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1.  Distinct frontal lobe morphology in girls and boys with ADHD 
NeuroImage : Clinical  2014;7:222-229.
Objective
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.
Method
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.
Results
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.
Conclusions
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.
Highlights
•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.
doi:10.1016/j.nicl.2014.12.010
PMCID: PMC4300006  PMID: 25610784
ADHD sex-differences; Cortical morphology; Development; Frontal lobe
2.  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.
doi:10.1093/arclin/act048
PMCID: PMC3807832  PMID: 23838684
Attention; Dyslexia; Variability; Processing speed; Executive function; Ex-Gaussian analyses
3.  Jitter Reduces Response-Time Variability in ADHD: An Ex-Gaussian Analysis 
Journal of attention disorders  2012;10.1177/1087054712464269.
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.
doi:10.1177/1087054712464269
PMCID: PMC3600392  PMID: 23190614
ADHD; executive function; attention; variability; response time; statistics; ex-Gaussian; jitter
4.  fMRI of Intrasubject Variability in ADHD: Anomalous Premotor Activity With Prefrontal Compensation 
Objective
Children with attention-deficit/hyperactivity disorder (ADHD) consistently display increased intrasubject variability (ISV) in response time across varying tasks, signifying inefficiency of response preparation compared to typically developing (TD) children. Children with ADHD also demonstrate impaired response inhibition; inhibitory deficits correlate with ISV, suggesting that similar brain circuits may underlie both processes. To better understand the neural mechanisms underlying increased ISV and inhibitory deficits in children with ADHD, functional magnetic resonance imaging was used to examine the neural correlates of ISV during Go/No-go task performance.
Method
Event-related functional magnetic resonance imaging was used to study 25 children with ADHD and 25 TD children ages 8 to 13 years performing a simplified Go/No-go task. Brain-behavior correlations were examined between functional magnetic resonance imaging activation and ISV within and between groups.
Results
For TD children, increased rostral supplementary motor area (pre–supplementary motor area) activation during No-go events was associated with less ISV, whereas the reverse was true for children with ADHD for whom increased pre–supplementary motor area activation was associated with more ISV. In contrast, children with ADHD with less ISV showed greater prefrontal activation, whereas TD children with more prefrontal activation demonstrated more ISV.
Conclusions
These findings add to evidence that dysfunction of premotor systems may contribute to increased variability and impaired response inhibition in children with ADHD and that compensatory strategies eliciting increased cognitive control may improve function. However, recruitment of prefrontal resources as a compensatory mechanism for motor task performance may preclude the use of those prefrontal resources for higher order, more novel executive functions with which children with ADHD often struggle.
doi:10.1097/CHI.0b013e3181825b1f
PMCID: PMC3932630  PMID: 18724253
attention-deficit/hyperactivity disorder; intrasubject variability; response inhibition
5.  Children with High Functioning Autism show increased prefrontal and temporal cortex activity during error monitoring 
Evidence exists for deficits in error monitoring in autism. These deficits may be particularly important because they may contribute to excessive perseveration and repetitive behavior in autism. We examined the neural correlates of error monitoring using fMRI in 8–12-year-old children with high-functioning autism (HFA, n=11) and typically developing children (TD, n=15) during performance of a Go/No-Go task by comparing the neural correlates of commission errors versus correct response inhibition trials. Compared to TD children, children with HFA showed increased BOLD fMRI signal in the anterior medial prefrontal cortex (amPFC) and the left superior temporal gyrus (STempG) during commission error (versus correct inhibition) trials. A follow-up region-of-interest analysis also showed increased BOLD signal in the right insula in HFA compared to TD controls. Our findings of increased amPFC and STempG activity in HFA, together with the increased activity in the insula, suggest a greater attention towards the internally-driven emotional state associated with making an error in children with HFA. Since error monitoring occurs across different cognitive tasks throughout daily life, an increased emotional reaction to errors may have important consequences for early learning processes.
doi:10.1016/j.dcn.2010.07.002
PMCID: PMC2999812  PMID: 21151713
error; response monitoring; autism; children; fmri
6.  White matter microstructural differences linked to left perisylvian language network in children with dyslexia 
Studies of dyslexia using diffusion tensor imaging (DTI) have reported fractional anisotropy (FA) differences in left inferior frontal gyrus (LIFG) and left temporo-parietal white matter, suggesting that impaired reading is associated with atypical white matter microstructure in these regions. These anomalies might reflect abnormalities in the left perisylvian language network, long implicated in dyslexia. While DTI investigations frequently report analyses on multiple tensor-derived measures (e.g., FA, orientation, tractography), it is uncommon to integrate analyses to examine the relationships between atypical findings. For the present study, semi-automated techniques were applied to DTI data in an integrated fashion to examine white matter microstructure in 14 children with dyslexia and 17 typically developing readers (ages 7-16 years). Correlations of DTI metrics (FA and fiber orientation) to reading skill (accuracy and speed) and to probabilistic tractography maps of the left perisylvian language tracts were examined. Consistent with previous reports, our findings suggest FA decreases in dyslexia in LIFG and left temporo-parietal white matter. The LIFG FA finding overlaps an area showing differences in fiber orientation in an anterior left perisylvian language pathway. Additionally,a positive correlation of FA to reading speed was found in a posterior circuit previously associated with activation on functional imaging during reading tasks. Overall, integrating results from several complementary semi-automated analyses reveals evidence linking atypical white matter microstructure in dyslexia to atypical fiber orientation in circuits implicated in reading including the left perisylvian language network.
doi:10.1016/j.cortex.2009.07.008
PMCID: PMC2847658  PMID: 19682675
dyslexia; perisylvian language network; left inferior frontal gyrus; diffusion tensor imaging; fractional anisotropy
7.  A dual DTI approach to analyzing white matter in children with dyslexia 
Psychiatry research  2009;172(3):215-219.
Using voxel-based (VBA) and region-of-interest (ROI) diffusion tensor imaging (DTI) analyses, we examined white matter (WM) organization in 7 children with dyslexia and 6 age-matched controls. Both methods demonstrated reduced fractional anisotropy (FA) in the left superior longitudinal fasciculus (SLF) and abnormal orientation in the right SLF in dyslexics. Application of this complementary dual DTI approach to dyslexia, which included novel analyses of fiber orientation, demonstrates its usefulness for analyzing mild and complex WM abnormalities.
doi:10.1016/j.pscychresns.2008.09.005
PMCID: PMC2720547  PMID: 19346108
reading disability; anisotropy; superior longitudinal fasciculus
8.  Multiple Task Interference is Greater in Children with ADHD 
Developmental Neuropsychology  2012;37(2):119-133.
There is considerable lay discussion that children with Attention-Deficit/Hyperactivity Disorder (ADHD) have increased difficult with multitasking, but there are few experimental data. In the current study, we examine the simultaneous processing of two stimulus-response tasks using the psychological refractory period (PRP) effect. We hypothesized that children with ADHD would show a greater PRP effect, suggesting a prolonged “bottleneck” in stimulus-response processing. A total of 19 school-aged children with ADHD showed a prolonged PRP effect compared with 25 control children, suggesting a higher cognitive cost in ADHD for multi-tasking.
doi:10.1080/87565641.2011.632459
PMCID: PMC3313619  PMID: 22339226
Multi-tasking; Executive Function; ADHD; Processing Speed; Psychological Refractory Period
9.  Factor structure of paediatric timed motor examination and its relationship with IQ 
AIM
Brain systems supporting higher cognitive and motor control develop in a parallel manner, dependent on functional integrity and maturation of related regions, suggesting neighbouring neural circuitry. Concurrent examination of motor and cognitive control can provide a window into neurological development. However, identification of performance-based measures that do not correlate with IQ has been a challenge.
METHOD
Timed motor performance from the Physical and Neurological Examination of Subtle Signs and IQ were analysed in 136 children aged 6 to 16 (mean age 10y 2.6mo, SD 2y 6.4mo; 98 female, 38male) attending an outpatient neuropsychology clinic and 136 right-handed comparison individuals aged 6 to 16 (mean age 10y 3.1mo, SD 2y 6.1mo; 98 female, 38male). Timed activities – three repetitive movements (toe tapping, hand patting, finger tapping) and three sequenced movements (heel–toe tap, hand pronate/supinate, finger sequencing) each performed on the right and left – were included in exploratory factor analyses.
RESULTS
Among comparison individuals, factor analysis yielded two factors – repetitive and sequenced movements – with the sequenced factor significantly predictive of Verbal IQ (VIQ) (ΔR2=0.018, p=0.019), but not the repetitive factor (ΔR2=0.004, p=0.39). Factor analysis within the clinical group yielded two similar factors (repetitive and sequenced), both significantly predictive of VIQ, (ΔR2=0.028, p=0.015; ΔR2=0.046, p=0.002 respectively).
INTERPRETATION
Among typical children, repetitive timed tasks may be independent of IQ; however, sequenced tasks share more variance, implying shared neural substrates. Among neurologically vulnerable populations, however, both sequenced and repetitive movements covary with IQ, suggesting that repetitive speed is more indicative of underlying neurological integrity.
doi:10.1111/j.1469-8749.2010.03670.x
PMCID: PMC3534928  PMID: 20412260
10.  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.
doi:10.1017/S1355617711001056
PMCID: PMC3534734  PMID: 21923979
Segmentation; Premotor; Prefrontal; Supplementary Motor Complex (SMC); Pre-SMA; Gender; Sex; Childhood
11.  Increased Regional Fractional Anisotropy in Highly Screened Attention-Deficit Hyperactivity Disorder (ADHD) 
Journal of child neurology  2011;26(10):1296-1302.
Diffusion tensor imaging data were collected at 3.0 Tesla from 16 children with attention-deficit hyperactivity disorder (ADHD) and 16 typically developing controls, ages 9 to 14 years. Fractional anisotropy images were calculated and normalized by linear transformation. Voxel-wise and atlas-based region-of-interest analyses were performed. Using voxel-wise analysis, fractional anisotropy was found to be significantly increased in the attention-deficit hyperactivity disorder group in the right superior frontal gyrus and posterior thalamic radiation, and left dorsal posterior cingulate gyrus, lingual gyrus, and parahippocampal gyrus. No regions showed significantly decreased fractional anisotropy in attention-deficit hyperactivity disorder. Region-of-interest analysis revealed increased fractional anisotropy in the left sagittal stratum, that is, white matter that connects the temporal lobe to distant cortical regions. Only fractional anisotropy in the left sagittal stratum was significantly associated with attention-deficit hyperactivity disorder symptom severity. Several recent studies have reported pathological increases in fractional anisotropy in other conditions, highlighting the relevance of diffusion tensor imaging in identifying atypical white matter structure associated with neurodevelopmental processes.
doi:10.1177/0883073811405662
PMCID: PMC3526818  PMID: 21628699
attention-deficit hyperactivity disorder (ADHD); development; cognitive; diffusion tensor imaging; magnetic resonance imaging (MRI)
12.  Working Memory Influences Processing Speed and Reading Fluency in ADHD 
Child Neuropsychology  2011;17(3):209-224.
Processing speed deficits affect reading efficiency, even among individuals who recognize and decode words accurately. Children with ADHD who decode words accurately can still have inefficient reading fluency, leading to a bottleneck in other cognitive processes. This “slowing” in ADHD is associated with deficits in fundamental components of executive function underlying processing speed, including response selection. The purpose of the present study was to deconstruct processing speed in order to determine which components of executive control best explain the “processing” speed deficits related to reading fluency in ADHD. Participants (41 ADHD, 21 controls), ages 9-14, screened for language disorders, word reading deficits, and psychiatric disorders, were administered measures of copying speed, processing speed, reading fluency, working memory, reaction time, inhibition, and auditory attention span. Compared to controls, children with ADHD showed reduced oral and silent reading fluency, and reduced processing speed—driven primarily by deficits on WISC-IV Coding. In contrast, groups did not differ on copying speed. After controlling for copying speed, sex, severity of ADHD-related symptomatology, and GAI, slowed “processing” speed (i.e., Coding) was significantly associated with verbal span and measures of working memory, but not with measures of response control/inhibition, lexical retrieval speed, reaction time, or intra-subject variability. Further, “processing” speed (i.e., Coding, residualized for copying speed) and working memory were significant predictors of oral reading fluency. Abnormalities in working memory and response selection (which are frontally-mediated and enter into the output side of processing speed) may play an important role in deficits in reading fluency in ADHD, potentially more than posteriorally-mediated problems with orienting of attention or perceiving the stimulus.
doi:10.1080/09297049.2010.532204
PMCID: PMC3309419  PMID: 21287422
Reading; Attention; Child; Dyslexia; Fluency; Working Memory; Executive Function
13.  Neuropsychological Profile of Executive Function in Girls with Attention-Deficit/Hyperactivity Disorder 
The majority of research on neurobehavioral functioning among children with Attention-Deficit/Hyperactivity Disorder (ADHD) is based on samples comprised primarily (or exclusively) of boys. Although functional impairment is well established, available research has yet to specify a neuropsychological profile distinct to girls with ADHD. The purpose of this study was to examine performance within four components of executive function (EF) in contemporaneously recruited samples of girls and boys with ADHD. Fifty-six children with ADHD (26 girls) and 90 controls (42 girls), ages 8–13, were administered neuropsychological tests emphasizing response inhibition, response preparation, working memory, and planning/shifting. There were no significant differences in age or SES between boys or girls with ADHD or their sex-matched controls; ADHD subtype distribution did not differ by sex. Compared with controls, children with ADHD showed significant deficits on all four EF components. Girls and boys with ADHD showed similar patterns of deficit on tasks involving response preparation and working memory; however, they manifested different patterns of executive dysfunction on tasks related to response inhibition and planning. Girls with ADHD showed elevated motor overflow, while boys with ADHD showed greater impairment during conscious, effortful response inhibition. Girls, but not boys with ADHD, showed impairment in planning. There were no differences between ADHD subtypes on any EF component. These findings highlight the importance of studying boys and girls separately (as well as together) when considering manifestations of executive dysfunction in ADHD.
doi:10.1093/arclin/acq050
PMCID: PMC2957961  PMID: 20639299
Attention; Response control; Working memory; Inhibition; Planning; Childhood; Development
14.  Oculomotor Anomalies in Attention-Deficit/Hyperactivity Disorder: Evidence for Deficits in Response Preparation and Inhibition 
Objective
To examine patterns of executive and oculomotor control in a group of both boys and girls with attention-deficit/hyperactivity disorder (ADHD).
Method
Cross-sectional study of 120 children aged 8 to 12 years, including 60 with ADHD (24 girls) and 60 typically developing controls (29 girls). Oculomotor paradigms included visually guided saccades (VGS), antisaccades, memory-guided saccades, and a go/no-go test, with variables of interest emphasizing response preparation, response inhibition, and working memory.
Results
As a group, children with ADHD demonstrated significant deficits in oculomotor response preparation (VGS latency and variability) and response inhibition but not working memory. Girls, but not boys with ADHD, had significantly longer VGS latencies, even after controlling for differences in ADHD symptom severity. The ADHD subtypes did not differ on response preparation or inhibition measures; however, children with the Inattentive subtype were less accurate on the working memory task than those with the Combined subtype.
Conclusions
Sex differences in children with ADHD extend beyond symptom presentation to the development of oculomotor control. Saccade latency may represent a specific deficit among girls with ADHD.
doi:10.1097/CHI.0b013e3181a565f1
PMCID: PMC3065070  PMID: 19465877
eye movement; inhibitory control; executive function; visual attention; frontal
15.  Toward a Narrower, More Pragmatic View of Developmental Dyspraxia 
Journal of child neurology  2010;25(1):71-81.
Apraxia traditionally refers to impaired ability to carry out skilled movements in the absence of fundamental sensorimotor, language, or general cognitive impairment sufficient to preclude them. The child neurology literature includes a much broader and varied usage of the term developmental dyspraxia. It has been used to describe a wide range of motor symptoms, including clumsiness and general coordination difficulties, in various developmental disorders (including autistic spectrum disorders, developmental language disorders, and perinatal stroke). We argue for the need to restrict use of the term developmental dyspraxia to describe impaired performance of skilled gestures, recognizing that, unlike acquired adult-onset apraxia, coexisting sensory and motor problems may also be present.
doi:10.1177/0883073809342591
PMCID: PMC2892896  PMID: 20032517
dyspraxia; ideomotor apraxia; limb-kinetic apraxia; motor skills; developmental coordination disorder; autistic disorder; developmental language disorders
16.  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.
doi:10.1162/jocn.2008.20032
PMCID: PMC2896028  PMID: 18004945
17.  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.
doi:10.1177/0883073809350221
PMCID: PMC2892283  PMID: 20139403
ADHD; corpus callosum; white matter; circumference; reaction time; response control
18.  Basal Ganglia Volume and Shape in Children With Attention Deficit Hyperactivity Disorder 
Objective
Volumetric abnormalities of basal ganglia have been associated with attention deficit hyperactivity disorder (ADHD), especially in boys. To specify localization of these abnormalities, large deformation diffeomorphic metric mapping (LDDMM) was used to examine the effects of ADHD, sex, and their interaction on basal ganglia shapes.
Method
The basal ganglia (caudate, putamen, globus pallidus) were manually delineated on magnetic resonance imaging from 66 typically developing children (35 boys) and 47 children (27 boys) with ADHD. LDDMM mappings from 35 typically developing children were used to generate basal ganglia templates. Shape variations of each structure relative to the template were modeled for each subject as a random field using Laplace-Beltrami basis functions in the template coordinates. Linear regression was used to examine group differences in volumes and shapes of the basal ganglia.
Results
Boys with ADHD showed significantly smaller basal ganglia volumes compared with typically developing boys, and LDDMM revealed the groups remarkably differed in basal ganglia shapes. Volume compression was seen bilaterally in the caudate head and body and anterior putamen as well as in the left anterior globus pallidus and right ventral putamen. Volume expansion was most pronounced in the posterior putamen. No volume or shape differences were revealed in girls with ADHD.
Conclusions
The shape compression pattern of basal ganglia in boys with ADHD suggests that ADHD-associated deviations from typical brain development involve multiple frontal-subcortical control loops, including circuits with premotor, oculomotor, and prefrontal cortices. Further investigations employing brain-behavior analyses will help to discern the task-dependent contributions of these circuits to impaired response control that is characteristic of ADHD.
doi:10.1176/appi.ajp.2008.08030426
PMCID: PMC2890266  PMID: 19015232
19.  Abnormal Cerebral Cortex Structure in Children with ADHD 
Human brain mapping  2009;30(1):175-184.
Objective
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1002/hbm.20496
PMCID: PMC2883170  PMID: 17985349
MRI; ADHD; cortical folding; gyrification; cortical thickness
20.  Interstimulus jitter facilitates response control in children with ADHD 
Interstimulus “jitter” involves randomization of intervals between successive stimulus events, and can facilitate performance on go/no-go tests among healthy adults, though its effect in clinical populations is unclear. Children with Attention-deficit/Hyperactivity Disorder (ADHD) commonly exhibit deficient response control, leading to increased intra-subject variability (ISV), which has been linked to anomalous functioning within frontal circuits, as well as their interaction with posterior “default mode” regions. We examined effects of interstimulus jitter on response variability in 39 children, ages 9–14 years (25 ADHD, 14 controls). Participants completed 2 computerized go/no-go tests: one with fixed interstimulus interval (ISI) and one with jittered ISI. Repeated measures analysis of variance (ANOVA) revealed a significant group-by test interaction, such that introduction of jitter produced a significant decrease in ISV among children with ADHD, but not among controls. Whereas children with ADHD were significantly more variable than controls on the go/no-go test with fixed ISI, their performance with jittered ISI was equivalent to that of controls. Jittering stimulus presentation provides a nonpharmacologic mechanism for improving response control in ADHD. This bottom-up approach may be mediated by increases in vigilance through noradrenergic circuits that facilitate maintenance of frontal circuits critical to response control.
doi:10.1017/S1355617709991305
PMCID: PMC2827644  PMID: 20003583
Executive function; Childhood; Variability; Attention; Continuous performance test; Noradrenergic; Locus ceruleus
21.  Response variability in rapid automatized naming predicts reading comprehension 
A total of 37 children ages 8 to 14 years, screened for word-reading difficulties (23 with attention-deficit/hyperactivity disorder, ADHD; 14 controls) completed oral reading and rapid automatized naming (RAN) tests. RAN trials were segmented into pause and articulation time and intraindividual variability. There were no group differences on reading or RAN variables. Color- and letter-naming pause times and number-naming articulation time were significant predictors of reading fluency. In contrast, number and letter pause variability were predictors of comprehension. Results support analysis of subcomponents of RAN and add to literature emphasizing intraindividual variability as a marker for response preparation, which has relevance to reading comprehension.
doi:10.1080/13803390802646973
PMCID: PMC2829106  PMID: 19221923
Reading; Attention-deficit/hyperactivity disorder; Dyslexia; Comprehension; Executive function; Variability
22.  Evidence for Impairments in Using Static Line Drawings of Eye Gaze Cues to Orient Visual-Spatial Attention in Children with High Functioning Autism 
We examined the ability to use static line drawings of eye gaze cues to orient visual-spatial attention in children with high functioning autism (HFA) compared to typically developing children (TD). The task was organized such that on valid trials, gaze cues were directed toward the same spatial location as the appearance of an upcoming target, while on invalid trials gaze cues were directed to an opposite location. Unlike TD children, children with HFA showed no advantage in reaction time (RT) on valid trials compared to invalid trials (i.e., no significant validity effect). The two stimulus onset asynchronies (200 ms, 700 ms) did not differentially affect these findings. The results suggest that children with HFA show impairments in utilizing static line drawings of gaze cues to orient visual-spatial attention.
doi:10.1007/s10803-007-0506-x
PMCID: PMC2693327  PMID: 18074212
Eye gaze; High functioning autism; Orienting; Attention; Cueing
23.  Prediction of ADHD in Boys and Girls Using the D-KEFS 
To examine patterns of executive dysfunction associated with ADHD, 123 children (54 ADHD, 69 controls) ages 8–16 years were administered selected subtests from the Delis-Kaplan Executive Function System (D-KEFS). Children with ADHD performed significantly worse than controls on measures of both basic (less executive demand) skills and those with more executive demand from the Color-Word Interference and Tower subtests; however, no group differences were noted on any of the D-KEFS contrast scores. Most subtype comparisons yielded no differences; however, children with the Combined subtype outperformed children with the Inattentive subtype on measures of both basic and executive skills from the Trail Making Test. Children with ADHD demonstrate executive dysfunction that is identified by both D-KEFS summary, but not contrast scores. In this carefully screened sample of children with ADHD, few significant differences were found between groups suggesting limited sensitivity or specificity of the D-KEFS for classifying children with ADHD.
doi:10.1016/j.acn.2007.12.004
PMCID: PMC2427435  PMID: 18243646
ADHD; Subtype; Executive Function; Classification; Children; Pediatrics
24.  PROCESS EXAMINATION OF EXECUTIVE FUNCTION IN ADHD: SEX AND SUBTYPE EFFECTS 
The Clinical neuropsychologist  2008;22(5):826-841.
To examine effects of group (Attention-Deficit/Hyperactivity Disorder [ADHD] versus Typically Developing [TD]), sex, and ADHD subtype on “process/optional” measures of executive functioning, children (n = 123; 54 ADHD, 69 TD) aged 8−16 completed subtests from the D-KEFS. No group, sex, or ADHD subtype effects were found on optional measures from the Trail Making, Color–Word Interference, and Tower tests. A significant interaction was found for Verbal Fluency Total Repetition Errors; boys with Combined/Hyperactive-Impulsive (ADHD-C/HI) type ADHD performed better than ADHD-C/HI girls, whereas girls with Inattentive type ADHD (ADHD-I) performed better than ADHDI boys. Overall, children with ADHD did not differ from TD on most optional measures from the D-KEFS. When sex and ADHD subtype were considered, children with the subtype of ADHD less common for sex were at greater risk for poorer performance.
doi:10.1080/13854040701563583
PMCID: PMC2575661  PMID: 18609314
Process approach; ADHD; Executive function; D-KEFS
25.  LEFT-RIGHT DIFFERENCES ON TIMED MOTOR EXAMINATION IN CHILDREN 
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.
doi:10.1080/09297040701370016
PMCID: PMC2564283  PMID: 17852124
Motor; PANESS; Laterality; Gender; Corpus callosum

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