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Introduction: Cognition and emotion are fundamentally integrated in the brain and mutually contribute to behavior. The relation between working memory (WM) and emotion is particularly suited to investigate cognition-emotion interaction since WM is an essential component of many higher cognitive functions. Ketamine affects not only WM but also has a profound impact on emotional processing. Effects of acute ketamine challenge are sensitive to modulation by pretreatment with lamotrigine, which inhibits glutamate release. Accordingly, a combination of these approaches should be particularly suited to investigate cognition-emotion interaction. Methods: Seventy five healthy subjects were investigated in a double-blind, placebo-controlled, randomized, single-dose, parallel-group study with three treatment conditions. All subjects underwent two scanning sessions (acute/post 24 h). Results: Compared to placebo, acute ketamine administration induced significant dissociative, psychotomimetic, and cognitive effects, as well as an increase in neural activity during WM for positive stimuli. Inhibition of glutamate release by pretreatment with lamotrigine did not influence ketamine’s subjective effects, but significantly attenuated its impact on emotional WM and associated neural activity. There was no effect on these measures 24 h after ketamine administration. Conclusion: Our results demonstrate differential acute effects of modulated glutamate release and a swift restoration of disturbed neurobehavioral homeostasis in healthy subjects.

Item does not contain fulltext OBJECTIVE: The male preponderance in prevalence of autism is among the most pronounced sex ratios across neurodevelopmental conditions. The authors sought to elucidate the relationship between autism and typical sex-differential neuroanatomy, cognition, and related gene expression. METHODS: Using a novel deep learning framework trained to predict biological sex based on T(1)-weighted structural brain images, the authors compared sex prediction model performance across neurotypical and autistic males and females. Multiple large-scale data sets comprising T(1)-weighted MRI data were employed at four stages of the analysis pipeline: 1) pretraining, with the UK Biobank sample (>10,000 individuals); 2) transfer learning and validation, with the ABIDE data sets (1,412 individuals, 5-56 years of age); 3) test and discovery, with the EU-AIMS/AIMS-2-TRIALS LEAP data set (681 individuals, 6-30 years of age); and 4) specificity, with the NeuroIMAGE and ADHD200 data sets (887 individuals, 7-26 years of age). RESULTS: Across both ABIDE and LEAP, features positively predictive of neurotypical males were on average significantly more predictive of autistic males (ABIDE: Cohen's d=0.48; LEAP: Cohen's d=1.34). Features positively predictive of neurotypical females were on average significantly less predictive of autistic females (ABIDE: Cohen's d=1.25; LEAP: Cohen's d=1.29). These differences in sex prediction accuracy in autism were not observed in individuals with ADHD. In autistic females, the male-shifted neurophenotype was further associated with poorer social sensitivity and emotional face processing while also associated with gene expression patterns of midgestational cell types. CONCLUSIONS: The results demonstrate an increased resemblance in both autistic male and female individuals' neuroanatomy with male-characteristic patterns associated with typically sex-differential social cognitive features and related gene expression patterns. The findings hold promise for future research aimed at refining the quest for biological mechanisms underpinning the etiology of autism.

BACKGROUND: The connectome, constituting a unique fingerprint of a person's brain, may be influenced by its prenatal environment, potentially affecting later-life resilience and mental health. METHODS: We conducted a prospective resting-state functional Magnetic Resonance Imaging study in 28-year-old offspring (N = 49) of mothers whose anxiety was monitored during pregnancy. Two offspring anxiety subgroups were defined: "High anxiety" (n = 13) group versus "low-to-medium anxiety" (n = 36) group, based on maternal self-reported state anxiety at 12-22 weeks of gestation. To predict resting-state functional connectivity of 32 by 32 ROIs, maternal state anxiety during pregnancy was included as a predictor in general linear models for both ROI-to-ROI and graph theoretical metrics. Sex, birth weight and postnatal anxiety were included as covariates. RESULTS: Higher maternal anxiety was associated with weaker functional connectivity of medial prefrontal cortex with left inferior frontal gyrus (t = 3.45, pFDR < 0.05). Moreover, network-based statistics (NBS) confirmed our finding and revealed an additional association of weaker connectivity between left lateral prefontal cortex with left somatosensory motor gyrus in the offspring. While our results showed a general pattern of lower functional connectivity in adults prenatally exposed to maternal anxiety, we did not observe significant differences in global brain networks between groups. CONCLUSIONS: Weaker (medial) prefrontal cortex functional connectivity in the high anxiety adult offspring group suggests a long-term negative impact of prenatal exposure to high maternal anxiety, extending into adulthood. To prevent mental health problems at population level, universal primary prevention strategies should aim at lowering maternal anxiety during pregnancy. ispartof: Brain Imaging And Behavior pages:1-13 ispartof: location:United States status: Published online

There is intriguing evidence suggesting that ketamine might have distinct acute and delayed neurofunctional effects, as its acute administration transiently induces schizophrenia-like symptoms, while antidepressant effects slowly emerge and are most pronounced 24 h after administration. Studies attempting to characterize ketamine’s mechanism of action by using blood oxygen level dependent (BOLD) imaging have yielded inconsistent results regarding implicated brain regions and direction of effects. This may be due to intrinsic properties of the BOLD contrast, while cerebral blood flow (CBF), as measured with arterial spin labeling, is a single physiological marker more directly related to neural activity. As effects of acute ketamine challenge are sensitive to modulation by pretreatment with lamotrigine, which inhibits glutamate release, a combination of these approaches should be particularly suited to offer novel insights. In total, 75 healthy participants were investigated in a double blind, placebo-controlled, randomized, parallel-group study and underwent two scanning sessions (acute/post 24 h.). Acute ketamine administration was associated with higher perfusion in interior frontal gyrus (IFG) and dorsolateral prefrontal cortex (DLPFC), but no other investigated brain region. Inhibition of glutamate release by pretreatment with lamotrigine abolished ketamine’s effect on perfusion. At the delayed time point, pretreatment with lamotrigine was associated with lower perfusion in IFG. These findings underscore the idea that regionally selective patterns of CBF changes reflect proximate effects of modulated glutamate release on neuronal activity. Furthermore, region- specific sustained effects indicate both a swift restoration of disturbed homeostasis in DLPFC as well changes occurring beyond the immediate effects on glutamate signaling in IFG.

Contains fulltext : 293775.pdf (Publisher’s version ) (Open Access) BACKGROUND: Neuroimaging studies of functional connectivity (FC) in autism have been hampered by small sample sizes and inconsistent findings with regard to whether connectivity is increased or decreased in individuals with autism, whether these alterations affect focal systems or reflect a brain-wide pattern, and whether these are age and/or sex dependent. METHODS: The study included resting-state functional magnetic resonance imaging and clinical data from the EU-AIMS LEAP (European Autism Interventions Longitudinal European Autism Project) and the ABIDE (Autism Brain Imaging Data Exchange) 1 and 2 initiatives of 1824 (796 with autism) participants with an age range of 5-58 years. Between-group differences in FC were assessed, and associations between FC and clinical symptom ratings were investigated through canonical correlation analysis. RESULTS: Autism was associated with a brainwide pattern of hypo- and hyperconnectivity. Hypoconnectivity predominantly affected sensory and higher-order attentional networks and correlated with social impairments, restrictive and repetitive behavior, and sensory processing. Hyperconnectivity was observed primarily between the default mode network and the rest of the brain and between cortical and subcortical systems. This pattern was strongly associated with social impairments and sensory processing. Interactions between diagnosis and age or sex were not statistically significant. CONCLUSIONS: The FC alterations observed, which primarily involve hypoconnectivity of primary sensory and attention networks and hyperconnectivity of the default mode network and subcortex with the rest of the brain, do not appear to be age or sex dependent and correlate with clinical dimensions of social difficulties, restrictive and repetitive behaviors, and alterations in sensory processing. These findings suggest that the observed connectivity alterations are stable, trait-like features of autism that are related to the main symptom domains of the condition.

Background: Although many studies have explored atypicalities in gray matter (GM) and white matter (WM) morphology of autism, most of them relied on unimodal analyses that did not benefit from the likelihood that different imaging modalities may reflect common neurobiology. We aimed to establish brain patterns of modalities that differentiate between individuals with and without autism and explore associations between these brain patterns and clinical measures in the autism group. Methods: We studied 183 individuals with autism and 157 nonautistic individuals (age range, 6–30 years) in a large, deeply phenotyped autism dataset (EU-AIMS LEAP [European Autism Interventions—A Multicentre Study for Developing New Medications Longitudinal European Autism Project]). Linked independent component analysis was used to link all participants’ GM volume and WM diffusion tensor images, and group comparisons of modality shared variances were examined. Subsequently, we performed univariate and multivariate brain-behavior correlation analyses to separately explore the relationships between brain patterns and clinical profiles. Results: One multimodal pattern was significantly related to autism. This pattern was primarily associated with GM volume in bilateral insula and frontal, precentral and postcentral, cingulate, and caudate areas and co-occurred with altered WM features in the superior longitudinal fasciculus. The brain-behavior correlation analyses showed a significant multivariate association primarily between brain patterns that involved variation of WM and symptoms of restricted and repetitive behavior in the autism group. Conclusions: Our findings demonstrate the assets of integrated analyses of GM and WM alterations to study the brain mechanisms that underpin autism and show that the complex clinical autism phenotype can be interpreted by brain covariation patterns that are spread across the brain involving both cortical and subcortical areas.

Contains fulltext : 251409.pdf (Publisher’s version ) (Open Access) BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) is associated with white matter (WM) microstructure. Our objective was to investigate how WM microstructure is longitudinally related to symptom remission in adolescents and young adults with ADHD. METHODS: We obtained diffusion-weighted imaging (DWI) data from 99 participants at two timepoints (mean age baseline: 16.91 years, mean age follow-up: 20.57 years). We used voxel-wise Tract-Based Spatial Statistics (TBSS) with permutation-based inference to investigate associations of inattention (IA) and hyperactivity-impulsivity (HI) symptom change with fractional anisotropy (FA) at baseline, follow-up, and change between time-points. RESULTS: Remission of combined HI and IA symptoms was significantly associated with reduced FA at follow-up in the left superior longitudinal fasciculus and the left corticospinal tract (CST; P (FWE) = 0.038 and P (FWE) = 0.044, respectively), mainly driven by an association between HI remission and follow-up CST FA (P (FWE) = 0.049). There was no significant association of combined symptom decrease with FA at baseline or with changes in FA between the two assessments. CONCLUSIONS: In this longitudinal DWI study of ADHD using dimensional symptom scores, we show that greater symptom decrease is associated with lower follow-up FA in specific WM tracts. Altered FA thus may appear to follow, rather than precede, changes in symptom remission. Our findings indicate divergent WM developmental trajectories between individuals with persistent and remittent ADHD, and support the role of prefrontal and sensorimotor tracts in the remission of ADHD.

ObjectivesThe male preponderance in autism spectrum conditions (ASC) prevalence is among the most pronounced sex ratios across different neurodevelopmental conditions. Here, we aimed to elucidate the relationship between autism and typical sex-differential neuroanatomy, cognition, and related gene expression.MethodsUsing a novel deep learning framework trained to predict biological sex, we compared sex prediction model performance across neurotypical and autistic males and females. Multiple large-scale datasets were employed at different stages of the analysis pipeline: a) Pre-training: the UK Biobank sample (>10.000 individuals); b) Transfer learning and validation: the ABIDE datasets (1,412 individuals, 5-56 years of age); c) Test and discovery: the EU-AIMS/AIMS-2-TRIALS LEAP dataset (681 individuals, 6-30 years of age) and d) Specificity: the Neuroimage and ADHD200 datasets (887 individuals, 7-26 years of age).ResultsAcross both ABIDE and LEAP we showed that features positively predictive of neurotypical males were on average more predictive of autistic males (P=1.1e-23). Features positively predictive of neurotypical females were on average less predictive of autistic females (P=1.2e-22). These accuracy differences in autism were not observed in individuals with ADHD. In autistic females the male-shifted neurophenotype was further associated with poorer social sensitivity and emotional face processing while also with associated gene expression patterns of midgestational cell types.ConclusionsOur results demonstrate a shift in both autistic male and female individuals’ neuroanatomy towards male-characteristic patterns associated with typically sex-differential, social cognitive features and related gene expression patterns. Findings hold promise for future research aimed at refining the quest for biological mechanisms underpinning the etiology of autism.

Neuroimaging studies on functional connectivity (FC) in autism have been hampered by small sample sizes and inconsistent findings with regard to whether connectivity is increased or decreased in individuals with autism, whether these alterations affect focal systems or reflect a brain-wide pattern, and whether these are age- and/or sex-dependent. The study included resting-state fMRI and clinical data from the LEAP and the ABIDE I and II initiatives, of 1824 (796 with autism) participants with age range 5-58 years. Between-group differences in FC were assessed, and associations between FC and clinical symptom ratings were investigated through canonical correlation analysis. Autism was associated with a brain-wide pattern of hypo- and hyperconnectivity. Hypoconnectivity predominantly affected sensory and higher-order attentional networks and correlated with social impairments, restrictive and repetitive behavior (RRB), and sensory processing. Hyperconnectivity was observed primarily between the default mode network and the rest of the brain, and between cortical and subcortical systems. This pattern was strongly associated with social impairments and sensory processing. Interactions between diagnosis and age or sex were not statistically significant. The FC alterations observed in this study, which primarily involve hypoconnectivity of primary sensory and attention networks and hyperconnectivity of the DMN and subcortex with the rest of the brain, do not appear to be age or sex-dependent and correlate with clinical dimensions of social difficulties, RRBs, and alterations in sensory processing. These findings suggest that the observed connectivity alterations are stable, trait-like features of autism that are related to the three main symptom domains.

Objectives: Social dysfunction is one of the most common signs of major neuropsychiatric disorders. The Default Mode Network (DMN) is crucially implicated in both psychopathology and social dysfunction, although the transdiagnostic properties of social dysfunction remains unknown. As part of the pan-European PRISM (Psychiatric Ratings using Intermediate Stratified Markers) project, we explored cross-disorder impact of social dysfunction on DMN connectivity. Methods: We studied DMN intrinsic functional connectivity in relation to social dysfunction by applying Independent Component Analysis and Dual Regression on resting-state fMRI data, among schizophrenia (SZ; N=48), Alzheimer disease (AD; N=47) patients and healthy controls (HC; N=55). Social dysfunction was operationalised via the Social Functioning Scale (SFS) and De Jong-Gierveld Loneliness Scale (LON). Results: Both SFS and LON were independently associated with diminished DMN connectional integrity within rostromedial prefrontal DMN subterritories (pcorrected range=0.02–0.04). The combined effect of these indicators (Mean.SFS + LON) on diminished DMN connectivity was even more pronounced (both spatially and statistically), independent of diagnostic status, and not confounded by key clinical or sociodemographic effects, comprising large sections of rostromedial and dorsomedial prefrontal cortex (pcorrected =0.01). Conclusions: These findings pinpoint DMN connectional alterations as putative transdiagnostic endophenotypes for social dysfunction and could aid personalised care initiatives grounded in social behaviour, The project leading to this application has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115916. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. This publication reflects only the author’s views and neither the IMI 2JU nor EFPIA nor the European Commission are liable for any use that may be made of the information contained therein

Abnormal emotional processing in major depressive disorder (MDD) has been associated with increased activation to negative stimuli in cortico-limbic brain regions. The authors investigated whether treatment with BI 1358894, a small-molecule inhibitor of the transient receptor potential cation channel subfamily C leads to attenuated activity in these areas in MDD patients. 73 MDD patients were randomized to receive a single oral dose of BI 1358894 (100 mg), citalopram (20 mg), or matching placebo. Brain responses to emotional faces and scenes were investigated using functional magnetic resonance imaging. Primary endpoints were BOLD signal changes in response to negative faces in cortico-limbic brain regions, i.e. bilateral amygdala (AMY), dorsolateral prefrontal cortex, anterior insula (AI), and anterior cingulate cortex. Secondary endpoints were BOLD signal changes in response to negative scenes. For each region, separate ANOVA models were computed for the comparison of treatments (BI 1358894 or citalopram) vs. placebo. The adjusted treatment differences in the % BOLD signal changes in the faces task showed that BI 1358894 induced signal reduction in bilateral AMY and left AI. In the scenes task, BI 1358894 demonstrated significant signal reduction in bilateral AMY, AI, anterior cingulate cortex and left dorsolateral prefrontal cortex. Citalopram failed to induce any significant reductions in BOLD signal in both tasks. BI 1358894-mediated inhibition of the transient receptor potential cation channel subfamily resulted in strong signal reduction in cortico-limbic brain regions, thereby supporting development of this mechanism of action for MDD patients.

Obsessive-compulsive disorder (OCD) is increasingly considered to be a neurodevelopmental disorder. However, despite insights in neural substrates of OCD in adults, less is known about mechanisms underlying compulsivity during brain development in children and adolescents. Therefore, we developed an adolescent rat model of compulsive checking behavior and investigated developmental changes in structural and functional measures in the frontostriatal circuitry. Five-weeks old Sprague Dawley rats were subcutaneously injected with quinpirole (n = 21) or saline (n = 20) twice a week for five weeks. Each injection was followed by placement in the middle of an open field table, and compulsive behavior was quantified as repeated checking behavior. Anatomical, resting-state functional and diffusion MRI at 4.7T were conducted before the first and after the last quinpirole/saline injection to measure regional volumes, functional connectivity and structural integrity in the brain, respectively. After consecutive quinpirole injections, adolescent rats demonstrated clear checking behavior and repeated travelling between two open-field zones. MRI measurements revealed an increase of regional volumes within the frontostriatal circuits and an increase in fractional anisotropy (FA) in white matter areas during maturation in both experimental groups. Quinpirole-injected rats showed a larger developmental increase in FA values in the internal capsule and forceps minor compared to control rats. Our study points toward a link between development of compulsive behavior and altered white matter maturation in quinpirole-injected adolescent rats, in line with observations in pediatric patients with compulsive phenotypes. This novel animal model provides opportunities to investigate novel treatments and underlying mechanisms for patients with early-onset OCD specifically.

Contains fulltext : 204848.pdf (Publisher’s version ) (Open Access) BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous neurodevelopmental disorder, putatively induced by dissociable dysfunctional biobehavioral pathways. Here, we present a proof-of-concept study to parse ADHD-related heterogeneity in its underlying neurobiology by investigating functional connectivity across multiple brain networks to 1) disentangle categorical diagnosis-related effects from dimensional behavior-related effects and 2) functionally map these neural correlates to neurocognitive measures. METHODS: We identified functional connectivity abnormalities related to ADHD across 14 networks within a large resting-state functional magnetic resonance imaging dataset (n = 409; age = 17.5 +/- 3.3 years). We tested these abnormalities for their association with the categorical ADHD diagnosis and with dimensional inattention and hyperactivity/impulsivity scores using a novel modeling framework, creating orthogonalized models. Next, we evaluated the relationship of these findings with neurocognitive measures (working memory, response inhibition, reaction time variability, reward sensitivity). RESULTS: Within the default mode network, we mainly observed categorical ADHD-related functional connectivity abnormalities, unrelated to neurocognitive measures. Clusters within the visual networks primarily related to dimensional scores of inattention and reaction time variability, while findings within the sensorimotor networks were mainly linked to hyperactivity/impulsivity and both reward sensitivity and working memory. Findings within the cerebellum network and salience network related to both categorical and dimensional ADHD measures and were linked to response inhibition and reaction time variability. CONCLUSIONS: This proof-of-concept study identified ADHD-related neural correlates across multiple functional networks, showing distinct categorical and dimensional mechanisms and their links to neurocognitive functioning.

Background Psychiatric medication that has a soothing effect on the limbic responses to affective stimuli could improve affective instability symptoms as observed in Borderline Personality Disorder (BPD). The objective of this study was to investigate whether Citalopram vs. Placebo reduces the response of the affective neural circuitry during emotional challenge. Methods N=30 femaie individuals with BPD diagnosis participated in a Placebo-controlled, double-blind crossover trial design. Three hours after oral drug intake, individuals with BPD viewed affective pictures while undergoing functional Magnetic Resonance Imaging. Blood Oxygenation Level Dependent responses to images of negative affective scenes and faces showing negative emotional expressions were assessed in regions-of-interest (amygdala, anterior cingulate cortex, anterior insula, dorsolateral prefrontal cortex). Blood perfusion at rest was assessed with arterial spin labeling. Results The neural response to pictures showing negative affective scenes was not significantly affected by Citalopram (N=23). Citalopram significantly reduced the amygdala response to pictures of faces with negative affective expressions (N=25, treatment difference left hemisphere: -0.06 ±0.16, P Conclusions Citalopram can alter the amygdala response to affective stimuli in BPD, which is characterized by overly responsive affective neural circuitry.

BackgroundAttention-deficit hyperactivity disorder (ADHD) is associated with white matter (WM) microstructure. Our objective was to investigate how WM microstructure is longitudinally related to symptom remission in adolescents and young adults with ADHD.MethodsWe obtained diffusion-weighted imaging (DWI) data from 99 participants at two time points (mean age baseline: 16.91 years, mean age follow-up: 20.57 years). We used voxel-wise Tract-Based Spatial Statistics (TBSS) with permutation-based inference to investigate associations of inattention (IA) and hyperactivity-impulsivity (HI) symptom change with fractional anisotropy (FA) at baseline, follow-up, and change between time points.ResultsRemission of combined HI and IA symptoms was significantly associated with reduced FA at follow-up in the left superior longitudinal fasciculus and the left corticospinal tract (CST) (PFWE=0.038 and PFWE=0.044, respectively), mainly driven by an association between HI remission and follow-up CST FA (PFWE=0.049). There was no significant association of combined symptom decrease with FA at baseline or with changes in FA between the two assessments.ConclusionsIn this longitudinal DWI study of ADHD using dimensional symptom scores, we show that greater symptom decrease is associated with lower follow-up FA in specific WM tracts. Altered FA thus may appear to follow, rather than precede, changes in symptom remission. Our findings indicate divergent WM developmental trajectories between individuals with persistent and remittent ADHD, and support the role of prefrontal and sensorimotor tracts in the remission of ADHD.

ObjectiveAttention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) are common neurodevelopmental disorders that frequently co-occur. We aimed to directly compare all three disorders. The ENIGMA consortium is ideally positioned to investigate structural brain alterations across these disorders.MethodsStructural T1-weighted whole-brain MRI of controls (n=5,827) and patients with ADHD (n=2,271), ASD (n=1,777), and OCD (n=2,323) from 151 cohorts worldwide were analyzed using standardized processing protocols. We examined subcortical volume, cortical thickness and surface area differences within a mega-analytical framework, pooling measures extracted from each cohort. Analyses were performed separately for children, adolescents, and adults using linear mixed-effects models adjusting for age, sex and site (and ICV for subcortical and surface area measures).ResultsWe found no shared alterations among all three disorders, while shared alterations between any two disorders did not survive multiple comparisons correction. Children with ADHD compared to those with OCD had smaller hippocampal volumes, possibly influenced by IQ. Children and adolescents with ADHD also had smaller ICV than controls and those with OCD or ASD. Adults with ASD showed thicker frontal cortices compared to adult controls and other clinical groups. No OCD-specific alterations across different age-groups and surface area alterations among all disorders in childhood and adulthood were observed.ConclusionOur findings suggest robust but subtle alterations across different age-groups among ADHD, ASD, and OCD. ADHD-specific ICV and hippocampal alterations in children and adolescents, and ASD-specific cortical thickness alterations in the frontal cortex in adults support previous work emphasizing neurodevelopmental alterations in these disorders.

Background Autism spectrum disorder (“autism”) is a highly heterogeneous neurodevelopmental condition with few effective treatments for core and associated features. To make progress we need to both identify and validate neural markers that help to parse heterogeneity to tailor therapies to specific neurobiological profiles. Atypical hemispheric lateralization is a stable feature across studies in autism, but its potential as a neural stratification marker has not been widely examined. Methods In order to dissect heterogeneity in lateralization in autism, we used the large EU-AIMS (European Autism Interventions—A Multicentre Study for Developing New Medications) Longitudinal European Autism Project dataset comprising 352 individuals with autism and 233 neurotypical control subjects as well as a replication dataset from ABIDE (Autism Brain Imaging Data Exchange) (513 individuals with autism, 691 neurotypical subjects) using a promising approach that moves beyond mean group comparisons. We derived gray matter voxelwise laterality values for each subject and modeled individual deviations from the normative pattern of brain laterality across age using normative modeling. Results Individuals with autism had highly individualized patterns of both extreme right- and leftward deviations, particularly in language, motor, and visuospatial regions, associated with symptom severity. Language delay explained most variance in extreme rightward patterns, whereas core autism symptom severity explained most variance in extreme leftward patterns. Follow-up analyses showed that a stepwise pattern emerged, with individuals with autism with language delay showing more pronounced rightward deviations than individuals with autism without language delay. Conclusions Our analyses corroborate the need for novel (dimensional) approaches to delineate the heterogeneous neuroanatomy in autism and indicate that atypical lateralization may constitute a neurophenotype for clinically meaningful stratification in autism.

BackgroundMarked sex differences in autism prevalence accentuate the need to understand the role of biological sex-related factors in autism. Efforts to unravel sex differences in the brain organization of autism have, however, been challenged by the limited availability of female data.MethodsWe addressed this gap by using a large sample of males and females with autism and neurotypical (NT) control individuals (ABIDE; Autism: 362 males, 82 females; NT: 409 males, 166 females; 7-18 years). Discovery analyses examined main effects of diagnosis, sex and their interaction across five resting-state fMRI (R-fMRI) metrics (voxel-level Z > 3.1, cluster-level P < 0.01, gaussian random field corrected). Secondary analyses assessed the robustness of the results to different pre-processing approaches and their replicability in two independent samples: the EU-AIMS Longitudinal European Autism Project (LEAP) and the Gender Explorations of Neurogenetics and Development to Advance Autism Research (GENDAAR).ResultsDiscovery analyses in ABIDE revealed significant main effects across the intrinsic functional connectivity (iFC) of the posterior cingulate cortex, regional homogeneity and voxel-mirrored homotopic connectivity (VMHC) in several cortical regions, largely converging in the default network midline. Sex-by-diagnosis interactions were confined to the dorsolateral occipital cortex, with reduced VMHC in females with autism. All findings were robust to different pre-processing steps. Replicability in independent samples varied by R-fMRI measures and effects with the targeted sex-by-diagnosis interaction being replicated in the larger of the two replication samples – EU-AIMS LEAP.LimitationsGiven the lack of a priori harmonization among the discovery and replication datasets available to date, sample-related variation remained and may have affected replicability.ConclusionsAtypical cross-hemispheric interactions are neurobiologically relevant to autism. They likely result from the combination of sex-dependent and sex-independent factors with a differential effect across functional cortical networks. Systematic assessments of the factors contributing to replicability are needed and necessitate coordinated large-scale data collection across studies.

The prenatal period is increasingly considered as a crucial target for the primary prevention of neurodevelopmental and psychiatric disorders. Understanding their pathophysiological mechanisms remains a great challenge. Our review reveals new insights from prenatal brain development research, involving (epi)genetic research, neuroscience, recent imaging techniques, physical modeling, and computational simulation studies. Studies examining the effect of prenatal exposure to maternal distress on offspring brain development, using brain imaging techniques, reveal effects at birth and up into adulthood. Structural and functional changes are observed in several brain regions including the prefrontal, parietal, and temporal lobes, as well as the cerebellum, hippocampus, and amygdala. Furthermore, alterations are seen in functional connectivity of amygdalar-thalamus networks and in intrinsic brain networks, including default mode and attentional networks. The observed changes underlie offspring behavioral, cognitive, emotional development, and susceptibility to neurodevelopmental and psychiatric disorders. It is concluded that used brain measures have not yet been validated with regard to sensitivity, specificity, accuracy, or robustness in predicting neurodevelopmental and psychiatric disorders. Therefore, more prospective long-term longitudinal follow-up studies starting early in pregnancy should be carried out, in order to examine brain developmental measures as mediators in mediating the link between prenatal stress and offspring behavioral, cognitive, and emotional problems and susceptibility for disorders. ispartof: Development And Psychopathology vol:30 issue:3 pages:743-762 ispartof: location:United States status: published

Contains fulltext : 193222.pdf (Publisher’s version ) (Closed access) OBJECTIVE: Research has implicated glutamatergic projections between the various frontal subregions in the pathogenesis of compulsivity and impulsivity. Reducing striatal glutamate release, or antagonising the action of glutamate at its receptors, may therefore represent viable treatment strategies. Several glutamatergic agents with regulatory approval for other indications are available and may be of potential benefit in the treatment of compulsivity/impulsivity in psychiatric disorders in paediatric patients. METHOD: This review was performed according to PRISMA guidelines and evaluates available scientific literature concerning the use of glutamatergic agents in these patients, in order to determine their reported effectiveness/efficacy and tolerability/safety. RESULTS: Out of a total of 1,426 publications, 21 trials examining six glutamatergic substances in patients with obsessive-compulsive disorder, autism spectrum disorders, and attention deficit/hyperactivity disorder were included. CONCLUSIONS: Trial designs as well as results were heterogeneous and thus comparability was limited. Available data support the hypothesis that glutamatergic agents are of potential value in the treatment of compulsivity/impulsivity in children and adolescents. Based on the data reviewed, memantine and N-acetylcysteine suggest the best risk-benefit profile for future trials. Riluzole should primarily be further investigated in adults. Clinical research of this nature is a key element of the TACTICS Consortium project funded by the European Union (FP7).

BackgroundAutism spectrum disorders (ASD) are characterized by substantial clinical, etiological and neurobiological heterogeneity. Despite this heterogeneity, previous imaging studies have highlighted the role of specific cortical and subcortical structures in ASD and have forwarded the notion of an ASD specific neuroanatomy in which abnormalities in brain structures are present that can be used for diagnostic classification approaches.MethodA large (N = 859, 6–27 years, IQ 70–130) multi-center structural magnetic resonance imaging dataset was examined to specifically test ASD diagnostic effects regarding (sub)cortical volumes.ResultsDespite the large sample size, we found virtually no main effects of ASD diagnosis. Yet, several significant two- and three-way interaction effects of diagnosis by age by gender were found.ConclusionThe neuroanatomy of ASD does not exist, but is highly age and gender dependent. Implications for approaches of stratification of ASD into more homogeneous subtypes are discussed.

Background Sociocommunicative difficulties, including abnormalities in eye contact, are core diagnostic features of autism spectrum disorder (ASD). Many studies have used eye tracking to measure reduced attention to faces in autistic people; however, most of this work has not taken advantage of eye-tracking temporal resolution to examine temporal profiles of attention. Methods We used growth curve analysis to model attention to static social scenes as a function of time in a large (N = 650) sample of autistic participants and neurotypical participants across a wide age range (6–30 years). Results The model yielded distinct temporal profiles of attention to faces in the groups. Initially, both groups showed a relatively high probability of attending to faces, followed by decline after several seconds. The neurotypical participants, however, were significantly more likely to return their attention to faces in the latter part of each 20-second trial, with increasing probability with age. In contrast, the probability of returning to the face in the autistic participants remained low across development. In participants with ASD, more atypical profiles of attention were associated with lower Vineland Adaptive Behavior Scales communication scores and a higher curvature in one data-driven cluster correlated with symptom severity. Conclusions These findings show that social attention not only is reduced in ASD, but also differs in its temporal dynamics. The neurotypical participants became more sophisticated in how they deployed their social attention across age, a pattern that was significantly reduced in the participants with ASD, possibly reflecting delayed acquisition of social expertise.

Functional connectivity between brain regions is modulated by cognitive states or experimental conditions. Such connectivity variations can be appreciated in covariance or correlation matrices obtained from fMRI data. A multivariate methodology that can capture fMRI connectivity maps in light of different experimental conditions would be of primary importance to learn about the specific roles of the different brain areas involved in the observed connectivity variations. Here we introduce Spatial Patterns for Discriminative Estimation (SP♠DE), a supervised dimensionality reduction model that provides a full multivariate characterization by achieving optimal discriminative linear spatial filters in terms of variance and provides interpretable spatial maps directly reflecting the brain areas involved in the accounted connectivity changes. We demonstrate the strength of SPADE using fMRI data from the Human connectome project to show that the model provides close to perfect discrimination between different fMRI tasks at low dimensionality. Additionally, the straightforward interpretability of the model is demonstrated by the obtained linear filters relating to anatomical areas well known to be involved in each considered fMRI task. Further, we also show that such an approach provides an alternative view to traditional task fMRI analyses by looking at changes in the covariance structure as a substitute to changes in the mean signal as the general linear model (GLM) analyses. We use 2-back and 0-back working memory task fMRI data from the Human connectome project to show that SPADE discovers connectivity changes in memory related areas during the 2-back periods, while attention network areas are involved during the 0-back task periods. We conclude that SPADE is a robust tool to investigate brain connectivity alterations across induced cognitive changes and has the potential to be used in pathological or pharmacological cohort studies.