title: Analysis of a large fMRI cohort: Statistical and methodological issues for group analyses Methylphenidate-Elicited Dopamine Increases in Ventral Striatum Are Associated with Long-Term Symptom Improvement in Adults with Attention Deficit Hyperactivity Disorder Shared and Drug-Specific Effects of Atomoxetine and Methylphenidate on Inhibitory Brain Dysfunction in Medication-Naive ADHD Boys 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. Impulsiveness as a timing disturbance: neurocognitive abnormalities in attention-deficit hyperactivity disorder during temporal processes and normalization with methylphenidate Psychostimulant treatment and the developing cortex in attention deficit hyperactivity disorder. Developmental trajectories of brain volume abnormalities in children and adolescents with attention-deficit/hyperactivity disorder. Common and unique therapeutic mechanisms of stimulant and nonstimulant treatments for attention-deficit/hyperactivity disorder. Colored noise and computational inference in neurophysiological (fMRI) time series analysis: resampling methods in time and wavelet domains. Methylphenidate Normalizes Resting-State Brain Dysfunction in Boys With Attention Deficit Hyperactivity Disorder The effects of methylphenidate on neural systems of attention in attention deficit hyperactivity disorder. 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 Right inferior prefrontal cortex mediates response inhibition while mesial prefrontal cortex is responsible for error detection Methylphenidate hydrochloride given with or before breakfast: II. Effects on plasma concentration of methylphenidate and ritalinic acid. Volumetric MRI differences in treatment-naïve vs chronically treated children with ADHD 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: The aim of group fMRI studies is to relate contrasts of tasks or stimuli to regional brain activity increases . These studies typically involve 10 to 16 subjects . The average regional activity statistical significance is assessed using the subject to subject variability of the effect ( r and om effects analyses ) . Because of the relatively small number of subjects included , the sensitivity and reliability of these analyses is question able and hard to investigate . In this work , we use a very large number of subject ( more than 80 ) to investigate this issue . We take advantage of this large cohort to study the statistical properties of the inter-subject activity and focus on the notion of reproducibility by bootstrapping . We asked simple but important method ological questions : Is there , from the point of view of reliability , an optimal statistical threshold for activity maps ? How many subjects should be included in group studies ? What method should be preferred for inference ? Our results suggest that i ) optimal thresholds can indeed be found , and are rather lower than usual corrected for multiple comparison thresholds , ii ) 20 subjects or more should be included in functional neuroimaging studies in order to have sufficient reliability , iii ) non-parametric significance assessment should be preferred to parametric methods , iv ) cluster-level thresholding is more reliable than voxel-based thresholding , and v ) mixed effects tests are much more reliable than r and om effects tests . Moreover , our study shows that inter-subject variability plays a prominent role in the relatively low sensitivity and reliability of group studies 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 stimulant methylpheni date ( MPX ) and the nonstimulant atomoxetine ( ATX ) are the most commonly prescribed medications for attention deficit hyperactivity disorder ( ADHD ) . However , no functional magnetic resonance imaging ( fMRI ) study has as yet investigated the effects of ATX on inhibitory or any other brain function in ADHD patients or compared its effects with those of MPX . A r and omized , double-blind , placebo-controlled , crossover pharmacological design was used to compare the neurofunctional effects of single doses of MPX , ATX , and placebo during a stop task , combined with fMRI within 19 medication-naive ADHD boys , and their potential normalization effects relative to 29 age-matched healthy boys . Compared with controls , ADHD boys under placebo showed bilateral ventrolateral prefrontal , middle temporal , and cerebellar underactivation . Within patients , MPX relative to ATX and placebo significantly upregulated right ventrolateral prefrontal activation , which correlated with enhanced inhibitory capacity . Relative to controls , both drugs significantly normalized the left ventrolateral prefrontal underactivation observed under placebo , while MPX had a drug-specific effect of normalizing right ventrolateral prefrontal and cerebellar underactivation observed under both placebo and ATX . The findings show shared and drug-specific effects of MPX and ATX on performance and brain activation during inhibitory control in ADHD patients with superior upregulation and normalization effects of MPX BACKGROUND 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 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 OBJECTIVE While there has been considerable concern over possible adverse effects of psychostimulants on brain development , this issue has not been examined in a prospect i ve study . The authors sought to determine prospect ively whether psychostimulant treatment for attention deficit hyperactivity disorder ( ADHD ) was associated with differences in the development of the cerebral cortex during adolescence . METHOD Change in cortical thickness was estimated from two neuroanatomic MRI scans in 43 youths with ADHD . The mean age at the first scan was 12.5 years , and at the second scan , 16.4 years . Nineteen patients not treated with psychostimulants between the scans were compared with an age-matched group of 24 patients who were treated with psychostimulants .  Further comparison was made against a template derived from 620 scans of 294 typically developing youths without ADHD . RESULTS Adolescents taking psychostimulants  differed from those not taking psychostimulants in the rate of change of the cortical thickness in the right motor strip , the left middle/inferior frontal gyrus , and the right parieto-occipital region . The group difference was due to more rapid cortical thinning in the group not taking psychostimulants ( mean cortical thinning of 0.16 mm/year [ SD=0.17 ] , compared with 0.03 mm/year [ SD=0.11 ] in the group taking psychostimulants ) . Comparison against the typically developing cohort without ADHD showed that cortical thinning in the group not taking psychostimulants was in excess of age-appropriate rates . The treatment groups did not differ in clinical outcome , however . CONCLUSIONS These findings show no evidence that psychostimulants were associated with slowing of overall growth of the cortical mantle CONTEXT Various anatomic brain abnormalities have been reported for attention-deficit/hyperactivity disorder ( ADHD ) , with varying methods , small sample s , cross-sectional design s , and without accounting for stimulant drug exposure . OBJECTIVE To compare regional brain volumes at initial scan and their change over time in  medicated and previously unmedicated male and female patients with ADHD and healthy controls . DESIGN , SETTING , AND PARTICIPANTS Case-control study conducted from 1991 - 2001 at the National Institute of Mental Health , Bethesda , Md , of 152 children and adolescents with ADHD ( age range , 5 - 18 years ) and 139 age- and sex-matched controls ( age range , 4.5 - 19 years ) recruited from the local community , who contributed 544 anatomic magnetic resonance images . MAIN OUTCOME MEASURES Using completely automated methods , initial volumes and prospect i ve age-related changes of total cerebrum , cerebellum , gray and white matter for the 4 major lobes , and cau date nucleus of the brain were compared in patients and controls . RESULTS On initial scan , patients with ADHD had significantly smaller brain volumes in all regions , even after adjustment for significant covariates . This global difference was reflected in smaller total cerebral volumes ( -3.2 % , adjusted F(1,280 ) = 8.30 , P = .004 ) and in significantly smaller cerebellar volumes ( -3.5 % , adjusted F(1,280 ) = 12.29 , P = .001 ) . Compared with controls , previously unmedicated children with ADHD demonstrated significantly smaller total cerebral volumes ( overall F(2,288 ) = 6.65 ; all pairwise comparisons Bonferroni corrected , -5.8 % ; P = .002 ) and cerebellar volumes ( -6.2 % , F ( 2,288 ) = 8.97 , P<.001 ) . Unmedicated children with ADHD also exhibited strikingly smaller total white matter volumes ( F(2,288 ) = 11.65 ) compared with controls ( -10.7 % , P<.001 ) and with medicated children with ADHD ( -8.9 % , P<.001 ) . Volumetric abnormalities persisted with age in total and regional cerebral measures ( P = .002 ) and in the cerebellum ( P = .003 ) . Cau date nucleus volumes were initially abnormal for patients with ADHD ( P = .05 ) , but diagnostic differences disappeared as cau date volumes decreased for patients and controls during adolescence . Results were comparable for male and female patients on all measures . Frontal and temporal gray matter , cau date , and cerebellar volumes correlated significantly with parent- and clinician-rated severity measures within the ADHD sample ( Pearson coefficients between -0.16 and -0.26 ; all P values were < .05 ) . CONCLUSIONS Developmental trajectories for all structures , except cau date , remain roughly parallel for patients and controls during childhood and adolescence , suggesting that genetic and /or early environmental influences on brain development in ADHD are fixed , nonprogressive , and unrelated to stimulant treatment 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 Even in the absence of an experimental effect , functional magnetic resonance imaging ( fMRI ) time series generally demonstrate serial dependence . This colored noise or endogenous autocorrelation typically has disproportionate spectral power at low frequencies , i.e. , its spectrum is (1/f)-like . Various pre-whitening and pre-coloring strategies have been proposed to make valid inference on st and ardised test statistics estimated by time series regression in this context of residually autocorrelated errors . Here we introduce a new method based on r and om permutation after orthogonal transformation of the observed time series to the wavelet domain . This scheme exploits the general whitening or decorrelating property of the discrete wavelet transform and is implemented using a Daubechies wavelet with four vanishing moments to ensure exchangeability of wavelet coefficients within each scale of decomposition . For (1/f)-like or fractal noises , e.g. , realisations of fractional Brownian motion ( fBm ) parameterised by Hurst exponent 0 < H < 1 , this resampling algorithm exactly preserves wavelet-based estimates of the second order stochastic properties of the ( possibly nonstationary ) time series . Performance of the method is assessed empirically using (1/f)-like noise simulated by multiple physical relaxation processes , and experimental fMRI data . Nominal type 1 error control in brain activation mapping is demonstrated by analysis of 13 images acquired under null or resting conditions . Compared to autoregressive pre-whitening methods for computational inference , a key advantage of wavelet resampling seems to be its robustness in activation mapping of experimental fMRI data acquired at 3 Tesla field strength . We conclude that wavelet resampling may be a generally useful method for inference on naturally complex time series We used resting-state functional magnetic resonance imaging ( RS-fMRI ) to investigate the acute effects of methylpheni date hydrochloride ( MPH ) on spontaneous brain activity in children with attention deficit hyperactivity disorder ( ADHD ) . In all , 23 boys with ADHD were scanned twice , under either 10 mg dose of MPH or placebo , in a r and omized , cross-over , counterbalanced placebo-controlled design . 32 Matched healthy controls were scanned once for comparison . Seven of the 23 ADHD boys participated in a follow-up 8-week MPH treatment . A regional homogeneity ( ReHo ) method was applied to characterize the local synchronization of spontaneous brain activity .  ADHD boys under placebo compared with controls showed decreased ReHo in bilateral dorsolateral prefrontal cortices and increased ReHo in bilateral sensorimotor and parieto-visual cortices . Relative to placebo , MPH upregulated ReHo in bilateral ventral prefrontal cortices and cerebellar vermis , and downregulated ReHo in right parietal and visual areas that overlapped with the abnormally enhanced activities . When under MPH , ReHo differences between patients and controls were no longer observed . The preliminary prediction analysis revealed that the decreased ReHo in right parietal cortex after the acute MPH was positively correlated with the decreased symptom scores after the 8-week MPH treatment in the seven patients . We show that an acute dose of MPH normalized all fronto-parieto-cerebellar dysfunctions in boys with ADHD during the resting state . Preliminary findings furthermore suggest the potential of RS-fMRI as a prognostic imaging tool to identify response to MPH treatment OBJECTIVE Recent studies have suggested that attention deficit hyperactivity disorder ( ADHD ) is associated with abnormalities in basal ganglia and prefrontal cortical functioning . However , these studies have primarily relied upon cognitive tasks that reflect impulse control rather than attentional mechanisms . METHOD The authors used functional magnetic resonance imaging to investigate the neural correlates of selective and divided attention in a r and omized , double-blind , placebo-controlled pharmacological challenge with methylpheni date in 15 adolescents with ADHD ( ages 14 - 17 ) , eight adolescents with reading disorder ( ages 12 - 17 ) , and four adolescents with both reading disorder and ADHD ( ages 14 - 18 ) who were scanned during both a methylpheni date and a placebo session . Fourteen healthy comparison subjects ( ages 12 - 20 ) who were not given methylpheni date served as the primary comparison group . RESULTS During the divided attention task , unmedicated subjects with ADHD or reading disorder  recruited the left ventral basal ganglia significantly less than the healthy comparison subjects . Methylpheni date led to an increase in activation in this region but had no effect on task performance .  Subjects with ADHD also recruited the middle temporal gyrus significantly less than the comparison subjects , but methylpheni date did not have a direct effect on activation in this region . CONCLUSIONS These results suggest that ADHD is associated with abnormal processing in attentional networks , with specific dysfunction in striatal circuitry . Methylpheni date may act to normalize activity within this network 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 Inhibitory control and error detection are among the highest evolved human self-monitoring functions . Attempts in functional neuroimaging to effectively isolate inhibitory motor control from other cognitive functions have met with limited success . Different brain regions in inferior , mesial , and dorsolateral prefrontal cortices and parietal and temporal lobes have been related to inhibitory control in go/no-go and stop tasks . The widespread activation reflects the fact that the design s used so far have comeasured additional noninhibitory cognitive functions such as selective attention , response competition , decision making , target detection , and inhibition failure . Here we use rapid , mixed trial , event-related functional magnetic resonance imaging to correlate brain activation with an extremely difficult situation of inhibitory control in a challenging stop task that controls for noninhibitory functions . The difficulty of the stop task , requiring withholding of a triggered motor response , was assured by an algorithm that adjusted the task individually so that each subject only succeeded on half of all stop trials , failing on the other half . This design allowed to elegantly separate brain activation related to successful motor response inhibition and to inhibition failure or error detection . Brain activation correlating with successful inhibitory control in 20 healthy volunteers could be isolated in right inferior prefrontal cortex . Failure to inhibit was associated with activation in mesial frontopolar and bilateral inferior parietal cortices , presumably reflecting an attention network for error detection Methylpheni date HCl ( Ritalin ) is often prescribed for the treatment of hyperactivity and is usually administered orally 30 minutes to 1 hour before meals , based on an assumption that meals may interfere with the absorption or metabolism of the drug . Seven boys who were taking methylpheni date regularly for the treatment of hyperactivity were hospitalized and given their established dose of the drug intravenously or orally , either with breakfast or in a fasted state . Blood sample s were taken to determine the pharmacokinetics of the drug in each condition . Few differences between the " fed " and " fasted " states were noted , but the statistically significant differences indicated that meals accelerate rather than impede the absorption of methylpheni date Objective : To determine if there are differences in the volume of the cau date and anterior cingulate cortex ( ACC ) between children with attention deficit hyperactivity disorder ( ADHD ) and controls , and if such differences are related to the subjects ’ history of stimulant treatment . Methods : We performed a case-control study in an academic medical center . Twenty-one healthy controls , 16 children with ADHD , combined type with a history of stimulant treatment , and 14 children with ADHD , combined type treatment naïve , underwent structural MRI . All children with ADHD were medication-free at the time of the MRI .  Regional hemispheric volumes ( in cm3 ) of cau date and anterior cingulate cortex were determined . Results : There were significant differences bilaterally on cau date volume for both ADHD groups vs controls , with no difference between the ADHD groups on either side . In contrast , the right ACC was significantly smaller for the ADHD-treatment naïve ( ADHD/TN ) group compared to the ADHD-treated ( ADHD/Rx ) and control group . The volume of left ACC approached significance contrast between ADHD/RX and ADHD/TN . There were no differences found between the ADHD/Rx and controls on the ACC volumes bilaterally . Conclusions : The results from this study indicate a relationship of previous treatment history with cau date and anterior cingulate volumetric changes in children with attention deficit hyperactivity disorder – combined type 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 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: 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 .