Subtly altered topological asymmetry of brain structural covariance networks in autism spectrum disorder across 43 datasets from the ENIGMA consortium.

Small average differences in the left-right asymmetry of cerebral cortical thickness have been reported in individuals with autism spectrum disorder (ASD) compared to typically developing controls, affecting widespread cortical regions. The possible impacts of these regional alterations in terms of structural network effects have not previously been characterized. Inter-regional morphological covariance analysis can capture network connectivity between different cortical areas at the macroscale level. Here, we used cortical thickness data from 1455 individuals with ASD and 1560 controls, across 43 independent datasets of the ENIGMA consortium's ASD Working Group, to assess hemispheric asymmetries of intra-individual structural covariance networks, using graph theory-based topological metrics. Compared with typical features of small-world architecture in controls, the ASD sample showed significantly altered average asymmetry of networks involving the fusiform, rostral middle frontal, and medial orbitofrontal cortex, involving higher randomization of the corresponding right-hemispheric networks in ASD. A network involving the superior frontal cortex showed decreased right-hemisphere randomization. Based on comparisons with meta-analyzed functional neuroimaging data, the altered connectivity asymmetry particularly affected networks that subserve executive functions, language-related and sensorimotor processes. These findings provide a network-level characterization of altered left-right brain asymmetry in ASD, based on a large combined sample. Altered asymmetrical brain development in ASD may be partly propagated among spatially distant regions through structural connectivity.

Consortium neuroscience of attention deficit/hyperactivity disorder and autism spectrum disorder: The ENIGMA adventure.

Neuroimaging has been extensively used to study brain structure and function in individuals with attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) over the past decades. Two of the main shortcomings of the neuroimaging literature of these disorders are the small sample sizes employed and the heterogeneity of methods used. In 2013 and 2014, the ENIGMA-ADHD and ENIGMA-ASD working groups were respectively, founded with a common goal to address these limitations. Here, we provide a narrative review of the thus far completed and still ongoing projects of these working groups. Due to an implicitly hierarchical psychiatric diagnostic classification system, the fields of ADHD and ASD have developed largely in isolation, despite the considerable overlap in the occurrence of the disorders. The collaboration between the ENIGMA-ADHD and -ASD working groups seeks to bring the neuroimaging efforts of the two disorders closer together. The outcomes of case-control studies of subcortical and cortical structures showed that subcortical volumes are similarly affected in ASD and ADHD, albeit with small effect sizes. Cortical analyses identified unique differences in each disorder, but also considerable overlap between the two, specifically in cortical thickness. Ongoing work is examining alternative research questions, such as brain laterality, prediction of case-control status, and anatomical heterogeneity. In brief, great strides have been made toward fulfilling the aims of the ENIGMA collaborations, while new ideas and follow-up analyses continue that include more imaging modalities (diffusion MRI and resting-state functional MRI), collaborations with other large databases, and samples with dual diagnoses.

Effects of motor action on affective preferences in autism spectrum disorders: different influences of embodiment.

In the embodied cognition framework, sensory, motor and emotional experiences are encoded along with sensorimotor cues from the context in which information was acquired. As such, representations retain an initial imprint of the manner in which information was acquired. The current study reports results indicating a lack of embodiment effects in ASD and, further, an association between embodiment differences and ASD symptomatology. The current results are consistent with an embodied account of ASD that goes beyond social experiences and could be driven by subtle deficits in sensorimotor coordination.

Attachment style impacts behavior and early oculomotor response to positive, but not negative, pictures.

The present study investigated whether oculomotor behavior is influenced by attachment styles. The Relationship Scales Questionnaire was used to assess attachment styles of forty-eight voluntary university students and to classify them into attachment groups (secure, preoccupied, fearful, and dismissing). Eye-tracking was recorded while participants engaged in a 3-seconds free visual exploration of stimuli presenting either a positive or a negative picture together with a neutral picture, all depicting social interactions. The task consisted in identifying whether the two pictures depicted the same emotion. Results showed that the processing of negative pictures was impermeable to attachment style, while the processing of positive pictures was significantly influenced by individual differences in insecure attachment. The groups highly avoidant regarding to attachment (dismissing and fearful) showed reduced accuracy, suggesting a higher threshold for recognizing positive emotions compared to the secure group. The groups with higher attachment anxiety (preoccupied and fearful) showed differences in automatic capture of attention, in particular an increased delay preceding the first fixation to a picture of positive emotional valence. Despite lenient statistical thresholds induced by the limited sample size of some groups (p < 0.05 uncorrected for multiple comparisons), the current findings suggest that the processing of positive emotions is affected by attachment styles. These results are discussed within a broader evolutionary framework.

Refining criteria for a neurodevelopmental sub-phenotype of bipolar disorders: a FondaMental Advanced Centers of Expertise for Bipolar Disorders study.

BACKGROUND: Bipolar disorder (BD) is a complex and heterogeneous psychiatric disorder. Neurodevelopmental factors were suggested to contribute to the etiology of BD, yet a specific neurodevelopmental phenotype of the disorder remains unidentified. Our objective was to define and characterize a neurodevelopmental phenotype (NDP) in BD and validate its associations with clinical outcomes, polygenic risk scores (PGS), and treatment responses. METHOD: We analyzed the FACE-BD cohort of 4,468 BD patients, a validation cohort of 101 BD patients, and two independent replication datasets of 274 and 89 BD patients. Using factor analyses, we identified a set of criteria for defining NDP. We next developed a scoring system for NDP-load and assessed its association with prognosis, neurological soft signs, polygenic risk scores for neurodevelopmental disorders, and responses to treatment using multiple regressions, adjusted for age and sex with bootstrap replications. RESULTS: Our study established a NDP in BD consisting of nine clinical features: advanced paternal age, advanced maternal age, childhood maltreatment, attention deficit hyperactivity disorder (ADHD), early onset of BD, early onset of substance use disorders, early onset of anxiety disorders, early onset of eating disorders, specific learning disorders. Patients with higher NDP-load showed a worse prognosis and increased neurological soft signs. Notably, these individuals exhibited a poorer response to lithium treatment. Furthermore, a significant positive correlation was observed between the NDP-load and PGS for ADHD suggesting potential overlapping genetic factors or pathophysiological mechanisms between BD and ADHD. CONCLUSIONS: The proposed NDP constitutes a promising clinical tool for patient stratification in BD.

fMRI evidence for dorsal stream processing abnormality in adults born preterm.

We investigated the consequences of premature birth on the functional neuroanatomy of the dorsal stream of visual processing. fMRI was recorded while sixteen healthy participants, 8 (two men) adults (19 years 6 months old, SD 10 months) born premature (mean gestational age 30 weeks), referred to as Premas, and 8 (two men) matched controls (20 years 1 month old, SD 13 months), performed a 1-back memory task of Object or Grip information using a hand grasping a drinking vessel as stimulus. While history of prematurity did not significantly affect task performance, Group by Task analysis of variance in regions of interest spanning the occipital, temporal and parietal lobes revealed main effects of Task and interactions between the two factors. Object processing activated the left inferior occipital cortex and bilateral ventral temporal regions, belonging to the ventral stream, with no effect of Group. Grip processing across groups activated the early visual cortex and the left supramarginal gyrus belonging to the dorsal stream. Group effect on the brain activity during Grip suggested that Controls represented the actions' goal while Premas relied more on low-level visual information. This shift from higher- to lower-order visual processing between Controls and Premas may reflect a more general trend, in which Premas inadequately recruit higher-order visual functions for dorsal stream task performance, and rely more on lower-level functions.

Global and local cortical folding alterations are associated with neurodevelopmental subtype in bipolar disorders: a sulcal pits analysis.

BACKGROUND: Analyzing cortical folding may provide insight into the biological underpinnings of neurodevelopmental diseases. A neurodevelopmental subtype of bipolar disorders (BD-ND) has been characterized by the combination of early age of onset and psychotic features. We investigate potential cortical morphology differences associated with this subtype. We analyze, for the first time in bipolar disorders, the sulcal pits, the deepest points in each fold of the cerebral cortex. METHODS: We extracted the sulcal pits from anatomical MRI among 512 participants gathered from 7 scanning sites. We compared the number of sulcal pits in each hemisphere as well as their regional occurrence and depth between the BD-ND subgroup (N = 184), a subgroup without neurodevelopmental features (BD, N = 77) and a group of healthy controls (HC, N = 251). RESULTS: In whole brain analysis, BD-ND group have a higher number of sulcal pits in comparison to the BD group. The local analysis revealed, after correction for multiple testing, a higher occurrence of sulcal pits in the left premotor cortex among the BD-ND subgroup compared to the BD and the HC groups. CONCLUSION: Our findings confirm that BD-ND is associated with a specific brain morphology revealed by the analysis of sulcal pits. These markers may help to better understand neurodevelopment in mood disorder and stratify patients according to a pathophysiological hypothesis.

Virtual Ontogeny of Cortical Growth Preceding Mental Illness.

BACKGROUND: Morphology of the human cerebral cortex differs across psychiatric disorders, with neurobiology and developmental origins mostly undetermined. Deviations in the tangential growth of the cerebral cortex during pre/perinatal periods may be reflected in individual variations in cortical surface area later in life. METHODS: Interregional profiles of group differences in surface area between cases and controls were generated using T1-weighted magnetic resonance imaging from 27,359 individuals including those with attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depressive disorder, schizophrenia, and high general psychopathology (through the Child Behavior Checklist). Similarity of interregional profiles of group differences in surface area and prenatal cell-specific gene expression was assessed. RESULTS: Across the 11 cortical regions, group differences in cortical area for attention-deficit/hyperactivity disorder, schizophrenia, and Child Behavior Checklist were dominant in multimodal association cortices. The same interregional profiles were also associated with interregional profiles of (prenatal) gene expression specific to proliferative cells, namely radial glia and intermediate progenitor cells (greater expression, larger difference), as well as differentiated cells, namely excitatory neurons and endothelial and mural cells (greater expression, smaller difference). Finally, these cell types were implicated in known pre/perinatal risk factors for psychosis. Genes coexpressed with radial glia were enriched with genes implicated in congenital abnormalities, birth weight, hypoxia, and starvation. Genes coexpressed with endothelial and mural genes were enriched with genes associated with maternal hypertension and preterm birth. CONCLUSIONS: Our findings support a neurodevelopmental model of vulnerability to mental illness whereby prenatal risk factors acting through cell-specific processes lead to deviations from typical brain development during pregnancy.

Laterality preference and cognition: cross-syndrome comparison of patients with trisomy 21 (Down), del7q11.23 (Williams-Beuren) and del22q11.2 (DiGeorge or Velo-Cardio-Facial) syndromes.

We report on a cross-syndrome comparison of hand, foot, eye and ear laterality in three groups of individuals with different genetic disorders (trisomy 21, del7q11.23, and del22q11.2) to test the relationship between atypical laterality and intellectual disability. These groups were compared to a group of typically developing persons. Hand, foot, eye and ear laterality was assessed using item tasks, conducted twice, and Bishop's card-reaching test. Ordering of the mean IQ score for each of the three groups was as follows: trisomy 21 < del7q11.23 < del22q11.2. We observed the same ordering as for IQ, particularly in mixed handedness, degree of laterality, hand and foot consistency. The existence of a cognitive threshold, below which lateral preference is atypical, advocates for a causal link between cognition and laterality in those with low IQ although unknown other factors underlying both could determine this association.

U-shape short-range extrinsic connectivity organisation around the human central sulcus.

The central sulcus is probably one of the most studied folds in the human brain, owing to its clear relationship with primary sensory-motor functional areas. However, due to the difficulty of estimating the trajectories of the U-shape fibres from diffusion MRI, the short structural connectivity of this sulcus remains relatively unknown. In this context, we studied the spatial organization of these U-shape fibres along the central sulcus. Based on high quality diffusion MRI data of 100 right-handed subjects and state-of-the-art pre-processing pipeline, we first define a connectivity space that provides a comprehensive and continuous description of the short-range anatomical connectivity around the central sulcus at both the individual and group levels. We then infer the presence of five major U-shape fibre bundles at the group level in both hemispheres by applying unsupervised clustering in the connectivity space. We propose a quantitative investigation of their position and number of streamlines as a function of hemisphere, sex and functional scores such as handedness and manual dexterity. Main findings of this study are twofold: a description of U-shape short-range connectivity along the central sulcus at group level and the evidence of a significant relationship between the position of three hand related U-shape fibre bundles and the handedness score of subjects.

Does preterm birth affect global and configural processing differently?

AIM: We investigated whether preterm birth affects later visuocognitive function and, in particular, whether it affects global and configural perceptual processing differently. METHOD: We compared the performance of 21 healthy preterm children (8 females, 13 males; mean age 7 y 8 mo, SD 8 mo; mean gestational age 29.3 wks, SD 1.9; mean birthweight 1186.5 g, SD 377.2) with that of a matched term comparison group (8 females, 13 males; mean age 7 y 11 mo, SD 1 y 1 mo; mean gestational age >37 wks; mean birthweight >2500 g) in two perceptual tasks pinpointing differences between local and global and between local and configural processing. RESULTS: There was no difference between preterm and term children's global processing, as both groups showed a bias towards global information (preterm: t[1,20]=2.6, p=0.01; comparison group: t[1,20]=3.0, p=0.01). By contrast, no such typical pattern of performance was found for configural processing as, unlike the comparison group (t[1,20]=7.1, p<0.001), preterm children preferentially relied on local rather than on configural information (t[1,20]=-15.4, p<0.001). INTERPRETATION: These findings suggest that preterm birth may have a greater influence on the development of later perceptual skills than originally envisaged. We discuss the results according to the current and dominant view of the visual system.

Acting on observed social exclusion and pro-social behaviour in autism spectrum disorder.

Humans are commonly motivated towards cooperation and prosociality. In this study, we examined this motivational predisposition in autistic individuals. Using an adaptation of the Cyberball paradigm, we investigated subsequent pro-social behaviour after witnessing social exclusion. Participants witnessed and played a series of Cyberball games, rated their affective state and valued emotional faces with respect to their approachability. Results showed that participants from both groups were aware of the social exclusion. However, while neurotypically developing participants engaged in pro-social behaviour in reaction to the exclusion, autistic participants showed less alterations, in terms of either behaviour or affective state. The current findings suggest a distinct motivational drive and processing of social reward stimuli in autism, which may result in behavioural responses divergent from typical development when engaging in the social world.

Group-level cortical surface parcellation with sulcal pits labeling.

Sulcal pits are the points of maximal depth within the folds of the cortical surface. These shape descriptors give a unique opportunity to access to a rich, fine-scale representation of the geometry and the developmental milestones of the cortical surface. However, using sulcal pits analysis at group level requires new numerical tools to establish inter-subject correspondences. Here, we address this issue by taking advantage of the geometrical information carried by sulcal basins that are the local patches of surfaces surrounding each sulcal pit. Our framework consists in two phases. First, we present a new method to generate a population-specific atlas of this sulcal basins organi- zation as a fold-level parcellation of the cortical surface. Then, we address the labeling of individual sulcal pits and corresponding basins with respect to this atlas. To assess their validity, we applied these methodological advances on two different populations of healthy subjects. The first database of 137 adults allowed us to compare our method to the state-of-the-art and the second database of 209 children, aged between 0 and 18 years, illustrates the adaptability and relevance of our method in the context of pediatric data showing strong variations in cortical volume and folding.

Emotion understanding in children with ADHD.

Several studies suggest that children with ADHD tend to perform worse than typically developing children on emotion recognition tasks. However, most of these studies have focused on the recognition of facial expression, while there is evidence that context plays a major role on emotion perception. This study aims at further investigating emotion processing in children with ADHD, by assessing not only facial emotion recognition (Experiment 1) but also emotion recognition on the basis of contextual cues (Experiment 2). Twenty-seven children and adolescents with ADHD were compared to age-matched typically developing controls. Importantly, findings of this study show that emotion-processing difficulties in children with ADHD extend beyond facial emotion and also affect the recognition of emotions on the basis of contextual information. Our data thus indicate that children with ADHD have an overall emotion-processing deficit.

When depression mediates the relationship between entity beliefs and performance.

The aim of this study was to determine whether depression can explain the negative relationship between academic performance and the belief that intelligence is a fixed trait, i.e., entity belief. A sample of 353 French volunteer adolescents (age 11-16) completed questionnaires assessing entity theory and depressive symptoms (Children Depression Inventory: CDI). Academic performance was assessed by math performance while controlling for baseline level of math ability. Results of this study revealed that entity theory is a significant negative predictor of academic performance and a significant positive predictor of depression. Importantly, our findings also show that depression plays a significant mediating role between entity theory and academic performance. Our findings indicate that individuals who consider their abilities to be non-malleable are more likely to develop depressive symptoms which, in turn, decrease academic performance. These findings contribute to tailoring specific prevention and treatment programs for childhood and adolescent depression.

Diffusion MRI: Assessment of the Impact of Acquisition and Preprocessing Methods Using the BrainVISA-Diffuse Toolbox.

Diffusion MR images are prone to severe geometric distortions induced by head movement, eddy-current and inhomogeneity of magnetic susceptibility. Various correction methods have been proposed that depend on the choice of the acquisition settings and potentially provide highly different data quality. However, the impact of this choice has not been evaluated in terms of the ratio between scan time and preprocessed data quality. This study aims at investigating the impact of six well-known preprocessing methods, each associated to specific acquisition settings, on the outcome of diffusion analyses. For this purpose, we developed a comprehensive toolbox called Diffuse which automatically guides the user to the best preprocessing pipeline according to the input data. Using MR images of 20 subjects from the HCP dataset, we compared the six pre-processing pipelines regarding the following criteria: the ability to recover brain's true geometry, the tensor model estimation and derived indices in the white matter, and finally the spatial dispersion of six well known connectivity pathways. As expected the pipeline associated to the longer acquisition fully repeated with reversed phase-encoding (RPE) yielded the higher data quality and was used as a reference to evaluate the other pipelines. In this way, we highlighted several significant aspects of other pre-processing pipelines. Our results first established that eddy-current correction improves the tensor-fitting performance with a localized impact especially in the corpus callosum. Concerning susceptibility distortions, we showed that the use of a field map is not sufficient and involves additional smoothing, yielding to an artificial decrease of tensor-fitting error. Of most importance, our findings demonstrate that, for an equivalent scan time, the acquisition of a b0 volume with RPE ensures a better brain's geometry reconstruction and local improvement of tensor quality, without any smoothing of the image. This was found to be the best scan time/data quality compromise. To conclude, this study highlights and attempts to quantify the strong dependence of diffusion metrics on acquisition settings and preprocessing methods.

Altered structural brain asymmetry in autism spectrum disorder in a study of 54 datasets.

Altered structural brain asymmetry in autism spectrum disorder (ASD) has been reported. However, findings have been inconsistent, likely due to limited sample sizes. Here we investigated 1,774 individuals with ASD and 1,809 controls, from 54 independent data sets of the ENIGMA consortium. ASD was significantly associated with alterations of cortical thickness asymmetry in mostly medial frontal, orbitofrontal, cingulate and inferior temporal areas, and also with asymmetry of orbitofrontal surface area. These differences generally involved reduced asymmetry in individuals with ASD compared to controls. Furthermore, putamen volume asymmetry was significantly increased in ASD. The largest case-control effect size was Cohen's d = -0.13, for asymmetry of superior frontal cortical thickness. Most effects did not depend on age, sex, IQ, severity or medication use. Altered lateralized neurodevelopment may therefore be a feature of ASD, affecting widespread brain regions with diverse functions. Large-scale analysis was necessary to quantify subtle alterations of brain structural asymmetry in ASD.

Typical emotion processing for cartoon but not for real faces in children with autistic spectrum disorders.

This study evaluated whether atypical face processing in autism extends from human to cartoon faces for which they show a greater interest. Twenty children with autistic spectrum disorders (ASD) were compared to two groups of typically developing children, matched on chronological and mental age. They processed the emotional expressions of real faces, human cartoon and nonhuman cartoon faces. Children with ASD were as capable as controls in processing emotional expressions, but strategies differed according to the type of face. Controls relied on a configural strategy with all faces. By contrast, ASD children exploited this typical configural strategy with cartoons but used a local strategy with real faces. This atypical visual processing style is discussed in the context of face expertise.

Recognition of biological motion in children with autistic spectrum disorders.

It is widely accepted that autistic children experience difficulties in processing and recognizing emotions. Most relevant studies have explored the perception of faces. However, context and bodily gestures are also sources from which we derive emotional meanings. We tested 23 autistic children and 23 typically developing control children on their ability to recognize point-light displays of a person's actions, subjective states and emotions. In a control task, children had to recognize point-light displays of everyday objects. The children with autism only differed from the control children in their ability to name the emotional point-light displays. This suggests that children with autism can extract complex meanings from bodily movements but may be less sensitive to higher-order emotional information conveyed by human movement. The results are discussed in the context of a specific deficit in emotion perception in children with autism.

Are friends really the family we choose? Local variations of hypothalamus activity when viewing personally known faces.

Sibling and friend relationships have significant impact on individuals' socio-emotional development. Hypothalamic supraoptic nucleus (SON) and paraventricular nucleus (PVN) synthesize and secrete neuropeptides, including oxytocin, associated with attachment behaviors. Here, using fMRI, we investigate the implication of these two hypothalamic nuclei in the visual processing of personally known faces.  Faces of same-sex sibling, best friend, celebrity, and unknown person appear in the middle of the screen while participants perform a task requiring a button click each time a central white dot turns red. Ratings of familiarity (time spent together) and emotionality (feelings toward individual) toward the four individuals are recorded. Local activation within the hypothalamus is assessed via two complementary methods: (1) voxel-based analyses within inclusive mask of the hypothalamus; (2) region-of-interest (ROI) analysis of partial hypothalamic volumes using SON and PVN as center of mass coordinates, with percent signal change extracted and analyzed within these ROIs. Results suggest that the SON responds to all familiar individuals while the PVN has increased response to sibling compared to friend faces and is correlated to familiarity but not emotionality. These findings support differential involvement of local hypothalamic substructures SON and PVN in response to faces of individuals with different social relationships.