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.

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.

No evidence of differences in cognitive control in children with autism spectrum disorder or obsessive-compulsive disorder: An fMRI study.

Repetitive behaviors are among the core symptoms of both Autism Spectrum Disorder (ASD) and Obsessive-Compulsive Disorder (OCD) and are thought to be associated with impairments in cognitive control. However, it is still unknown how deficits in cognitive control and associated neural circuitry relate to the quality or severity of repetitive behavior in children with these disorders. Therefore, we investigated the behavioral and neural correlates of cognitive control using a modified stop-signal task in a multicenter study of children (aged 8-12 years) with ASD, OCD and typically developing (TD) children (N = 95). As both ASD and OCD have high levels of comorbidity with Attention Deficit/Hyperactivity Disorder (ADHD), we did an exploratory analysis addressing ADHD-symptoms. We found that children with ASD and OCD did not show deficits in cognitive control or changes in brain activity in task-relevant neural networks when compared to TD children. However, increased activity in prefrontal brain areas was associated with increased symptoms of comorbid ADHD. As such, this study does not support differences in cognitive control or associated neural circuitry in children with ASD and OCD, but rather suggests that changes in cognitive control in these disorders may be related to symptoms of comorbid ADHD.

A multicohort, longitudinal study of cerebellar development in attention deficit hyperactivity disorder.

BACKGROUND: The cerebellum supports many cognitive functions disrupted in attention deficit hyperactivity disorder (ADHD). Prior neuroanatomic studies have been often limited by small sample sizes, inconsistent findings, and a reliance on cross-sectional data, limiting inferences about cerebellar development. Here, we conduct a multicohort study using longitudinal data, to characterize cerebellar development. METHODS: Growth trajectories of the cerebellar vermis, hemispheres and white matter were estimated using piecewise linear regression from 1,656 youth; of whom 63% had longitudinal data, totaling 2,914 scans. Four cohorts participated, all contained childhood data (age 4-12 years); two had adolescent data (12-25 years). Growth parameters were combined using random-effects meta-analysis. RESULTS: Diagnostic differences in growth were confined to the corpus medullare (cerebellar white matter). Here, the ADHD group showed slower growth in early childhood compared to the typically developing group (left corpus medullare z = 2.49, p = .01; right z = 2.03, p = .04). This reversed in late childhood, with faster growth in ADHD in the left corpus medullare (z = 2.06, p = .04). Findings held when gender, intelligence, comorbidity, and psychostimulant medication were considered. DISCUSSION: Across four independent cohorts, containing predominately longitudinal data, we found diagnostic differences in the growth of cerebellar white matter. In ADHD, slower white matter growth in early childhood was followed by faster growth in late childhood. The findings are consistent with the concept of ADHD as a disorder of the brain's structural connections, formed partly by developing cortico-cerebellar white matter tracts.

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.

XKR4 Gene Effects on Cerebellar Development Are Not Specific to ADHD.

A single-nucleotide polymorphism (SNP) of the XKR4 gene has been linked to Attention-Deficit/Hyperactivity Disorder (ADHD). This gene is preferentially expressed in cerebellum, a brain structure implicated in this disorder. This study investigated the effects of this SNP on cerebellar development in children with and without ADHD. We collected 279 longitudinal T1-weighted structural images and DNA from 58 children with ADHD and 64 typically developing (TD) children matched for age, IQ, and gender. Groups were divided by the XKR4 rs2939678 SNP into A-allele carriers versus subjects homozygous for the G-allele. Cerebellar lobular volumes were segmented into 35 regions of interest using MAGeTBrain, an automated multi-atlas segmentation pipeline for anatomical MRI, and statistically analyzed using linear mixed models. We found decreased gray matter (GM) volumes in ADHD compared to TD children in bilateral lobules VIIIA, left VIIIB, right VIIB, and vermis VI. Furthermore, we found a linear age by gene interaction in left lobule VIIB where subjects homozygous for the G-allele showed a decrease in volume over time compared to A-allele carriers. We further found quadratic age × gene and age × diagnosis interactions in left lobule IV. Subjects homozygous for the G-allele (the genotype overtransmitted in ADHD) showed more suppressed, almost flat quadratic growth curves compared to A-allele carriers, similar to individuals with ADHD compared to controls. However, there was no interaction between genotype and diagnosis, suggesting that any effects of this SNP on cerebellar development are not specific to the disorder.

Neural basis of implicit memory for socio-emotional information in schizophrenia.

Individuals with schizophrenia are impaired in processing social signals such as facial expressions of emotion. Perceiving facial expressions is a complex process that depends on a distributed neural network of regions involved in affective, cognitive, and visual processing. We examined repetition priming, a non-conscious form of perceptual learning, to explore the visual-perceptual processes associated with perceiving facial expression in people with schizophrenia. Functional magnetic resonance imaging (fMRI) was also employed to probe the sensitivity of face-responsive regions in the ventral pathway to the repetition of stimuli. Subjects viewed blocks of novel and repeated faces displaying fear expressions and neutral expressions and identified each face as male or female. Gender decisions were faster for repeated encoding relative to initial encoding of faces, indicating significant priming for facial expressions. Priming was normal in schizophrenia patients, but, as expected, recognition memory for the expressions was impaired. Neuroimaging findings showed that priming-related activation for patients was reduced in the left fusiform gyrus, relative to controls, regardless of facial expression. The findings suggest that schizophrenia patients have altered neural sensitivity in regions of the ventral visual processing stream that underlie early perceptual learning of objects and faces.

Controlling attention to gaze and arrows in childhood: an fMRI study of typical development and Autism Spectrum Disorders.

Functional magnetic resonance imaging was used to examine functional anatomy of attention to social (eye gaze) and nonsocial (arrow) communicative stimuli in late childhood and in a disorder defined by atypical processing of social stimuli, Autism Spectrum Disorders (ASD). Children responded to a target word ('LEFT'/'RIGHT') in the context of a distracting arrow or averted gaze pointing in a direction that was congruent, incongruent, or neutral (bar without arrowheads, central gaze) relative to the target word. Despite being irrelevant to the target task, both arrow and averted gaze facilitated responses (Congruent vs. Neutral trials) to the same extent in the two groups and led to interference (Incongruent vs. Congruent trials), which was greater from arrows in ASD than control children. In the brain, interaction between group and distracter-domain was observed in frontal-temporal regions during facilitation and frontal-striatal regions during interference. During facilitation, regions associated with attention to gaze in control children (left superior temporal sulcus, premotor) were associated with attention to arrows in ASD children; gaze was associated with medial temporal involvement in ASD children. During interference, regions associated with arrows in control children (anterior cingulate, right caudate) were activated in response to gaze in ASD children; further, left dorsolateral prefrontal cortex, a region not observed in control children, was activated during gaze-interference in ASD children. Thus, functional anatomy was atypical in ASD children during spontaneous processing of social and nonsocial communicative cues.

Effect of dopamine transporter genotype on caudate volume in childhood ADHD and controls.

Polymorphism of the dopamine transporter genotype (DAT1) confers a small but significant susceptibility to attention deficit hyperactivity disorder (ADHD). We examined whether the volume of the head of caudate, a striatal structure with high DAT expression that is important for inhibitory function, differs by DAT1 in children diagnosed with the disorder relative to age and IQ matched controls. Volume of the head of caudate was delineated in the right and left hemisphere and compared between 7- and 13-year-old children with and without ADHD (combined type) who were carriers of two (10/10) or one (9/10) copy of the 10-repeat DAT1 allele. Caudate volumes were overall smaller in 10/10 than 9/10 children, particularly in the left than right hemisphere. While DAT1 effects did not vary by ADHD diagnosis, overall caudate volumes were smaller in ADHD relative to control children. Altered caudate development associated with 10-repeat homozygosity of DAT1 may contribute susceptibility to ADHD.

Attention deficit/hyperactivity disorder symptoms moderate cognition and behavior in children with autism spectrum disorders.

Recent estimates suggest that 31% of children with autism spectrum disorders (ASD) meet diagnostic criteria for attention deficit/hyperactivity disorder (ADHD), and another 24% of children with ASD exhibit subthreshold clinical ADHD symptoms. Presence of ADHD symptoms in the context of ASD could have a variety of effects on cognition, autistic traits, and adaptive/maladaptive behaviors including: exacerbating core ASD impairments; adding unique impairments specific to ADHD; producing new problems unreported in ASD or ADHD; having no clear impact; or producing some combination of these scenarios. Children with ASD and co-morbid ADHD symptoms (ASD+ADHD; n = 21), children with ASD without ADHD (ASD; n = 28), and a typically developing control group (n = 21) were included in the study; all groups were matched on age, gender-ratio, IQ, and socioeconomic status. Data were collected on verbal and spatial working memory, response inhibition, global executive control (EC), autistic traits, adaptive functioning, and maladaptive behavior problems. In this sample, the presence of ADHD symptoms in ASD exacerbated impairments in EC and adaptive behavior and resulted in higher autistic trait, and externalizing behavior ratings. ADHD symptoms were also associated with greater impairments on a lab measure of verbal working memory. These findings suggest that children with ASD+ADHD symptoms present with exacerbated impairments in some but not all domains of functioning relative to children with ASD, most notably in adaptive behavior and working memory. Therefore, ADHD may moderate the expression of components of the ASD cognitive and behavioral phenotype, but ASD+ADHD may not represent an etiologically distinct phenotype from ASD alone.

The fMRI success rate of children and adolescents: typical development, epilepsy, attention deficit/hyperactivity disorder, and autism spectrum disorders.

Functional magnetic resonance imaging (fMRI) in children is increasingly used in clinical application and in developmental research; however, little is known how pediatric patient and typically developing populations successfully complete studies. We examined pediatric success rates with epilepsy, attention deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD), and typically developing children (TYP). We also examined the affect of age, and, for ADHD populations, medication status on success rates. We defined a successful fMRI individual run when the data were interpretable and included in group statistics. For unsuccessful runs, datasets with excessive motion or floor task performance were categorized when possible. All clinical groups scanned less successfully than controls; medication status did not affect ADHD success (epilepsy, 80%; ADHD (off methylphenidate), 77%; ADHD (on methylphenidate), 81%; ASD, 70%; TYP, 87%). Ten to 18-year-old had a significantly greater scan success rate than 4- to 6-year-old; adolescents (13- to 18-year-old) demonstrated greater scan success rates than 7- to 9-year-old. Success rate for completing an entire battery of experimental runs (n = 2-6), varied between 50-59% for patient populations and 69% for TYP (79% when excluding 4- to 6-year-old). Success rate for completing one run from a battery was greater than 90% for all groups, except for ASD (81%). These data suggest 20-30% more children should be recruited in these patient groups, but only 10-20% for TYP for research studies. Studies with 4- to 6-year-olds may require 20-40% additional participants; studies with 10- to 18-year-olds may require 10-15% additional participants.

Ecotoxicology: basic approaches

A expansäo das atividades agrícolas e industriais fez emergir necessidades de planos de manejo das atividades antropogênicas e o meio ambiente natural; a revoluçäo ambiental procura agora soluçöes de gerenciamento para os seus modos estruturais e funcionais. Muitos problemas de poluiçäo ambiental relacionam-se diretamente com as atuaçöes políticas, oriundas das administraçöes governamentais. Informaçöes a respeito dos efeitos de agentes químicos em ecossistemas naturais säo altamente polêmicas e cheias de incertezas. A sociedade tem acumulado cada vez mais conhecimento, agora é o tempo das açöes efetivas para se prevenir futuras degradaçöes