Electrophysiological Biomarkers of ASD and Cognitive Impairment in Infants with Tuberous Sclerosis Complex (TSC)

Background: Tuberous sclerosis complex (TSC) is an autosomal-dominant genetic syndrome highly penetrant for neurodevelopmental disorders, with estimates of ASD diagnosis in 25-60% (Jeste et al., 2008; Granader et al., 2010; Vignoli et al., 2015), and cognitive impairment in 50-75% (Yang et al., 2017). Disrupted patterns of neuronal connectivity account for atypical neurodevelopment in TSC (Peters et al., 2012; Julich & Sahin, 2014). No studies to date have measured disrupted patterns of neural function and connectivity in infancy that precede behavioral signs of ASD in TSC. EEG studies in infants with TSC can help elucidate neural mechanisms underlying atypical development and inform the development of biomarkers of change with early intervention.

Objectives: We examined electrophysiological (EEG) metrics of alpha oscillations (6-12 Hz) in infants TSC, with focus on alpha phase coherence (APC) and peak alpha frequency (PAF) (Dickinson et al., 2017).We had three specific aims: (1) Do PAC and PAF differ between infants with TSC and infants without TSC? (2) Do APC and PAF differentiate those infants with TSC who develop ASD from those that do not develop ASD? (3) Does PAF predict cognitive function at 36 months in infants with TSC?

Methods: As part of a longitudinal multi-site study of ASD prediction in TSC (PI: Nelson), spontaneous EEG data were collected at several time points across the first two years of life in infants with TSC, alongside a low risk (LR) comparison group without TSC. Infants with TSC were then subdivided into TSC/ASD or TSC/no ASD based on clinical evaluation of ASD symptoms at 36 months (Jeste et al, 2014). After extensive cleaning using independent component analysis (ICA), EEG data were transformed into current source density (CSD) estimates using a Laplacian transform. Alpha phase coherence was computed between every possible electrode pair combination. Peak alpha frequency was estimated using a robust curve-fitting procedure for three regions of interest: frontal, central and occipital.

Results: (1)At 12 months, infants with TSC (M=.24, SD=.03; N=18) showed hypoconnectivity in long range interhemispheric alpha phase coherence compared to LR controls (M=.31, SD=.09; N=20) (P<0.00013, adj P<0.04). At 24 months, PAF was lower in TSC (N=28) infants compared to LR controls (N=12) across frontal (P=.009) and central (P=.026) regions. (2) At 24 months, infants with TSC/ASD (M=0.23; N=14) showed a pattern of long range hypoconnectivity compared to TSC/no ASD (M=0.28; N=13). (3) Across all participants, PAF at 24 months was associated with verbal (P=.001) and non-verbal cognition (P<.001) at 36 months.

Conclusions: Alterations in functional neural development can be quantified in infants with TSC, with patterns of long range hypoconnectivity and slower peak alpha frequency, most prominent in those with ASD and developmental delay. These biomarkers of atypical development in TSC can (1) help us to further stratify risk, identifying those infants requiring targeted developmental interventions from very early in life; and can (2) inform future studies examining the effect of intervention on neural function and connectivity, as these brain changes may mediate developmental gains in these infants at high risk for ASD.