Neocortical Localization and Thalamocortical Modulation of Neuronal Hyperexcitability in Fragile X Syndrome

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 novel 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 these 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 novel role for disrupted thalamocortical modulation in local hyperexcitability. This systems-level mechanism has received limited preclinical attention but has significant implications for understanding fundamental disease mechanisms.