human
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: 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 
    Output:
    
agent
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
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: 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 
    Output:
    