Common and unique therapeutic mechanisms of stimulant and nonstimulant treatments for attention-deficit/hyperactivity disorder. Methylphenidate Enhances Working Memory by Modulating Discrete Frontal and Parietal Lobe Regions in the Human Brain Time-response analysis of the effect of stimulant medication on the learning ability of children referred for hyperactivity. Effects of methylphenidate on working memory functioning in children with attention deficit/hyperactivity disorder. The effects of methylphenidate on neural systems of attention in attention deficit hyperactivity disorder. Clinical efficacy of methylphenidate in conduct disorder with and without attention deficit hyperactivity disorder. Functional magnetic resonance imaging of methylphenidate and placebo in attention-deficit/hyperactivity disorder during the multi-source interference task. Therapeutic Doses of Oral Methylphenidate Significantly Increase Extracellular Dopamine in the Human Brain Exercise impact on sustained attention of ADHD children, methylphenidate effects The specificity of the effects of stimulant medication on classroom learning-related measures of cognitive processing for Attention Deficit Disorder children Methylphenidate-Elicited Dopamine Increases in Ventral Striatum Are Associated with Long-Term Symptom Improvement in Adults with Attention Deficit Hyperactivity Disorder Effects of Methylphenidate on Impulsive Responding in Children With Attention-Deficit Hyperactivity Disorder Sustained release and standard methylphenidate effects on cognitive and social behavior in children with attention deficit disorder. The effect of methylphenidate on prefrontal cognitive functioning, inattention, and hyperactivity in velocardiofacial syndrome. A randomised controlled trial of combined EEG feedback and methylphenidate therapy for the treatment of ADHD. Randomized controlled double-blind trial of optimal dose methylphenidate in children and adolescents with severe attention deficit hyperactivity disorder and intellectual disability. Dose-response effects of methylphenidate on ecologically valid measures of academic performance and classroom behavior in adolescents with 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 indirect catecholamine agonist methylpheni date ( Ritalin ) is the drug treatment of choice in attention deficit/hyperactivity disorder ( AD/HD ) , one of the most common behavioral disorders of childhood ( DSM-IV ) , although symptoms may persist into adulthood . Methylpheni date can enhance cognitive performance in adults and children diagnosed with AD/HD ( Kempton et al. , 1999 ; Riordan et al. , 1999 ) and also in normal human volunteers on tasks sensitive to frontal lobe damage , including aspects of spatial working memory ( SWM ) performance ( Elliott et al. , 1997 ) . The present study investigated changes in regional cerebral blood flow ( rCBF ) induced by methylpheni date during performance of a self-ordered SWM task to define the neuroanatomical loci of the beneficial effect of the drug . The results show that the methylpheni date -induced improvements in working memory performance occur with task-related reductions in rCBF in the dorsolateral prefrontal cortex and posterior parietal cortex . The beneficial effects of methylpheni date on working memory were greatest in the subjects with lower baseline working memory capacity . This is to our knowledge the first demonstration of a localization of a drug-induced improvement in SWM performance in humans and has relevance for underst and ing the treatment of AD/HD This report introduces a method for obtaining behavioral time-response information for a short-acting psychotropic drug ( methylpheni date [ Ritalin ] ) that is widely used to treat behaviorally hyperactive children . We used a laboratory learning task to document that between one and two hours after the administration of a single dose of methylpheni date , the drug exerts its maximum effect on performance in a learning task in the laboratory . This effect on cognitive performance dissipates within the same day . This rapid and transient effect of methylpheni date makes it possible to classify patients in a single day into those who respond favorably and those who respond adversely to the drug in terms of its effect on cognitive behavior 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 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 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 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 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 Attention deficit hyperactivity disorder ( ADHD ) is related to a deficiency of central catecholamines ( CA ) in cognitive , biochemical , and physical tests , and pharmaceutical intervention may have no effect if it is not accompanied by changes in the environment . The objective of our study was to test the hypothesis that central CA are responsible for the increase in speed reaction seen after physical activity ( PA ) and to measure the impact of high intensity PA on the sustained attention of 25 children diagnosed with ADHD consistent with the Disease Statistical Mental-IV ( DSM-IV ) criteria . It is possible that practicing sports assists in the management of the disorder . The children were divided between users ( US ) and non-users ( NUS ) of methylpheni date ( MTP ) , and the groups were compared to evaluate the effect of the drug on cognition after PA . Post-exercise performance on Conner ’s Continuous Performance Test-II ( CPT ) was not affected by MTP , we observed significant improvements in response time , and we saw normalization in the impulsivity and vigilance measures . These results suggest that the improvements in cognition after physical effort are not CA dependent . Additionally , our results suggest that  children ’s attention deficits can be minimized through PA irrespective of treatment with MTP . Additional studies are necessary to confirm that exercise mitigates the harmful symptoms of ADHD There appear to be beneficial effects of stimulant medication on daily classroom measures of cognitive functioning for Attention Deficit Disorder ( ADD ) children , but the specificity and origin of such effects is unclear . Consistent with previous results , 0.3 mg/kg methylpheni date improved ADD children 's  performance on a classroom reading comprehension measure . Using the Posner letting-matching task and four additional measures of phonological processing , we attempted to isolate the effects of methylpheni date to parameter estimates of ( a ) selective attention , ( b ) the basic cognitive process of retrieving name codes from permanent memory , and ( c ) a constant term that represented nonspecific aspects of information processing . Responses to the letter-matching stimuli were faster and more accurate with medication compared to placebo . The improvement in performance was isolated to the parameter estimate that reflected nonspecific aspects of information processing . A lack of medication effect on the other measures of phonological processing supported the Posner task findings in indicating that methylpheni date appears to exert beneficial effects on academic processing through general rather than specific aspects of information processing 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 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 ) Two studies were conducted to investigate the relative effects of sustained release methylpheni date ( Ritalin [ SR-20 ] ) and st and ard methylpheni date ( Ritalin , 10 mg , administered twice daily ) . In the first study , 13 boys with attention deficit disorder participating in a summer treatment program went through a double-blind , within-subject trial of each form of methylpheni date and placebo . Measures of social and cognitive behavior were gathered in classroom and play setting s. Although group analyses of the data showed that both drugs were effective and there were few differences between them , st and ard methylpheni date was superior to SR-20 on several important measures of disruptive behavior . Furthermore , analyses of individual responsivity showed clearly that most boys responded more positively to st and ard methylpheni date than to SR-20 . The second study involved a partially overlapping group of nine boys with attention deficit disorder participating in the same summer treatment program . Also double-blind , within-subject , and placebo controlled , this study tracked the time courses of the two forms of methylpheni date . Both were shown to have similar time courses on the Abbreviated Conners Rating Scale and other measures , but SR-20 had a slower onset than did the st and ard drug form on a continuous performance task . Effects of SR-20 were still evident eight hours after ingestion OBJECTIVE Methylpheni date ( MPH ) is commonly used to treat attention-deficit/hyperactivity disorder ( ADHD ) in all children , including those with velocardiofacial syndrome ( VCFS ) . Yet concerns have been raised regarding its safety and efficacy in VCFS . The goal of this study was to examine the safety and efficacy of MPH in children with VCFS . METHODS Thirty-four children and adolescents with VCFS and ADHD participated in a r and omized , controlled trial with a 2:1 ratio of MPH versus placebo . All subjects underwent a cardiological evaluation before and after MPH administration . The primary outcome measure was prefrontal cognitive performance following a single dose of MPH or placebo . A follow-up assessment was conducted after a 6-month treatment with MPH . RESULTS Compared with placebo , single MPH administration was associated with a more robust improvement in prefrontal cognitive performance , including achievements in the Hearts and Flowers executive function task and the visual continuous performance task . After 6 months of treatment , a 40 % reduction in severity of ADHD symptoms was reported by parents on the Revised Conners Rating Scale . All subjects treated with MPH reported at least one side effect , but it did not necessitate discontinuation of treatment . MPH induced an increase in heart rate and blood pressure that was usually minor , but was clinical ly significant in two cases . No differences in response to MPH were observed between catechol-O-methyltransferase Met versus Val carriers . CONCLUSION The use of MPH in children with VCFS appears to be effective and relatively safe . A comprehensive cardiovascular evaluation for children with VCFS before and during stimulant treatment is recommended PURPOSE To evaluate the efficacy of combined methylpheni date and EEG feedback treatment for children with ADHD . METHODS Forty patients with ADHD were r and omly assigned to the combination group ( methylpheni date therapy and EEG feedback training ) or control group ( methylpheni date therapy and non-feedback attention training ) in a 1:1 ratio using the double-blind method . These patients , who met the DSM-IV diagnostic criteria and were aged between 7 and 16 years , had obtained optimal therapeutic effects by titrating the methylpheni date dose prior to the trial . The patients were assessed using multiple parameters at baseline , after 20 treatment sessions , after 40 treatment sessions , and in 6-month follow-up studies . RESULTS Compared to the control group , patients in the combination group had reduced ADHD symptoms and improved in related behavioural and brain functions . CONCLUSION The combination of EEG feedback and methylpheni date treatment is more effective than methylpheni date alone . The combined therapy is especially suitable for children and adolescents with ADHD who insufficiently respond to single drug treatment or experience drug side effects BACKGROUND Attention deficit hyperactivity disorder is increased in children with intellectual disability . Previous research has suggested stimulants are less effective than in typically developing children but no studies have titrated medication for individual optimal dosing or tested the effects for longer than 4 weeks . METHOD One hundred and twenty two drug-free children aged 7 - 15 with hyperkinetic disorder and IQ 30 - 69 were recruited to a double-blind , placebo-controlled trial that r and omized participants using minimization by probability , stratified by referral source and IQ level in a one to one ratio .  Methylpheni date was compared with placebo . Dose titration comprised at least 1 week each of low ( 0.5 mg/kg/day ) , medium ( 1.0 mg/kg/day ) and high dose ( 1.5 mg/kg/day ) . Parent and teacher Attention deficit hyperactivity disorder ( ADHD ) index of the Conners Rating Scale-Short Version at 16 weeks provided the primary outcome measures . Clinical response was determined with the Clinical Global Impressions scale ( CGI-I ) . Adverse effects were evaluated by a parent-rated question naire , weight , pulse and blood pressure . Analyses were by intention to treat . TRIAL REGISTRATION IS RCT N 68384912 . RESULTS Methylpheni date was superior to placebo with effect sizes of 0.39 [ 95 % confidence intervals ( CIs ) 0.09 , 0.70 ] and 0.52 ( 95 % CIs 0.23 , 0.82 ) for the parent and teacher Conners ADHD index . Four ( 7 % ) children on placebo versus 24 ( 40 % ) of those on methylpheni date were judged improved or much improved on the CGI . IQ and autistic symptoms did not affect treatment efficacy . Active medication was associated with sleep difficulty , loss of appetite and weight loss but there were no significant differences in pulse or blood pressure . CONCLUSIONS Optimal dosing of methylpheni date is practical and effective in some children with hyperkinetic disorder and intellectual disability . Adverse effects typical of methylpheni date were seen and medication use may require close monitoring in this vulnerable group The effects of methylpheni date on the academic performance and classroom behavior of 45 adolescents with attention deficit hyperactivity disorder were studied . During a 6-week , placebo-controlled medication assessment in the context of a summer treatment program , participants received a double-blind , crossover trial of 3 doses of methylpheni date . Dependent measures included note-taking quality , quiz and worksheet scores , written language usage and productivity , teacher ratings , on-task and disruptive behavior , and homework completion . Group data showed positive effects of methylpheni date on academic measures ; however , the greatest benefit came with the lowest dose . Although additional benefit did occur for some participants with higher doses , the largest increment of change usually occurred between the placebo and 10-mg dose . Many adolescents did not experience added benefit with increased dosages , and in some cases they experienced deterioration . Guidelines for assessment of medication effects are discussed
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 .