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1.  Oculomotor Anomalies in Attention-Deficit/Hyperactivity Disorder: Evidence for Deficits in Response Preparation and Inhibition 
To examine patterns of executive and oculomotor control in a group of both boys and girls with attention-deficit/hyperactivity disorder (ADHD).
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.
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.
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.
PMCID: PMC3065070  PMID: 19465877
eye movement; inhibitory control; executive function; visual attention; frontal
2.  Moment-to-moment dynamics of ADHD behaviour in South African children 
The behaviour of children with Attention-Deficit/Hyperactivity Disorder is characterized by low predictability of responding. Low behavioural predictability is one way of operationalizing intra-individual ADHD-related variability. ADHD-related variability may be caused by inefficient behavioural selection mechanisms linked to reinforcement and extinction, as suggested by the recently published dynamic developmental theory (DDT) of ADHD. DDT argues that ADHD is a basic neurobehavioural disorder, caused by dysfunctioning dopamine systems. For establishing ADHD as a neurobehavioural disorder, findings from studies conducted in Western countries should be replicated in other cultural populations. The present study replicated the study conducted in Norway, with children from the Limpopo province in the Republic of South Africa.
Boys and girls, aged 6–9 yr, from seven ethnic groups participated. Scores by teachers on the Disruptive Behavior Disorders rating scale defined participation in either ADHD-hyperactive/impulsive (-HI), ADHD-predominantly inattentive (-PI), or ADHD-combined (-C) groups. Children below the 86th percentile were matched on gender and age and comprised the non-ADHD group. The children completed a computerized game-like task where mouse clicks on one of two squares on the screen resulted in delivery of a reinforcer according to a variable interval schedule of reinforcement. Reinforcers were cartoon pictures presented on the screen together with a sound. Predictability of response location and timing were measured in terms of explained variance.
Overall, the results replicated findings from Norway. Specifically, the ADHD-C group showed significantly lower predictability of responding than the non-ADHD group, while the ADHD-HI and the ADHD-PI groups were in-between. In accordance with the previous study, response location, but not response timing, was a sensitive behavioural measure. There were no significant gender differences. Cartoon pictures were effective reinforcers as the non-ADHD group showed learning of the task. There was no relation between behavioural predictability and motor functions.
The present study makes a strong case for ADHD as a basic, neurobehavioural disorder, not a cultural phenomenon, by replicating findings from a wealthy Western country in a poor province of a developing country. The results were, generally, in line with predictions from the dynamic developmental theory of ADHD by indicating that reinforcers were less efficient in the ADHD group than in the non-ADHD group. Finally, the results substantiated ADHD-related variability as an etiologically important characteristic of ADHD behaviour.
PMCID: PMC1489933  PMID: 16569228
3.  Attention Deficit/Hyperactivity Disorder: A Focused Overview for Children’s Environmental Health Researchers 
Environmental Health Perspectives  2010;118(12):1646-1653.
Attention deficit/hyperactivity disorder (ADHD) is the most frequently diagnosed childhood neurobehavioral disorder. Much research has been done to identify genetic, environmental, and social risk factors for ADHD; however, we are still far from fully understanding its etiology. In this review we provide an overview of diagnostic criteria for ADHD and what is known about its biological basis. We also review the neuropsychological functions that are affected in ADHD. The goal is to familiarize the reader with the behavioral deficits that are hallmarks of ADHD and to facilitate comparisons with neurobehavioral deficits associated with environmental chemical exposures.
Data sources
Relevant literature on ADHD is reviewed, focusing in particular on meta-analyses conducted between 2004 and the present that evaluated associations between measures of neuropsychological function and ADHD in children. Meta-analyses were obtained through searches of the PubMed electronic database using the terms “ADHD,” “meta-analysis,” “attention,” “executive,” and “neuropsychological functions.” Although meta-analyses are emphasized, nonquantitative reviews are included for particular neuropsychological functions where no meta-analyses were available.
Data synthesis
The meta-analyses indicate that vigilance (sustained attention), response inhibition, and working memory are impaired in children diagnosed with ADHD. Similar but somewhat less consistent meta-analytic findings have been reported for impairments in alertness, cognitive flexibility, and planning. Additionally, the literature suggests deficits in temporal information processing and altered responses to reinforcement in children diagnosed with ADHD. Findings from brain imagining and neurochemistry studies support the behavioral findings.
Behavioral, neuroanatomical, and neurochemical data indicate substantial differences in attention and executive functions between children diagnosed with ADHD and non-ADHD controls. Comparisons of the neurobehavioral deficits associated with ADHD and those associated with exposures to environmental chemicals may help to identify possible environmental risk factors for ADHD and/or reveal common underlying biological mechanisms.
PMCID: PMC3002183  PMID: 20829148
ADHD; attention; executive function
4.  Age-related changes in motor subtle signs among girls and boys with ADHD 
Neurology  2008;71(19):1514-1520.
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).
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.
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.
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.
= attention-deficit hyperactivity disorder;
= Conners’ Parent Rating Scale;
= Diagnostic Interview for Children and Adolescents;
= Diagnostic and Statistical Manual of Mental Disorders;
= Wechsler Intelligence Scale for Children.
PMCID: PMC2597066  PMID: 18981373
5.  Age-related changes in motor subtle signs among girls and boys with ADHD 
Neurology  2008;71(19):1514-1520.
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).
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.
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.
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.
PMCID: PMC2597066  PMID: 18981373
6.  Inhibition, flexibility, working memory and planning in autism spectrum disorders with and without comorbid ADHD-symptoms 
Recent studies have not paid a great deal of attention to comorbid attention-deficit/hyperactivity disorder (ADHD) symptoms in autistic children even though it is well known that almost half of children with autism spectrum disorder (ASD) suffer from hyperactivity, inattention and impulsivity. The goal of this study was to evaluate and compare executive functioning (EF) profiles in children with ADHD and in children with ASD with and without comorbid ADHD.
Children aged 6 to 18 years old with ADHD (n = 20) or ASD (High-Functioning autism or Asperger syndrome) with (n = 20) and without (n = 20) comorbid ADHD and a typically developing group (n = 20) were compared on a battery of EF tasks comprising inhibition, flexibility, working memory and planning tasks. A MANOVA, effect sizes as well as correlations between ADHD-symptomatology and EF performance were calculated. Age- and IQ-corrected z scores were used.
There was a significant effect for the factor group (F = 1.55; dF = 42; p = .02). Post-hoc analysis revealed significant differences between the ADHD and the TD group on the inhibition task for false alarms (p = .01) and between the ADHD group, the ASD+ group (p = .03), the ASD- group (p = .02) and the TD group (p = .01) for omissions. Effect sizes showed clear deficits of ADHD children in inhibition and working memory tasks. Participants with ASD were impaired in planning and flexibility abilities. The ASD+ group showed compared to the ASD- group more problems in inhibitory performance but not in the working memory task.
Our findings replicate previous results reporting impairment of ADHD children in inhibition and working memory tasks and of ASD children in planning and flexibility abilities. The ASD + group showed similarities to the ADHD group with regard to inhibitory but not to working memory deficits. Nevertheless the heterogeneity of these and previous results shows that EF assessment is not useful for differential diagnosis between ADHD and ASD. It might be useful for evaluating strengths and weaknesses in individual children.
PMCID: PMC2276205  PMID: 18237439
7.  Quantifying excessive mirror overflow in children with attention-deficit/hyperactivity disorder 
Neurology  2011;76(7):622-628.
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.
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.
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.
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.
PMCID: PMC3053337  PMID: 21321336
8.  Basal Ganglia Volume and Shape in Children With Attention Deficit Hyperactivity Disorder 
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.
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.
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.
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.
PMCID: PMC2890266  PMID: 19015232
9.  How Distinctive are ADHD and RD? Results of a Double Dissociation Study 
Journal of Abnormal Child Psychology  2009;37(7):1007-1017.
The nature of the comorbidity between Attention-Deficit/Hyperactivity Disorder (ADHD) and Reading Disability (RD) was examined using a double dissociation design. Children were between 8 and 12 years of age and entered into four groups: ADHD only (n = 24), ADHD+RD (n = 29), RD only (n = 41) and normal controls (n = 26). In total, 120 children participated in the study; 38 girls and 82 boys. Both ADHD and RD were associated with impairments in inhibition and lexical decision, although inhibition and lexical decision were more severely impaired in RD than in ADHD. Visuospatial working memory deficits were specific to children with only ADHD. It is concluded that there was overlap on lexical decision and to a lesser extent on inhibition between ADHD and RD. In ADHD, impairments were dependent on IQ, which suggest that the overlap in lexical decision and inhibition is different in origin for ADHD and RD. The ADHD only group was specifically characterized by deficits in visuospatial working memory. Hence, no double dissociation between ADHD and RD was found on executive functioning and lexical decision.
PMCID: PMC2734255  PMID: 19488850
ADHD; RD; Comorbidity; Executive functioning; Lexical decision
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.
PMCID: PMC2575661  PMID: 18609314
Process approach; ADHD; Executive function; D-KEFS
11.  Neuropsychological functioning in children with Tourette Syndrome with and without Attention-Deficit/Hyperactivity Disorder 
Neuropsychological functioning in children with Tourette Syndrome (TS) has been characterized by subtle deficits in response inhibition, visual-motor integration and fine-motor coordination. The association of these deficits with the tics of the TS versus co-occurring attention-deficit/hyperactivity disorder (ADHD) has not been well understood due to small sample sizes and lack of adequate control conditions. We examined neuropsychological functioning in relatively large and well-characterized samples of children with TS, TS-plus-ADHD, ADHD, and unaffected controls.
Fifty-six children with TS-only, 45 with TS-plus-ADHD, 64 with ADHD and 71 healthy community control subjects were assessed on a battery of neuropsychological measures including the Connors’ Continuous Performance Test (CPT), the Stroop Color-Word Interference Test (Stroop), the Beery Visual-Motor Integration Test (VMI), and the Purdue Pegboard Test.
There were no differences between children with TS-only and unaffected controls on the measures of response inhibition and visual-motor integration. Boys with TS-only but not girls with TS-only were impaired in the dominant hand Purdue performance. Children with ADHD were impaired on all study measures. Children with TS-plus-ADHD revealed no deficits on the Stroop, VMI and Purdue tests but were impaired on the sustained attention portion of the CPT.
These results indicate that co-occurring ADHD may be responsible for the neuropsychological deficits, or at least those assessed in the present study, in children with TS. Explanations in terms of neurobiological mechanisms of co-occurring TS and ADHD as well as possible compensatory mechanisms in children with TS are discussed.
PMCID: PMC2965169  PMID: 20970703
12.  Oculomotor Performance Identifies Underlying Cognitive Deficits in Attention-Deficit/Hyperactivity Disorder 
To evaluate cognitive control in children with attention-deficit/hyperactivity disorder (ADHD) using oculomotor tests of executive function.
Cross-sectional study of children aged 8 to 13 years with ADHD (n = 26) and controls (n = 33) used oculomotor tasks to assess sensorimotor function (visually guided saccades), resistance to peripheral distractors (fixation), response inhibition (antisaccades), and spatial working memory (memory-guided saccades).
All children had intact sensorimotor function and working memory. Children with ADHD showed susceptibility to peripheral distractors and deficits in response inhibition. Increased interstimulus (IS) fixation periods on the antisaccade task were associated with improved performance and decreased reaction times on correct trials for controls but not for children with ADHD. Attention-deficit/hyperactivity disorder–combined and inattentive subtypes showed different patterns of reaction time as a function of IS periods.
Response inhibition deficits in ADHD on oculomotor tasks are consistent with other studies. The failure of children with ADHD to use IS time to decrease response inhibition errors and reaction time suggests that IS time is not used to prepare a response. These findings highlight the importance of considering cognitive processing components affected by ADHD in addition to core behavioral symptoms, particularly in designing new treatment strategies.
PMCID: PMC3045710  PMID: 19238098
ADHD; oculomotor; antisaccade; response inhibition; response preparation
13.  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
14.  Preparatory neural networks are impaired in adults with attention-deficit/hyperactivity disorder during the antisaccade task☆ 
NeuroImage : Clinical  2012;2:63-78.
Adults with attention-deficit/hyperactivity disorder (ADHD) often display executive function impairments, particularly in inhibitory control. The antisaccade task, which measures inhibitory control, requires one to suppress an automatic prosaccade toward a salient visual stimulus and voluntarily make an antisaccade in the opposite direction. ADHD patients not only have longer saccadic reaction times, but also make more direction errors (i.e., a prosaccade was executed toward the stimulus) during antisaccade trials. These deficits may stem from pathology in several brain areas that are important for executive control. Using functional MRI with a rapid event-related design, adults with combined subtype of ADHD (coexistence of attention and hyperactivity problems), who abstained from taking stimulant medication 20 h prior to experiment onset, and age-match controls performed pro- and antisaccade trials that were interleaved with pro- and anti-catch trials (i.e., instruction was presented but no target appeared, requiring no response). This method allowed us to examine brain activation patterns when participants either prepared (during instruction) or executed (after target appearance) correct pro or antisaccades. Behaviorally, ADHD adults displayed several antisaccade deficits, including longer and more variable reaction times and more direction errors, but saccade metrics (i.e., duration, velocity, and amplitude) were normal. When preparing to execute an antisaccade, ADHD adults showed less activation in frontal, supplementary, and parietal eye fields, compared to controls. However, activation in these areas was normal in the ADHD group during the execution of a correct antisaccade. Interestingly, unlike controls, adults with ADHD produced greater activation than controls in dorsolateral prefrontal cortex during antisaccade execution, perhaps as part of compensatory mechanisms to optimize antisaccade production. Overall, these data suggest that the saccade deficits observed in adults with ADHD do not result from an inability to execute a correct antisaccade but rather the failure to properly prepare (i.e., form the appropriate task set) for the antisaccade trial. The data support the view that the executive impairments, including inhibitory control, in ADHD adults are related to poor response preparation.
► The neural correlates of inhibitory control in adults with ADHD were examined. ► We used an interleaved pro and antisaccade task simultaneously with functional MRI. ► This enabled the dissociation of automatic versus voluntary control. ► Patients had less activity in fronto-parietal areas during antisaccade preparation. ► Overall, antisaccade deficits in ADHD adults likely arise from poor preparation.
PMCID: PMC3777763  PMID: 24179760
ADHD; Saccade; fMRI; Preparation; Inhibition
15.  Can Motivation Normalize Working Memory and Task Persistence in Children with Attention-Deficit/Hyperactivity Disorder? The Effects of Money and Computer-Gaming 
Visual-spatial Working Memory (WM) is the most impaired executive function in children with Attention-Deficit/Hyperactivity Disorder (ADHD). Some suggest that deficits in executive functioning are caused by motivational deficits. However, there are no studies that investigate the effects of motivation on the visual-spatial WM of children with- and without ADHD. Studies examining this in executive functions other than WM, show inconsistent results. These inconsistencies may be related to differences in the reinforcement used. The effects of different reinforcers on WM performance were investigated in 30 children with ADHD and 31 non-ADHD controls. A visual-spatial WM task was administered in four reinforcement conditions: Feedback-only, 1 euro, 10 euros, and a computer-game version of the task. In the Feedback-only condition, children with ADHD performed worse on the WM measure than controls. Although incentives significantly improved the WM performance of children with ADHD, even the strongest incentives (10 euros and Gaming) were unable to normalize their performance. Feedback-only provided sufficient reinforcement for controls to reach optimal performance, while children with ADHD required extra reinforcement. Only children with ADHD showed a decrease in performance over time. Importantly, the strongest incentives (10 euros and Gaming) normalized persistence of performance in these children, whereas 1 euro had no such effect. Both executive and motivational deficits give rise to visual-spatial WM deficits in ADHD. Problems with task-persistence in ADHD result from motivational deficits. In ADHD-reinforcement studies and clinical practice (e.g., assessment), reinforcement intensity can be a confounding factor and should be taken into account. Gaming can be a cost-effective way to maximize performance in ADHD.
PMCID: PMC3375007  PMID: 22187093
ADHD; Working memory; Reinforcement; Executive functioning; Motivation; Computer gaming; Cognitive functioning; WM
16.  Atomoxetine for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) in children with ADHD and dyslexia 
The objective of this study was to assess the effects of atomoxetine on treating attention-deficit/hyperactivity disorder (ADHD), on reading performance, and on neurocognitive function in youth with ADHD and dyslexia (ADHD+D).
Patients with ADHD (n = 20) or ADHD+D (n = 36), aged 10-16 years, received open-label atomoxetine for 16 weeks. Data from the ADHD Rating Scale-IV (ADHDRS-IV), Kaufman Test of Educational Achievement (K-TEA), Working Memory Test Battery for Children (WMTB-C), and Life Participation Scale for ADHD-Child Version (LPS-C) were assessed.
Atomoxetine demonstrated significant improvement for both groups on the ADHDRS-IV, LPS-C, and K-TEA reading comprehension standard and composite scores. K-TEA spelling subtest improvement was significant for the ADHD group, whereas the ADHD+D group showed significant reading decoding improvements. Substantial K-TEA reading and spelling subtest age equivalence gains (in months) were achieved for both groups. The WMTB-C central executive score change was significantly greater for the ADHD group. Conversely, the ADHD+D group showed significant phonological loop score enhancement by visit over the ADHD group. Atomoxetine was well tolerated, and commonly reported adverse events were similar to those previously reported.
Atomoxetine reduced ADHD symptoms and improved reading scores in both groups. Conversely, different patterns and magnitude of improvement in working memory component scores existed between ADHD and ADHD+D patients. Though limited by small sample size, group differences in relation to the comparable changes in improvement in ADHD symptoms could suggest that brain systems related to the therapeutic benefit of atomoxetine in reducing ADHD symptoms may be different in individuals with ADHD+D and ADHD without dyslexia.
Trial Registration
Clinical Trial Registry: NCT00191048
PMCID: PMC2805604  PMID: 20003507
17.  Towards systems neuroscience of ADHD: A meta-analysis of 55 fMRI studies 
The American journal of psychiatry  2012;169(10):10.1176/appi.ajp.2012.11101521.
To perform a comprehensive meta-analysis of task-based functional MRI studies of Attention-Deficit/Hyperactivity Disorder (ADHD).
PubMed, Ovid, EMBASE, Web of Science, ERIC, CINHAL, and NeuroSynth were searched for studies published through 06/30/2011. Significant differences in activation of brain regions between individuals with ADHD and comparisons were detected using activation likelihood estimation meta-analysis (p<0.05, corrected). Dysfunctional regions in ADHD were related to seven reference neuronal systems. We performed a set of meta-analyses focused on age groups (children; adults), clinical characteristics (history of stimulant treatment; presence of psychiatric comorbidities), and specific neuropsychological tasks (inhibition; working memory; vigilance/attention).
Fifty-five studies were included (39 in children, 16 in adults). In children, hypoactivation in ADHD vs. comparisons was found mostly in systems involved in executive functions (frontoparietal network) and attention (ventral attentional network). Significant hyperactivation in ADHD vs. comparisons was observed predominantly within the default, ventral attention, and somatomotor networks. In adults, ADHD-related hypoactivation was predominant in the frontoparietal system, while ADHD-related hyperactivation was present in the visual, dorsal attention, and default networks. Significant ADHD-related dysfunction largely reflected task features and was detected even in the absence of comorbid mental disorders or history of stimulant treatment.
A growing literature provides evidence of ADHD-related dysfunction within multiple neuronal systems involved in higher-level cognitive functions but also in sensorimotor processes, including the visual system, and in the default network. This meta-analytic evidence extends early models of ADHD pathophysiology focused on prefrontal-striatal circuits.
PMCID: PMC3879048  PMID: 22983386
18.  The Neurobiological Profile of Girls with ADHD 
Since boys are more commonly diagnosed with Attention Deficit Hyperactivity Disorder (ADHD) than girls, the majority of theories and published research studies of ADHD have been based on samples comprised primarily (or exclusively) of boys. While psychosocial impairment in girls with ADHD is well established, the neuropsychological and neurobiological basis of these deficits is less consistently observed. There is growing evidence that boys’ and girls’ brains develop and mature at different rates, suggesting that the trajectory of early anomalous brain development in ADHD may also be sex-specific. It remains unclear, however, whether earlier brain maturation observed in girls with ADHD is protective. In this review, we outline the current theory and research findings that seek to establish a unique neurobiological profile of girls with ADHD, highlighting sex differences in typical brain development and among children with ADHD. The review highlights findings from neurological, neurocognitive, and behavioral studies. Future research directions are suggested, including the need for longitudinal neuroimaging and neurobehavioral investigation beginning as early as the preschool years, and continuing through adolescence and adulthood, with consideration of identified sex differences in the development of ADHD.
PMCID: PMC3534724  PMID: 19072756
childhood; development; executive functions; neuroimaging; ADHD; gender
19.  fMRI of Intrasubject Variability in ADHD: Anomalous Premotor Activity With Prefrontal Compensation 
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.
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.
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.
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.
PMCID: PMC3932630  PMID: 18724253
attention-deficit/hyperactivity disorder; intrasubject variability; response inhibition
20.  Attention deficit/hyperactivity disorder symptoms moderate cognition and behavior in children with autism spectrum disorders 
Recent estimates suggest that over 30% of children with autism spectrum disorders (ASD) meet diagnostic criteria for attention deficit/hyperactivity disorder (ADHD), and another 20% of children with ASD exhibit subthreshold clinical ADHD symptoms. Presence of ADHD symptoms in the context of ASD could have a variety of effects on cognition, autistic traits, and adaptive/maladaptive behaviors including: exacerbating core ASD impairments; adding unique impairments specific to ADHD; producing new problems unreported in ASD or ADHD; having no clear impact; or producing some combination of these scenarios. Children with ASD and co-morbid ADHD symptoms (ASD+ADHD; n=21), children with ASD without ADHD (ASD; n=28), and a typically developing control group (n=21) were included in the study; all groups were matched on age, gender-ratio, IQ, and socioeconomic status. Data were collected on verbal and spatial working memory, response inhibition, global executive control, autistic traits, adaptive functioning, and maladaptive behavior problems. In this sample, the presence of ADHD symptoms in ASD exacerbated impairments in executive control and adaptive behavior and resulted in higher autistic trait, and externalizing behavior ratings. ADHD symptoms were also associated with greater impairments on a lab measure of verbal working memory. These findings suggest that children with ASD+ADHD symptoms present with exacerbated impairments in some but not all domains of functioning relative to children with ASD, most notably in adaptive behavior and working memory. Therefore, ADHD may moderate the expression of components of the ASD cognitive and behavioral phenotype, but ASD+ADHD may not represent an etiologically distinct phenotype from ASD alone.
PMCID: PMC3012375  PMID: 19998356
21.  Event-related fMRI of inhibitory control in the Predominantly Inattentive and Combined Subtypes of AD/HD 
Background and Purpose
To examine the neurophysiological basis for the pronounced differences in hyperactivity and impulsiveness that distinguish the Predominantly Inattentive type of Attention-Deficit/Hyperactivity Disorder (ADHD-PI) from the combined type of the disorder (ADHD-C).
Event-related brain responses to a go/no-go test of inhibitory control were measured with functional magnetic resonance imaging (fMRI) in 11 children with ADHD-C and nine children with ADHD-PI, aged 7 to 13 years, who were matched for age, sex, and intelligence.
There were no significant group differences in task performance. Children with ADHD-C and ADHD-PI activated overlapping regions of right inferior frontal gyrus, right superior temporal lobe, and left inferior parietal lobe during inhibitory control. However, the magnitude of the activation in the temporal and parietal regions, as well as in the bilateral middle frontal gyrus, was greater in children with ADHD-PI than those with ADHD-C. Conversely, children with ADHD-C activated bilateral medial occipital lobe to a greater extent than children with ADHD-PI.
The results provide preliminary evidence that phenotypic differences between the ADHD-C and ADHD-PI subtypes are associated with differential activation of regions that have previously been implicated in the pathophysiology of ADHD and are thought to mediate executive and attentional processes.
PMCID: PMC2711513  PMID: 19594667
22.  Effects of methylphenidate in children with attention deficit hyperactivity disorder: a near-infrared spectroscopy study with CANTAB® 
A wide range of evidence supports the methylphenidate (MPH)-induced enhancement of prefrontal cortex (PFC) functioning and improvements in behavioral symptoms in patients with attention deficit hyperactivity disorder (ADHD). Although working memory (WM) has been hypothesized to be impaired in patients with ADHD, no pharmacological studies have examined visuospatial WM (VSWM) with near-infrared spectroscopy (NIRS).
Study aim
The present study was designed to investigate the acute effects of MPH on neuropsychological performance and hemodynamic activation in children with ADHD during VSWM tasks.
The subject group included 10 boys and 1 girl previously diagnosed with ADHD. Two VSWM tasks of differing degrees of difficulty were conducted. This is the first study on the pharmacological effects of MPH in children with ADHD to evaluate hemodynamic responses in the PFC with simultaneous NIRS.
No significant differences were found in the scores for both spatial working memory (SWM) and score of spatial span (SSP) tasks between the MPH-off and MPH–on conditions. However, a significant MPH-effect on changes in oxy-hemoglobin levels in the PFC was found only in the SWM task.
These findings suggest that PFC activation might be affected by MPH, depending on the degree of difficulty of the particular task. Although the MPH-induced change on behavior may or may not be obvious, NIRS measurements might be useful for assessing the psychological effects of MPH even when performance changes were not observed in the cognitive tasks.
PMCID: PMC4298959  PMID: 25606052
Attention Deficit Hyperactivity Disorder (ADHD); Cambridge automated neuropsychological testing battery (CANTAB®); Near-infrared spectroscopy (NIRS); Visuospatial working memory (VSWM); Executive function (EF); Methylphenidate (MPH)
23.  Performance variability, impulsivity errors and the impact of incentives as gender-independent endophenotypes for ADHD 
Attention-deficit hyperactivity disorder (ADHD) is one of the most common and highly heritable child psychiatric disorders. There is strong evidence that children with ADHD show slower and more variable responses in tasks such as Go/Nogo tapping aspects of executive functions like sustained attention and response control which may be modulated by motivational factors and/or state-regulation processes. The aim of this study was (1) to determine if these executive functions may constitute an endophenotype for ADHD; (2) to investigate for the first time whether known modulators of these executive functions may also be familial and (3) to explore whether gender has an impact on these measures.
Two hundred and five children with ADHD combined type, 173 nonaffected biological siblings and 53 controls with no known family history of ADHD were examined using a Go/Nogo-Task in the framework of a multi-centre study. Performance-measures and modulating effects of event-rate and incentives were examined. Shared familial effects on these measures were assessed, and the influence of gender was tested.
Children with ADHD responded more slowly and variably than nonaffected siblings or controls. Nonaffected siblings showed intermediate scores for reaction-time variability, false alarms and omission errors under fast and slow event rates.
A slower event-rate did not led to reduced performance specific for ADHD. In the incentive condition, mean reaction times speeded-up and became less variable only in children with ADHD and their nonaffected siblings, while accuracy was improved in all groups. Males responded faster, but also committed more false alarms. There were no interactions of group by gender.
Reaction-time variability and accuracy parameters could be useful neuropsychological endophenotypes for ADHD. Performance modulating effects of incentives suggested a familially-driven motivational dysfunction which may play an important role on etiologic pathways and treatment approaches for ADHD. The effects of gender were independent of familial effects or ADHD-status, which in turn suggests that the proposed endophenotypes are independent of gender.
PMCID: PMC2921046  PMID: 19929943
attention-deficit hyperactivity disorder; ADHD; endophenotype; executive function; reaction time variability; false alarms; state regulation; incentives
24.  Response Inhibition Impairment in High Functioning Autism and Attention Deficit Hyperactivity Disorder: Evidence from Near-Infrared Spectroscopy Data 
PLoS ONE  2012;7(10):e46569.
Response inhibition, an important domain of executive function (EF), involves the ability to suppress irrelevant or interfering information and impulses. Previous studies have shown impairment of response inhibition in high functioning autism (HFA) and attention deficit hyperactivity disorder (ADHD), but more recent findings have been inconsistent. To date, almost no studies have been conducted using functional imaging techniques to directly compare inhibitory control between children with HFA and those with ADHD.
Nineteen children with HFA, 16 age- and intelligence quotient (IQ)-matched children with ADHD, and 16 typically developing (TD) children were imaged using functional near-infrared spectroscopy (NIRS) while performing Go/No-go and Stroop tasks.
Compared with the TD group, children in both the HFA and ADHD groups took more time to respond during the No-go blocks, with reaction time longest for HFA and shortest for TD. Children in the HFA and ADHD groups also made a greater number of reaction errors in the No-go blocks than those in the TD group. During the Stroop task, there were no significant differences between these three groups in reaction time and omission errors. Both the HFA and ADHD groups showed a higher level of inactivation in the right prefrontal cortex (PFC) during the No-go blocks, relative to the TD group. However, no significant differences were found between groups in the levels of oxyhemoglobin concentration in the PFC during the Stroop task.
Functional brain imaging using NIRS showed reduced activation in the right PFC in children with HFA or ADHD during an inhibition task, indicating that inhibitory dysfunction is a shared feature of both HFA and ADHD.
PMCID: PMC3467210  PMID: 23056348
25.  Comparison of spatial working memory in children with prenatal alcohol exposure and those diagnosed with ADHD; A functional magnetic resonance imaging study 
Alcohol related neurodevelopmental disorder (ARND) falls under the umbrella of fetal alcohol spectrum disorder (FASD), but individuals do not demonstrate the facial characteristics associated with fetal alcohol syndrome (FAS), making diagnosis difficult. While attentional problems in ARND are similar to those found in attention-deficit/hyperactivity disorder (ADHD), the underlying impairment in attention pathways may be different.
Functional magnetic resonance imaging (fMRI) of a working memory (1-back) task of 63 children, 10 to 14 years old, diagnosed with ARND and ADHD, as well as typically developing (TD) controls, was conducted at 3 T. Diffusion tensor imaging (DTI) data were also acquired.
Activations were observed in posterior parietal and occipital regions in the TD group and in dorsolateral prefrontal and posterior parietal regions in the ARND group, whereas the ADHD group activated only dorsolateral prefrontal regions, during the working memory component of the task (1-back minus 0-back contrast). The increases in frontal and parietal activity were significantly greater in the ARND group compared to the other groups. This increased activity was associated with reduced accuracy and increased response time variability, suggesting that ARND subjects exert greater effort to manage short-term memory load. Significantly greater intra-subject variability, demonstrated by fMRI region-of-interest analysis, in the ADHD and ARND groups compared to the TD group suggests that moment-to-moment lapses in attention contributed to their poorer task performance. Differences in functional activity in ARND subjects with and without a diagnosis of ADHD resulted primarily from reduced activation by the ARND/ADHD + group during the 0-back task. In contrast, children with ADHD alone clearly showed reduced activations during the 1-back task. DTI analysis revealed that the TD group had significantly higher total tract volume and number of fibers than the ARND group. These measures were negatively correlated with errors on the 1-back task, suggesting a link between white matter integrity and task performance.
fMRI activations suggest that the similar behavior of children with ARND and ADHD on a spatial working memory task is the result of different cognitive events. The nature of ADHD in children with ARND appears to differ from that of children with ADHD alone.
PMCID: PMC3436669  PMID: 22958510
Fetal Alcohol Spectrum Disorder (FASD); Alcohol related neurodevelopmental disorder (ARND); Attention-deficit/hyperactivity disorder (ADHD); Functional magnetic resonance imaging (fMRI); Spatial working memory; White matter; Gray matter; Diffusion tensor imaging (DTI); Region of interest (ROI)

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