Background
The significant etiologic and phenotypic heterogeneity of autism spectrum disorder (ASD) [
1] has made it challenging to target underlying mechanisms of ASD pathology. Considering that more than 1000 genes have been implicated in ASD [
1,
2], recent initiatives have targeted genetic pathways [
3,
4] and rare de novo likely gene-disrupting mutations (LGDMs) [
5]. As such, a burgeoning “genetics-first” approach has been proposed to improve identification and characterization of genetic subtypes of individuals with ASD [
6]. For instance, genetics-first studies have identified phenotypically distinct subtypes of autism for
CHD8 [
7] and
DYRK1A [
8,
9] based upon behavioral and physical features within both children and animal models. However, the relevant contribution of genetic risk to aspects of the ASD phenotype (i.e., social communicative impairments) is poorly understood, especially for low-functioning individuals with ASD.
Recent work supports social perception as a possible neural index related to the hallmark social deficits in ASD [
10‐
15]. Although the neural indices have been targeted in relation to copy number variations, such as the 16p11.2 locus [
16,
17], little is known about neural patterns associated with LGDMs, likely due to the wide range of variability of specific gene expression across LGDMs. Our objective was to examine patterns of neural heterogeneity associated with LGDMs by completing a series of diagnostic and genetics-guided analyses of social perception. We hypothesized a diagnostic approach would indicate atypical social perception in ASD, consistent with theories of social brain dysfunction in ASD [
15]. Then, as a preliminary exploration, we predicted that the heterogeneity associated with LGDMs would indicate potentially divergent patterns of social perception based upon LGDM function. Following work suggesting distinct functional roles for genes strongly expressed during embryonic development [
5,
18], we tested children with and without a LGDM associated with embryonic development as a possible functional neurodevelopment pathway that contributes to a shared phenotype. There is a growing body of evidence suggesting early embryonic disruptions may be related to impairments in social behavior (e.g., lack of interest in conspecific proximity) [
19,
20] and/or dysfunctional information encoding (i.e., intellectual or developmental delays) [
21,
22]
. The current study sought to add to this literature by addressing whether individuals with an embryonically expressed LGDM exhibit dysfunctional information habituation within the social domain.
We opted to target mu attenuation, which is specifically sensitive to detecting the movements associated with biological motion and is known as a reliable index of social perception in typical populations [
23,
24]. Mu rhythm is typically defined as neural activity oscillations within the 8–12-Hz frequency range of electroencephalography (EEG) across electrodes above the sensorimotor cortex. During the observation and execution of biological motion, the underlying neural assemblies of the mu rhythm desynchronize [
25,
26]. This desynchronization results in the reduction of oscillatory power (i.e.,
attenuation of the signal), with a greater reduction for conditions with social significance (i.e., biological motion relative to nonbiological motion) in children and adults; for a review, see [
27].
In ASD, several studies suggest atypical mu attenuation in ASD (e.g., no discrimination for social relative to nonsocial observed motion) [
12,
28‐
30] while other studies indicate no difference in ASD compared to typical controls [
31‐
33]. Recent work by Dumas and colleagues [
34] suggests that this discrepancy may be driven by the functional significance of the lower and upper mu rhythm bands. Notably, there is evidence that the lower mu rhythm (8–10 Hz) is more responsive to observed motion than the upper mu rhythm (10–12 Hz) [
35], which may be indicative of bottom-up sensory processing [
36,
37]. Previous studies also implicate that upper mu (or alpha) is more sensitive to top-down cognitive processing, such as self-monitoring within social contexts [
38] or increasing cognitive demands [
39,
40].
It is also possible that conflicting mu attenuation results reflect the underlying heterogeneity in ASD, potentially driven by genetic etiology. For instance, both disrupted social cognition and information habituation are associated with embryonically expressed LGDMs (e.g.,
ADNP [
21],
POGZ [
22]). Yet, it is unclear whether social information habituation is also disrupted and the extent to which this profile is unique to children with an embryonically expressed LGDM. To date, only one study has tested the rate at which mu attenuation is modulated (i.e., habituates, sensitizes) in ASD [
17]. In that study, children with ASD and an ASD-associated deletion or duplication at the
16p11.2 locus demonstrated divergent dynamic patterns of mu attenuation providing additional insight into the relationship between ASD-associated copy number variations (CNVs) and social neural phenotypes.
This study sought to characterize social motion discrimination in ASD within the upper and lower mu bands continuously over time to capture dynamic neural social indices that may be associated with LGDMs expressed in embryonic development. We tested mu attenuation and habituation first via diagnostic comparisons between typically developing (TYP) and ASD children and, second, via genetics-guided comparisons between children with and without LGDMs expressed preferentially in embryonic development (LGDM E+ vs. LGDM E−). Based upon prior work [
12,
28‐
30], we predicted a lack of social motion discrimination in ASD relative to TYP and anticipated no habituation to either condition in ASD, consistent with [
17]. We predicted that children with an embryonically expressed ASD-associated LGDM might have a more severely impacted social profile relative to LGDM E−, in part due to embryonic development as a (more) critical period for regulation of gene expression in support of brain development [
41]. Lastly, we evaluated relationships between the neural social indices and individual predictors of social and cognitive behavioral features to better assess the specificity of mu attenuation to capture social processing.
Discussion
Social impairments are a hallmark of ASD, yet phenotypic and genetic heterogeneity is thought to contribute to discrepant evidence in the literature. We explore a neural mechanism associated with ASD by considering patterns of social discrimination as measured by mu attenuation over time for children with different genetic etiologies. From the diagnostic comparisons, we show aberrant patterns of mu attenuation in ASD are specific to the upper mu band, while the lower mu band reflects less atypical patterns, consistent with prior work [
34]. The dynamic patterns indicate that children with ASD show an increasing lower mu difference between social and nonsocial motions, which may help resolve diagnostic inconsistencies within the literature. For instance, prior evidence of atypical mu attenuation in ASD between observed motion conditions (i.e., social relative to nonsocial motion, as in the current study) [
12,
28‐
30] has relied on individual averages. Our findings suggest that the discrimination pattern may not be evident if there are too few trials (i.e., before children with ASD habituated to nonsocial motion observations). Although it is a concern that children with ASD did contribute fewer trials than the typical controls, the eventual condition differentiation in ASD (i.e., noted by approximately trial 15 in Fig.
2) indicates that our study had a sufficient number of trials.
Mu attenuation has been proposed to reflect a human corollary to the mirror neuron system [
24,
61], which describes activation recorded over the sensorimotor cortex during both action execution and observation of human actions. Although it is possible that mu attenuation reflects the conductance of occipital or posterior alpha rhythm more broadly (i.e., responsivity to general motion information) [
62], our results indicate differentiation of social and nonsocial motions. One working hypothesis of ASD suggests mirror neuron system deficits that disrupt neural correlates supporting the action/observation system, subsequently eliciting atypical mu attenuation [
63]. Aligned with this theory, other evidence suggest that atypical functioning of the mirror neuron system may lead to a downstream effect of poor imitative abilities [
33] or disrupted higher order social cognitive abilities (i.e., theory of mind) [
64]. However, it is important to note that similar to prior work by Dumas and colleagues, we found mu attenuation diagnostic differences within the upper mu band (10–12 Hz), but no group difference within the lower mu band (8–10 Hz). This is consistent with prior work suggesting that this lower frequency may reflect primary sensory processing [
36,
37] that habituates over the course of the exposure. Yet, sensory processing of biological motion occurred more rapidly in the TYP group compared to longer processing in the ASD group, perhaps indicative of functional connectivity reductions related to social cognition [
65]. Our results offer further evidence of atypical mu attenuation patterns in ASD, although unique neural mechanisms underlying atypical social discrimination may be derived from specific genetic etiologies. In other words, a mirror neuron hypothesis may indeed describe a subset of children with ASD, while a more general, distributed network of neural correlates may be impacted in other ASD subgroups.
As part of a preliminary analysis, we examined the neural social indices associated with different functional genetic roles of LGDMs as a first step to explore a possible shared neural social phenotype. We implemented a post hoc clustering strategy in order to examine potential convergent pathways between LGDMs that are and are not functionally expressed during embryonic development [
18,
66]. The choice to cluster LGDMs around functional expression during embryonic development is based on early genetic regulatory control supporting regional differentiation within the embryonic brain [
67,
68], including key social neural structures (e.g., amygdala). We had predicted that the LGDM within the embryonic development group would have a more severely disrupted neural social index due to evidence from animal and human models indicating significant impairments related to social behavior [
19,
20] and/or information encoding [
21,
22]. The results indicated that children with an LGDM primarily expressed during embryonic development exhibit sensitization of lower mu attenuation to social motion. In other words, these children initially exhibited more mu attenuation for nonsocial motion, but eventually demonstrate more for social motion. This pattern was distinct from children with an LGDM not primarily expressed during embryonic development that exhibited greater lower mu attenuation discrimination throughout the entire experiment (i.e., greater mu attenuation to social than nonsocial motion beginning at the first few trials).
Our results suggest that social motion perception may be conserved despite early genetic disruption, though the delayed processing supports the notion of potentially delayed information processing. It is important to note that this delay was specific to the social motion condition (increasing neural response over time) but not the nonsocial motion condition (i.e., no change over time), which may help clarify the mechanism by which prior models [
19,
20] derive impaired social behavior. An interpretation of the results may be that children with an LGDM primarily expressed during embryonic development are increasing their attention to, or interest in, social stimuli after an initial period, which may reflect a delayed social engagement (e.g., motivation or salience). One explanation may be that the impact of embryonic genes on social perception is greater [
69], suggesting that functional timing of genetic expression may differentially affect the neural social phenotype. Importantly, these findings align with genetics research indicating that ASD genes converge on several select pathways [
70,
71], which may help to further explain the underlying neural social heterogeneity.
An important limitation of the current study is the continued genetic heterogeneity despite functionally classifying the expression of LGDM within early development. Within our LGDM groups, there are only several children with a shared LGDM (i.e.,
SETD2,
n = 2;
DYRK1A,
n = 2;
CHD8,
n = 2). Thus, the discoveries of this work are not to be taken as firm conclusions, but rather considered in order to motivate and guide continued use of a genetics-first approach to elucidate potential etiological mechanisms of ASD. For instance, most of the children within the early embryonic LGDM group exhibit the social sensitization pattern described here (six out of eight cases; see Additional file
3: Figure S1 for individual patterns), except for one child with
MED13L and one child with
DYRK1A. In part, this qualitative finding is consistent with the overall group clustering approach indicating delayed social processing, suggesting a potential neural index associated with this particular genetic etiology. However, the specificity for specific LGDMs may be poor, considering that only two out of three children with a
DYRK1A LGDM exhibited this pattern. Similar to prior work linking core social symptoms to biomarkers of ASD [
11,
72‐
76], we encourage the use of this data as a way to bridge the gap between genetic and phenotypic characterization as a means to facilitate the discovery of ASD etiological mechanisms and accelerate progress for ASD therapeutic interventions.
It may be surprising that our task elicited mu attenuation during nonsocial motion observation (i.e., ball bouncing, tubes swinging) that is not biological and subsequently should not be simulated within the action/observation system. However, to a large extent, the majority of studies implementing mu attenuation as an outcome utilized comparisons between self-executed, social observed, and nonsocial observed motion. It may be the case that by engaging the motor execution system during these tasks, the threshold for the action/observation system is elevated, reducing the amount of mu attenuation for nonsocial comparisons. In fact, neural regions implicated in mu suppression during execution vs. observation [
77] involve regions that also play a role in general motion perception, including the occipital, premotor, and somatosensory cortices. Moreover, this study replicated prior work with this same task that indicated a modest degree of mu attenuation to nonsocial motion, in addition to social motion [
17]. We posit that our task measured more globally distributed neural differences between social and nonsocial motions compared to other tasks that have used self-initiated actions to target the premotor cortex. Of note, this passive viewing task is more conducive for children with reduced capacity for following behavioral instructions (i.e., to make self-initiated motions), while still providing a robust neural index, which specifies individual patterns.
The neural social indices were correlated with features of social cognition (i.e., social responsiveness), particularly with the lower mu band. This finding is compelling evidence that these indices accurately capture subtle levels of social impairments in vivo, as opposed to relying on parental reports (e.g., SRS-2). Additionally, average patterns of mu attenuation were unaffected by general cognition, despite drastic cognitive differences for children with a LGDM. Although this may not negate a contributory role of cognitive ability for higher-order operations related to social motion (e.g., action prediction), this evidence from this study suggests that motion perception is intact for children with lower cognitive abilities (i.e., cognitive scores under 50). Much of the existing research investigating neural social indices is restricted to children and adults with moderate to average cognitive capabilities. The majority of ASD-LGDM cases with low verbal IQ show typical mu attenuation patterns (i.e., greater for social motion in five out of eight cases with verbal IQ < 50). Taken together, these neural social indices can provide a robust characterization of the underlying neural mechanisms supporting social cognition, regardless of level of cognitive function, thereby improving our understanding of the social phenotype.
This study is the first to use a genetics-first approach to explore the genetic etiologies of autism associated with severe LGDMs in the context of neural social indices. Our use of a unique statistical method to measure ongoing dynamic changes associated with social motion perception demonstrates the utility of this method to better understand underlying processes relevant to ASD and LGDMs. Although this study is limited by a small sample size and thus should be considered exploratory, the analysis of neural social phenotypes based on functional clustering offers a promising approach for narrowing in on convergent pathways that may reflect shared phenotypes and provide insight for targeted treatment [
5,
18]. Future research will need to take into account the variety and combination of genetic functional roles. Ongoing efforts to recruit a larger, more genetically homogenous group will help target specific functional outcomes during early childhood and adolescence. However, due to the rarity of this population, these preliminary results are informative and can help guide future research by better describing the functional processes during social motion perception and similar processes that are impaired in ASD.
Acknowledgements
We would like to thank the children and families for their participation in this study. We are grateful to all of the families at the participating Simons Simplex Collection (SSC) sites, as well as the principal investigators (A. Beaudet, R. Bernier, J. Constantino, E. Cook, E. Fombonne, D. Geschwind, R. Goin-Kochel, E. Hanson, D. Grice, A. Klin, D. Ledbetter, C. Lord, C. Martin, D. Martin, R. Maxim, J. Miles, O. Ousley, K. Pelphrey, B. Peterson, J. Piggot, C. Saulnier, M. State, W. Stone, J. Sutcliffe, C. Walsh, Z. Warren, E. Wijsman). We appreciate obtaining access to phenotypic data on SFARI Base. E.E.E. is an investigator of the Howard Hughes Medical Institute. The computerized dancer stimuli were provided courtesy of Nick Neave and Kristofor McCarty at Northumbria University.