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

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.

SUBMITTER: Ethridge LE

PROVIDER: S-EPMC4872406 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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

Ethridge L E LE White S P SP Mosconi M W MW Wang J J Byerly M J MJ Sweeney J A JA

Translational psychiatry 20160419

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- ...[more]

PMID: 27093069

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Project description:(1) To characterize the influence of type 2 diabetes mellitus (DM) on cortical auditory-evoked potentials (CAEPs) separate from the effects of normal aging, and (2) to determine whether the disease-related effects are modified by insulin dependence.A cross-sectional study was conducted in a large cohort of Veterans to investigate the relationships among type 2 DM, age, and CAEPs in randomly selected participants with (N = 108) and without (N = 114) the disease and who had no more than a moderate hearing loss. Participants with DM were classified as insulin-dependent (IDDM, N = 47) or noninsulin-dependent (NIDDM, N = 61). Other DM measures included concurrent serum glucose, HbA1c, and duration of disease. CAEPs were evoked using a passive homogeneous paradigm (single repeating stimulus) by suprathreshold tones presented to the right ear, left ear, or both ears. Outcome measures were adjusted for the pure-tone threshold average for frequencies of 0.5, 1, and 2 kHz and analyzed for differences in age effects between participant groups using multiple regression.There is little variation across test ear conditions (left, right, binaural) on any CAEP peak in any of the groups. Among no-DM controls, P2 latency increases about 9 msec per decade of life. DM is associated with an additional delay in the P2 latency of 7 and 9 msec for the IDDM and NIDDM groups, respectively. Moreover, the slope of the function relating P2 latency with age is similar across participant groups and thus the DM effect appears constant across age. Effects on N1 latency are considerably weaker, with age effects of less than 4 msec per decade across all groups, and DM effects of only 2 (IDDM) or 3 msec (NIDDM). In the NIDDM group, the slope relating N1 latency to age is steeper relative to that observed for the no-DM group, providing some evidence of accelerated "aging" for this CAEP peak. DM does not substantially reduce N1-P2 amplitude and age relationships with N1-P2 amplitude are effectively absent. There is no association between pure-tone average at 0.5, 1, and 2 kHz and any aspect of CAEPs in this cohort.In a large cohort of Veterans, we found that type 2 DM is associated with prolonged N1 and P2 latencies regardless of whether insulin is required to manage the disease and independent of peripheral hearing thresholds. The DM-related effects on CAEP latencies are threefold greater for P2 compared with N1, and there is little support that at the cortical level, IDDM participants had poorer responses compared with NIDDM participants, although their responses were more variable. Overall, these results indicate that DM is associated with slowed preattentive neural conduction. Moreover, the observed 7 to 9 msec P2 latency delay due to DM is substantial compared with normal age changes in P2, which are 9 msec per decade of life in this cohort. Results also suggest that whereas N1 latency changes with age are more pronounced among individuals with DM versus without DM, there was no evidence for more rapid aging of P2 among patients with DM. Thus, the damage responsible for the major DM-related differences may occur early in the DM disease process. These cross-sectional results should be verified using a longitudinal study design.

Project description:ObjectivesWith the advent of newborn hearing screening and early intervention, there is a growing interest in using supra-threshold obligatory cortical auditory evoked potentials (CAEPs) to complement established pediatric clinical test procedures. The aim of this study was to assess the feasibility, and parent acceptability, of recording infant CAEPs.DesignTypically developing infants (n = 104) who had passed newborn hearing screening and whose parents expressed no hearing concerns were recruited. Testing was not possible in 6 infants, leaving 98, age range 5 to 39 weeks (mean age = 21.9, SD = 9.4). Three short duration speech-like stimuli (/m/, /g/, /t/) were presented at 65 dB SPL via a loudspeaker at 0° azimuth. Three criteria were used to assess clinical feasibility: (i) median test duration <30 min, (ii) >90% completion rate in a single test session, and (iii) >90% response detection for each stimulus. We also recorded response amplitude, latency, and CAEP signal to noise ratio. Response amplitudes and residual noise levels were compared for Fpz (n = 56) and Cz (n = 42) noninverting electrode locations. Parental acceptability was based on an 8-item questionnaire (7-point scale, 1 being best). In addition, we explored the patient experience in semistructured telephone interviews with seven families.ResultsThe median time taken to complete 2 runs for 3 stimuli, including preparation, was 27 min (range 17 to 59 min). Of the 104 infants, 98 (94%) were in an appropriate behavioral state for testing. A further 7 became restless during testing and their results were classified as "inconclusive." In the remaining 91 infants, CAEPs were detected in every case with normal bilateral tympanograms. Detection of CAEPs in response to /m/, /g/, and /t/ in these individuals was 86%, 100%, and 92%, respectively. Residual noise levels and CAEP amplitudes were higher for Cz electrode recordings. Mean scores on the acceptability questionnaire ranged from 1.1 to 2.6. Analysis of interviews indicated that parents found CAEP testing to be a positive experience and recognized the benefit of having an assessment procedure that uses conversational level speech stimuli.ConclusionsTest duration, completion rates, and response detection rates met (or were close to) our feasibility targets, and parent acceptability was high. CAEPs have the potential to supplement existing practice in 3- to 9-month olds.

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

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

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