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Objective: To investigate shared versus distinct differences in brain structure among children with ADHD and obesity, we examined the morphology of regions implicated in cognitive control and reward function in a single cross-sectional cohort of children with and without ADHD and overweight/obesity (OV/OB)., Method: Participants included 471 children ages 8-12 years with ADHD (n = 244; 58 OV/OB) and neurotypical (NT) controls (n = 227; 81 OV/OB) classified as healthy-weight (HW; BMI %ile 5th to <85th) vs. having OV/OB (BMI %ile≥85th). Structural MRI was performed to obtain measures of cortical and subcortical morphology and compared across ADHD × BMI groups., Results: Surface area was generally lower in ADHD vs. NT including in anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (dlPFC), medial (m)PFC, and primary motor (M1) cortex. In contrast, cortical thickness was generally lower in OV/OB vs. HW for ACC, dlPFC, orbitofrontal cortex (OFC), mPFC, and supplementary motor cortex (SMC). Furthermore, ADHD × OV/OB interactions were observed for the ACC and OFC, with the lowest ACC volume in the ADHD + OV/OB group and the highest OFC surface area in the NT + OV/OB group. Subcortical volumes did not differ between groups., Conclusions: Our findings reveal distinct alterations in cortical morphology in association with ADHD and overweight, with cortical surface area reduced in ADHD vs. thickness reduced in OV/OB. Additionally, the findings provide evidence of combined effects of ADHD × OV/OB in brain regions integral to cognition and motivation. Our results support further investigation of causes and correlates of shared and distinct ADHD- and OV/OB-associated differences in developing frontocingulate morphology., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier Ltd.)

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

Objective: To determine whether girls and boys with ADHD show distinct impairments in components of cognitive control across multiple tasks (go/no-go, stop signal, and flanker) and performance metrics (response speed, variability, and errors)., Method: A total of 300 children, ages 8 to 12 years with ADHD ( n  = 210, 58 girls) or typically developing (TD; n  = 99, 37 girls), completed all tasks. Traditional response measures (e.g., mean and standard deviation of reaction time, inhibition errors, and stop signal reaction time) and ex-Gaussian modeling of reaction times (mu, sigma, and tau) were analyzed., Results: Girls showed intact response inhibition in the context of slower response speed, while boys made more inhibition errors and did not slow their response speed. Both girls and boys with ADHD showed higher response variability and poorer interference control than TD children., Conclusion: Girls and boys with ADHD show distinct impairments in cognitive control that may be important for understanding the pathophysiology of ADHD., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

To investigate developmental changes in emotion dysregulation (ED) and associated symptoms of emotional lability, irritability, anxiety, and depression, among girls and boys with and without ADHD from childhood through adolescence. Data were collected from a sample of 8-18-year-old children with (n = 264; 76 girls) and without (n = 153; 56 girls) ADHD, with multiple time-points from a subsample of participants (n = 121). Parents and youth completed rating scales assessing child ED, emotional lability, irritability, anxiety, and depression. Mixed effects models were employed to examine effects and interactions of diagnosis, sex [biological sex assigned at birth], age among boys and girls with and without ADHD. Mixed effects analyses showed sexually dimorphic developmental patterns between boys and girls, such that boys with ADHD showed a greater reduction in ED, irritability, and anxiety with age compared to girls with ADHD, whose symptom levels remained elevated relative to TD girls. Depressive symptoms were persistently elevated among girls with ADHD compared to boys with ADHD, whose symptoms decreased with age, relative to same-sex TD peers. While both boys and girls with ADHD showed higher levels of ED during childhood (compared to their sex-matched TD peers), mixed effects analyses revealed substantial sexually dimorphic patterns of emotional symptom change during adolescence: Boys with ADHD showed robust improvements in emotional symptoms from childhood to adolescence while girls with ADHD continued to show high and/or increased levels of ED, emotional lability, irritability, anxiety and depression., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

The cerebellum contributes to motor and higher-order control throughout neurodevelopment, with marked growth during childhood. Few studies have investigated differential associations of cerebellar morphometry with function in males and females. The present study examines sex differences in regional cerebellar gray matter volume (GMV) and the moderating effect of sex on the relationship between GMV and motor, cognitive, and emotional functions in a large cohort of typically developing (TD) children. Participants included 371 TD children (123 females, age 8-12 years). A convolutional neural network-based approach was employed for cerebellar parcellation. Volumes were harmonized using ComBat to adjust for hardware-induced variations. Regression analyses examined the effect of sex on GMV and whether sex moderated the relationship between GMV and motor, cognitive, and emotional functions. Males showed larger GMV in right lobules I-V, bilateral lobules VI, crus II/VIIb, and VIII, left lobule X, and vermis regions I-V and VIII-X. Greater motor function correlated with less vermis VI-VII GMV in females. Greater cognitive function correlated with greater left lobule VI GMV in females and less left lobule VI GMV in males. Finally, greater internalizing symptoms correlated with greater bilateral lobule IX GMV in females but less in males. These findings reveal sexually dimorphic patterns of cerebellar structure and associations with motor, cognitive, and emotional functions. Males generally show larger GMV than females. Larger GMV was associated with better cognitive functioning for females and better motor/emotional functioning for males., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The Simple View of Reading model suggests that intact language processing and word decoding lead to proficient reading comprehension, with recent studies pointing at executive functions as an important component contributing to reading proficiency. Here, we aimed to determine the underlying mechanism(s) for these changes. Participants include 120 8- to 12-year-old children (n = 55 with dyslexia, n = 65 typical readers) trained on an executive functions-based reading program, including pre/postfunctional MRI and behavioral data collection. Across groups, improved word reading was related to stronger functional connections within executive functions and sensory networks. In children with dyslexia, faster and more accurate word reading was related to stronger functional connections within and between sensory networks. These results suggest greater synchronization of brain systems after the intervention, consistent with the "neural noise" hypothesis in children with dyslexia and support the consideration of including executive functions as part of the Simple View of Reading model., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Background: The tendency to prefer smaller, immediate rewards over larger, delayed rewards is known as delay discounting (DD). Developmental deviations in DD may be key in characterizing psychiatric and neurodevelopmental disorders. Recent work empirically supported DD as a transdiagnostic process in various psychiatric disorders. Yet, there is a lack of research relating developmental changes in DD from mid-childhood to adolescence to psychiatric and neurodevelopmental disorders. Additionally, examining the interplay between socioeconomic status/total household income (THI) and psychiatric symptoms is vital for a more comprehensive understanding of pediatric pathology and its complex relationship with DD., Methods: The current study addresses this gap in a robust psychiatric sample of 1843 children and adolescents aged 5-18 (M = 10.6, SD = 3.17; 1,219 males, 624 females). General additive models (GAMs) characterized the shape of age-related changes in monetary and food reward discounting for nine psychiatric disorders compared with neurotypical youth (NT; n = 123). Over 40% of our sample possessed a minimum of at least three psychiatric or neurodevelopmental disorders. We used bootstrap-enhanced Louvain community detection to map DD-related comorbidity patterns. We derived five subtypes based on diagnostic categories present in our sample. DD patterns were then compared across each of the subtypes. Further, we evaluated the effect of cognitive ability, emotional and behavioral problems, and THI in relation to DD across development., Results: Higher discounting was found in six of the nine disorders we examined relative to NT. DD was consistently elevated across development for most disorders, except for depressive disorders, with age-specific DD differences compared with NTs. Community detection analyses revealed that one comorbidity subtype consisting primarily of Attention-Deficit/Hyperactivity Disorder (ADHD) Combined Presentation and anxiety disorders displayed the highest overall emotional/behavioral problems and greater DD for the food reward. An additional subtype composed mainly of ADHD, predominantly Inattentive Presentation, learning, and developmental disorders, showed the greatest DD for food and monetary rewards compared with the other subtypes. This subtype had deficits in reasoning ability, evidenced by low cognitive and academic achievement performance. For this ADHD-I and developmental disorders subtype, THI was related to DD across the age span such that participants with high THI showed no differences in DD compared with NTs. In contrast, participants with low THI showed significantly worse DD trajectories than all others. Our results also support prior work showing that DD follows nonlinear developmental patterns., Conclusions: We demonstrate preliminary evidence for DD as a transdiagnostic marker of psychiatric and neurodevelopmental disorders in children and adolescents. Comorbidity subtypes illuminate DD heterogeneity, facilitating the identification of high-risk individuals. Importantly, our findings revealed a marked link between DD and intellectual reasoning, with children from lower-income households exhibiting lower reasoning skills and heightened DD. These observations underscore the potential consequences of compromised self-regulation in economically disadvantaged individuals with these disorders, emphasizing the need for tailored interventions and further research to support improved outcomes., (© 2023 Association for Child and Adolescent Mental Health.)

Children with attention-deficit/hyperactivity disorder (ADHD) demonstrate reduced response inhibition, increased response time variability, and atypical frontal lobe white matter microstructure with emerging evidence of sex differences. This study aims to examine whether frontal lobe white matter microstructure is differentially impacted in ADHD by sex and whether this relates to Go/No-Go (GNG) task performance. Diffusion tensor imaging (DTI) from 187 children (8-12 years), including ADHD (n = 94) and typically developing controls (TD; n = 93). Participants completed three GNG tasks with varying cognitive demands and incentives (standard, cognitive, and motivational). Fractional anisotropy (FA) was examined as an index of white matter microstructure within bilateral frontal lobe regions of interest. Children with ADHD showed reduced FA in primary motor (M1) and supplementary motor area (SMA) regardless of sex. Sex-based dissociation for the effect of diagnosis was observed in medial orbitofrontal cortex (mOFC), with higher FA in girls with ADHD and lower FA in boys with ADHD. Both diagnosis and sex contributed to performance on measures of response inhibition and reaction time (RT) variability, with all children with ADHD demonstrating poorer performance on all GNG tasks, but boys with ADHD demonstrating more impulsivity on standard and motivational behavioral paradigms compared to girls with ADHD. Analyses revealed associations between reduced FA in M1, SMA, and mOFC and increased response inhibition and RT variability with some sex-based differences. These findings provide novel insights regarding the brain basis of ADHD and associated impairments in response inhibition and RT variability, and contribute to our understanding of sexual dimorphic behavioral outcomes., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Atypical fronto-subcortical neural circuitry has been implicated in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD), including connections between prefrontal cortical regions involved in top-down cognitive control and subcortical limbic structures (striatum and amygdala) involved in bottom-up reward and emotional processing. The integrity of fronto-subcortical connections may also relate to interindividual variability in delay discounting, or a preference for smaller, immediate over larger, delayed rewards, which is associated with ADHD, with recent evidence of ADHD-related sex differences., Methods: We applied diffusion tensor imaging to compare the integrity of the white matter connections within fronto-subcortical tracts among 187 8-12 year-old children either with ADHD ((n = 106; 29 girls) or typically developing (TD) controls ((n = 81; 28 girls). Analyses focused on diagnostic group differences in fractional anisotropy (FA) within fronto-subcortical circuitry implicated in delay discounting, connecting subregions of the striatum (dorsal executive and ventral limbic areas) and amygdala with prefrontal regions of interest (dorsolateral [dlPFC], orbitofrontal [OFC] and anterior cingulate cortex [ACC]), and associations with two behavioral assessments of delay discounting., Results: Children with ADHD showed reduced FA in tracts connecting OFC with ventral striatum, regardless of sex, whereas reduced FA in the OFC-amygdala and ventral ACC-amygdala tracts were specific to boys with ADHD. Across diagnostic groups and sex, reduced FA in the dorsal ACC-executive striatum tract correlated with greater game time delay discounting., Conclusions: These results suggest a potential neurobiological substrate of heightened delay discounting in children with ADHD and support the need for additional studies including larger sample sizes of girls with ADHD to further elucidate ADHD-related sex differences in these relationships., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Attention-deficit/hyperactivity disorder (ADHD) and obesity have been independently associated with deficient cognitive control (CC) and heightened preference for immediate reward., Objectives: We aimed to identify specific shared and distinct neurobehavioral phenotypes of child obesity and ADHD by simultaneously measuring CC and preference for immediate reward in children with and without ADHD who varied in body weight., Methods: This case-control study included 323 8-12 year olds (ADHD n = 215, typically developing (TD) screened for ADHD symptoms [TD] controls n = 108) varying in body weight. Children completed a go/no-go task (assessing CC), as well as a classical money delay discounting (DD) task and novel experiential game time DD task (assessing preference for immediate over delayed rewards)., Results: For game time DD, there was a body mass index z-score (BMIz)*ADHD interaction, such that TD children with overweight/obesity showed game time DD levels that were greater than those of TD children without overweight/obesity and similar to those of children with ADHD. Only children with ADHD showed poorer CC compared to TD children, with no effects of body weight., Conclusions: Heightened game time DD with delays and rewards experienced in real-time may represent a neurobehavioral phenotype that is shared between ADHD and overweight/obesity in childhood, whereas deficient CC may be specific to children with ADHD., (© 2023 World Obesity Federation.)

Executive Functions (EF) is an umbrella term for a set of mental processes geared towards goal-directed behavior supporting academic skills such as reading abilities. One of the brain's functional networks implicated in EF is the Default Mode Network (DMN). The current study uses measures of inhibitory control, a main sub-function of EF, to create cognitive and neurobiological "inhibitory control profiles" and relate them to reading abilities in a large sample (N = 5055) of adolescents aged 9-10 from the Adolescent Brain Cognitive Development (ABCD) study. Using a Latent Profile Analysis (LPA) approach, data related to inhibitory control was divided into four inhibition classes. For each class, functional connectivity within the DMN was calculated from resting-state data, using a non-parametric algorithm for detecting group similarities. These inhibitory control profiles were then related to reading abilities. The four inhibitory control groups showed significantly different reading abilities, with neurobiologically different DMN segregation profiles for each class versus controls. The current study demonstrates that a community sample of children is not entirely homogeneous and is composed of different subgroups that can be differentiated both behaviorally/cognitively and neurobiologically, by focusing on inhibitory control and the DMN. Educational implications relating these results to reading abilities are noted., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Preliminary evidence has supported the notion that mindful movement-based practices may offer benefits for self-regulation, particularly for vulnerable children. However, this evidence has principally stemmed from subjective assessments of behavioral change, leaving the underlying mechanisms undetermined. The present study aimed to investigate the efficacy of an in-school mindful movement intervention (MMI) for at-risk children within an urban public school for enhancing motor, cognitive, and emotional-behavioral regulation, including control of disruptive and inattentive behaviors characteristic of ADHD., Method: Participants included 38 (age 7-8 years) children who received twice weekly, in-school MMI, including a modified Tai Chi sequence, yoga and biomechanical warm-ups, imaginative play, and reflection. Parent and teacher ratings of disruptive behaviors, and objective measures of motor and cognitive control, were collected at baseline and after 5 months of MMI., Results: Significant improvements in teacher ratings of inattentive, hyperactive/impulsive, oppositional, and other disruptive behaviors were observed. Significant improvements were also observed for objective measures of both cognitive control and motor control with particular reductions in both right and left dysrhythmia., Conclusions: MMI was associated with improvements across objective and subjective assessments of motor, cognitive, and behavioral control. This proof-of-principle investigation provides preliminary support for the efficacy and feasibility of a novel MMI implemented as part of the school day in an urban school setting with 7-8-year-old children to augment development of at-risk youth., Supplementary Information: The online version contains supplementary material available at 10.1007/s12671-022-02063-7., Competing Interests: Conflict of InterestThe authors declare no competing interests., (© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2023.)

Dopamine-related abnormalities in the basal ganglia have been implicated in attention-deficit/hyperactivity disorder (ADHD). Iron plays a critical role in supporting dopaminergic function, and reduced brain iron and serum ferritin levels have been linked to ADHD symptom severity in children. Furthermore, the basal ganglia is a central brain region implicated in ADHD psychopathology and involved in motor and reward functions as well as emotional responding. The present study repurposed diffusion tensor imaging (DTI) to examine effects of an ADHD diagnosis and sex on iron deposition within the basal ganglia in children ages 8-12 years. We further explored associations between brain iron levels and ADHD symptom severity and affective symptoms. We observed reduced iron levels in children with ADHD in the bilateral limbic region of the striatum, as well as reduced levels of iron-deposition in males in the sensorimotor striatal subregion, regardless of diagnosis. Across the whole sample, iron-deposition increased with age in all regions. Brain-behavior analyses revealed that, across diagnostic groups, lower tissue-iron levels in bilateral limbic striatum correlated with greater ADHD symptom severity, whereas lower tissue-iron levels in the left limbic striatum only correlated with anxious, depressive and affective symptom severity. This study sheds light on the neurobiological underpinnings of ADHD, specifically highlighting the localization of tissue-iron deficiency in limbic regions, and providing support for repurposing DTI for brain iron analyses. Our findings highlight the need for further investigation of iron as a biomarker in the diagnosis and treatment of ADHD and sex differences., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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

Background: Studies of brain functional connectivity (FC) typically involve massive univariate tests, performing statistical analysis on each individual connection. In this study we apply a novel whole-matrix regression approach referred to as Covariate Assisted Principal (CAP) regression to identify resting-state FC brain networks associated with attention-deficit/hyperactivity disorder (ADHD) and response control., Methods: Participants included 8-12 year-old children with ADHD (n=115, 29 girls) and typically developing controls (n=102, 35 girls) who completed a resting-state fMRI scan and a go/no-go task (GNG). We modeled three sets of covariates to identify resting-state networks associated with an ADHD diagnosis, sex, and response inhibition (commission errors) and variability (ex-Gaussian parameter tau)., Results: The first network includes FC between striatal-cognitive control (CC) network subregions and thalamic-default mode network (DMN) subregions and is positively related to age. The second consists of FC between CC-visual-somatomotor regions and between CC-DMN subregions and is positively associated with response variability in boys with ADHD. The third consists of FC within the DMN and between DMN-CC-visual regions and differs between boys with and without ADHD. The fourth consists of FC between visual-somatomotor regions and between visual-DMN regions and differs between girls and boys with ADHD and is associated with response inhibition and variability in boys with ADHD. Unique networks were also identified in each of the three models suggesting some specificity to the covariates of interest., Conclusions: These findings demonstrate the utility of our novel covariance regression approach to studying functional brain networks relevant for development, behavior, and psychopathology., Competing Interests: Financial Disclosures Drs. Zhao, Nebel, Mostofsky, Caffo and Rosch reported no biomedical financial interests or potential conflicts of interests. 1These participants were drawn from a larger sample of 690 8–12 year-old children who participated in one of several neuroimaging studies of ADHD conducted at our center between 2008 and 2019, including 318 children with ADHD (228 boys) and 372 TD children (258 boys). Analyses focused on a subset of this sample after excluding participants who did not complete the rs-fMRI scan due to non-compliance (n=23; 16 ADHD), moved excessively during the rs-fMRI scan (n=154; 90 ADHD), or did not have relevant behavioral data (n=296; 97 ADHD).

Attention-deficit/hyperactivity disorder is associated with impaired cognitive functioning and increased delay discounting (i.e., a stronger preference for immediate reward). At the group level, stimulant medication improves cognition and delay discounting, yet not all children exhibit problems in these domains, and previous work has not examined whether stimulant-induced improvements are moderated by baseline performance. To address this question in the current study, 82 children with attention-deficit/hyperactivity disorder (9-12 years old) attended a week-long research camp. On the baseline day (Monday), participants completed tasks of inhibitory control, visuospatial working memory, reaction time variability, and delay discounting. Children then completed a 3-day, randomized, double-blind, placebo-controlled trial of ∼1 mg/kg and 2 mg/kg long-acting methylphenidate (mean doses = 39.1 and 74.3 mg, respectively), during which they were readministered the battery of tasks. Cognitive composites (mean of inhibitory control, working memory, and reaction time variability performance) were created for the baseline and medication evaluation phases. As predicted, the extent to which cognition was improved with medication compared with placebo and with 2 mg/kg compared with 1 mg/kg was greatest among children with poorer baseline cognitive function. Children with stronger baseline cognition exhibited less improvement with methylphenidate compared with placebo and did not benefit from the 2 compared with the 1 mg/kg dose. In contrast, medication-related improvement in delay discounting was unrelated to baseline discounting. Given that improving cognitive function is one potential mechanisms by which stimulants exert their therapeutic effects, this study has significant implications for understanding how and for whom stimulant medication works. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Default mode network (DMN) dysfunction is theorized to play a role in attention lapses and task errors in children with attention-deficit/hyperactivity disorder (ADHD). In ADHD, the DMN is hyperconnected to task-relevant networks, and both increased functional connectivity and reduced activation are related to poor task performance. The current study extends existing literature by considering interactions between the DMN and task-relevant networks from a brain network perspective and by assessing how these interactions relate to response control. We characterized both static and time-varying functional brain network organization during the resting state in 43 children with ADHD and 43 age-matched typically developing (TD) children. We then related aspects of network integration to go/no-go performance. We calculated participation coefficient (PC), a measure of a region's inter-network connections, for regions of the DMN, canonical cognitive control networks (fronto-parietal, salience/cingulo-opercular), and motor-related networks (somatomotor, subcortical). Mean PC was higher in children with ADHD as compared to TD children, indicating greater integration across networks. Further, higher and less variable PC was related to greater commission error rate in children with ADHD. Together, these results inform our understanding of the role of the DMN and its interactions with task-relevant networks in response control deficits in ADHD., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This study examined whether girls and boys with ADHD show similar impairments in cognitive control from childhood into adolescence and the developmental relationship between cognitive control and ADHD symptoms. Participants include 8-17-year-old children with ADHD (n = 353, 104 girls) and typically developing (TD) controls (n = 241, 86 girls) with longitudinal data obtained from n = 137. Participants completed two go/no-go (GNG) tasks that varied in working memory demand. Linear mixed-effects models were applied to compare age-related changes in cognitive control for each GNG task among girls and boys with ADHD and TD controls and in relation to ADHD symptoms. Boys with ADHD showed impaired response inhibition and increased response variability across tasks. In contrast, girls with ADHD showed impaired response inhibition only with greater working memory demands whereas they displayed increased response variability regardless of working memory demands. Analysis of age-related change revealed that deficits in cognitive control under minimal working memory demands increase with age among girls with ADHD and decrease with age among boys with ADHD. In contrast, deficits in cognitive control with greater working memory demands decrease with age among both boys and girls with ADHD compared to TD peers. Among children with ADHD poor response inhibition during childhood predicted inattentive symptoms in adolescence and was associated with less age-related improvement in inattentive symptoms. These findings suggest that girls and boys with ADHD show differential impairment in cognitive control across development and response inhibition in childhood may be an important predictor of ADHD symptoms in adolescence.

Attention-deficit/hyperactivity disorder, the most prevalent developmental disorder in childhood, is a biologically heterogenous condition characterized by impaired attention and impulse control as well as motoric hyperactivity and anomalous motor skill development. Neuropsychological testing often demonstrates impairments in motivation and reward-related decision making in attention-deficit/hyperactivity disorder, believed to indicate dysfunction of the dopamine reward pathway. Development of reliable, non-invasive, easily obtained and quantitative biomarkers correlating with the presence and severity of clinical symptoms and impaired domains of function could aid in identifying meaningful attention-deficit/hyperactivity disorder subgroups and targeting appropriate treatments. To this end, 55 (37 male) 8-12-year-old children with attention-deficit/hyperactivity disorder and 50 (32 male) age-matched, typically-developing controls were enrolled in a transcranial magnetic stimulation protocol-used previously to quantify cortical disinhibition in both attention-deficit/hyperactivity disorder and Parkinson's Disease-with a child-friendly reward motivation task. The primary outcomes were reward task-induced changes in short interval cortical inhibition and up-modulation of motor evoked potential amplitudes, evaluated using mixed model, repeated measure regression. Our results show that both reward cues and reward receipt reduce short-interval cortical inhibition, and that baseline differences by diagnosis (less inhibition in attention-deficit/hyperactivity disorder) were no longer present when reward was cued or received. Similarly, both reward cues and reward receipt up-modulated motor evoked potential amplitudes, but, differentiating the two groups, this Task-Related-Up-Modulation was decreased in children with attention-deficit/hyperactivity disorder. Furthermore, more severe hyperactive/impulsive symptoms correlated significantly with less up-modulation with success in obtaining reward. These results suggest that in children with attention-deficit/hyperactivity disorder, short interval cortical inhibition may reflect baseline deficiencies as well as processes that normalize performance under rewarded conditions. Task-Related-Up-Modulation may reflect general hypo-responsiveness in attention-deficit/hyperactivity disorder to both reward cue and, especially in more hyperactive/impulsive children, to successful reward receipt. These findings support transcranial magnetic stimulation evoked cortical inhibition and task-induced excitability as biomarkers of clinically relevant domains of dysfunction in childhood attention-deficit/hyperactivity disorder., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Previous studies in children with attention-deficit/hyperactivity disorder (ADHD) have observed functional brain network disruption on a whole-brain level, as well as on a sub-network level, particularly as related to the default mode network, attention-related networks, and cognitive control-related networks. Given behavioral findings that children with ADHD have more difficulty sustaining attention and more extreme moment-to-moment fluctuations in behavior than typically developing (TD) children, recently developed methods to assess changes in connectivity over shorter time periods (i.e., "dynamic functional connectivity"), may provide unique insight into dysfunctional network organization in ADHD. Thus, we performed a dynamic functional connectivity (FC) analysis on resting state fMRI data from 38 children with ADHD and 79 TD children. We used Hidden semi-Markov models (HSMMs) to estimate six network states, as well as the most probable sequence of states for each participant. We quantified the dwell time, sojourn time, and transition probabilities across states. We found that children with ADHD spent less total time in, and switched more quickly out of, anticorrelated states involving the default mode network and task-relevant networks as compared to TD children. Moreover, children with ADHD spent more time in a hyperconnected state as compared to TD children. These results provide novel evidence that underlying dynamics may drive the differences in static FC patterns that have been observed in ADHD and imply that disrupted FC dynamics may be a mechanism underlying the behavioral symptoms and cognitive deficits commonly observed in children with ADHD., (Copyright © 2021. Published by Elsevier Inc.)

This study examined the developmental trajectory of neurodevelopmental motor signs among boys and girls with attention-deficit/hyperactivity disorder (ADHD) and typically-developing (TD) children. Seventy children with ADHD and 48 TD children, aged 8-17 years, were evaluated on at least two time-points using the Physical and Neurological Assessment of Subtle Signs (PANESS). Age-related changes in subtle motor signs (overflow, dysrhythmia, speed) were modeled using linear mixed-effects models to compare the developmental trajectories among four subgroups (ADHD girls and boys and TD girls and boys). Across visits, both boys and girls with ADHD showed greater overflow, dysrhythmia, and slower speed on repetitive motor tasks compared to TD peers; whereas, only girls with ADHD were slower on sequential motor tasks than TD girls. Developmental trajectory analyses revealed a greater reduction in overflow with age among boys with ADHD than TD boys; whereas, trajectories did not differ among girls with and without ADHD, or among boys and girls with ADHD. For dysrhythmia and speed, there were no trajectory differences between the subgroups, with all groups showing similar reductions with age. Children with ADHD show developmental trajectories of subtle motor signs that are consistent with those of TD children, with one clear exception: Boys with ADHD show more significant reductions in overflow from childhood to adolescence than do their TD peers. Our findings affirm the presence of subtle motor signs in children with ADHD and suggest that some of these signs, particularly motor overflow in boys, resolve through adolescence while dysrhythmia and slow speed, may persist.

Attention-deficit/hyperactivity disorder (ADHD) is associated with increased risk of detrimental life outcomes. Recent research also indicates that ADHD is associated with sexual risk behavior, such as unprotected sex. Some risky sexual behaviors may be driven, in part, by preference for immediate rewards, referred to as delay discounting, which is prominent in etiological models of ADHD. Therefore, the present study examined the effect of delay on preference for both monetary and sexual outcomes in adults with many ADHD symptoms (both on and off medication) and with fewer ADHD symptoms. Online participants (N = 275; n = 161 males, n = 114 females) completed a monetary delay discounting task, assessing preference for smaller sooner versus larger delayed hypothetical money, and the Sexual Delay Discounting Task, assessing preference for condom use in hypothetical casual sex scenarios based on delay until condom availability. Those with greater ADHD symptoms discounted delayed monetary outcomes as well as delayed condom-protected sex (i.e., preferred sooner money rewards and immediate unprotected sex) significantly more than those with fewer symptoms; however, no effect of current medication use was found across monetary or sexual delay discounting among those with greater ADHD symptoms. This study is the first to demonstrate the relation between ADHD symptoms and reduced condom-use likelihood. Increased discounting of delayed condom-protected sex might constitute one mechanism of risky sexual behavior among individuals with ADHD symptoms. Interventions geared toward increasing condom use in situations in which condoms may otherwise be unavailable, may mitigate risky sexual behaviors and their associated harms in this population.

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

Irritability refers to a proneness for anger, and is a symptom of internalizing and externalizing psychopathology. Since irritability is associated with significant cross-sectional and longitudinal impairments, research on the behavioral and neural correlates of pediatric irritability in populations at risk for significant irritability is of paramount importance. Irritability can be assessed in the laboratory using behavioral paradigms that elicit frustration. Few behavioral frustration paradigms have been designed to measure the effects of frustration on cognitive control. Therefore, the goal of the present study was to validate a behavioral frustration paradigm for use in school-age children which addressed some of the limitations of prior research. Participants included children, ages 8-12 years, who were either typically developing (TD; n = 38) or diagnosed with attention-deficit/hyperactivity disorder (ADHD; n = 67), which provided a sample of children with a range of baseline irritability. All participants completed the Frustration Go/No-Go (GNG) task, and self-reported irritability was assessed using the Affective Reactivity Index. Results showed that across participants, self-reported frustration, commission error rate, and tau all increased with the addition of frustration, with similar effect sizes in ADHD and TD groups. Further, self-reported irritability, moreso than ADHD symptoms, predicted changes in self-reported frustration during the task. Together, these results support the construct validity of the Frustration GNG task as a means of assessing the effect of frustration on cognitive control. Clinical applications and future directions are discussed., (Copyright © 2019. Published by Elsevier Ltd.)

Background MRI performed with echo-planar imaging (EPI) sequences is sensitive to susceptibility artifacts in the presence of metallic objects, which presents a substantial barrier for performing functional MRI and diffusion tensor imaging (DTI) in patients with metallic orthodontic material and other head implants. Purpose To evaluate the ability to reduce susceptibility artifacts in healthy human participants wearing metallic orthodontic braces for two alternative approaches: T2-prepared functional MRI and diffusion-prepared DTI with three-dimensional fast gradient-echo readout. Materials and Methods In this prospective study conducted from February to September 2018, T2-prepared functional MRI and diffusion-prepared DTI were performed in healthy human participants. Removable dental braces with bonding trays were used so that MRI could be performed with braces and without braces in the same participants. Results were evaluated in regions with strong (EPI dropout regions for functional MRI and the inferior fronto-occipital fasciculus for DTI) and minimal (motor cortex for functional MRI and the posterior limb of internal capsule for DTI) susceptibility artifacts. Signal-to-noise ratio (SNR), contrast-to-noise ratio for functional MRI, apparent diffusion coefficient and fractional anisotropy for DTI, and degree of distortion (quantified with the Jaccard index, which measures the similarity of geometric shapes) were compared in regions with strong or minimal susceptibility effects between the current standard EPI sequences and the proposed alternatives by using paired t test. Results Six participants were evaluated (mean age ± standard deviation, 40 years ± 6; three women). In brain regions with strong susceptibility effects from the metallic braces, T2-prepared functional MRI showed significantly higher SNR (37.8 ± 2.4 vs 15.5 ± 5.3; P < .001) and contrast-to-noise ratio (0.83 ± 0.16 vs 0.29 ± 0.10; P < .001), whereas diffusion-prepared DTI showed higher SNR (5.8 ± 1.5 vs 3.8 ± 0.7; P = .03) than did conventional EPI methods. Apparent diffusion coefficient and fractional anisotropy were consistent with the literature. Geometric distortion was substantially reduced throughout the brain with the proposed methods (significantly higher Jaccard index, 0.95 ± 0.12 vs 0.81 ± 0.61; P < .001). Conclusion T2-prepared functional MRI and diffusion-prepared diffusion tensor imaging can acquire functional and diffusion MRI, respectively, in healthy human participants wearing metallic dental braces with less susceptibility artifacts and geometric distortion than with conventional echo-planar imaging. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Dietrich in this issue.

Anomalous basal ganglia morphology may contribute to deficient motor response control in children with attention-deficit/hyperactivity disorder (ADHD). This study expands upon recent evidence of sex differences in subcortical morphology and motor response control deficits among children with ADHD to examine basal ganglia volume and shape in relation to motor response control. Participants included 8-12 year-old children with ADHD (n = 52, 21 girls) and typically developing (TD) controls (n = 45, 19 girls). High resolution T1-weighted 3D MPRAGE images covering the whole brain were acquired for all participants on a 3 T scanner. Participants performed two computer-based go/no-go tasks that differed in the extent to which working memory was necessary to guide response selection. Shape-based morphometric analyses were performed in addition to traditional volumetric comparisons and correlations with measures of motor response control were examined. Boys with ADHD consistently demonstrated increased commission error rate and response variability, regardless of task demands, suggesting broad response control deficits. In contrast, response control deficits among girls with ADHD varied depending on task demands and performance measures. Volumetric reductions and inward deformation (compression) on the dorsal surface of the globus pallidus and within subregions of the putamen receiving projections from limbic, executive and motor cortices were observed in boys, but not girls, with ADHD relative to TD children. Mediation analyses revealed that putamen and globus pallidus volumes mediated the relationship between diagnosis and commission error rate. Furthermore, reduced volumes of these structures and localized inward deformation within executive and motor circuits correlated with poorer response control, particularly under conditions of increased cognitive load. These findings suggest that anomalous basal ganglia morphology is related to impaired motor response control among boys with ADHD., (Copyright © 2019. Published by Elsevier B.V.)

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

Background: Attention-deficit/hyperactivity disorder (ADHD) is associated with atypical fronto-subcortical neural circuitry and heightened delay discounting, or a stronger preference for smaller, immediate rewards over larger, delayed rewards. Recent evidence of ADHD-related sex differences in brain structure and function suggests anomalies in fronto-subcortical circuitry may differ among girls and boys with ADHD. The current study examined whether the functional connectivity (FC) within fronto-subcortical neural circuitry differs among girls and boys with ADHD compared to same-sex typically developing (TD) controls and relates to delay discounting., Methods: Participants include 8-12-year-old children with ADHD (n = 72, 20 girls) and TD controls (n = 75, 21 girls). Fronto-subcortical regions of interest were functionally defined by applying independent component analysis to resting-state fMRI data. Intrinsic FC between subcortical components, including the striatum and amygdala, and prefrontal components, including ventromedial prefrontal cortex (vmPFC), anterior cingulate cortex (ACC), and anterior dorsolateral prefrontal cortex (dlPFC), was compared across diagnostic groups overall and within sex. Correlations between intrinsic FC of the six fronto-subcortical pairs and delay discounting were also examined., Results: Both girls and boys with ADHD show atypical FC between vmPFC and subcortical regions including the striatum (stronger positive FC in ADHD) and amygdala (weaker negative FC in ADHD), with the greatest diagnostic effects among girls. In addition, girls with ADHD show atypical intrinsic FC between the striatum and dlPFC components, including stronger positive FC with ACC and stronger negative FC with dlPFC. Further, girls but not boys, with ADHD, show heightened real-time delay discounting. Brain-behavior correlations suggest (1) stronger negative FC between the striatal and dlPFC components correlated with greater money delay discounting across all participants and (2) stronger FC between the amygdala with both the dlPFC and ACC components was differentially related to heightened real-time discounting among girls and boys with and without ADHD., Conclusions: Our findings suggest fronto-subcortical functional networks are affected in children with ADHD, particularly girls, and relate to delay discounting. These results also provide preliminary evidence of greater disruptions in fronto-subcortical FC among girls with ADHD that is not due to elevated inattention symptom severity, intellectual reasoning ability, age, or head motion.

Background: Stimulant medications such as methylphenidate (MPH) are the frontline treatment for Attention-Deficit/Hyperactivity Disorder (ADHD). Despite their well-documented efficacy, the mechanisms by which stimulants improve clinical outcomes are not clear. The current study evaluated whether MPH effects on classroom behavior were mediated by improved cognitive functioning., Methods: Children with ADHD (n = 82; 9-12 years old) participated in a week-long summer research camp, consisting of cognitive testing, classroom periods, and recreational activities. After a baseline day, participants completed a 3-day randomized, double-blind, placebo-controlled trial of MPH (at doses approximating 0.3 and 0.6 mg/kg of immediate-release MPH dosed TID). Cognitive domains included inhibitory control (Stop Signal Task and prepulse inhibition of startle), attention (Continuous Performance Task and reaction time variability), and working memory (forward and backward spatial span). Clinical outcomes included math seatwork productivity and teacher-rated classroom behavior. A within-subjects path-analytic approach was used to test mediation. MPH-placebo and dose-response contrasts were used to evaluate drug effects., Results: Methylphenidate improved seatwork productivity and teacher ratings (ds = 1.4 and 1.1) and all domains of cognition (ds = 0.3-1.1). Inhibitory control (Stop Signal Task, SST) and working memory backward uniquely mediated the effect of MPH (vs. placebo) on productivity. Only working memory backward mediated the impact of MPH on teacher-rated behavior. The dose-response (0.6 vs. 0.3 mg/kg) effects were more modest for clinical outcomes (ds = 0.4 and 0.2) and cognition (ds = 0-0.3); there was no evidence of cognitive mediation of the clinical dose-response effects., Conclusions: These findings are novel in demonstrating that specific cognitive processes mediate clinical improvement with stimulant treatment for ADHD. They converge with work on ADHD theory, neurobiology, and treatment development in suggesting that inhibitory control and working memory may be mechanisms of stimulant treatment response in ADHD. More work is necessary to evaluate the degree to which these findings generalize to chronic treatment, a broader array of clinical outcomes, and nonstimulant treatments., (© 2018 Association for Child and Adolescent Mental Health.)

Cognitive neuroscience models suggest both reward valuation and cognitive control contribute to reward-based decision-making. The current study examined the relationship between cognitive control and delay discounting (i.e., choosing smaller, immediate over larger, delayed rewards) in a large sample of boys and girls diagnosed with attention-deficit/hyperactivity disorder (ADHD; N = 95) and typically developing control children (TD; N = 59). Specifically, we examined performance on multiple measures of cognitive control (i.e., Go/No-Go task, Stop Signal task, and Spatial Span task) and delay discounting (i.e., Classic Delay Discounting and Real-Time Delay Discounting tasks), as well as the relationship between these measures. Results indicated that sex moderated the effects of group on task performance. Specifically, girls with ADHD, but not boys with the disorder, exhibited atypical delay discounting of real-time rewards. Results from correlational analyses indicated that delay discounting and cognitive control were not significantly correlated in the overall sample. Multiple regression analyses demonstrated that among girls with ADHD poorer spatial working memory and inhibitory control predicted greater real-time discounting. Collectively, findings provide support for distinct patterns of cognitive control and delay discounting among school-aged girls and boys with ADHD. Additionally, findings suggest that among girls with ADHD, those who exhibit relatively poor working memory and inhibitory control might be a particularly vulnerable subgroup with the greatest propensity to exhibit maladaptive decision-making.

The current study examined whether children with ADHD were more distracted by a stimulus previously associated with reward, but currently goal-irrelevant, than their typically-developing peers. In addition, we also probed the associated cognitive and motivational mechanisms by examining correlations with other behavioral tasks. Participants included 8-12 year-old children with ADHD (n = 30) and typically developing controls (n = 26). Children were instructed to visually search for color-defined targets and received monetary rewards for accurate responses. In a subsequent search task in which color was explicitly irrelevant, we manipulated whether a distractor item appeared in a previously reward-associated color. We examined whether children responded more slowly on trials with the previously-rewarded distractor present compared to trials without this distractor, a phenomenon referred to as value-driven attentional capture (VDAC), and whether children with and without ADHD differed in the extent to which they displayed VDAC. Correlations among working memory performance, immediate reward preference (delay discounting) and attentional capture were also examined. Children with ADHD were significantly less affected by the presence of the previously rewarded distractor than were control participants. Within the ADHD group, greater value-driven attentional capture was associated with poorer working memory. Although both ADHD and control participants were initially distracted by previously reward-associated stimuli, the magnitude of distraction was larger and persisted longer among control participants.

The authors would like to correct a few minor errors in our article, none of which change the conclusions or interpretations presented.

Anomalous brain structure and function are implicated in children with attention-deficit/hyperactivity disorder (ADHD). Most neuroimaging research, however, has examined school-aged children, despite the typical onset of symptoms in early childhood. This study compared the volumes of subcortical structures (caudate nucleus, putamen, globus pallidus, and thalamus) among preschoolers with ADHD and typically developing (TD) children. High resolution T1-weighted 3D MPRAGE images covering the whole brain were acquired on a 3T scanner and subcortical volumes were automatically extracted. Analyses were conducted in a total of 87 medication-naïve preschoolers, ages 4-5 years (47 with ADHD, 40 controls; 63% boys). ADHD was diagnosed using modified DSM-IV criteria based on review of developmental history, structured psychiatric interview and caregiver ratings. Compared to typically developing children, subcortical volumes were reduced among preschoolers with ADHD, with largest reductions in the caudate, globus pallidus, and thalamus. Among girls (but not boys) with ADHD, putamen and thalamus volumes were associated with ADHD symptom severity. The observed patterns of subcortical differences in preschoolers with ADHD (larger reductions in girls), contrasted with differences observed among school-aged children, (larger reductions in boys) suggests that children with ADHD show sexual dimorphism in neuroanatomical development that parallels early trajectory of symptom onset and attenuation., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Spatial normalization of brains to a standardized space is a widely used approach for group studies in functional magnetic resonance imaging (fMRI) data. Commonly used template-based approaches are complicated by signal dropout and distortions in echo planar imaging (EPI) data. The most widely used software packages implement two common template-based strategies: (1) affine transformation of the EPI data to an EPI template followed by nonlinear registration to an EPI template (EPInorm) and (2) affine transformation of the EPI data to the anatomic image for a given subject, followed by nonlinear registration of the anatomic data to an anatomic template, which produces a transformation that is applied to the EPI data (T1norm). EPI distortion correction can be used to adjust for geometric distortion of EPI relative to the T1 images. However, in practice, this EPI distortion correction step is often skipped. We compare these template-based strategies empirically in four large datasets. We find that the EPInorm approach consistently shows reduced variability across subjects, especially in the case when distortion correction is not applied. EPInorm also shows lower estimates for coregistration distances among subjects (i.e., within-dataset similarity is higher). Finally, the EPInorm approach shows higher T values in a task-based dataset. Thus, the EPInorm approach appears to amplify the power of the sample compared to the T1norm approach when not using distortion correction (i.e., the EPInorm boosts the effective sample size by 12-25%). In sum, these results argue for the use of EPInorm over the T1norm when no distortion correction is used. Hum Brain Mapp 38:5331-5342, 2017. © 2017 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc., (© 2017 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.)

Attention-deficit/hyperactivity disorder (ADHD) is characterized by deficits in impulse control across a range of behaviors, from simple actions to those involving complex decision-making (e.g., preference for smaller-sooner versus larger later rewards). This study investigated whether changes in motor response control with increased cognitive load and motivational contingencies are associated with decision-making in the form of delay discounting among 8-12 year old children with and without ADHD. Children with ADHD (n = 26; 8 girls) and typically developing controls (n = 40; 11 girls) completed a standard go/no-go (GNG) task, a GNG task with motivational contingencies, a GNG task with increased cognitive load, and two measures of delay discounting: a real-time task in which the delays and immediately consumable rewards are experienced in real-time, and a classic task involving choices about money at longer delays. Children with ADHD, particularly girls, exhibited greater delay discounting than controls during the real-time discounting task, whereas diagnostic groups did not significantly differ on the classic discounting task. The effect of cognitive load on response control was uniquely associated with greater discounting on the real-time task for children with ADHD, but not for control children. The effect of motivational contingencies on response control was not significantly associated with delay discounting for either diagnostic group. The findings from this study help to inform our understanding of the factors that influence deficient self-control in ADHD, suggesting that impairments in cognitive control may contribute to greater delay discounting in ADHD.

There has been limited investigation of volume and shape difference in subcortical structures in children with ADHD and a paucity of examination of the influence of sex on these findings. The objective of this study was to examine morphology (volume and shape) of subcortical structures and their association with emotion dysregulation (ED) in girls and boys with ADHD as compared to their typically-developing (TD) counterparts. Participants included 218 children ages 8-12 years old with and without DSM-IV ADHD. Structural magnetic resonance images were obtained, and shape analyses were conducted using large deformation diffeomorphic metric mapping (LDDMM). Compared to TD boys, boys with ADHD showed reduced volumes in the bilateral globus pallidus and amygdala. There were no volumetric differences in any structure between ADHD and TD girls. Shape analysis revealed localized compressions within the globus pallidus, putamen and amygdala in ADHD boys relative to TD boys, as well as significant correlations between increased ED and unique subregion expansion in right globus pallidus, putamen, and right amygdala. Our findings suggest a sexually dimorphic pattern of differences in subcortical structures in children with ADHD compared to TD children, and a possible neurobiological mechanism by which boys with ADHD demonstrate increased difficulties with ED., (Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.)

This study examined the degree to which reinforcement, stimulant medication, and their combination impact response inhibition in children with Attention-Deficit/Hyperactivity Disorder (ADHD). Across three studies, participants with ADHD (n = 111, 25 girls) and typically-developing (TD) controls (n = 33, 6 girls) completed a standard version of the stop signal task (SST) and/or a reinforcement-manipulation SST with performance-contingent points. In two of these studies, these tasks were performed under placebo or 0.3 and 0.6 mg/kg methylphenidate (MPH) conditions. Cross-study comparisons were conducted to test hypotheses regarding the separate and combined effects of reinforcement and methylphenidate on response inhibition among children with ADHD relative to TD controls. Baseline response inhibition was worse among children with ADHD compared to controls. MPH produced dose-related improvements in response inhibition in children with ADHD; compared to non-medicated TD controls, 0.3 mg/kg MPH normalized deficient response inhibition, and 0.6 mg/kg MPH resulted in better inhibition in children with ADHD. Reinforcement improved response inhibition to a greater extent for children with ADHD than for TD children, normalizing response inhibition. The combination of MPH and reinforcement improved response inhibition among children with ADHD compared to reinforcement alone and MPH alone, also resulting in normalization of response inhibition despite repeated task exposure. Deficient response inhibition commonly observed in children with ADHD is significantly improved with MPH and/or reinforcement, normalizing inhibition relative to TD children tested under standard conditions.

Children with attention-deficit hyperactivity disorder (ADHD) consistently show impaired response control, including deficits in response inhibition and increased intrasubject variability (ISV) compared to typically-developing (TD) children. However, significantly less research has examined factors that may influence response control in individuals with ADHD, such as task or participant characteristics. The current study extends the literature by examining the impact of increasing cognitive demands on response control in a large sample of 81children with ADHD (40 girls) and 100 TD children (47 girls), ages 8-12 years. Participants completed a simple Go/No-Go (GNG) task with minimal cognitive demands, and a complex GNG task with increased cognitive load. Results showed that increasing cognitive load differentially impacted response control (commission error rate and tau, an ex-Gaussian measure of ISV) for girls, but not boys, with ADHD compared to same-sex TD children. Specifically, a sexually dimorphic pattern emerged such that boys with ADHD demonstrated higher commission error rate and tau on both the simple and complex GNG tasks as compared to TD boys, whereas girls with ADHD did not differ from TD girls on the simple GNG task, but showed higher commission error rate and tau on the complex GNG task. These findings suggest that task complexity influences response control in children with ADHD in a sexually dimorphic manner. The findings have substantive implications for the pathophysiology of ADHD in boys versus girls with ADHD.

The aim of this study was to examine delay discounting in girls and boys with ADHD-Combined type (ADHD-C) relative to typically developing (TD) children on two tasks that differ in the extent to which the rewards and delays were experienced by participants. Children ages 8-12 years with ADHD-C (n=65; 19 girls) and TD controls (n=55; 15 girls) completed two delay discounting tasks involving a series of choices between smaller, immediate and larger, delayed rewards. The classic delay discounting task involved choices about money at delays of 1-90 days and only some of the outcomes were actually experienced by the participants. The novel real-time discounting task involved choices about an immediately consumable reward (playing a preferred game) at delays of 25-100 s, all of which were actually experienced by participants. Participants also provided subjective ratings of how much they liked playing the game and waiting to play. Girls with ADHD-C displayed greater delay discounting compared to boys with ADHD-C and TD girls and boys on the real-time discounting task. Diagnostic group differences were not evident on the classic discounting task. In addition, children with ADHD-C reported wanting to play the game more and liking waiting to play the game less than TD children. This novel demonstration of greater delay discounting among girls with ADHD-C on a discounting task in which the rewards are immediately consumable and the delays are experienced in real-time informs our understanding of sex differences and motivational processes in children with ADHD. (JINS, 2016, 22, 12-23).

Objective: Sexual dimorphism is evident in attention-deficit/hyperactivity disorder (ADHD), including subtype prevalence, adverse outcomes, and neural phenotype. Neurobiological studies of ADHD suggest that boys show more abnormalities in motor and premotor structure and function, whereas girls differ from typically developing (TD) peers in prefrontal circuitry. We applied diffusion tensor imaging (DTI) to identify ADHD-related sex-specific differences in motor/premotor and prefrontal white matter (WM) microstructure in children., Method: DTI estimated differences in WM microstructure among 120 children 8 to 12 years of age, 60 with ADHD (30 boys and 30 girls) and 60 controls (30 boys and 30 girls), matched on age, IQ, and handedness. Effects of diagnosis and sex on fractional anisotropy (FA) were assessed in motor/premotor and prefrontal regions. Group differences in FA and associations with response control (e.g., reaction time variability [CVRT] and commission error rate) were examined separately within sex., Results: Sex-by-diagnosis interactions were observed for FA in primary motor (M1) and medial orbitofrontal (MOFC) cortex. Post hoc tests revealed that boys with ADHD showed bilateral reductions in FA within M1, compared with TD peers; in contrast, girls with ADHD showed higher FA bilaterally within MOFC. Decreased M1 FA was associated with higher CVRT in boys and higher commission error rates in girls. For MOFC, lower FA was associated with greater CVRT and commission error rates across all participants with ADHD., Conclusion: ADHD affects the white matter of boys and girls differently; boys appear to be more affected in regions responsible for control of basic actions, whereas girls show more abnormalities in regions responsible for higher-level, top-down control., (Copyright © 2015 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Motor overflow is a developmental phenomenon that typically disappears by late childhood. Abnormal persistence of motor overflow is often present in children with attention-deficit/hyperactivity disorder (ADHD). This study employed functional magnetic resonance imaging (fMRI) during a finger-sequencing task to examine whether excessive motor overflow in children with ADHD is associated with decreased extent of motor circuit activation. Thirty-four right-handed children (18 typically developing controls, 16 ADHD) completed fMRI while performing a finger-sequencing task. Motor overflow was evaluated during a finger-sequencing task and a motor examination (the PANESS) performed outside the scanner. Diagnostic differences in behavioral measures of overflow and extent of activation in the contralateral and ipsilateral motor network ROIs were examined, along with correlations between overflow and extent of activation. Children with ADHD demonstrated greater overflow and lesser extent of activation in left primary motor cortex (BA4) and bilateral premotor cortex (BA6) and supplementary motor area (SMA) during right-hand finger-sequencing compared to controls. Decreased extent of primary motor and premotor activation correlated with increased hand-related overflow movements in children with ADHD but not controls. These findings suggest that overflow movements in children with ADHD may reflect decreased recruitment of neural circuitry involved in active inhibition of homologous motor circuitry unnecessary to task execution., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

This study examined the impact of motivational contingencies (reinforcement and punishment) on go/no-go (GNG) task performance in girls and boys with ADHD relative to typically developing (TD) children and associations with prefrontal anatomy. Children ages 8-12 with ADHD (n=107, 36 girls) and TD controls (n=95, 34 girls) completed a standard and a motivational GNG task and associations with prefrontal cortex (PFC) surface area were examined. Intrasubject variability (ISV) was lower during the motivational compared to the standard GNG among TD girls and boys, and boys with ADHD, but not among girls with ADHD. A greater reduction in ISV was associated with greater PFC surface area among children with ADHD. This novel demonstration of improvement in ISV with motivational contingencies for boys, but not girls, with ADHD and associations with PFC anatomy informs our understanding of sex differences and motivational factors contributing to ISV in children with ADHD., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Attention Deficit/Hyperactivity Disorder is associated with cognitive deficits and dysregulated motivation. Reinforcement improves cognitive performance, often to a greater degree among children with ADHD compared to typically-developing controls. The current study tests the degree to which cognitive (individual differences in baseline cognition) and/or motivational (individual differences in Sensitivity to Reward; SR) processes can account for diagnostic group differences in reinforcement effects., Methods: Participants were 58 children (25 ADHD, 33 control) ages 9-12. Children completed measures of inhibitory control (Stop Signal Task), working memory (n-back), and sustained attention (Continuous Performance Task) during a baseline week and again one week later under reinforcement and no-reinforcement conditions; composites were computed across cognitive domains. Parent-and child-reported trait SR (SPSRQ; BIS/BAS) were combined to index a child's response towards appetitive, rewarding stimuli., Results: In separate analyses, diagnostic group, individual differences in baseline cognition, and individual differences in SR all moderated the impact of reinforcement on cognition. When considered together, the Diagnostic Group × Reinforcement and Baseline Cognition × Reinforcement interactions both remained robust. In contrast, neither the Diagnostic Group × Reinforcement nor the SR × Reinforcement interactions accounted for unique variance when evaluated together., Conclusions: Both baseline cognition and trait SR predict reinforcement effects on cognition, but only SR shares significant variance with diagnostic group. These results suggest that ADHD children's greater response to reinforcement on cognition is strongly related to their heightened trait sensitivity to rewarding stimuli, consistent with motivational models of ADHD.

Sustained attention and reinforcement are posited as causal mechanisms in Attention-Deficit/Hyperactivity Disorder (ADHD), but their interaction has received little empirical study. In two studies, we examined the impact of performance-based reinforcement on sustained attention over time, or vigilance, among 9- to 12-year-old children. Study 1 demonstrated the expected vigilance deficit among children with ADHD (n = 25; 12% female) compared to typically developing (TD) controls (n = 33; 22% female) on a standard continuous performance task (CPT). During a subsequent visit, reinforcement improved attention more among children with ADHD than controls. Study 2 examined the separate and combined effects of reinforcement and acute methylphenidate (MPH) on CPT performance in children with ADHD (n = 19; 21% female). Both reinforcement and MPH enhanced overall target detection and attenuated the vigilance decrement that occurred in no-reinforcement, placebo condition. Cross-study comparisons suggested that the combination of MPH and reinforcement eliminated the vigilance deficit in children with ADHD, normalizing sustained attention. This work highlights the clinically and theoretically interesting intersection of reinforcement and sustained attention.

Rewards have been shown to improve behavior and cognitive processes implicated in attention-deficit hyperactivity disorder (ADHD), but the information-processing mechanisms by which these improvements occur remain unclear. We examined the effect of performance-based rewards on ERPs related to processing of the primary task stimuli, errors, and feedback in children with ADHD and typically developing controls. Participants completed a flanker task containing blocks with and without performance-based rewards. Children with ADHD showed reduced amplitude of ERPs associated with processing of the flanker stimuli (P3) and errors (ERN, Pe), but did not differ in feedback-processing (FRN). Rewards enhanced flanker-related P3 amplitude similarly across groups and error-related Pe amplitude differentially for children with ADHD. These findings suggest that rewards may improve cognitive deficits in children with ADHD through enhanced processing of relevant stimuli and increased error evaluation., (Copyright © 2013 Society for Psychophysiological Research.)

Rationale: Abstinence from smoking disrupts performance in multiple cognitive domains, and such cognitive effects may serve to maintain smoking behavior. Rather than having specific effects on a narrow domain of processing, abstinence may disrupt more general cognitive control processes and/or motivation., Objectives: The present study tested the prediction that overnight abstinence from smoking would disrupt a general performance monitoring system indexed via the error-related negativity (ERN). A secondary aim was to determine the extent to which performance-based monetary rewards improved the ERN among smokers and whether the effect of the reward was diminished during abstinence., Methods: The ERN was assessed during a flanker task among 25 heavy, non-treatment-seeking smokers both when smoking as usual and after overnight abstinence; reward and no-reward trial blocks occurred within each session., Results: As predicted, mean ERN amplitude was reduced during abstinence. The ERN was enhanced by reward; this effect did not vary with smoking abstinence., Conclusion: This study provides novel data which suggest that acute abstinence from smoking disrupts a neurophysiological index of a general performance monitoring system that is involved in a range of cognitive functions. The ERN may be a useful complement to narrow-band cognitive studies of abstinence and interventions designed to target cognition in addiction. Because the ERN was concurrently sensitive to abstinence and performance-based incentives, it may be particularly useful for examining the interplay of cognition and motivation in smoking and smoking cessation.