Methylphenidate normalises activation and functional connectivity deficits in attention and motivation networks in medication-naïve children with ADHD during a rewarded continuous performance task Methylphenidate Normalizes Frontocingulate Underactivation During Error Processing in Attention-Deficit/Hyperactivity Disorder Methylphenidate Normalizes Resting-State Brain Dysfunction in Boys With Attention Deficit Hyperactivity Disorder Effects of methylphenidate on working memory functioning in children with attention deficit/hyperactivity disorder. Methylphenidate Normalizes Fronto-Striatal Underactivation During Interference Inhibition in Medication-Naïve Boys with Attention-Deficit Hyperactivity Disorder Methylphenidate and if-then plans are comparable in modulating the P300 and increasing response inhibition in children with ADHD Reward processing in male adults with childhood ADHD—a comparison between drug-naïve and methylphenidate-treated subjects Pattern Classification of Working Memory Networks Reveals Differential Effects of Methylphenidate, Atomoxetine, and Placebo in Healthy Volunteers Methylphenidate improves diminished error and feedback sensitivity in ADHD: An Evoked Heart Rate analysis The effect of methylphenidate on prefrontal cognitive functioning, inattention, and hyperactivity in velocardiofacial syndrome. Motivational incentives and methylphenidate enhance electrophysiological correlates of error monitoring in children with attention deficit/hyperactivity disorder Misinterpreting Emotional Expressions in Attention-Deficit/Hyperactivity Disorder: Evidence for a Neural Marker and Stimulant Effects The effectiveness of methylphenidate in the management of Attention Deficit Hyperactivity Disorder (ADHD) in people with intellectual disabilities: A systematic review. Clinical evaluation of subjective and objective changes in motor activity and attention in children with attention-deficit/hyperactivity disorder in a double-blind methylphenidate trial. Unexpected effects of methylphenidate in attention-deficit/hyperactivity disorder reflect decreases in core/secondary symptoms and physical complaints common to all children. A large, double-blind, randomized clinical trial of methylphenidate in the treatment of adults with attention-deficit/hyperactivity disorder Effects of methylphenidate, desipramine, and l-dopa on attention and inhibition in children with Attention Deficit Hyperactivity Disorder Executive Impairment Determines ADHD Medication Response: Implications for Academic Achievement Erratum to: Long-acting methylphenidate formulations in the treatment of attention-deficit/hyperactivity disorder: a systematic review of head-to-head studies A Randomized Controlled Trial Investigating the Effects of Neurofeedback, Methylphenidate, and Physical Activity on Event-Related Potentials in Children with Attention-Deficit/Hyperactivity Disorder. Mediators of Methylphenidate Effects on Math Performance in Children with Attention-Deficit Hyperactivity Disorder Treatment of ADHD in children with tics: A randomized controlled trial Methylphenidate combined with aripiprazole in children and adolescents with bipolar disorder and attention-deficit/hyperactivity disorder: a randomized crossover trial.
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 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 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 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 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 A disturbed functioning of the prefrontal cortex , the anterior cingulate cortex , and an accordingly reduced P300 presumably underlies executive function deficits of children with attention deficit hyperactivity disorder ( ADHD ) . Using a combined classification and Go/NoGo task paradigm , the present study investigated whether medication with methylpheni date ( MPH ) modulates the P300 as measured by a high-density electroencephalogram ( EEG ) and facilitates response inhibition in children with ADHD . Further , effects of MPH were compared with effects of self-regulation by if-then plans ( Gollwitzer in Am Psychol 54 : 493–503 , 1999 ) . MPH as well as if-then plans modulated the P300 and improved inhibition of an unwanted response on a Go/NoGo task to the same level observed in children without ADHD . Importantly , self-regulation strategies might be a valuable alternative to medication with MPH in children with ADHD 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 and non-stimulant drugs can reduce symptoms of attention deficit/hyperactivity disorder ( ADHD ) . The stimulant drug methylpheni date ( MPH ) and the non-stimulant drug atomoxetine ( ATX ) are both widely used for ADHD treatment , but their differential effects on human brain function remain unclear . We combined event-related fMRI with multivariate pattern recognition to characterize the effects of MPH and ATX in healthy volunteers performing a rewarded working memory ( WM ) task . The effects of MPH and ATX on WM were strongly dependent on their behavioral context . During non-rewarded trials , only MPH could be discriminated from placebo ( PLC ) , with MPH producing a similar activation pattern to reward . During rewarded trials both drugs produced the opposite effect to reward , that is , attenuating WM networks and enhancing task-related deactivations ( TRDs ) in regions consistent with the default mode network ( DMN ) . The drugs could be directly discriminated during the delay component of rewarded trials : MPH produced greater activity in WM networks and ATX produced greater activity in the DMN . Our data provide evidence that : ( 1 ) MPH and ATX have prominent effects during rewarded WM in task-activated and -deactivated networks ; ( 2 ) during the delay component of rewarded trials , MPH and ATX have opposing effects on activated and deactivated networks : MPH enhances TRDs more than ATX , whereas ATX attenuates WM networks more than MPH ; and ( 3 ) MPH  mimics reward during encoding . Thus , interactions between drug effects and motivational state are crucial in defining the effects of MPH and ATX Attention Deficit Hyperactivity Disorder ( ADHD ) is a developmental disorder that has previously been related to a decreased sensitivity to errors and feedback . Supplementary to the traditional performance measures , this study uses autonomic measures to study this decreased sensitivity in ADHD and the modulating effects of medication . Children with ADHD , on and off Methylpheni date ( Mph ) , and typically developing ( TD ) children performed a selective attention task with three feedback conditions : reward , punishment and no feedback .  Evoked Heart Rate ( EHR ) responses were computed for correct and error trials . All groups performed more efficiently with performance feedback than without . EHR analyses , however , showed that enhanced EHR decelerations on error trials seen in TD children , were absent in the medication-free ADHD group for all feedback conditions . The Mph-treated ADHD group showed ' normalised ' EHR decelerations to errors and error feedback , depending on the feedback condition . This study provides further evidence for a decreased physiological responsiveness to errors and error feedback in children with ADHD and for a modulating effect of Mph 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 Background Children with attention deficit hyperactivity disorder ( ADHD ) are characterised by developmentally inappropriate levels of hyperactivity , impulsivity and /or inattention and are particularly impaired when performing tasks that require a high level of cognitive control . Methylpheni date ( MPH ) and motivational incentives may help improve cognitive control by enhancing the ability to monitor response accuracy and regulate performance accordingly . Methods Twenty-eight children with DSM-IV ADHD ( combined type ) aged 9–15 years and pairwise-matched typically developing children ( CTRL ) performed a go/no-go task in which the incentives attached to performance on no-go trials were manipulated . The ADHD group performed the task off and on their usual dose of MPH . CTRL children performed the task twice but were never medicated . EEG data were recorded simultaneously and two electrophysiological indices of error monitoring , the error-related negativity ( ERN ) and error positivity ( Pe ) were measured . Amplitudes of each ERP were compared between diagnostic groups ( CTRL , ADHD ) , medication days ( Off MPH , On MPH ) and motivational conditions ( baseline – low incentive , reward , response cost ) . Results Error rates were lower in the reward and response cost conditions compared with baseline across diagnostic groups and medication days . ERN and Pe amplitudes were significantly reduced in ADHD compared with CTRL , and were significantly enhanced by MPH . Incentives significantly increased ERN and Pe amplitudes in the ADHD group but had no effect in CTRL . The effects of incentives did not interact with the effects of MPH on either ERP . Effect sizes were computed and revealed larger effects of MPH than incentives on ERN and Pe amplitudes . Conclusions The findings reveal independent effects of motivational incentives and MPH on two electrophysiological markers of error monitoring in children with ADHD , suggesting that each may be important tools for enhancing or restoring cognitive control in these children 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 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 aim of this study was to determine drug-dependent effects on attention and motor activity in children with attention-deficit/hyperactivity disorder ( ADHD ) in a double-blind methylpheni date ( MPH ) trial using both subjective behavior ratings and objective measures of function . In particular , we were interested in the relationship between changes of those subjective and objective measures . A total of 44 ADHD children with the combined subtype completed a r and omized , double-blind , placebo-controlled , crossover trial with 2 doses of MPH ( 0.25 ; 0.5 mg/kg body weight ) and placebo . In each condition , computerized attention tasks were performed , teacher-behavior ratings were obtained , and actigraph data were collected in both clinical and naturalistic setting s. Trend tests revealed linear effects of MPH dose on actigraph data in the test session ( p = 0.02 ) and at school ( p = 0.001 ) , as well as on sustained attention ( p < 0.001 ) , while inhibitory control showed a quadratic dose-response curve ( p < 0.001 ) . Multivariate regression analyses revealed that changes of both , hyperactive-impulsive symptoms ( 28 % ) and inattentive symptoms ( 23 % ) could be explained by objective changes of motor activity . Thus , for clinical practice , it should be taken into account that behavior ratings of ADHD symptoms seemed to be predominantly influenced by changes of motor activity Abstract Hypotheses concerning unexpected , psychostimulant-related effects reported in previous studies were examined by separating behavioral/physical complaints highly specific to methylpheni date ( MPH ) from those that ( a ) may mimic core/ secondary symptoms of the disorder , or ( b ) are commonly reported by unmedicated children in the general population . Sixty-five children with attention-deficit/hyperactivity disorder ( ADHD ) participated in a double-blind , placebo-controlled , within-subject ( crossover ) experimental design and received a placebo and four MPH doses in counterbalanced order following baseline assessment . Behavioral and physical complaints were significantly higher under baseline relative to placebo and the four immediate-release MPH conditions ( 5 mg , 10 mg , 15 mg , and 20 mg ) across three symptom categories : ADHD core/ secondary symptoms ; symptoms commonly reported in the general population , including unmedicated children with ADHD ; and symptoms highly specific to MPH . No significant differences were found among active drug conditions . Past unexpected findings of psychostimulant effects in ADHD may be due to the inclusion of scale items that reflect core/ secondary features of ADHD and normally occurring behavioral/physical complaints in children BACKGROUND The few controlled studies of methylpheni date ( MPH ) in adults with attention deficit/hyperactivity disorder ( ADHD ) have reported equivocal results . A previous , pilot study by our group suggested that these results were due to inadequate dosing . METHOD We conducted a r and omized , 6-week , placebo-controlled , parallel study of MPH in 146 adult patients with DSM-IV ADHD using st and ardized instruments for diagnosis , separate assessment s of ADHD , depressive and anxiety symptoms , and a robust average oral daily dose of 1.1 mg/kg/day . RESULTS We found a marked therapeutic response for the MPH treatment of ADHD symptoms that exceeded the placebo response ( 76 % vs. 19 % ) . Treatment was safe and well tolerated . Response to MPH was independent of socioeconomic status , gender , and lifetime history of psychiatric comorbidity . CONCLUSIONS These results confirm that robust doses of MPH are effective in the treatment of adult ADHD The objective of this study was to investigate the effects of methylpheni date ( MPH ) on attention and inhibition in children with Attention Deficit Hyperactivity Disorder ( ADHD ) and to establish what the relative contributions of the noradrenergic and dopaminergic systems to this effect were . In addition to MPH , two other drugs were administered in order to affect both transmitter systems more selectively , L-dopa ( dopamine ( DA ) agonist ) and desipramine ( DMI ) ( noradrenaline ( NA ) re-uptake inhibitor ) . Sixteen children with ADHD performed a stop-task , a laboratory task that measures the ability to inhibit an ongoing action , in a double-blind r and omized within-subjects design . Each child received an acute clinical dose of MPH , DMI , L-dopa , and placebo ;  measures of performance and plasma were determined . The results indicated that inhibition performance was improved under DMI but not under MPH or L-dopa . The response-time to the stop-signal was marginally shortened after intake of DMI . MPH decreased omission and choice-errors and caused faster reaction times to the trials without the stop-tone . No effects of L-dopa whatsoever were noted . Prolactin levels were increased and 5-HIAA levels were lowered under DMI relative to placebo . It is suggested that the effects of MPH on attention are due to a combination of noradrenergic and dopaminergic mechanisms . The improved inhibition under DMI could be serotonergically mediated Methylpheni date ( MPH ) often ameliorates attention-deficit/hyperactivity disorder ( ADHD ) behavioral dysfunction according to indirect informant reports and rating scales . The st and ard of care behavioral MPH titration approach seldom includes direct neuropsychological or academic assessment data to determine treatment efficacy . Documenting “ cool ” executive-working memory ( EWM ) and “ hot ” self-regulation ( SR ) neuropsychological impairments could aid in differential diagnosis of ADHD subtypes and determining cognitive and academic MPH response . In this study , children aged 6 to 16 with ADHD inattentive type ( IT ; n = 19 ) and combined type ( n = 33)/hyperactive-impulsive type ( n = 4 ) ( CT ) participated in double-blind placebo-controlled MPH trials with baseline and r and omized placebo , low MPH dose , and high MPH dose conditions . EWM/ SR measures and behavior ratings/classroom observations were rank ordered separately across conditions , with nonparametric r and omization tests conducted to determine individual MPH response . Participants were subsequently grouped according to their level of cool EWM and hot SR circuit dysfunction . Robust cognitive and behavioral MPH response was achieved for children with significant baseline EWM/SR impairment , yet response was poor for those with adequate EWM/ SR baseline performance . Even for strong MPH responders , the best dose for neuropsychological functioning was typically lower than the best dose for behavior . Findings offer one possible explanation for why long-term academic MPH treatment gains in ADHD have not been realized . Implication s for academic achievement and medication titration practice s for children with behaviorally diagnosed ADHD will be discussed Background : The stimulant methylpheni date ( MPH ) has been a mainstay of treatment for attention-deficit/hyperactivity disorder ( ADHD ) for many years . Owing to the short half-life and the issues associated with multiple daily dosing of immediate-release MPH formulations , a new generation of long-acting MPH formulations has emerged . Direct head-to-head studies of these long-acting MPH formulations are important to facilitate an evaluation of their comparative pharmacokinetics and efficacy ; however , to date , relatively few head-to-head studies have been performed . The objective of this systematic review was to compare the evidence available from head-to-head studies of long-acting MPH formulations and provide information that can guide treatment selection . Methods : A systematic literature search was conducted in MEDLINE and PsycINFO in March 2012 using the MeSH terms : attention deficit disorder with hyperactivity/drug therapy ; methylpheni date /therapeutic use and All Fields : Concerta ; Ritalin LA ; OROS and ADHD ; Medikinet ; Equasym XL and ADHD ; long-acting methylpheni date ; Diffucaps and ADHD ; SODAS and methylpheni date . No filters were applied and no language , publication date or publication status limitations were imposed . Articles were selected if the title indicated a comparison of two or more long-acting MPH preparations in human subjects of any age ; non- systematic review articles and unpublished data were not included . Results : Of 15,295 references returned in the literature search and screened by title , 34 articles were identified for inclusion : nine articles from pharmacokinetic studies ( nine studies ) ; nine articles from laboratory school studies ( six studies ) ; two articles from r and omized controlled trials ( two studies ) ; three articles from switching studies ( two studies ) and three articles from one observational study . Conclusions : Emerging head-to-head studies provide important data on the comparative efficacy of the formulations available . At a group level , efficacy across the day generally follows the pharmacokinetic profile of the MPH formulation . No formulation is clearly superior to another ; careful consideration of patient needs and subtle differences between formulations is required to optimize treatment . For patients achieving suboptimal symptom control , switching long-acting MPH formulations may be beneficial . When switching formulations , it is usually appropriate to titrate the immediate-release component of the formulation ; a limitation of current studies is a focus on total daily dose rather than equivalent immediate-release components . Further studies are necessary to provide guidance in clinical practice , particularly in the treatment of adults and pre-school children and the impact of comorbidities and symptom severity on treatment response OBJECTIVE Electroencephalographic ( EEG ) neurofeedback ( NF ) is considered a nonpharmacological alternative for medication in attention-deficit/hyperactivity disorder ( ADHD ) . Comparisons of the behavioral efficacy of NF and medication have produced inconsistent results . EEG measures can provide insight into treatment mechanisms , but have received little consideration . In this r and omized controlled trial ( RCT ) , effects of NF were compared with methylpheni date ( MPH ) , and physical activity ( PA ) in children with ADHD on event-related potential ( ERP ) indices of response inhibition , which are involved in ADHD psychopathology . METHODS Using a multicenter three way parallel group RCT design , 112 children with a Diagnostic and Statistical Manual of Mental Disorders , 4th ed . ( DSM-IV ) ( American Psychiatric Association 1994 ) diagnosis of ADHD , between 7 and 13 years of age , were initially included .  NF training consisted of 30 sessions of theta/beta training at Cz over a 10 week period . PA training was a semiactive control group , matched in frequency and duration . MPH was titrated using a double-blind placebo controlled procedure in 6 weeks , followed by a stable dose for 4 weeks . ERP measures of response inhibition , N2 and P3 , were available for 81 children at pre- and postintervention ( n = 32 NF , n = 25 MPH , n = 24 PA ) . RESULTS Only the medication group showed a specific increase in P3 amplitude compared with NF ( partial eta-squared [ ηp(2 ) ] = 0.121 ) and PA ( ηp(2 ) = 0.283 ) , which was related to improved response inhibition . Source localization of medication effects on P3 amplitude indicated increased activation primarily in thalamic and striatal nuclei . CONCLUSIONS This is the first study that simultaneously compared NF with stimulant treatment and a semiactive control group . Only stimulant treatment demonstrated specific improvements in brain function related to response inhibition . These results are in line with recent doubts on the efficacy and specificity of NF as treatment for ADHD . CLINICAL TRIALS REGISTRATION Train Your Brain ? Exercise and Neurofeedback Intervention for ADHD , https:// clinical trials.gov/show/NCT01363544 , Ref . No. NCT01363544 Objective : Stimulant medications , such as methylpheni date ( MPH ) , improve the academic performance of children with attention-deficit hyperactivity disorder ( ADHD ) . However , the mechanism by which MPH exerts an effect on academic performance is unclear . We examined MPH effects on math performance and investigated possible mediation of MPH effects by changes in time on-task , inhibitory control , selective attention , and reaction time variability . Methods : Children with ADHD aged 7 to 11 years ( N = 93 ) completed a timed math worksheet ( with problems tailored to each individual 's level of proficiency ) and 2 neuropsychological tasks ( Go/No-Go and Child Attention Network Test ) at baseline , then participated in a 4-week , r and omized , controlled , titration trial of MPH . Children were then r and omly assigned to their optimal MPH dose or placebo for 1 week ( administered double-blind ) and repeated the math and neuropsychological tasks ( posttest ) . Baseline and posttest videorecordings of children performing the math task were coded to assess time on-task . Results : Children taking MPH completed 23 more math problems at posttest compared to baseline , whereas the placebo group completed 24 fewer problems on posttest versus baseline , but the effects on math accuracy ( percent correct ) did not differ . Path analyses revealed that only change in time on-task was a significant mediator of MPH 's improvements in math productivity . Conclusions : MPH-derived  math productivity improvements may be explained in part by increased time spent on-task , rather than improvements in neurocognitive parameters , such as inhibitory control , selective attention , or reaction time variability Background The treatment of children with attention deficit hyperactivity disorder ( ADHD ) and Tourette syndrome ( TS ) has been problematic because methylpheni date (MPH)—the most commonly used drug to treat ADHD — has been reported to worsen tics and because clonidine (CLON)—the most commonly prescribed alternative — has unproven efficacy . Methods The authors conducted a multicenter , r and omized , double-blind clinical trial in which 136 children with ADHD and a chronic tic disorder were r and omly administered CLON alone , MPH alone , combined CLON + MPH , or placebo ( 2 × 2 factorial design ) . Each subject participated for 16 weeks ( weeks 1–4 CLON/placebo dose titration , weeks 5–8 added MPH/placebo dose titration , weeks 9–16 maintenance therapy ) . Results Thirty-seven children were administered MPH alone , 34 were administered CLON alone , 33 were administered CLON + MPH , and 32 were administered placebo . For our primary outcome measure of ADHD ( Conners Abbreviated Symptom Question naire – Teacher ) , significant improvement occurred for subjects assigned to CLON ( p < 0.002 ) and those assigned to MPH ( p < 0.003 ) . Compared with placebo , the greatest benefit occurred with combined CLON + MPH ( p < 0.0001 ) . CLON appeared to be most helpful for impulsivity and hyperactivity ; MPH appeared to be most helpful for inattention . The proportion of individual subjects reporting a worsening of tics as an adverse effect was no higher in those treated with MPH ( 20 % ) than those being administered CLON alone ( 26 % ) or placebo ( 22 % ) . Compared with placebo , measured tic severity lessened in all active treatment groups in the following order : CLON + MPH , CLON alone , MPH alone . Sedation was common with CLON treatment ( 28 % reported moderate or severe sedation ) , but otherwise the drugs were tolerated well , including absence of any evident cardiac toxicity . Conclusions Methylpheni date and clonidine ( particularly in combination ) are effective for ADHD in children with comorbid tics . Prior recommendations to avoid methylpheni date in these children because of concerns of worsening tics are unsupported by this trial In clinical sample s , juvenile bipolar disorder ( JBPD ) is frequently accompanied by co-morbid attention-deficit/hyperactivity disorder ( ADHD ) . Clinical trials assessing combined psychopharmacological interventions in this population are scarce , and methylpheni date ( MPH ) may worsen manic symptoms . We conducted a r and omized crossover trial with MPH and placebo ( 2 weeks each ) combined with aripiprazole in children and adolescents ( n = 16 ; 8 - 17 years old ) with JBPD and ADHD who had a significant response in manic symptoms with aripiprazole but still presented clinical ly significant symptoms of ADHD .  ADHD , manic , and depressive symptoms were assessed by means of st and ard scales . Fourteen out of the 16 subjects completed the trial . No significant differences between the effects of methylpheni date and placebo were detected in ADHD ( F(1 , 43.22 ) = 0.00 ; p = 0.97 ) or manic ( F(1 , 40.19 ) = 0.93 ; p = 0.34 ) symptoms . Significant improvement in depressive symptoms was observed in the MPH group ( F(1,19.03 ) = 7.75 ; p = 0.01 ) according to a secondary self-reported outcome measure . One patient using aripiprazole  and MPH discontinued the trial due to the onset of a severe mixed episode . No other significant adverse events were observed . Although MPH did not worsen manic symptoms , it was not more effective than placebo in improving ADHD symptoms in children and adolescents with JBPD co-morbid with ADHD stabilized with aripiprazole . Further investigations are warranted . This study is registered at www . clinical trials.gov under the identifier NCT00305370
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
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 .