and autism in which well-established knockout (KO) animal models point to neuronal hyperexcitability and abnormal gamma-frequency physiology as a basis for key disorder features. Translating these findings into patients may identify tractable treatment targets. Using source modeling of resting-state electroencephalography data, we report findings in FXS, including 1) increases in localized gamma activity, 2) pervasive changes of theta/alpha activity, indicative of disrupted thalamocortical modulation coupled with elevated gamma power, 3) stepwise moderation of low and high-frequency abnormalities based on female sex, and 4) relationship of this physiology to intellectual disability and neuropsychiatric symptoms. Our observations extend findings in Fmr1 KO mice to patients with FXS and raise a key role for disrupted thalamocortical modulation in local hyperexcitability. This systems-level mechanism has received limited preclinical attention but has implications for understanding fundamental disease mechanisms.
脆性 X 综合征（FXS）是一种单基因形式的智力残疾和自闭症，其中经过充分证实的敲除（KO）动物模型指出神经元过度兴奋和异常的伽马频生理是关键障碍特征的基础。将这些发现转化为患者可能确定可行的治疗靶点。我们使用静息态脑电图数据的源模型，报告了 FXS 的发现，包括 1）局部伽马活动增加，2）theta/alpha 活动普遍变化，表明丘脑皮质调制中断，同时伽马功率升高，3）基于女性的低频和高频异常的逐步调节，以及 4）这种生理学与智力残疾和神经精神症状的关系。我们的观察结果将 Fmr1 KO 小鼠的发现扩展到 FXS 患者，并提出了丘脑皮质调制中断在局部过度兴奋中的关键作用。这种系统水平的机制受到了临床前研究的限制，但对理解疾病的基本机制具有重要意义。
