Abstract
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.
Highlights
There were no significant differences between Fragile X Syndrome (FXS) and Typically developing controls (TDC) in age or proportion of gender
The current study findings replicate and extend our previous findings of increased auditory N1 event-related potential (ERP) amplitude, decreased gamma phase locking to a chirp stimulus, and increased gamma single trial power during the chirp task
We did not strongly replicate our prior finding of reduced habituation, the general patterns seen across ERP repetitions is remarkably similar between our original study and the current
Summary
While there are many drug interventions that reduce behavioral deficits in Fmr mice and efforts to translate these preclinical breakthroughs into clinical trials for Fragile X Syndrome (FXS) (Tranfaglia, 2011; Wijetunge et al, 2013; Budimirovic et al, 2017; Berry-Kravis et al, 2018; Erickson et al, 2018), evidence-based clinical interventions are almost non-existent (Berry-Kravis et al, 2018). Our previous findings showed significantly increased nonspecific gamma activity (gamma single-trial power) in FXS that was associated with a decreased ability to (1) transiently synchronize evoked gamma (the “gamma spike” during early stimulus registration), (2) to synchronize evoked gamma to a rapidly changing oscillatory “chirp” stimulus (Ethridge et al, 2017) and (3) to habituate the neural response to repeated tones (Ethridge et al, 2016) These abnormalities were associated with increased clinical measures of sensory hypersensitivity, suggesting altered gamma oscillations/neural hyper-excitability are a potential biomarker of sensory issues in FXS. Still whether this potential biomarker has clinical relevance beyond sensory issues, including links to cardinal behavioral and cognitive features, remains unknown
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