Background
Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects more than 1 % of the US population [
1]. Individuals with ASD experience difficulty with social communication and display restrictive interests and repetitive behaviors [
2,
3]. Reliable diagnosis of ASD can be made by 18 months to 3 years for most individuals, and the average age of diagnosis is around age 4 years in the USA [
4], but parent concerns begin earlier, particularly if there is an older sibling with ASD in the family [
5]. Understanding the causal paths to ASD requires studying infants prior to the onset of autism-specific behavioral symptoms [
6]. Over the last 10 years, a number of investigators have begun to address these questions using prospective studies of infants with older siblings with ASD. Since infants with an older sibling with ASD have close to a 20 % risk of developing ASD themselves [
7], researchers can examine the neural and cognitive precursors to symptom emergence by following a cohort of “infant siblings” from early infancy to early childhood.
Infant sibling studies have led to significant progress in characterizing the emergence of behavioral symptoms of ASD [
6], in part replicating findings from earlier case report, parent report, and retrospective videotape studies [
8‐
10]. Such work has broadly revealed that infants start to fall behind their peers in their social and communication skills early in the second half of the first year of life [
11]. Findings hold significant promise for improvements in early screening [
12]. However, far less is known about the disruptions to perception, attention, or learning that precede the progressive failure to develop social and communication skills at the typical pace in infants with later ASD. Shifting the level of analysis from behavioral symptoms to the developmental mechanisms that underlie their emergence is critical to the design of more effective interventions and will help to bridge the gap between genetics and clinical presentation.
Social attention models of ASD propose that deficits in social attention and orienting begin to emerge in the second half of the first year of life, leading to reduced engagement with social stimuli, and thus reduced opportunities for social learning [
13‐
16]. These early deficits may thus have cascading effects on social communication development. Such models suggest that early social attention may be a fruitful target for early intervention. Thus, testing social attention/motivation models has been a strong focus of work with infant siblings [
6]. The majority of such studies have focused on examining
where infants direct their attention during naturalistic live and video-based social experiences because this reveals the type of information infants are sampling from their environment. Such work presents a mixed picture of early social attention in ASD. Some studies have observed disruptions in early social attention: for example, 6-month-old infants with later ASD show reduced visual attention to inner facial features when faces are speaking [
17] and reduced attention to an actress in a naturalistic scene [
18]. However, in other studies, 7- and 14-month-old infants show typical patterns of orienting to faces in static displays [
19] and typical modulation of attention to different types of facial movement in complex social displays [
20]. Other studies have observed gradual reductions in attention to the eyes of a naturalistic “caregiver” video between 2 and 24 months [
21] and to faces during a live observational assessment between 6 and 36 months [
11]. Reasons for the disparity in findings on the
direction of attention over the first year of life remain unclear.
Developmental decreases in allocation of attention to social stimuli in ASD could be a consequence of earlier-emerging difficulties with processing social information [
6,
14,
22]. Under such models, initial subcortically mediated social orienting mechanisms are intact in ASD [
23], but difficulties with processing incoming social information make social experiences progressively less rewarding, leading to decreases in social attention over developmental time. Chawarksa and colleagues have argued that the depth of processing afforded to social stimuli may be atypical in infants with later ASD, causing cascading consequences for subsequent learning [
24]. For example, they propose that while typically developing toddlers may examine a novel face and spontaneously compute its category (face or non-face?), familiarity (mother or stranger?), and affect (happy or sad?), toddlers with ASD may engage in more limited processing. This is expected to lead to poorer face learning because work with adults indicates that deeper processing facilitates later retention (e.g., [
25]). In the hypothesis of reduced depth of processing for face stimuli, toddlers with ASD show more rapid disengagement from a face than an object stimulus [
24], are less distracted by the presence of a face in a gaze cuing task [
26], and show slowed face learning [
22]. Further, toddlers with ASD show developmental delays in how facial familiarity modulates attention-related neural responses, and the extent of the developmental delay relates to their general social level [
27]. However, to establish whether these disruptions could contribute to the emergence of ASD (rather than representing a consequence of spending less time attending to other people), it is necessary to examine whether they are present prior to ASD symptom expression. Thus, in the present study, we set out to test whether a reduced depth of attention to social stimuli is present in infants at high risk for ASD in the first year of life.
We selected two widely used paradigms to test this proposal. First, we used a habituation paradigm to examine the duration of individual epochs of attention to social and nonsocial stimuli. In a habituation task, infants are presented with a stimulus that is repeated until the infant’s looking declines to a predefined level. In such paradigms, the duration of the longest look to the stimulus produced prior to the habituation criteria partly reflects individual differences in sustained attention [
28], with a longer peak look associated with higher levels of attention engagement to the stimulus. In typical development, individual differences in peak look duration are relatively reliable, show robust relations to long-term cognitive outcomes [
29], and are stable across different screen-based paradigms [
30]. Measurement of concurrent heart rate indicate that over 50 % of the duration of the infant’s peak look is spent in a state of “sustained attention” to the stimulus, and this proportion is particularly high around the age of 6 months [
28]. A second related measure of attention engagement derived from habituation paradigms is the position of the peak look in the looking sequence. About two thirds of “typical” infants do not show a monotonic decrease in look duration during habituation [
31]. The “dual-process” account [
32] of habituation posits that in addition to progressive habituation to stimulus characteristics, an additional process of “sensitization” operates that is associated with a spike in parasympathetic arousal that
increases attention to the stimulus [
33]. Sensitization is thought to be important in engaging deeper levels of processing in response to communicative cues, including the facilitation of learning by infant-directed speech [
34,
35]. Thus, a peak look that is later in the habituation sequence would indicate delayed sensitization to the stimulus. Taken together, a peak look that was shorter in duration and later in the habituation sequence would be associated with reduced attention engagement to social stimuli.
Secondly, we examined event-related potentials (ERPs) to faces and objects. In an ERP paradigm, EEG is continuously recorded while infants view briefly presented stimuli. The neural response time-locked to each stimulus presentation is averaged within each category, producing a characteristic pattern of components that are sensitive to the time-course of information processing. Such paradigms have already shown sensitivity to detecting atypical social processing in infants with later ASD; for example, 8-month-old infants with later ASD show an attenuated P400 response to shifts in gaze direction [
36]. Here, we were interested in two components (the P400 and the Nc) that have been previously shown to be sensitive to depth of attention engagement and processing of social stimuli in ASD. The Nc is a negative-going deflection that peaks around 500 ms after the onset of a particular stimulus [
37]. Because it is modulated by novelty [
38], and stimulus salience [
37], and is larger to stimuli presented during physiologically defined states of attention [
39], the Nc is thought to reflect attention engagement [
40]. Previous work with toddlers with ASD has shown that the modulation of the Nc by facial familiarity is atypical [
27]. In the present study, we examined Nc amplitude (as a measure of initial depth of engagement) and the duration of the Nc as a measure of the degree to which attention was sustained. We predicted that a smaller and less sustained Nc component would reflect reduced attention engagement with faces in infants with later ASD.
Secondly, the P400 is a positive-going deflection that typically peaks around 300 to 600 ms after stimulus onset [
40‐
42]. In infancy, this component is sensitive to complex aspects of face processing. For example, in typical development, the P400 is modulated by face inversion [
43], dynamic gaze shifts [
36], and peaks earlier and with smaller amplitude to faces than objects, consistent with greater attention capture or depth of processing by unfamiliar objects than faces in this age range [
41,
44]. Taken together, researchers have argued that the P400 reflects the processing of semantic and structural aspects of faces and may be the precursor to the adult N170 [
40]. We predicted that if infants with later ASD show reduced depth of engagement with faces, the P400 response to faces would peak even more rapidly and be of even smaller amplitude in infants with later ASD than in typically developing infants. Of note, a faster P400 latency to faces versus objects would replicate findings in a previous study of 6- to 10-month-old infants with later ASD [
36].
We tested infants at 6 and 12 months because this represents the timescale over which clear symptoms of ASD in social and communication domains begin to emerge [
6]. Thus, we were particularly interested in differences in attention engagement that may be apparent at 6 months and could thus potentially contribute to autism-specific symptom emergence. Interestingly, recent studies of high-risk infants have suggested that some deficits in basic aspects of development may be apparent in early infancy but appear to resolve in later development. For example, Libertus and colleagues [
45] recently showed deficits in reaching and grasping in 6-month-old infants at high risk for ASD that apparently resolved at 10 months. Further, a recent large study also found motor delays at 6 months in infants with a later ASD diagnosis; these delays appeared to resolve by 12 months but emerged again by 24 months [
46]. At older ages, deficits in more complex aspects of development may become more apparent (e.g., the onset of walking [
47]). This may reflect transient delays in the acquisition of newly emerging skills that accumulate into cascading effects over the infancy period [
6,
48]. Because our paradigms are simple and suitable for very young infants, it may similarly be that deficits would be detected at 6 months (representing a transient delay) but apparently resolved by 12 months. Of note, other previous studies that have observed deficits in social processing at 6 months [
17,
18,
36] have not examined the same variables at older ages, making this an important question.
Although there has been a long tradition of work with typically developing infants using our paradigms, we first sought to establish that the particular test format we had chosen elicited the expected pattern of normative performance in a large group of typically developing infants at 6 and 12 months (Experiment 1). Comparison of our findings to previous work indicates that our paradigms produce the expected developmental effects. Secondly, in Experiment 2, we examined performance in an independent sample of infants at high and low familial risk from a prospective longitudinal study who did and did not later develop ASD.
Results
Habituation to faces and objects
Peak look duration
In a repeated-measures ANOVA on peak look duration by age (6 or 12 months), gender (male, female), and stimulus (face, object), peak look duration was longer to face than objects (
F(1,100) = 9.40.
p = 0.003,
η
2 = 0.09), and peak look duration was shorter at 12 months than 6 months (
F(1,100) = 21.77,
p < 0.001,
η
2 = 0.18). There was no significant interaction between stimulus and age (
F(1,100) = 0.82,
p = 0.37,
η
2 = 0.008), and no main effects or interactions with gender (
Fs < 1,
ps > 0.3). These patterns are consistent with previous work [
28,
29,
63], confirming that our paradigm was robustly designed.
Peak look position
In a repeated-measures ANOVA on peak look position by age (6 or 12 months), gender (male, female), and stimulus (face, object), there were no differences in the position of the peak look in the sequence for faces and objects (
F(1,100) = 0.061,
p = 0.81,
η
2 = 0.001) or for the two age groups (
F(1,100) = 1.33.
p = 0.25,
η
2 = 0.013) and no interaction with age and stimulus (
F(1,100) = 0.33,
p = 0.6,
η
2 = 0.003). However, broadly in line with previous work [
50], 60 % of 6-month-olds and 50 % of 12-month-olds tended to produce their peak look after the first look in the habituation function. This confirms that our stimuli produce effects consistent with sensitization in a substantial proportion of infants.
Dishabituation
Finally, analysis of dishabituation times separately for each age group (6 and 12 months), delay (short, long), and stimulus (face, object) indicated that dishabituation magnitudes were significant for all tasks (F(1,68) = 126.5, p < 0.001). Repeated-measures ANOVAs on dishabituation magnitudes by age (6, 12 months), gender (male, female), stimulus (face, object), and delay interval (short, long) showed no significant interactions between familiarity and stimulus, delay interval, or age groups, indicating no general differences in dishabituation magnitude as a function of these factors (Fs < 1, ps > 0.5). This confirms that habituation measures resulted from habituation to the specific stimulus presented, rather than general features of the test setting.
P400 neural responses to faces and objects
In a repeated-measures ANOVA on P400 latency by age (6 or 12 months), gender (male, female), stimulus (face, object), and laterality (left, right), P400 latency peaked earlier to faces than objects (
F(1,99) = 6.70,
p = 0.011,
η
2 = 0.011), was faster over right than left electrodes (
F(1,99) = 4.77,
p = 0.031,
η
2 = 0.046), and had a shorter latency at 12 than 6 months (
F(1,99) = 18.1,
p < 0.001,
η
2 = 0.15). Male infants also showed faster P400 latencies than female infants (
M female = 539.5,
M male = 506.1;
F(1,101) = 4.9,
p = 0.03,
η
2 = 0.045). In a repeated-measures ANOVA on P400 amplitude by age (6 or 12 months), gender (male, female), stimulus (face, object), and laterality (left, right), P400 amplitude was greater to objects than faces (
F
(1,99) = 23.4,
p < 0.001,
η
2 = 0.19). This is consistent with previous work [
41,
43,
64].
Nc neural responses to faces and objects
In repeated-measures ANOVAs on Nc amplitude for early and late subcomponents separately by age (6 or 12 months), gender (male, female), and stimulus (face, object), Nc overall amplitude was more negative to objects than faces for both the early and late subcomponents (early F(1,104) = 9.9, p < 0.001, η
2 = 0.09; late F(1,104) = 7.0, p = 0.009, η
2 = 0.063). For the early Nc component, there was a significant interaction between age and gender (F(1,104) = 5.1, p = 0.026, η
2 = 0.047) and a main effect of gender (early: F(1,104) = 4.01, p = 0.048, η
2 = 0.037), driven by the fact that age-related change was significant in males (F(1,53) = 3.94, p = 0.05, η
2 = 0.07) but not females (F(1,51) = 1.53, p = 0.22, η
2 = 0.03). For the late Nc component, amplitudes were generally more negative at 12 than 6 months (F(1,104) = 10.3, p = 0.002, η
2 = 0.09).
In repeated-measures ANOVAs on Nc duration by age (6 or 12 months), gender (male, female), and stimulus (face, object), the duration of the Nc was longer to objects than faces (
F(1,84) = 3.9,
p = 0.05,
η
2 = 0.045) and longer at 6 months than 12 months (
F(1,84) = 19.9,
p < 0.001,
η
2 = 0.19). Again, these results are comparable to previous work; for example, typically developing 3- to 4-year-old children show a more negative Nc to objects than faces [
41].
Correlations within neural responses
To establish which of the ERP findings were interrelated, we examined patterns of correlations between P400 latency and amplitude and Nc latency and amplitude to faces. At 6 months but not 12 months, faster P400 latency to faces over the left hemisphere was correlated with a shorter duration Nc to faces (r(41) = 0.38, p = 0.014) and a less negative Nc response to faces (r(50) = −0.4, p = 0.006). Similarly, a less negative Nc to faces was highly correlated with a shorter Nc latency (r(42) = −0.9, p < 0.001). Taken together, these findings confirm (as expected) that a fast P400 latency to faces and a shorter and less negative Nc are interrelated and may be associated with lesser attention capture by social stimuli.
Summary
Experiment 1 confirmed that our paradigms elicit normative patterns of responding in typically developing infants. This includes a faster and smaller P400 to faces than objects, a smaller and shorter Nc to faces than objects, and a longer peak look to faces than objects during habituation.
In Experiment 2, we used these paradigms to examine differences in attention capture by faces and objects in infants at high risk for ASD. We reasoned that if attention capture by social stimuli were reduced in infants with later ASD, we would see an exaggeration of the faster P400 to faces and the smaller and shorter Nc to faces versus objects (reflecting an exaggeration of the typical tendency for greater attention capture by objects versus faces in this age range). Further, we predicted that we would see a reduction in the duration of the peak look to faces during the habituation paradigm.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
GD, SW, and AE conceived the study. EJ, SW, and GD designed the experimental tasks and stimuli. EJ, RL, RE, KV, KB, and SW collected and processed the data. EJ, SW, analyzed the data, performed the statistical analyses, and wrote the manuscript. All authors read and approved the final manuscript.