title: Therapeutic Doses of Oral Methylphenidate Significantly Increase Extracellular Dopamine in the Human Brain Clinically Relevant Doses of Methylphenidate Significantly Occupy Norepinephrine Transporters in Humans In Vivo Functional magnetic resonance imaging of methylphenidate and placebo in attention-deficit/hyperactivity disorder during the multi-source interference task. Methylphenidate Normalizes Frontocingulate Underactivation During Error Processing in Attention-Deficit/Hyperactivity Disorder A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. The MTA Cooperative Group. Multimodal Treatment Study of Children with ADHD. Impulsiveness as a timing disturbance: neurocognitive abnormalities in attention-deficit hyperactivity disorder during temporal processes and normalization with methylphenidate Methylphenidate Normalizes Fronto-Striatal Underactivation During Interference Inhibition in Medication-Naïve Boys with Attention-Deficit Hyperactivity Disorder Young adult outcome of attention deficit hyperactivity disorder: a controlled 10-year follow-up study. Efficacy of a new pattern of delivery of methylphenidate for the treatment of ADHD: effects on activity level in the classroom and on the playground. The effects of methylphenidate on neural systems of attention in attention deficit hyperactivity disorder. Effects of methylphenidate on working memory functioning in children with attention deficit/hyperactivity disorder. A right hemispheric frontocerebellar network for time discrimination of several hundreds of milliseconds Effects of long-term methylphenidate treatment: A pilot follow-up clinical and SPECT study Methylphenidate normalises activation and functional connectivity deficits in attention and motivation networks in medication-naïve children with ADHD during a rewarded continuous performance task
abstract: 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 BACKGROUND Attention-deficit/hyperactivity disorder is a psychiatric disorder that starts in childhood . The mechanism of action of methylpheni date , the most common treatment for attention deficit hyperactivity disorder , is unclear . In vitro , the affinity of methylpheni date for the norepinephrine transporter ( NET ) is higher than that for the dopamine transporter ( DAT ) . The goal of this study was to use positron emission tomography to measure the occupancy of brain norepinephrine transporter by methylpheni date in vivo in humans . METHODS We used (S , S)-[¹¹C ] methylreboxetine ( [¹¹C]MRB ) to determine the effective dose 50 ( ED₅₀ ) of methylpheni date for NET . In a within-subject design , healthy subjects ( n = 11 ) received oral , single-blind placebo and 2.5 , 10 , and 40 mg of methylpheni date 75 min before [¹¹C]MRB injection . Dynamic positron emission tomography imaging was performed for 2 hours with the High Resolution Research Tomograph . The multilinear reference tissue model with occipital cortex as the reference region was used to estimate binding potential non-displaceable ( BP(ND ) ) in the thalamus and other NET-rich regions . RESULTS BP(ND ) was reduced by methylpheni date in a dose-dependent manner in thalamus and other NET-rich regions . The global ED₅₀ was estimated to be .14 mg/kg ; therefore , the average clinical maintenance dose of methylpheni date ( .35-.55 mg/kg ) produces 70 % to 80 % occupancy of NET . CONCLUSIONS For the first time in humans , we demonstrate that oral methylpheni date significantly occupies NET at clinical ly relevant doses . The ED₅₀ is lower than that for DAT ( .25 mg/kg ) , suggesting the potential relevance of NET inhibition in the therapeutic effects of methylpheni date in 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 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 BACKGROUND Previous studies have demonstrated the short-term efficacy of pharmacotherapy and behavior therapy for attention-deficit/hyperactivity disorder ( ADHD ) , but no longer-term ( i.e. , > 4 months ) investigations have compared these 2 treatments or their combination . METHODS A group of 579 children with ADHD Combined Type , aged 7 to 9.9 years , were assigned to 14 months of medication management ( titration followed by monthly visits ) ; intensive behavioral treatment ( parent , school , and child components , with therapist involvement gradually reduced over time ) ; the two combined ; or st and ard community care ( treatments by community providers ) . Outcomes were assessed in multiple domains before and during treatment and at treatment end point ( with the combined treatment and medication management groups continuing medication at all assessment points ) . Data were analyzed through intent-to-treat r and om-effects regression procedures . RESULTS All 4 groups showed sizable reductions in symptoms over time , with significant differences among them in degrees of change . For most ADHD symptoms , children in the combined treatment and medication management groups showed significantly greater improvement than those given intensive behavioral treatment and community care . Combined and medication management treatments did not differ significantly on any direct comparisons , but in several instances ( oppositional/aggressive symptoms , internalizing symptoms , teacher-rated social skills , parent-child relations , and reading achievement )  combined treatment proved superior to intensive behavioral treatment and /or community care while medication management did not . Study medication strategies were superior to community care treatments , despite the fact that two thirds of community-treated subjects received medication during the study period . CONCLUSIONS For ADHD symptoms , our carefully crafted medication management was superior to behavioral treatment and to routine community care that included medication . Our combined treatment did not yield significantly greater benefits than medication management for core ADHD symptoms , but may have provided modest advantages for non-ADHD symptom and positive functioning outcomes 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 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 BACKGROUND Our objective was to estimate the lifetime prevalence of psychopathology in a sample of youth with and without attention deficit hyperactivity disorder ( ADHD ) through young adulthood using contemporaneous diagnostic and analytic techniques . METHOD We conducted a case-control , 10-year prospect i ve study of ADHD youth . At baseline , we assessed consecutively referred male , Caucasian children with ( n=140 ) and without ( n=120 ) DSM-III-R ADHD , aged 6 - 18 years , ascertained from psychiatric and pediatric sources to allow for generalizability of results . At the 10-year follow-up , 112 ( 80 % ) and 105 ( 88 % ) of the ADHD and control children , respectively , were reassessed ( mean age 22 years ) . We created the following categories of psychiatric disorders : Major Psychopathology ( mood disorders and psychosis ) , Anxiety Disorders , Antisocial Disorders ( conduct , oppositional-defiant , and antisocial personality disorder ) , Developmental Disorders ( elimination , language , and tics disorder ) , and Substance Dependence Disorders ( alcohol , drug , and nicotine dependence ) , as measured by blinded structured diagnostic interview . RESULTS The lifetime prevalence for all categories of psychopathology were significantly greater in ADHD young adults compared to controls , with hazard ratios and 95 % confidence intervals of 6.1 ( 3.5 - 10.7 ) , 2.2 ( 1.5 - 3.2 ) , 5.9 ( 3.9 - 8.8 ) , 2.5 ( 1.7 - 3.6 ) , and 2.0 ( 1.3 - 3.0 ) , respectively , for the categories described above . CONCLUSIONS By their young adult years , ADHD youth were at high risk for a wide range of adverse psychiatric outcomes including markedly elevated rates of antisocial , addictive , mood and anxiety disorders . These prospect i ve findings provide further evidence for the high morbidity associated with ADHD across the life-cycle and stress the importance of early recognition of this disorder for prevention and intervention strategies OBJECTIVES To evaluate the pharmacodynamic effects of an experimental ( EXP ) delivery of methylpheni date ( MPH ) in children with attention-deficit/hyperactivity disorder and to investigate the situational nature of effects in laboratory classroom and playground setting s. METHOD A " sipping " study methodology was used to deliver a bolus followed by small but increasing MPH doses as the EXP regimen . A r and omized , double-blind crossover design was used to compare the EXP regimen to a thrice-daily ( TID ) regimen and a placebo ( PLA ) regimen . Measures of efficacy were obtained from a Motionlogger actigraph to quantify activity and from the Swanson , Kotkin , Agler , M-Flynn , and Pelham ( SKAMP ) rating scale to quantify two domains of behavior ( attention and deportment ) . RESULTS Compared with PLA , both EXP and TID delivery of MPH produced large , significant reductions in activity and inappropriate behavior in the classroom , but the two MPH regimens did not differ in onset or duration of effects across the day . The MPH effects were situationally dependent and were smaller for the playground than for the classroom setting s. CONCLUSIONS The findings of this " proof of concept " study support the efficacy of a continuous , ascending delivery of MPH . The situational effects of MPH provide support for the theory of selective effects of stimulants , dependent on the dem and s of the environment 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 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 Debate still surrounds the nature of the role of the dorsolateral prefrontal gyrus ( DLPFC ) in time perception . This region is frequently associated with working memory and is thus implicated as a so-called " accumulator " within a hypothesized internal clock model . However , we hypothesized that this region may have a more primary role in time perception . To test this hypothesis we used functional magnetic resonance imaging ( fMRI ) to examine the neural correlates of relatively pure time perception with a temporal discrimination task where intervals of 1 s had to be discriminated from those of 1.3 , 1.4 , and 1.5 s. Time perception in this particular time domain within the " perceived present " has not previously been investigated using fMRI . By using relatively short time periods to be discriminated and also contrasting activation with an order judgment task , we aim ed to minimize the confounding aspects of sustained attention and working memory . In a group of 20 healthy right-h and ed adult males , neural activation associated with time discrimination was found in a predominantly right hemispheric network of right dorsolateral and inferior prefrontal cortices , right supplementary motor area , and left cerebellum . We conclude that right DLPFC , rather than having a purely working memory function , might be more central ly involved in time perception than previously thought BACKGROUND Although abnormalities in the regional cerebral blood flow ( rCBF ) responses to methylpheni date ( MPH ) treatment have been reported in children with attention deficit hyperactivity disorder ( ADHD ) , there are few prospect i ve longitudinal studies assessing the long-term effects of MPH and discontinuation effects after chronic treatment . METHODS The authors studied ten drug-naive children ( 2 girls , 8 boys , mean age+/-S.D.=9.60+/-1.96 ) diagnosed with ADHD by the Diagnostic and Statistical Manual of Mental Disorders ( DSM-IV ) diagnostic criteria , using (99m)Tc-HMPAO-single photon emission computed tomography ( SPECT ) .  Patients were studied at baseline ( visit 1 ) , after 2 months of MPH treatment ( visit 2 ) and after a drug-free period of 2 months following 12 months of MPH treatment ( visit 3 ) at doses of 1 mg/kg/day . We evaluated SPECT data visually and semi-quantitatively . RESULTS Two months of chronic MPH treatment result ed in visually detectable improvement in hypoperfusion in the right frontal cortex and all areas of temporal cortex with the exception of left lateral temporal cortex . This improvement was still detectable on visual evaluations of SPECT data after 2 months of treatment discontinuation . The treatment effects that were detected visually were not statistically significant in semi-quantitative analyses . CONCLUSIONS Treatment effects of chronic MPH treatment may persist long after the discontinuation of the treatment 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
target: RESULTS In ADHD patients the middle and inferior frontal gyri , basal ganglia , and cerebellum were most often affected by MPH .
  The middle and inferior frontal gyri were frequently affected by MPH during inhibitory control tasks .
  Throughout nine task-based fMRI studies investigating MPH 's effect on the brains of pediatric patients with ADHD , MPH result ed in increased activation within frontal lobes , basal ganglia , and cerebellum .
  In most cases , this increase " normalized " activation of at least some brain areas to that seen in typically developing children
background: OBJECTIVE Attention-deficit/hyperactivity disorder ( ADHD ) is a psychiatric disorder affecting 5 % of children .
  Methylpheni date ( MPH ) is a common medication for ADHD .
  Studies examining MPH 's effect on pediatric ADHD patients ' brain function using functional magnetic resonance imaging ( fMRI ) have not been compiled .
  The goals of this systematic review were to determine ( 1 ) which areas of the brain in pediatric ADHD patients are modulated by a single dose of MPH , ( 2 ) whether areas modulated by MPH differ by task type performed during fMRI data acquisition , and ( 3 ) whether changes in brain activation due to MPH relate to clinical improvements in ADHD-related symptoms .