Visual evoked potentials detect cortical processing deficits in Rett syndrome

Abstract

Objective: Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutation of the X-linked MECP2 gene and characterized by developmental regression during the first few years of life. The objective of this study was to investigate if the visual evoked potential (VEP) could be used as an unbiased, quantitative biomarker to monitor brain function in RTT.

Methods: We recorded pattern-reversal VEPs in Mecp2 heterozygous female mice and 34 girls with RTT. The amplitudes and latencies of VEP waveform components were quantified, and were related to disease stage, clinical severity, and MECP2 mutation type in patients. Visual acuity was also assessed in both mice and patients by modulating the spatial frequency of the stimuli.

Results: Mecp2 heterozygous female mice and RTT patients exhibited a similar decrease in VEP amplitude that was most striking in the later stages of the disorder. RTT patients also displayed a slower recovery from the principal peak of the VEP response that was impacted by MECP2 mutation type. When the spatial frequency of the stimulus was increased, both patients and mice displayed a deficit in discriminating smaller patterns, indicating lower visual spatial acuity in RTT.

Interpretation: VEP is a method that can be used to assess brain function across species and in children with severe disabilities like RTT. Our findings support the introduction of standardized VEP analysis in clinical and research settings to probe the neurobiological mechanism underlying functional impairment and to longitudinally monitor progression of the disorder and response to treatment.

Conflict of interest statement

Potential Conflicts of Interest

None to report.

© 2015 American Neurological Association.

Figures

FIGURE 1:

Mecp2 heterozygous mice exhibit reduced amplitude visual evoked potentials (VEPs) and diminished acuity. (A) Average VEP responses to 0.05 cycles per degree (cpd) gratings for each individual mouse (thin traces) and each group (thick traces). Wild-type (WT) mice are shown in black (n = 14), and Mecp2 heterozygous (Het) mice are shown in red (n = 16). (B) Amplitude of the main negative component of the VEP quantified from traces shown in A, displayed in a box and whiskers plot. Boxes extend from 25th to 75th percentiles, lines are at the median, and whiskers represent minimum and maximum values. (C) Average VEP responses for each group. Mecp2 Het mice are sorted into 2 groups based on phenotypic score: Rett syndrome (RTT) 0–4 = absent to mild symptoms (purple, n = 7) and RTT 5–10 = moderate to severe symptoms (orange, n = 9). Black represents WT (n = 14). (D) Amplitude of the main negative component of the VEP quantified from traces shown in C. Lines represent median. (E) Comparison of averaged VEP amplitude as a function of spatial frequency (SF; black = WT, n = 14; red = Mecp2 Het, n = 15). Only SFs for which data were collected from all mice are shown in the plot. (F) Acuity threshold for each mouse. Lines indicate median. WT, n = 14; Mecp2 Het, n = 15. **p < 0.01; ****p < 0.0001.

FIGURE 2:

Children with Rett syndrome (RTT) exhibit reduced amplitude visual evoked potentials (VEPs) and prolonged signal recovery. (A) Average VEP responses for each individual participant (thin traces) and each group (thick traces). Typically developing (TD) subjects are shown in black (n = 20), and RTT subjects are shown in red (n = 34). (B) VEP quantification methods are shown for a representative averaged VEP waveform from a 3-year-old TD participant. The time period from −100 to 0 milliseconds represents the baseline signal prior to stimulus onset at 0 milliseconds. The dotted lines indicate the coordinates of the N1, P1, and N2 components. The horizontal dashed lines represent time measurements, and the vertical dashed lines represent amplitude measurements. Measurements: (a) N1 latency, (b) P1 latency, (c) N2 latency, (d) P1–N2 time, (e) N1 amplitude, (f) N1–P1 amplitude, (g) P1–N2 amplitude. (C) Quantified N1–P1 amplitude of VEP traces shown in A displayed in a box and whiskers plot. Box extends from 25th to 75th percentiles, lines are at the median, and whiskers represent minimum and maximum values.(D) Quantified P1–N2 time of VEP traces shown in A displayed in a box and whiskers plot. **p < 0.01; ***p < 0.001.

FIGURE 3:

Disorder stage and MECP2 mutation type differentially shape visual evoked potential (VEP) waveform morphology in children with Rett syndrome. (A) Average VEP responses for each group according to disorder stage (black 5 typically developing [TD], n = 20; green = active regression [AR], n = 11; blue = postregression [PR], n= 22). (B) Quantified N1–P1 amplitude of VEP traces shown in A. Lines represent median. (C) Quantified P1–N2 time of VEP traces shown in A. Lines represent median. (D) Average VEP responses for each group according to mutation type (black = TD, n = 20; salmon = mild mutations, n = 15; magenta 5 severe mutations, n= 18). (E) Quantified N1–P1 amplitude of VEP traces shown in D. Lines represent median. (F) Quantified P1–N2 time of VEP traces shown in D. Lines represent median. *p < 0.05; **p < 0.01.

FIGURE 4:

Children with Rett syndrome (RTT) exhibit reduced spatial frequency (SF) sensitivity and diminished acuity. (A) Group average visual evoked potential waveforms to several different SF stimuli (black = typically developing [TD], n = 8; red = RTT, n = 11). (B) SF tuning plot graphing mean N1–P1 amplitude for each group at each SF stimulus (black = TD; red = RTT). (C) Histogram of number of individuals who displayed a peak response to each SF (black, TD; red, RTT). (D) Acuity threshold for each participant. Lines are at median. The RTT data point designated as a triangle represents an outlier that is described in the text. cpd = cycles per degree. **p < 0.01.