Methylphenidate normalises activation and functional connectivity deficits in attention and motivation networks in medication-naïve children with ADHD during a rewarded continuous performance task Neural Correlates of the Propensity for Retaliatory Behavior in Youths With Disruptive Behavior Disorders. Brain gray matter deficits at 33-year follow-up in adults with attention-deficit/hyperactivity disorder established in childhood. Preschool children with disruptive behavior: three-year outcome as a function of adaptive disability. Clinical symptoms and performance on the continuous performance test in children with attention deficit hyperactivity disorder between subtypes: a natural follow-up study for 6 months A Randomized, Double-Blind, Sham-Controlled Trial of Transcranial Direct Current Stimulation in Attention-Deficit/Hyperactivity Disorder Methylphenidate Normalizes Fronto-Striatal Underactivation During Interference Inhibition in Medication-Naïve Boys with Attention-Deficit Hyperactivity Disorder Longitudinal mapping of cortical thickness and clinical outcome in children and adolescents with attention-deficit/hyperactivity disorder. Methylphenidate Normalizes Frontocingulate Underactivation During Error Processing in Attention-Deficit/Hyperactivity Disorder Real‐time fMRI neurofeedback in adolescents with attention deficit hyperactivity disorder Association and linkage of alpha-2A adrenergic receptor gene polymorphisms with childhood ADHD. Impulsiveness as a timing disturbance: neurocognitive abnormalities in attention-deficit hyperactivity disorder during temporal processes and normalization with methylphenidate Reward processing in male adults with childhood ADHD—a comparison between drug-naïve and methylphenidate-treated subjects Co-morbid disruptive behavior disorder and aggression predict functional outcomes and differential response to risperidone versus divalproex in pharmacotherapy for pediatric bipolar disorder. Developmental trajectories of brain volume abnormalities in children and adolescents with attention-deficit/hyperactivity disorder. A Randomized Controlled Trial Investigating the Effects of Neurofeedback, Methylphenidate, and Physical Activity on Event-Related Potentials in Children with Attention-Deficit/Hyperactivity Disorder. Methylphenidate Normalizes Resting-State Brain Dysfunction in Boys With Attention Deficit Hyperactivity Disorder
BACKGROUND Children with Attention Deficit Hyperactivity Disorder ( ADHD ) have deficits in motivation and attention that can be ameliorated with the indirect dopamine agonist Methylpheni date ( MPH ) . We used functional magnetic resonance imaging ( fMRI ) to investigate the effects of MPH in medication-naïve children with ADHD on the activation and functional connectivity of " cool " attentional as well as " hot " motivation networks . METHODS 13 medication-naïve children with ADHD were scanned twice , under either an acute clinical dose of MPH or Placebo , in a r and omised , double-blind design , while they performed a rewarded continuous performance task that measured vigilant selective attention and the effects of reward . Brain activation and functional connectivity was compared to that of 13 healthy age-matched controls to test for normalisation effects of MPH . RESULTS MPH normalised performance deficits that were observed in children with ADHD compared to controls . Under placebo , children with ADHD showed reduced activation and functional inter-connectivity in bilateral fronto-striato-parieto-cerebellar networks during the attention condition , but enhanced activation in the orbitofrontal and superior temporal cortices for reward . MPH within children with ADHD enhanced the activation of fronto-striato-cerebellar and parieto-temporal regions . Compared to controls , MPH normalised differences during vigilant attention in parieto-temporal activation and fronto-striatal and fronto-cerebellar connectivity ;  MPH also normalised the enhanced orbitofrontal activation in children with ADHD in response to reward . CONCLUSIONS MPH normalised attention differences between children with ADHD and controls by both up-regulation of dysfunctional fronto-striato-thalamo-cerebellar and parieto-temporal attention networks and down-regulation of hyper-sensitive orbitofrontal activation for reward processing . MPH thus shows context -dependent dissociative modulation of both motivational and attentional neuro-functional networks in children with ADHD OBJECTIVE Youths with disruptive behavior disorders ( DBD ) ( conduct disorder and oppositional defiant disorder ) have an elevated risk for maladaptive reactive aggression . Theory suggests that this is due to an elevated sensitivity of basic threat circuitry implicated in retaliation ( amygdala/periaqueductal gray ) in youths with DBD and low levels of callous-unemotional traits and dysfunctional regulatory activity in the ventromedial prefrontal cortex in youths with DBD irrespective of callous-unemotional traits . METHOD A total of 56 youths 10 - 18 years of age ( 23 of them female ) participated in the study : 30 youths with DBD , divided by median split into groups with high and low levels of callous-unemotional traits , and 26 healthy youths . All participants completed an ultimatum game task during functional MRI . RESULTS Relative to the other groups , youths with DBD and low levels of callous-unemotional traits showed greater increases in activation of basic threat circuitry when punishing others and dysfunctional down-regulation of the ventromedial prefrontal cortex during retaliation . Relative to healthy youths , all youths with DBD showed reduced amygdala-ventromedial prefrontal cortex connectivity during high provocation . Ventromedial prefrontal cortex responsiveness and ventromedial prefrontal cortex-amygdala connectivity were related to patients ' retaliatory propensity ( behavioral responses during the task ) and parent-reported reactive aggression . CONCLUSIONS These data suggest differences in the underlying neurobiology of maladaptive reactive aggression in youths with DBD who have relatively low levels of callous-unemotional traits . Youths with DBD and low callous-unemotional traits alone showed significantly greater threat responses during retaliation relative to comparison subjects . These data also suggest that ventromedial prefrontal cortex-amygdala connectivity is critical for regulating retaliation/reactive aggression and , when dysfunctional , contributes to reactive aggression , independent of level of callous-unemotional traits CONTEXT Volumetric studies have reported relatively decreased cortical thickness and gray matter volumes in adults with attention-deficit/hyperactivity disorder ( ADHD ) whose childhood status was retrospectively recalled . We present , to our knowledge , the first prospect i ve study combining cortical thickness and voxel-based morphometry in adults diagnosed as having ADHD in childhood . OBJECTIVES To test whether adults with combined-type childhood ADHD exhibit cortical thinning and decreased gray matter in regions hypothesized to be related to ADHD and to test whether anatomic differences are associated with a current ADHD diagnosis , including persistent vs remitting ADHD . DESIGN Cross-sectional analysis embedded in a 33-year prospect i ve follow-up at a mean age of 41.2 years . SETTING Research outpatient center . PARTICIPANTS We recruited prob and s with ADHD from a cohort of 207 white boys aged 6 to 12 years . Male comparison participants ( n = 178 ) were free of ADHD in childhood . We obtained magnetic resonance images in 59 prob and s and 80 comparison participants ( 28.5 % and 44.9 % of the original sample s , respectively ) . MAIN OUTCOME MEASURES Whole-brain voxel-based morphometry and vertexwise cortical thickness analyses . RESULTS The cortex was significantly thinner in ADHD prob and s than in comparison participants in the dorsal attentional network and limbic areas ( false discovery rate < 0.05 , corrected ) . In addition , gray matter was significantly decreased in prob and s in the right cau date , right thalamus , and bilateral cerebellar hemispheres . Prob and s with persistent ADHD ( n = 17 ) did not differ significantly from those with remitting ADHD ( n = 26 ) ( false discovery rate < 0.05 ) . At uncorrected P < .05 , individuals with remitting ADHD had thicker cortex relative to those with persistent ADHD in the medial occipital cortex , insula , parahippocampus , and prefrontal regions . CONCLUSIONS Anatomic gray matter reductions are observable in adults with childhood ADHD , regardless of the current diagnosis . The most affected regions underpin top-down control of attention and regulation of emotion and motivation . Exploratory analyses suggest that diagnostic remission may result from compensatory maturation of prefrontal , cerebellar , and thalamic circuitry A significant discrepancy between intelligence and daily adaptive functioning , or adaptive disability ( AD ) , has been previously found to be a associated with significant psychological morbidity in preschool children with disruptive behavior ( DB ) . The utility of AD as a predictor of later developmental risks was examined in a 3-year longitudinal study of normal ( N = 43 ) and DB preschool children . The DB children were grouped into those with AD ( DB+AD ; N = 28 ) and those without AD ( DB-only ; N = 98 ) . All children were followed with annual evaluations to the end of second grade . Both DB groups demonstrated substantial and pervasive psychological and educational morbidity at 3-year follow-up . In comparison to DB-only children , DB+AD children had more symptoms of attention-deficit hyperactivity disorder ( ADHD ) and conduct disorder ( CD ) , more severe and pervasive behavior problems at home , more parent-rated externalizing and internalizing , and lower academic competence and more behavioral problems at school . Parents of DB+AD children also reported greater parenting stress than did parents in the other groups . A significant contribution of AD to adverse outcomes in the DB group remained on some measures even after controlling for initial severity of DB . AD also contributed significantly to CD symptoms at follow-up after controlling for initial DB severity and initial CD symptoms . The results corroborate and extend earlier findings of the utility of AD as a risk indicator above severity of DB alone . They also imply that AD in the context of normal intellectual development may arise from both the deficient self-regulation associated with ADHD and from disrupted parenting . with exposure to kindergarten moderating these adverse effects Background The aims of this study were to determine the time course of improvements in attention deficit hyperactivity disorder ( ADHD ) clinical symptoms and neurocognitive function in a realistic clinical setting , and the differences in ADHD symptom improvement using different classifications of ADHD subtypes . Methods The Child Behavior Checklist ( CBCL ) was completed by parents of ADHD children at the initial visit . The  computerized Continuous Performance Test ( CPT ) , Swanson , Nolan , and Pelham , and Version IV Scale for ADHD ( SNAP-IV ) , and  ADHD Rating Scale ( ADHD-RS ) were performed at baseline , one month , three months , and six months later , respectively . Patient care including drug therapy was performed at the discretion of the psychiatrist . The ADHD patients were divided into DSM-IV subtypes ( Inattentive , Hyperactive-impulsive and Combined type ) , and were additionally categorized into aggressive and non-aggressive subtypes by aggression scale in CBCL for comparisons . Results There were 50 ADHD patients with a mean age of 7.84 ± 1.64 years ; 15 of them were inattentive type , 11 were hyperactive-impulsive type , and 24 were combined type . In addition , 28 of the ADHD patients were grouped into aggressive and 22 into non-aggressive subtypes . There were significant improvements in clinical symptoms of hyperactivity and inattention , and impulsivity performance in CPT during the 6-month treatment . The clinical hyperactive symptoms were significantly different between ADHD patients sub-grouping both by DSM-IV and aggression . Non-aggressive patients had significantly greater changes in distraction and impulsivity performances in CPT from baseline to month 6 than aggressive patients . Conclusions We found that ADHD symptoms , which included impulsive performances in CPT and clinical inattention and hyperactivity dimensions , had improved significantly over 6 months under pragmatic treatments . The non-aggressive ADHD patients might have a higher potential for improving in CPT performance than aggressive ones . However , it warrant further investigation whether the different classifications of ADHD patients could be valid for predicting the improvements in ADHD patients ' clinical symptoms and neurocognitive performance Background Current st and ardized treatments for cognitive impairment in attention-deficit/hyperactivity disorder remain limited and their efficacy restricted . Transcranial direct current stimulation ( tDCS ) is a promising tool for enhancing cognitive performance in several neuropsychiatric disorders . Nevertheless , the effects of tDCS in reducing cognitive impairment in patients with attention-deficit/hyperactivity disorder ( ADHD ) have not yet been investigated . Methods A parallel , r and omized , double-blind , sham-controlled trial was conducted to examine the efficacy of tDCS on the modulation of inhibitory control in adults with ADHD . Thirty patients were r and omly allocated to each group and performed a go/no-go task before and after a single session of either anodal stimulation ( 1 mA ) over the left dorsolateral prefrontal cortex or sham stimulation . Results A nonparametric two- sample Wilcoxon rank-sum ( Mann-Whitney ) test revealed no significant differences between the two groups of individuals with ADHD ( tDCS vs. sham ) in regard to behavioral performance in the go/no go tasks . Furthermore , the effect sizes of group differences after treatment for the primary outcome measures —correct responses , impulsivity and omission errors — were small . No adverse events result ing from stimulation were reported . Conclusion According to these findings , there is no evidence in support of the use of anodal stimulation over the left dorsolateral prefrontal cortex as an approach for improving inhibitory control in ADHD patients . To the best of our knowledge , this is the first clinical study to assess the cognitive effects of tDCS in individuals with ADHD . Further research is needed to assess the clinical efficacy of tDCS in this population . Trial Registration Clinical Trials.gov Youth with attention deficit hyperactivity disorder ( ADHD ) have deficits in interference inhibition , which can be improved with the indirect catecholamine agonist methylpheni date ( MPH ) . Functional magnetic resonance imaging was used to investigate the effects of a single dose of MPH on brain activation during interference inhibition in medication-naïve ADHD boys . Medication-naïve boys with ADHD were scanned twice , in a r and omized , double-blind design , under either a single clinical dose of MPH or placebo , while performing a Simon task that measures interference inhibition and controls for the oddball effect of low-frequency appearance of incongruent trials . Brain activation was compared within patients under either drug condition . To test for potential normalization effects of MPH , brain activation in ADHD patients under either drug condition was compared with that of healthy age-matched comparison boys . During incongruent trials compared with congruent – oddball trials , boys with ADHD under placebo relative to controls showed reduced brain activation in typical areas of interference inhibition , including right inferior prefrontal cortex , left striatum and thalamus , mid-cingulate/supplementary motor area , and left superior temporal lobe . MPH relative to placebo  upregulated brain activation in right inferior prefrontal and premotor cortices . Under the MPH condition , patients relative to controls no longer showed the reduced activation in right inferior prefrontal and striato-thalamic regions . Effect size comparison , furthermore , showed that these normalization effects were significant . MPH significantly normalized the fronto-striatal underfunctioning in ADHD patients relative to controls during interference inhibition , but did not affect medial frontal or temporal dysfunction .  MPH therefore appears to have a region-specific upregulation effect on fronto-striatal activation CONTEXT Data from a previous prospect i ve study of lobar volumes in children with attention-deficit/hyperactivity disorder ( ADHD ) are reexamined using a measure of cortical thickness . OBJECTIVE To determine whether regional differences in cortical thickness or cortical changes across time characterize ADHD and predict or reflect its clinical outcome . DESIGN , SETTING , AND PARTICIPANTS Longitudinal study of 163 children with ADHD ( mean age at entry , 8.9 years ) and 166 controls recruited mainly from a local community in Maryl and . Participants were assessed with magnetic resonance imaging . Ninety-seven patients with ADHD ( 60 % ) had 2 or more images and baseline and follow-up clinical evaluations  ( mean follow-up , 5.7 years ) . MAIN OUTCOME MEASURES Cortical thickness across the cerebrum . Patients with ADHD were divided into better and worse outcome groups on the basis of a mean split in scores on the Children 's Global Assessment Scale and persistence/remission of DSM-IV-defined ADHD . RESULTS Children with ADHD had global thinning of the cortex ( mean reduction , -0.09 mm ; P=.02 ) , most prominently in the medial and superior prefrontal and pre central regions . Children with worse clinical outcome had a thinner left medial prefrontal cortex at baseline than the better outcome group ( -0.38 mm ; P=.003 ) and controls ( -0.25 mm ; P=.002 ) . Cortical thickness developmental trajectories did not differ significantly between the ADHD and control groups throughout except in the right parietal cortex , where trajectories converged . This normalization of cortical thickness occurred only in the better outcome group . CONCLUSIONS Children with ADHD show relative cortical thinning in regions important for attentional control . Children with a worse outcome have " fixed " thinning of the left medial prefrontal cortex , which may compromise the anterior attentional network and encumber clinical improvement . Right parietal cortex thickness normalization in patients with a better outcome may represent compensatory cortical change Background Children with attention-deficit/hyperactivity disorder ( ADHD ) have deficits in performance monitoring often improved with the indirect catecholamine agonist methylpheni date ( MPH ) . We used functional magnetic resonance imaging to investigate the effects of single-dose MPH on activation of error processing brain areas in medication-naive boys with ADHD during a stop task that elicits 50 % error rates . Methods Twelve medication-naive boys with ADHD were scanned twice , under either a single clinical dose of MPH or placebo , in a r and omized , double-blind design while they performed an individually adjusted tracking stop task , design ed to elicit 50 % failures . Brain activation was compared within patients under either drug condition . To test for potential normalization effects of MPH , brain activation in ADHD patients under either drug condition was compared with that of 13 healthy age-matched boys . Results During failed inhibition , boys with ADHD under placebo relative to control subjects showed reduced brain activation in performance monitoring areas of dorsomedial and left ventrolateral prefrontal cortices , thalamus , cingulate , and parietal regions . MPH , relative to placebo , upregulated activation in these brain regions within patients and normalized all activation differences between patients and control subjects . During successful inhibition , MPH normalized reduced activation observed in patients under placebo compared with control subjects in parietotemporal and cerebellar regions . Conclusions MPH normalized brain dysfunction in medication-naive ADHD boys relative to control subjects in typical brain areas of performance monitoring , comprising left ventrolateral and dorsomedial frontal and parietal cortices . This could underlie the amelioration of MPH of attention and academic performance in ADHD Abstract Attention Deficit Hyperactivity Disorder ( ADHD ) is associated with poor self‐control , underpinned by inferior fronto‐striatal deficits . Real‐time functional magnetic resonance neurofeedback ( rtfMRI‐NF ) allows participants to gain self‐control over dysregulated brain regions . Despite evidence for beneficial effects of electrophysiological‐NF on ADHD symptoms , no study has applied the spatially superior rtfMRI‐NF neurotherapy to ADHD . A r and omized controlled trial tested the efficacy of rtfMRI‐NF of right inferior prefrontal cortex ( rIFG ) , a key region that is compromised in ADHD and upregulated with psychostimulants , on improvement of ADHD symptoms , cognition , and inhibitory fMRI activation . To control for region‐specificity , an active control group received rtfMRI‐NF of the left parahippocampal gyrus ( lPHG ) . Thirty‐one ADHD boys were r and omly allocated and had to learn to upregulate their target brain region in an average of 11 rtfMRI‐NF runs over 2 weeks . Feedback was provided through a video‐clip of a rocket that had to be moved up into space . A transfer session without feedback tested learning retention as a proximal measure of transfer to everyday life . Both NF groups showed significant linear activation increases with increasing number of runs in their respective target regions and significant reduction in ADHD symptoms after neurotherapy and at 11‐month follow‐up . Only the group targeting rIFG , however , showed a transfer effect , which correlated with ADHD symptom reductions , improved at trend level in sustained attention , and showed increased IFG activation during an inhibitory fMRI task . This proof‐of‐concept study demonstrates for the first time feasibility , safety , and shorter‐ and longer‐term efficacy  of rtfMRI‐NF of rIFG in adolescents with ADHD . Hum Brain Mapp 38:3190–3209 , 2017 . © 2017 The Authors Human Brain Mapping Published by Wiley Periodicals , Attention-deficit hyperactivity disorder ( ADHD ) is a heritable disorder , prevalent from childhood through adulthood . Although the noradrenergic ( NA ) system is thought to mediate a portion of the pathophysiology of ADHD , genes in this pathway have not been investigated as frequently as those in the dopaminergic system . Previous association studies of one c and i date gene in the NA system , ADRA2A , showed inconsistent results with regard to an MspI polymorphism . In the current study , two nearby single-nucleotide polymorphisms , which define HhaI and DraI restriction fragment length polymorphisms , were also genotyped and were in significant linkage disequilibrium with the MspI RFLP . Transmission disequilibrium tests ( TDTs ) in a sample of 177 nuclear families showed significant association and linkage of the DraI polymorphism with the ADHD combined subtype ( P=0.03 ) , and the quantitative TDT showed association of this polymorphism with the inattentive ( P=0.003 ) and hyperactive-impulsive ( P=0.015 ) symptom dimensions . The haplotype that contained the less common allele of the DraI polymorphism likewise showed a strong relationship with the inattentive ( P=0.001 ) and hyperactive-impulsive ( P=0.004 ) symptom dimensions . This study supports the hypothesis that an allele of the ADRA2A gene is associated and linked with the ADHD combined subtype and suggests that the DraI polymorphism of ADRA2A is linked to a causative polymorphism We argue that impulsiveness is characterized by compromised timing functions such as premature motor timing , decreased tolerance to delays , poor temporal foresight and steeper temporal discounting . A model illustration for the association between impulsiveness and timing deficits is the impulsiveness disorder of attention-deficit hyperactivity disorder ( ADHD ) . Children with ADHD have deficits in timing processes of several temporal domains and the neural substrates of these compromised timing functions are strikingly similar to the neuropathology of ADHD . We review our published and present novel functional magnetic resonance imaging data to demonstrate that ADHD children show dysfunctions in key timing regions of prefrontal , cingulate , striatal and cerebellar location during temporal processes of several time domains including time discrimination of milliseconds , motor timing to seconds and temporal discounting of longer time intervals . Given that impulsiveness , timing abnormalities and more specifically ADHD have been related to dopamine dysregulation , we tested for and demonstrated a normalization effect of all brain dysfunctions in ADHD children during time discrimination with the dopamine agonist and treatment of choice , methylpheni date . This review together with the new empirical findings demonstrates that neurocognitive dysfunctions in temporal processes are crucial to the impulsiveness disorder of ADHD and provides first evidence for normalization with a dopamine reuptake inhibitor Rationale Dysfunctional reward processing has been proposed as a main deficit in attention-deficit/hyperactivity disorder ( ADHD ) , which could be modulated by treatment with methylpheni date ( MPH ) . Objectives We examined differences in reward processing in adulthood ( independent of actual ADHD ) depending on MPH treatment during childhood . Methods Eleven males with childhood ADHD treated with MPH , 12 drug-naïve males with childhood ADHD , and 12 controls matched by age , h and edness , and smoking behavior were studied drug-free using functional magnetic resonance imaging . BOLD-responses  were compared during a monetary incentive delay task using an ANOVA design focusing on the ventral striatum during anticipation and the orbitofrontal cortex during outcome . Results Controls , drug-naïve , and treated subjects did not differ significantly in their activations in the ventral striatum and orbitofrontal cortex . Explorative analyses revealed decreased insula activation during outcome of loss avoidance in drug-naïve subjects in comparison to both groups , while treated subjects did not differ from controls . Insula activation correlated significantly positive with harm avoidance in the treated group . Furthermore , comparing subjects with actual ADHD symptoms , remitters and controls we observed decreased putamen activition in ADHD persisters . Conclusions Basal ganglia reward processing seemed to be unrelated to MPH pretreatment , but was related to remission . On the other h and , the revealed differences between treated and drug-naïve subjects with childhood ADHD , i.e. , in the insula , give evidence for more pronounced abnormal activation in reward-associated brain regions in untreated subjects with childhood ADHD and underpin the need of prospect i ve studies on long-term effects of psychostimulant treatment OBJECTIVE Co-morbid diagnoses , such as disruptive behavior disorders ( DBDs ) and high levels of aggression , are extremely common among youth with pediatric bipolar disorder ( PBD ) and may interfere with treatment response ; however , they have rarely been examined as predictors of response to pharmacotherapy . The current study examines co-morbid DBD and aggression prospect ively as predictors of pharmacotherapy outcome , as well as potential moderators of response to a specific medication ( risperidone vs. divalproex ) , among children with PBD . METHODS Data are from a prospect i ve 6-week double-blind , placebo-controlled , r and omized outpatient medication treatment trial of risperidone versus divalproex for manic episodes in 65 children 8 - 18 with PBD . Outcome measures were administered at pretest , post-test , and weekly during the 6 weeks of treatment . Mixed-effects regression models were used to examine pharmacotherapy response . RESULTS Results indicated that youth with co-morbid DBD experienced greater improvement in manic symptoms in response to risperidone versus divalproex , whereas youth with non-co-morbid DBD experienced similar trajectories of symptom improvement in both medication groups . In addition , the non-DBD group experienced greater improvement in global functioning over time as compared with youth with co-morbid-DBD , and this gap increased over the course of treatment . Results also indicated that high-aggression youth experienced worse global functioning by end treatment versus low-aggression youth . CONCLUSIONS In conclusion , a co-morbid diagnosis of DBD and /or high levels of aggressive symptoms in youth with PBD may be important clinical predictors of variation in treatment response to pharmacotherapy . These findings may help research ers and clinicians develop tailored treatment approaches that optimize symptom and functional outcomes CONTEXT Various anatomic brain abnormalities have been reported for attention-deficit/hyperactivity disorder ( ADHD ) , with varying methods , small sample s , cross-sectional design s , and without accounting for stimulant drug exposure . OBJECTIVE To compare regional brain volumes at initial scan and their change over time in  medicated and previously unmedicated male and female patients with ADHD and healthy controls . DESIGN , SETTING , AND PARTICIPANTS Case-control study conducted from 1991 - 2001 at the National Institute of Mental Health , Bethesda , Md , of 152 children and adolescents with ADHD ( age range , 5 - 18 years ) and 139 age- and sex-matched controls ( age range , 4.5 - 19 years ) recruited from the local community , who contributed 544 anatomic magnetic resonance images . MAIN OUTCOME MEASURES Using completely automated methods , initial volumes and prospect i ve age-related changes of total cerebrum , cerebellum , gray and white matter for the 4 major lobes , and cau date nucleus of the brain were compared in patients and controls . RESULTS On initial scan , patients with ADHD had significantly smaller brain volumes in all regions , even after adjustment for significant covariates . This global difference was reflected in smaller total cerebral volumes ( -3.2 % , adjusted F(1,280 ) = 8.30 , P = .004 ) and in significantly smaller cerebellar volumes ( -3.5 % , adjusted F(1,280 ) = 12.29 , P = .001 ) . Compared with controls , previously unmedicated children with ADHD demonstrated significantly smaller total cerebral volumes ( overall F(2,288 ) = 6.65 ; all pairwise comparisons Bonferroni corrected , -5.8 % ; P = .002 ) and cerebellar volumes ( -6.2 % , F ( 2,288 ) = 8.97 , P<.001 ) . Unmedicated children with ADHD also exhibited strikingly smaller total white matter volumes ( F(2,288 ) = 11.65 ) compared with controls ( -10.7 % , P<.001 ) and with medicated children with ADHD ( -8.9 % , P<.001 ) . Volumetric abnormalities persisted with age in total and regional cerebral measures ( P = .002 ) and in the cerebellum ( P = .003 ) . Cau date nucleus volumes were initially abnormal for patients with ADHD ( P = .05 ) , but diagnostic differences disappeared as cau date volumes decreased for patients and controls during adolescence . Results were comparable for male and female patients on all measures . Frontal and temporal gray matter , cau date , and cerebellar volumes correlated significantly with parent- and clinician-rated severity measures within the ADHD sample ( Pearson coefficients between -0.16 and -0.26 ; all P values were < .05 ) . CONCLUSIONS Developmental trajectories for all structures , except cau date , remain roughly parallel for patients and controls during childhood and adolescence , suggesting that genetic and /or early environmental influences on brain development in ADHD are fixed , nonprogressive , and unrelated to stimulant treatment OBJECTIVE Electroencephalographic ( EEG ) neurofeedback ( NF ) is considered a nonpharmacological alternative for medication in attention-deficit/hyperactivity disorder ( ADHD ) . Comparisons of the behavioral efficacy of NF and medication have produced inconsistent results . EEG measures can provide insight into treatment mechanisms , but have received little consideration . In this r and omized controlled trial ( RCT ) , effects of NF were compared with methylpheni date ( MPH ) , and physical activity ( PA ) in children with ADHD on event-related potential ( ERP ) indices of response inhibition , which are involved in ADHD psychopathology . METHODS Using a multicenter three way parallel group RCT design , 112 children with a Diagnostic and Statistical Manual of Mental Disorders , 4th ed . ( DSM-IV ) ( American Psychiatric Association 1994 ) diagnosis of ADHD , between 7 and 13 years of age , were initially included .  NF training consisted of 30 sessions of theta/beta training at Cz over a 10 week period . PA training was a semiactive control group , matched in frequency and duration . MPH was titrated using a double-blind placebo controlled procedure in 6 weeks , followed by a stable dose for 4 weeks . ERP measures of response inhibition , N2 and P3 , were available for 81 children at pre- and postintervention ( n = 32 NF , n = 25 MPH , n = 24 PA ) . RESULTS Only the medication group showed a specific increase in P3 amplitude compared with NF ( partial eta-squared [ ηp(2 ) ] = 0.121 ) and PA ( ηp(2 ) = 0.283 ) , which was related to improved response inhibition . Source localization of medication effects on P3 amplitude indicated increased activation primarily in thalamic and striatal nuclei . CONCLUSIONS This is the first study that simultaneously compared NF with stimulant treatment and a semiactive control group . Only stimulant treatment demonstrated specific improvements in brain function related to response inhibition . These results are in line with recent doubts on the efficacy and specificity of NF as treatment for ADHD . CLINICAL TRIALS REGISTRATION Train Your Brain ? Exercise and Neurofeedback Intervention for ADHD , https:// clinical trials.gov/show/NCT01363544 , Ref . No. NCT01363544 We used resting-state functional magnetic resonance imaging ( RS-fMRI ) to investigate the acute effects of methylpheni date hydrochloride ( MPH ) on spontaneous brain activity in children with attention deficit hyperactivity disorder ( ADHD ) . In all , 23 boys with ADHD were scanned twice , under either 10 mg dose of MPH or placebo , in a r and omized , cross-over , counterbalanced placebo-controlled design . 32 Matched healthy controls were scanned once for comparison . Seven of the 23 ADHD boys participated in a follow-up 8-week MPH treatment . A regional homogeneity ( ReHo ) method was applied to characterize the local synchronization of spontaneous brain activity .  ADHD boys under placebo compared with controls showed decreased ReHo in bilateral dorsolateral prefrontal cortices and increased ReHo in bilateral sensorimotor and parieto-visual cortices . Relative to placebo , MPH upregulated ReHo in bilateral ventral prefrontal cortices and cerebellar vermis , and downregulated ReHo in right parietal and visual areas that overlapped with the abnormally enhanced activities . When under MPH , ReHo differences between patients and controls were no longer observed . The preliminary prediction analysis revealed that the decreased ReHo in right parietal cortex after the acute MPH was positively correlated with the decreased symptom scores after the 8-week MPH treatment in the seven patients . We show that an acute dose of MPH normalized all fronto-parieto-cerebellar dysfunctions in boys with ADHD during the resting state . Preliminary findings furthermore suggest the potential of RS-fMRI as a prognostic imaging tool to identify response to MPH treatment
Results : In ADHD , deviant prefrontal and cingulate functional activity was associated with increased IA .
Structural alterations were most pronounced in the cingulate cortex .
Subjects with DBDs showed marked cortico‐subcortical dysfunctions .
ADHD and DBDs share similar cortico‐limbic structural and functional alterations .
RI deficits in ADHD highlighted hypoactivity in the dorso/ventro‐lateral PFC , insula , and striatum , while the paralimbic system was primarily dysfunctional in DBDs .
Across disorders , extensively altered cortico‐limbic dysfunctions underlie IA , while RI was mostly associated with aberrant prefrontal activity .
Conclusion : Control network deficits were evidence d across clinical phenotypes in IA and RI .
Dysfunctions at any level within these cortico‐subcortical projections lead to deficient cognitive‐affective control by ascribing emotional salience to otherwise irrelevant stimuli .
HighlightsImpulsive aggression and dysfunctional response inhibition are present in ADHD and DBDs .
Broad fronto‐striatal‐cerebellar dysfunctions have been implicated in ADHD and DBDs .
Prefrontal and cingulate cortical deficits are associated with IA in ADHD.Severe widespread cortico‐subcortical breakdowns are associated with IA in DBDs .
RI deficits have been attributed to hypoactivity in the lateral PFC , insula , and amygdala .
Whether reduced gray matter volumes relate to ADHD and DBDs or if present as an IA epiphenomenon remains debatable .
Background : Although impulsive aggression ( IA ) and dysfunctional response inhibition ( RI ) are hallmarks of attention‐deficit/hyperactivity disorder ( ADHD ) and disrupted behavioral disorders ( DBDs ) , little is known about their shared and distinct deviant neural mechanisms .