Neural Correlates of the Propensity for Retaliatory Behavior in Youths With Disruptive Behavior Disorders. Impulsiveness as a timing disturbance: neurocognitive abnormalities in attention-deficit hyperactivity disorder during temporal processes and normalization with methylphenidate Impact of treatments for depression on comorbid anxiety, attentional, and behavioral symptoms in adolescents with selective serotonin reuptake inhibitor-resistant depression. Methylphenidate Normalizes Fronto-Striatal Underactivation During Interference Inhibition in Medication-Naïve Boys with Attention-Deficit Hyperactivity Disorder Brain gray matter deficits at 33-year follow-up in adults with attention-deficit/hyperactivity disorder established in childhood. Risperidone effects in the presence/absence of psychostimulant medicine in children with ADHD, other disruptive behavior disorders, and subaverage IQ. Methylphenidate normalises activation and functional connectivity deficits in attention and motivation networks in medication-naïve children with ADHD during a rewarded continuous performance task The effects of methylphenidate on neural systems of attention in attention deficit hyperactivity disorder. Methylphenidate Normalizes Frontocingulate Underactivation During Error Processing in Attention-Deficit/Hyperactivity Disorder
OBJECTIVE Youths with disruptive behavior disorders ( DBD ) ( conduct disorder and oppositional defiant disorder ) have an elevated risk for maladaptive reactive aggression . Theory suggests that this is due to an elevated sensitivity of basic threat circuitry implicated in retaliation ( amygdala/periaqueductal gray ) in youths with DBD and low levels of callous-unemotional traits and dysfunctional regulatory activity in the ventromedial prefrontal cortex in youths with DBD irrespective of callous-unemotional traits . METHOD A total of 56 youths 10 - 18 years of age ( 23 of them female ) participated in the study : 30 youths with DBD , divided by median split into groups with high and low levels of callous-unemotional traits , and 26 healthy youths . All participants completed an ultimatum game task during functional MRI . RESULTS Relative to the other groups , youths with DBD and low levels of callous-unemotional traits showed greater increases in activation of basic threat circuitry when punishing others and dysfunctional down-regulation of the ventromedial prefrontal cortex during retaliation . Relative to healthy youths , all youths with DBD showed reduced amygdala-ventromedial prefrontal cortex connectivity during high provocation . Ventromedial prefrontal cortex responsiveness and ventromedial prefrontal cortex-amygdala connectivity were related to patients ' retaliatory propensity ( behavioral responses during the task ) and parent-reported reactive aggression . CONCLUSIONS These data suggest differences in the underlying neurobiology of maladaptive reactive aggression in youths with DBD who have relatively low levels of callous-unemotional traits . Youths with DBD and low callous-unemotional traits alone showed significantly greater threat responses during retaliation relative to comparison subjects . These data also suggest that ventromedial prefrontal cortex-amygdala connectivity is critical for regulating retaliation/reactive aggression and , when dysfunctional , contributes to reactive aggression , independent of level of callous-unemotional traits 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 To assess the relative efficacy of antidepressant medication , alone and in combination with cognitive behavioral therapy ( CBT ) , on comorbid symptoms of anxiety , attention , and disruptive behavior disorders in participants in the Treatment of Resistant Depression in Adolescents ( TORDIA ) trial . METHOD Adolescents with selective serotonin reuptake inhibitor (SSRI)-resistant depression ( N = 334 ) were r and omly assigned to a medication switch alone ( to another SSRI or to venlafaxine ) or to a medication switch plus CBT .  Anxiety , attention-deficit/hyperactivity disorder ( ADHD ) , and disruptive behavior disorder ( DBD ) symptoms were assessed by psychiatric interview and self-report at regular intervals between baseline and 24 weeks . The differential effects of medication and of CBT , and the impact of remission on the course of comorbid symptoms and diagnoses , were assessed using generalized linear mixed models . RESULTS Remission was associated with a greater reduction in scalar measures of anxiety , ADHD , and DBDs , and a greater decrease in the rate of diagnosed anxiety disorders . The correlations between the changes in symptoms of depression on the CDRS-R and anxiety , ADHD , and oppositional symptoms were modest , ranging from r = 0.12 to r = 0.28 . There were no significant differential treatment effects on diagnoses , or corresponding symptoms . CONCLUSION The achievement of remission had a beneficial effect on anxiety , ADHD , and DBD symptoms , regardless of the type of treatment received . There were no differential effects of medication or CBT on outcome , except for a nonsignificant trend that those adolescents treated with SSRIs showed a greater decrease in rates of comorbid DBDs relative to those treated with venlafaxine . Clinical trial registration information-Treatment of SSRI-Resistant Depression In Adolescents ( TORDIA ) ; http:// clinical trials.gov/ ; NCT00018902 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 CONTEXT Volumetric studies have reported relatively decreased cortical thickness and gray matter volumes in adults with attention-deficit/hyperactivity disorder ( ADHD ) whose childhood status was retrospectively recalled . We present , to our knowledge , the first prospect i ve study combining cortical thickness and voxel-based morphometry in adults diagnosed as having ADHD in childhood . OBJECTIVES To test whether adults with combined-type childhood ADHD exhibit cortical thinning and decreased gray matter in regions hypothesized to be related to ADHD and to test whether anatomic differences are associated with a current ADHD diagnosis , including persistent vs remitting ADHD . DESIGN Cross-sectional analysis embedded in a 33-year prospect i ve follow-up at a mean age of 41.2 years . SETTING Research outpatient center . PARTICIPANTS We recruited prob and s with ADHD from a cohort of 207 white boys aged 6 to 12 years . Male comparison participants ( n = 178 ) were free of ADHD in childhood . We obtained magnetic resonance images in 59 prob and s and 80 comparison participants ( 28.5 % and 44.9 % of the original sample s , respectively ) . MAIN OUTCOME MEASURES Whole-brain voxel-based morphometry and vertexwise cortical thickness analyses . RESULTS The cortex was significantly thinner in ADHD prob and s than in comparison participants in the dorsal attentional network and limbic areas ( false discovery rate < 0.05 , corrected ) . In addition , gray matter was significantly decreased in prob and s in the right cau date , right thalamus , and bilateral cerebellar hemispheres . Prob and s with persistent ADHD ( n = 17 ) did not differ significantly from those with remitting ADHD ( n = 26 ) ( false discovery rate < 0.05 ) . At uncorrected P < .05 , individuals with remitting ADHD had thicker cortex relative to those with persistent ADHD in the medial occipital cortex , insula , parahippocampus , and prefrontal regions . CONCLUSIONS Anatomic gray matter reductions are observable in adults with childhood ADHD , regardless of the current diagnosis . The most affected regions underpin top-down control of attention and regulation of emotion and motivation . Exploratory analyses suggest that diagnostic remission may result from compensatory maturation of prefrontal , cerebellar , and thalamic circuitry OBJECTIVE The aim of this study was to examine the safety and efficacy of risperidone , with or without concomitant psychostimulant use , in the treatment of children with conduct disorder ( CD ) or other disruptive behavior disorders [ oppositional defiant disorder ( ODD ) , disruptive behavior disorder-not otherwise specified ( DBD-NOS ) ] , and comorbid attention-deficit hyperactivity disorder ( ADHD ) . METHODS Data from two 6-week placebo-controlled trials assessing risperidone therapy in children with subaverage IQs and CD , ODD , DBD-NOS were combined , and patients with comorbid ADHD were selected for this post hoc analysis . Patients were grouped according to r and omized drug therapy ( risperidone or placebo ) , and then subgrouped according to their use of a concomitant psychostimulant .  Safety outcomes included adverse events and weight change , while efficacy outcomes included changes in scores on disruptive behavior and hyperactivity-based subscales of two behavior-rating instruments ( Nisonger Child Behavior Rating Form and the Aberrant Behavior Checklist ) . RESULTS The analysis included 155 of 208 originally tested children divided into four sub-groups ( 35 - 43 patients each ) . There was no significant difference in the frequency of adverse events in patients who received  risperidone  alone and those who received risperidone plus a stimulant . The most common adverse events in risperidone-treated patients were somnolence , headache , dyspepsia , rhinitis , and vomiting . Within each r and omized treatment group , actual weight gain was comparable , regardless of concomitant stimulant use . Risperidone-treated patients had clinical ly and statistically significant reductions in both disruptive behavior and hyperactivity subscale scores , compared to placebo , regardless of concomitant stimulant use . The addition of risperidone to a psychostimulant result ed in significantly better control of hyperactivity ( p < 0.001 ) than was achieved with stimulant treatment alone , without causing an increase in adverse events . CONCLUSION Risperidone was a safe and effective treatment , with or without a combined psychostimulant , for both disruptive behavior disorders and comorbid ADHD in children 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 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 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
Results : In ADHD , deviant prefrontal and cingulate functional activity was associated with increased IA .
Structural alterations were most pronounced in the cingulate cortex .
Subjects with DBDs showed marked cortico‐subcortical dysfunctions .
ADHD and DBDs share similar cortico‐limbic structural and functional alterations .
RI deficits in ADHD highlighted hypoactivity in the dorso/ventro‐lateral PFC , insula , and striatum , while the paralimbic system was primarily dysfunctional in DBDs .
Across disorders , extensively altered cortico‐limbic dysfunctions underlie IA , while RI was mostly associated with aberrant prefrontal activity .
Conclusion : Control network deficits were evidence d across clinical phenotypes in IA and RI .
Dysfunctions at any level within these cortico‐subcortical projections lead to deficient cognitive‐affective control by ascribing emotional salience to otherwise irrelevant stimuli .
HighlightsImpulsive aggression and dysfunctional response inhibition are present in ADHD and DBDs .
Broad fronto‐striatal‐cerebellar dysfunctions have been implicated in ADHD and DBDs .
Prefrontal and cingulate cortical deficits are associated with IA in ADHD.Severe widespread cortico‐subcortical breakdowns are associated with IA in DBDs .
RI deficits have been attributed to hypoactivity in the lateral PFC , insula , and amygdala .
Whether reduced gray matter volumes relate to ADHD and DBDs or if present as an IA epiphenomenon remains debatable .
Background : Although impulsive aggression ( IA ) and dysfunctional response inhibition ( RI ) are hallmarks of attention‐deficit/hyperactivity disorder ( ADHD ) and disrupted behavioral disorders ( DBDs ) , little is known about their shared and distinct deviant neural mechanisms .