Neocortical localization and thalamocortical modulation of neuronal hyperexcitability contribute to Fragile X Syndrome

Abstract

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.

Temporal and frontal lobe contributions to neural synchronization dysfunction and auditory attention in Fragile X Syndrome

“…Alpha activity can be viewed as a continuum, such that low alpha power is associated with continuous cortical processing, but high alpha power states can lead to inhibition of cortical circuits though alpha phase dynamics 60 . Recently, we detected a marked reduction in resting absolute and relative alpha power in males with FXS, but relatively spared in females 50, 61 . Our conclusion suggested that males with FXS have evidence of thalamocortical dysfunction which leads to slower peak frequency, reduced alpha activity, and localized increases in broadband gamma power.…”

“…Recently, we detected a marked reduction in resting absolute and relative alpha power in males with FXS, but relatively spared in females 50,61 . Our conclusion suggested that males with FXS have evidence of thalamocortical dysfunction which leads to slower peak frequency, reduced alpha activity, and localized increases in broadband gamma power.…”

“…The MNE model generates a current dipole, in the units of A-m, for each vertex which is a spatially filtered and greatly attenuated compared to the original scalp amplitude. We recently showed that relative and absolute resting source power has comparable directional relationship between FXS and controls 61 . ITPC measures were also used and are standardized within each frequency.…”

Baclofen-associated neurophysiologic target engagement across species in fragile X syndrome

“…FXS patients precise gamma synchrony to sensory input is impaired [18] and asynchronous background gamma activity is increased [18,25,55]. In full mutation, nonmosaic males with FXS, increased gamma power is associated with increased severity across behavioral domains (i.e., irritability, abnormal speech, hyperactivity) as well as cognitive function [55].…”

“…FXS patients precise gamma synchrony to sensory input is impaired [18] and asynchronous background gamma activity is increased [18,25,55]. In full mutation, nonmosaic males with FXS, increased gamma power is associated with increased severity across behavioral domains (i.e., irritability, abnormal speech, hyperactivity) as well as cognitive function [55]. Our finding of co-occurring RBAC-associated theta band power increase and gamma band reduction is consistent with our prior hypothesis that in FXS increased theta may be recruited to downregulate gamma activity and thus potentially suppress sensory hyperexcitability [25] thus showing a potential mechanistic signature of RBAC use in FXS.…”