Atypical processing of tones and phonemes in Rett Syndrome as biomarkers of disease progression

Abstract

Due to severe motor impairments and the lack of expressive language abilities seen in most patients with Rett Syndrome (RTT), it has proven extremely difficult to obtain accurate measures of auditory processing capabilities in this population. Here, we examined early auditory cortical processing of pure tones and more complex phonemes in females with Rett Syndrome (RTT), by recording high-density auditory evoked potentials (AEP), which allow for objective evaluation of the timing and severity of processing deficits along the auditory processing hierarchy. We compared AEPs of 12 females with RTT to those of 21 typically developing (TD) peers aged 4-21 years, interrogating the first four major components of the AEP (P1: 60-90 ms; N1: 100-130 ms; P2: 135-165 ms; and N2: 245-275 ms). Atypicalities were evident in RTT at the initial stage of processing. Whereas the P1 showed increased amplitude to phonemic inputs relative to tones in TD participants, this modulation by stimulus complexity was absent in RTT. Interestingly, the subsequent N1 did not differ between groups, whereas the following P2 was hugely diminished in RTT, regardless of stimulus complexity. The N2 was similarly smaller in RTT and did not differ as a function of stimulus type. The P2 effect was remarkably robust in differentiating between groups with near perfect separation between the two groups despite the wide age range of our samples. Given this robustness, along with the observation that P2 amplitude was significantly associated with RTT symptom severity, the P2 has the potential to serve as a monitoring, treatment response, or even surrogate endpoint biomarker. Compellingly, the reduction of P2 in patients with RTT mimics findings in animal models of RTT, providing a translational bridge between pre-clinical and human research.

Fig. 1. Auditory evoked potentials (AEPs) in response to Tones and Phonemes in TD and RTT groups.

The vertical dashed line corresponds to the onset of the stimuli, and the horizontal dashed line indicates baseline value. Blue and red lines correspond to TD and RTT AEPs respectively. Opaque blue and red shading illustrates the standard error of the mean.

Fig. 2. Modulation of P1 amplitude by stimulus type in TD (left) and RTT (right) groups.

Each individual’s data are represented by connected dots corresponding to values in the Tone and Phoneme conditions. Note the significantly smaller P1 in the Tone than in the Phoneme condition in TD, a pattern that is not observed in the RTT group.

Fig. 3. Reduction of P2 and N2 components in RTT.

The figure represents data averaged across conditions (Tone and Phoneme). Each dot corresponds to an individual participant. a Amplitude of the P2 component in TD and RTT groups. Two short horizontal lines indicate the means of the group values. The dashed horizontal green line is drawn at the decision threshold of + 0.63 µV, where RTT and TD participants are discriminated with 100% specificity and 75% sensitivity. b Relationship between P2 component and Rett Syndrome Severity Scores (RSSS) in patients with RTT. Note that larger RSSS values indicate more severe symptoms. c Amplitude of N2 component in TD and RTT participants. Two short horizontal lines indicate the mean of each group.

Fig. 4. Topography of auditory evoked potentials in response to Tone and Phoneme conditions in TD and RTT groups.

While topography for P1, P2, and N2 components are plotted based on averaged amplitude over corresponding time intervals, N1 topography is plotted in relation to P1 meaning that averaged over N1 latency AEP amplitudes were subtracted from AEP amplitudes averaged over P1 latency interval.