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1.  Different Neural Patterns Are Associated With Trials Preceding Inhibitory Errors in Children With and Without Attention-Deficit/Hyperactivity Disorder 
Attention-deficit/hyperactivity disorder (ADHD) is associated with difficulty inhibiting impulsive, hyperactive, and off-task behavior. However, no studies have examined whether a distinct pattern of brain activity precedes inhibitory errors in typically developing (TD) children and children with ADHD. In healthy adults, increased activity in the default mode network, a set of brain regions more active during resting or internally focused states, predicts commission errors, suggesting that momentary lapses of attention are related to inhibitory failures.
Event-related functional magnetic resonance imaging and a go/no-go paradigm were used to explore brain activity preceding errors in 13 children with ADHD and 17 TD controls.
Comparing pre-error with pre-correct trials, TD children showed activation in the precuneus/posterior cingulate cortex and parahippocampal and middle frontal gyri. In contrast, children with ADHD demonstrated activation in the cerebellum, dorsolateral prefrontal cortex (DLPFC), and basal ganglia. Between-group comparison for the pre-error versus pre-correct contrast showed that children with ADHD showed greater activity in the cerebellum, DLPFC, and ventrolateral PFC compared with TD controls. Results of region-of-interest analysis confirmed that the precuneus/posterior cingulate cortex are more active in TD children compared with children with ADHD.
These preliminary data suggest that brain activation patterns immediately preceding errors differ between children with ADHD and TD children. In TD children, momentary lapses of attention precede errors, whereas pre-error activity in children with ADHD may be mediated by different circuits, such as those involved in response selection and control.
PMCID: PMC3971481  PMID: 21703498
ADHD; children; functional magnetic resonance imaging; commission error; go/no-go task
2.  Precentral gyrus functional connectivity signatures of autism 
Motor impairments are prevalent in children with autism spectrum disorders (ASD) and are perhaps the earliest symptoms to develop. In addition, motor skills relate to the communicative/social deficits at the core of ASD diagnosis, and these behavioral deficits may reflect abnormal connectivity within brain networks underlying motor control and learning. Despite the fact that motor abnormalities in ASD are well-characterized, there remains a fundamental disconnect between the complexity of the clinical presentation of ASD and the underlying neurobiological mechanisms. In this study, we examined connectivity within and between functional subregions of a key component of the motor control network, the precentral gyrus, using resting state functional Magnetic Resonance Imaging data collected from a large, heterogeneous sample of individuals with ASD as well as neurotypical controls. We found that the strength of connectivity within and between distinct functional subregions of the precentral gyrus was related to ASD diagnosis and to the severity of ASD traits. In particular, connectivity involving the dorsomedial (lower limb/trunk) subregion was abnormal in ASD individuals as predicted by models using a dichotomous variable coding for the presence of ASD, as well as models using symptom severity ratings. These findings provide further support for a link between motor and social/communicative abilities in ASD.
PMCID: PMC4030180  PMID: 24860442
autism; functional connectivity; motor cortex; multi-center studies; logistic regression; resting state fMRI
3.  Specificity of Dyspraxia in Children with Autism 
Neuropsychology  2012;26(2):165-171.
To explore the specificity of impaired praxis and postural knowledge to autism by examining three samples of children, including those with autism spectrum disorder (ASD), attention-deficit hyperactivity disorder (ADHD), and typically developing (TD) children.
Twenty-four children with ASD, 24 children with ADHD, and 24 TD children, ages 8–13, completed measures assessing basic motor control (the Physical and Neurological Exam for Subtle Signs; PANESS), praxis (performance of skilled gestures to command, with imitation, and tool use) and the ability to recognize correct hand postures necessary to perform these skilled gestures (the Postural Knowledge Test; PKT).
Children with ASD performed significantly worse than TD children on all three assessments. In contrast, children with ADHD performed significantly worse than TD controls on PANESS but not on the praxis examination or PKT. Furthermore, children with ASD performed significantly worse than children with ADHD on both the praxis examination and PKT, but not on the PANESS.
Whereas both children with ADHD and children with ASD show impairments in basic motor control, impairments in performance and recognition of skilled motor gestures, consistent with dyspraxia, appear to be specific to autism. The findings suggest that impaired formation of perceptual-motor action models necessary to development of skilled gestures and other goal directed behavior is specific to autism; whereas, impaired basic motor control may be a more generalized finding.
PMCID: PMC3312580  PMID: 22288405
imitation; motor learning; procedural learning; premotor cortex; inferior parietal lobe
4.  Distinct frontal lobe morphology in girls and boys with ADHD 
NeuroImage : Clinical  2014;7:222-229.
This study investigated whether frontal lobe cortical morphology differs for boys and girls with ADHD (ages 8–12 years) in comparison to typically developing (TD) peers.
Participants included 226 children between the ages of 8–12 including 93 children with ADHD (29 girls) and 133 TD children (42 girls) for which 3T MPRAGE MRI scans were obtained. A fully automated frontal lobe atlas was used to generate functionally distinct frontal subdivisions, with surface area (SA) and cortical thickness (CT) assessed in each region. Analyses focused on overall diagnostic differences as well as examinations of the effect of diagnosis within boys and girls.
Girls, but not boys, with ADHD showed overall reductions in total prefrontal cortex (PFC) SA. Localization revealed that girls showed widely distributed reductions in the bilateral dorsolateral PFC, left inferior lateral PFC, right medial PFC, right orbitofrontal cortex, and left anterior cingulate; and boys showed reduced SA only in the right anterior cingulate and left medial PFC. In contrast, boys, but not girls, with ADHD showed overall reductions in total premotor cortex (PMC) SA. Further localization revealed that in boys, premotor reductions were observed in bilateral lateral PMC regions; and in girls reductions were observed in bilateral supplementary motor complex. In line with diagnostic group differences, PMC and PFC SAs were inversely correlated with symptom severity in both girls and boys with ADHD.
These results elucidate sex-based differences in cortical morphology of functional subdivisions of the frontal lobe and provide additional evidence of associations among SA and symptom severity in children with ADHD.
•Children with ADHD showed reductions in cortical surface area.•Boys with ADHD showed overall reductions in total premotor cortex surface area.•Girls with ADHD showed overall reductions in total prefrontal cortex surface area.•Surface area in the ADHD group was associated with symptom severity.
PMCID: PMC4300006  PMID: 25610784
ADHD sex-differences; Cortical morphology; Development; Frontal lobe
5.  The Autism Brain Imaging Data Exchange: Towards Large-Scale Evaluation of the Intrinsic Brain Architecture in Autism 
Molecular psychiatry  2013;19(6):659-667.
Autism spectrum disorders (ASD) represent a formidable challenge for psychiatry and neuroscience because of their high prevalence, life-long nature, complexity and substantial heterogeneity. Facing these obstacles requires large-scale multidisciplinary efforts. While 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) datasets with corresponding structural MRI and phenotypic information from 539 individuals with ASD and 573 age-matched typical controls (TC; 7–64 years) ( Here, we present this resource and demonstrate its suitability for advancing knowledge of ASD neurobiology based on analyses of 360 males with ASD and 403 male age-matched TC. 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, though hypoconnectivity dominated, particularly for cortico-cortical and interhemispheric functional connectivity. Exploratory analyses using an array of regional metrics of intrinsic brain function converged on common loci of dysfunction in ASD (mid and posterior insula, posterior cingulate cortex), and highlighted less commonly explored regions such as thalamus. The survey of the ABIDE R-fMRI datasets provides unprecedented demonstrations of both replication and novel discovery. By pooling multiple international datasets, ABIDE is expected to accelerate the pace of discovery setting the stage for the next generation of ASD studies.
PMCID: PMC4162310  PMID: 23774715
Resting state fMRI; Intrinsic functional connectivity; Data sharing; Large-scale networks; Default network; Interhemispheric connectivity; Thalamus
6.  Connectivity supporting attention in children with attention deficit hyperactivity disorder 
NeuroImage : Clinical  2014;7:68-81.
Intra-subject variability (ISV) is the most consistent behavioral deficit in Attention Deficit Hyperactivity Disorder (ADHD). ISV may be associated with networks involved in sustaining task control (cingulo-opercular network: CON) and self-reflective lapses of attention (default mode network: DMN). The current study examined whether connectivity supporting attentional control is atypical in children with ADHD. Group differences in full-brain connection strength and brain–behavior associations with attentional control measures were examined for the late-developing CON and DMN in 50 children with ADHD and 50 typically-developing (TD) controls (ages 8–12 years).
Children with ADHD had hyper-connectivity both within the CON and within the DMN. Full-brain behavioral associations were found for a number of between-network connections. Across both groups, more anti-correlation between DMN and occipital cortex supported better attentional control. However, in the TD group, this brain–behavior association was stronger and occurred for a more extensive set of DMN–occipital connections. Differential support for attentional control between the two groups occurred with a number of CON–DMN connections. For all CON–DMN connections identified, increased between-network anti-correlation was associated with better attentional control for the ADHD group, but worse attentional control in the TD group. A number of between-network connections with the medial frontal cortex, in particular, showed this relationship. Follow-up analyses revealed that these associations were specific to attentional control and were not due to individual differences in working memory, IQ, motor control, age, or scan motion.
While CON–DMN anti-correlation is associated with improved attention in ADHD, other circuitry supports improved attention in TD children. Greater CON–DMN anti-correlation supported better attentional control in children with ADHD, but worse attentional control in TD children. On the other hand, greater DMN–occipital anti-correlation supported better attentional control in TD children.
•Children with ADHD are hyper-connected within both the CON and DMN.•More DMN–Visual antagonism supports better attention, particularly in controls.•More DMN–CON antagonism supports better attention only in children with ADHD.•CON–DMN compensation for attention may be due to stimulant medication use.
PMCID: PMC4299959  PMID: 25610768
ADHD; Intra-subject variability; Attention; Resting-state connectivity; Network; Default mode network
7.  Performance Lapses in Children with Attention-Deficit/Hyperactivity Disorder Contribute to Poor Reading Fluency 
Children with Attention-Deficit/Hyperactivity Disorder (ADHD) demonstrate increased response variability compared with controls, which is thought to be associated with deficits in attention regulation and response control that subsequently affect performance of more cognitively demanding tasks, such as reading. The present study examined response variability during a computerized simple reaction time (RT) task in 67 children. Ex-Gaussian analyses separated the response time distribution into normal (mu and sigma) and exponential (tau) components; the association of each with reading fluency was examined. Children with ADHD had significantly slower, more variable, and more skewed RTs compared with controls. After controlling for ADHD symptom severity, tau (but not mu or mean RT) was significantly associated with reduced reading fluency, but not with single word reading accuracy. These data support the growing evidence that RT variability, but not simply slower mean response speed, is the characteristic of youth with ADHD and that longer response time latencies (tau) may be implicated in the poorer academic performance associated with ADHD.
PMCID: PMC3807832  PMID: 23838684
Attention; Dyslexia; Variability; Processing speed; Executive function; Ex-Gaussian analyses
8.  Decreased connectivity and cerebellar activity in autism during motor task performance 
Brain  2009;132(9):2413-2425.
Although motor deficits are common in autism, the neural correlates underlying the disruption of even basic motor execution are unknown. Motor deficits may be some of the earliest identifiable signs of abnormal development and increased understanding of their neural underpinnings may provide insight into autism-associated differences in parallel systems critical for control of more complex behaviour necessary for social and communicative development. Functional magnetic resonance imaging was used to examine neural activation and connectivity during sequential, appositional finger tapping in 13 children, ages 8–12 years, with high-functioning autism (HFA) and 13 typically developing (TD), age- and sex-matched peers. Both groups showed expected primary activations in cortical and subcortical regions associated with motor execution [contralateral primary sensorimotor cortex, contralateral thalamus, ipsilateral cerebellum, supplementary motor area (SMA)]; however, the TD group showed greater activation in the ipsilateral anterior cerebellum, while the HFA group showed greater activation in the SMA. Although activation differences were limited to a subset of regions, children with HFA demonstrated diffusely decreased connectivity across the motor execution network relative to control children. The between-group dissociation of cerebral and cerebellar motor activation represents the first neuroimaging data of motor dysfunction in children with autism, providing insight into potentially abnormal circuits impacting development. Decreased cerebellar activation in the HFA group may reflect difficulty shifting motor execution from cortical regions associated with effortful control to regions associated with habitual execution. Additionally, diffusely decreased connectivity may reflect poor coordination within the circuit necessary for automating patterned motor behaviour. The findings might explain impairments in motor development in autism, as well as abnormal and delayed acquisition of gestures important for socialization and communication.
PMCID: PMC2732264  PMID: 19389870
pediatric; movement; neuroimaging; motor learning; development; connections
9.  Functional Magnetic Resonance Imaging Evidence for Abnormalities in Response Selection in Attention Deficit Hyperactivity Disorder: Differences in Activation Associated with Response Inhibition but Not Habitual Motor Response 
Journal of cognitive neuroscience  2008;20(3):478-493.
Impaired response inhibition is thought to be a core deficit in attention deficit hyperactivity disorder (ADHD). Prior imaging studies investigating response inhibition in children with ADHD have used tasks involving different cognitive resources, thereby complicating the interpretation of their findings. In this study, a classical go/no-go task with a well-ingrained stimulus–response association (green = go; red = no-go) was used in order to minimize extraneous cognitive demands. Twenty-five children with ADHD and 25 typically developing (TD) children between the ages of 8 and 13 years and group-matched for IQ and performance on the go/no-go task were studied using event-related functional magnetic resonance imaging (fMRI). Analyses were used to examine differences in activation between the ADHD and TD groups for “go” (habitual motor response) and “no-go” (requiring inhibition of the motor response) events. Region-of-interest analyses revealed no between-group difference in activation in association with “go” events. For “no-go” events, the children with ADHD demonstrated significantly less activation than did TD controls within a network important for inhibiting a motor response to a visual stimulus, with frontal differences localized to the pre-supplementary motor area. Although blood oxygenation level-dependent fMRI data show no differences between children with ADHD and TD children in association with a habituated motor “go” response, during “no-go” events, which require selecting not to respond, children with ADHD show diminished recruitment of networks important for response inhibition. The findings suggest that abnormalities in circuits important for motor response selection contribute to deficits in response inhibition in children with ADHD and lend support to the growing awareness of ADHD-associated anomalies in medial frontal regions important for the control of voluntary actions.
PMCID: PMC2896028  PMID: 18004945
10.  Corpus Callosum Segment Circumference Is Associated With Response Control in Children With Attention-Deficit Hyperactivity Disorder (ADHD) 
Journal of child neurology  2010;25(4):453-462.
Response control is impaired in attention-deficit hyperactivity disorder (ADHD). Given the corpus callosum's role in response control, we compared callosal morphology in 64 children with ADHD and 64 typically developing children, aged 7 to 13 years, and investigated the relationships between callosal morphology and response control. Area and circumference of 5 callosal segments (genu, rostral body, midbody, isthmus, and splenium) were normalized for cerebral volume and examined for correlation with mean reaction time, intrasubject variability, and/or commission error rate from a go/no-go task. There were no between-group differences in segment areas or circumferences. Reaction time correlated with midbody circumference for boys with ADHD and isthmus circumference for girls with ADHD. For the entire cohort, rostral body circumference correlated with intra-subject variability. Impaired response control in ADHD is associated with anomalies in frontal interhemispheric connections. Future studies examining callosal shape will illuminate the anatomic basis of correlations between callosal segment circumference and response control.
PMCID: PMC2892283  PMID: 20139403
ADHD; corpus callosum; white matter; circumference; reaction time; response control
11.  Evidence That the Pattern of Visuomotor Sequence Learning is Altered in Children With Autism 
Motor deficits are commonly reported in autism, with one of the most consistent findings being impaired execution of skilled movements and gestures. Given the developmental nature of autism, it is possible that deficits in motor/procedural learning contribute to impaired acquisition of motor skills. Thus, careful examination of mechanisms underlying learning and memory may be critical to understanding the neural basis of autism. A previous study reported impaired motor learning in children with high-functioning autism (HFA); however, it is unclear whether the observed deficits in motor learning are due, in part, to impaired motor execution and whether these deficits are specific to autism. In order to examine these questions, 153 children (52 with HFA, 39 with attention-deficit/hyperactivity disorder (ADHD) and 62 typically developing (TD) children) participated in two independent experiments using a Rotary Pursuit task, with change in performance across blocks as a measure of learning. For both tasks, children with HFA demonstrated significantly less change in performance than did TD children, even when differences in motor execution were minimized. Differences in learning were not seen between ADHD and TD groups on either experiment. Analyses of the pattern of findings revealed that compared with both ADHD and TD children, children with HFA showed a similar degree of improvement in performance; however, they showed significantly less decrement in performance when presented with an alternate (“interference”) pattern. The findings suggest that mechanisms underlying acquisition of novel movement patterns may differ in children with autism. These findings may help explain impaired skill development in children with autism and help to guide approaches for helping children learn novel motor, social and communicative skills.
PMCID: PMC2892291  PMID: 19360689
procedural memory; declarative memory; cerebellum; visuomotor learning
12.  Abnormal Cerebral Cortex Structure in Children with ADHD 
Human brain mapping  2009;30(1):175-184.
Examination of cerebral cortical structure in children with Attention-Deficit/Hyperactivity Disorder (ADHD) has thus far been principally limited to volume measures. In the current study, an automated surface-based analysis technique was used to examine the ADHD-associated differences in additional morphologic features of cerebral cortical gray matter structure, including surface area, thickness, and cortical folding.
MPRAGE images were acquired from 21 children with ADHD (9 girls) and 35 typically developing controls (15 girls), aged 8–12 years. Statistical difference maps were used to compare mean cortical thickness between groups along the cortical surface. Cortical volume, surface area, mean thickness, and cortical folding were measured within regions of interest, including the right/left hemispheres, frontal, temporal, parietal, and occipital lobes within each hemisphere, and sub-lobar regions.
Children with ADHD showed a decrease in total cerebral volume and total cortical volume of over 7 and 8%, respectively; volume reduction was observed throughout the cortex, with significant reduction in all four lobes bilaterally. The ADHD group also showed a decrease in surface area of over 7% bilaterally, and a significant decrease in cortical folding bilaterally. No significant differences in cortical thickness were detected.
Results from the present study reveal that ADHD is associated with decreased cortical volume, surface area, and folding throughout the cerebral cortex. The findings suggest that decreased cortical folding is a key morphologic feature associated with ADHD. This would be consistent with onset early in neural development and could help to identify neurodevelopmental mechanisms that contribute to ADHD.
PMCID: PMC2883170  PMID: 17985349
MRI; ADHD; cortical folding; gyrification; cortical thickness
13.  A vibrotactile behavioral battery for investigating somatosensory processing in children and adults 
Journal of neuroscience methods  2013;218(1):39-47.
The cortical dynamics of somatosensory processing can be investigated using vibrotactile psychophysics. It has been suggested that different vibrotactile paradigms target different cortical mechanisms, and a number of recent studies have established links between somatosensory cortical function and measurable aspects of behavior. The relationship between cortical mechanisms and sensory function is particularly relevant with respect to developmental disorders in which altered inhibitory processing has been postulated, such as in ASD and ADHD. In this study, a vibrotactile battery consisting of nine tasks (incorporating reaction time, detection threshold, and amplitude- and frequency discrimination) was applied to a cohort of healthy adults and a cohort of typically developing children to assess the feasibility of such a vibrotactile battery in both cohorts, and the performance between children and adults was compared. These results showed that children and adults were both able to perform these tasks with a similar performance, although the children were slightly less sensitive in frequency discrimination. Performance within different task-groups clustered together in adults, providing further evidence that these tasks tap into different cortical mechanisms, which is also discussed. This clustering was not observed in children, which may be potentially indicative of development and a greater variability. In conclusion, in this study, we showed that both children and adults were able to perform an extensive vibrotactile battery, and we showed the feasibility of applying this battery to other (e.g., neurodevelopmental) cohorts to probe different cortical mechanisms.
PMCID: PMC4106128  PMID: 23660524
Vibrotactile; Behavioral; GABA; Pediatric; Somatosensory; Stimulator
14.  Meta-analysis of Go/No-go tasks demonstrating that fMRI activation associated with response inhibition is task-dependent. 
Neuropsychologia  2007;46(1):224-232.
FMRI studies of response inhibition consistently reveal frontal lobe activation. Localization within the frontal cortex, however, varies across studies and appears dependent on the nature of the task. Activation likelihood estimate (ALE) meta-analysis is a powerful quantitative method of establishing concurrence of activation across functional neuroimaging studies. For this study, ALE was used to investigate concurrent neural correlates of successfully inhibited No-go stimuli across studies of healthy adults performing a Go/No-go task, a paradigm frequently used to measure response inhibition. Due to the potential overlap of neural circuits for response selection and response inhibition, the analysis included only event-related studies contrasting No-go activation with baseline, which allowed for inclusion of all regions that may be critical to visually-guided motor response inhibition, including those involved in response selection. These Go/No-go studies were then divided into two groups: “simple” Go/No-go tasks in which the No-go stimulus was always the same, and “complex” Go/No-go tasks, in which the No-go stimulus changed depending on context, requiring frequent updating of stimulus-response associations in working memory. The simple and complex tasks demonstrated distinct patterns of concurrence, with right dorsolateral prefrontal and inferior parietal circuits recruited under conditions of increased working memory demand. Common to both simple and complex Go/No-go tasks was concurrence in the pre-SMA and the left fusiform gyrus. As the pre-SMA has also been shown to be involved in response selection, the results support the notion that the pre-SMA is critical for selection of appropriate behavior, whether selecting to execute an appropriate response or selecting to inhibit an inappropriate response.
PMCID: PMC2327217  PMID: 17850833
activation likelihood estimate; ALE; pre-SMA; response selection
15.  Normal Rates of Neuroradiological Findings in Children with High Functioning Autism 
Magnetic resonance imaging (MRI) has been used to analyze highly specific volumetric and morphological features of the brains of individuals with autism spectrum disorder (ASD). To date, there are few comprehensive studies examining the prevalence of neuroradiologic findings seen on routine MRI scans in children with ASD. This study examined the prevalence of neuroradiologic findings in children with high functioning ASD, and compared these rates to those in children with Attention-Deficit/Hyperactivity Disorder (ADHD) and children who are typically developing (TD). Results showed that approximately 90% of children had normal MRI scans. There was no significant effect of diagnosis on the total number of neuroradiological findings or the number of specific brain findings. Implications and future research directions are discussed.
PMCID: PMC3999957  PMID: 22105143
Autism; Magnetic resonance imaging; Neuroradiological findings
16.  Increased Intrasubject Variability in Boys with ADHD Across Tests of Motor and Cognitive Control 
Increased intrasubject variability (ISV), or short-term, within-person fluctuations in behavioral performance is consistently found in Attention-Deficit/Hyperactivity Disorder (ADHD). ADHD is also associated with impairments in motor control, particularly in boys. The results of the few studies that have examined variability in self-generated motor output in children with ADHD have been inconsistent. The current study examined variability in motor control during a finger sequencing task among boys with and without ADHD as well as the relationship between intrasubject variability during motor and cognitive control tasks. Changes in performance over the course of the task and associations with ADHD symptom domains were also examined to elucidate the nature of impaired motor control in children with ADHD. Fifty-one boys (ages 8 to 12 years) participated in the study, including 28 boys with ADHD and 23 typically developing (TD) boys. Participants completed a finger sequencing task and a Go/No-Go task providing multiple measures of response speed and variability. Boys with ADHD were slower and more variable in both intertap interval on the finger sequencing task and reaction time on the Go/No-Go task, with measures of speed and variability correlated across the two tasks. For the entire cohort, the only unique predictor of parent ratings of hyperactive-impulsive symptoms was variability in intertap interval during finger sequencing, whereas inattentive symptoms were only predicted by reaction time variability on the Go/No-Go task. These findings suggest that inefficient motor control is implicated in the pathophysiology of ADHD, particularly in regards to developmentally inappropriate levels of hyperactivity and impulsivity.
PMCID: PMC3978063  PMID: 23135288
Intrasubject variability; Motor; Cognitive control; Reaction time; ADHD
17.  Altered Connectivity and Action Model Formation in Autism Is Autism 
Internal action models refer to sensory-motor programs that form the brain basis for a wide range of skilled behavior and for understanding others’ actions. Development of these action models, particularly those reliant on visual cues from the external world, depends on connectivity between distant brain regions. Studies of children with autism reveal anomalous patterns of motor learning and impaired execution of skilled motor gestures. These findings robustly correlate with measures of social and communicative function, suggesting that anomalous action model formation may contribute to impaired development of social and communicative (as well as motor) capacity in autism. Examination of the pattern of behavioral findings, as well as convergent data from neuroimaging techniques, further suggests that autism-associated action model formation may be related to abnormalities in neural connectivity, particularly decreased function of long-range connections. This line of study can lead to important advances in understanding the neural basis of autism and, more critically, can be used to guide effective therapies targeted at improving social, communicative, and motor function.
PMCID: PMC3974163  PMID: 21467306
action models; autism; cerebral connectivity; EEG; motor function
18.  Reduced GABA Concentration in Attention-Deficit/Hyperactivity Disorder 
Archives of general psychiatry  2012;69(7):750-753.
Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder characterized by a deficit in behavioral inhibition. Recent evidence also suggests a deficit in cortical inhibition via the GABA (γ-aminobutyric acid)–ergic system.
To investigate the GABAergic component of ADHD using magnetic resonance spectroscopy.
Cross-sectional study.
Participants were recruited through local schools, local pediatric and other community clinics, and through advertisement in regional publications. Magnetic resonance spectroscopy was performed within the research institute.
Children (age range, 8–12 years) in a typically developing control group vs a group with ADHD were compared.
Main Outcome Measures
J-difference–edited magnetic resonance spectroscopy at 3 T was used to measure GABA concentration in a volume that included primary somatosensory and motor cortices.
GABA concentration is reduced in children with ADHD compared with typically developing control subjects.
Our finding of reduced GABA concentration in ADHD is concordant with recently reported deficits in short intracortical inhibition in ADHD and suggests a GABAergic deficit in ADHD.
PMCID: PMC3970207  PMID: 22752239
19.  Analytic Programming with fMRI Data: A Quick-Start Guide for Statisticians Using R 
PLoS ONE  2014;9(2):e89470.
Functional magnetic resonance imaging (fMRI) is a thriving field that plays an important role in medical imaging analysis, biological and neuroscience research and practice. This manuscript gives a didactic introduction to the statistical analysis of fMRI data using the R project, along with the relevant R code. The goal is to give statisticians who would like to pursue research in this area a quick tutorial for programming with fMRI data. References of relevant packages and papers are provided for those interested in more advanced analysis.
PMCID: PMC3938835  PMID: 24586801
20.  Disruption of Functional Organization Within the Primary Motor Cortex in Children With Autism 
Human brain mapping  2012;35(2):567-580.
Accumulating evidence suggests that motor impairments are prevalent in autism spectrum disorder (ASD), relate to the social and communicative deficits at the core of the diagnosis and may reflect abnormal connectivity within brain networks underlying motor control and learning. Parcellation of resting-state functional connectivity data using spectral clustering approaches has been shown to be an effective means of visualizing functional organization within the brain but has most commonly been applied to explorations of normal brain function. This article presents a parcellation of a key area of the motor network, the primary motor cortex (M1), a key area of the motor control network, in adults, typically developing (TD) children and children with ASD and introduces methods for selecting the number of parcels, matching parcels across groups and testing group differences. The parcellation is based solely on patterns of connectivity between individual M1 voxels and all voxels outside of M1, and within all groups, a gross dorsomedial to ventrolateral organization emerged within M1 which was left–right symmetric. Although this gross organizational scheme was present in both groups of children, statistically significant group differences in the size and segregation of M1 parcels within regions of the motor homunculus corresponding to the upper and lower limbs were observed. Qualitative comparison of the M1 parcellation for children with ASD with that of younger and older TD children suggests that these organizational differences, with a lack of differentiation between lower limb/trunk regions and upper limb/hand regions, may be due, at least in part, to a delay in functional specialization within the motor cortex.
PMCID: PMC3864146  PMID: 23118015
resting state; functional connectivity; clustering; motor cortex; autistic disorder
21.  Developmental Changes In Within- and Between-Network Connectivity Between Late Childhood and Adulthood 
Neuropsychologia  2012;51(1):156-167.
A number of behavioral changes occur between late childhood and adulthood, including maturation of social cognition, reward receptivity, impulsiveness, risk-taking and cognitive control. Although some of these abilities show linear improvements with age, some abilities may temporarily worsen, reflecting both the restructuring and/or strengthening of connections within some brain systems. The current study uses resting state functional connectivity to examine developmental differences between late childhood and adulthood in task positive (TP) regions, which play a role in cognitive control functions, and task negative (TN) regions, which play a role in social cognition, self-referential, and internally-directed thought. Within the TP network, developmental differences in connectivity were found with the left dorsolateral prefrontal cortex. Within the TN network, developmental differences in connectivity were found with a broad area of the medial prefrontal cortex and the right parahippocampal gyrus. Connections between the two networks also showed significant developmental differences. Stronger anticorrelations were found in the TN maps of the adult group for the right anterior insula/inferior frontal gyrus, bilateral anterior inferior parietal lobule, bilateral superior parietal lobule and an anterior portion of the right posterior cingulate cortex. There was a significant brain-behavior relationship between the strength of anticorrelation in these regions and inhibitory control performance on two Go/No-go tasks suggesting that the development of anticorrelations between late childhood and adulthood supports mature inhibitory control. Overall, maturation of these networks occurred in specific regions which are associated with cognitive control of goal-directed behavior, including those involved in working memory, social cognition, and inhibitory control.
PMCID: PMC3543510  PMID: 23174403
development; resting-state connectivity; network; anticorrelation; response inhibition; cognitive control
22.  Transcranial Magnetic Stimulation Measures in Attention-Deficit/Hyperactivity Disorder 
Pediatric neurology  2012;47(3):177-185.
Children affected by Attention-Deficit/Hyperactivity Disorder have diminished intra-hemispheric inhibition (Short Interval Cortical Inhibition) as measured by Transcranial Magnetic Stimulation. This study’s objective is to determine whether inter-hemispheric inhibition (Ipsilateral Silent Period Latency) correlates with clinical behavioral rating and motor control deficits of affected children. In 114 8–12 year old, right-handed children (age/sex-matched, 50 affected, 64 controls), we performed comprehensive assessments of behavior, motor skills and cognition. Using Transcranial Magnetic Stimulation, we reliably elicited Ipsilateral Silent Period in 54 children (23 affected) - all were on average older than those who had unobtainable measures. Mean Ipsilateral Silent Period latency was 5 milliseconds longer in the affected group (p=0.007). Longer latencies correlated with more severe behavioral symptom scores (r=0.38, p=0.007), particularly hyperactivity (r=0.39, p=0.006), as well as with worse motor ratings on the Physical and Neurological Examination for Soft Signs (r=0.27, p=0.05). Longer latency also correlated with Short Interval Cortical Inhibition (r=0.36, p=0.008). In conclusion, longer Ipsilateral Silent Period latencies suggest interhemispheric inhibitory signaling is slower in affected children. The deficit in this inhibitory measure may underlie developmental, behavioral and motor impairments in children with Attention-Deficit/Hyperactivity Disorder.
PMCID: PMC3418513  PMID: 22883282
23.  Effects of Working Memory Demand on Neural Mechanisms of Motor Response Selection and Control 
Journal of cognitive neuroscience  2013;25(8):1235-1248.
Inhibitory control commonly recruits a number of frontal regions: pre-supplementary motor area (pre-SMA), frontal eye fields (FEFs), and right-lateralized posterior inferior frontal gyrus (IFG), dorsal anterior insula (DAI), dorsolateral prefrontal cortex (DLPFC), and inferior frontal junction (IFJ). These regions may directly implement inhibitory motor control or may be more generally involved in executive control functions. Two go/no-go tasks were used to distinguish regions specifically recruited for inhibition from those that additionally show increased activity with working memory demand. The pre-SMA and IFG were recruited for inhibition in both tasks and did not have greater activation for working memory demand on no-go trials, consistent with a role in inhibitory control. Activation in pre-SMA also responded to response selection demand and was increased with working memory on go trials specifically. The bilateral FEF and right DAI were commonly active for no-go trials. The FEF was also recruited to a greater degree with working memory demand on go trials and may bias top–down information when stimulus–response mappings change. The DAI, additionally responded to increased working memory demand on both go and no-go trials and may be involved in accessing sustained task information, alerting, or autonomic changes when cognitive demands increase. DLPFC activation was consistent with a role in working memory retrieval on both go and no-go trials. The inferior frontal junction, on the other hand, had greater activation with working memory specifically for no-go trials and may detect salient stimuli when the task requires frequent updating of working memory representations.
PMCID: PMC3743681  PMID: 23530923
24.  Motor Learning Relies on Integrated Sensory Inputs in ADHD, but Over-Selectively on Proprioception in Autism Spectrum Conditions 
Autism Research  2012;5(2):124-136.
Lay Abstract
Children with autism spectrum disorder (ASD) show deficits in development of motor skills, in addition to core deficits in social skill development. In a previous study (Haswell et al., 2009) we found that children with autism show a key difference in how they learn motor actions, with a bias for relying on joint position rather than visual feedback; further, this pattern of motor learning predicted impaired motor, imitation and social abilities. We were interested in finding out whether this altered motor learning pattern was specific to autism. To do so, we examined children with Attention Deficit Hyperactivity Disorder (ADHD), who also show deficits in motor control. Children learned a novel movement and we measured rates of motor learning, generalization patterns of motor learning, and variability of motor speed during learning. We found children with ASD show a slower rate of learning and, consistent with previous findings, an altered pattern of generalization that was predictive of impaired motor, imitation, and social impairment. In contrast, children with ADHD showed a normal rate of learning and a normal pattern of generalization; instead, they (and they alone), showed excessive variability in movement speed. The findings suggest that there is a specific pattern of altered motor learning associated with autism.
Scientific Abstract
The brain builds an association between action and sensory feedback to predict the sensory consequence of self-generated motor commands. This internal model of action is central to our ability to adapt movements, and may also play a role in our ability to learn from observing others. Recently we reported that the spatial generalization patterns that accompany adaptation of reaching movements were distinct in children with Autism Spectrum Disorder (ASD) as compared to typically developing (TD) children. To test whether the generalization patterns are specific to ASD, here we compared the patterns of adaptation to those in children with Attention Deficit Hyperactivity Disorder (ADHD). Consistent with our previous observations, we found that in ASD the motor memory showed greater than normal generalization in proprioceptive coordinates compared with both TD children and children with ADHD; children with ASD also showed slower rates of adaptation compared with both control groups. Children with ADHD did not show this excessive generalization to the proprioceptive target, but did show excessive variability in the speed of movements with an increase in the exponential distribution of responses (τ) as compared with both TD children and children with ASD. The results suggest that slower rate of adaptation and anomalous bias towards proprioceptive feedback during motor learning is characteristic of autism; whereas increased variability in execution is characteristic of ADHD.
PMCID: PMC3329587  PMID: 22359275
25.  Comprehensive Examination of Frontal Regions in Boys and Girls with Attention-Deficit/Hyperactivity Disorder 
The current study examined regional frontal lobe volumes based on functionally relevant subdivisions in contemporaneously recruited samples of boys and girls with and without attention-deficit/hyperactivity disorder (ADHD). Forty-four boys (21 ADHD, 23 control) and 42 girls (21 ADHD, 21 control), ages 8–13 years, participated. Sulcal–gyral landmarks were used to manually delimit functionally relevant regions within the frontal lobe: primary motor cortex, anterior cingulate, deep white matter, premotor regions [supplementary motor complex (SMC), frontal eye field, lateral premotor cortex (LPM)], and prefrontal cortex (PFC) regions [medial PFC, dorsolateral PFC (DLPFC), inferior PFC, lateral orbitofrontal cortex (OFC), and medial OFC]. Compared to sex-matched controls, boys and girls with ADHD showed reduced volumes (gray and white matter) in the left SMC. Conversely, girls (but not boys) with ADHD showed reduced gray matter volume in left LPM; while boys (but not girls) with ADHD showed reduced white matter volume in left medial PFC. Reduced left SMC gray matter volumes predicted increased go/no–go commission rate in children with ADHD. Reduced left LPM gray matter volumes predicted increased go/no–go variability, but only among girls with ADHD. Results highlight different patterns of anomalous frontal lobe development among boys and girls with ADHD beyond that detected by measuring whole lobar volumes.
PMCID: PMC3534734  PMID: 21923979
Segmentation; Premotor; Prefrontal; Supplementary Motor Complex (SMC); Pre-SMA; Gender; Sex; Childhood

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