Functional magnetic resonance imaging of methylphenidate and placebo in attention-deficit/hyperactivity disorder during the multi-source interference task. Common and unique therapeutic mechanisms of stimulant and nonstimulant treatments for attention-deficit/hyperactivity disorder. Shared and Drug-Specific Effects of Atomoxetine and Methylphenidate on Inhibitory Brain Dysfunction in Medication-Naive ADHD Boys Methylphenidate normalises activation and functional connectivity deficits in attention and motivation networks in medication-naïve children with ADHD during a rewarded continuous performance task Effects of methylphenidate on working memory functioning in children with attention deficit/hyperactivity disorder. Aerobic exercise and attention deficit hyperactivity disorder: brain research. Methylphenidate Normalizes Frontocingulate Underactivation During Error Processing in Attention-Deficit/Hyperactivity Disorder Methylphenidate Normalizes Fronto-Striatal Underactivation During Interference Inhibition in Medication-Naïve Boys with Attention-Deficit Hyperactivity Disorder Methylphenidate Normalizes Resting-State Brain Dysfunction in Boys With Attention Deficit Hyperactivity Disorder The effects of methylphenidate on neural systems of attention in attention deficit hyperactivity disorder. Impulsiveness as a timing disturbance: neurocognitive abnormalities in attention-deficit hyperactivity disorder during temporal processes and normalization with methylphenidate Misinterpreting Emotional Expressions in Attention-Deficit/Hyperactivity Disorder: Evidence for a Neural Marker and Stimulant Effects Multisite controlled study of OROS methylphenidate in the treatment of adolescents with attention-deficit/hyperactivity disorder. Real‐time fMRI neurofeedback in adolescents with attention deficit hyperactivity disorder Reward processing in male adults with childhood ADHD—a comparison between drug-naïve and methylphenidate-treated subjects Methylphenidate-Elicited Dopamine Increases in Ventral Striatum Are Associated with Long-Term Symptom Improvement in Adults with Attention Deficit Hyperactivity Disorder The effectiveness of methylphenidate in the management of Attention Deficit Hyperactivity Disorder (ADHD) in people with intellectual disabilities: A systematic review. Effects of Methylphenidate on Impulsive Responding in Children With Attention-Deficit Hyperactivity Disorder Neurocognitive performance and behavioral symptoms in patients with attention-deficit/hyperactivity disorder during twenty-four months of treatment with methylphenidate. Therapeutic Doses of Oral Methylphenidate Significantly Increase Extracellular Dopamine in the Human Brain Symptomatic improvement in children with ADHD treated with long-term methylphenidate and multimodal psychosocial treatment. Clinical efficacy of methylphenidate in conduct disorder with and without attention deficit hyperactivity disorder. Methylphenidate improves response inhibition in adults with attention-deficit/hyperactivity disorder
CONTEXT Previous studies have reported hypofunction , structural abnormalities , and biochemical abnormalities of the dorsal anterior midcingulate cortex ( daMCC ) in attention-deficit/hyperactivity disorder ( ADHD ) . Stimulant medications are effective treatments for ADHD , but their neural effects have not been fully characterized . OBJECTIVE To determine whether the methylpheni date hydrochloride osmotic-release oral system ( OROS ) would increase functional magnetic resonance imaging ( fMRI ) activation , compared with placebo , in the daMCC and other frontoparietal regions subserving attention during the Multi- Source Interference Task ( MSIT ) . DESIGN R and omized , placebo-controlled , 6-week , before-after fMRI study . SETTING Academic medical center ambulatory clinic . PATIENTS Twenty-one adults with ADHD r and omized to 6 weeks of treatment with methylpheni date OROS ( n = 11 ) or placebo ( n = 10 ) . INTERVENTIONS Patients underwent fMRI twice while performing the MSIT ( scan 1 at baseline and scan 2 at 6 weeks ) . MAIN OUTCOME MEASURES Group-averaged , r and om-effects , repeated- measures , general linear model analyses were used to compare daMCC ( and whole-brain ) fMRI activation during the MSIT . Individual-based daMCC volume-of-interest confirmatory analyses and behavioral data are also presented . RESULTS Performance and baseline fMRI measures in the daMCC and other a priori brain regions did not differ between groups . Group comparisons showed a group x scan interaction and t test confirmation of higher activation in the daMCC at 6 weeks in the methylpheni date OROS group than in the placebo group ( P < 1 x 10(-4 ) , cluster corrected for multiple comparisons ) . Individual daMCC volume-of-interest analyses confirmed group-averaged findings and suggested that daMCC activity might be related to clinical response . Methylpheni date OROS also produced higher activation in the dorsolateral prefrontal cortex and the parietal cortex at 6 weeks . CONCLUSION Methylpheni date OROS increased daMCC activation during the MSIT and may act , in part , by normalizing daMCC hypofunction in ADHD CONTEXT Attention-deficit/hyperactivity disorder ( ADHD ) is a highly prevalent and impairing psychiatric disorder that affects both children and adults . There are Food and Drug Administration-approved stimulant and nonstimulant medications for treating ADHD ; however , little is known about the mechanisms by which these different treatments exert their therapeutic effects . OBJECTIVE To contrast changes in brain activation related to symptomatic improvement with use of the stimulant methylpheni date hydrochloride vs the nonstimulant atomoxetine hydrochloride . DESIGN Functional magnetic resonance imaging before and after 6 to 8 weeks of treatment with methylpheni date ( n = 18 ) or atomoxetine ( n = 18 ) using a parallel-groups design . SETTING Specialized ADHD clinical research program at Mount Sinai School of Medicine , New York , New York . PARTICIPANTS Thirty-six youth with ADHD ( mean [ SD ] age , 11.2 [ 2.7 ] years ; 27 boys ) recruited from r and omized clinical trials . MAIN OUTCOME MEASURES Changes in brain activation during a go/no-go test of response inhibition and investigator-completed ratings on the ADHD Rating Scale-IV-Parent Version . RESULTS Treatment with methylpheni date vs atomoxetine was associated with comparable improvements in both response inhibition on the go/no-go test and mean ( SD ) improvements in ratings of ADHD symptoms ( 55 % [ 30 % ] vs 57 % [ 25 % ] ) . Improvement in ADHD symptoms was associated with common reductions in bilateral motor cortex activation for both treatments . Symptomatic improvement was also differentially related to gains in task-related activation for atomoxetine and reductions in activation for methylpheni date in the right inferior frontal gyrus , left anterior cingulate/supplementary motor area , and bilateral posterior cingulate cortex . These findings were not attributable to baseline differences in activation . CONCLUSIONS Treatment with methylpheni date and atomoxetine produces symptomatic improvement via both common and divergent neurophysiologic actions in frontoparietal regions that have been implicated in the pathophysiology of ADHD . These results represent a first step in delineating the neurobiological basis of differential response to stimulant and nonstimulant medications for ADHD The stimulant methylpheni date ( MPX ) and the nonstimulant atomoxetine ( ATX ) are the most commonly prescribed medications for attention deficit hyperactivity disorder ( ADHD ) . However , no functional magnetic resonance imaging ( fMRI ) study has as yet investigated the effects of ATX on inhibitory or any other brain function in ADHD patients or compared its effects with those of MPX . A r and omized , double-blind , placebo-controlled , crossover pharmacological design was used to compare the neurofunctional effects of single doses of MPX , ATX , and placebo during a stop task , combined with fMRI within 19 medication-naive ADHD boys , and their potential normalization effects relative to 29 age-matched healthy boys . Compared with controls , ADHD boys under placebo showed bilateral ventrolateral prefrontal , middle temporal , and cerebellar underactivation . Within patients , MPX relative to ATX and placebo significantly upregulated right ventrolateral prefrontal activation , which correlated with enhanced inhibitory capacity . Relative to controls , both drugs significantly normalized the left ventrolateral prefrontal underactivation observed under placebo , while MPX had a drug-specific effect of normalizing right ventrolateral prefrontal and cerebellar underactivation observed under both placebo and ATX . The findings show shared and drug-specific effects of MPX and ATX on performance and brain activation during inhibitory control in ADHD patients with superior upregulation and normalization effects of MPX 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 BACKGROUND AND AIMS Children with attention deficit/hyperactivity disorder ( ADHD ) often show deficits in working memory performance .  Methylpheni date ( MPH ) is an effective medication to improve these cognitive difficulties . This study aim ed to clarify which effect MPH induces on the underlying functional networks of working memory . METHODS Fourteen boys diagnosed with ADHD and 12 healthy controls were investigated using functional magnetic resonance imaging ( fMRI ) . Each patient was tested twice , once with medication and once without . The fMRI experiments consisted of three verbal N-back tasks with increasing difficulty . Functional images were acquired on a 3 Tesla head scanner . RESULTS On the behavioral level , medicated patients performed similar to healthy controls and significantly better than without medication . On the functional level , patients showed the expected frontal and parietal activations , which were more pronounced in the 2- and 3-back tasks . Healthy controls showed significantly more activation in these regions and additional activation in the cerebellum . Interestingly , patients showed an additional effect of laterality . Left-sided frontal and parietal activation in patients was significantly less pronounced than in controls . CONCLUSION Functional data indicate different activation patterns in verbal working memory tasks between healthy controls and patients with ADHD irrespective of medication condition . Intake of MPH led to a clear improvement on a behavioral level . However , this effect was not reflected by changes in functional brain organization . MPH-induced changes leading to better performance in verbal working memory tasks might be very subtle and therefore not detectable by fMRI PURPOSE As adjuvant therapy for enhancing the effects of stimulants and thereby minimizing medication doses , we hypothesized that aerobic exercise might be an effective adjunctive therapy for enhancing the effects of methylpheni date on the clinical symptoms , cognitive function , and brain activity of adolescents with attention deficit hyperactivity disorder ( ADHD ) . METHODS Thirty-five adolescents with ADHD were r and omly assigned to one of two groups in a 1/1 ratio ; methylpheni date treatment + 6-wk exercise ( sports-ADHD ) or methylpheni date treatment + 6-wk education ( edu-ADHD ) . At baseline and after 6 wk of treatment , symptoms of ADHD , cognitive function , and brain activity were evaluated using the Dupaul attention deficit hyperactivity disorder rating scale -- Korean version ( K-ARS ) , the Wisconsin Card Sorting Test , and 3-T functional magnetic resonance imaging , respectively . RESULTS The K-ARS total score and perseverative errors in the sports-ADHD group decreased compared with those in the edu-ADHD group . After the 6-wk treatment period , the mean β value of the right frontal lobe in the sports-ADHD group increased compared with that in the edu-ADHD group . The mean β value of the right temporal lobe in the sports-ADHD group decreased . However , the mean β value of the right temporal lobe in the edu-ADHD group did not change . The change in activity within the right prefrontal cortex in all adolescents with ADHD was negatively correlated with the change in K-ARS scores and perseverative errors . CONCLUSIONS The current results indicate that aerobic exercise increased the effectiveness of methylpheni date on clinical symptoms , perseverative errors , and brain activity within the right frontal and temporal cortices in response to the Wisconsin card sorting test stimulation 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 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 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 OBJECTIVE Recent studies have suggested that attention deficit hyperactivity disorder ( ADHD ) is associated with abnormalities in basal ganglia and prefrontal cortical functioning . However , these studies have primarily relied upon cognitive tasks that reflect impulse control rather than attentional mechanisms . METHOD The authors used functional magnetic resonance imaging to investigate the neural correlates of selective and divided attention in a r and omized , double-blind , placebo-controlled pharmacological challenge with methylpheni date in 15 adolescents with ADHD ( ages 14 - 17 ) , eight adolescents with reading disorder ( ages 12 - 17 ) , and four adolescents with both reading disorder and ADHD ( ages 14 - 18 ) who were scanned during both a methylpheni date and a placebo session . Fourteen healthy comparison subjects ( ages 12 - 20 ) who were not given methylpheni date served as the primary comparison group . RESULTS During the divided attention task , unmedicated subjects with ADHD or reading disorder  recruited the left ventral basal ganglia significantly less than the healthy comparison subjects . Methylpheni date led to an increase in activation in this region but had no effect on task performance .  Subjects with ADHD also recruited the middle temporal gyrus significantly less than the comparison subjects , but methylpheni date did not have a direct effect on activation in this region . CONCLUSIONS These results suggest that ADHD is associated with abnormal processing in attentional networks , with specific dysfunction in striatal circuitry . Methylpheni date may act to normalize activity within this network 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 BACKGROUND In addition to cognitive impairment , there are disruptions to mood and emotion processing in attention-deficit/hyperactivity disorder ( ADHD ) but little is known about their neural basis . We examined ADHD disturbances in mood and emotion recognition and underlying neural systems before and after treatment with stimulant medication . METHODS Participants were 51 unmedicated ADHD adolescents and 51 matched healthy control subjects rated for depressed and anxious mood and accuracy for identifying facial expressions of basic emotion . Brain function was recorded using event-related potentials ( ERPs ) while subjects viewed these expressions . ADHD subjects were retested after 4 weeks , following treatment with methylpheni date ( MPH ) . RESULTS ADHD subjects showed a profile of emotion-related impairment : higher depression and anxiety , deficits in identifying threat-related emotional expressions in particular , and alterations in ERPs . There was a pronounced reduction in occipital activity during the early perceptual analysis of emotional expression ( within 120 msec ) , followed by an exaggeration of activity associated with structural encoding ( 120 - 220 msec ) and subsequent reduction and slowing of temporal brain activity subserving context processing ( 300 - 400 msec ) . Methylpheni date normalized neural activity and produced some improvement of emotion recognition but had no impact on negative mood . Improvements in neural activity with MPH were consistent predictors of improvement in clinical features of emotional lability and hyperactivity . CONCLUSIONS Objective behavioral and brain function measures of emotion processing may provide a valuable addition to the clinical armamentarium for assessing emotional disturbances in ADHD and the efficacy of stimulants for treating these disturbances BACKGROUND Despite the persistence of attention-deficit/hyperactivity disorder ( ADHD ) into adolescence , little is known about the efficacy and tolerability of stimulant medications in this age group . OBJECTIVE To report the results of a multisite controlled study among adolescents with ADHD evaluating the efficacy and tolerability of osmotic-release oral system ( OROS ) methylpheni date . DESIGN Adolescents ( N = 220 ) having a confirmed Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition diagnosis of ADHD underwent dose titration to identify dosages of OROS methylpheni date that improved symptoms to predefined criteria . Subjects successfully completing the dose titration phase ( n = 177 ) ( ie , tolerated and responded to treatment and adhered to the protocol ) were r and omized to receive 2 weeks ' treatment with their individualized dosage of OROS methylpheni date ( 18 , 36 , 54 , or 72 mg once daily ) or placebo .  Treatment effectiveness was measured using investigator , parent , and adolescent assessment s of ADHD . RESULTS A significant reduction from baseline in the investigator-rated ADHD Rating Scale , the primary efficacy measure , was found with OROS methylpheni date treatment compared with placebo . Similar findings were noted with parent- and adolescent-report measures . Based on a Clinical Global Impression improvement subscale score of much or very much improved , 52 % of subjects in the OROS methylpheni date group improved compared with 31 % receiving placebo . Thirty-seven percent of subjects required the maximum dosage of 72 mg/d . The incidence of drug-related adverse events was similar between the 2 study groups . CONCLUSION In adolescents , once-daily OROS methylpheni date significantly reduced ADHD symptoms and was well tolerated using dosages up to 72 mg/d 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 , 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 Stimulant medications , such as methylpheni date , which are effective treatments for attention deficit hyperactivity disorder ( ADHD ) , enhance brain dopamine signaling . However , the relationship between regional brain dopamine enhancement and treatment response has not been evaluated . Here , we assessed whether the dopamine increases elicited by methylpheni date are associated with long-term clinical response . We used a prospect i ve design to study 20 treatment-naive adults with ADHD who were evaluated before treatment initiation and after 12 months of clinical treatment with a titrated regimen of oral methylpheni date . Methylpheni date -induced dopamine changes were evaluated with positron emission tomography and [11C]raclopride ( D2/D3 receptor radiolig and sensitive to competition with endogenous dopamine ) . Clinical responses were assessed using the Conners ' Adult ADHD Rating Scale and revealed a significant reduction in symptoms of inattention and hyperactivity with long-term methylpheni date treatment . A challenge dose of 0.5 mg/kg intravenous methylpheni date significantly increased dopamine in striatum ( assessed as decreases in D2/D3 receptor availability ) . In the ventral striatum , these dopamine increases were associated with the reductions in ratings of symptoms of inattention with clinical treatment . Statistical parametric mapping additionally showed dopamine increases in prefrontal and temporal cortices with intravenous methylpheni date that were also associated with decreases in symptoms of inattention . Our findings indicate that dopamine enhancement in ventral striatum ( the brain region involved with reward and motivation ) was associated with therapeutic response to methylpheni date , further corroborating the relevance of the dopamine reward/motivation circuitry in ADHD . It also provides preliminary evidence that methylpheni date -elicited dopamine increases in prefrontal and temporal cortices may also contribute to the clinical response BACKGROUND The effectiveness of psychostimulants , primarily methylpheni date ( MPH ) , in the treatment of Attention Deficit Hyperactivity Disorder ( ADHD ) in the general population of typically growing children and adolescents is well established through many R and omised Controlled Trials ( RCTs ) . AIMS AND METHODS We carried out a systematic review of all the RCTs in people with intellectual disabilities ( ID ) that assessed effectiveness of MPH on the core ADHD symptoms . OUTCOMES AND RESULTS We included 15 papers from 13 studies that were all on children and adolescents with ID ( 315 participants were on MPH and placebo respectively ) , 12 of which used a cross over design , and one used a parallel design . On average around 40 - 50 % responded to MPH in the ID group whereas around 70 - 80 % response rate is reported among the non-ID children . Because of the heterogeneity of the outcome data it was not possible to carry out a meta- analysis . Significant adverse events included sleep difficulties and poor appetite along with weight loss and also irritability , social withdrawal and increased motor activities including tic . CONCLUSIONS AND IMPLEMENTATION On the basis of the poor quality evidence that is available , it seems that MPH may be effective in some but not all children and adolescents with ID and ADHD The present investigation examined the effects of methylpheni date on impulsivity in children with attention-deficit hyperactivity disorder ( ADHD ) . A task was design ed to measure empirically the ADHD child 's proclivity to blurt out incorrect answers before giving a final and /or correct response . Twenty-six ADHD children referred for double-blind placebo-controlled assessment of medication responsiveness and 14 non-ADHD controls were given a visual search word-matching task to assess impulsive responding . An analysis of covariance showed that ADHD children on methylpheni date made fewer impulsive errors than ADHD children on placebo . The control group made fewer impulsive errors than the ADHD children in the placebo condition , but the performance of the ADHD children on medication approximated the performance of the children without ADHD . These preliminary findings suggest that the word-matching task may be a useful tool for assessing impulsive responding and determining the benefits of stimulant medication on impulsivity . ( J Child Neurol 1993;8:157 - 163 ) OBJECTIVE This study investigated the trends in neurocognitive function and behavioral symptoms among patients with attention-deficit/hyperactivity disorder ( ADHD ) during 24 months of treatment with methylpheni date in a clinical setting . METHODS Study participants consisted of 181 ADHD patients with a mean age of 13.4±2.5 years ( ages ranged from 8 to 18 years ; 151 boys and 30 girls ) who were prescribed oral short-acting methylpheni date two or three times daily , with each dose ranging between 0.3 and 1.0 mg/kg . At baseline and 6 , 12 , 18 , and 24 months from baseline , neurocognitive function was assessed using the  Test of Variables of Attention ( TOVA ) on the day the patient was off medication , and behavioral symptoms were evaluated using the Swanson , Nolan , and Pelham Version IV Scale for ADHD ( SNAP-IV ) parent form , the SNAP-IV teacher form , and the ADHD-Rating Scale ( completed by a child psychiatrist ) . RESULTS Of the 181 ADHD patients at the initial visit , 103 ( 56.9 % ) completed the study . During the 24-month methylpheni date treatment , only the commission errors in TOVA significantly improved ; however , the omission errors , response time , response time variability , response sensitivity , and ADHD score did not . The behavioral symptoms of ADHD , observed by various informants , all declined substantially , and were significantly correlated with each other during the long-term follow-up . The severity of teacher ratings was lower than that of parent and psychiatrist ratings . However , the teacher-rated inattention symptoms showed the strongest correlations with TOVA performance . CONCLUSIONS Findings suggest that neurocognitive deficits in ADHD patients , except inhibition ability , might be long lasting in realistic setting s. In addition , obtaining behavior profile assessment s from multiple informants , especially from teachers , is vital for establishing a complete underst and ing of ADHD patients Methylpheni date ( Ritalin ) is the most commonly prescribed psychoactive drug in children for the treatment of attention deficit hyperactivity disorder ( ADHD ) , yet the mechanisms responsible for its therapeutic effects are poorly understood . Whereas methylpheni date blocks the dopamine transporter ( main mechanism for removal of extracellular dopamine ) , it is unclear whether at doses used therapeutically it significantly changes extracellular dopamine ( DA ) concentration . Here we used positron emission tomography and [(11)C]raclopride ( D2 receptor radiolig and that competes with endogenous DA for binding to the receptor ) to evaluate whether oral methylpheni date changes extracellular DA in the human brain in 11 healthy controls . We showed that oral methylpheni date ( average dose 0.8 + /- 0.11 mg/kg ) significantly increased extracellular DA in brain , as evidence d by a significant reduction in B(max)/K(d ) ( measure of D2 receptor availability ) in striatum ( 20 + /- 12 % ; p < 0.0005 ) . These results provide direct evidence that oral methylpheni date at doses within the therapeutic range significantly increases extracellular DA in human brain . This result coupled with recent findings of increased dopamine transporters in ADHD patients ( which is expected to result in reductions in extracellular DA ) provides a mechanistic framework for the therapeutic efficacy of methylpheni date . The increase in DA caused by the blockade of dopamine transporters by methylpheni date predominantly reflects an amplification of spontaneously released DA , which in turn is responsive to environmental stimulation . Because DA decreases background firing rates and increases signal-to-noise in target neurons , we postulate that the amplification of weak DA signals in subjects with ADHD by methylpheni date would enhance task-specific signaling , improving attention and decreasing distractibility . Alternatively methylpheni date -induced increases in DA , a neurotransmitter involved with motivation and reward , could enhance the salience of the task facilitating the " interest that it elicits " and thus improving performance OBJECTIVE To test the hypotheses that in children with attention-deficit/hyperactivity disorder ( ADHD ) ( 1 ) symptoms of ADHD , oppositional defiant disorder , and overall functioning are significantly improved by methylpheni date combined with intensive multimodal psychosocial treatment compared with methylpheni date alone and with methylpheni date plus attention control and ( 2 ) more children receiving combined treatment can be taken off methylpheni date . METHOD One hundred three children with ADHD ( ages 7 - 9 ) , free of conduct and learning disorders , who responded to short-term methylpheni date were r and omized for 2 years to ( 1 ) methylpheni date alone ; ( 2 ) methylpheni date plus psychosocial treatment that included parent training and counseling , social skills training , psychotherapy , and academic assistance , or ( 3 ) methylpheni date plus attention psychosocial control treatment . Assessment s included parent , teacher , and psychiatrist ratings , and observations in academic and gym classes . RESULTS Combination treatment did not lead to superior functioning and did not facilitate methylpheni date discontinuation . Significant improvement occurred across all treatments and continued over 2 years . CONCLUSIONS In stimulant-responsive children with ADHD , there is no support for adding ambitious long-term psychosocial intervention to improve ADHD and oppositional defiant disorder symptoms . Significant benefits from methylpheni date were stable over 2 years BACKGROUND Stimulants are not considered appropriate for the treatment of children with conduct disorders ( CDs ) . The postulated differences in stimulant effect between children with attention deficit hyperactivity disorder ( ADHD ) and CD led to the hypothesis that methylpheni date hydrochloride , which is effective in ADHD , would not significantly improve symptoms of CD . METHODS We r and omly assigned 84 children with CD , between the ages of 6 and 15 years , to receive methylpheni date hydrochloride ( up to 60 mg/d ) or placebo for 5 weeks . Behavior was evaluated by parent , teacher , and clinician reports and by direct classroom observations . Two thirds of the children also met criteria for ADHD . RESULTS Contrary to prediction , ratings of antisocial behaviors specific to CD were significantly reduced by methylpheni date treatment . The magnitude of methylpheni date effect indicated meaningful clinical benefit . Partialling out severity of ADHD did not alter the significant superiority of methylpheni date on CD ratings specifically ( P < .001 ) . CONCLUSIONS Methylpheni date has short-term positive effects on children and adolescents with CD . Key aspects of antisocial adjustment appear to be treatment responsive . This effect was independent of severity of the children 's initial ADHD symptoms BACKGROUND Response inhibition is an executive function that requires voluntary control over responses when there is a change of context . The right inferior frontal cortex is necessary for response inhibition , and a deficit in right frontostriatal circuitry might underlie attention-deficit/hyperactivity disorder ( ADHD ) . Many studies of childhood ADHD have demonstrated impaired response inhibition and its amelioration by methylpheni date ( MPH ) . The current study tested response inhibition and the effect of MPH in adult ADHD . METHODS Response inhibition was assessed with the " tracking " stop-signal test in 13 adults with a diagnosis of ADHD , both while taking and while not taking medication , and 13 healthy , unmedicated , age- and intelligence quotient-matched control subjects . RESULTS Stop-signal reaction time was significantly slower in unmedicated adults with ADHD relative to healthy control subjects , and this deficit was significantly ameliorated by medication . CONCLUSIONS Adult ADHD patients had a response inhibition profile similar to that produced by lesions to the right inferior frontal cortex , which was remedied by stimulant medication
RESULTS The fMRI analysis showed that methylpheni date significantly enhanced activation in bilateral inferior frontal cortex (IFC)/insula during inhibition and time discrimination but had no effect on working memory networks .
The meta- analysis , including 14 fMRI data sets and 212 children with ADHD , showed that stimulants most consistently enhanced right IFC/insula activation , which also remained for a subgroup analysis of methylpheni date effects alone .
A more lenient threshold also revealed increased putamen activation .
CONCLUSIONS Psychostimulants most consistently increase right IFC/insula activation , which are key areas of cognitive control and also the most replicated neurocognitive dysfunction in ADHD .
These neurocognitive effects may underlie their positive clinical effects
BACKGROUND Psychostimulant medication , most commonly the catecholamine agonist methylpheni date , is the most effective treatment for attention-deficit/hyperactivity disorder ( ADHD ) .
However , relatively little is known on the mechanisms of action .
Acute effects on brain function can eluci date underlying neurocognitive effects .
We tested methylpheni date effects relative to placebo in functional magnetic resonance imaging ( fMRI ) during three disorder-relevant tasks in medication-naïve ADHD adolescents .
In addition , we conducted a systematic review and meta- analysis of the fMRI findings of acute stimulant effects on ADHD brain function .