Investigation of cool and hot executive function in ODD/CD independently of ADHD

REVIEW

“Cool” Inferior Frontostriatal Dysfunction inAttention-Deficit/Hyperactivity Disorder Versus“Hot” Ventromedial Orbitofrontal-LimbicDysfunction in Conduct Disorder: A ReviewKatya Rubia

Attention-deficit/hyperactivity disorder (ADHD) and conduct disorder overlap behaviorally, clinically, and cognitively. An important ques-tion of potential future clinical relevance is whether these two overlapping disorders are mediated by similar or distinct underlying brainsubstrates. This article reviews the modern neuroimaging literature on brain structure, function, and connectivity in both disorders, shapingout commonalities and differences. Findings show that ADHD is characterized predominantly by abnormalities in inferior frontal, striatal,parietotemporal, and cerebellar regions and networks that mediate “cool”-cognitive, i.e., inhibitory, attention and timing functions associ-ated with the disorder. Conduct disorder, by contrast, has consistently been associated with abnormalities of the “hot” paralimbic systemthat regulates motivation and affect, comprising lateral orbital and ventromedial prefrontal cortices, superior temporal lobes, and underly-ing limbic structures, most prominently the amygdala. Direct comparisons in functional imaging show that these associations of cool inferiorfronto-striato-cerebellar dysfunction in ADHD and of hot orbitofrontal-paralimbic dysfunction in conduct disorder are disorder-specific.There is, hence, evidence for dissociated underlying pathophysiologies for these two disorders that may have implications for future
anatomy-based differential diagnosis and prevention and intervention.
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Key Words: ADHD, attention-deficit/hyperactive disorder, CD, con-duct disorder, executive functions, fMRI, frontal lobe, functionalmagnetic resonance imaging, motivation, MRI

A ttention-deficit/hyperactivity disorder (ADHD) is character-ized by symptoms of age-inappropriate inattention, impul-siveness, and hyperactivity (DSM-IV) (1). It disrupts academic

and social development and is associated with significant psychiat-ric comorbidities (2) and mental health problems in adult life (3,4).

Conduct disorder (CD) is defined by the violation of the rights ofothers and societal rules and the persistent display of antisocialbehaviors such as deception, theft, vandalism, and violence withina 6- to 12-month period before age 18 (DSM-IV) (1). Conduct disor-der is considered a risk factor for various psychiatric conditionsbeginning in adolescence or adulthood, including antisocial per-sonality disorder and mood disorders (5–13). Oppositional defiantdisorder (ODD) is characterized by recurrent patterns of negativis-tic, defiant, disobedient, and hostile behavior toward authority fig-ures. Oppositional defiant disorder is often comorbid with CD andhas been considered a less severe subtype, although there is em-piric evidence to distinguish the two disorders. In the DSM-IV, adiagnosis of CD is given if an individual meets criteria for both CDand ODD. The lower age of onset of CD before age 10 has beenassociated with a worse outcome, such as a greater risk for adultantisocial behavior and for emotional and behavioral dysregulation(14). A more pervasive subtype of CD is seen in those with callous-unemotional (CU) traits, defined as low fearfulness and a lack ofempathy, guilt, and emotion (15), present in approximately 25% ofcases of child-onset conduct disorder (16,17). This subtype is asso-ciated with poorer outcomes compared with non-CU CD groups,

From the Department of Child Psychiatry/Medical Research Council Centerfor Social, Genetic and Developmental Psychiatry, Institute of Psychiatry,London, United Kingdom.

Address correspondence to Katya Rubia, Ph.D., Institute of Psychiatry, King’sCollege, Department of Child Psychiatry, 16 De Crespigny Park, LondonSE5 8AF, United Kingdom; E-mail: [email protected].

mReceived Apr 20, 2010; revised Sep 16, 2010; accepted Sep 18, 2010.

0006-3223/$36.00doi:10.1016/j.biopsych.2010.09.023

ncluding substance use disorders, criminality, violent offending,nd increased risk of psychopathy, as well as higher genetic riskactors (15,16,18 –20).

europsychological Findings

Attention-deficit/hyperactivity disorder is associated most con-istently with neuropsychological deficits in tasks of motor re-ponse and cognitive inhibition (such as tasks of interference inhi-ition or cognitive switching), sustained attention, and timing

unctions (21–23). Children with CD have also shown deficits inasks of motor and cognitive inhibition (24 –27). Furthermore, likeDHD patients, they are also impaired in tasks of cognitive switch-

ng and reversal (28 –31), as well as of sustained attention (32–37).owever, studies have included comorbidity with ADHD, and thevidence for impairment in CD without comorbid ADHD comparedith control subjects is less consistent; in fact, several studies foundo independent deficits from ADHD for these tasks (37– 43).

An exception, however, is in functions of motivation control,here children with CD seem as impaired or more impaired than

hildren with ADHD. Thus, children with CD or psychopathy areonsistently impaired in reversal tasks, where previously valid and

earned rewarded stimulus-response contingencies change and areo longer rewarded or even punished (28,44). This seems to be due

o a reduced sensitivity to punishment in children with CD com-ared with control subjects or children with ADHD. In fact, responseerseveration (i.e., hyposensitivity to increasing punishment) using

he Newman Card Playing Task paradigm (45) or other task variantsas been found to be independently related to CD but not “nonco-orbid” ADHD (39,46,47). In gambling tasks that measure reward-

elated long-term advantageous decision making versus impulsivehort-term decisions, both pathologies have been shown to bempaired, although none of these studies excluded comorbidity

ith the other disorder (48 –50). Regression analyses, however,howed that the antisocial behavior traits were responsible for thempulsive reward-related choice pattern in this task, whereas ADHDraits accounted for the “cool” executive function deficits in tasks of

otor inhibition and attention (50).

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Cool and Hot Executive Functions and TheirUnderlying Neurobiology

Recent developmental theorists have proposed the distinction be-tween cool cognitive executive functions such as attention, workingmemory, planning, and inhibition that are known to be mediated bylateral inferior and dorsolateral frontostriatal and frontoparietal net-works (51–54) and “hot” executive functions that involve incentivesand motivation (55) and are mediated by the paralimbic orbitomedialand ventromedial frontolimbic structures (51,56–60).

Emotion regulation and motivation are mediated by lateral or-bitofrontal and ventromedial frontal regions, including the anteriorcingulate, amygdala, insula, hippocampus and hypothalamus, theventral striatum, and other connected areas (61,62). The amygdalais important for the processing of negative affect and threat andtogether with ventral striatum mediates stimulus-reward associa-tions and motivation functions (63– 66). Orbitofrontal and temporallobes have been associated with impulsivity and aggression in le-sion, animal, and imaging studies (67– 69). Together with ventro-medial frontal cortex, including anterior cingulate, they mediatetop-down affect regulation in their interconnection to underlyinglimbic areas (61,62,65,66). These networks of affect regulation andmotivation have been shown to be implicated in hot executivefunctions (70).

Cool higher level cognitive processes are mediated by fronto-striato-temporo-parietal and frontocerebellar circuitries in childrenand adults (51–54). Higher order temporal and parietal sensorycortices mediate bottom-up attention based on stimulus salience,with the temporoparietal junction being crucial for visual-spatialand executive attention functions (71–73). The prefrontal cortex(PFC) provides goal-directed top-down attention and cognitivecontrol through several functions: inhibitory control of irrelevantacts and attention to irrelevant stimuli; sustaining, dividing, andselecting attention; working memory; and cognitive flexibility, aswell as timing functions such as temporal foresight (74 –76). Frontal,temporal, and parietal cortical areas are reciprocally intercon-nected with each other and project to basal ganglia and thalamus,as well as cerebellum in fronto-parieto-striatal and corticocerebel-lar circuitries that, in concert, mediate these attention and cognitivecontrol functions (65,66,72,73).

It thus seems that the neuropsychological evidence shows def-icits in children with ADHD in cool executive function tasks medi-ated by fronto-striato-cerebellar and frontoparietal neural net-works, while children with CD appear to be more prominentlyimpaired in tasks of affect and motivation control, such as gam-bling, or stimulus-response contingency reversal tasks that are me-diated by ventromedial and orbitofrontal limbic neural networks.The association between motivation control deficits and antisocialbehaviors is in line with behavioral studies showing that contin-gency association learning involving reward and punishment isstrongly implicated in the development and maintenance of anti-social behaviors (77).

Comorbidity Between ADHD and CDConduct disorder and ODD overlap clinically, behaviorally, and

cognitively with ADHD. The odds ratio for comorbidity with ADHDin children with CD is over 40, while this increases to 79 in childrenwith ODD (78,79). Comorbid patients are often considered severecases of ADHD (28) and the notion of a separate neurobiologicalbasis for CD has been debated (80). Comorbid cases have a moresevere clinical outcome than the individual diagnoses (81,82).

An important question yet to be addressed is whether these two
similar and often clinically and neuropsychologically overlapping d
www.sobp.org/journal

isorders differ in their underlying etiopathophysiology. The sepa-ation of associated neural networks for each disorder would po-entially be very helpful for the development of a more objectiveifferential diagnosis and of disorder-specific prevention and inter-entions.

tructural and Functional Neuroimaging of ADHD

tructural StudiesNeuroimaging studies in children with ADHD have shown con-

istent abnormalities relative to control subjects in late-developingnferior frontostriatal and frontocerebellar circuitries that mediatehese cognitive control functions that are impaired in the disorder.hus, structural magnetic resonance imaging (MRI) studies foundeduced volume and cortical thickness in inferior prefrontal cortexIFC) but also other frontal brain regions, as well as parietotemporalegions, the basal ganglia, the splenium of the corpus callosum, andhe cerebellum (83– 86). Two recent meta-analyses of structuralata in childhood ADHD have been published. The first meta-anal-sis was conducted on region of interest studies showing the great-st significant reductions relative to control subjects in posterior

nferior vermis of the cerebellum, the splenium of the corpus callo-um, total and right cerebral volumes, right caudate, and variousrontal regions (87). The other meta-analysis was of whole-brainoxel-based morphometry imaging studies, avoiding the a prioriias of region selection, and identified a significant regional grayatter reduction in ADHD children compared with control subjects

n right putamen and globus pallidus (88). Diffusion tensor imagingtudies have furthermore provided evidence for abnormalities athe neural network level, showing abnormalities in multiple white

atter tracts in cingulate and frontostriatal, as well as frontoparie-al, frontocerebellar, and parieto-occipital white matter tracts, inhildren, as well as adults, with ADHD compared with comparisonubjects (89 –92). Longitudinal imaging studies have provided evi-ence that the structural abnormalities in these late-developing

ronto-striato-cerebellar and frontoparietal systems are due to aate structural maturation of these regions (86,93). Thus, the peak ofortical thickness maturation has been shown to be delayed inhildren with ADHD compared with healthy peers by an average ofyears, with some regions, including frontal and temporal areas,

eing delayed in their cortical maturation by up to 4 to 5 years (93).

unctional Imaging StudiesIn line with the frontostriatal hypothesis of ADHD, functional

maging studies have shown reduced activation compared withontrol subjects, in particular in the IFC, anterior cingulate, andaudate, but also in temporoparietal regions, during tasks of motoresponse inhibition (69,94 –100), interference inhibition (101–103),nd of sustained, selective, and flexible attention (100,102,104 –11) (for meta-analysis, see [112]). Furthermore, ADHD childrenave also shown reduced activation in dorsal and ventrolateralrefrontal, cingulate, and cerebellar brain regions during tem-oral processes, including tasks of motor timing, time discrimi-ation, and temporal foresight (94,113–115), as well as temporalnpredictability (116). The cerebellum has furthermore beenhown to be dysfunctional in children with ADHD relative toealthy control subjects during tasks of attention and timing

unctions (108,109,114,116). A few recent studies have alsoested for neurofunctional deficits in children with ADHD relativeo healthy control subjects during tasks of motivation, finding ab-ormalities in ventral striatum, orbitofrontal, and cingulate cortices
uring reward-related processes (108,109,114,117).

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More recent functional imaging studies have tested for deficitsin interregional functional connectivity. During the resting state,children with ADHD have been shown to have reduced functionalconnectivity relative to healthy control subjects in frontostriatal,frontoparietal, temporoparietal, and frontocerebellar networks(118 –120), although increased interregional connectivity betweenanterior cingulate, striatum, and temporocerebellar regions hasalso been reported (118,121–123). In the context of cognitive tasks,I am only aware of two published papers in childhood ADHD. Onefound a reduced degree of functional connectivity relative tohealthy control subjects between IFC and the basal ganglia, parietallobes, and cerebellum, as well as between cerebellum and parietaland striatal brain regions during sustained attention (108); theother study found reduced connectivity between frontoparietaland frontocerebellar regions during interference inhibition andtime estimation, respectively (124). These findings suggest that thedysfunctions observed in ADHD patients not only affect isolatedbrain regions but also the functional interregional interconnectivitybetween affected regions, thus demonstrating deficits in fronto-striato-cerebellar and frontoparietal neural networks.

Relatively fewer studies have been conducted in adult ADHDand findings have been more inconsistent. This is likely due to thefact that confounding factors are more pronounced in adult com-pared with childhood ADHD imaging studies, such as the inclusionof small sample sizes, the elevated rate of comorbid conditions inadult ADHD, long-term medication history, and the need for retro-spective diagnosis (125). Structural imaging studies in adult ADHDobserved abnormalities in the volumes of left orbitofrontal cortex(126); in overall cortical gray matter, right anterior cingulate, andleft superior/dorsolateral prefrontal cortex (127); and cortical thick-ness in bilateral dorsolateral and orbitofrontal cortices, anterior andposterior cingulate, and in the temporo-occipitoparietal junction(128), as well as reduced structural connectivity between theseregions (91). Functional underactivation has been observed in adultADHD relative to healthy control subjects in orbital and dorsolateralprefrontal cortices and striatal, anterior cingulate, cerebellar, andparietotemporal brain regions, with, however, also some evidencefor compensatory increased activation in some of these regions insome studies (for review, see [125]). Functional task-related connec-tivity studies show deficits in interregional connectivity relative tohealthy control subjects during motor response inhibition betweenright and left IFC cortices and between the right inferior frontal lobeand other areas, including basal ganglia, anterior and posteriorcingulate, and parietotemporal and cerebellar areas (129), whichwas also observed by another study in adult ADHD patients duringworking memory (130). However, in the study of Wolf et al. (130),compensatory-increased connectivity was also observed betweenleft dorsal anterior cingulate, superior frontal lobe, and cerebellum.Rest-associated functional connectivity studies have found abnor-mal functional connectivity between anterior and posterior cingu-late (91,131,132).

ConclusionsIn summary, childhood ADHD is characterized by structural and

functional deficits compared with healthy children in predomi-nantly inferior but also medial and dorsolateral prefrontal cortices,anterior cingulate, the basal ganglia, cerebellum, and temporopa-rietal brain regions and their functional and structural interconnec-tivity, causing poor top-down control over inhibitory, attention,and timing functions. An important caveat, however, is that themajority of imaging studies in children with ADHD have not ex-
cluded comorbidity with ODD or CD. The extent to which antisocial c
roblems may have confounded the neuroimaging literature ofDHD can therefore not be assessed.

tructural and Functional Neuroimaging of CD

tructural Imaging StudiesUnfortunately, the imaging literature in CD is very confounded

y ADHD comorbidity. Very few imaging studies have tested chil-ren with CD independently of ADHD. A small, underpoweredtructural study compared 7 comorbid children with ADHD � CD, 5hildren with noncomorbid ADHD, and 19 healthy control subjects133). While the children with noncomorbid ADHD did not differrom those with comorbid ADHD and CD, both groups differedrom control subjects in the volume of the left and total posterioruperior and inferior lobes of the cerebellar vermis (133) (Table 1).ore recent structural studies found reduced volume and grayatter concentration/thickness of temporal lobes and other limbic

nd paralimbic regions in childhood-onset CD relative to healthyontrol subjects (134,135). In the study of Kruesi et al. (134), allhildren had lower IQ and a history of ADHD, with 6 out of 10hildren having current ADHD and 4 having substance abuse. Pa-ients relative to control subjects showed reduced total temporalobe and reduced right temporal gray matter volumes, and findingsemained after controlling for IQ and substance abuse. Attention-eficit/hyperactivity disorder, however, was not controlled for in

he study. In the study of Huebner et al. (135), most CD patientsere comorbid with ADHD (17 of 23 patients) but had no affectiveisorder. They showed reduced total gray matter volumes relative

o control subjects, in particular in bilateral temporal lobes, leftmygdala and hippocampus, and orbitofrontal and ventromedialrontal regions, but increased gray matter in bilateral cerebellum.lthough the majority of CD children also had ADHD, regressionnalyses within patients revealed significant associations betweenD symptoms and gray matter reductions in temporal, limbic

amygdala, hippocampus), cerebellar, medial, and mesial frontalray matter, while hyperactivity/impulsiveness symptoms corre-

ated inversely with gray matter reductions in left inferior frontalnd parietal cortices and bilateral temporo-occipital regions (135).study by Sterzer et al. (136) scanned 10 patients with CD; 7 of the

atients also met criteria for ADHD and scored high for anxiety andepression. Reduced gray matter volumes were observed relative

o healthy control subjects in bilateral insula and left amygdala,oth of which correlated with aggressive and inattentive but notnxiety/depression symptoms. A study by DeBrito et al. (137) com-ared 23 community adolescent boys with no psychiatric abnor-alities or mood or anxiety problems but high levels of callous-

nemotional (CD-CU), as well as CD and ADHD problems, with theirealthy twins. Covarying for both inattentive-hyperactivity symp-

oms and IQ, they found that gray matter concentration was in-reased compared with control boys in posterior medial orbitofron-al cortex, dorsal and rostral anterior cingulate, as well as in gray

atter concentration and volumes in superior parietotemporal anduperior frontal regions, cerebellum, insula, posterior cingulate,nd hippocampus. The most interesting finding of their study was aignificant deviation in CD-CU children from the norm-typical neg-tive correlation between age and cortical thickness in orbitofron-al and left dorsal anterior cingulate. The fact that patients, unlikeontrol subjects, showed no negative age correlation in this mea-ure could potentially indicate a delay of normal brain maturation137), similar to that observed in ADHD (93). Longitudinal studies

ill be needed, however, to corroborate this observation based on
ross-sectional data.

Table 1. Summary of Main Findings of Structural and Functional Magnetic Resonance Imaging Studies that Directly Compared Children with ADHD and with CD

StudyImagingMethod Task WB/ROI Subjects F/M

AgeRange

Med/MedHistory Results

Bussing et al.2002 (133)

sMRI — WB 5 ADHD only7 CD/ADHD10 control subjects

F and M 8 –12 Yes CD/ADHD and ADHD alone versus control subjects: reduced mean volumesin total and L posterior superior and inferior cerebellar vermis. Nodifferences between the pure and the comorbid groups. No groupdifferences in cerebral hemispheres or caudate.

Rubia et al.2008 (96)

fMRI Stop taska) Successful

stopb) Failed stop

WB 20 ADHD13 CD20 control subjects

M 9 –17 No 3-group interaction effects:a) Successful stop: ADHD versus CD and versus control subjects: reduced

activation in L DLPFC/IFCb) Failed stop: CD versus ADHD and versus control subjects: reduced

activation in L and R IPL and R STLBoth patient groups versus control subjects: reduced activation in L and R

PCC/precuneus.Rubia et al.

2009 (109)fMRI Rewarded CPT WB 18 ADHD

14 CD16 control subjects

M 9 –17 No 3-group interaction effects:CPT: ADHD versus CD and control subjects: reduced L and R IFC and

enhanced L and R Cb/hippocampus/PCC activation.L and R IFC activation was correlated with omission errors that were

enhanced at trend level in ADHD.CD versus ADHD and control subjects: reduced activation in R insula,

hippocampus, PMC, ACC.Reward effect: CD versus ADHD and control subjects: reduced activation

in R ventromedial OFC.ADHD versus CD and control subjects: reduced activation in precuneus

and PCC.Rubia et al.

2009 (102)fMRI Simon and oddball

tasksROI 8 ADHD

8 control subjectsM 10 –17 No 3-group interaction effects:

Oddball: ADHD versus CD and control subjects: reduced activation in LDLPFC/IFC.

ADHD and CD versus control subjects: reduced activation in R DLPFC butno differences between patient groups.

Simon: ADHD and CD versus control subjects: reduced activation in R STLand MTL and R precuneus but no differences between patient groups.

Rubia et al.2010 (107)

fMRI Switch task WB 14 ADHD14 CD20 control subjects

M 9 –17 No 3-group interaction effects:ADHD versus CD and control subjects: reduced activation in L and R IFC/

DLPFC.2-group comparisons:CD versus control subjects: reduced activation in L and R IPL and R STL/

precuneus but no differences between patient groups.Marsh et al.

2008 (148)fMRI Neutral, fearful,

and angryfaces

ROI 12 ADHD/CD/ODD � CU12 ADHD12 control subjects

M 10 –17 Yes Group by expression effect:ADHD/CD/ODD � CU versus ADHD pure and control subjects: reduced R

amygdala activation for fearful faces (trend). Also reduced functionalconnectivity between R amygdala and R OFC.

Connectivity abnormalities correlated with CU severity. No groupdifferences for angry or neutral faces.

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In conclusion, the structural evidence, therefore, points towardbnormalities in CD of the paralimbic system, comprising the or-itofrontal cortex (OFC), anterior cingulate, superior temporal

obes, and underlying limbic structures that are known to mediateotivation and affect (29,138). So far, however, there are no studies

f structural connectivity in CD that have tested for potential distur-ance of white matter tracts belonging to the paralimbic system toonfirm a neural network disturbance.

unctional Imaging StudiesFunctional imaging studies in children with CD have been con-

istent with the structural evidence, finding abnormalities in theentromedial orbitofrontal temporolimbic system in CD. The ma-

ority of functional magnetic resonance imaging (fMRI) studies inD have used emotion processing tasks. A study by Sterzer et al.

139) found more pronounced deactivation in right dorsal anterioringulate gyrus in children with CD relative to healthy control sub-ects during the viewing of pictures with negative valence, which

as interpreted by the authors as reduced inhibition of emotionalehavior. Although 62% of patients also met criteria for ADHD and

he group scored high on depression-anxiety, the anterior cingu-ate deactivation correlated negatively with the aggressive behav-or scores and remained when controlling for attention, depres-ion/anxiety scores, and IQ (139). This is in line with the notion ofeduced emotion processing as the basis of aggression, given thathe amygdala is a key region for the processing of negative affect140). A subsequent correlation analysis on the same dataset found

correlation between abnormal functioning of anterior cingulatend sensation seeking (141). A later study on a group of 22 childrenith CD with no affective disorder, 16 of which had ADHD, found

nhanced left amygdala activation compared with healthy controlubjects to the same negative affect stimulation, suggesting emo-ional hyperresponsivity. The effect remained when controlling forffective/depressive symptoms and was not observed in a patientontrol group with ADHD only (142). Although the findings re-ained when covaried for affective symptoms, the group was char-

cterized by high symptoms of emotion and anxiety, which could,t least partly, explain the enhanced amygdala activation that isypically enhanced in anxiety in relation to negative emotions suchs fear (143).

A recent fMRI study in children with early-onset childhood CD,8% of which also met criteria for ADHD, found abnormal activationompared with control subjects in relation to empathy and sympa-hy. Children with CD had reduced activation in the somatosensoryain matrix, typically activated in healthy children in response to

he observation of pictures showing humans undergoing acciden-al body harm, but enhanced activation in anterior midcingulate,eft amygdala, right caudate, and bilateral temporal pole (144).urthermore, the extent of prefrontal and amygdala activation toiewing pain in others was significantly positively correlated toheir number of aggressive acts and their ratings of daring andadism score on behavioral questionnaires.

The comparison of pictures showing intentional versus acciden-al body harm also showed enhanced activation in the antisocialatients compared with healthy control subjects in somatosensoryain regions of left anterior insula, supplementary motor area, andrecentral gyrus but decreased activation in lateral IFC, posterioringulate, and the temporoparietal junction. Furthermore, the acti-ation in the temporoparietal junction and insula correlated withhe subjective ratings of the pain experienced by the individuals inhe pictures (144). Connectivity analyses showed that pain inflictedy others versus accidental pain led to enhanced connectivity be-

tween ventromedial prefrontal cortex and amygdala in control sub-Tab

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jects but not in CD patients (144). The findings suggest that highlyaggressive antisocial youth are hypersensitive in their brain re-sponse to seeing victims in pain and show diminished regulation ofemotion-processing networks, as shown by reduced PFC/amygdalaconnectivity relative to control subjects. The fact that these activa-tion and connectivity patterns correlated with sadism and antiso-cial behavioral ratings suggests either that the hypersensitivity re-flects greater enjoyment of the other’s pain or enhanced reactivityand reduced control over networks that process negative emotions(144). The correlation findings also suggest that the brain abnor-malities are associated with the antisocial core ratings, which isimportant, given the high comorbidity. Aggression may thus berelated to poor regulation over hypersensitive negative affect pro-cessing brain regions, resulting in harmful patterns of interpersonalbehavior (144 –146).

Another more recent fMRI study found reduced activation com-pared with healthy control subjects in the amygdala in patientswith CD and callous-unemotional traits who had elevated ADHDscores but no elevated affective symptoms (147). The findings re-mained after covarying for ADHD symptoms.

In conclusion, parallel to structural studies, functional imagingstudies show evidence that children with CD and CD-CU suffer froma dysregulation of ventromedial prefrontal amygdala regions andnetworks that mediate affect regulation (29,138).

Overall ConclusionIn conclusion, imaging studies of children with CD show struc-

tural and functional abnormalities compared with healthy controlsubjects in ventromedial and orbital prefrontal, superior temporal,and limbic brain regions that are known to regulate motivation andaffect and abnormal functional connectivity within these frontolim-bic networks. A caveat is that all studies have included a largeproportion of patients that were comorbid with ADHD, with themajority of studies including over 50% comorbidity. The observedabnormalities in brain abnormalities, however, were shown to cor-relate with antisocial symptoms or to survive covariation for ADHDin several structural (135–137) and functional imaging studies(139,144,148). Some studies, however, did not control for ADHD(136) or found that the main findings correlated with both CD andADHD symptoms (136) or only presented the correlation with CD,but not ADHD, symptoms (144). Anxiety and depression are othercommon comorbidities with CD. The majority of studies, however,have either excluded comorbidity with affective disorders and/orcovaried for anxiety and depression (139,142,147,148). However,while this suggests that anxiety and depression cannot alone ac-count for the deficits, this does not exclude the possibility that theymay have contributed to some extent. Lastly, all imaging studiesfocused on children with CD, and ODD was not assessed separatelyin any study. Future studies will need to investigate the neuroimag-ing correlates of ODD and whether they differ from those associ-ated with CD.

Structural and Functional Neuroimaging ComparisonsBetween ADHD and CD

Given the substantial clinical overlap between ADHD and CDsymptoms, with between 50% and 90% comorbidity (19,149), thepossibility of an objective differentiation through imaging technol-ogy is attractive. Modern functional neuroimaging could be animportant aid in the differentiation of clinically and behaviorallysimilar disorders, if it can identify differences in the objectivelymeasurable underlying pathophysiological mechanisms, the bio-markers that underlie overlapping behavior features of these two
disorders. Disentangling the disorder-specific underlying patho- r

hysiology of behaviorally and cognitively overlapping disordersill be crucial to develop more objective differential diagnostics

nd more informed and disorder-specific targeted methods on pre-ention and early intervention.

Very few studies, however, have directly compared these twoisorders in neuroimaging. As mentioned, only one structural im-ging study compared whole brain volume abnormalities in smallroups of comorbid children with CD and ADHD and noncomorbidDHD, finding no significant differences between the disorders,hereas both groups showed reduced volumes in the posterior

nd inferior cerebellar vermis (133) (Table 1).Few fMRI studies have compared the neurofunctional sub-

trates between the two disorders. Furthermore, few of them haveontrolled for differences in IQ or tested medication-naive patientsith ADHD or CD that were clinically not comorbid. Long-termedication with stimulants appears to have effects on both brain

tructure (150,151) and brain function development (152), andedication naivety is, hence, crucial when comparing between

hild psychiatric disorders.

omparison Between Noncomorbid Groups of ADHD and CDn Tasks of Executive Functions and Reward

A series of fMRI studies from our group compared well-differen-iated, medication-naive IQ-matched groups of children with CD,ho had no clinical diagnosis of ADHD and scored significantly

ower on ADHD symptoms on a questionnaire of symptom severitythe Strength and Difficulties Questionnaire [153]), with children

ith ADHD, who had no clinical diagnosis of CD and scored signif-cantly lower on the questionnaire for CD symptoms. Affective dis-rders and anxiety were excluded and both patient groups did notiffer from control subjects in their affective symptom scores. Theisorders were compared in their neurofunctional activation dur-

ng five disorder-relevant executive function tasks, shown to bempaired in both disorders: motor response inhibition, sustainedttention, cognitive switching, interference inhibition, and atten-ional oddball. One of the tasks, the sustained attention task, in-luded an additional motivational aspect, where sustained atten-ion was compared in both rewarded and nonrewarded conditionso assess the effects of motivation on attention networks. Despitehe fact that performance measures did not differ between patientroups, in four of the five tasks we observed disorder-specific re-uced activation in patients with ADHD compared with bothealthy control subjects and CD patients in the IFC (96,102,107,109)

Table 1). The location of disorder-specific abnormality was moreorsolateral for the stop and oddball tasks and more ventrolateral

or the sustained attention and switching tasks. Furthermore, theysfunction was bilateral for the sustained attention and switching

asks (107,109) but left hemispheric for the stop and oddball tasks96,102) (Figure 1A, Table 1). During the sustained attention condi-ion, we also observed a disorder-dissociated effect in a large pos-erior activation cluster comprising the cerebellum, hippocampus,nd inferior temporal lobe, which was enhanced in activation inhildren with ADHD but reduced in children with CD comparedith each other and healthy control subjects (109) (Figure 1A, Table

). The cerebellum is an essential part of frontocerebellar networks72), and in particular, the later-developing anterior cerebellum haseen shown to be crucially implicated in attention functions

154,155). We hypothesized that the disorder-specific enhancederebellar/temporal activation in children with ADHD was compen-atory for the reduced IFC activation during the task, corroboratedy the finding of a negative correlation between these two brain

egions in ADHD children but not the other two groups.

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The disorder-specific reduced IFC activation in ADHD patientsacross four different tasks is a consistent finding that may suggestthat IFC dysfunction is a disorder-specific neurofunctional bio-marker for ADHD, at least when compared with CD. This is in linewith the fact that we also found disorder-specific reduction in IFCactivation in children with ADHD during two tasks, motor responseinhibition and switching, when compared with healthy childrenand children with obsessive-compulsive disorder (156). Obsessive-compulsive disorder patients, in turn, had shared abnormalities

Figure 1. (A) Disorder-specific underactivation in inferior prefrontal cortconduct disorder (CD) and healthy children. Disorder-specific underactivat

ge-matched healthy control children (n � 20) and children with conduct dcontinuous performance task), attention allocation (oddball task), and cogut decreased in CD children relative to control subjects and each other. Inrefrontal activation that was reduced in ADHD compared with healthy contompared with ADHD and healthy children in areas of the paralimbic systemith healthy children and children with ADHD in areas of the paralimbic sy

ttention task); the ventromedial orbitofrontal cortex (during rewarded comnterior cingulate, insula and hippocampus (sustained attention task). For m

with ADHD patients in other prefrontal regions, including the OFC m

nd dorsolateral prefrontal cortex (106,156) (Figure 2). The IFC haseen associated with a range of cognitive control processes. It has arominent role in motor response inhibition, more prominently butot exclusively in the right hemisphere, as demonstrated by fMRItudies of children and adults during motor inhibition tasks22,52,53,157), as well as lesion (158) and transcranial magneticesonance imaging studies (159). The IFC, however, is also a keyegion for other related functions that may share elements of inhib-tory control, such as interference inhibition, which has more com-

attention-deficit/hyperactivity disorder (ADHD) children compared withinferior prefrontal cortex in children with ADHD (n � 20) compared with

er (n � 14) during tasks of motor inhibition (stop task), sustained attentionswitching. The cerebellum activation was increased in activation in ADHDpatients, the cerebellum activation correlated negatively with the inferior

bjects and CD children. (B) Disorder-specific underactivation in CD childrenorder-specific underactivation in children with conduct disorder comparedincluding the temporal lobe (inhibition failures in the stop task; sustained

d with nonrewarded attention trials); and in underlying limbic structures ofetails, see Rubia et al. (96,102,107,109).

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frontal cortex (51,53,160 –162). It is also involved in cognitiveswitching, in a typically bilateral location, presumably mediatingthe inhibition of previously valid but no longer relevant stimulus-response associations (right IFC) and the re-engagement of novelstimulus-response associations (left IFC) (51,53,163). It has alsobeen suggested that the IFC junction may have a more generic rolefor the update of information in tasks of cognitive control, whichcould explain its ubiquitous activation across cognitive controltasks (160). Furthermore, the bilateral IFC is also consistently acti-vated in children and adults during tasks of selective and sustainedattention (108,164) and attention allocation in oddball tasks(54,110). The finding that IFC may be a disorder-specific neurofunc-tional biomarker of ADHD, when compared with CD, is in line withneuropsychological findings. Attention-deficit/hyperactivity disor-der children have consistent impairment in tasks that are mediatedby IFC (21,23,113) and this is more prominent than in children withCD (24). Furthermore, children with CD or ODD are often not im-paired in these tasks when ADHD is controlled for (38 – 43). It is alsoparallel to regression analyses that show that ADHD, but not CD,traits account for poor performance in these IFC mediated coolexecutive function tasks (50).

For the reward contrast, however, it was the CD children whoshowed deficits in the recruitment of task-relevant prefrontal brainregions (109). Children with CD, relative to control subjects andchildren with ADHD, showed reduced activation in ventromedialOFC, which is known to be crucial for executive reward processingand the mediation of motivation (51,165,166) (Figure 1B, Table 1).The orbitofrontal cortex is thought to be important for holdinginformation in representational memory, as well as incentive moti-vation (58), and thus mediates stimulus-reinforcement learning(58,167). The ventromedial part, in particular, is associated withreward as opposed to punishment-driven processes (168 –170).The disorder-specific abnormality in ventromedial PFC for CD is inline with evidence for abnormal activation in ventromedial PFC andOFC in patients with impulsive aggression and psychopathy duringemotional tasks. For example, reduced orbitofrontal activation was

Figure 2. Disorder-specific underactivation in attention-deficit/hyperactivihildren in inferior prefrontal cortex. Disorder-specific underactivation in ch

cortex compared with children with obsessive-compulsive disorder (n � 10)and cognitive switching (switch task). For more details, see Rubia et al. (156

observed in patients with impulsive aggression in relation to nega- d


ive emotional stimuli (171), as well as in patients with psychopathy172,173).

Furthermore, the lateral and ventromedial orbitofrontal cortexlso plays a crucial role in the modulation of paralimbic brain re-ions that mediate aggression (138,174). As mentioned, the orbito-

rontal cortex, together with temporal areas including amygdaland hippocampus, was reduced in gray matter in adolescent boysith CD (135). It has been hypothesized that abnormalities in re-ard computations mediated by orbitofrontal cortex leading to

nhanced frustration could trigger reactive aggression, whichould explain the link between aggression, abnormalities with the

eward system, and orbitofrontal abnormalities (174). The disorderpecificity of the dysfunction of the ventromedial frontal cortex inelation to reward compared with ADHD is also in line with evi-ence of reduced autonomic response in patients with CD com-ared with ADHD and healthy control subjects during emotionaltimuli (175).

It thus seems that there is a disorder-specific and process-re-ated dissociation in prefrontal lobe deficits, where ADHD childrenave consistent problems with the recruitment of IFC systems in theontext of cool executive inhibitory and attention control acrosseveral cognitive domains, while CD children have problems withhe recruitment of hot ventromedial OFC systems that mediate

otivation in the context of reward processing (109) (Figure 1B,able 1).

Attention-deficit/hyperactivity disorder children, during the re-ard contrast, showed disorder-specific reduced activation relative

o control and CD children in the posterior cingulate and precu-eus, brain regions known to mediate visual-spatial attention pro-essing of saliency (176,177). The posterior cingulate and precu-eus are reciprocally connected with the anterior cingulate cortex

ACC) (178), which monitors action outcomes to support learninghe value of actions (179), and the parietal cortex, which directsisual attention (180) and has hence been associated with the inte-ration of incentives with attention modulation (181). The posterioringulate and precuneus are typically reduced in activation in chil-

order children compared with obsessive-compulsive disorder and healthywith attention-deficit/hyperactivity disorder (n � 18) in inferior prefrontal

ealthy children (n � 20) during tasks of motor response inhibition (stop task)

ty disildren

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oddball or incongruent targets (102,108,110). Reduced activation ina region of saliency processing is consistent with the catecholaminedeficiency hypothesis of ADHD, given that catecholamine defi-ciency diminishes and catecholamine agonists enhance the sa-lience of stimuli (182). In fact, methylphenidate, the treatment ofchoice and an indirect catecholamine agonist, has been shown toupregulate the activation of posterior cingulate in children withADHD, leading to better attention performance (108). Abnormalcingulate activation in ADHD children may thus be the neurobio-logical substrate of catecholamine deficiency-related abnormal sa-lience processing.

Apart from the abnormal ventromedial OFC activation, conductdisorder patients demonstrated disorder-specific reductions of ac-tivation compared with control subjects in several other regions ofthe paralimbic system during all tasks. During the sustained atten-tion task, where ADHD children showed disorder-specific inferiorfrontal underactivation relative to control and CD children, thatfurthermore correlated with the main performance indicator (i.e.,omission errors), children with CD showed reduced activation rela-tive to ADHD and control children in areas of the limbic system thathave been shown to contribute to sustained attention throughtheir mediation of motivation, such as hippocampus, the insula,superior temporal lobe, and the dorsal ACC. Furthermore, they alsoshowed reduced activation relative to control and ADHD children ina cluster comprising the cerebellum, the hippocampus, and theinferior temporal lobes (109) (Figure 1B, Table 1). These regions ofthe paralimbic system lie at the interface between emotion andcognition. The dorsal anterior cingulate is connected to frontal-parietal attentional networks but is also crucial for motivation andarousal (183,184). Hippocampus and insula form part of the limbicsystem and visuomotor pathways and are an interface betweenmotivation and spatial attention (185). Thus, a more anterior part ofthe insula has been shown to contribute to sustained attention(164), while the hippocampus plays a role in selective visual atten-tion to targets (186). As mentioned, the cerebellar hemispheresform part of frontocerebellar attention systems (72,154,155,187).The superior and inferior temporal lobes are closely connected tothe limbic system and contribute to cognitive functions such asperceptual selective attention (188). Together, it thus appears thatCD children show disorder-specific underactivation in subcorticaland paralimbic brain regions that lie at the interface between mo-tivation and attention and contribute to attention functions, pre-sumably through their mediating role between motivation andcognition. The key performance measure of omission errors did notdiffer between patient groups but were lower than those of controlsubjects, which reached significance for ADHD. This suggests thatthe underrecruitment of cool IFC networks, as well as the reducedrecruitment of motivational paralimbic brain regions, can lead tosimilar performance underachievement.

In addition, CD children showed disorder-specific underactiva-tion of the superior temporal lobes during failures in the stop taskcompared with both ADHD children and healthy control subjects(96) (Figure 1B, Table 1). The reduced activation of superior tempo-ral regions after mistakes may reflect reduced recruitment of per-formance monitoring systems, in line with evidence that CD chil-dren care less about their mistakes and respond less to negativefeedback than healthy children (39,47). Disorder-specific reducedactivation in this brain region was also observed in children with CDcompared with control subjects, but not ADHD patients, duringcognitive switching (107) and sustained attention (109) (Figure 1B,Table 1).

Dysfunction of the temporal lobes during attention and perfor-
mance monitoring in patients with CD is in line with evidence for s
tructural abnormalities in this brain region (134,135,137). Fur-hermore, temporal lobe lesions have been associated with ag-ression and antisocial behavior (189,190), as well as with empa-

hy (191).In conclusion, the findings of disorder-specific deficits in these

wo clinically overlapping disorders suggest distinct underlyingeurofunctional abnormalities, both of which may be related toverlapping behavioral features. Attention-deficit/hyperactivityisorder appears to be associated with disorder-specific cool top-own inferior prefrontal and bottom-up cerebellar-posterior cingu-

ate cognitive control/attention networks, presumably causing re-uced top-down executive inhibitory and attention control.onduct disorder, by contrast, appears to be associated with neu-

ofunctional deficits in areas of the paralimbic system, in top-downentromedial OFC and underlying bottom-up limbic and paralim-ic structures (anterior cingulate, superior temporal lobes insula,ippocampus) that together mediate motivation and affect and arenown to feed into attention systems (164,183,184,186).

The findings of disorder-specific abnormalities in areas of thearalimbic system in CD are in line with neuropsychological evi-ence that shows specific impairment in these children in tasks ofotivation control compared with children with ADHD. They show

yposensitivity to punishment in reward-related paradigms39,45– 47,192). Furthermore, symptom-regression analyses showhat CD/ODD symptoms account for the deficits in hot reward-elated gambling tasks, while ADHD symptoms accounts for deficitsn cool executive function tasks (50). This neuropsychological evi-ence, combined with our imaging findings of disorder-specificaralimbic dysfunction, suggests that impairment in cool executive

unctions in CD may be related to an underlying pathophysiology ofhe motivational limbic system—that is different from that ofDHD—that disturbs the normal interaction between motivationnd cognition, leading to reduced motivational upregulation of theool executive system, necessary for normal optimal performance.iven that motivation and reward upregulate cognitive processes

185,193,194), both a dysfunction of the hot motivation system, asppears to be the case in CD, as well as a dysfunction of the coolxecutive system directly, as observed in ADHD, would lead toognitive impairment. The difference is that the neurobiologicaleficit in ADHD is directly affecting the cool cognitive control sys-

ems, while the deficit in CD affects these systems indirectly, via aysregulation of the neuronal interplay between motivation andognition. The dissociative imaging findings hence show that func-ional imaging is more sensitive than performance to differentiateetween behaviorally and cognitively overlapping patient groups.his is illustrated, in particular, for the sustained attention task,here both disorders shared the same number of omission errorsut the underlying disorder-specific dysfunctions were in perfor-ance correlated cool IFC frontocerebellar activation in patientsith ADHD and in hot paralimbic motivation regions in CD thatere not directly related to task performance.

We also observed shared abnormalities in the two disorders.oth disorders showed reduced posterior cingulate and precuneusctivation during inhibition failures and during incongruent stimuliompared with control subjects, presumably reflecting shared re-uced activation to salience, given that both errors and incongru-nt trials are salient stimuli (96,102). Another brain region that waseduced in activation in both disorders compared with control sub-ects was the right medial frontal lobe during visual-spatial atten-ion to oddball stimuli (102) (Table 1). It thus appears that a sharedbnormality in both disorders is the recruitment of dorsolateralrefrontal and posterior parietal brain regions that mediate visual-
patial attention to salient events.

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Comparisons Between Children with CD-CU and ComorbidADHD with Noncomorbid Children with ADHD

Two fMRI studies from within the same research group com-pared children with callous-unemotional traits and either CD orODD with children with noncomorbid ADHD as well as controlsubjects (148,195). The groups were not well separated in clinicalsymptomatology because the group with CD/ODD-CU also hadADHD symptoms (7 out of 12). Hence, the comparison was betweenchildren with ADHD and no comorbidities and children with ADHDand/or CD or ODD and CU symptoms and healthy control subjects.Mood and anxiety disorders were excluded. Furthermore, the ma-jority of children with ADHD in either group were medicated withpsychostimulants. In the study of Marsh et al. (148), reduced rightamygdala activation was found to fearful compared with neutralfaces in the group with CD/ODD-CU and ADHD relative to controlsubjects and relative to noncomorbid ADHD, while the lattergroups did not differ from each other (148). No group effects wereobserved for angry or neutral faces. Furthermore, both control sub-jects and ADHD patients without CD/ODD-CU had a higher degreeof functional connectivity between right amygdala and right ven-tromedial prefrontal activation during fear compared with the CD/ODD-CU and ADHD group, which furthermore correlated with theseverity of the psychopathy symptom scores (Table 1). Theamygdala plays an important role in fear processing and socializa-tion (140), and its abnormal response may be the neural substratefor reduced distress cue processing and socialization problems inpsychopathy (29,138,196). The underconnectivity findings are in-teresting with respect to evidence showing that the closely inter-connected ventromedial prefrontal cortex and amygdala (197) arecrucial to affect control (198). Together, they mediate appropriatebehavioral decision making based on positive and negative feed-back (51,199) and moral decision making (200 –202). These twostructures are also known to regulate reactive aggression (174,203).

The second study by Finger et al. (195), on the same sample,compared 14 children with CD/ODD-CU, allowing for ADHD symp-toms, with 14 children with noncomorbid ADHD with low scores onantisocial traits and 14 healthy control subjects in a reversal task.While healthy and ADHD children showed reduced activation inbilateral ventromedial prefrontal cortex and caudate during pun-ished reversal errors compared with rewarded correct responses,this effect was not observed in children with CD-CU who showedenhanced activation in this region during punished reversal errorsrelative to the other two groups. The disorder-specific abnormali-ties in ventromedial prefrontal activation in the CD-CU and ADHDgroup were furthermore correlated with total scores on antisocialand callous-unemotional traits (Table 1). Although some of thepatients were medicated, the findings remained when these wereexcluded from the analysis (195). Both the ADHD only group andthe group with psychopathy and CD/ODD/ADHD showed en-hanced activation in left precuneus and right superior frontal gyrusrelative to control subjects (Table 1). The enhanced activation in thegroup of ADHD without comorbid CD-CU compared with controlsubjects in precuneus and medial frontal lobe is unusual and not inline with the underactivation findings of the majority of fMRI stud-ies of ADHD during tasks of cognitive flexibility (100,107) or errorprocessing (95,96,156). The negative findings may potentially berelated to the fact that the children in this group had a higher IQcompared with the other two groups. While at first the findings ofenhanced ventromedial frontal activation may seem in the oppo-site direction to our finding of reduced ventromedial OFC activationin children with CD during rewarded attention trials (109), theyare, in fact, consistent with each other. The children with psychop-
athy in the study of Finger et al. (195) also showed reduced ventro- b

edial PFC activation during rewarded correct trials, even thoughhis did not reach significance, but showed enhanced activation inhis region during punished error trials relative to control subjectsnd ADHD patients. It thus may be that reward and punishmentesult in patients with CD in dissociated abnormal response pat-erns in ventromedial and orbitofrontal brain regions, showing hy-osensitive activation in the context of reward and hypersensitivectivation during punishment, suggesting a contingency-sensitiverbitofrontal dysregulation. Alternatively, it is also possible thatsychopathy and CD have qualitatively different underlying neuralubstrates, as demonstrated with evidence with respect tomygdala hyperactivation in CD (139,144) and hypoactivation inD-CU (148). The disorder-specific abnormality findings in ventro-edial prefrontal and amygdala activation in the children with

sychopathy compared with control and ADHD children are in lineith evidence for dysfunction and dysmorphology of these two

tructures in adults with psychopathy (29,138,145,204 –206).Another interesting dissociation was found for the caudate acti-

ation, which was exclusively enhanced in patients with psychopa-hy compared with control subjects and ADHD patients for pun-shed reversal errors compared with correct rewarded trials, thepposite pattern as in control subjects. However, the caudate hy-eractivation did not differ from ADHD patients (195) (Table 1). Theaudate is a key region of typically reduced activation in childrenith ADHD during tasks of cognitive control (94,97,113,207), in-

luding tasks of cognitive flexibility (100,156,208). The finding ofnhanced caudate activation in antisocial pathologies comparedith ADHD may potentially be related to different dopamine levels

n these disorders.In summary, the disorder-specific functional imaging findings

uggest that CD and CD-CU compared with ADHD are associatedith disorder-specific abnormalities of the paralimbic system of

entromedial and OFC, the limbic part of the anterior cingulate, themygdala, hippocampus, and the superior temporal lobes, knowno regulate affect and motivation. The disorder-specific dysfunc-ions in children with ADHD, by contrast, appear to be in brainegions that mediate a more cognitive form of top-down inhibitorynd attention control, most prominently in IFC-striatal circuitries.

enetic Associations

The findings of disorder-specific cool IFC dysfunction in ADHDnd disorder-specific hot ventromedial-paralimbic dysfunction inD is further interesting with respect to the genotypes that haveeen associated most prominently with each of the two disorders.

n ADHD, dopamine dysregulation is thought to play a crucial rolend the dopamine genotypes of DAT1 and dopamine receptor D4DRD4) 7-repeat allele are most commonly associated with theisorder (209). The DRD4-7-7 genotype has been associated with

educed volume and cortical thickness of the right IFC in normalevelopment, which was, furthermore, particularly pronounced inDHD children with the genotype (210). The DAT1 genotypes haveeen associated with abnormal caudate volume, as well as activa-

ion in patients with ADHD (211,212). Antisocial behaviors, includ-ng psychopathy and CD, have more commonly been associated

ith serotonin genotypes. Thus, the short allele of the serotoninransporter has been associated with impulsive and antisocial be-avior features in alcohol abuse (213,214) and violent crime (215) indults. In children, the short variant has been associated with anti-ocial and aggressive behavioral features in adoptees (216) andith childhood aggression (217). Furthermore, the short allele

howed an interaction with childhood adversity on later-life violent
ehavior (218). In healthy adults, the short allele of the serotonin

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transporter has consistently been associated with the brain struc-tures that have been associated with CD. It has been related to adysmorphology and dysregulation of the ventromedial prefrontalcortex, including anterior cingulate and medial frontal cortex, andthe amygdala, as well as the functional connectivity between bothstructures (219 –221) (for review, see [222]). Abnormal connectivitybetween amygdala hyperactivity and orbitofrontal hyporesponsiv-ity in relation to negative emotions has been suggested to underlieimpulsive aggression (171). Genetic predisposition, hence, mayplay a role in the development of the disorder-specific dysregula-tion of IFC-striatal and ventromedial-limbic neural networks inADHD and antisocial-aggressive behaviors, respectively.

Conclusion and Future Directions

This review shows that ADHD is most prominently associatedwith the dysmorphology, dysfunction, and the underconnectivityof cool fronto-striato-cerebellar and frontoparietal neural networksthat regulate cognition and attention. Furthermore, these regions,most prominently the IFC, are disorder-specific underfunctioningwhen compared with CD. Antisocial and aggressive behaviors inthe form of CD and CD-CU, by contrast, are associated with struc-tural and functional deficits in areas of the paralimbic system, in-cluding the orbitofrontal cortex, superior temporal lobes, and un-derlying limbic structures, as well as ventromedial frontolimbicunderconnectivity. Furthermore, compared with ADHD, this para-limbic system dysfunction and underconnectivity are disorder-spe-cific (Figure 3).

Comorbidity Between DisordersThere are several potential caveats, however, that need to be

taken into account. All structural studies have tested children with

Figure 3. Schematic representation of the magnetic resonance imagingchildren with attention-deficit/hyperactivity disorder and those with condufrom head-to-head functional and structural imaging comparisons betweencontrol studies may suggest overlapping abnormalities in several of these re
figure is focusing on evidence for disorder-specific association findings between rconduct disorder. ADHD, attention-deficit/hyperactivity disorder; CD, conduct di
D with over 50% comorbidity with ADHD. Consequently, struc-ural abnormality findings apply mostly to the comorbid presenta-ion of CD and ADHD. This is also the case for all functional imagingtudies, except for those conducted in my laboratory, where weompared noncomorbid patient groups. Although in the majorityf studies, brain structure and function abnormalities correlatedith antisocial behaviors or survived covariance with ADHD, it can-ot be excluded that the comorbid ADHD features may have con-

ributed to the abnormalities. The fact that the studies from ouraboratory, however, were conducted in noncomorbid groups andhowed disorder-specific functional brain abnormalities in nonco-

orbid CD relative to noncomorbid ADHD in paralimbic regions,ncluding superior temporal lobes, orbitofrontal cortex, insula, an-erior cingulate, and hippocampus, reinforces the association be-ween these paralimbic functional deficits, also observed in thetudies of comorbid cases and antisocial behaviors. However, non-omorbid patient groups may be less representative of the typicalD or ADHD population. According to epidemiological studies,hildren with noncomorbid CD or noncomorbid ADHD are rela-ively rare (19,78,149). An epidemiological prevalence study inorth England schools showed that while hyperactivity prevalenceithout CD can be relatively high (30%), CD without ADHD is rela-

ively uncommon (1.5%) (223). Epidemiological data from the Brit-sh Child Mental Health Survey, however, using diagnostic criteriahat elicit a relatively conservative ADHD prevalence of 1.5%,howed that only 23% of children with CD had ADHD comorbidity,hile 50% of ADHD children had CD comorbidity (224). In US sam-les, this ratio appears to be higher, however, with odds ratios of1.3 for concurrent comorbidity of ADHD given CD and of 79 forDHD given ODD (78). The comorbid presentation is likely to suffer

nce for disorder-specific structural and functional brain abnormalities insorder. The figure is based on evidence for disorder-specific abnormalitiesomorbid and comorbid disorders. While evidence from individual disorder-(such as anterior cingulate, dorsolateral prefrontal, or temporal lobes), the

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from a dysregulation of both cool fronto-striato-parieto-cerebellaras well as hot ventromedial fronto-temporo-limbic neural net-works. Future studies will need to compare 100% comorbid caseswith noncomorbid CD and noncomorbid ADHD patients to eluci-date to what extent the comorbid presentation shares the etio-pathophysiology of the noncomorbid disorders or whether it is amore complex disorder, characterized by a qualitatively differentunderlying pathology.

Furthermore, although most studies in ADHD and CD have ex-cluded affective comorbidity and controlled for anxiety and depres-sive symptoms, it cannot be completely excluded that underlyingproblems of anxiety and depression may have contributed to theobserved brain abnormalities. Future studies are needed to assessthe contribution of affective symptomatology on brain abnormali-ties in these disorders, by comparing children with noncomorbiddepression and anxiety with children with noncomorbid ADHD andCD, as well as comorbid presentations of these disorders.

Bias in Structural and Functional Imaging StudiesThere has been a bias in structural studies, where regions of

interest in ADHD have more commonly targeted frontal and striatalbrain regions, while areas of the paralimbic motivation circuitrieshave more commonly been selected as regions of interest in struc-tural studies in CD. More recent structural imaging studies of ADHDthat have selected limbic areas as regions of interest have, in fact,found limbic structural abnormalities in ADHD children. A study byPlessen et al. (225) found enhanced volumes in the head of thehippocampus in 51 children with the combined type of ADHDcompared with 63 healthy control subjects. This structural abnor-mality, however, was associated with fewer ADHD symptoms andhence interpreted as a compensatory plastic hypertrophic re-sponse, possibly for reduced prefrontal parts of frontal-hippocam-pal circuitries. Surface morphology analyses also showed reducedsize bilaterally of the basolateral complex of the amygdala in ADHDchildren relative to control subjects, which correlated with prefron-tal cortex size, suggesting reduced frontal-amygdala connectivity.The amygdala surface morphology was negatively associated withinattention but positively associated with hyperactivity symptoms,suggesting distinct associations between amygdala neurobiologyand different ADHD symptoms (225). Although there were poten-tial confounds such as history or current symptoms of depression/anxiety, ODD, or medication history and status, these were notassociated with the findings. Abnormalities in medial frontal re-gions and their connections to amygdala and hippocampus couldbe associated with abnormal performance in some of the hot exec-utive functions associated with ADHD, most typically reward-re-lated decision making in the form of delay aversion or hypersensi-tivity to immediate rewards, as well as attention and mnemonicprocesses. Another recent structural study found smaller volume ofthe pulvinar of the thalamus in 46 children with ADHD comparedwith healthy control subjects. A dissociation of thalamic volumeswith ADHD symptoms was observed, with hyperactivity being as-sociated with smaller left ventrolateral and pulvinar regions andinattention with larger right pulvinar and medial dorsal thalamicregions (226). The pulvinar is part of fronto-parieto-cortico-tha-lamic networks important for attentional saliency processing(227,228). However, this region is also connected to the limbicsystem, including the amygdala (229,230), and hence part of anemotional regulation network (228). Moreover, recent positronemission tomography studies that carefully selected noncomorbidadults with ADHD observed abnormal dopamine transporter levelsrelative to healthy adults in areas of the limbic system including
nucleus accumbens and midbrain, amygdala, and hippocampus m

hat furthermore correlated with inattention but not hyperactivityymptoms (231,232).

In fMRI studies of both disorders, there has also been a bias inaradigm selection, where cool cognitive paradigms have beenpplied in the majority of fMRI studies of ADHD to test the hypoth-sis of frontostriatal deficits, while hot motivational paradigmsave been more commonly chosen for fMRI research of CD. In fact,ore recent fMRI studies that have tested for deficits in motiva-

ional networks in ADHD using paradigms of emotion processing oreward-related functions have, indeed, found underfunctioning inhildren and adults with ADHD in limbic brain regions, includingrbital and ventromedial prefrontal cortex, amygdala, and ventraltriatum (114,117,233–235). Comorbidity with antisocial behaviors,owever, was not excluded and could potentially have confounded

he results. This, however, also applies to the majority of fMRI stud-es that observed frontostriatal dysfunctions during cool executiveunction in ADHD patients and did not exclude comorbid cases withD. In support of an association with ADHD, however, is the fact

hat several of these studies found a correlation between activationn limbic regions, such as ventral striatum and amygdala, with hy-eractive/impulsive but not inattentive symptoms (117,233,235). Inonclusion, given the bias in the neuroimaging literature of ADHDnd CD in the selection of regions of interest in structural imagingtudies and paradigm selection for fMRI studies, future imagingtudies should combine structural and functional analyses in largeatient numbers to conduct head-to-head comparisons betweenhildren with noncomorbid CD, noncomorbid ADHD, and comor-id cases using whole-brain structural imaging analyses and using

MRI tasks that tap into both hot and cool executive functions.

otential Overlap Between Disorders in Brain Structure andunction Abnormalities

Ventromedial-limbic circuitries and mesolimbic dopamine re-ard pathways may potentially be a shared abnormality betweenoth ADHD and CD. The nucleus accumbens is located betweennd reciprocally connected to both cool frontocortical as well as hot

imbic areas and is thought to be a key mediator between motiva-ion and attention functions (64). It is ideally placed to integratemotional salience and contextual constraints, processed inmygdala and hippocampus, respectively, and goal-directed exec-tive plans from the PFC. The mesolimbic dopamine system main-

ains the balance between limbic and cortical drive within thisegion (64). This region is closely interconnected with anterior cin-ulate, ventromedial frontal cortex, and amygdala, which, in con-ert, mediate reward-related decision making (67,236,237). Fur-hermore, abnormalities in these circuitries have been associatedith impulsiveness and behavioral disinhibition (67,238), overlap-ing features between ADHD and CD (28). While orbital and ventro-edial frontal cortices, anterior cingulate, amygdala, and hip-

ocampus have been shown to be associated with CD, no structuralr functional MRI study, however, has as yet tested for structuralbnormalities of nucleus accumbens in children with CD or forotential activation abnormalities in reward-related paradigms

hat specifically activate this region. It is likely that the ventral stria-um, in its role as interface between motivation and attention, is notnly impaired in ADHD but also in children with CD, and this shoulde tested in future studies.

Another area of potential overlap could be the anterior cingu-ate. This paralimbic area lies at the interface between the frontalobes and the limbic system and has been associated with severalunctions, depending on exact location, including performance

onitoring, error detection, arousal, motivation, and outcome
onitoring to modulate executive attention (157,179,183,184,239).

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Both rostral and dorsal anterior cingulate have consistently beenfound to be abnormal in structural and functional imaging studiesof CD (see above). This brain region has also been found to beabnormal in brain structure and function in ADHD children(94,102,110,156,240) and adults (125,127,241,242). Direct compari-sons between ADHD and CD, however, point toward more severeabnormalities in this region in CD. Functional MRI comparisonshave found dorsal ACC underactivation to be specifically associatedwith noncomorbid CD when contrasted with noncomorbid ADHD(109) and dysfunction in this area remained when ADHD was con-trolled for (139) or correlated specifically with antisocial and CUsymptoms (144). Structural studies found ACC to be specificallyassociated with CD but not ADHD symptoms in regression analyses(135) and to be associated with CD when ADHD was covaried (137).

he ACC abnormality may thus be more strongly associated withntisocial behavioral features than ADHD symptoms and abnor-ality findings in ACC in ADHD patients—more commonly ob-

erved in adult than childhood ADHD (for review, see 125])—mayotentially be associated with underlying, and mostly uncon-

rolled, antisocial features.Lastly, we found that in children with ADHD and emotional

ysregulation, both the DRD4 7-repeat allele as well as the shortllele of the serotonin transporter have been associated with emo-ion dysregulation, suggesting that this behavioral feature, which isommon in ADHD children and associated with CD and/or ODDehavior, may be mediated by the abnormality of both top-downFC control systems, the cool executive lateral PFC-striatal controletwork as well as the hot ventromedial PFC-limbic pathway thatontrols affect and motivation (243).

In conclusion, there is evidence that some brain regions thatintermediate between hot motivation and cool attention functionsmay be affected in both disorders, but this needs to be furthertested in head-to-head comparisons between noncomorbid andcomorbid patient groups.

Heterogeneity Within ADHD and CDBoth ADHD and CD are heterogeneous disorders. More effort

needs to be undertaken to disentangle the neurobiological sub-strates within subgroups of these disorders. For example, childrenwith inattention only are likely to suffer from different neurobiolog-ical abnormalities than children with the combined type ADHD.Children with inattention are less likely to have oppositional defiantdisorder than those with the combined subtype (244), while impul-siveness is a key feature shared between the impulsive-hyperactivesubtype of ADHD and CD, in particular the impulsive-aggressivesubtype of CD. It has been argued that the inattentive symptoms ofADHD may be associated with deficits in frontostriatal mediatedcool EF, whereas hyperactivity/impulsivity symptoms may reflecthot executive function deficits, mediated by paralimbic brain re-gions (245). This would suggest that the different subtypes of ADHDmay be mediated by different brain abnormalities, with the impul-sive-hyperactive subtype resembling more CD than the inattentivesubtype. This is, however, only in part supported by evidence. In linewith this theory, limbic brain abnormalities in orbitofrontal,amygdala, and ventral striatum correlated with impulsive-hyperac-tive but not inattentive symptoms (117,233,235). Symptoms of in-attention, however, and not impulsive-hyperactive symptoms havebeen shown to correlate with limbic abnormalities in children withADHD and CD in structural MRI and positron emission tomographystudies (136,231). By contrast, hyperactivity/impulsiveness symp-toms and not inattention symptoms correlated inversely with graymatter reductions in cool fronto-temporo-parietal brain regions
(135). Furthermore, there is some evidence to suggest that children
ith inattention and sluggish cognitive tempo have more anxietynd depression and fewer externalizing problems (246). This would,y contrast, point toward abnormalities in orbitofrontal-limbicrain regions that are typically associated with depression (72) and

hat overlap substantially with the observed brain abnormalities inD. Clearly, large-scale imaging studies that compare children with

he inattentive, impulsive-hyperactive, and the combined subtypesre needed to clarify potential differences in the underlying neuralubstrates of each of the subtypes.

Along the same lines, future imaging studies should investigateubtypes of CD because there are likely to be differences in thenderlying neurobiological substrates of CD children with andithout callous-unemotional traits or with either reactive or instru-ental aggression. Lastly, there are likely to be neurophysiological

ifferences between children with CD and ODD. To my knowledge,owever, no imaging studies have as yet investigated the neuroim-ging substrates of ODD, independent from CD, or compared be-ween different subtypes of CD.

eed for Longitudinal and Combined Structure-Functiontudies

All published studies comparing ADHD and CD have been cross-ectional. Longitudinal imaging studies will be needed to assessifferences in the developmental trajectories of the disorders.hile in ADHD there is evidence for a maturational delay (93,247),

othing is known on the longitudinal trajectories of CD. Childhoodisorders are more likely to differ in the temporal dynamics of theirrain abnormalities, i.e., in the onset of their deviance from normalevelopment and/or in their developmental trajectories, rather

han at any chosen cross-sectional time point.Furthermore, no studies have combined structural and func-

ional information. Future, large-scale multimodal imaging studieshould compare ADHD and CD in brain structure, brain function,nd structural and functional connectivity. Modern multivariateattern recognition analysis classification systems applied to MRIata, which differentiate cases and control subjects on the basis ofuantitative, spatially distributed neural networks rather than iso-

ated brain regions with the ability to make individual classifications248 –250), could potentially be of clinical use by providing a morebjective, neuroimaging-based differential diagnosis. A successfullassification of these two patient groups based on their underlyingeurobiological abnormalities would not only provide a more ob-

ective differential diagnosis but also deliver a target for disorder-pecific preventions and interventions aimed at normalizing disor-er-specific abnormal brain and neurotransmitter systems and

heir abnormal development.

The research reported in this article has been funded by Grants fromhe Wellcome Trust (053272/Z/98/Z/JRS/JP/JAT), the Medical Researchouncil (G9900839), and the PPP Healthcare Foundation (1206/1140)nd (1206/1568), United Kingdom.

KR has received funding from Eli Lilly for another research projectnd speakers honoraria from Eli Lilly and Medice.

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Investigation of cool and hot executive function in ODD/CD independently of ADHD

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