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.

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.

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.

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.

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.

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.

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.

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.

Cortical and Subcortical Brain Morphometry Differences Between Patients With Autism Spectrum Disorder and Healthy Individuals Across the Lifespan: Results From the ENIGMA ASD Working Group.

OBJECTIVE: Neuroimaging studies show structural differences in both cortical and subcortical brain regions in children and adults with autism spectrum disorder (ASD) compared with healthy subjects. Findings are inconsistent, however, and it is unclear how differences develop across the lifespan. The authors investigated brain morphometry differences between individuals with ASD and healthy subjects, cross-sectionally across the lifespan, in a large multinational sample from the Enhancing Neuroimaging Genetics Through Meta-Analysis (ENIGMA) ASD working group. METHOD: The sample comprised 1,571 patients with ASD and 1,651 healthy control subjects (age range, 2-64 years) from 49 participating sites. MRI scans were preprocessed at individual sites with a harmonized protocol based on a validated automated-segmentation software program. Mega-analyses were used to test for case-control differences in subcortical volumes, cortical thickness, and surface area. Development of brain morphometry over the lifespan was modeled using a fractional polynomial approach. RESULTS: The case-control mega-analysis demonstrated that ASD was associated with smaller subcortical volumes of the pallidum, putamen, amygdala, and nucleus accumbens (effect sizes [Cohen's d], 0.13 to -0.13), as well as increased cortical thickness in the frontal cortex and decreased thickness in the temporal cortex (effect sizes, -0.21 to 0.20). Analyses of age effects indicate that the development of cortical thickness is altered in ASD, with the largest differences occurring around adolescence. No age-by-ASD interactions were observed in the subcortical partitions. CONCLUSIONS: The ENIGMA ASD working group provides the largest study of brain morphometry differences in ASD to date, using a well-established, validated, publicly available analysis pipeline. ASD patients showed altered morphometry in the cognitive and affective parts of the striatum, frontal cortex, and temporal cortex. Complex developmental trajectories were observed for the different regions, with a developmental peak around adolescence. These findings suggest an interplay in the abnormal development of the striatal, frontal, and temporal regions in ASD across the lifespan.

Altered sleep architecture during the first months of life in infants born to depressed mothers.

OBJECTIVE: This study investigated sleep architecture in newborn and six-month-old infants who were born to depressed mothers. METHOD: Sixty-four healthy full-term infants (32 males and 32 females) participated in the study. Of these, 32 were high-risk infants who were born to mothers diagnosed with depression, and 32 were low-risk infants born to mothers without a personal history of depression. 24-hour polysomnography was recorded at zero and six months of age (M0 and M6). Sleep macro-structural parameters (total sleep time, TST; awake time; non-rapid eye movement, NREM sleep (%); rapid eye movement, REM sleep %; arousal index; and sleep efficiency) were analysed at M0 and M6. Micro-architectural sleep features (slow-wave activity, SWA; delta sleep ratio, DSR; spindle density; and rapid eye movement density) were calculated at M6. The data between high-risk and low-risk groups were compared using Student's t-tests. RESULTS: At M0 and M6, the high-risk infants showed more awake time and fewer arousals than the low-risk infants. However, the high-risk group had less NREM% at M0 and a shorter TST as well as less REM% at M6 than the low-risk group. At M6, the high-risk group showed higher SWA, higher DSR and lower spindle density in comparison with the low-risk group. CONCLUSIONS: Altered sleep structure was observed during their first months of life in infants born from depressed mothers, thereby suggesting that the prenatal environment could enhance the depression vulnerability of the child and potentially decrease their neuroplasticity.

Behavioral characterization of prediction and internal models in adolescents with autistic spectrum disorders.

Autism has been considered as a deficit in prediction of the upcoming event or of the sensory consequences of our own movements. To test this hypothesis, we recorded eye movements from high-functioning autistic adolescents and from age-matched controls during a blanking paradigm. In this paradigm, adolescents were instructed to follow a moving target with their eyes even during its transient disappearance. Given the absence of visual information during the blanking period, eye movements during this period are solely controlled on the basis of the prediction of the ongoing target motion. Typical markers of predictive eye movements such as the number and accuracy of predictive saccades and the predictive reacceleration before target reappearance were identical in the two populations. In addition, the synergy of predictive saccades and smooth pursuit observed during the blanking periods, which is a marker for the quality of internal models about target/eye motions, was comparable between these two populations. These results suggest that, in our large population of high-functioning autistic adolescent, both predictive abilities and internal models are left intact in Autism, at least for low-level sensorimotor transformations.

Localized Misfolding Within Broca's Area as a Distinctive Feature of Autistic Disorder.

BACKGROUND: Recent neuroimaging studies suggest that autism spectrum disorder results from abnormalities in the cortical folding pattern. Usual morphometric measurements have failed to provide reliable neuroanatomic markers. Here, we propose that sulcal pits, which are the deepest points in each fold, are suitable candidates to uncover this atypical cortical folding. METHODS: Sulcal pits were extracted from a magnetic resonance imaging database of 102 children (1.5-10 years old) distributed in three groups: children with autistic disorder (n = 59), typically developing children (n = 22), and children with pervasive developmental disorder not otherwise specified (n = 21). The geometrical properties of sulcal pits were compared between these three groups. RESULTS: Fold-level analyses revealed a reduced pit depth in the left ascending ramus of the Sylvian fissure in children with autistic disorder only. The depth of this central fold of Broca's area was correlated with the social communication impairments that are characteristic of the pathology. CONCLUSIONS: Our findings support an atypical gyrogenesis of this specific fold in autistic disorder that could be used for differential diagnosis. Sulcal pits constitute valuable markers of the cortical folding dynamics and could help for the early detection of atypical brain maturation.

Focal atrophy of the hypothalamus associated with third ventricle enlargement in autism spectrum disorder.

The hypothalamus is a brain structure containing multiple nuclei that mediate essential behavioral, autonomic, and endocrine functions including oxytocin synthesis. Oxytocin is a neuropeptide linked to complex social cognition and behaviors necessary for an effective social interaction. Oxytocinergic system dysfunction has been linked to social deficits in autism spectrum disorders (ASD). Limited studies have been carried out on the hypothalamus because of its small size and methodological constraints in current technologies. This neuroimaging study examines hypothalamic atrophy in ASD in comparison with a typically developing population (a) by directly measuring gray matter (GM) density with a region-of-interest analysis using voxel-based morphometry in a homogenous sample of participants controlled for age and intelligence quotient; (b) for generalization, by measuring third ventricular volume, on the basis of its position bilaterally surrounded by the hypothalamus, using Freesurfer in a heterogeneous sample of participants. A voxel-based morphometry analysis of cerebrospinal fluid density on the first sample provides a link between GM density and third ventricle volume. Our results show decreased hypothalamic GM density and increased third ventricle volume in ASD compared with typically developing patients. Our findings provide neuroanatomical insights into social deficits in ASD within the hypothalamus that might be relevant for other psychiatric conditions.

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.

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.

Anthropomorphic bias found in typically developing children is not found in children with autistic spectrum disorder.

The anthropomorphic bias describes the finding that the perceived naturalness of a biological motion decreases as the human-likeness of a computer-animated agent increases. To investigate the anthropomorphic bias in autistic children, human or cartoon characters were presented with biological and artificial motions side by side on a touchscreen. Children were required to touch one that would grow while the other would disappear, implicitly rewarding their choice. Only typically developing controls depicted the expected preference for biological motion when rendered with human, but not cartoon, characters. Despite performing the task to report a preference, children with autism depicted neither normal nor reversed anthropomorphic bias, suggesting that they are not sensitive to the congruence of form and motion information when observing computer-animated agents' actions.

Neural responses to emotional expression information in high- and low-spatial frequency in autism: evidence for a cortical dysfunction.

Despite an overall consensus that Autism Spectrum Disorder (ASD) entails atypical processing of human faces and emotional expressions, the role of neural structures involved in early facial processing remains unresolved. An influential model for the neurotypical brain suggests that face processing in the fusiform gyrus and the amygdala is based on both high-spatial frequency (HSF) information carried by a parvocellular pathway, and low-spatial frequency (LSF) information separately conveyed by a magnocellular pathway. Here, we tested the fusiform gyrus and amygdala sensitivity to emotional face information conveyed by these distinct pathways in ASD individuals (and matched Controls). During functional Magnetical Resonance Imaging (fMRI), participants reported the apparent gender of hybrid face stimuli, made by merging two different faces (one in LSF and the other in HSF), out of which one displayed an emotional expression (fearful or happy) and the other was neutral. Controls exhibited increased fusiform activity to hybrid faces with an emotional expression (relative to hybrids composed only with neutral faces), regardless of whether this was conveyed by LSFs or HSFs in hybrid stimuli. ASD individuals showed intact fusiform response to LSF, but not HSF, expressions. Furthermore, the amygdala (and the ventral occipital cortex) was more sensitive to HSF than LSF expressions in Controls, but exhibited an opposite preference in ASD. Our data suggest spared LSF face processing in ASD, while cortical analysis of HSF expression cues appears affected. These findings converge with recent accounts suggesting that ASD might be characterized by a difficulty in integrating multiple local information and cause global processing troubles unexplained by losses in low spatial frequency inputs.