Automatic cortical representation of auditory pitch changes in Rett syndrome

Abstract

BackgroundOver the typical course of Rett syndrome, initial language and communication abilities deteriorate dramatically between the ages of 1 and 4 years, and a majority of these children go on to lose all oral communication abilities. It becomes extremely difficult for clinicians and caretakers to accurately assess the level of preserved auditory functioning in these children, an issue of obvious clinical import. Non-invasive electrophysiological techniques allow for the interrogation of auditory cortical processing without the need for overt behavioral responses. In particular, the mismatch negativity (MMN) component of the auditory evoked potential (AEP) provides an excellent and robust dependent measure of change detection and auditory sensory memory. Here, we asked whether females with Rett syndrome would produce the MMN to occasional changes in pitch in a regularly occurring stream of auditory tones.MethodsFourteen girls with genetically confirmed Rett syndrome and 22 age-matched neurotypical controls participated (ages 3.9–21.1 years). High-density electrophysiological recordings from 64 scalp electrodes were made while participants passively listened to a regularly occurring stream of 503-Hz auditory tone pips that was occasionally (15 % of presentations) interrupted by a higher-pitched deviant tone of 996 Hz. The MMN was derived by subtracting the AEP to these deviants from the AEP produced to the standard.ResultsDespite clearly anomalous morphology and latency of the AEP to simple pure-tone inputs in Rett syndrome, the MMN response was evident in both neurotypicals and Rett patients. However, we found that the pitch-evoked MMN was both delayed and protracted in duration in Rett, pointing to slowing of auditory responsiveness.ConclusionsThe presence of the MMN in Rett patients suggests preserved abilities to process pitch changes in auditory sensory memory. This work represents a beginning step in an effort to comprehensively map the extent of auditory cortical functioning in Rett syndrome. These easily obtained objective brain measures of auditory processing have promise as biomarkers against which future therapeutic efforts can be assayed.

Auditory processing atypicalities for pure tones and complex speech sounds in Rett Syndrome – towards neuromarkers of disease progression

“…This lack of modulation in RTT may reflect a deficit in increasing synchronization of neural response to more complex stimuli, or a breakdown in the fundamental tonotopic representation of spectral information within core auditory cortical regions. Our previous finding that the MMN to frequency deviations was both attenuated and delayed in RTT accords well with the latter interpretation, suggesting that even fundamental tonotopic representation in early auditory core regions may be weakened (Foxe et al, 2016).…”

“…Pa, N1 and P2), and Stauder and colleagues (Stauder et al, 2006) uncovered atypical developmental changes in the latency of the N2. Recent work from our group accords well this notion of slowed auditory processing, as we found substantial delay in the mismatch negativity (MMN) response, an AEP component that is automatically generated when occasional deviant stimuli interrupt a stream of standard stimuli (Foxe et al, 2016). In that study, we specifically assessed MMN responses to large changes in pitch, and the implications of our results were that cortical representation of even such a basic feature as frequency representation was atypical and delayed in RTT.…”

“…Early electrophysiological studies in RTT mostly focused on the auditory brainstem response (ABR), with findings indicating that initial subcortical stages of auditory signal processing appeared mostly unaffected (Stach et al, 1994). In contrast, AEP studies assessing later cortical stages of auditory processing have tended to show quite significant impairments (Bader et al, 1989; Stach et al, 1994; Stauder et al, 2006; Foxe et al, 2016; Peters et al, 2017; Brima et al, 2019; Key et al, 2019). For example, Stach and colleagues (Stach et al, 1994) reported that more than 50% of individuals with RTT showed atypical AEPs, although they did not precisely specify what these abnormalities were.…”

Intellectual and developmental disabilities research centers: Fifty years of scientific accomplishments

“…Given that both Rett syndrome and the duplication disorder can be reversed in mouse models, 32,33 there is hope that a treatment can be developed and optimized to help people with these disorders. 35 Gathering key clinical information about the rate of disease progression and its course through natural history and brain function studies will guide clinical trials (pharmacological, genetic, or electrophysiological) in the future. 34 The challenges for any intervention will be safety, sustainability of benefits, and reliable measures to assess potential benefits in a clinical setting.…”

Spoken word processing in Rett syndrome: Evidence from event‐related potentials

“…Electrophysiological studies of auditory processing in RTT are limited. Examination of sensory processes relied primarily on detection of pure tone pitch changes and reported delays in auditory responsiveness (Foxe et al, 2016; Stauder et al, 2006). Conversely, studies using more complex, word‐level stimuli to investigate higher‐order speech and language processing in RTT reported discrimination of familiar voices from novel distractors (Peters et al, 2015) but no evidence of recognizing own name, suggesting general attention to auditory inputs but potentially reduced speech content processing (Peters et al, 2017).…”