Introduction
Autism Spectrum Disorders (ASD) are complex conditions characterized by atypical social communication, as well as restricted or stereotyped behaviors and interests (RRBI) (DSM-5, APA), affecting 1–2% of individuals from the general population [
69]. One source of this complexity relies on the heterogeneity of symptoms depicted by autistic individuals, specifically when considering the RRBI. These symptoms could be dichotomized in ‘motor-driven’ symptoms gathering the stereotyped movements (e.g. head banging) and the repetitive behaviors, and in ‘cognitively driven’ symptoms, including obsessive–compulsive like symptoms and cognitive inflexibility [
39,
56]. The determinants of this differential expression remain largely unknown, although the individual's cognitive skills seem to be a major modulator of RRBI. Autistic individuals with a comorbid intellectual deficiency predominantly display motor-related symptoms, cognitively driven symptoms, if they exist, are probably underestimated due to a reporting bias. In contrast, autistic individuals without such deficiency express more those which are cognitively driven [
15]. Other modulators affect the expressiveness of these symptoms, such as the individual's age [
18] or the associated social communication skills themselves. Studies exploring the familial aggregation of RRBI in autism report that the repetitive/stereotyped behaviors are mainly observed in probands and the obsessive-like symptoms in their non-affected relatives, independently of their cognitive abilities [
29,
67]. The apparent dichotomy of the RRBI is also reinforced by the use of distinct screening tools, opposing those dedicated to the exploration of RRBI in the context of autism, such as the Repetitive Behaviors Scale-Revised (RBS-R, [
35]) and those measuring them in individuals with obsessive–compulsive disorders with the Y-BOCS as a gold standard [
23]. However, contrary to an approach divided into repetitive behaviors for some individuals and obsessive symptoms for others, some authors have developed new tools to consider the wide diversity of RRBI better and offer a unifying approach to these symptoms. Although preliminary and performed in the general population, one study showed a high intra-familial correlation of RRBI, whether the index case has associated autistic symptoms [
18]. These findings encourage researchers to reconsider the nosology of RRBI and to adopt a more dimensional approach than a categorical to these symptoms.
It also seems consistent with what the literature reports about the involvement of a similar pattern of brain structures in RRBI. Animal models suggest a critical role of the cortico-basal-ganglia-thalamo-cortical loop in the emergence and maintenance of RRBI [
12]. Induced deletion of Shank3 (
SHANK3 being a major gene associated with autism) in inhibitory neurons of the striatum results in repetitive/stereotyped-like behaviors, and conversely, deletion of Shank3 in excitatory neurons of the prefrontal cortex results in excessive self-grooming behaviors considered as an equivalent of obsessive–compulsive symptoms [
4]. In humans, studies exploring RRBI in autistic individuals also report abnormalities in subcortical structures, specifically the striatum. For example, using T1-weighted anatomical images from the Autism Brain Imaging Data Exchange, Schuetze et al. [
58] reported that stereotyped behaviors were positively associated with increased bilateral globus pallidus surface area. Paralleling these findings, the ENIGMA-OCD working group observed larger thalamic volume affecting the lateral, pulvinar, and ventral regions in children with OCD [
66]. However, another mega-analysis by the OCD Brain Imaging Consortium (OBIC) pointed more toward the ventrolateral and dorsomedial prefrontal in obsessive–compulsive behaviors in humans [
20]. Moreover, multiple strands of evidence indicate deviations in brain growth and maturation trajectories rather than static alterations in autism and OCD [
25,
41,
49].
Altogether the literature presents a certain coherence between the results of clinical, genetic and brain imaging studies suggesting a commonality of the RRBI with a differential expression according to the individual phenotypic characteristics. To better understand the heterogeneity and familial patterns of RRBI in autism, as well as the structural brain abnormalities that underlie them, we performed this study exploring RRBI in a sample of 792 individuals gathering autistic patients (
n = 267), their non-affected first-degree relatives (
n = 370) and typically developing individuals from the general population (TD) (
n = 155). To embrace the diversity of the whole pattern of RRBI, we explored each enrolled individual with the Repetitive Behavior Scale-Revised (RBS-R) [
35] and the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) [
23], both considered as gold standard questionnaires to explore repetitive/stereotyped behaviors and obsessive–compulsive symptoms in clinical populations. We then ran a factor analysis on all RRBI to apprehend further the distribution of these symptoms independently of the subject's status (affected, non-affected relatives, or typically developing participants). We finally performed a multiple linear regression model on a subsample of 152 subjects to explore the relationship between these RRBI-related factors, and the cortical/subcortical brain volumes based on MRI. We hypothesized that two main factors would emerge from the factor analysis, mirroring the dichotomized model of RRBI (repetitive/stereotyped
vs obsessive/compulsive symptoms), but displaying common and specific associations with brain structures of the cortico-striatal-thalamo-cortical loop.
Discussion
The challenges in identifying biomarkers in neurodevelopmental disorders, particularly in autism, stem from the difficulties researchers have in considering the inter-individual phenotypic variability. It ranges from those with a developmental trajectory in the normal range (although carrying environmental and/or genetic vulnerability risk factors) to individuals with mild to severe impairment. The purpose of our study was, therefore, to account for this inter-individual variability by exploring the spectrum of RRBI assessed in a large population of individuals with autism, their unaffected first-degree relatives, and controls from the general population. Interestingly, our results underlined the potential implication of the putamen in the RRBI: an increase in the volume of the putamen was associated with 'low-order' symptoms (mainly stereotyped behaviors) and on the opposite, a decrease in the putamen volume with cognitively driven symptoms (mainly obsessive–compulsive symptoms).
Dimensionality of the RRBI symptoms
The factor analysis revealed the multidimensionality of RRBI by identifying three dimensions: FA1 gathered the RBS-R-related items typically observed in autism [
13,
32]; FA2 put together the items related to rigidity/insistence on sameness from the Y-BOCS, symptoms which were trait features of the individuals with autism but also those with obsessive–compulsive symptoms [
65,
68]; and FA3 that included only Y-BOCS related items usually displayed by individuals with OCD [
17]. Interestingly, FA2 put together the symmetry and ordering of obsessions/compulsions and the need to repeat things. These symptoms were described in the literature as settled clinical characteristics of autistic children with comorbid OCD [
55]. Symmetry and ordering symptoms are frequently reported in the developmental subtype of OCD, which—beyond its juvenile onset—is characterized by an increased proportion of neurodevelopmental comorbidities, including Tourette's syndrome, ADHD, and autism, but also by significant impairment in executive functions [
11,
16,
24]. A few studies have highlighted the link between the intensity of symmetry/ordering symptoms and poor verbal working memory, visuospatial planning, inhibitory control, and cognitive flexibility abilities [
11]. Thus, among the characteristics shared by children with autism and OCD, executive dysfunction may play a critical role in these disorders [
10,
30]. Interestingly, unaffected first-degree parents of children with OCD or autism also showed executive impairments [
17,
47,
59]. Overall, FA2 dimension we identified may be a testimony of the cumulative impact of executive impairment and the presence of RRBI. Finally, the FA3 dimension was driven by OCD-related symptoms since gathering the washing, checking, contamination, and aggressive symptoms [
36,
55]. This dimension was probably less related to autism but more a proxy of obsessive–compulsive symptoms [
40,
45].
Correlation between structural brain volumes and RRBI-related dimensions
Our results were in line with publications stressing the critical role of the cortico-thalamic-striatal-cortical loop in RRBI. Our study revealed a central implication of the putamen across the 3 distinct dimensions we reported, as well as specific roles of subcortical and cortical structures per FA, which may shape the diversity of symptoms, agglomerated on the dimensions. The positive association of the putamen and the left amygdala with FA1 was consistent with the role of the putamen in autonomic movements, described in complex motor stereotypies [
43] and in autism [
19,
37,
46,
53]. Including the putamen, the basal ganglia play important roles in regulating repetitive behaviors (notably in autism) in association with the hippocampus, the hypothalamus, but also other neuroanatomical structures of the limbic system (including the amygdala) [
22]. Obviously, amygdala volume abnormalities were more usually related to anxiety, and more specifically to social anxiety in autism [
3,
22,
31].
In contrast to the positive association of the putamen volume with FA1, we observed a negative relationship with FA2 and FA3. Interestingly, our results replicated those of the ENIGMA-OCD consortium, which also reported a reduced putamen volume in OCD [
62,
63]. This reduced putamen volume may relate more to the compulsive component than the obsessive one in OCD [
9]. FA2 was associated in addition to the decreased volume of the parietal cortex. Similar parietal abnormalities in cortical thickness, volume or surface area, may reflect the cortical dysmaturation in this area, frequently reported in children with OCD and autism [
6,
53,
54]. Interestingly, the parietal cortex is involved in social interactions, motor learning and repetitive behaviors in autism [
64] but also participates in cognitive in/flexibility, which is coherent with the sameness nature of RRBI-related symptoms encompassed by FA2 [
26]. Bidirectional associations between RRBI and putamen volume highlighted its pivotal role, implying the presence of modulators beyond the putamen. Although FA1, FA2 and FA3 were distinct factors, shared neural underpinnings might contribute to their clinical similarity.
Limitations
Our study was conducted retrospectively in relation to the initial research project using a 1.5 T MRI and FreeSurfer, which reduced the data acquisition and segmentation precision of the brain structure, especially the subcortical ones such as the putamen. Nevertheless, we maintained the quality of FreeSurfer segmentations through a visual quality check in our study. Furthermore, the use of FreeSurfer segmentation facilitated comparisons with large cohorts such as ENIGMA, enhancing the relevance of our results. The lack of power of the brain imaging part of our study did not allow us to explore the brain asymmetry structures associated with the dimensions we reported. We, however, observed a trend for a leftward asymmetry (based on
p value and coefficients
L >
R). A similar leftward brain asymmetry involving the putamen was previously reported in autism and OCD [
7,
28,
34,
51,
54]. The role and impact of this brain asymmetry on the symptomatology of ASD and OCD remained unclear but may result from aberrant brain development trajectories.
When exploring the dimensions gathering the RRBI phenotypic variability, we did not investigate the gender’s impact on RRBI due to the limited sample size of females, which was a significant limitation [
1,
2,
21,
60]. Nevertheless, we conducted sub-analyses exclusively on male subjects, maintaining the consistent item composition of the three FAs. (Additional file
1: Table S5). We also did not include the effect of potential covariates, such as the whole pattern of comorbidities or the effect of executive dysfunctions, as mentioned above. For example, planning strategy impairments consistently reported in probands, and their first-degree relatives may specifically participate in FA2 [
8]. Based on scales (RBS-R and Y-BOCS), respectively, dedicated to repetitive behaviors in autism and obsessive–compulsive symptoms, our study was limited by their own constructions, which impacted on the dimensional approach. Future research would explore whether similar dimensions emerge when using a single integrated scale [
48].
Finally, one additional limitation may result from the wide range of ages of individuals enrolled in our study. This might have biased the volume estimates of the small brain structures, specifically subcortical structures such as the putamen or the amygdala, since it relied on a limited number of voxels [
27,
42,
57]. This effect may result from the opposite coefficient direction of the regression analysis, we reported between FA1 and the neuroanatomical structures (positive regression) and between FA2 or FA3 (negative regression) and these. FA1 more reflected the autistic-related symptoms and thus was mainly based on symptoms displayed by probands with autism, younger than relatives and controls enrolled in our study. Moreover, our study was based on cross-sectional, not longitudinal, which limited the exploration of changes in trajectories reported in autism and OCD [
25,
41,
49].
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