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      Reduced habituation of auditory evoked potentials indicate cortical hyper-excitability in Fragile X Syndrome

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          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.

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          Most cited references43

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          Characterization of N200 and P300: Selected Studies of the Event-Related Potential

          The Event-Related Potential (ERP) is a time-locked measure of electrical activity of the cerebral surface representing a distinct phase of cortical processing. Two components of the ERP which bear special importance to stimulus evaluation, selective attention, and conscious discrimination in humans are the P300 positivity and N200 negativity, appearing 300 ms and 200 ms post-stimulus, respectively. With the rapid proliferation of high-density EEG methods, and interdisciplinary interest in its application as a prognostic, diagnostic, and investigative tool, an understanding of the underpinnings of P300 and N200 physiology may support its application to both the basic neuroscience and clinical medical settings. The authors present a synthesis of current understanding of these two deflections in both normal and pathological states.
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            Imbalance of neocortical excitation and inhibition and altered UP states reflect network hyperexcitability in the mouse model of fragile X syndrome.

            Despite the pronounced neurological deficits associated with mental retardation and autism, it is unknown if altered neocortical circuit function occurs in these prevalent disorders. Here we demonstrate specific alterations in local synaptic connections, membrane excitability, and circuit activity of defined neuron types in sensory neocortex of the mouse model of Fragile X Syndrome-the Fmr1 knockout (KO). Overall, these alterations result in hyperexcitability of neocortical circuits in the Fmr1 KO. Specifically, we observe a substantial deficit in local excitatory drive ( approximately 50%) targeting fast-spiking (FS) inhibitory neurons in layer 4 of somatosensory, barrel cortex. This persists until at least 4 wk of age suggesting it may be permanent. In contrast, monosynaptic GABAergic synaptic transmission was unaffected. Overall, these changes indicate that local feedback inhibition in neocortical layer 4 is severely impaired in the Fmr1 KO mouse. An increase in the intrinsic membrane excitability of excitatory neurons may further contribute to hyperexcitability of cortical networks. In support of this idea, persistent neocortical circuit activity, or UP states, elicited by thalamic stimulation was longer in duration in the Fmr1 KO mouse. In addition, network inhibition during the UP state was less synchronous, including a 14% decrease in synchrony in the gamma frequency range (30-80 Hz). These circuit changes may be involved in sensory stimulus hypersensitivity, epilepsy, and cognitive impairment associated with Fragile X and autism.
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              Spontaneous EEG oscillations reveal periodic sampling of visual attention.

              An important effect of sustained attention is the facilitation of perception. Although the term "sustained" suggests that this beneficial effect endures continuously as long as something is attended, we present electrophysiological evidence that perception at attended locations is actually modulated periodically. Subjects detected brief light flashes that were presented peripherally at locations that were either attended or unattended. We analyzed the correlation between detection performance for attended and unattended stimuli and the phase of ongoing EEG oscillations, which relate to subsecond fluctuations of neuronal excitability. Although on average, detection performance was improved by attention--indicated by reduced detection thresholds at attended locations--we found that detection performance for attended stimuli actually fluctuated over time along with the phase of spontaneous oscillations in the (≈7 Hz) frequency band just before stimulus onset. This fluctuation was absent for unattended stimuli. This pattern of results suggests that "sustained" attention in fact exerts its facilitative effect on perception in a periodic fashion.
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                Author and article information

                Journal
                Transl Psychiatry
                Transl Psychiatry
                Translational Psychiatry
                Nature Publishing Group
                2158-3188
                April 2016
                19 April 2016
                1 April 2016
                : 6
                : 4
                : e787
                Affiliations
                [1 ]Department of Pediatrics, Section on Developmental and Behavioral Pediatrics, University of Oklahoma Health Sciences Center , Oklahoma City, OK, USA
                [2 ]Department of Psychology, University of Oklahoma , Norman, OK, USA
                [3 ]Department of Psychiatry, Center for Autism and Developmental Disabilities, University of Texas Southwestern Medical Center , Dallas, TX, USA
                [4 ]Department of Pediatrics, University of Texas Southwestern Medical Center , Dallas, TX, USA
                [5 ]Departments of Applied Behavioral Science and Psychology, Schiefelbusch Institute for Life Span Studies and Clinical Child Psychology Program, University of Kansas , Lawrence, KS, USA
                Author notes
                [* ]Department of Pediatrics, Section on Developmental and Behavioral Pediatrics, University of Oklahoma Health Sciences Center , 1100 North East 13th Street, Nicholson Tower, Suite 4900, Oklahoma City, OK 73104, USA. E-mail: Lauren-Ethridge@ 123456ouhsc.edu
                Article
                tp201648
                10.1038/tp.2016.48
                4872406
                27093069
                42378b1d-d763-4aef-9f02-461b84f3e810
                Copyright © 2016 Macmillan Publishers Limited

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 16 October 2015
                : 11 February 2016
                : 15 February 2016
                Categories
                Original Article

                Clinical Psychology & Psychiatry
                Clinical Psychology & Psychiatry

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