Abstract
Sensory hypersensitivities are common, clinically distressing features of Fragile X Syndrome (FXS). Preclinical evidence suggests this abnormality may result from synaptic hyper-excitability in sensory systems. This model predicts reduced sensory habituation to repeated stimulus presentation. Fourteen adolescents and adults with FXS and 15 age-matched controls participated in a modified auditory gating task using trains of 4 identical tones during dense array electroencephalography (EEG). Event-related potential and single trial time–frequency analyses revealed decreased habituation of the N1 event-related potential response in FXS, and increased gamma power coupled with decreases in gamma phase-locking during the early-stimulus registration period. EEG abnormalities in FXS were associated with parent reports of heightened sensory sensitivities and social communication deficits. Reduced habituation and altered gamma power and phase-locking to auditory cues demonstrated here in FXS patients parallels preclinical findings with Fmr1 KO mice. Thus, the EEG abnormalities seen in FXS patients support the model of neocortical hyper-excitability in FXS, and may provide useful translational biomarkers for evaluating novel treatment strategies targeting its neural substrate.
Highlights
Fragile X Syndrome (FXS) is a neurodevelopmental disorder associated with intellectual disability, facial dysmorphology and social deficits such as extreme shyness and anxiety.[1]
Most of the patients scored in the intellectually disabled range, with three patients scoring in the low-normal range; EEG and clinical values did not differ for these patients, so they were retained in the analyses
We believe the current study provides the first direct clinical evidence for a contribution of gamma band abnormalities, suggesting an imbalance of excitatory vs inhibitory activity, an effect found in mouse models of FXS, and the first evidence that these are clinically relevant by virtue of their relationship to parental reports of sensory sensitivities in FXS
Summary
Fragile X Syndrome (FXS) is a neurodevelopmental disorder associated with intellectual disability, facial dysmorphology and social deficits such as extreme shyness and anxiety.[1]. Animal models of FXS point to neuronal network hyperexcitability as a possible cause of sensory hypersensitivity. Local circuit hyper-excitability in Fmr[1] knockout mouse models of FXS has been demonstrated, including prolonged ‘UP’ states in the gamma frequency range, decreased glutamatergic drive on fastspiking GABAergic inhibitory neurons in sensory cortex[5] and heightened neurophysiological response to auditory stimuli.[6] Inhibitory circuit deficits in these mouse models have been linked to abnormalities in both fast-spiking parvalbumin-expressing inhibitory interneurons[5,7] and somatostatin-expressing lowthreshold-spiking inhibitory interneurons;[8] these alterations may contribute directly to local circuit disorganization and hyperexcitability. Disorganized and hyper-excitable networks can have increased cortical ‘noise’ or desynchronous firing in the gamma frequency range that reduces stimulus selectivity and lowers the impact of local network output on postsynaptic circuits.[9]
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