Specificity of Atypical Neural Development for Language in Infants at Risk for ASD Yang, J.F.1,2, Reuman, H.S.1, Brooks, E.D.2, Hashim, P.W.2, Travieso, R.2, Levy, E.J.1, Law, K.1, Stavropoulos, K.K.M.1, Steinbacher, D.M.2, Landi, N.3, Mayes, L.C.1, Persing, J.A.2 & McPartland, J.1 1McPartland Lab, Child Study Center, Yale University School of Medicine 2SecQon of PlasQc and ReconstrucQve Surgery, Yale University School of Medicine 3Haskins Laboratories, New Haven, CT Experimental Design: • Auditory presentations of two different consonant phonemes: the dental /da/ and retroflex /da/. • 5 blocks, 20 trials per block (10 dental; 10 retroflex). • Stimulus duration = 250 ms; ISI = 610 ms. Non-syndromic craniosynostosis (CSO; Fig. 1) • Congenital headshape deformity resulting from premature fusion of skull sutures; associated with language delay and subsequent learning disability.3 • Is a non-ASD condition that affects auditory processing. • Used as a clinical comparison group to investigate the specificity and timing of onset of atypical language processing in ASD. ® Objectives: • To contrast specific patterns of hemispheric dominance and discrimination of phonemes in infants at high risk for ASD (HR), eO infants with CSO, and infants at normal risk for ASD (NR). gYAd A !_u ® ® ® ® Amplitude (uV) -‐100 • P150 • Initial positive inflection from 100-300 ms Apost-stimulus gYAd !_u • N450 • Negative slow wave from 400-550 ms post-stimulus • Responses over left and right temporal regions (Fig. 2) were contrasted to evaluate hemispheric lateralization. • Repeated measures analyses of variance (ANOVAs) were computed for P150 and N450 ERP components at temporal locations, with participant group as a between-subjects factor and brain hemisphere and consonant as withinsubjects factors. 6 5 5 3 Data Acquisition and Analysis: • EEG was recorded at 250Hz with a 128 channel HydroCel Geodesic Sensor Net. • Data was processed using Net Station 4.5 software. • Peak amplitudes of the P150 and N450 ERP components were analyzed, given their reported correlation with future language ability.2 eO 6 4 Dent Le] 2 0 0 100 Methods * 300 400 Time (ms) 500 600 700 Ret Right -‐100 Dent Le] 2 Dent Right 1 Ret Le] 0 -‐1 -‐2 -‐2 -‐3 -‐3 0 100 200 300 400 500 600 700 Ret Right Time (ms) Figure 5. HR grand averaged waveforms 5 4 -‐100 Figure 2. Electrode layout and selected clusters (Left: 29, 30, 35, 36; Right: 104, 105, 110, 111) 3 Dent Le] 2 Dent Right 1 Ret Le] 0 0 100 -‐1 *= p < 0.05 NR = normal risk HR = high risk CSO = craniosynostosis 200 300 400 500 600 700 Figure 6. CSO grand averaged waveforms Ret Right Time (ms) -‐2 Conclusions -‐3 • No significant differences in amplitude of neural response to the different phonemes across the HR, CSO, and NR infants (Fig. 3). • Significant Hemisphere x Group interaction at N450 (p < 0.05) - NR infants displayed lateralized response to language (p < 0.01) - HR and CSO infants displayed no detectable hemisphere lateralization (p = 0.32 and p = 0.60, respectively) • Marginal Hemisphere x Group interaction at P150 (p = 0.06) - NR infants displayed right lateralization of response to language (p = 0.04) - HR and CSO infants displayed no detectable hemisphere lateralization (p = 0.25 and p = 0.57, respectively) 6 200 3 -‐1 • Our study utilized a non-ASD clinical comparison group in order to examine the specificity of atypical auditory ERPs in infants at high risk for ASD. • Infants at NR displayed hemisphere lateralization of neural response while infants at HR and CSO did not, suggesting reduced speech perception in both patient groups. • Shared patterns of abnormality in the two patient groups suggests that atypical language lateralization may reflect a general disruption of brain development rather than a specific biomarker of ASD. • Ongoing research examines hemispheric lateralization in larger, equivalent samples of children across a longitudinal development span. Acknowledgements 8 Figure 1. An infant with Ret Le] 4 6 Results CFDVRA ©Ê ±² PÄ~¦¯~Ä\ÎÕ~ ¯¦Î¦Ä\¯ ¦ ¦ÓÄ¡¦£Î¦w ¡\~ ÖÎ ¡~Φ¯n ÆØ£¦ÆΦÆÆ \£w ÎĦ£¦n~¯\Ø´ ±² P¦ÆΦ¯~Ä\ÎÕ~ ¯¦Î¦Ä\¯ Ʀ֣ Ä~ÆÓÎ ÎÖ¦ Ø~\ÄÆ \Î~Ä ~£w¦Æn¦¯n n¦ÄÄ~nΦ£´ ±² PÄ~¦¯~Ä\ÎÕ~ ¡~Φ¯n ÆØ£¦ÆΦÆÆ 4 CSO skull deformity ÖÎ ÎĦ£¦n~¯\Ø´ ±@² TÖ¦ Ø~\ÄÆ \Î~Ä ~£w¦Æn¦¯n n¦ÄÄ~nΦ£ ¦ ¡~Φ¯n ÆØ£¦ÆΦÆÆ´ Dent Right . 1 Figure 4. NR grand averaged waveforms showing lateralization at P150 and N450 Amplitude (uV) Background: • Atypical language development is a characteristic feature of Autism Spectrum Disorder (ASD). • An important skill that develops before children produce speech is the ability to discriminate speech sounds. • Abnormalities have been identified in the developmental trajectory of language perception in ASD.1 • However, given that multiple developmental conditions are associated with language delay, it is unknown whether these atypicalities are specific to ASD or reflective of non-specific developmental disturbance. • Infant ERPs to speech stimuli can predict future language ability.2 ® Results Methods Amplitude (uV) Introduc.on We would like to thank the support staff from the Yale Child Study Center, the Yale Section of Plastic Surgery, and the Office of Student Research at the Yale School of Medicine. We are especially indebted to all the families who graciously agreed to participate in this study. 4 Peak Amplitude (uV) \!_\!\gdu !\dQ 2gbp_AA: YA _!A !_ J gdg[g )\!_ !d: pA \g g )\!_ gAggb\A8 ! p! !bA:\!d gAggb \ b!:A !_gdQ YA bAgp\2 Au YA J gdg[g )\!_ AQbAd Participants: 2!d dg )A :\Q\!__ gJ !2 A: !d: !:!d2A: r\Qu su !)\_\!\gd \ !2Y\AA: \Y ! 2 HR NR pA2\!__ 2 Ag )!)_A bAY ! :A2 \)A: Jg bAgp\2 dgg\ r\Qu jsu YA p AgpA !\A gJ ! \[bgdY[g_: Q\ _ \Y \QY d\2g gd!_ dgg\ ! A Ygd \d \Q A 8 Normal Risk pYggQ !pY H igh R isk for Craniosynostosis 8 Y\_A YA pggpA !\A A_ ! \ bgdY r\Qu 8s !d: ! gdA A! r\Qu 8s 0 for ASD ASD ! A :\p_!A:u NR j :\p_! ! HR CSO Ap AAd!\A p\2 A gJ !2!_ p!\Ad ! A :Abgd !A:u \Q A b\d\b!__ \d!\A !Q\!_ A2gb Y\2Y \__ )A Jg__gA: -‐2 ) )\J gd!_ !d: )\p! \A!_ gAggb\Au p_!dd\dQb! ^\dQ \ :Abgd !A: \d \Q A ju \Q A j # ParQcipants 24 12 YA b\d\b!__ \d!\A13 ® Yg®!d ppA )_ApYA gp_! \d2\\gd )A\dQ pA Jg bA:u YA b\d\b!__ \d!\A 2g gd!_ \d7.0 \Q A j Y\_A YA J gdg[g )\!_ !:!d2AbAd \ Ygd Mean age 6.66 ± 1.9 gAggb 6.46 ±\ 2:Abgd !A: .4 ± 2.1 -‐4 P150 CFDVRA ©Ê ±² PÄ~¦¯~Ä\ÎÕ~ ¯¦Î¦Ä\¯ ¦ ¦ÓÄ¡¦£Î¦w ¡\~ ¡~Φ¯n \£w ÎĦ£¦n~¯\Ø´ ±² \Q A je :Abgd !A !d \bbA:\!A \d \Q A jBuÖÎ JA !__ ÆØ£¦ÆΦÆÆ YA !pp gp \!A gAggb\A8 (months) 2g A2\gd P¦ÆΦ¯~Ä\ÎÕ~ ¯¦Î¦Ä\¯ Ʀ֣ Ä~ÆÓÎ ÎÖ¦ Ø~\ÄÆ \Î~Ä ~£w¦Æn¦¯n ±² PÄ~¦¯~Ä\ÎÕ~ ¡~Φ¯n ÆØ£¦ÆΦÆÆ \d !gpA !\An¦ÄÄ~nΦ£´ Jg__gA: ) Ag )!)_A p_!\dQ Ygd \d \Q A !d: u \Q A ÖÎ ÎĦ£¦n~¯\Ø´ ±@² TÖ¦ Ø~\ÄÆ \Î~Ä ~£w¦Æn¦¯n n¦ÄÄ~nΦ£ ¦ ¡~Φ¯n ÆØ£¦ÆΦÆÆ´ N450 \ ! p\2 A !^Ad \Y YA Ad:g2gpA Yg\dQ YA 2gbp_AA: -‐6 gAggb !d: bA!d Jg : !_ \dpA2\gdu A Y!A \d2 A!\dQ_ dA: g \bp_A A2gb rj 2b \ps Jg Figure 3. Hemisphere contrasts in participant groups d\2g gd!_ dgg\ !d: Y!A Jgd: YA A_ g )A A J!g !)_A \d b\_: g bg:A !A_ CSO Le] Right This research was supported by NIMH K23MH086785 (JM), Simons Foundation 94924 (JM), CTSA Grant Number UL1 RR024139 (LM, JM), the American Society of Maxillofacial Surgeons (JP), the Plastic Surgery Foundation (JP), and the Office of Student Research at the Yale School of Medicine (PH). References 1. Seery AM, Vogel-Farley V, Tager-Flusberg H, et al. Atypical lateralization of ERP response to native and non-native speech in infants at risk for autism spectrum disorder. Dev Cogn Neurosci 2012; 5C:10-24. 2. Molfese DL. Predicting dyslexia at 8 years of age using neonatal brain responses. Brain Lang 2000;72:238–245. 3. Magge SN, Westerveld M, Pruzinsky T, Persing JA. Long-term neuropsychological effects of sagittal craniosynostosis on child development. J Craniofac Surg 2002;13:99-104. 4. Thaller S, Bradley JP, Garri JI. Craniofacial Surgery. CRC Press 2008.
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