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Adolescents who have sustained a concussion or mild traumatic brain injury (mTBI) are prone to repeat injuries which may be related to subtle motor deficits persisting after clinical recovery. Cross-sectional research has found that these deficits are associated with altered functional connectivity among somatomotor, dorsal attention, and default mode networks. However, our understanding of how these brain-behavior relationships change over time after clinical recovery is limited. In this study, we examined categorical and dimensional trajectories of functional connectivity and subtle motor performance in youth clinically recovered from mTBI and never-injured controls (10-17 years). All participants completed task-based and resting-state functional magnetic resonance imaging scans and the Physical and Neurological Examination of Subtle Signs (PANESS) at initial and 3-month follow-up visits. We examined somatomotor-dorsal attention and somatomotor-default mode network connectivity and their association with PANESS performance. Compared with controls, a larger proportion of youth recovered from mTBI showed increases in somatomotor-dorsal attention functional connectivity over time; in contrast, there were no differences in somatomotor-default mode connectivity trajectories between youth recovered from mTBI and controls. Relative to controls, youth recovered from mTBI who showed greater increases in somatomotor-dorsal attention connectivity over time also completed motor tasks more slowly at the 3-month compared with the initial visit. Collectively, these findings suggest that longitudinal changes in somatomotor-dorsal attention functional connectivity may be associated with lingering motor learning deficits after clinical recovery from pediatric mTBI. Further research is necessary to understand how trajectories of functional connectivity and motor performance can inform individual-level outcomes, for instance, susceptibility to future injuries in both youth who are never injured and those clinically recovered from mTBI., (© The Author(s) 2025. Published by Mary Ann Liebert, Inc.)

Subtle motor signs are a common feature in children with attention-deficit/hyperactivity disorder (ADHD). It has long been suggested that white matter abnormalities may be involved in their presentation, though no study has directly probed this question. The aim of this study was to investigate the relationship between white matter organization and the severity of subtle motor signs in children with and without ADHD. Participants were 92 children with ADHD aged between 8 and 12 years, and 185 typically developing controls. Subtle motor signs were examined using the Physical and Neurological Examination for Soft Signs (PANESS). Children completed diffusion MRI, and fixel-based analysis was performed after preprocessing. Tracts of interest were delineated using TractSeg including the corpus callosum (CC), the bilateral corticospinal tracts (CST), superior longitudinal fasciculus, and fronto-pontine tracts (FPT). Fiber cross-section (FC) was calculated for each tract. Across all participants, lower FC in the CST was associated with higher PANESS Total score (greater motor deficits). Within the PANESS, similar effects were observed for Timed Left and Right maneuvers of the hands and feet, with lower FC of the CST, CC, and FPT associated with poorer performance. No significant group differences were observed in FC in white matter regions associated with PANESS performance. Our data are consistent with theoretical accounts implicating white matter organization in the expression of motor signs in childhood. However, rather than contributing uniquely to the increased severity of soft motor signs in those with ADHD, white matter appears to contribute to these symptoms in childhood in general., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

Background: Difficulties with praxis, the ability to perform learned skilled movements, have been robustly demonstrated in autism spectrum disorder (autism). However, praxis assessment is not routinely included in autism characterization batteries, in part because it is traditionally time consuming to administer and score. We test whether dyspraxia in autism can be captured with a brief measure., Method: Youth with autism ( n = 41) and matched typically developing controls ( n = 32), aged 8 to 16 years, completed a 5-minute praxis battery. The 19-item battery included four subtests: gesture to command, tool use, familiar imitation, and meaningless imitation. Video recordings were coded for error types and compared to participant characterization variables., Results: Consistent with research using a lengthy battery, autistic youth made more errors overall, with a large effect size. Groups demonstrated similar distributions of error types, suggesting that dyspraxia in autism is not limited to a particular error form. In the autism group, praxis was associated with adaptive functioning, but not autism traits., Conclusions: A shortened battery is sufficiently sensitive to praxis differences between autistic and typically developing youth, increasing the feasibility of including praxis within clinical assessments or larger research batteries aimed at testing relationships with downstream skills., Competing Interests: Conflict of interest statement: The authors report no conflicts of interest. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

The stop-signal paradigm has become ubiquitous in investigations of inhibitory control. Tasks inspired by the paradigm, referred to as stop-signal tasks, require participants to make responses on go trials and to inhibit those responses when presented with a stop-signal on stop trials. Currently, the most popular version of the stop-signal task is the 'choice-reaction' variant, where participants make choice responses, but must inhibit those responses when presented with a stop-signal. An alternative to the choice-reaction variant of the stop-signal task is the 'anticipated response inhibition' task. In anticipated response inhibition tasks, participants are required to make a planned response that coincides with a predictably timed event (such as lifting a finger from a computer key to stop a filling bar at a predefined target). Anticipated response inhibition tasks have some advantages over the more traditional choice-reaction stop-signal tasks and are becoming increasingly popular. However, currently, there are no openly available versions of the anticipated response inhibition task, limiting potential uptake. Here, we present an open-source, free, and ready-to-use version of the anticipated response inhibition task, which we refer to as the OSARI (the Open-Source Anticipated Response Inhibition) task., (© 2021. Crown.)

Objectives: The presence of excessive mirror overflow in children with Attention Deficit/Hyperactivity Disorder (ADHD) is discussed in numerous published reports. These reports, however, include a limited age range in their samples. The objective of this study is to examine the effects of diagnosis and sex on mirror overflow and standard deviation (SD) of tap time in children with and without ADHD across a larger age range (5-12 years) of children., Methods: One-hundred and forty-eight children with ADHD and 112 age- and sex-matched typically developing (TD) children completed a finger sequencing task. Mirror overflow, SD of tap time, and mean tap time were measured using finger twitch transducers., Results: Results reveal a significant diagnostic effect on mirror overflow such that boys and girls with ADHD demonstrate increased overflow compared to same-sex TD children. Boys with ADHD demonstrated more variable tap times compared to TD boys; no diagnostic effect was observed in the girls., Conclusions: Boys with ADHD exhibit anomalous motor variability; girls with ADHD show similar levels of variability as TD girls. Boys and girls with ADHD exhibit similar levels of excessive mirror overflow. This lack of sex differences on mirror overflow is distinct from reports finding sex effects on overflow and could result from an examination of a broader age range than is included in prior reports. Adolescent data would provide a greater understanding of the trajectory of anomalous mirror overflow across development. Examination of functional and structural connectivity would expand the current understanding of the neurobiological foundation of motor overflow.

We propose a novel integrated framework that jointly models complementary information from resting-state functional MRI (rs-fMRI) connectivity and diffusion tensor imaging (DTI) tractography to extract biomarkers of brain connectivity predictive of behavior. Our framework couples a generative model of the connectomics data with a deep network that predicts behavioral scores. The generative component is a structurally-regularized Dynamic Dictionary Learning (sr-DDL) model that decomposes the dynamic rs-fMRI correlation matrices into a collection of shared basis networks and time varying subject-specific loadings. We use the DTI tractography to regularize this matrix factorization and learn anatomically informed functional connectivity profiles. The deep component of our framework is an LSTM-ANN block, which uses the temporal evolution of the subject-specific sr-DDL loadings to predict multidimensional clinical characterizations. Our joint optimization strategy collectively estimates the basis networks, the subject-specific time-varying loadings, and the neural network weights. We validate our framework on a dataset of neurotypical individuals from the Human Connectome Project (HCP) database to map to cognition and on a separate multi-score prediction task on individuals diagnosed with Autism Spectrum Disorder (ASD) in a five-fold cross validation setting. Our hybrid model outperforms several state-of-the-art approaches at clinical outcome prediction and learns interpretable multimodal neural signatures of brain organization., (Copyright © 2021. Published by Elsevier Inc.)

Mirror overflow is a developmental phenomenon defined as unintentional movements that mimic the execution of intentional movements in homologous muscles on the opposite side of the body. In children with attention-deficit/hyperactivity disorder (ADHD), mirror overflow is commonly excessive, abnormally persistent, and correlated with ADHD symptom severity. As such, it represents a promising clinical biomarker for disinhibited behavior associated with ADHD. Yet, the neural underpinnings of mirror overflow in ADHD remain unclear. Our objective was to test whether intrinsic interhemispheric functional connectivity between homologous regions of the somatomotor network (SMN) is associated with mirror overflow in school age children with and without ADHD using resting state functional magnetic resonance imaging. To this end, we quantified mirror overflow in 119 children (8-12 years old, 62 ADHD) during a finger sequencing task using finger twitch transducers affixed to the index and ring fingers. Group ICA was used to identify right- and left-lateralized SMNs and subject-specific back reconstructed timecourses were correlated to obtain a measure of SMN interhemispheric connectivity. We found that children with ADHD showed increased mirror overflow (p < 0.001; d = 0.671) and interhemispheric SMN functional connectivity (p = 0.023; d = 0.521) as compared to typically developing children. In children with ADHD, but not the typically developing children, there was a significant relationship between interhemispheric SMN functional connectivity and mirror overflow (t = 2.116; p = 0.039). Our findings of stronger interhemispheric functional connectivity between homologous somatomotor regions in children with ADHD is consistent with previous transcranial magnetic stimulation and diffusion-tractography imaging studies suggesting that interhemispheric cortical inhibitory mechanisms may be compromised in children with ADHD. The observed brain-behavior correlation further suggests that abnormally strong interhemispheric SMN connectivity in children with ADHD may diminish their ability to suppress overflow movements., (Copyright © 2021. Published by Elsevier Inc.)

Body weight is substantially determined by eating behaviors, which are themselves driven by biological factors interacting with the environment. Previous studies in young children suggest that genetic influences on dopamine function may confer differential susceptibility to the environment in such a way that increases behavioral obesity risk in a lower socioeconomic status (SES) environment but decreases it in a higher SES environment. We aimed to test if this pattern of effect could also be observed in adolescence, another critical period for development in brain and behavior, using a novel measure of predicted expression of the dopamine receptor 4 (DRD4) gene in prefrontal cortex. In a sample of 76 adolescents (37 boys and 39 girls from Baltimore, Maryland/US, aged 14-18y), we estimated individual levels of DRD4 gene expression (PredDRD4) in prefrontal cortex from individual genomic data using PrediXcan, and tested interactions with a composite SES score derived from their annual household income, maternal education, food insecurity, perceived resource availability, and receipt of public assistance. Primary outcomes were snack intake during a multi-item ad libitum meal test, and food-related impulsivity assessed using a food-adapted go/no-go task. A linear regression model adjusted for sex, BMI z-score, and genetic ethnicity demonstrated a PredDRD4 by composite SES score interaction for snack intake (p = 0.009), such that adolescents who had lower PredDRD4 levels exhibited greater snack intake in the lower SES group, but lesser snack intake in the higher SES group. Exploratory analysis revealed a similar pattern for scores on the Perceived Stress Scale (p = 0.001) such that the low PredDRD4 group reported higher stress in the lower SES group, but less stress in the higher SES group, suggesting that PredDRD4 may act in part by affecting perceptions of the environment. These results are consistent with a differential susceptibility model in which genes influencing environmental responsiveness interact with environments varying in obesogenicity to confer behavioral obesity risk in a less favorable environment, but behavioral obesity protection in a favorable one., Competing Interests: The authors have declared that no competing interests exist.

The goal of the current study was to evaluate the impact of Tubulin Polymerization Promoting Protein (TPPP) methylation on structural and fractional anisotropy (FA) corpus callosum (CC) measures. TPPP is involved in the development of white matter tracts in the brain and was implicated in stress-related psychiatric disorders in an unbiased whole epigenome methylation study. The cohort included 63 participants (11.73 y/o ±1.91) from a larger study investigating risk and resilience in maltreated children. Voxel-based morphometry (VBM) was used to process the structural data, fractional anisotropy (FA) was determined using an atlas-based approach, and DNA specimens were derived from saliva in two batches using the 450 K (N = 39) and 850 K (N = 24) Illumina arrays, with the data from each batch analyzed separately. After controlling for multiple comparisons and relevant covariates (e.g., demographics, brain volume, cell composition, 3 PCs), 850 K derived TPPP methylation values, in interaction with a dimensional measure of children's trauma experiences, predicted left and right CC body volumes and genu, body and splenium FA (p < .007, all comparisons). The findings in the splenium replicated in subjects with the 450 K data. The results extend prior investigations and suggest a role for TPPP in brain changes associated with stress-related psychiatric disorders., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to report., (Copyright © 2020. Published by Elsevier B.V.)

Background: Child abuse and other forms of adversity are associated with alterations in threat processing and emotion regulation brain circuits., Objective: The goal of the current investigation is to determine if the availability of positive social support can ameliorate the negative impact of adversity on these brain systems., Participants and Setting: Subjects included 55 children ages 7-16 (X = 11.8, SD = 2.0). Approximately one-third of the cohort had no significant history of adversity, one-third had a history of moderate adversity, and one-third had a history of severe adversity. Brain imaging was conducted at the University of Vermont using a 3.0 T Philips scanner., Methods: The Emotional Go-NoGo task with fearful and calm facial stimuli was used to assess the neural correlates of threat processing and emotion regulation in children during functional magnetic resonance imaging (fMRI). Dimensional measures of anxiety, social supports, and children's adverse experiences were also obtained., Results: A conjunction analysis was used to test if trauma-related brain activation in responding to fearful vs. calm targets was impacted by social support. This approach identified multiple activation foci, including a cluster extending from the left amygdala to several other key brain regions involved in emotion regulation, including the orbitofrontal cortex, anterior cingulate cortex (ACC), anterior insula, nucleus accumbens, and frontal pole (Family Wise Error (FWE) correction, p < 0.05)., Conclusions: Greater social support may reduce the effect that adversity has on neural processing of threat stimuli, consistent with the protective role of positive supports in promoting resilience and recovery demonstrated in the literature., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

We propose a novel optimization framework to predict clinical severity from resting state fMRI (rs-fMRI) data. Our model consists of two coupled terms. The first term decomposes the correlation matrices into a sparse set of representative subnetworks that define a network manifold. These subnetworks are modeled as rank-one outer-products which correspond to the elemental patterns of co-activation across the brain; the subnetworks are combined via patient-specific non-negative coefficients. The second term is a linear regression model that uses the patient-specific coefficients to predict a measure of clinical severity. We validate our framework on two separate datasets in a ten fold cross validation setting. The first is a cohort of fifty-eight patients diagnosed with Autism Spectrum Disorder (ASD). The second dataset consists of sixty three patients from a publicly available ASD database. Our method outperforms standard semi-supervised frameworks, which employ conventional graph theoretic and statistical representation learning techniques to relate the rs-fMRI correlations to behavior. In contrast, our joint network optimization framework exploits the structure of the rs-fMRI correlation matrices to simultaneously capture group level effects and patient heterogeneity. Finally, we demonstrate that our proposed framework robustly identifies clinically relevant networks characteristic of ASD., (Copyright © 2019. Published by Elsevier Inc.)

Background: Impairment of executive function (EF), the goal-directed regulation of thoughts, actions, and emotions, drives negative outcomes and is common across neurodevelopmental disorders including attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). A primary challenge to its amelioration is heterogeneity in symptom expression within and across disorders. Parsing this heterogeneity is necessary to attain diagnostic precision, a goal of the NIMH Research Domain Criteria Initiative. We aimed to identify transdiagnostic subtypes of EF that span the normal to impaired spectrum and establish their predictive and neurobiological validity., Methods: Community detection was applied to clinical parent-report measures in 8-14-year-old children with and without ADHD and ASD from two independent cohorts (discovery N = 320; replication N = 692) to identify subgroups with distinct behavioral profiles. Support vector machine (SVM) classification was used to predict subgroup membership of unseen cases. Preliminary neurobiological validation was obtained with existing functional magnetic resonance imaging (fMRI) data on a subsample (N = 84) by testing hypotheses about sensitivity of EF subgroups versus DSM categories., Results: We observed three transdiagnostic EF subtypes characterized by behavioral profiles that were defined by relative weakness in: (a) flexibility and emotion regulation; (b) inhibition; and (c) working memory, organization, and planning. The same tripartite structure was also present in the typically developing children. SVM trained on the discovery sample and tested on the replication sample classified subgroup membership with 77.0% accuracy. Split-half SVM classification on the combined sample (N = 1,012) yielded 88.9% accuracy (this SVM is available for public use). As hypothesized, frontal-parietal engagement was better distinguished by EF subtype than DSM diagnosis and the subgroup characterized with inflexibility failed to modulate right IPL activation in response to increased executive demands., Conclusions: The observed transdiagnostic subtypes refine current diagnostic nosology and augment clinical decision-making for personalizing treatment of executive dysfunction in children., (© 2019 Association for Child and Adolescent Mental Health.)

Development of the frontal lobe is critical to acquisition, execution, and control of a wide range of functions, from basic motor response to complex decision-making. These functions are influenced by contingency-based (e.g., reward and response-cost/punishment) feedback that is mediated through the adaptive integration of fronto-subcortical neural circuitry. The frontal lobe manages incoming information and chooses the appropriate action based on one's goals in a particular context. This aspect of frontal function, while only one component, is crucial to development and maintenance of approach and avoidance behavior central to all human (and animal) behavior. Furthermore, disruptions in fronto-subcortical circuitry governing motivated behavior appear to contribute to a range of developmental disorders, including attention-deficit/hyperactivity disorder (ADHD), and confer vulnerability for psychopathology more broadly. The particular deficits that manifest in altered behavior depend upon the specific circuitry that is compromised due to the functional specificity of distinct regions of the frontal lobe and its interconnections with subcortical structures. Neurobiologic models of motivated behavior provide a valuable framework for characterizing developmental disorders from a transdiagnostic dimensional systems perspective. Improved characterization of approach and avoidance motivation across neurodevelopmental disorders has the potential to inform the development of novel interventions and personalized medicine., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Through unbiased transcriptomics and multiple molecular tools, transient downregulation of the Orthodenticle homeobox 2 (OTX2) gene was recently causatively associated with the development of depressive-like behaviors in a mouse model of early life stress. The analyses presented in this manuscript test the translational applicability of these findings by examining peripheral markers of methylation of OTX2 and OTX2-regulated genes in relation to measures of depression and resting-state functional connectivity data collected as part of a larger study examining risk and resilience in maltreated children. The sample included 157 children between the ages of 8 and 15 years (χ = 11.4, SD = 1.9). DNA specimens were derived from saliva samples and processed using the Illumina 450 K beadchip. A subset of children (N = 47) with DNA specimens also had resting-state functional MRI data. After controlling for demographic factors, cell heterogeneity, and three principal components, maltreatment history and methylation in OTX2 significantly predicted depression in the children. In terms of the imaging data, increased OTX2 methylation was found to be associated with increased functional connectivity between the right vmPFC and bilateral regions of the medial frontal cortex and the cingulate, including the subcallosal gyrus, frontal pole, and paracingulate gyrus-key structures implicated in depression. Mouse models of early stress hold significant promise in helping to unravel the mechanisms by which child adversity confers risk for psychopathology, with data presented in this manuscript supporting a potential role for OTX2 and OTX2-related (e.g., WNT1, PAX6) genes in the pathophysiology of stress-related depressive disorders in children.

Pediatric traumatic brain injury (TBI) is a heterogeneous condition, varying in both severity and sequelae. The long-term motor deficits following severe TBI requiring inpatient rehabilitation are better established than those following milder forms of TBI. The authors examined motor performance 2 and 12 months postinjury in children without overt motor impairment using standard measures of upper limb function and the Physical and Neurological Examination for Subtle Signs (PANESS). The PANESS was sensitive to differences between children with TBI and uninjured children as well as to changes in children with TBI over time. These data suggest that subtle motor deficits are present after milder forms of TBI and, particularly those related to balance and gait, may persist even 12 months postinjury.

Anxiety is a risk factor for many adverse neuropsychiatric and socioeconomic outcomes, and has been linked to functional and structural changes in the ventromedial prefrontal cortex (VMPFC). However, the nature of these differences, as well as how they develop in children and adolescents, remains poorly understood. More effective interventions to minimize the negative consequences of anxiety require better understanding of its neurobiology in children. Recent research suggests that structural imaging studies may benefit from clearly delineating between cortical surface area and thickness when examining these associations, as these distinct cortical phenotypes are influenced by different cellular mechanisms and genetic factors. The present study examined relationships between cortical surface area and thickness of the VMPFC and a self-report measure of anxiety (SCARED-R) in 287 youths aged 7-20 years from the Pediatric Imaging, Neurocognition, and Genetics (PING) study. Age and gender interactions were examined for significant associations in order to test for developmental differences. Cortical surface area and thickness were also examined simultaneously to determine whether they contribute independently to the prediction of anxiety. Anxiety was negatively associated with relative cortical surface area of the VMPFC as well as with global cortical thickness, but these associations diminished with age. The two cortical phenotypes contributed additively to the prediction of anxiety. These findings suggest that higher anxiety in children may be characterized by both delayed expansion of the VMPFC and an altered trajectory of global cortical thinning. Further longitudinal studies will be needed to confirm these findings., Competing Interests: Jean A. Frazier has received research support from GlaxoSmithKline, Pfizer, Inc., Neuren, Roche, and Seaside Therapeutics, NICHD, NIMH, NINDS and has served on a Data Safety Monitoring Board for Forest Pharmaceuticals. Anders M. Dale is a founder of and holds equity interest in CorTechs Labs, La Jolla, CA and serves on its scientific advisory board. The terms of this arrangement have been reviewed and approved by UC San Diego, in accordance with its conflict of interest policies. All other authors reported no biomedical financial interests or potential conflicts of interest.

Dyslexia and language impairment (LI) are complex traits with substantial genetic components. We recently completed an association scan of the DYX2 locus, where we observed associations of markers in DCDC2, KIAA0319, ACOT13, and FAM65B with reading-, language-, and IQ-related traits. Additionally, the effects of reading-associated DYX3 markers were recently characterized using structural neuroimaging techniques. Here, we assessed the neuroimaging implications of associated DYX2 and DYX3 markers, using cortical volume, cortical thickness, and fractional anisotropy. To accomplish this, we examined eight DYX2 and three DYX3 markers in 332 subjects in the Pediatrics Imaging Neurocognition Genetics study. Imaging-genetic associations were examined by multiple linear regression, testing for influence of genotype on neuroimaging. Markers in DYX2 genes KIAA0319 and FAM65B were associated with cortical thickness in the left orbitofrontal region and global fractional anisotropy, respectively. KIAA0319 and ACOT13 were suggestively associated with overall fractional anisotropy and left pars opercularis cortical thickness, respectively. DYX3 markers showed suggestive associations with cortical thickness and volume measures in temporal regions. Notably, we did not replicate association of DYX3 markers with hippocampal measures. In summary, we performed a neuroimaging follow-up of reading-, language-, and IQ-associated DYX2 and DYX3 markers. DYX2 associations with cortical thickness may reflect variations in their role in neuronal migration. Furthermore, our findings complement gene expression and imaging studies implicating DYX3 markers in temporal regions. These studies offer insight into where and how DYX2 and DYX3 risk variants may influence neuroimaging traits. Future studies should further connect the pathways to risk variants associated with neuroimaging/neurocognitive outcomes.

The main objective of the multi-site Pediatric Imaging, Neurocognition, and Genetics (PING) study was to create a large repository of standardized measurements of behavioral and imaging phenotypes accompanied by whole genome genotyping acquired from typically-developing children varying widely in age (3 to 20 years). This cross-sectional study produced sharable data from 1493 children, and these data have been described in several publications focusing on brain and cognitive development. Researchers may gain access to these data by applying for an account on the PING portal and filing a data use agreement. Here we describe the recruiting and screening of the children and give a brief overview of the assessments performed, the imaging methods applied, the genetic data produced, and the numbers of cases for whom different data types are available. We also cite sources of more detailed information about the methods and data. Finally we describe the procedures for accessing the data and for using the PING data exploration portal., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: "Jitter" involves randomization of intervals between stimulus events. Compared with controls, individuals with ADHD demonstrate greater intrasubject variability (ISV) performing tasks with fixed interstimulus intervals (ISIs). Because Gaussian curves mask the effect of extremely slow or fast response times (RTs), ex-Gaussian approaches have been applied to study ISV., Method: This study applied ex-Gaussian analysis to examine the effects of jitter on RT variability in children with and without ADHD. A total of 75 children, aged 9 to 14 years (44 ADHD, 31 controls), completed a go/no-go test with two conditions: fixed ISI and jittered ISI., Results: ADHD children showed greater variability, driven by elevations in exponential (tau), but not normal (sigma) components of the RT distribution. Jitter decreased tau in ADHD to levels not statistically different than controls, reducing lapses in performance characteristic of impaired response control., Conclusion: Jitter may provide a nonpharmacologic mechanism to facilitate readiness to respond and reduce lapses from sustained (controlled) performance., (© 2012 SAGE Publications.)

A recent interest in resting state functional magnetic resonance imaging (rsfMRI) lies in subdividing the human brain into anatomically and functionally distinct regions of interest. For example, brain parcellation is often a necessary step for defining the network nodes used in connectivity studies. While inference has traditionally been performed on group-level data, there is a growing interest in parcellating single subject data. However, this is difficult due to the inherent low signal-to-noise ratio of rsfMRI data, combined with typically short scan lengths. A large number of brain parcellation approaches employ clustering, which begins with a measure of similarity or distance between voxels. The goal of this work is to improve the reproducibility of single-subject parcellation using shrinkage-based estimators of such measures, allowing the noisy subject-specific estimator to "borrow strength" in a principled manner from a larger population of subjects. We present several empirical Bayes shrinkage estimators and outline methods for shrinkage when multiple scans are not available for each subject. We perform shrinkage on raw inter-voxel correlation estimates and use both raw and shrinkage estimates to produce parcellations by performing clustering on the voxels. While we employ a standard spectral clustering approach, our proposed method is agnostic to the choice of clustering method and can be used as a pre-processing step for any clustering algorithm. Using two datasets - a simulated dataset where the true parcellation is known and is subject-specific and a test-retest dataset consisting of two 7-minute resting-state fMRI scans from 20 subjects - we show that parcellations produced from shrinkage correlation estimates have higher reliability and validity than those produced from raw correlation estimates. Application to test-retest data shows that using shrinkage estimators increases the reproducibility of subject-specific parcellations of the motor cortex by up to 30%., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Socioeconomic disparities are associated with differences in cognitive development. The extent to which this translates to disparities in brain structure is unclear. We investigated relationships between socioeconomic factors and brain morphometry, independently of genetic ancestry, among a cohort of 1,099 typically developing individuals between 3 and 20 years of age. Income was logarithmically associated with brain surface area. Among children from lower income families, small differences in income were associated with relatively large differences in surface area, whereas, among children from higher income families, similar income increments were associated with smaller differences in surface area. These relationships were most prominent in regions supporting language, reading, executive functions and spatial skills; surface area mediated socioeconomic differences in certain neurocognitive abilities. These data imply that income relates most strongly to brain structure among the most disadvantaged children.

To evaluate evidence for motor impairment specificity in autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD). Children completed performance-based assessment of motor functioning (Movement Assessment Battery for Children: MABC-2). Logistic regression models were used to predict group membership. In the models comparing typically developing and developmental disability (DD), all three MABC subscale scores were significantly negatively associated with having a DD. In the models comparing ADHD and ASD, catching and static balance items were associated with ASD group membership, with a 1 point decrease in performance increasing odds of ASD by 36 and 39 %, respectively. Impairments in motor skills requiring the coupling of visual and temporal feedback to guide and adjust movement appear specifically deficient in ASD.

Current theories of the neurobiological basis of autism spectrum disorder (ASD) posit an altered pattern of connectivity in large-scale brain networks. Here we used diffusion tensor imaging to investigate the microstructural properties of the white matter (WM) that mediates interregional connectivity in 36 high-functioning children with ASD (HF-ASD) as compared with 37 controls. By employing an atlas-based analysis using large deformation diffeometric morphic mapping registration, a widespread but left-lateralized pattern of abnormalities was revealed. The mean diffusivity (MD) of water in the WM of HF-ASD children was significantly elevated throughout the left hemisphere, particularly in the outer-zone cortical WM. Across diagnostic groups, there was a significant effect of age on left-hemisphere MD, with a similar reduction in MD during childhood in both typically developing and HF-ASD children. The increased MD in children with HF-ASD suggests hypomyelination and may reflect increased short-range cortico-cortical connections subsequent to early WM overgrowth. These findings also highlight left-hemispheric connectivity as relevant to the pathophysiology of ASD and indicate that the spatial distribution of microstructural abnormalities in HF-ASD is widespread and left-lateralized. This altered left-hemispheric connectivity may contribute to deficits in communication and praxis observed in ASD., (© 2014 International Society for Autism Research, Wiley Periodicals, Inc.)

Purpose: Functionally relevant alterations in resting state fMRI (rs-fMRI) connectivity have been identified in adults with traumatic brain injury (TBI). We evaluated rs-fMRI connectivity in children with TBI and explored the relationship between altered connectivity and measures of neurological function., Methods: Rs-fMRI was obtained in 14 children after TBI and 14 controls matched for age, sex, and handedness. Whole-brain connectivity was evaluated separately for the default mode network (DMN) and dorsal attention network (DAN); Between-group contrasts identified regions with altered connectivity between TBI and control cohorts. In children with TBI, the relationships between regions of altered connectivity and performance on relevant functional measures were examined., Results: Compared to controls, children with TBI showed significantly greater connectivity between DMN and right dorsal premotor cortex (RdPM) and between DAN and bilateral sensorimotor cortex (SM1). In children with TBI, greater DMN-RdPM connectivity was associated with worse motor performance whereas greater DAN-LSM1 connectivity was associated with better motor performance; furthermore, DMN-RdPM and DAN-LSM1 connectivity were negatively correlated., Conclusion: Rs-fMRI reveals significant altered connectivity in children with TBI compared to controls. After TBI in children, patterns of altered connectivity appear divergent, with increased DMN-motor network connectivity associated with worse motor control whereas increased DAN-motor network connectivity appears compensatory.

Resting-state functional magnetic resonance imaging (rs-fMRI) is used to investigate synchronous activations in spatially distinct regions of the brain, which are thought to reflect functional systems supporting cognitive processes. Analyses are often performed using seed-based correlation analysis, allowing researchers to explore functional connectivity between data in a seed region and the rest of the brain. Using scan-rescan rs-fMRI data, we investigate how well the subject-specific seed-based correlation map from the second replication of the study can be predicted using data from the first replication. We show that one can dramatically improve prediction of subject-specific connectivity by borrowing strength from the group correlation map computed using all other subjects in the study. Even more surprisingly, we found that the group correlation map provided a better prediction of a subject's connectivity than the individual's own data. While further discussion and experimentation are required to understand how this can be used in practice, results indicate that shrinkage-based methods that borrow strength from the population mean should play a role in rs-fMRI data analysis., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Autism spectrum disorders (ASDs) represent a formidable challenge for psychiatry and neuroscience because of their high prevalence, lifelong nature, complexity and substantial heterogeneity. Facing these obstacles requires large-scale multidisciplinary efforts. Although the field of genetics has pioneered data sharing for these reasons, neuroimaging had not kept pace. In response, we introduce the Autism Brain Imaging Data Exchange (ABIDE)-a grassroots consortium aggregating and openly sharing 1112 existing resting-state functional magnetic resonance imaging (R-fMRI) data sets with corresponding structural MRI and phenotypic information from 539 individuals with ASDs and 573 age-matched typical controls (TCs; 7-64 years) (http://fcon&#95;1000.projects.nitrc.org/indi/abide/). Here, we present this resource and demonstrate its suitability for advancing knowledge of ASD neurobiology based on analyses of 360 male subjects with ASDs and 403 male age-matched TCs. We focused on whole-brain intrinsic functional connectivity and also survey a range of voxel-wise measures of intrinsic functional brain architecture. Whole-brain analyses reconciled seemingly disparate themes of both hypo- and hyperconnectivity in the ASD literature; both were detected, although hypoconnectivity dominated, particularly for corticocortical and interhemispheric functional connectivity. Exploratory analyses using an array of regional metrics of intrinsic brain function converged on common loci of dysfunction in ASDs (mid- and posterior insula and posterior cingulate cortex), and highlighted less commonly explored regions such as the thalamus. The survey of the ABIDE R-fMRI data sets provides unprecedented demonstrations of both replication and novel discovery. By pooling multiple international data sets, ABIDE is expected to accelerate the pace of discovery setting the stage for the next generation of ASD studies.

Objective: The NIH Toolbox Cognition Battery (NTCB) was designed to provide a brief, efficient computerized test of key neuropsychological functions appropriate for use in children as young as 3 years of age. This report describes the performance of a large group of typically developing children and adolescents and examines the impact of age and sociocultural variables on test performance., Method: The NTCB was administered to a sample of 1,020 typically developing males and females ranging in age from 3 to 20 years, diverse in terms of socioeconomic status (SES) and race/ethnicity, as part of the new publicly accessible Pediatric Imaging, Neurocognition, and Genetics (PING) data resource, at 9 sites across the United States., Results: General additive models of nonlinear age-functions were estimated from age-differences in test performance on the 8 NTCB subtests while controlling for family SES and genetic ancestry factors (GAFs). Age accounted for the majority of the variance across all NTCB scores, with additional significant contributions of gender on some measures, and of SES and race/ethnicity (GAFs) on all. After adjusting for age and gender, SES and GAFs explained a substantial proportion of the remaining unexplained variance in Picture Vocabulary scores., Conclusions: The results highlight the sensitivity to developmental effects and efficiency of this new computerized assessment battery for neurodevelopmental research. Limitations are observed in the form of some ceiling effects in older children, some floor effects, particularly on executive function tests in the youngest participants, and evidence for variable measurement sensitivity to cultural/socioeconomic factors.

Written and verbal languages are neurobehavioral traits vital to the development of communication skills. Unfortunately, disorders involving these traits-specifically reading disability (RD) and language impairment (LI)-are common and prevent affected individuals from developing adequate communication skills, leaving them at risk for adverse academic, socioeconomic and psychiatric outcomes. Both RD and LI are complex traits that frequently co-occur, leading us to hypothesize that these disorders share genetic etiologies. To test this, we performed a genome-wide association study on individuals affected with both RD and LI in the Avon Longitudinal Study of Parents and Children. The strongest associations were seen with markers in ZNF385D (OR = 1.81, P = 5.45 × 10(-7) ) and COL4A2 (OR = 1.71, P = 7.59 × 10(-7) ). Markers within NDST4 showed the strongest associations with LI individually (OR = 1.827, P = 1.40 × 10(-7) ). We replicated association of ZNF385D using receptive vocabulary measures in the Pediatric Imaging Neurocognitive Genetics study (P = 0.00245). We then used diffusion tensor imaging fiber tract volume data on 16 fiber tracts to examine the implications of replicated markers. ZNF385D was a predictor of overall fiber tract volumes in both hemispheres, as well as global brain volume. Here, we present evidence for ZNF385D as a candidate gene for RD and LI. The implication of transcription factor ZNF385D in RD and LI underscores the importance of transcriptional regulation in the development of higher order neurocognitive traits. Further study is necessary to discern target genes of ZNF385D and how it functions within neural development of fluent language., (© 2013 The Authors. Genes, Brain and Behavior published by International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd.)

This study investigates the storage vs. composition of inflected forms in typically-developing children. Children aged 8-12 were tested on the production of regular and irregular past-tense forms. Storage (vs. composition) was examined by probing for past-tense frequency effects and imageability effects--both of which are diagnostic tests for storage--while controlling for a number of confounding factors. We also examined sex as a factor. Irregular inflected forms, which must depend on stored representations, always showed evidence of storage (frequency and/or imageability effects), not only across all children, but also separately in both sexes. In contrast, for regular forms, which could be either stored or composed, only girls showed evidence of storage. This pattern is similar to that found in previously-acquired adult data from the same task, with the notable exception that development affects which factors influence the storage of regulars in females: imageability plays a larger role in girls, and frequency in women. Overall, the results suggest that irregular inflected forms are always stored (in children and adults, and in both sexes), whereas regulars can be either composed or stored, with their storage a function of various item- and subject-level factors.

In recent years, there has been growing enthusiasm that functional magnetic resonance imaging (MRI) could achieve clinical utility for a broad range of neuropsychiatric disorders. However, several barriers remain. For example, the acquisition of large-scale datasets capable of clarifying the marked heterogeneity that exists in psychiatric illnesses will need to be realized. In addition, there continues to be a need for the development of image processing and analysis methods capable of separating signal from artifact. As a prototypical hyperkinetic disorder, and movement-related artifact being a significant confound in functional imaging studies, ADHD offers a unique challenge. As part of the ADHD-200 Global Competition and this special edition of Frontiers, the ADHD-200 Consortium demonstrates the utility of an aggregate dataset pooled across five institutions in addressing these challenges. The work aimed to (1) examine the impact of emerging techniques for controlling for "micro-movements," and (2) provide novel insights into the neural correlates of ADHD subtypes. Using support vector machine (SVM)-based multivariate pattern analysis (MVPA) we show that functional connectivity patterns in individuals are capable of differentiating the two most prominent ADHD subtypes. The application of graph-theory revealed that the Combined (ADHD-C) and Inattentive (ADHD-I) subtypes demonstrated some overlapping (particularly sensorimotor systems), but unique patterns of atypical connectivity. For ADHD-C, atypical connectivity was prominent in midline default network components, as well as insular cortex; in contrast, the ADHD-I group exhibited atypical patterns within the dlPFC regions and cerebellum. Systematic motion-related artifact was noted, and highlighted the need for stringent motion correction. Findings reported were robust to the specific motion correction strategy employed. These data suggest that resting-state functional connectivity MRI (rs-fcMRI) data can be used to characterize individual patients with ADHD and to identify neural distinctions underlying the clinical heterogeneity of ADHD.

It is now recognized that a number of cognitive, behavioral, and mental health outcomes across the lifespan can be traced to fetal development. Although the direct mediation is unknown, the substantial variance in fetal growth, most commonly indexed by birth weight, may affect lifespan brain development. We investigated effects of normal variance in birth weight on MRI-derived measures of brain development in 628 healthy children, adolescents, and young adults in the large-scale multicenter Pediatric Imaging, Neurocognition, and Genetics study. This heterogeneous sample was recruited through geographically dispersed sites in the United States. The influence of birth weight on cortical thickness, surface area, and striatal and total brain volumes was investigated, controlling for variance in age, sex, household income, and genetic ancestry factors. Birth weight was found to exert robust positive effects on regional cortical surface area in multiple regions as well as total brain and caudate volumes. These effects were continuous across birth weight ranges and ages and were not confined to subsets of the sample. The findings show that (i) aspects of later child and adolescent brain development are influenced at birth and (ii) relatively small differences in birth weight across groups and conditions typically compared in neuropsychiatric research (e.g., Attention Deficit Hyperactivity Disorder, schizophrenia, and personality disorders) may influence group differences observed in brain parameters of interest at a later stage in life. These findings should serve to increase our attention to early influences.

Self-regulation refers to the ability to control behavior, cognition, and emotions, and self-regulation failure is related to a range of neuropsychiatric problems. It is poorly understood how structural maturation of the brain brings about the gradual improvement in self-regulation during childhood. In a large-scale multicenter effort, 735 children (4-21 y) underwent structural MRI for quantification of cortical thickness and surface area and diffusion tensor imaging for quantification of the quality of major fiber connections. Brain development was related to a standardized measure of cognitive control (the flanker task from the National Institutes of Health Toolbox), a critical component of self-regulation. Ability to inhibit responses and impose cognitive control increased rapidly during preteen years. Surface area of the anterior cingulate cortex accounted for a significant proportion of the variance in cognitive performance. This finding is intriguing, because characteristics of the anterior cingulum are shown to be related to impulse, attention, and executive problems in neurodevelopmental disorders, indicating a neural foundation for self-regulation abilities along a continuum from normality to pathology. The relationship was strongest in the younger children. Properties of large-fiber connections added to the picture by explaining additional variance in cognitive control. Although cognitive control was related to surface area of the anterior cingulate independently of basic processes of mental speed, the relationship between white matter quality and cognitive control could be fully accounted for by speed. The results underscore the need for integration of different aspects of brain maturation to understand the foundations of cognitive development.

Functional magnetic resonance imaging (fMRI) is a powerful tool for the in vivo study of the pathophysiology of brain disorders and disease. In this manuscript, we propose an analysis stream for fMRI functional connectivity data and apply it to a novel study of Alzheimer's disease. In the first stage, spatial independent component analysis is applied to group fMRI data to obtain common brain networks (spatial maps) and subject-specific mixing matrices (time courses). In the second stage, functional principal component analysis is utilized to decompose the mixing matrices into population-level eigenvectors and subject-specific loadings. Inference is performed using permutation-based exact logistic regression for matched pairs data. The method is applied to a novel fMRI study of Alzheimer's disease risk under a verbal paired associates task. We found empirical evidence of alternative ICA-based metrics of connectivity when comparing subjects evidencing mild cognitive impairment relative to carefully matched controls.

Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder that, by current definition, has onset prior to age 7 years. MRI studies have provided some insight into brain differences associated with ADHD, but thus far have almost exclusively focused on children ages 7 years and older. To better understand the neurobiological development of ADHD, cortical and subcortical brain development should be systematically examined in younger children presenting with symptoms of the disorder. High-resolution anatomical (MPRAGE) images, acquired on a 3.0T scanner, were analyzed in a total of 26 preschoolers, ages 4-5 years (13 with ADHD, 13 controls, matched on age and sex). The ADHD sample was diagnosed using DSM-IV criteria, and screened for language disorders. Cortical regions were delineated and measured using automated methods in Freesurfer; basal ganglia structures were manually delineated. Children with ADHD showed significantly reduced caudate volumes bilaterally; in contrast there were no significant group differences in cortical volume or thickness in this age range. After controlling for age and total cerebral volume, left caudate volume was a significant predictor of hyperactive/impulsive, but not inattentive symptom severity. Anomalous basal ganglia, particularly caudate, development appears to play an important role among children presenting with early onset symptoms of ADHD.

Objectives: Qualitative observations have revealed that children with attention-deficit/hyperactivity disorder (ADHD) show increased overflow movements, a motor sign thought to reflect impaired inhibitory control. The goal of this study was to develop and implement methods for quantifying excessive mirror overflow movements in children with ADHD., Methods: Fifty right-handed children aged 8.2-13.3 years, 25 with ADHD (12 girls) and 25 typically developing (TD) control children (10 girls), performed a sequential finger-tapping task, completing both left-handed (LHFS) and right-handed finger sequencing (RHFS). Phasic overflow of the index and ring fingers was assessed in 34 children with video recording, and total overflow in 48 children was measured by calculating the total angular displacement of the index and ring fingers with electrogoniometer recordings., Results: Phasic overflow and total overflow across both hands were greater in children with ADHD than in TD children, particularly during LHFS. Separate gender analyses revealed that boys, but not girls, with ADHD showed significantly more total phasic overflow and total overflow than did their gender-matched control children., Conclusions: The quantitative overflow measures used in this study support past qualitative findings that motor overflow persists to a greater degree in children with ADHD than in age-matched TD peers. The quantitative findings further suggest that persistence of mirror overflow is more prominent during task execution of the nondominant hand and reveal gender-based differences in developmental neural systems critical to motor control. These quantitative measures will assist future physiologic investigation of the brain basis of motor control in ADHD.

Objective: Attention-deficit/hyperactivity disorder (ADHD) is a childhood-onset behavioral diagnosis in which children often fail to meet age norms in development of motor control, particularly timed repetitive and sequential movements, motor overflow, and balance. The neural substrate of this motor delay may include mechanisms of synaptic inhibition in or adjacent to the motor cortex. The primary objective of this study was to determine whether transcranial magnetic stimulation (TMS)-evoked measures, particularly short interval cortical inhibition (SICI), in motor cortex correlate with the presence and severity of ADHD in childhood as well as with commonly observed delays in motor control., Methods: In this case-control study, behavioral ratings, motor skills, and motor cortex physiology were evaluated in 49 children with ADHD (mean age 10.6 years, 30 boys) and 49 typically developing children (mean age 10.5 years, 30 boys), all right-handed, aged 8-12 years. Motor skills were evaluated with the Physical and Neurological Examination for Subtle Signs (PANESS) and the Motor Assessment Battery for Children version 2. SICI and other physiologic measures were obtained using TMS in the left motor cortex., Results: In children with ADHD, mean SICI was reduced by 40% (p < 0.0001) and less SICI correlated with higher ADHD severity (r = -0.52; p = 0.002). Mean PANESS motor development scores were 59% worse in children with ADHD (p < 0.0001). Worse PANESS scores correlated modestly with less SICI (r = -.30; p = 0.01)., Conclusion: Reduced TMS-evoked SICI correlates with ADHD diagnosis and symptom severity and also reflects motor skill development in children.

In daily activities, humans must attend and respond to a range of important items and inhibit and not respond to unimportant distractions. Our current understanding of these processes is largely based on perceptually simple stimuli. This study investigates the interaction of conceptual-semantic categorization and inhibitory processing using Event Related Potentials (ERPs). Participants completed three Go-NoGo tasks that increased systematically in the degree of conceptual-semantic information necessary to respond correctly (from single items to categories of objects and animals). Findings indicate that the N2 response reflects inhibitory processing but does not change significantly with task difficulty. The P3 NoGo amplitude, on the other hand, is attenuated by task difficulty. Further, the latency of the peak of the P3 NoGo response elicited by the most difficult task is significantly later than are the peaks detected during performance of the other two tasks. Thus, the level of complexity of conceptual-semantic representations influences inhibitory processing in a systematic way. This inhibition paradigm may be a key for investigating inhibitory dysfunction in patient populations.

Objective: To examine differences in age-related improvement in motor speed and neurologic subtle signs (overflow and dysrhythmia) among boys and girls with and without attention-deficit hyperactivity disorder (ADHD)., Method: Diagnosis of ADHD was determined by structured parent interview and administration of ADHD-specific and broad behavior rating scales. Motor function was assessed using the revised Physical and Neurological Assessment of Subtle Signs. Three primary outcome variables were obtained: 1) total time, 2) total overflow, and 3) total dysrhythmia. Effects of age, group, and sex were assessed., Results: Both control and ADHD groups showed improvement on timed tasks with age; however, controls were consistently faster across the age span. Controls and girls with ADHD showed steady age-related reduction of overflow and dysrhythmia, whereas boys with ADHD had little improvement in these signs through age 14 years., Conclusion: Results indicated that girls with attention-deficit hyperactivity disorder (ADHD) performed similarly to age-matched controls on a quantified motor examination. These results parallel patterns of findings from neuroimaging studies, in which neurologic anomalies in areas related to motor control are present in boys with ADHD, but more equivocal in girls with ADHD. Sex-related differences observed in children with ADHD likely extend beyond symptom presentation to development of motor control, and are likely related to earlier brain maturation in girls.

Age-related change in the difference between left- and right-side speed on motor examination may be an important indicator of maturation. Cortical maturation and myelination of the corpus callosum are considered to be related to increased bilateral skill and speed on timed motor tasks. We compared left minus right foot, hand, and finger speed differences using the Revised Physical and Neurological Assessment for Subtle Signs (PANESS; Denckla, 1985); examining 130 typically developing right-handed children (65 boys, 65 girls) ages 7-14. Timed tasks included right and left sets of 20 toe taps, 10 toe-heel alternation sequences, 20 hand pats, 10 hand pronate-supinate sets, 20 finger taps, and 5 sequences of each finger-to-thumb apposition. For each individual, six difference scores between left- and right-sided speeded performances of timed motor tasks were analyzed. Left-right differences decreased significantly with age on toe tapping, heel-toe alternations, hand pronation-supination, finger repetition, and finger sequencing. There were significant gender effects for heel-toe sequences (boys showing a greater left-right difference than girls), and a significant interaction between age and gender for hand pronation-supination, such that the magnitude of the left-right difference was similar for younger, compared with older girls, while the difference was significantly larger for younger, compared to older boys. Speed of performing right and left timed motor tasks equalizes with development; for some tasks, the equalization occurs earlier in girls than in boys.

Impaired performance of skilled gestures, referred to as dyspraxia, is consistently reported in children with autism; however, its neurological basis is not well understood. Basic motor skill deficits are also observed in children with autism and it is unclear whether dyspraxia observed in children with autism can be accounted for by problems with motor skills. Forty-seven high-functioning children with an autism spectrum disorder (ASD), autism, or Asperger syndrome (43 males, four females; mean age 10y 7m [SD 1y 10m], mean Full-scale IQ (FSIQ) 99.4 [SD 15.9]), and 47 typically developing (TD) controls (41 males, six females; mean age 10y 6m [SD 1y 5m], mean FSIQ 113.8 [SD 12.3], age range 8-4y) completed: (1) the Physical and Neurological Assessment of Subtle Signs, an examination of basic motor skills standardized for children, and (2) a praxis examination that included gestures to command, to imitation, and with tool-use. Hierarchical regression was used to examine the association between basic motor skill performance (i.e. times to complete repetitive limb movements) and praxis performance (total praxis errors). After controlling for age and IQ, basic motor skill was a significant predictor of performance on praxis examination. Nevertheless, the ASD group continued to show significantly poorer praxis than controls after accounting for basic motor skill. Furthermore, praxis performance was a strong predictor of the defining features of autism, measured using the Autism Diagnostic Observation Schedule, and this correlation remained significant after accounting for basic motor skill. Results indicate that dyspraxia in autism cannot be entirely accounted for by impairments in basic motor skills, suggesting the presence of additional contributory factors. Furthermore, praxis in children with autism is strongly correlated with the social, communicative, and behavioral impairments that define the disorder, suggesting that dyspraxia may be a core feature of autism or a marker of the neurological abnormalities underlying the disorder.

Sex differences on language and visuospatial tasks are of great interest, with differences in hemispheric laterality hypothesized to exist between males and females. Some functional imaging studies examining sex differences have shown that males are more left lateralized on language tasks and females are more right lateralized on visuospatial tasks; however, findings are inconsistent. Here we used functional magnetic resonance imaging to study thirty participants, matched on task performance, during phonological and visuospatial tasks. For each task, region-of-interest analyses were used to test differences in cerebral laterality. Results indicate that lateralization differences exist, with males more left lateralized during the phonological task and showing greater bilateral activity during the visuospatial task, whereas females showed greater bilateral activity during the phonological task and were more right lateralized during the visuospatial task. Our data provide clear evidence for differences in laterality between males and females when processing language versus visuospatial information.

To provide insight into what aspects of the emotional circuit might be affected in high-functioning autism, we measured indices of physiological emotions and of the expression of conscious feelings in 10 children with high-functioning autism or Asperger syndrome and 10 comparison participants. Pleasant, unpleasant, and neutral pictures were presented while skin conductance responses were measured. Self-report ratings of pleasantness and interestingness were taken between pictures. Skin conductance responses did not differ between the groups. Self report ratings were different, with the children with autism giving more similar answers to the two questions than the comparison children. Impairments in socio-emotional expression in autism may be related to deficits in perception and/or expression of conscious feelings; physiological emotions may be relatively preserved.

Background: The executive functions of inhibition, planning, flexible shifting of actions, and working memory are commonly reported to be impaired in neurodevelopmental disorders., Method: We compared these abilities in children (8-12 years) with high functioning autism (HFA, n = 17), attention deficit-hyperactivity disorder (ADHD, n = 21) and healthy controls (n = 32). Response inhibition was assessed using the Stroop Color and Word Test (Golden, 1978). Problem solving, set-shifting, and nonverbal memory were assessed using three tasks, respectively, from the CANTAB (Cambridge Cognition, 1996): the Stockings of Cambridge task; the Intra-Dimensional/Extra-Dimensional set-shifting task; and the Spatial Working Memory task (SWM) with tokens hidden behind 3, 4, 6, and 8 boxes., Results: There were no group differences on the response inhibition, planning, or set-shifting tasks. On the SWM task, children with HFA made significantly more between-search errors compared with controls on both the most difficult problems (8-box) and on the mid-difficulty problems (6-box); however, children with ADHD made significantly more errors compared to controls on the most difficult (8-box) problems only., Conclusion: Our findings suggest that spatial working memory is impaired in both ADHD and HFA, and more severely in the latter. More detailed investigation is needed to examine the mechanisms that differentially impair spatial working memory, but on this set of tasks there appears to be sparing of other executive functions in these neuropsychiatric developmental disorders.

Background: Megalencephaly is a frequent CNS manifestation in neurofibromatosis type 1 (NF1); however, its tissue composition, modification by attention deficit hyperactivity disorder (ADHD), and relationship with unidentified bright objects (UBO) remain controversial., Methods: Eighteen male patients with NF1, seven of whom had ADHD (NF1+ADHD), were compared with 18 age- and sex-matched controls in terms of MRI-, Talairach-based brain, cerebral, lobar, and sublobar gray and white matter volumes. Twelve subjects with NF1 had UBO in the centrencephalic region, whereas six had no UBO or exclusively infratentorial lesions., Results: Patients with NF1 without ADHD (NF1-pure) had the largest total cerebral, gray, and white matter volumes with larger parietal/somatosensory white matter volumes than controls, particularly if UBO were present in the basal ganglia. All subjects with NF1 (including NF1+ADHD) had larger total and frontal white matter volumes than controls. Smaller frontal/right prefrontal gray matter volumes were found in NF1+ADHD when compared with NF1-pure patients., Conclusions: The increase in frontal and parietal white matter volumes in male patients with NF1, including the preferential centrencephalic distribution, supports the hypothesis that NF1's white matter pathology encompasses but is not limited to visible UBO. Male patients with NF1+ADHD, as compared with NF1-pure patients, showed frontal reductions that are largely consistent with those found in idiopathic ADHD.

Objective: Based on previous findings implicating abnormalities of cortico-striatal-thalamo-cortical circuitry in Tourette syndrome (TS), the authors performed a volumetric analysis of frontal and nonfrontal tissue (gray + white matter) in boys with TS, with and without attention deficit hyperactivity disorder (ADHD)., Methods: Frontal and nonfrontal gray and white matter compartment volumes, obtained by a MRI protocol, were analyzed with a 2 x 2 factorial multivariate analysis of variance approach for associations with a TS or ADHD factor in 11 boys with TS only, 14 with TS + ADHD, 12 with ADHD only, and 26 healthy boys., Results: In subjects with TS, the right frontal lobe showed a larger proportion of white matter. In addition, results were consistent with previous reports of reduced frontal lobe volumes associated with ADHD. Our analyses suggested these reductions to be mainly the consequence of smaller gray matter volumes, particularly on the left., Conclusions: These findings, suggesting the volumetric composition of frontal lobe tissue to be different in TS, support the hypothesis proposing frontostriatal pathway involvement in the pathophysiology of the disorder. Differences in composition of right frontal lobe attributable to white matter do not definitively implicate the hypothesized fiber pathways; however, considered in the context of the unilateral directionality of frontal-striatal circuitry, these results suggest the white matter connections as one explanation for basal ganglia anomalies (loss of normal left > right asymmetry) in TS.

Objective: To assess saccadic eye movements in boys with Tourette syndrome (TS) with and without attention-deficit hyperactivity disorder (ADHD), comparing performance with that of an age-matched group of male controls., Method: Three different saccade tasks (prosaccades, antisaccades, and memory-guided saccades) were used to examine functions necessary for the planning and execution of eye movements, including motor response preparation, response inhibition, and working memory. The study included 14 boys with TS without ADHD (TS-only), 11 boys with TS and ADHD (TS+ADHD), and 10 male controls., Results: Latency of prosaccades was prolonged in boys with TS (both with and without ADHD) compared with controls. Variability in prosaccade latency was greater in the groups of boys with TS+ADHD compared with both the TS-only and control groups. Response inhibition errors on both the antisaccade task (directional errors) and memory-guided saccade task (anticipatory errors) were increased in boys with TS+ADHD compared with those with TS-only. There were no significant differences among the three groups in accuracy of memory-guided saccades., Conclusions: Oculomotor findings suggest that TS is associated with delay in initiation of motor response as evidenced by excessive latency on prosaccades. Signs of impaired response inhibition and variability in motor response appear to be associated with the presence of ADHD.

Background: Prevailing hypotheses suggest that attention deficit hyperactivity disorder (ADHD) is secondary to dysfunction of motor intentional systems mediated by prefrontal circuitry. Oculomotor paradigms provide a mechanism for examining and localizing dysfunction at the interface between movement and cognition., Objective: Three different saccade tasks (reflexive or prosaccades, antisaccades, and memory-guided saccades) were used to examine functions necessary for the planning and the execution of eye movements, including motor response preparation, response inhibition, and working memory., Methods: The study included 19 children with ADHD, divided into two groups: a group of 8 children on methylphenidate at the time of testing and a group of 11 children not taking any psychoactive medication. Results from the two groups were compared with those from 25 age- and gender-matched normal control children., Results: Both groups of children with ADHD made significantly more directional errors than did controls on the antisaccade task and significantly more anticipatory errors than did controls on the memory-guided saccade task, findings that are consistent with deficits in response inhibition. There were no significant differences in prosaccade latency, although unmedicated children with ADHD showed significantly greater variability in latency on the prosaccade task than did controls. On the memory-guided saccade task there were no significant differences in saccade accuracy; however, unmedicated children with ADHD showed longer saccade latency than did either controls or medicated children with ADHD., Conclusions: Oculomotor findings suggest that deficits in prefrontal functions, in particular response inhibition, contribute to behavioral abnormalities observed in ADHD. Findings also suggest that the administration of methylphenidate is associated with improvements in the consistency of motor response. Although there were no observed improvements in response inhibition with methylphenidate, conclusions await a design in which subjects complete testing both on and off medication.

To examine the hypothesis that abnormalities in those cognitive functions for which cerebellar components have been implicated contribute to the pathophysiology of autism, tests of judgment of explicit time intervals and procedural learning were administered to 11 participants with autism and 17 age-and-IQ-matched controls. Results indicated that the group with autism demonstrated significant impairments in procedural learning compared with the group of controls. No significant difference in judgment of explicit time intervals was found. The data suggest that deficits in procedural learning may contribute to the cognitive and behavioral phenotype of autism; these deficits may be secondary to abnormalities in cerebellar-frontal circuitry.

Several clinical investigations with adults suggest that the cerebellum may be critical for judgment of explicit time intervals; however, little work has been done in populations with lesions of the cerebellum acquired during development. We evaluated 17 individuals with ataxia-telangiectasia (AT), an autosomal recessive disorder with on-set in early childhood characterized by diffuse, almost selective, degeneration of the cerebellar cortex, and 21 normal controls, matched for age. Because patients with AT have motor impairment, verbal IQ (VIQ) was used to estimate intelligence; VIQ was significantly lower in the group with AT (p < .0001). Participants were tested using a test of judgment of duration that has been found to be impaired in adults with cerebellar lesions and a contrasting auditory control task (not impaired in adults with cerebellar lesions) involving judgment of pitch. After statistically controlling for VIQ, the 2 groups did not differ significantly on judgment of pitch, but those with AT performed significantly worse than controls on judgment of duration (p = .01). Children and adolescents with AT show deficits in judgment of duration but not of pitch, suggesting that the cerebellum may be critical for judgment of explicit time intervals at all ages.

The objective of this study was to examine whether abnormalities in corpus callosum morphology, previously reported in boys with Tourette syndrome (TS), were also present in girls with this disorder. Among the three groups of girls-TS, TS and attention deficit hyperactivity disorder, and controls-there were no significant differences in the size of the corpus callosum or any of five individual subregions. The findings suggest that abnormalities in corpus callosum morphology in TS are a gender-related phenomenon.