Context-Specific Dyadic Attention Vulnerabilities During the First Year in Infants Later Developing Autism Spectrum Disorder

Journal Pre-proof Context-Specific Dyadic Attention Vulnerabilities During the First Year in Infants Later Developing Autism Spectrum Disorder Suzanne Macari, PhD, Anna Milgramm, BA, Jessa Reed, PhD, Frederick Shic, PhD, Kelly K. Powell, PhD, Deanna Macris, MS, Katarzyna Chawarska, PhD PII:

S0890-8567(20)30074-5

DOI:

https://doi.org/10.1016/j.jaac.2019.12.012

Reference:

JAAC 2910

To appear in:

Journal of the American Academy of Child & Adolescent Psychiatry

Received Date: 18 April 2019 Revised Date:

18 December 2019

Accepted Date: 20 December 2019

Please cite this article as: Macari S, Milgramm A, Reed J, Shic F, Powell KK, Macris D, Chawarska K, Context-Specific Dyadic Attention Vulnerabilities During the First Year in Infants Later Developing Autism Spectrum Disorder, Journal of the American Academy of Child & Adolescent Psychiatry (2020), doi: https://doi.org/10.1016/j.jaac.2019.12.012. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Inc. on behalf of the American Academy of Child and Adolescent Psychiatry.

Context-Specific Dyadic Attention Vulnerabilities During the First Year in Infants Later Developing Autism Spectrum Disorder RH = Attention in Infants With ASD Suzanne Macari, PhD, Anna Milgramm, BA, Jessa Reed, PhD, Frederick Shic, PhD, Kelly K. Powell, PhD, Deanna Macris, MS, Katarzyna Chawarska, PhD Supplemental Material Accepted February 7, 2020 Drs. Macari, Reed, Shic, Powell, and Chawarska and Mss. Milgramm and Macris are with Yale Child Study Center, Yale School of Medicine, New Haven, CT. The study was supported by the National Institute of Child Health and Development grant P01 HD003008 (to Dr. Chawarska), the Simons Foundation 187398 (to Ami Klin), and the National Institute of Mental Health grant R01 MH087554 (to Dr. Chawarska). Ethical Considerations: All parents provided permission for their infants to participate via informed consent and the study was approved by the University’s Human Investigation Committee. Drs. Chawarska and Macari served as the statistical experts for this research. The authors wish to express our deep appreciation to the families and their infants for their participation. Disclosure: Dr. Shic has served as a consultant for Janssen and Roche. Drs. Macari, Reed, Powell, and Chawarska and Mss. Milgramm and Macris have reported no biomedical financial interests or potential conflicts of interest. Correspondence to Suzanne Macari, PhD, Yale Child Study Center, Yale School of Medicine, 230 S Frontage Rd, New Haven, CT 06519; e-mail: [email protected]

Abstract: Objective. Although some eye-tracking studies demonstrate atypical attention to faces by six months of age in autism spectrum disorder (ASD), behavioral studies in early infancy return largely negative results. We examined the effects of context and diagnosis on attention to faces during face-to-face live interactions in infants at high (HR) and low (LR) familial risk for ASD. Method. Participants were 6-, 9-, and 12-month-old siblings of children with ASD later determined to have ASD (n=21), other developmental challenges (HR-C; n=74), or typical development (TD) (HR-TD; n=32), and low-risk typically-developing controls (LR-TD; n=49). Infants were administered the Social Orienting Probes task, consisting of five conditions: Dyadic Bid, Song, Peek-a-boo, Tickle, and Toy Play. Attention to an unfamiliar examiner’s face was coded by blinded raters from video recordings. Results. At all ages, the ASD group spent less time looking at the examiner’s face than the HRC, HR-TD, and LR-TD groups during the Dyadic Bid and Tickle conditions (ps<.05), but not during the Song, Peek-a-Boo, or Toy Play conditions (ps >.23). Lower attention to faces during Dyadic Bid and Tickle conditions was significantly correlated with higher severity of autism symptoms at 18 months. Conclusion. During the prodromal stages of the disorder, infants with ASD exhibited subtle impairments in attention to faces of interactive partners during interactions involving eye contact and child-directed speech (with and without physical contact), but not in contexts involving singing, familiar anticipatory games, or toy play. Considering the convergence with eye-tracking findings on limited attention to faces in infants later diagnosed with ASD, reduced attention to faces of interactive partners in specific contexts may constitute a promising candidate behavioral marker of ASD in infancy. Key words: autism, infancy, attention, social interaction, social behavior

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Introduction Autism spectrum disorder (ASD) is a syndrome involving pervasive deficits in social interaction and presence of repetitive behavior with an onset in early childhood1. A characteristic feature of the condition, especially during the toddler years, is limited attention to the faces of interactive partners2-8. This attentional capacity to focus on faces is robustly evident in typically-developing children from early infancy, with faces serving as a window into individuals’ emotional and intentional states and providing critical information for navigation of the social world. For young infants, face-to-face communication achieves several important functions, including fostering early emotion regulation as well as social, cognitive, and communicative development9-11. Moreover, infants’ gaze at their mothers’ faces triggers increased maternal positive affect12 and serves to maintain reciprocal interactions13. Accordingly, newborns orient preferentially to faces and face-like stimuli as well as to direct gaze and gaze cues in the first weeks after birth14-20. Such attentional biases that are either innate or acquired early in the postnatal period are likely to provide a foundation for the development of selective attention to social targets such as faces and gaze cues in real-world situations. Recent eye-tracking studies suggest that such innate or early-emerging attentional biases for faces may be largely intact within the first few months of life in infants who later develop ASD21-23. However, studies examining selective social attention to faces in dynamic free-viewing paradigms, in which infants are free to explore video scenes as they wish, report a limited ability in 6-month-old infants with ASD to selectively attend to faces of interactive partners24, particularly when the person is speaking25. Attention to silent video stimuli containing a person using communication and peek-a-boo cues, however, elicited no ASD-specific differences at 7 or 14 months of age26. In a face habituation paradigm, the longest looks of 6-

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month-old infants with ASD were shorter and occurred later than that of HR and LR control groups27. Thus, limited selective attention and other atypical processing of facial stimuli at 6 months may constitute neurobehavioral markers of ASD that are specific to the early part of infancy and are present before frank, clinically-observed symptoms become apparent. In contrast to results using computer-administered paradigms, the search for behavioral markers of ASD before the first birthday regarding infants’ attention to or affective responses to live partners has returned largely negative results. Several studies involved analysis of interactions, either between the infant and mother28-30 or the infant with an unfamiliar examiner7. Data have been collected in three contexts: the face-to-face still face paradigm31, which manipulates the level of maternal engagement28,30, during standard developmental testing in which an examiner interacted with the child around several object-related tasks7, and in face-toface free play sessions either with toys29 or without toys in which the mother was instructed to interact with her infant as usual28. Coding of infant attention suggests that at 6 months, high-risk infants who later developed ASD (HR-ASD) attended to the mother’s face during the entire stillface paradigm and during an unstructured free play session in similar proportions28,30 and frequencies29 as infants with typical and other atypical outcomes. Similarly, the frequency of 6month-old infants’ gaze to the examiner’s face during developmental testing was comparable between HR-ASD infants and LR-TD infants7. A study utilizing a structured observational measure of autism symptoms at 6 months (the Autism Observation Scale for Infants (AOSI)32 reported similar results: global quality of eye contact with the parent and examiner rated as consistent and sustained for infants later diagnosed with ASD.33 While these studies all noted little evidence that 6-month-old infants with ASD can be differentiated on the basis of attentional differences during live interactions with social partners, 3

by the first birthday it is indeed the case7,28,33-38. Do the previous behavioral findings at 6 months represent the natural course of development in ASD? Possibly, but the results to date, i.e., no behavioral differences in infants with ASD below the age of one year, are inconsistent with neurobehavioral studies of selective attention to faces23-25, neural activation to faces27, and longer visual orienting latencies39, as well as with neuroimaging studies of brain development40-42. In addition to the level of measurement, the context and the interactive partner may also play roles in determining whether ASD-specific abnormalities become apparent. In a structured developmental testing protocol, focus on objects is not only required for completion of the task but also encouraged. Thus, such contexts may not be ideal for the evaluation of social attention. In the still face or parent-infant free play paradigms, it is the mother who is tasked with playing with her infant and eliciting interactive behaviors in ways that are typical in daily life. It is very difficult to standardize such behaviors, however, and variability is expected. Moreover, mothers and infants establish an entrainment of interactional rhythms during the first months of infancy unique to each dyad43, consisting of “exquisitely tuned” complex sequences of temporal patterning44. Thus, utilizing trained examiners without such history as interactive partners may provide some methodological advantages. In addition, investigating play tasks with different social features (e.g., child-directed speech, gesture games, songs) in the presence or absence of toys may be useful for identifying conditions under which social difficulties may become apparent in infants at risk for autism. In summary, although neurobehavioral23-25,27,39 and neuroimaging40-42 work suggests that early markers of ASD may be present already at 6 months, there is little evidence that these abnormalities are apparent in the context of real-world interactions. Specific design features of past studies of directly-assessed behavior raise the question, however, as to whether this 4

evidence is fully exhaustive. To address some of the methodological concerns, we designed a novel behavioral task, the Social Orienting Probes (SOP) protocol, in which an experienced and trained examiner presents an infant with five 1-minute structured and graduated bids for social attention, affect, and engagement. The SOP task varied in type and amount of social content and consisted of five conditions: child-directed speech (Dyadic Bid), singing, a peek-a-boo game, a tickle game, and a toy demonstration. The infant’s visual attention to the examiner was subsequently coded off-line. By implementing the SOP protocol in a sample of infants at high familial risk for ASD, we aimed to examine if early attentional markers of ASD can be detected using this novel approach. We hypothesized that infants with ASD would attend less to the examiner’s face at 6, 9, and 12 months of age compared to HR infants with and without developmental delays and LR controls. This decrement in attention may either be specific to the Dyadic Bid condition, as observed in previous studies24-25, or it may be more generalized, in which case the deficit would be observed across all five conditions. Furthermore, varying the types of dyadic, perceptual, and physical cues allows for the examination of potential factors that may enhance or reduce attention to faces in infants at risk. METHOD Participants Participants included infants enrolled prior to the age of 6 months (mean age at enrollment: 1.5 months (SD=3.8 months); mean age at first visit: 3.8 months (SD=2.4 months)) in a prospective longitudinal study of social development. Out of 176 participants, 127 infants were younger siblings of children with ASD and thus at high risk (HR) for ASD. Forty-nine infants had no history of ASD in 1st or 2nd degree relatives and were considered low risk (LR) for

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ASD. Exclusionary criteria were gestational age below 34 weeks, any hearing or visual impairment, nonfebrile seizure disorders, or known genetic syndromes. The study was approved by the University’s Human Investigation Committee and all parents provided written permission for their infants to participate and be video-recorded. All infants received the Mullen Scales of Early Learning at 6 and 12 months of age. Each infant underwent diagnostic evaluations at 18 (97.7%), 24 (98.3%) and 36 months (80.2% in the HR group) by a psychologist and a speech-language pathologist blinded to risk group and previous diagnosis. By design only a portion of the LR group was followed to 36 months. The clinical best estimate (CBE) diagnosis was based on a multidisciplinary evaluation. The psychologist conducted assessments using the Mullen Scales of Early Learning45, and the Autism Diagnostic Observation Schedule-2 (ADOS-2)46, while the Vineland Adaptive Behavior Scales47 was conducted by a clinical social worker. The team, utilizing all the available information, assigned a CBE diagnosis by consensus and if consensus could not be reached, another clinician (KC) reviewed the materials and assisted with the diagnostic process. Based on a combination of risk status and CBE, the following groups were created: ASD; n=21 (1 infant was from the LR group); HR with complex developmental trajectories (HR-C; n=74), HR with typical development (HR-TD; n=32), and LR typically-developing (LRTD, n=49). Whether LR or HR, the TD groups included children who showed no evidence of delays or atypicalities on the ADOS or Mullen or by clinical impressions at all ages at which they were clinically evaluated (i.e., 18, 24, and 36 months). The HR-C group included children with delays and abnormalities that were either persistent (n=55) or manifested transiently (n=19). Infants exhibiting Broader Autism Phenotype features, (BAP; n=46), language delays (n=18), subthreshold symptoms of language or other disorders (n=2) global developmental delays (n=1), 6

other problems such as disruptive behavior (n=4), or early ASD symptoms that subsequently resolved (n=3) were included in the HR-C group. The presence of such difficulties was interpreted as the early expression of vulnerabilities related to ASD risk. The TD groups were defined strictly in order to enable examination of risk-related vulnerabilities or compensatory processes amongst HR infants without ASD but who nonetheless evidence developmental challenges (HR-C). As noted by others, HR infants without ASD are prone to long-term difficulties48-50. Please see Table 1 for participant characterization at 6, 12, 18, and 24 months. The distribution of male and female infants differed significantly across groups, χ2(3)=15.89, p=.001, with the highest proportion of male infants in the ASD group (80.0%) and the lowest in the LR-TD group (40.8%). There were no differences across the four groups on the Mullen at 6 months. Beginning at 12 months, the ASD and HR-C groups had significantly lower Verbal DQ scores than the HR-TD and LR-TD groups (ps<.001) and, starting at 18 months, these two groups also had significantly lower Nonverbal DQ scores than the TD groups. On the ADOS, the ASD group had the highest Social Affect (SA) scores (reflecting the greatest presence of autism symptoms) at 12, 18, and 24 months, followed by the HR-C group, who in turn had higher SA scores than both TD groups. At 12 months, the ASD group’s RRB scores were highest, and at 18 months, the ASD group had the highest RRB scores, while the HR-C and the HR-TD group’s scores were similar and higher than those of the LR-TD infants. At 24 months, the RRB scores in the ASD group were highest, with the two TD groups lowest and the HR-C group in between. Most parents identified their child’s race as Caucasian (87.5%; the remaining 12.5% consisted of other races), and their ethnicity as non-Hispanic (88.6%; with 11.4% Hispanic). There were no differences between outcome groups in either race or ethnicity (p=.70; p=.59, 7

respectively). The level of educational attainment of both mothers and fathers was high, corresponding to slightly more than a 4-year college degree on average, and did not differ significantly across groups (p=.07 for mothers; p=.38 for fathers). Procedure Infants were administered the Social Orienting Probes (SOP) at 6, 9, and 12 months of age. Trained examiners administered a series of five face-to-face standardized one-minute interactions in a set order of five conditions: Dyadic Bid (speaking using infant-directed speech); Song (singing a popular nursery rhyme); Peek-a-Boo (examiner covering face with her hands and revealing it, with a “peek-a-boo” exclamation); Toy Play (demonstrating a Ferris wheel toy); and Tickle (approaching slowly with hands saying, “I’m gonna get you!” and tickling the infant on the belly and under the chin). Infants were seated in a table-top seat approximately 50 cm away from the examiner at 6 and 9 months, and in a toddler seat approximately 60 cm away from the examiner at 12 months, with a parent seated diagonally behind them within their view. Examiners were trained on all aspects of administration including pace, intensity of affect, and infant-directed speech prosody. The purpose of the Dyadic Bid condition was to engage the infants using verbal means along with eye contact and positive affect. Examiners were trained to speak more slowly, and with higher and more variable pitch than their usual speaking voice. The content of their monologue consisted of a few developmentally-appropriate themes (e.g., compliments regarding the infants’ appearance, the weather, etc.). No touching of the infants occurred except during the Tickle condition. Sessions were videotaped in a split-screen view with one side a frontal view of the infant and the other side a profile view of the infant and examiner (Please see Figure 1).

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=============================== Insert Figure 1 about here =============================== Videos of the sessions were coded offline in real time using Noldus: The Observer behavioral software (versions 5.0, XT 9, and XT 12) by coders blinded to the infants’ risk group, developmental outcomes, and the hypotheses of the study. Codes were mutually-exclusive duration codes and included infant attention to the examiner’s face, the examiner’s body, the self, objects, parent, or unknown target of attention; only the primary dependent variable of attention to examiner’s face is reported here. Coders recorded onset and offset of the infants’ focus of attention through Observer. All coders were trained to reliability by establishing >.80 ICCs with gold standard sessions. Ongoing interrater reliability was calculated by double-coding a randomly-selected 10% of the sessions utilizing a two-way random ICC model; the mean ICC for all rater pairs for attention to examiner’s face was r = 0.991. Data reduction Of the 176 infants included in the study, 119 (67.6%) were administered the SOP at all three time points. Sixteen (9.1%) had data at 6 and 9 months only; 9 (5.1%) had data at 6 and 12 months only; and 32 (18.2%) had data at 9 and 12 months only. Missing versus complete data did not vary as a function of risk status (p=.67) or outcome group (p=.82). Of the 57 missing data points, 12 were due to a missed visit; in 41 cases, the infants were too tired or fussy to complete the procedure; an additional 4 were not codeable due to recording errors.

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Attention to the examiner’s face was standardized over the duration of each condition during which the target of attention was known (i.e., excluding segments coded as “unknown”). Each condition lasted approximately 60 seconds (M=56.7, SD=12.8). Given the hypotheses of the study, we considered the proportion of time the infant looked at the examiner’s face (%Face). There were no group differences in the proportion of time the infants’ target of attention was known versus unknown (%Unknown; (F(3,168)= 1.50, p=.22). Statistical Analyses Hypotheses were evaluated using linear mixed models with age (6, 9, and 12 months) and condition (Dyadic Bid, Song, Peek-a-Boo, Toy, and Tickle) as the within-subjects factors, and diagnostic group (ASD, HR-C, HR-TD, and LR-TD) and sex (M, F) as the between-subjects factors. Sex was included in the model given the significant differences in sex distribution across groups (see Participants). We tested main effects of group, age, and condition, as well as their interactions, and main effects of sex. All significant interactions involving group were tested using planned contrasts comparing the ASD group with the three other groups. Other significant interaction effects were tested using post-hoc comparisons with Holm-Bonferroni correction, adjusting the alpha to the number of comparisons, i.e., for the ten comparisons across conditions at each age point, the Holm-Bonferroni-adjusted alpha was .005, and for the three comparisons across groups for each condition, Holm-Bonferroni-adjusted alpha was .017. Pearson’s r correlations partialled for sex were employed to assess the relationship between attention to the examiner’s face during conditions in which performance differed across groups and social and verbal ability at 18 months, the age at which the majority of children with ASD exhibited clear and clinically-significant symptoms and before intervention effects occurred. All analyses were implemented using SAS51. 10

RESULTS Analysis of %Face revealed a main effect of condition (F(4,692 = 808.86, p<.001), and no main effects of age (p=.10), group (p=.24), or sex (p=.50). There was a significant condition by group interaction (F(12,686) = 2.11, p=.015) and a significant age by condition interaction (F(8,1213) = 3.98, p<.001). Neither the group by age interaction (p=.53) nor the three-way interaction were significant (p=.41). See Figure S1 (available online) for an illustration of all conditions at all time points by group. Group x condition interaction. Planned contrasts indicated that, as hypothesized, the ASD group looked significantly less at the examiner’s face in the Dyadic Bid condition compared to the HR-C (p<.05, d=.53), HR-TD (p<.01, d=.82) and LR-TD (p<.01, d=.83) groups. The ASD group also spent less time looking at the examiner’s face in the Tickle condition compared to the HR-C (p<.01, d=.66), HR-TD (p<.01, d=.64) and LR-TD (p<.01, d=.73) groups. There were no differences between the ASD group and the comparison groups in the Peek-a-Boo, Song, or Toy Play conditions (all p-values >=.23) (see Figure 2). =============================== Insert Figure 1 about here =============================== Age x condition interaction. Age by condition interactions were explored in a post-hoc manner, thus were Holm-Bonferroni corrected. Within each age, there was a significant difference in %Face across the five conditions (see Figure 3). At 6 months, %Face differed significantly across all conditions, with the highest attention to the examiner’s face registered in 11

the Peek-a-Boo condition followed by Song, Dyadic Bid, Tickle, and the Toy Play condition. At 9 months, results for %Face were the same as at 6 months, except that Dyadic Bid and Tickle received a similar amount of attention to the examiner’s face. At 12 months, Song and Peek-aBoo elicited the highest levels of attention to the examiner’s face, followed by Dyadic Bid and Tickle, and Toy Play again attracting the lowest amount of attention. All significant p-values were less than .005 and Cohen’s ds ranged from d=.26 (between Dyadic Bid and Tickle at 6 months) to d=4.96 (between Peek-a-Boo and Toy Play at 9 months). Age effects were observed within each condition. Attention to examiner’s face declined from 6 to 12 months in the Dyadic Bid condition (p<.01, d=.25) and in the Peek-a-Boo condition from 6 to 9 and from 9 to 12 months (ps<.001, d=.44, d=.37, respectively). In the Toy Play condition, attention to the examiner’s face increased from 6 months to 9 months and then decreased from 9 months to 12 months (ps<.001, d=.54, d=.32 respectively). Attention to the examiner’s face was stable over time in the Song and Tickle conditions. ===================================== Insert Figure 2 about here ==================================== Pearson’s r correlation analysis conducted between attention to the examiner’s face during the Dyadic Bid at 6, 9, and 12 months and clinical measures at 18 months (ADOSToddler Social Affect Score and Mullen Verbal DQ) partialled for sex showed nonsignificant and marginal associations at 6 months (r= -.11, ns; r=.17, p=.054, respectively), and modest but

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significant associations at both 9 months (r= -.26, p=.001; r=.19, p=.016, respectively) and 12 months (r= -.25, p=.002; r=.21, p=.010 respectively). See Figure 4A. Pearson’s r correlation analysis conducted between attention to the examiner’s face during the Tickle condition at 6, 9, and 12 months and clinical measures at 18 months (ADOSToddler Social Affect Score and Mullen Verbal DQ) partialled for sex showed nonsignificant associations at 6 and 9 months, while at 12 months, there was a modest but significant association with the ADOS Social Affect score (r= -.21, p=.009). See Figure 4B. Correlations were also run using 24-month clinical measures with similar results. See Table S1, available online.

DISCUSSION This is the first prospective study of infant siblings of children with ASD to document ASD-specific impairments in attention to speaking faces during the early prodromal stage of the disorder in a context of live face-to-face interactions. The specific interactive contexts which separated infants later diagnosed with ASD from the comparison groups consisted of standard bids for social engagement involving eye contact and child-directed speech as well as those that involved a combination of eye contact, speech, and physical contact. The contexts that failed to elicit significant differences were those in which either familiar songs or anticipatory routines were present or the interaction involved a demonstration of an attractive toy. The current findings diverge, however, from prior work employing behavioral methods with infants between 6 and 12 months of age. Several factors could be in play, including granularity of measurement (global clinician rating)33, measurement context (object-based play, still face paradigm)7,28,30, and familiarity of the social partner (mother)28-30. The current study addressed these issues, utilizing 13

granular continuous behavioral coding, a task that emphasized social interactions, and unfamiliar but friendly female adults who implemented the task in a standardized manner. The finding of attentional vulnerabilities in infants with ASD during the Dyadic Bid episode, which consisted of one minute of speaking to the infant using child-directed speech, is concordant with the eye-tracking results of Shic and colleagues25, wherein 6-month-old infants with ASD looked significantly less at the inner facial features of a person reciting a nursery rhyme than HR and LR controls, yet all groups attended in similar proportions to inner features of silent, smiling dynamic faces and static faces. The results are also consistent with two reports of toddlers with ASD reporting diminished attention to the face and to the scene in general when these included social engagement consisting of eye contact with speech52 or speech with or without eye contact53. Together, all these studies suggest reduced visual interest in infants with ASD toward social partners who are attempting to engage with them using child-directed speech, where diminished interest in child-directed speech may be key54,55. Significant associations between attention to the face during Dyadic Bid in the first year and language and socialcommunication skills at 18 months provide additional support for the notion that this difference in attention represents an early behavioral marker of aberrant development of socialcommunication ability. The Tickle routine, the second condition during which infants with ASD exhibited diminished attention to the social partner, is unique among the conditions due to its sensory complexity. As in Peek-a-Boo, there is repetition, the use of hands, and speech infused with high positive affect; but in Tickle, the examiner approached with her hands in an anticipatory manner and tickled the infant. Such complex components characteristic of early parent child-interactions, including combinations of gaze, speech and touch, have been shown to enhance learning. For 14

example, providing touch to body parts effectively aided 4-month-olds in segmenting spoken body part labels during continuous speech streams56. In 11-month-olds, addition of vocal cues to gaze cues during a joint attention task enhanced object information processing compared to gaze alone59. While such multimodal input can impede attention to unimodal details early in development, experience gradually allows more flexible attention to stimuli, resulting in the ability to attend to multisensory properties of events in a single bout58. By this reasoning, the visual, auditory, and tactile stimulation that occur during the Tickle condition all compete for attentional resources and the infants with ASD may have difficulty attending to all channels59. Alternatively, tactile input may induce additional physiological arousal that negatively impacts the already vulnerable social-attentional abilities of infants with ASD. The study suggests, however, that singing, anticipatory routines, and introduction of a toy into the interaction all attenuate attentional differences between infants later diagnosed with ASD and comparison groups. Indeed, object-based interactions did not elicit marked differences in social attention in young infants with ASD in another study7. In the current study, human song elicited visual interest to the examiner’s face from all groups equally. This result is consistent with recent neuroimaging studies showing intact activation and connectivity of frontal-temporal regions during music or sung speech alongside decreased activation and connectivity during perception of spoken words in school-age children and adolescents with ASD60,61. The highly familiar routine of Peek-a-Boo attracted a large proportion of attention to the face for all infants including those with ASD. Peek-a-Boo is a ritualized game with salient speech and gesture components that follow the prototypical tension fluctuation structure of crescendo-peakdecrescendo62. Detection of information specifying these “vitality contours”63 during social interactions begins early in infancy, with such contours serving as scaffolding for intersubjective

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experiences64. It appears that the peek-a-boo interaction offered here in a “package”65 of familiar visual-auditory stimulation is not subject to the emerging vulnerabilities in attention of the infants later diagnosed with ASD. A similar phenomenon has been observed in preschoolers with ASD, whose responsive social behaviors were indistinguishable from those of their DD and TD peers during such highly structured social routines with both caregivers and strangers66. As seen in the “goldilocks effect”67 for attention to visual and auditory stimuli in TD infants68,69, there may be an optimal amount of multimodal stimulation that supports social attention in infants with ASD. The contours of the u-shaped curve representing stimulus complexity for infants with ASD may be shifted, however, such that the Dyadic Bid stimuli were not complex enough to hold the infants’ social attention at levels similar to controls and the Tickle stimuli were too complex. By the same token, the song, peek-a-boo, and toy conditions were just complex enough to elicit similar levels of social attention from infants with ASD as from peers. Furthermore, the between-condition results suggest that social engagement stimuli can be adjusted or titrated to reveal the vulnerabilities in social attention in infants later diagnosed with ASD. In the case of the task utilized in this study, the abnormalities in the ASD group appeared at a midrange of attention to the examiner’s face (Dyadic Bid and Tickle conditions), while other social stimuli produced either low levels of attention to the examiner (Toy Play) or high levels of attention (Song and Peek-a-Boo; see Figure S2, available online) consistently across all groups of infants. Previous studies have demonstrated similar contextual effects on attention to a social partner in children with ASD52,54,70. Other notable findings were the age-related trends in social attention. During the 6-12month time frame, a trend was observed in all groups during the Dyadic Bid and Peek-a-Boo conditions for declining attention to the examiner’s face. Similar age-related declines over the

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first year have been reported in the amount of time infants spent gazing to their mothers71 and in mean duration of looks72. In addition, in the Toy Play condition, there was a tendency in all groups to increase attention to the examiner’s face from 6 to 9 months, then decrease from 9 to 12 months. Relative heightening of attention to the social partner at this time point may reflect the “9-month social-cognitive revolution”73 wherein infants first recognize the intentionality of others and therefore begin to monitor partners’ faces while exploring objects74. Finally, the correlations between face gaze at 9 and 12 months and later Mullen verbal and ADOS Social Affect scores are indicative of a relationship between early social attention and the development of social and communication skills. Gaze is the earliest communication system to emerge between infants and adults13 and forms the basis of primary intersubjectivity, including states of synchronized or reciprocal communication75. Mutual gaze within a face-toface interaction is an essential social-communicative behavior12,13 and thus highly relevant to the core domains affected by ASD. Moreover, dyadic attention and other dyadic skills may affect future triadic behavior75, which in turn influences language and communication development76. Since attention was coded from videorecordings, it was not possible to code specific regions of the face. Also, given prior reports in which parents were the social partners28-30, these results are not likely to generalize to situations involving familiar people. However, diminished attention to faces in infants with ASD may be reproducible with less familiar partners, for example, pediatricians, nurses77, daycare providers, or other adults. Replication and extension studies are necessary to further elucidate factors affecting attention to faces in infants at high risk for ASD.

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This is the first study to document atypical gaze behavior within specific kinds of face-toface interactions in 6-12-month-old infants later diagnosed with ASD. Given that learning about people is a highly experience-dependent process78,79, the presence of abnormal attention to these essential social cues in early infancy may impact the development of social cognition and communication as well as specialization of the neural networks involved in processing social stimuli. Furthermore, these early differences in social attention in infants with ASD could signal difficulties processing multimodal stimuli, which may interfere with learning about the world from social partners. Future research should explore how early these highly conserved attentional abilities begin to go awry in this population during early postnatal months as well as test the mechanisms that drive reduced attention to faces at this stage in infancy.

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Table 1. Participant Characterization HR-ASD

HR-C

HR-TD

LR-TD

21

74

32

49

%Male

81.0

70.3

50.0

40.8

Age in months

6.4a (0.6)

6.5a (1.0)

6.4a (0.6)

6.2a (0.3)

MSEL VDQ

78.7a (12.2) 94.1a (13.7)

77.5a (17.1) 93.1a (23.8)

79.1a (13.2) 97.9a (23.8)

84.3a (13.2) 97.8a (16.5)

Age in months

12.5a (0.5)

12.4a (0.7)

12.5a (0.6)

12.3a (0.6)

MSEL VDQ

75.0a (20.3) 103.3a (12.0)

82.3a (16.9) 112.9b (13.7)

96.7b (16.5) 113.4b (12.0)

95.6b (19.1) 118.9b (11.7)

ADOS-T SA

12.4a (4.9)

8.5b (4.1)

5.9c (4.1)

4.9c (2.8)

ADOS-T RRB

1.7a (1.4)

0.9b (1.2)

0.6b (0.9)

0.8b (1.1)

Age in months

18.2a (0.5)

18.5a (0.8)

18.4a (0.8)

18.6a (0.9)

MSEL VDQ

78.8a (30.4) 97.2a (11.2)

85.6a (23.6) 100.9a (10.9)

114.2b (19.4) 109.3b (10.7)

115.1b (18.3) 110.8b (11.7)

ADOS-T SA

10.4a (5.5)

6.6b (3.7)

2.4c (1.8)

3.1c (2.1)

ADOS-T RRB

2.2a (1.6)

1.3b (1.2)

0.8b (1.0)

0.5c (0.8)

Age in months

24.5a (1.1)

24.8a (1.3)

24.7a (1.6)

24.5a (1.0)

n

6 months n=144

MSEL NVDQ 12 months n=160

MSEL NVDQ

18 months n=172

MSEL NVDQ

24 months

30

n=173 92.6a (25.7) 94.7a (17.2)

103.6a (20.9) 103.1a (13.4)

120.2b (16.5) 113.8b (14.1)

127.1b (18.6) 116.6b (13.2)

ADOS-T SA

9.8a (5.1)

5.6b (4.0)

1.9c (1.8)

2.6c (2.0)

ADOS-T RRB

2.3a (1.5)

1.2b (1.0)

0.5c (0.6)

0.5c (0.7)

MSEL VDQ MSEL NVDQ

Note: Values with different superscripts differed from each other at p < .05 or less. ADOS-T = Autism Diagnostic Observation Schedule-Toddler Module; ASD = Autism Spectrum Disorder; HR-C = High-Risk Complex; HR-TD = High-Risk Typically Developing; LR-TD = Low-Risk Typically Developing; MSEL = Mullen Scales of Early Learning; NVDQ = Nonverbal Developmental Quotient; RRB = Restricted, Repetitive Behaviors; SA = Social Affect; VDQ = Verbal Developmental Quotient.

31

Figure 1. Social Orienting Probe During the Dyadic Bid Condition

Figure 2. Proportion of Time Spent Looking at the Examiner’s Face During Each Condition of the Social Orienting Probe, Collapsed Across 6-, 9-, and 12-Month Measurement Points Note: Error bars denote +/- 1 standard error. ASD = autism spectrum disorder; HR = high-risk; HR-C = infants from the high-risk group with complex developmental trajectories; LR = lowrisk; TD = infants with no evidence of clinically significant symptoms in the second or third year. *p < .05; **p < .01.

Figure 3. Proportion of Time Spent Looking at the Examiner’s Face During Each Condition of the Social Orienting Probe, Collapsed Across Outcome Groups Note: Error bars denote +/- 1 standard error. ASD = autism spectrum disorder; HR = high-risk; HR-C = infants from the high-risk group with complex developmental trajectories; LR = lowrisk; TD = infants with no evidence of clinically significant symptoms in the second or third year.

Figure 4. Proportion of Time Spent Looking at the Examiner’s Face During the Dyadic Bid Condition at 9 Months (A) and During the Tickle Condition at 12 months (B), Both Plotted Against Autism Diagnostic Observation Schedule-2, Toddler Module (ADOS-T) Social Affect Total Score at 18 Months Note: (A): Pearson’s r = -.26, p = .001. (B) Pearson’s r = -.21, p = .009. SA = social affect.

32

Context-Specific Dyadic Attention Vulnerabilities During the First Year in Infants Later Developing Autism Spectrum Disorder Suzanne Macari, PhD, Anna Milgramm, BA, Jessa Reed, PhD, Frederick Shic, PhD, Kelly K. Powell, PhD, Deanna Macris, MS, Katarzyna Chawarska, PhD

The study was supported by the National Institute of Child Health and Development grant P01 HD003008 (to Dr. Chawarska), the Simons Foundation 187398 (to Ami Klin), and the National Institute of Mental Health grant R01 MH087554 (to Dr. Chawarska). Ethical Considerations: All parents provided permission for their infants to participate via informed consent and the study was approved by the University’s Human Investigation Committee. Drs. Chawarska and Macari served as the statistical experts for this research. The authors wish to express our deep appreciation to the families and their infants for their participation. Disclosure: Dr. Shic has served as a consultant for Janssen and Roche. Drs. Macari, Reed, Powell, and Chawarska and Mss. Milgramm and Macris have reported no biomedical financial interests or potential conflicts of interest.