Sulcation in children with autism spectrum disorders

doi:10.21203/rs.3.rs-4611888/v1

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Research Article

Sulcation in children with autism spectrum disorders

https://doi.org/10.21203/rs.3.rs-4611888/v1

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Background

The neurobiology of autism remains poorly understood. Brain sulcation is a promising proxy to assess the cortical developmental trajectory in autism spectrum disorders. We aimed to explore this neurodevelopmental marker in children with autism and its association with symptoms in a large multicentric dataset.

Methods

841 children with autism spectrum disorders (ASD), including 145 females, and 872 controls, including 251 females, underwent a high-resolution T1-weighted brain MRI. We processed images with the Brain VISA automatized pipeline to extract the local sulcal indices (l-SI) (the proportion of buried cortex) from 12 a priori determined brain regions for each hemisphere, covering the whole brain. We studied how the variations in regional sulcation were associated with clinical autism assessment scales (ADOS, ADI, SRS, RME), controlling for age and sex.

Results

Between children with ASD and controls, we found a significantly higher sulcation (l-SI) in control children compared with children with ASD in the left (p = 0.015) and right (p = 0.048) precentral regions. Within ASD children, a significant positive association was found between ADOS scores and sulcation in the right intra-parietal fissure (p = 0.049). Significant positive correlations were also found between ADI communication scores and sulcation in the left parietal region (p = 0.037), in the right medial frontal region (p = 0.035) and in the left posterior medial region (p = 0.049). Finally, significant correlations were found between l-SI and RME scores in right parietal (p = 0.037), right calcarine (p = 0.049) (positive) and left precentral regions (p = 0.014) (negative). Of note, most results were driven by girls.

Limitations:

p-values were not corrected for multiple comparisons. Sample size is reduced for girls’ analyses.

Conclusions

Our results suggest that clinical features of ASD are correlated with localized changes in cortical folding in children, mainly driven by girls. Increased symptomatic levels were associated with an increased right and decreased left sulcation, consistent with the decreased asymmetry theory of ASD. The study of cortical sulcation appears to be a promising marker of neurodevelopmental processes and their clinical correlates in ASD.

Autism

Neurodevelopment

Neuroanatomy

MRI

Sulcation

ASD

Autism spectrum disorders

Autism spectrum disorders (ASD) are lifelong neurodevelopmental conditions. Their prevalence worldwide is estimated around 1% [1] and affects around 3 times as many males as females [2]. ASDs appear to be multifactorial, but their origins are still very poorly understood. Some genetic components play an important role in these disorders [3, 4], and several environmental risk factors have also been identified, such as advanced parental age, birth trauma [5], gestational diabetes, or valproate exposure during pregnancy [6].

According to the DSM-5, ASD is characterized by atypicalities of functioning in 2 main areas: impaired communication and deficits in social interaction, and the presence of stereotyped and restricted behaviors. The presence of alterations in these two areas is necessary for clinicians to make a diagnosis of ASD. This diagnosis requires a detailed account of the child's developmental history to be obtained from parents or other adults who have cared for the child (e.g. Autism Diagnostic Interview-Revised - ADI-R), as well as an interaction with the individuals themselves to observe various aspects of their behavior (e.g. Autism Diagnostic Observation Schedule - ADOS).

At the brain level, anatomical and functional brain differences have been observed in ASD in various post-mortem, neuroimaging, and electrophysiology studies. However, its neurobiology remains poorly understood. Anatomical features such as cortical folding and burrowing (gyrification and sulcation) have been repeatedly described in subjects with psychiatric disorders, including ASD [7]. Sulcation and gyrification are cortical developmental processes that occur as early as 10 weeks of gestation and extend up to 44 weeks in the fetal brain [8]. Sulcal patterns are trait markers of neurodevelopment; they are determined in utero, cease to evolve at birth and remain stable throughout the subject's life [9]. The study of sulcal anatomy and morphometry (length, depth, cortical burial) is therefore of interest in exploring early markers of ASD [10].

Previous research has highlighted specific autism-related features in temporal regions and more specifically in the right superior temporal sulcus (STS). Boddaert et al. have shown that autism is associated with bilateral anatomical abnormalities localized in the STS [11]. The temporal regions around the STS are involved in the social perception skills and in social cognition [12], which are characteristically impaired in autism spectrum disorders. Hotier et al. studied the organization of the caudal branches of the right superior temporal sulcus [13]. They used the Reading the Mind in the Eyes (RME) test, and found increased RME scores, reflecting better theory of mind abilities, associated with a reduced length of the right anterior caudal ramus of the STS. They also identified a significantly longer right anterior caudal ramus of the STS in ASD patients compared to controls.

In neuroimaging studies, cortical folding can be investigated by measuring the degree of gyrification, corresponding to the degree of cortical folding [14] or the degree of sulcation, reflecting the degree of cortical burial. The sulcation index is thus considered an indirect retrospective marker of neurodevelopmental processes. As ASDs are neurodevelopmental disorders, the study of sulcation can provide a new understanding of the formation of these disorders and attest to early developmental constraints [10]. Variations in sulcation are thus interesting and promising parameters for studying cortical development trajectories in ASD.

Moreover, ASDs are a very broad and heterogeneous category. Symptom intensity, occurrence, etiology and development vary greatly from one individual to another [15, 16]. It is necessary to determine more clearly whether ASD corresponds to different neurodevelopmental patterns according to the specificities of the symptoms, or whether it is a single diagnostic category at the neurobiological level with little homogeneity and variable symptomatology [17]. It thus seems important to study correlations between measures of cortical folding (sulcation) and clinical features.

Aims of the study

In a large sample of children (aged 2 to 20), this study aims at 1) characterizing the particularities of cortical sulcation between participants with ASD and control participants; 2) studying, in children with ASD, the links between these cortical features and the clinical dimensions of autism. We expect to find sulcation differences between ASD and control participants. We also expect to identify sulcation differences within the ASD group, depending on the degree of autism severity (sulcation linked to clinical scores), mostly on social dimensions. Several studies have shown insufficient synaptic pruning, accompanied by greater brain volume and a more folded cerebral cortex in children with ASD [18]. We thus hypothesize that local sulcation indices (l-SI) are higher (attesting a more folded cerebral cortex) in subjects with higher scores on clinical ASD assessment scales.

Population

Data from 4 international cohorts were pooled to form our final sample of children – aged 2 to 20 – with ASD and control children. The Robert Debré Hospital cohort is a French, retrospective, monocentric database of 210 children with ASD and 94 controls[19]. The ABIDE 1 and ABIDE 2 (Autism Brain Imaging Database Exchange) cohorts were pooled, representing a sample of 800 children with ASD and 876 controls [20]. These are retrospective multicentric cohorts available in open access (https://fcon_1000.projects.nitrc.org/indi/abide/). Finally, we used the EU-AIMS LEAP cohort, which is a prospective and multicentric European study. LEAP includes 243 children with ASD [21] and 185 controls.

All these 4 cohorts include both males and females (assigned-at-birth). We selected only children (ASD and controls) with an IQ above 70 (i.e. without intellectual disability), to ensure that the final sample remained homogeneous and that the results did not reflect any effects linked to intellectual disability. Sites with fewer than 15 ASD participants were excluded from the statistical analyses. Two participants whose l-SI was superior to the median + 3 MAD (Median Absolute Deviations) were considered outliers and excluded from the analyses (2 participants in ABIDE 2: 1 with ASD, 1 without). In total, after these exclusions, the combined cohorts comprise 841 children with ASD and 872 control children (Table 1).

Rating scales

All participants took an intellectual efficiency test (WISC-V) to calculate their intelligence quotient (IQ) and identify any intellectual deficiencies. Autism rating scales were also administered for participants with ASD, the ADI-R (Autism Diagnostic Interview-Revised) [22]. We analyzed the social interaction, communication, and restrictive and repetitive behavioral domains of the ADI; the ADOS-2 (Autism Diagnostic Observation Schedule-2nd Edition) [23]. The Calibrated Severity Score (CSS) was used as a measure of total observed symptom severity; the SRS (Social Responsiveness Scale) [24]. We used the Total T-score (combined parent- and self-report with parent-report scores prioritized); the RME assesses the ability to infer a person's state of mind from their eyes [25]. Higher scores are thought to reflect better Theory of Mind abilities. We used the proportion of correct answers as the relevant variable in our study.

Anatomical MRI acquisition

We used 2 different 1.5 Tesla MRI (Ingenia et Intera) to acquire data for the Robert Debré Hospital cohort, using the following parameters: spoiled gradient recalled echo (SPGR), 1mm isotropic, repetition time (TR) = 25ms, echo time (TE) = 6ms, ip angle = 30º (for more details, see Lefebvre et al., 2023). ABIDE cohort (38 different scanners) data have been downloaded from http://fcon_1000.projects.nitrc.org/indi/abide/. At the various EU-AIMS cohort sites, MRI scans were acquired on 6 3T scanners from different manufacturers (Siemens, Philips, General Electric) [21, 26].

Data processing

We performed calculation of local sulcation indices from T1 MRI data following the method of Cachia et al. [27], also used in Sarrazin et al. [28]. We used BrainVISA 5.0.3 software (http://brainvisa.info) with standard parameters to process the raw T1 images and achieve automatic delineation of the internal sulcus surface and automatic neuroanatomical labeling of cortical sulci in subjects' native space with minimal manual intervention [29]. This method was chosen because of the large number of participants included in our sample, and to avoid operator bias and potential shape distortion resulting from group normalization. Previous studies have already applied this procedure in schizophrenia, major depressive disorder and bipolar disorder [27, 30–32].

Sulcus recognition

The sample of 639 subjects was used in the EU-AIMS cohort, as in [26]. T1 MRI were skull-stripped, and brain tissues were segmented by an automated pre-processing step. A warping process may give rise to a few biases linked to the deformations of the sulcus shape. To overcome this issue, we did not apply any spatial normalization on MRIs. The skeleton of the gray matter/cerebrospinal fluid mask (a negative cast of white matter) was used to automatically delineate the cortical folds throughout the brain cortex. Cortical folds correspond to the crevasse bottoms in the "landscape", whose altitude is determined by intensity on MRI scans. This definition offers a reliable and robust representation of the sulcal surface that is unaffected by changes in cortical thickness or gray matter/white matter contrast [33] brought on by, for instance, developmental processes or medical treatments. Images were visually inspected using the viewer Anatomist of BrainVISA [34]. There were no obvious segmentation errors (such as cortical ribbon thinned, gyrus or sulcus absent) found.

The Morphologist 2021 pipeline of BrainVISA 5.0.3 was used to perform image analysis, with standard parameters (http://brainvisa.info). The cortex's folds were then transformed into a graph-based representation that included details on the sulci shape, area, depth, and length as well as their spatial organization (position and orientation). A Deep Learning CNN-based method was then used to automatically identify sulci. Without requiring any manual intervention, this recognition stage produced labelled sulcus graphs for each participant’s hemispheres using a previously validated approach [29].

Surface area

Each participant’s estimated outer brain surface area was calculated using a brain mask. For the left and right hemispheres of each participant, the surface area of the resulting envelope that swaddles the brain surface (referred to as the "hull") was calculated.

Sulcation indexes

3D mesh-based sulcal indexes were used to analyze cortical sulcation. These indexes reflect the degree of cortical burying, as described by Cachia et al. [27]. In each hemisphere, the g-SI (global sulcation index) corresponds to the ratio between the total sulcal area (i.e. the sum of the areas of all segmented cortical folds) and the total outer cortex area (i.e. the hull area) of the corresponding hemisphere (Fig. 1) [27, 28]. The g-SI represents cortical burial. It is different from the gyrification index (GI), which corresponds to the ratio between the outer surface of the brain, including the sulci, and the outer surface of the same region, excluding the sulci [14, 35]. The sulcation index is related to the gyrification index [36] but, unlike gyrification measurements, it does not depend on cortical thickness or sulcus opening [27, 28]. The l-SI (local sulcation index) were calculated in each hemisphere of each subject from 12 a priori determined brain regions covering the whole brain: the parietal region, the lateral-external temporal region, the posterior basal temporal region, the central sulcus, the intra-parietal fissure, the sylvian fissure, the calcarine complex, the medial frontal region, the posterior medial region, the occipital region, the frontal lateral region, and the precentral region (Fig. 2) [28]. For each of these regions, the l-SI was determined as the ratio between the sum of the areas of the cortical folds included in the region of interest and the hull area of the corresponding hemisphere. The lower the g-SI or the l-SI (closer to zero), the smoother the cortical surface and the less wrinkled the cortex.

After all this treatment with BrainVISA, among all subjects, we excluded those with aberrant l-SI values. This involved two subjects, resulting in a final sample of 1713 subjects.

Statistical analysis

All statistical analyses were performed using R version 4.2.2 software. Linear mixed models were used to compare the l-SI of children with ASD with those of control children, and to investigate the relationship between l-SI and symptoms in children with ASD. These linear models included diagnosis, age, and sex as fixed-effect independent variables, and scanner as random-effect independent variables. We chose this model according to the AIC (Akaike Information Criteria) metric, which compares the fit of several regression models. We tested different models, including age squared, total IQ, performance IQ and brain hull area, and according to AIC, these variables made no significant contribution and were thus not added to the model. The normality of the residuals of these linear models was verified with qq-plots and the Shapiro-Wilk test. No correction for multiple comparisons was applied, so our results should be regarded as exploratory. We also re-run all these analyses with ComBat [37]: the p-values showed some slight variations, with all the significant results remained significant and no new significant results appeared.

Sample characteristics

We included only participants with an IQ above 70. Our initial sample included 44 different scanners. After excluding sites with fewer than 15 ASD participants, our sample was down to 25 different scanners. We also excluded 2 participants whose l-SI was superior to the median + 3 MA, leading to a sample of 1713 children (841 with ASD and 872 controls). Cohort characteristics are detailed in Table 1. However, due to some missing MRI data, imaging data was available for 1480 children.

Within the group of children with ASD (723 ASD children for whom imaging data are available), not all clinical data were available either. The ADOS scores were available for 519 children, the ADI scores for 633 children for criterion A, 629 children for criterion B, and 632 children for criterion C. The SRS scores were available for 468 participants and the RME scores for 187 participants.

Table 1: Sample characteristics

ASD vs controls comparisons

Between children with ASD and controls, significant sulcation differences were found in the left precentral region (p_unc = 0.015, R² = 0.055, n =1480) and in the right precentral region (p_unc = 0.048, R² = 0.031, n =1480), with l-SI significantly higher in control children than in children with ASD in these regions (see results in Table 2). There was a positive interaction with sex in the left precentral region (p_unc= 0.003), with a significantly higher l-SI in control girls than in ASD girls (p_unc= 0.048, R² = 0.094, n = 357), but no significant difference in l-SI in boys (p_unc = 0.101, R² = 0.057, n = 1123). Age had no effect on sulcation in this region.

Table 2: Comparison of Local Sulcal indexes (l-SI) between children with ASD and control children for the 24 regions (12 by hemisphere)

n, number; SD, standard deviation; df, degrees of freedom, bold when statistically significant difference

Global sulcation index

There were no significant differences between g-SI of ASD participants and those of controls, either in the left hemisphere (p_unc= 0.178) or in the right hemisphere (p_unc= 0.156). There were also no significant correlations between GSI measurements and clinical scores.

Brain hull surfaces areas

No significant difference was found between the brain hull surface areas of subjects with ASD compared to controls, and no significant correlation was found between brain hull surface areas and clinical scores in subjects with ASD.

l-SI and autism clinical scores correlations

In the group of children with ASD, we found a significant positive association between ADOS scores and sulcation in the right intra-parietal fissure (p_unc= 0.049, R² = 0.115, n = 519), with a significant interaction with sex (p_unc = 0.008), without age effects. This positive association was only present in girls (p_unc = 0.047, R² = 0.075, n = 97) and not in boys (p_unc = 0.104, R² = 0.120, n = 422).

We identified significant positive correlations between ADI communication scores and sulcation in the left parietal (p_unc= 0.037, R² = 0.039, n = 629), the right medial frontal (p_unc= 0.035, R² = 0.144, n = 629) and the left posterior medial regions (p_unc= 0.049, R² = 0.093, n = 629). In the right medial frontal region, there was a significant interaction with sex (p_unc= 0.028), the association being present only in girls (p_unc= 0.047, R² = 0.175, n = 119) and not in boys (p_unc= 0.395, R² = 0.147, n = 510).

There was a significant negative correlation between SRS scores and sulcation indices in the left parietal region (p_unc= 0.026, R² = 0.060, n = 468), without any interaction effect.

Finally, we found significant negative correlations between l-SI and RME scores in the right parietal region (p_unc= 0.037, R² = 0.079, n = 187) and right calcarine complex (p_unc= 0.050, R² = 0.082, n = 187), and identified a significant positive correlation between l-SI and RME scores in the left precentral region (p_unc= 0.014, R² = 0.062, n = 187). In this last region, there was a significant interaction with sex (p_unc= 0.031), with girls l-SI significantly positively correlated to RME scores in left precentral region (p_unc= 0.008, R² = 0.116, n = 53), and no association in boys (p_unc= 0.794, R² = 0.050, n = 134).

Table 3: Correlation between Local Sulcal indexes (l-SI) in children with ASD and clinical scores for the 24 regions (12 by hemisphere)

n, number; df, degrees of freedom

In this large multicentric study of children with ASD and controls, we identified significantly higher l-SI (more folding) in control children than in those with ASD in precentral regions. Within the group of children with ASD, higher ADOS scores, indicative of more severe autistic traits, were significantly correlated with higher l-SI in the right intra-parietal fissure. This correlation between the sulcation of this region and the severity of autistic symptoms measured by the ADOS was found particularly in girls. Greater communication impairments as measured by the ADI were also significantly correlated with higher l-SI, and thus with a more folded cortex in the left parietal region (however also being associated with lower SRS), in the right medial frontal region (particularly in girls), and in the left posterior medial region. Finally, lower (i.e. poorer) RME scores were significantly correlated with higher l-SI in the right parietal region and right calcarine complex. These scores were also correlated with lower l-SI in the left precentral region, particularly in girls.

For most of these scales and in most of the regions where significant correlations between clinical scores and sulcation were found, autism severity scores and lower social cognition tests (RME) were associated with higher l-SI and therefore with more folded brains. More specifically, greater severity was associated with increased folding in right sided regions (right intra-parietal fissure, right medial frontal, right parietal and right calcarine) except for left medial (and left parietal, but this one was ambiguous as it was also associated with decreased SRS).

Cortical folds formation is greatly influenced by early neurodevelopment. Indeed, mature cortical morphology results from in utero constraints that convolute the surface [38]. The cortical folding and burial resulting from these early processes, which can be measured with global or local sulcation indices, represent interesting retrospective markers to attest of these early cortical constraints [8]. Cortical growth, apoptosis, differential expansion of superior and inferior cortical layers, differential growth of the progyral vs the prosulcal regions [10] and/or variations of white matter connections are all factors likely to contribute to the prenatal processes that influence how the cortex will fold [14, 39]. These different mechanisms may potentially play a part in the differences in cortical folding between the brain regions we observe here. Previous studies have shown an insufficient synaptic pruning in children with ASD, associated with a larger brain volume and a more folded cerebral cortex [18]. The increased sulcation associated with the severity of ASD that we found in some brain regions (right intra-parietal fissure, left parietal, right medial frontal, left posterior medial, right parietal region, right calcarine complex) in participants with ASD is in line with this literature. Our results may reflect a history of increased early cortical proliferation and/or insufficient cortical pruning in ASD, with a morphological trace of early developmental abnormalities in these regions.

We did not find any differences in GSI between participants with ASD and controls, nor associations of GSI with any clinical score. This suggests that differences in sulcation between children with ASD and control children may be more regional (as measured by l-SI) than global. The specificities of autistic functioning would be observed in the sulcation of specific regions, in relationship with the clinical symptoms measured.

Several associations between clinical scores and l-SI were driven only by the population of females with ASD despite the smaller number of females compared to males. A few hypotheses may explain this intriguing pattern of our results: a greater homogeneity of ASD in females or different mechanisms in females with ASD (including a greater neurodevelopmental loading because of diagnosis or camouflaging biases). However, these results must be interpreted with caution, due to the smaller size of the girl’s sample.

Previous research has found specific features linked to autism at the right posterior STS / temporoparietal junction (rTPJ) [13], very close to the right intraparietal fissure and the right parietal region where we found several l-SI variations associated with autism symptoms (measured by ADOS and RME). Right temporoparietal regions are known to be involved in social cognition [12]. Atypical anatomy of the right intraparietal sulcus has already been described in subjects with ASD vs. controls but also correlates with ADOS scores [40–42]. Functional neuroimaging has shown that rTPJ is specifically associated with deficits in social functioning in subjects with ASD [43]. Several lines of evidence suggest that rTMS or tDCS of the rTPJ may represent an effective treatment for improving social functioning in ASD [44]. Our results are therefore in line with these previous findings, showing sulcation specificities in these regions linked to clinically measured social cognition frailties.

We also found that higher SRS scores reflecting more marked autistic traits were significantly associated with lower l-SI and thus with a less folded cortex in the left parietal region. This result may seem somewhat surprising given that we found a significant positive correlation between ADI communication scores and l-SI in this same left parietal region (results unshown). A more folded cortex in this left parietal region is therefore associated with ADI greater communication impairments but also with milder autism symptoms overall (SRS). This may be explained by the fact that these scales do not measure exactly the same aspects of autism. Another interpretation may be that this is an inconsistent result.

One interesting pattern in our results is that in our sample, an increased level of social symptoms was generally associated with an increased right-sided sulcation (in the right intra-parietal fissure with ADOS, right medial frontal with ADI-B, right parietal and right calcarine with RME) and decreased left-sided sulcation levels (left parietal with SRS and left precentral with RME) with the exceptions of left posterior medial region (but with a borderline significance level of 0.049) and left parietal region with ADI-B (but as previously discussed, this is an inconsistent result with the association with SRS scores). As the left side of the brain is generally considered as being more folded than the right side, an increased level of social symptoms may be accompanied by a loss of asymmetry [45]. Several studies, including within our consortium [46] have suggested altered asymmetry or atypical lateralization as a neuro-phenotype for autism. This has been replicated either anatomically, with structural MRI or DTI [47] or functionally [48]. Our results thus support the decreased asymmetry theory of ASD [49] and reduced interhemispheric connectivity in ASD [50].

Limitations

Although our sample size is substantial, we performed many analyses and p-values were not corrected for multiple comparisons, which is a limitation of our results. In addition, the analyses performed by sex when there were significant interactions between sex and clinical scores in certain regions should be treated with caution, as this significantly reduces the sample size, particularly for girls, which may result in a loss of representativeness and robustness.

Future research may aim at extending our study to compare sulcation in participants with ASD with other neurodevelopmental disorders or other language and interaction disorders. This should allow us to understand if the effects observed in this study are typical of autism or rather representative of symptoms that can also be found in other neurodevelopmental disorders. Similar studies should be also carried out in adults, to see if the regions involved and the correlations between sulcation and clinical symptoms are the same as in children.

This study is based on a large sample size, combining several international cohorts. Our results point to an increased sulcation associated with more severe symptoms on clinical scales assessing ASD. These correlations are observed more specifically in girls with ASD, in several right-sided regions associated with social cognition (temporo-parietal regions). We now need to better understand how these neurodevelopmental features are associated with genetic and white matter changes in ASD.

ABIDE: Autism Brain Imaging Database Exchange

ADI-R: Autism Diagnostic Interview-Revised

ADOS: Autism Diagnostic Observation Schedule

AIC: Akaike Information Criteria

ASD: Autism Spectrum Disorders

CSS: Calibrated Severity Score

g-SI: Global Sulcation Index

GI: Gyrification Index

IQ: Intelligence Quotient

l-SI: Local Sulcation Index

MAD : Median Absolute Deviations

r-TPJ : Right TemporoParietal Junction

RME: Reading the Mind in the Eyes

SRS: Social Responsiveness Scale

STS: Superior Temporal Sulcus

Ethics approval and consent to participate

Robert Debré: the study was granted approval by the local Ethics Committee (ref: 2008-A00019-46) and registered in a public trial registry (NCT02628808). The study was carried out in accordance with Good Clinical Practice (ICH GCP) standards. Written informed consent was obtained from all participants. For patients who were unable to consent for themselves, a parent or legal guardian consented to the study on their behalf.

ABIDE I and II: All contributions were based on studies approved by the local Institutional Review Boards, and all have approved both the initial data collection and the sharing of fully anonymized data (removing face information from structural images and all 18 Health Insurance Portability and Accountability (HIPAA)-protected health information identifiers). The written informed consent was obtained from all subjects. Detailed information on ethical statements for ABIDE can be found at http://fcon_1000.projects.nitrc.org/indi/abide/.

EUAIMS LEAP: The ethical approval to conduct the present research was obtained via the EU AIMS LEAP consortium. Specifically, ethical approval was provided by the external ethics advisory board to AIMS-2-TRIALS. Local ethics committees in each participating centre approved the study and written informed consent was provided by all participants and/or their legal guardians (for those < 16/18 years old [country dependent] or legally incapacitated).

Availability of data and materials

Due to medical privacy reasons, individual level data are not available. Group data are available from authors upon reasonable request.

Acknowledgments

The authors gratefully acknowledge the contributions of the EU-AIMS LEAP Group: Jumana Ahmad, Sara Ambrosino, Bonnie Auyeung, Tobias Banaschewski, Simon Baron-Cohen, Sarah Baumeister, Christian F. Beckmann, Sven Bölte, Thomas Bourgeron, Carsten Bours, Michael Brammer, Daniel Brandeis, Claudia Brogna, Yvette de Bruijn, Jan K. Buitelaar, Bhismadev Chakrabarti, Tony Charman, Ineke Cornelissen, Daisy Crawley, Flavio Dell’Acqua, Guillaume Dumas, Sarah Durston, Christine Ecker, Jessica Faulkner, Vincent Frouin, Pilar Garcés, David Goyard, Lindsay Ham, Hannah Hayward, Joerg Hipp, Rosemary Holt, Mark H. Johnson, Emily J.H. Jones, Prantik Kundu, Meng-Chuan Lai, Xavier Liogier D’Ardhuy, Michael V. Lombardo, Eva Loth, David J. Lythgoe, René Mandl, Andre Marquand, Luke Mason, Maarten Mennes, Andreas Meyer-Lindenberg, Carolin Moessnang, Nico Mueller, Declan G.M. Murphy, Bethany Oakley, Laurence O’Dwyer, Marianne Oldehinkel, Bob Oranje, Gahan Pandina, Antonio M. Persico, Barbara Ruggeri, Amber Ruigrok, Jessica Sabet, Roberto Sacco, Antonia San José Cáceres, Emily Simonoff, Will Spooren, Julian Tillmann, Roberto Toro, Heike Tost, Jack Waldman, Steve C.R. Williams, Caroline Wooldridge, and Marcel P. Zwiers.

Funding, competing interests

This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No. 115300 (for the project EU-AIMS) and No. 777394 (for the project AIMS-2-TRIALS). This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme, the European Federation of Pharmaceutical Industries and Associates, the AUTISM SPEAKS, Autistica, and SFARI. Any views expressed are those of the author(s) and not necessarily those of the funders.

Dr. Tillmann has served as a consultant for Hoffmann–La Roche. Dr. Banaschewski has served as an adviser or consultant for Actelion, ADHS Digital, Eli Lilly, Hexal Pharma, Infectopharm, Lundbeck, Medice, Neurim Pharmaceuticals, Novartis, Oberberg GmbH, Otsuka, Oxford Outcomes, PCM Scientific, Roche, Shire, Takeda, and Vifor Pharma; he has received conference support or speaking fees from Medice, Novartis, Shire, and Takeda; he has been involved in clinical trials conducted by Shire and Vifor Pharma; and he has received royalties from CIP Medien, Hogrefe, Kohlhammer, and Oxford University Press. Dr. Jones has received funding from Action Medical Research, EU Horizon 2020, the Innovative Medicines Initiative, the Medical Research Council (UK), MQ: Transforming Mental Health, and the Economic and Social Research Council. Dr. Bölte has served as an author, consultant, or lecturer for Ability Partner, Eli Lilly, Expo Medica, GLGroup, Kompetento, Medice, Prima Psychiatry, Prophase, Roche, Shire, and System Analytic, and he receives royalties for textbooks and diagnostic tools from Huber/Hogrefe, Kohlhammer, and UTB. Dr. Meyer-Lindenberg has served as a consultant for the Agence Nationale de la Recherche, the American Association for the Advancement of Science, Atheneum Partners, Blueprint Partnership, Boehringer Ingelheim, the Brain Mind Institute, BrainsWay, the Catania International Summer School of Neuroscience, Daimler und Benz Stiftung, Elsevier, the Fondation FondaMental, Janssen-Cilag, Hoffmann–La Roche, ICARE Schizophrenia, K.G. Jebsen Foundation, L.E.K. Consulting, The LOOP Zürich, Lundbeck A/S, Lundbeck International Neuroscience Foundation, MedinCell, Roche Pharma, Sage Therapeutics, Sumitomo Dainippon Pharma, Synapsis Foundation–Alzheimer Research Switzerland, System Analytics, Techspert.io, Thieme Verlag, and von Behring Röntgen Stiftung, and he has received speaking fees from BAG Psychiatrie Oberbayern, Biotest AG, Boehringer Ingelheim, Fama Public Relations, Forum Werkstatt Karlsruhe, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), the International Society of Psychiatric Genetics, Janssen-Cilag, Klinik für Psychiatrie und Psychotherapie, Klinikum Christophsbad, Göppingen, Lilly Deutschland, Lundbeck SAS France, Luzerner Psychiatrie, LVR Klinikum Düsseldorf, LWL Psychiatrie Verbund Westfalen-Lippe, Med Update GmbH, Merz-Stiftung, Otsuka Pharmaceuticals, Reunions i Ciencia S.L., Siemens Healthineers, Spanish Society of Psychiatry, Südwestrundfunk Fernsehen, Stern TV, and Vitos Klinikum Kurhessen. Dr. Baron-Cohen has served as an author, consultant, or lecturer for Ability Partner, Clarion Healthcare, Expo Medica, Eli Lilly, GLGroup, Kompetento, Medice, Prima Psychiatry, Prophase, Roche, Shire, and System Analytic; he receives royalties for textbooks and diagnostic tools from Huber/Hogrefe, Kohlhammer, and UTB. Dr. Spooren is an employee of F. Hoffmann–La Roche. Dr. Freitag receives royalties for books on autism spectrum disorder, ADHD, and major depressive disorder. Dr. Charman has received consultancy from Roche and Servier and received book royalties from Guildford Press and Sage. Dr. Beckmann is co-founder of SBGneuro. Dr. Buitelaar has been in the past 3 years a consultant to / member of advisory board of / and/or speaker for Takeda, Roche, Medice, Angelini, Neuraxpharm, and Servier. He is not an employee of any of these companies, and not a stock shareholder of any of these companies. He has no other financial or material support, including expert testimony, patents, royalties. Dr. Murphy has received honoraria from Roche and Servier, and he has received grant support from the Medical Research Council (UK), the National Institute for Health Research, and Horizon 2020 and the Innovative Medicines Initiative (European Commission). The other authors report no financial relationships with commercial interests.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Authors' contributions

SB designed the analysis plan, analyzed the data, interpreted the data, drafted the manuscript and revised it. ID, YL, MG, VF, ED, CF analyzed the data, interpreted the data, substantively revised the manuscript. AB, AL and MA acquired the data, and substantively revised the manuscript. AC and JFM created the software used in the work, interpreted the data, substantively revised the manuscript. ML, RD, TC, TW, SD, CM, FDA, CE, EL, DM, SBC, JK, AM and CB interpreted the data and substantively revised the initial draft. JH conceived and designed the work, interpreted the data and substantively revised the initial draft.

All authors approved the submitted version and to have agreed both to be personally accountable for the author's own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.

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Competing interest reported. Dr. Tillmann has served as a consultant for Hoffmann–La Roche. Dr. Banaschewski has served as an adviser or consultant for Actelion, ADHS Digital, Eli Lilly, Hexal Pharma, Infectopharm, Lundbeck, Medice, Neurim Pharmaceuticals, Novartis, Oberberg GmbH, Otsuka, Oxford Outcomes, PCM Scientific, Roche, Shire, Takeda, and Vifor Pharma; he has received conference support or speaking fees from Medice, Novartis, Shire, and Takeda; he has been involved in clinical trials conducted by Shire and Vifor Pharma; and he has received royalties from CIP Medien, Hogrefe, Kohlhammer, and Oxford University Press. Dr. Jones has received funding from Action Medical Research, EU Horizon 2020, the Innovative Medicines Initiative, the Medical Research Council (UK), MQ: Transforming Mental Health, and the Economic and Social Research Council. Dr. Bölte has served as an author, consultant, or lecturer for Ability Partner, Eli Lilly, Expo Medica, GLGroup, Kompetento, Medice, Prima Psychiatry, Prophase, Roche, Shire, and System Analytic, and he receives royalties for textbooks and diagnostic tools from Huber/Hogrefe, Kohlhammer, and UTB. Dr. Meyer-Lindenberg has served as a consultant for the Agence Nationale de la Recherche, the American Association for the Advancement of Science, Atheneum Partners, Blueprint Partnership, Boehringer Ingelheim, the Brain Mind Institute, BrainsWay, the Catania International Summer School of Neuroscience, Daimler und Benz Stiftung, Elsevier, the Fondation FondaMental, Janssen-Cilag, Hoffmann–La Roche, ICARE Schizophrenia, K.G. Jebsen Foundation, L.E.K. Consulting, The LOOP Zürich, Lundbeck A/S, Lundbeck International Neuroscience Foundation, MedinCell, Roche Pharma, Sage Therapeutics, Sumitomo Dainippon Pharma, Synapsis Foundation–Alzheimer Research Switzerland, System Analytics, Techspert.io, Thieme Verlag, and von Behring Röntgen Stiftung, and he has received speaking fees from BAG Psychiatrie Oberbayern, Biotest AG, Boehringer Ingelheim, Fama Public Relations, Forum Werkstatt Karlsruhe, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), the International Society of Psychiatric Genetics, Janssen-Cilag, Klinik für Psychiatrie und Psychotherapie, Klinikum Christophsbad, Göppingen, Lilly Deutschland, Lundbeck SAS France, Luzerner Psychiatrie, LVR Klinikum Düsseldorf, LWL Psychiatrie Verbund Westfalen-Lippe, Med Update GmbH, Merz-Stiftung, Otsuka Pharmaceuticals, Reunions i Ciencia S.L., Siemens Healthineers, Spanish Society of Psychiatry, Südwestrundfunk Fernsehen, Stern TV, and Vitos Klinikum Kurhessen. Dr. Baron-Cohen has served as an author, consultant, or lecturer for Ability Partner, Clarion Healthcare, Expo Medica, Eli Lilly, GLGroup, Kompetento, Medice, Prima Psychiatry, Prophase, Roche, Shire, and System Analytic; he receives royalties for textbooks and diagnostic tools from Huber/Hogrefe, Kohlhammer, and UTB. Dr. Spooren is an employee of F. Hoffmann–La Roche. Dr. Freitag receives royalties for books on autism spectrum disorder, ADHD, and major depressive disorder. Dr. Charman has received consultancy from Roche and Servier and received book royalties from Guildford Press and Sage. Dr. Beckmann is co-founder of SBGneuro. Dr. Buitelaar has been in the past 3 years a consultant to / member of advisory board of / and/or speaker for Takeda, Roche, Medice, Angelini, Neuraxpharm, and Servier. He is not an employee of any of these companies, and not a stock shareholder of any of these companies. He has no other financial or material support, including expert testimony, patents, royalties. Dr. Murphy has received honoraria from Roche and Servier, and he has received grant support from the Medical Research Council (UK), the National Institute for Health Research, and Horizon 2020 and the Innovative Medicines Initiative (European Commission). The other authors report no financial relationships with commercial interests. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Sulcation in children with autism spectrum disorders

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Version 1

Abstract

Background

Methods

Results

Limitations:

Conclusions

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Background

Autism spectrum disorders

Aims of the study

Methods

Population

Rating scales

Anatomical MRI acquisition

Data processing

Statistical analysis

Results

Discussion

Limitations

Conclusions

Abbreviations

Declarations

References

Additional Declarations

Status:

Version 1