Cross-sectional and longitudinal neuroanatomical profiles of distinct clinical (adaptive) outcomes in autism.

Individuals with autism spectrum disorder (henceforth referred to as autism) display significant variation in clinical outcome. For instance, across age, some individuals' adaptive skills naturally improve or remain stable, while others' decrease. To pave the way for 'precision-medicine' approaches, it is crucial to identify the cross-sectional and, given the developmental nature of autism, longitudinal neurobiological (including neuroanatomical and linked genetic) correlates of this variation. We conducted a longitudinal follow-up study of 333 individuals (161 autistic and 172 neurotypical individuals, aged 6-30 years), with two assessment time points separated by ~12-24 months. We collected behavioural (Vineland Adaptive Behaviour Scale-II, VABS-II) and neuroanatomical (structural magnetic resonance imaging) data. Autistic participants were grouped into clinically meaningful "Increasers", "No-changers", and "Decreasers" in adaptive behaviour (based on VABS-II scores). We compared each clinical subgroup's neuroanatomy (surface area and cortical thickness at T1, ∆T (intra-individual change) and T2) to that of the neurotypicals. Next, we explored the neuroanatomical differences' potential genomic associates using the Allen Human Brain Atlas. Clinical subgroups had distinct neuroanatomical profiles in surface area and cortical thickness at baseline, neuroanatomical development, and follow-up. These profiles were enriched for genes previously associated with autism and for genes previously linked to neurobiological pathways implicated in autism (e.g. excitation-inhibition systems). Our findings suggest that distinct clinical outcomes (i.e. intra-individual change in clinical profiles) linked to autism core symptoms are associated with atypical cross-sectional and longitudinal, i.e. developmental, neurobiological profiles. If validated, our findings may advance the development of interventions, e.g. targeting mechanisms linked to relatively poorer outcomes.

Processing of social and monetary rewards in autism spectrum disorders.

BACKGROUND: Reward processing has been proposed to underpin the atypical social feature of autism spectrum disorder (ASD). However, previous neuroimaging studies have yielded inconsistent results regarding the specificity of atypicalities for social reward processing in ASD. AIMS: Utilising a large sample, we aimed to assess reward processing in response to reward type (social, monetary) and reward phase (anticipation, delivery) in ASD. METHOD: Functional magnetic resonance imaging during social and monetary reward anticipation and delivery was performed in 212 individuals with ASD (7.6-30.6 years of age) and 181 typically developing participants (7.6-30.8 years of age). RESULTS: Across social and monetary reward anticipation, whole-brain analyses showed hypoactivation of the right ventral striatum in participants with ASD compared with typically developing participants. Further, region of interest analysis across both reward types yielded ASD-related hypoactivation in both the left and right ventral striatum. Across delivery of social and monetary reward, hyperactivation of the ventral striatum in individuals with ASD did not survive correction for multiple comparisons. Dimensional analyses of autism and attention-deficit hyperactivity disorder (ADHD) scores were not significant. In categorical analyses, post hoc comparisons showed that ASD effects were most pronounced in participants with ASD without co-occurring ADHD. CONCLUSIONS: Our results do not support current theories linking atypical social interaction in ASD to specific alterations in social reward processing. Instead, they point towards a generalised hypoactivity of ventral striatum in ASD during anticipation of both social and monetary rewards. We suggest this indicates attenuated reward seeking in ASD independent of social content and that elevated ADHD symptoms may attenuate altered reward seeking in ASD.

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.

Hidden in plain sight: how individual ADHD stakeholders have conflicting ideas about ADHD but do not address their own ambivalence.

Psychiatric classifications refer to clusters of behavioral symptoms. We know much about how psychiatric classifications are intended to be used in theory. Yet the scientific study of the practice of classification to date is limited. We aimed to explore how individuals navigate and make sense of the complexity surrounding an ADHD classification. We used thematic analysis to analyse stakeholder perspectives from seven focus groups: adults classified with ADHD, adolescents classified with ADHD, parents of children classified with ADHD, clinicians, researchers, teachers, and policy makers. We found seven themes in how stakeholders navigate the classification ADHD. Yet, what stood out was an overarching discursive pattern: individual stakeholders expressed highly ambivalent ideas about ADHD but did not address their own ambivalence. We suggest that promoting a social kinds perspective on ADHD may help us navigate the complexity and ambivalence associated with ADHD more competently.

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.

Lost in explanation: internal conflicts in the discourse of ADHD psychoeducation.

BACKGROUND: Psychiatric classifications are understood in many different ways. For children with ADHD and their parents, psychoeducation is an important source of information for shaping their understanding. Moreover, psychoeducation is often taken by children and parents to represent how their story is understood by the therapist. As a result, the way psychoeducation is formulated may affect the therapeutic alliance, one of the most robust mediators of treatment outcome. In addition, psychoeducation may indirectly influence the way we understand psychological differences as a society. METHODS: To better understand how the classification ADHD is given meaning through psychoeducation, we analyzed 41 written psychoeducational materials from four different countries; the USA, UK, Netherlands and Hungary. RESULTS: We identified five patterns of how the materials construct the discourse on ADHD. Notably, tension between biomedical and psychosocial perspectives resulted in conflict within a single thematic stance on ADHD as opposed to a conflict between parties with a different vision on ADHD. There were only few differences between countries in the way they constructed the discourse in the materials. CONCLUSIONS: These conflicts cause confusion, misrepresentation and decontextualization of ADHD. Ultimately, for those diagnosed with ADHD and their parents, conflicting information in psychoeducation materials may hamper their ability to understand themselves in the context of their difficulties.

Analysis of structural brain asymmetries in attention-deficit/hyperactivity disorder in 39 datasets.

OBJECTIVE: Some studies have suggested alterations of structural brain asymmetry in attention-deficit/hyperactivity disorder (ADHD), but findings have been contradictory and based on small samples. Here, we performed the largest ever analysis of brain left-right asymmetry in ADHD, using 39 datasets of the ENIGMA consortium. METHODS: We analyzed asymmetry of subcortical and cerebral cortical structures in up to 1,933 people with ADHD and 1,829 unaffected controls. Asymmetry Indexes (AIs) were calculated per participant for each bilaterally paired measure, and linear mixed effects modeling was applied separately in children, adolescents, adults, and the total sample, to test exhaustively for potential associations of ADHD with structural brain asymmetries. RESULTS: There was no evidence for altered caudate nucleus asymmetry in ADHD, in contrast to prior literature. In children, there was less rightward asymmetry of the total hemispheric surface area compared to controls (t = 2.1, p = .04). Lower rightward asymmetry of medial orbitofrontal cortex surface area in ADHD (t = 2.7, p = .01) was similar to a recent finding for autism spectrum disorder. There were also some differences in cortical thickness asymmetry across age groups. In adults with ADHD, globus pallidus asymmetry was altered compared to those without ADHD. However, all effects were small (Cohen's d from -0.18 to 0.18) and would not survive study-wide correction for multiple testing. CONCLUSION: Prior studies of altered structural brain asymmetry in ADHD were likely underpowered to detect the small effects reported here. Altered structural asymmetry is unlikely to provide a useful biomarker for ADHD, but may provide neurobiological insights into the trait.

Frontostriatal functional connectivity correlates with repetitive behaviour across autism spectrum disorder and obsessive-compulsive disorder.

BACKGROUND: Autism spectrum disorder (ASD) and obsessive-compulsive disorder (OCD) are neurodevelopmental disorders with considerable overlap in terms of their defining symptoms of compulsivity/repetitive behaviour. Little is known about the extent to which ASD and OCD have common versus distinct neural correlates of compulsivity. Previous research points to potentially common dysfunction in frontostriatal connectivity, but direct comparisons in one study are lacking. Here, we assessed frontostriatal resting-state functional connectivity in youth with ASD or OCD, and healthy controls. In addition, we applied a cross-disorder approach to examine whether repetitive behaviour across ASD and OCD has common neural substrates. METHODS: A sample of 78 children and adolescents aged 8-16 years was used (ASD n = 24; OCD n = 25; healthy controls n = 29), originating from the multicentre study COMPULS. We tested whether diagnostic group, repetitive behaviour (measured with the Repetitive Behavior Scale-Revised) or their interaction was associated with resting-state functional connectivity of striatal seed regions. RESULTS: No diagnosis-specific differences were detected. The cross-disorder analysis, on the other hand, showed that increased functional connectivity between the left nucleus accumbens (NAcc) and a cluster in the right premotor cortex/middle frontal gyrus was related to more severe symptoms of repetitive behaviour. CONCLUSIONS: We demonstrate the fruitfulness of applying a cross-disorder approach to investigate the neural underpinnings of compulsivity/repetitive behaviour, by revealing a shared alteration in functional connectivity in ASD and OCD. We argue that this alteration might reflect aberrant reward or motivational processing of the NAcc with excessive connectivity to the premotor cortex implementing learned action patterns.

Tackling Missing Heritability by Use of an Optimum Curve: A Systematic Review and Meta-Analysis.

Missing heritability is a common problem in psychiatry that impedes precision medicine approaches to autism and other heritable complex disorders. This proof-of-concept study uses a systematic review and meta-analysis of the association between variants of the serotonin transporter promoter (5-HTTLPR) and autism to explore the hypothesis that some missing heritability can be explained using an optimum curve. A systematic literature search was performed to identify transmission disequilibrium tests on the short/long (S/L) 5-HTTLPR polymorphism in relation to autism. We analysed five American, seven European, four Asian and two American/European samples. We found no transmission preference in the joint samples and in Europe, preferential transmission of S in America and preferential transmission of L in Asia. Heritability will be underestimated or missed in genetic association studies if two alternative genetic variants are associated with the same disorder in different subsets of a sample. An optimum curve, relating a multifactorial biological variable that incorporates genes and environment to a score for a human trait, such as social competence, can explain this. We suggest that variants of functionally related genes will sometimes appear in fixed combinations at both sides of an optimum curve and propose that future association studies should account for such combinations.

A multisample study of longitudinal changes in brain network architecture in 4-13-year-old children.

Recent advances in human neuroimaging research have revealed that white-matter connectivity can be described in terms of an integrated network, which is the basis of the human connectome. However, the developmental changes of this connectome in childhood are not well understood. This study made use of two independent longitudinal diffusion-weighted imaging data sets to characterize developmental changes in the connectome by estimating age-related changes in fractional anisotropy (FA) for reconstructed fibers (edges) between 68 cortical regions. The first sample included 237 diffusion-weighted scans of 146 typically developing children (4-13 years old, 74 females) derived from the Pediatric Longitudinal Imaging, Neurocognition, and Genetics (PLING) study. The second sample included 141 scans of 97 individuals (8-13 years old, 62 females) derived from the BrainTime project. In both data sets, we compared edges that had the most substantial age-related change in FA to edges that showed little change in FA. This allowed us to investigate if developmental changes in white matter reorganize network topology. We observed substantial increases in edges connecting peripheral and a set of highly connected hub regions, referred to as the rich club. Together with the observed topological differences between regions connecting to edges showing the smallest and largest changes in FA, this indicates that changes in white matter affect network organization, such that highly connected regions become even more strongly imbedded in the network. These findings suggest that an important process in brain development involves organizing patterns of inter-regional interactions. Hum Brain Mapp 39:157-170, 2018. © 2017 Wiley Periodicals, Inc.

Children with ADHD symptoms show deficits in reactive but not proactive inhibition, irrespective of their formal diagnosis.

BACKGROUND: Attenuated inhibitory control is one of the most robust findings in the neuropsychology of attention-deficit/hyperactivity disorder (ADHD). However, it is unclear whether this represents a deficit in outright stopping (reactive inhibition), whether it relates to a deficit in anticipatory response slowing (proactive inhibition), or both. In addition, children with other development disorders, such as autism spectrum disorder (ASD), often have symptoms of inattention, impulsivity, and hyperactivity similar to children with ADHD. These may relate to similar underlying changes in inhibitory processing. METHODS: In this study, we used a modified stop-signal task to dissociate reactive and proactive inhibition. We included not only children with ADHD, but also children primarily diagnosed with an ASD and high parent-rated levels of ADHD symptoms. RESULTS: We replicated the well-documented finding of attenuated reactive inhibition in children with ADHD. In addition, we found a similar deficit in children with ASD and a similar level of ADHD symptoms. In contrast, we found no evidence for deficits in proactive inhibition in either clinical group. CONCLUSIONS: These findings re-emphasize the role of reactive inhibition in children with ADHD and ADHD symptoms. Moreover, our findings stress the importance of a trans-diagnostic approach to the relationship between behavior and neuropsychology.

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.

What can Cortical Development in Attention-Deficit/Hyperactivity Disorder Teach us About the Early Developmental Mechanisms Involved?

Studies of Attention-Deficit/Hyperactivity Disorder (ADHD) have shown developmental changes in the cortical mantle. Different dimensions of cortical morphology, such as surface area and thickness, relate to different neurodevelopmental mechanisms. As such, studying multiple dimensions may inform us about the developmental origins of ADHD. Furthermore, results from existing longitudinal samples await replication. Therefore, we conducted a longitudinal study of multiple cortical dimensions in a sizable, independent ADHD sample. We analyzed 297 anatomical MRI scans from two matched groups of 94 subjects with ADHD and 94 controls, aged 6-28 years. We estimated the developmental trajectories of cortical volume, surface, thickness and gyrification for 68 regions using mixed-effects regression analysis. Subjects with ADHD had smaller overall cortical volume, predominantly driven by decreases in frontal lobe volume that were associated with reduced surface area and gyrification. Nearly all decreases were stable across development. Only a few decreases survived stringent Bonferroni correction for multiple comparisons, with the smallest detectable Cohen's d |0.43|. There were no between-group differences in cortical thickness, or in subcortical volumes. Our results suggest that ADHD is associated with developmentally persistent reductions in frontal cortical volume, surface area, and gyrification. This may implicate early neurodevelopmental mechanisms regulating cortical expansion and convolution in ADHD.

Glutamatergic Agents in the Treatment of Compulsivity and Impulsivity in Child and Adolescent Psychiatry: a Systematic Review of the Literature.

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).

Individual prediction of long-term outcome in adolescents at ultra-high risk for psychosis: Applying machine learning techniques to brain imaging data.

An important focus of studies of individuals at ultra-high risk (UHR) for psychosis has been to identify biomarkers to predict which individuals will transition to psychosis. However, the majority of individuals will prove to be resilient and go on to experience remission of their symptoms and function well. The aim of this study was to investigate the possibility of using structural MRI measures collected in UHR adolescents at baseline to quantitatively predict their long-term clinical outcome and level of functioning. We included 64 UHR individuals and 62 typically developing adolescents (12-18 years old at recruitment). At six-year follow-up, we determined resilience for 43 UHR individuals. Support Vector Regression analyses were performed to predict long-term functional and clinical outcome from baseline MRI measures on a continuous scale, instead of the more typical binary classification. This led to predictive correlations of baseline MR measures with level of functioning, and negative and disorganization symptoms. The highest correlation (r = 0.42) was found between baseline subcortical volumes and long-term level of functioning. In conclusion, our results show that structural MRI data can be used to quantitatively predict long-term functional and clinical outcome in UHR individuals with medium effect size, suggesting that there may be scope for predicting outcome at the individual level. Moreover, we recommend classifying individual outcome on a continuous scale, enabling the assessment of different functional and clinical scales separately without the need to set a threshold. Hum Brain Mapp 38:704-714, 2017. © 2016 Wiley Periodicals, Inc.

Children with ADHD symptoms show decreased activity in ventral striatum during the anticipation of reward, irrespective of ADHD diagnosis.

BACKGROUND: Changes in reward processing are thought to be involved in the etiology of attention-deficit/hyperactivity disorder (ADHD), as well as other developmental disorders. In addition, different forms of therapy for ADHD rely on reinforcement principles. As such, improved understanding of reward processing in ADHD could eventually lead to more effective treatment options. However, differences in reward processing may not be specific to ADHD, but may be a trans-diagnostic feature of disorders that involve ADHD-like symptoms. METHODS: In this event-related fMRI study, we used a child-friendly version of the monetary incentive delay task to assess performance and brain activity during reward anticipation. Also, we collected questionnaire data to assess reward sensitivity in daily life. For final analyses, data were available for 27 typically developing children, 24 children with ADHD, and 25 children with an autism spectrum disorder (ASD) and ADHD symptoms. RESULTS: We found decreased activity in ventral striatum during anticipation of reward in children with ADHD symptoms, both for children with ADHD as their primary diagnosis and in children with autism spectrum disorder and ADHD symptoms. We found that higher parent-rated sensitivity to reward was associated with greater anticipatory activity in ventral striatum for children with ADHD symptoms. In contrast, there was no relationship between the degree of ADHD symptoms and activity in ventral striatum. CONCLUSIONS: We provide evidence of biological and behavioral differences in reward sensitivity in children with ADHD symptoms, regardless of their primary diagnosis. Ultimately, a dimensional brain-behavior model of reward sensitivity in children with symptoms of ADHD may be useful to refine treatment options dependent on reward processing.

Structural and functional connectivity in children and adolescents with and without attention deficit/hyperactivity disorder.

BACKGROUND: Attention deficit/hyperactivity disorder (ADHD) has frequently been associated with changes in resting-state functional connectivity, and decreased white matter (WM) integrity. In the current study, we investigated functional connectivity within Default Mode and frontal control resting-state networks (RSNs) in children with and without ADHD. We hypothesized the RSNs of interest would show a pattern of impaired functional integration and segregation and corresponding changes in WM structure. METHODS: Resting-state fMRI and diffusion-weighted imaging data were acquired from 35 participants with ADHD and 36 matched typically developing peers, aged 6 through 18 years. Functional connectivity was assessed using independent component analysis. Network topology and WM connectivity were further investigated using graph theoretical measures and tract-based spatial statistics (TBSS). RESULTS: Resting-state fMRI analyses showed increased functional connectivity in right inferior frontal gyrus (IFG), and bilateral medial prefrontal cortex (mPFC) within the Default Mode and frontal control networks. Furthermore, a more diffuse spatial pattern of functional connectivity was found in children with ADHD. We found no group differences in structural connectivity as assessed with TBSS or graph theoretical measures. CONCLUSIONS: Resting-state networks show a more diffuse pattern of connectivity in children with ADHD. The increases in functional connectivity in right IFG and bilateral mPFC in children with ADHD may reflect reduced or delayed functional segregation of prefrontal brain regions. As these functional changes were not accompanied by changes in WM, they may precede the development of the frequently reported changes in WM structure.

What to expect and when to expect it: an fMRI study of expectancy in children with ADHD symptoms.

Changes in cognitive control and timing have both been implicated in ADHD. Both are involved in building and monitoring expectations about the environment, and altering behavior if those expectations are violated. In ADHD, problems with expectations about future events have high face validity, as this would be associated with behavior that is inappropriate only given a certain context, similar to symptoms of the disorder. In this fMRI study, we used a timing manipulated go/nogo task to assess brain activity related to expectations about what (cognitive control) and when (timing) events would occur. We hypothesized that problems in building expectations about the environment are a more general, trans-diagnostic characteristic of children with hyperactive, impulsive and inattentive symptoms. To address this, we included children with ASD and symptoms of ADHD, in addition to children with ADHD and typically developing children. We found between-group differences in brain activity related to expectations about when (timing), but not what events will occur (cognitive control). Specifically, we found timing-related hypo-activity that was in part unique to children with a primary diagnosis of ADHD (left pallidum) and in part shared by children with similar levels of ADHD symptoms and a primary diagnosis of ASD (left subthalamic nucleus). Moreover, we found poorer task performance related to timing, but only in children with ASD and symptoms of ADHD. Ultimately, such neurobiological changes in children with ADHD symptoms may relate to a failure to build or monitor expectations and thereby hinder the efficiency of their interaction with the environment.

The development of brain network architecture.

Brain connectivity shows protracted development throughout childhood and adolescence, and, as such, the topology of brain networks changes during this period. The complexity of these changes with development is reflected by regional differences in maturation. This study explored age-related changes in network topology and regional developmental patterns during childhood and adolescence. We acquired two sets of Diffusion Weighted Imaging-scans and anatomical T1-weighted scans. The first dataset included 85 typically developing individuals (53 males; 32 females), aged between 7 and 23 years and was acquired on a Philips Achieva 1.5 Tesla scanner. A second dataset (N = 38) was acquired on a different (but identical) 1.5 T scanner and was used for independent replication of our results. We reconstructed whole brain networks using tractography. We operationalized fiber tract development as changes in mean diffusivity and radial diffusivity with age. Most fibers showed maturational changes in mean and radial diffusivity values throughout childhood and adolescence, likely reflecting increasing white matter integrity. The largest age-related changes were observed in association fibers within and between the frontal and parietal lobes. Furthermore, there was a simultaneous age-related decrease in average path length (P < 0.0001), increase in node strength (P < 0.0001) as well as network clustering (P = 0.001), which may reflect fine-tuning of topological organization. These results suggest a sequential maturational model where connections between unimodal regions strengthen in childhood, followed by connections from these unimodal regions to association regions, while adolescence is characterized by the strengthening of connections between association regions within the frontal and parietal cortex. Hum Brain Mapp 37:717-729, 2016. © 2015 Wiley Periodicals, Inc.

Changes in thickness and surface area of the human cortex and their relationship with intelligence.

Changes in cortical thickness over time have been related to intelligence, but whether changes in cortical surface area are related to general cognitive functioning is unknown. We therefore examined the relationship between intelligence quotient (IQ) and changes in cortical thickness and surface over time in 504 healthy subjects. At 10 years of age, more intelligent children have a slightly thinner cortex than children with a lower IQ. This relationship becomes more pronounced with increasing age: with higher IQ, a faster thinning of the cortex is found over time. In the more intelligent young adults, this relationship reverses so that by the age of 42 a thicker cortex is associated with higher intelligence. In contrast, cortical surface is larger in more intelligent children at the age of 10. The cortical surface is still expanding, reaching its maximum area during adolescence. With higher IQ, cortical expansion is completed at a younger age; and once completed, surface area decreases at a higher rate. These findings suggest that intelligence may be more related to the magnitude and timing of changes in brain structure during development than to brain structure per se, and that the cortex is never completed but shows continuing intelligence-dependent development.