“Cool” Inferior Frontostriatal Dysfunction in
Attention-Deficit/Hyperactivity Disorder Versus
“Hot” Ventromedial Orbitofrontal-Limbic
Dysfunction in Conduct Disorder: A Review
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 brain
out 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 system
fronto-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.
duct disorder, executive functions, fMRI, frontal lobe, functional
magnetic resonance imaging, motivation, MRI
ric comorbidities (2) and mental health problems in adult life (3,4).
others and societal rules and the persistent display of antisocial
behaviors such as deception, theft, vandalism, and violence within
a 6- to 12-month period before age 18 (DSM-IV) (1). Conduct disor-
der is considered a risk factor for various psychiatric conditions
beginning in adolescence or adulthood, including antisocial per-
sonality disorder and mood disorders (5–13). Oppositional defiant
disorder (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 and
has been considered a less severe subtype, although there is em-
piric evidence to distinguish the two disorders. In the DSM-IV, a
diagnosis of CD is given if an individual meets criteria for both CD
and ODD. The lower age of onset of CD before age 10 has been
associated with a worse outcome, such as a greater risk for adult
(14). A more pervasive subtype of CD is seen in those with callous-
unemotional (CU) traits, defined as low fearfulness and a lack of
empathy, guilt, and emotion (15), present in approximately 25% of
cases of child-onset conduct disorder (16,17). This subtype is asso-
ciated with poorer outcomes compared with non-CU CD groups,
ttention-deficit/hyperactivity disorder (ADHD) is character-
ized by symptoms of age-inappropriate inattention, impul-
including substance use disorders, criminality, violent offending,
and increased risk of psychopathy, as well as higher genetic risk
Attention-deficit/hyperactivity disorder is associated most con-
sistently with neuropsychological deficits in tasks of motor re-
sponse and cognitive inhibition (such as tasks of interference inhi-
bition or cognitive switching), sustained attention, and timing
functions (21–23). Children with CD have also shown deficits in
tasks of motor and cognitive inhibition (24–27). Furthermore, like
ADHD patients, they are also impaired in tasks of cognitive switch-
ing and reversal (28–31), as well as of sustained attention (32–37).
However, studies have included comorbidity with ADHD, and the
no independent deficits from ADHD for these tasks (37–43).
An exception, however, is in functions of motivation control,
where children with CD seem as impaired or more impaired than
children with ADHD. Thus, children with CD or psychopathy are
consistently impaired in reversal tasks, where previously valid and
to a reduced sensitivity to punishment in children with CD com-
morbid” ADHD (39,46,47). In gambling tasks that measure reward-
short-term decisions, both pathologies have been shown to be
impaired, although none of these studies excluded comorbidity
with the other disorder (48–50). Regression analyses, however,
showed that the antisocial behavior traits were responsible for the
motor inhibition and attention (50).
From the Department of Child Psychiatry/Medical Research Council Center
London, United Kingdom.
College, Department of Child Psychiatry, 16 De Crespigny Park, London
SE5 8AF, United Kingdom; E-mail: firstname.lastname@example.org.
Received Apr 20, 2010; revised Sep 16, 2010; accepted Sep 18, 2010.
BIOL PSYCHIATRY 2011;69:e69–e87
© 2011 Society of Biological Psychiatry
Cool and Hot Executive Functions and Their
tween cool cognitive executive functions such as attention, working
memory, planning, and inhibition that are known to be mediated by
lateral inferior and dorsolateral frontostriatal and frontoparietal net-
works (51–54) and “hot” executive functions that involve incentives
Emotion regulation and motivation are mediated by lateral or-
cingulate, amygdala, insula, hippocampus and hypothalamus, the
ventral striatum, and other connected areas (61,62). The amygdala
is important for the processing of negative affect and threat and
together with ventral striatum mediates stimulus-reward associa-
lobes 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 mediate
top-down affect regulation in their interconnection to underlying
limbic areas (61,62,65,66). These networks of affect regulation and
motivation have been shown to be implicated in hot executive
Cool higher level cognitive processes are mediated by fronto-
and adults (51–54). Higher order temporal and parietal sensory
cortices mediate bottom-up attention based on stimulus salience,
with the temporoparietal junction being crucial for visual-spatial
and executive attention functions (71–73). The prefrontal cortex
(PFC) provides goal-directed top-down attention and cognitive
control through several functions: inhibitory control of irrelevant
acts and attention to irrelevant stimuli; sustaining, dividing, and
selecting attention; working memory; and cognitive flexibility, as
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-
control 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 prominently
impaired in tasks of affect and motivation control, such as gam-
diated by ventromedial and orbitofrontal limbic neural networks.
The association between motivation control deficits and antisocial
behaviors is in line with behavioral studies showing that contin-
gency association learning involving reward and punishment is
strongly implicated in the development and maintenance of anti-
social behaviors (77).
Comorbidity Between ADHD and CD
Conduct disorder and ODD overlap clinically, behaviorally, and
cognitively with ADHD. The odds ratio for comorbidity with ADHD
in children with CD is over 40, while this increases to 79 in children
with ODD (78,79). Comorbid patients are often considered severe
cases of ADHD (28) and the notion of a separate neurobiological
basis for CD has been debated (80). Comorbid cases have a more
severe clinical outcome than the individual diagnoses (81,82).
similar and often clinically and neuropsychologically overlapping
disorders differ in their underlying etiopathophysiology. The sepa-
ration of associated neural networks for each disorder would po-
tentially be very helpful for the development of a more objective
Structural and Functional Neuroimaging of ADHD
Neuroimaging studies in children with ADHD have shown con-
inferior frontostriatal and frontocerebellar circuitries that mediate
these cognitive control functions that are impaired in the disorder.
Thus, structural magnetic resonance imaging (MRI) studies found
reduced volume and cortical thickness in inferior prefrontal cortex
the cerebellum (83–86). Two recent meta-analyses of structural
data in childhood ADHD have been published. The first meta-anal-
est significant reductions relative to control subjects in posterior
inferior vermis of the cerebellum, the splenium of the corpus callo-
sum, total and right cerebral volumes, right caudate, and various
frontal regions (87). The other meta-analysis was of whole-brain
voxel-based morphometry imaging studies, avoiding the a priori
bias of region selection, and identified a significant regional gray
studies have furthermore provided evidence for abnormalities at
the neural network level, showing abnormalities in multiple white
matter tracts in cingulate and frontostriatal, as well as frontoparie-
tal, frontocerebellar, and parieto-occipital white matter tracts, in
children, as well as adults, with ADHD compared with comparison
subjects (89–92). Longitudinal imaging studies have provided evi-
dence that the structural abnormalities in these late-developing
fronto-striato-cerebellar and frontoparietal systems are due to a
cortical thickness maturation has been shown to be delayed in
3 years, with some regions, including frontal and temporal areas,
Functional Imaging Studies
In line with the frontostriatal hypothesis of ADHD, functional
imaging studies have shown reduced activation compared with
control subjects, in particular in the IFC, anterior cingulate, and
response inhibition (69,94–100), interference inhibition (101–103),
and of sustained, selective, and flexible attention (100,102,104–
111) (for meta-analysis, see ). Furthermore, ADHD children
have also shown reduced activation in dorsal and ventrolateral
prefrontal, cingulate, and cerebellar brain regions during tem-
poral processes, including tasks of motor timing, time discrimi-
nation, and temporal foresight (94,113–115), as well as temporal
unpredictability (116). The cerebellum has furthermore been
shown to be dysfunctional in children with ADHD relative to
healthy control subjects during tasks of attention and timing
functions (108,109,114,116). A few recent studies have also
tested for neurofunctional deficits in children with ADHD relative
to healthy control subjects during tasks of motivation, finding ab-
during reward-related processes (108,109,114,117).
e70 BIOL PSYCHIATRY 2011;69:e69–e87
More recent functional imaging studies have tested for deficits
in interregional functional connectivity. During the resting state,
children with ADHD have been shown to have reduced functional
connectivity relative to healthy control subjects in frontostriatal,
frontoparietal, temporoparietal, and frontocerebellar networks
(118–120), although increased interregional connectivity between
anterior cingulate, striatum, and temporocerebellar regions has
I am only aware of two published papers in childhood ADHD. One
found a reduced degree of functional connectivity relative to
lobes, and cerebellum, as well as between cerebellum and parietal
and striatal brain regions during sustained attention (108); the
other study found reduced connectivity between frontoparietal
and frontocerebellar regions during interference inhibition and
dysfunctions observed in ADHD patients not only affect isolated
between affected regions, thus demonstrating deficits in fronto-
striato-cerebellar and frontoparietal neural networks.
Relatively fewer studies have been conducted in adult ADHD
and findings have been more inconsistent. This is likely due to the
fact that confounding factors are more pronounced in adult com-
of small sample sizes, the elevated rate of comorbid conditions in
adult ADHD, long-term medication history, and the need for retro-
spective diagnosis (125). Structural imaging studies in adult ADHD
observed abnormalities in the volumes of left orbitofrontal cortex
(126); in overall cortical gray matter, right anterior cingulate, and
posterior cingulate, and in the temporo-occipitoparietal junction
(128), as well as reduced structural connectivity between these
prefrontal cortices and striatal, anterior cingulate, cerebellar, and
parietotemporal brain regions, with, however, also some evidence
for compensatory increased activation in some of these regions in
tivity studies show deficits in interregional connectivity relative to
and other areas, including basal ganglia, anterior and posterior
cingulate, and parietotemporal and cerebellar areas (129), which
working memory (130). However, in the study of Wolf et al. (130),
compensatory-increased connectivity was also observed between
Rest-associated functional connectivity studies have found abnor-
mal functional connectivity between anterior and posterior cingu-
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-
tivity, causing poor top-down control over inhibitory, attention,
and timing functions. An important caveat, however, is that the
majority of imaging studies in children with ADHD have not ex-
problems may have confounded the neuroimaging literature of
ADHD can therefore not be assessed.
Structural and Functional Neuroimaging of CD
Structural Imaging Studies
Unfortunately, the imaging literature in CD is very confounded
by ADHD comorbidity. Very few imaging studies have tested chil-
dren with CD independently of ADHD. A small, underpowered
(133). While the children with noncomorbid ADHD did not differ
from those with comorbid ADHD and CD, both groups differed
from control subjects in the volume of the left and total posterior
superior and inferior lobes of the cerebellar vermis (133) (Table 1).
More recent structural studies found reduced volume and gray
and paralimbic regions in childhood-onset CD relative to healthy
control subjects (134,135). In the study of Kruesi et al. (134), all
children had lower IQ and a history of ADHD, with 6 out of 10
children having current ADHD and 4 having substance abuse. Pa-
tients relative to control subjects showed reduced total temporal
remained after controlling for IQ and substance abuse. Attention-
deficit/hyperactivity disorder, however, was not controlled for in
the study. In the study of Huebner et al. (135), most CD patients
were comorbid with ADHD (17 of 23 patients) but had no affective
disorder. They showed reduced total gray matter volumes relative
to control subjects, in particular in bilateral temporal lobes, left
amygdala and hippocampus, and orbitofrontal and ventromedial
frontal regions, but increased gray matter in bilateral cerebellum.
Although the majority of CD children also had ADHD, regression
analyses within patients revealed significant associations between
CD symptoms and gray matter reductions in temporal, limbic
(amygdala, hippocampus), cerebellar, medial, and mesial frontal
gray matter, while hyperactivity/impulsiveness symptoms corre-
lated inversely with gray matter reductions in left inferior frontal
and parietal cortices and bilateral temporo-occipital regions (135).
A study by Sterzer et al. (136) scanned 10 patients with CD; 7 of the
depression. Reduced gray matter volumes were observed relative
to healthy control subjects in bilateral insula and left amygdala,
both of which correlated with aggressive and inattentive but not
anxiety/depression symptoms. A study by DeBrito et al. (137) com-
pared 23 community adolescent boys with no psychiatric abnor-
malities or mood or anxiety problems but high levels of callous-
healthy twins. Covarying for both inattentive-hyperactivity symp-
toms and IQ, they found that gray matter concentration was in-
tal cortex, dorsal and rostral anterior cingulate, as well as in gray
superior frontal regions, cerebellum, insula, posterior cingulate,
significant deviation in CD-CU children from the norm-typical neg-
ative correlation between age and cortical thickness in orbitofron-
tal and left dorsal anterior cingulate. The fact that patients, unlike
control subjects, showed no negative age correlation in this mea-
sure could potentially indicate a delay of normal brain maturation
(137), similar to that observed in ADHD (93). Longitudinal studies
will be needed, however, to corroborate this observation based on
BIOL PSYCHIATRY 2011;69:e69–e87 e71
Table 1. Summary of Main Findings of Structural and Functional Magnetic Resonance Imaging Studies that Directly Compared Children with ADHD and with CD
MethodTask WB/ROI SubjectsF/M
sMRI— WB 5 ADHD only
10 control subjects
F and M8–12Yes CD/ADHD and ADHD alone versus control subjects: reduced mean volumes
in total and L posterior superior and inferior cerebellar vermis. No
differences between the pure and the comorbid groups. No group
differences in cerebral hemispheres or caudate.
3-group interaction effects:
a) Successful stop: ADHD versus CD and versus control subjects: reduced
activation in L DLPFC/IFC
b) Failed stop: CD versus ADHD and versus control subjects: reduced
activation in L and R IPL and R STL
Both patient groups versus control subjects: reduced activation in L and R
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
3-group interaction effects:
Oddball: ADHD versus CD and control subjects: reduced activation in L
ADHD and CD versus control subjects: reduced activation in R DLPFC but
no differences between patient groups.
Simon: ADHD and CD versus control subjects: reduced activation in R STL
and MTL and R precuneus but no differences between patient groups.
3-group interaction effects:
ADHD versus CD and control subjects: reduced activation in L and R IFC/
CD versus control subjects: reduced activation in L and R IPL and R STL/
precuneus but no differences between patient groups.
Group by expression effect:
ADHD/CD/ODD ? CU versus ADHD pure and control subjects: reduced R
amygdala activation for fearful faces (trend). Also reduced functional
connectivity between R amygdala and R OFC.
Connectivity abnormalities correlated with CU severity. No group
differences for angry or neutral faces.
fMRI Stop task
b) Failed stop
WB 20 ADHD
20 control subjects
fMRI Rewarded CPTWB 18 ADHD
16 control subjects
M 9–17 No
fMRI Simon and oddball
ROI 8 ADHD
8 control subjects
fMRISwitch taskWB 14 ADHD
20 control subjects
fMRI Neutral, fearful,
ROI 12 ADHD/CD/ODD ? CU
12 control subjects
e72 BIOL PSYCHIATRY 2011;69:e69–e87
In conclusion, the structural evidence, therefore, points toward
abnormalities in CD of the paralimbic system, comprising the or-
bitofrontal cortex (OFC), anterior cingulate, superior temporal
lobes, and underlying limbic structures that are known to mediate
confirm a neural network disturbance.
Functional Imaging Studies
Functional imaging studies in children with CD have been con-
sistent with the structural evidence, finding abnormalities in the
ventromedial orbitofrontal temporolimbic system in CD. The ma-
jority of functional magnetic resonance imaging (fMRI) studies in
CD have used emotion processing tasks. A study by Sterzer et al.
(139) found more pronounced deactivation in right dorsal anterior
cingulate gyrus in children with CD relative to healthy control sub-
jects during the viewing of pictures with negative valence, which
was interpreted by the authors as reduced inhibition of emotional
behavior. Although 62% of patients also met criteria for ADHD and
the group scored high on depression-anxiety, the anterior cingu-
late deactivation correlated negatively with the aggressive behav-
ior scores and remained when controlling for attention, depres-
sion/anxiety scores, and IQ (139). This is in line with the notion of
reduced emotion processing as the basis of aggression, given that
the amygdala is a key region for the processing of negative affect
a correlation between abnormal functioning of anterior cingulate
with CD with no affective disorder, 16 of which had ADHD, found
enhanced left amygdala activation compared with healthy control
subjects to the same negative affect stimulation, suggesting emo-
tional hyperresponsivity. The effect remained when controlling for
affective/depressive symptoms and was not observed in a patient
control group with ADHD only (142). Although the findings re-
acterized by high symptoms of emotion and anxiety, which could,
at least partly, explain the enhanced amygdala activation that is
as fear (143).
A recent fMRI study in children with early-onset childhood CD,
pain matrix, typically activated in healthy children in response to
the observation of pictures showing humans undergoing acciden-
tal body harm, but enhanced activation in anterior midcingulate,
left amygdala, right caudate, and bilateral temporal pole (144).
Furthermore, the extent of prefrontal and amygdala activation to
viewing pain in others was significantly positively correlated to
their number of aggressive acts and their ratings of daring and
sadism score on behavioral questionnaires.
tal body harm also showed enhanced activation in the antisocial
pain regions of left anterior insula, supplementary motor area, and
precentral gyrus but decreased activation in lateral IFC, posterior
vation in the temporoparietal junction and insula correlated with
the subjective ratings of the pain experienced by the individuals in
by others versus accidental pain led to enhanced connectivity be-
Table 1. Continued
12 ADHD/CD/ODD ? CU
14 ADHD 14 control subjects
Diagnosis by response type interaction:
ADHD/CD/ODD ? CU versus control subjects and versus ADHD:
enhanced activation in L and R vmPFC during punished reversal errors.
Correlation between vmPFC activation and antisocial and CU traits.
ADHD/CD/ODD ? CU versus control subjects: enhanced caudate
activation during punished reversal errors. No difference to ADHDalone.
Diagnosis effect: both ADHD/CD/ODD ? CU and ADHD alone versus
control subjects have enhanced activation in L precuneus and R SFC.
All fMRI tasks were event-related designs. ACC, anterior cingulate cortex; ADHD, attention deficit hyperactivity disorder; Cb, cerebellum; CD, conduct disorder; CPT, continuous performance task; CU, callous-unemotional symptoms; DLPFC,
dorsolateral prefrontal cortex; F, female; fMRI, functional MRI; IFC, inferior frontal cortex; IPL, inferior parietal lobe; L, left; M, male; Med, medication; MFC, medial frontal cortex; MRI, magnetic resonance
imaging; MTL, medial temporal lobe; ODD, oppositional defiant disorder; OFC, orbitofrontal cortex; PCC, posterior cingulate cortex; PMC, premotor cortex; R, right; ROI, region of interest analysis; SFC,
superior frontal cortex; sMRI, structural MRI; STL, superior temporal lobe; Stop, stop signal task; vmPFC, ventromedial prefrontal cortex; WB, whole brain analysis.
BIOL PSYCHIATRY 2011;69:e69–e87 e73
jects but not in CD patients (144). The findings suggest that highly
aggressive antisocial youth are hypersensitive in their brain re-
connectivity 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 reactivity
(144). The correlation findings also suggest that the brain abnor-
malities are associated with the antisocial core ratings, which is
important, given the high comorbidity. Aggression may thus be
related to poor regulation over hypersensitive negative affect pro-
pared with healthy control subjects in the amygdala in patients
with CD and callous-unemotional traits who had elevated ADHD
scores but no elevated affective symptoms (147). The findings re-
mained after covarying for ADHD symptoms.
In conclusion, parallel to structural studies, functional imaging
a dysregulation of ventromedial prefrontal amygdala regions and
networks that mediate affect regulation (29,138).
In conclusion, imaging studies of children with CD show struc-
tural and functional abnormalities compared with healthy control
subjects in ventromedial and orbital prefrontal, superior temporal,
bic networks. A caveat is that all studies have included a large
proportion of patients that were comorbid with ADHD, with the
majority of studies including over 50% comorbidity. The observed
abnormalities in brain abnormalities, however, were shown to cor-
relate with antisocial symptoms or to survive covariation for ADHD
in 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 and
ADHD symptoms (136) or only presented the correlation with CD,
but not ADHD, symptoms (144). Anxiety and depression are other
common comorbidities with CD. The majority of studies, however,
have either excluded comorbidity with affective disorders and/or
covaried for anxiety and depression (139,142,147,148). However,
while this suggests that anxiety and depression cannot alone ac-
may have contributed to some extent. Lastly, all imaging studies
ing correlates of ODD and whether they differ from those associ-
ated with CD.
Structural and Functional Neuroimaging Comparisons
Between ADHD and CD
Given the substantial clinical overlap between ADHD and CD
symptoms, with between 50% and 90% comorbidity (19,149), the
ogy is attractive. Modern functional neuroimaging could be an
important aid in the differentiation of clinically and behaviorally
similar disorders, if it can identify differences in the objectively
measurable underlying pathophysiological mechanisms, the bio-
markers that underlie overlapping behavior features of these two
disorders. Disentangling the disorder-specific underlying patho-
physiology of behaviorally and cognitively overlapping disorders
will be crucial to develop more objective differential diagnostics
vention and early intervention.
Very few studies, however, have directly compared these two
disorders in neuroimaging. As mentioned, only one structural im-
aging study compared whole brain volume abnormalities in small
ADHD, finding no significant differences between the disorders,
whereas both groups showed reduced volumes in the posterior
and inferior cerebellar vermis (133) (Table 1).
Few fMRI studies have compared the neurofunctional sub-
strates between the two disorders. Furthermore, few of them have
with ADHD or CD that were clinically not comorbid. Long-term
medication with stimulants appears to have effects on both brain
structure (150,151) and brain function development (152), and
medication naivety is, hence, crucial when comparing between
child psychiatric disorders.
Comparison Between Noncomorbid Groups of ADHD and CD
on Tasks of Executive Functions and Reward
tiated, medication-naive IQ-matched groups of children with CD,
who had no clinical diagnosis of ADHD and scored significantly
(the Strength and Difficulties Questionnaire ), with children
with ADHD, who had no clinical diagnosis of CD and scored signif-
icantly lower on the questionnaire for CD symptoms. Affective dis-
differ from control subjects in their affective symptom scores. The
disorders were compared in their neurofunctional activation dur-
ing five disorder-relevant executive function tasks, shown to be
impaired in both disorders: motor response inhibition, sustained
attention, cognitive switching, interference inhibition, and atten-
tional oddball. One of the tasks, the sustained attention task, in-
cluded an additional motivational aspect, where sustained atten-
to assess the effects of motivation on attention networks. Despite
the fact that performance measures did not differ between patient
groups, in four of the five tasks we observed disorder-specific re-
duced activation in patients with ADHD compared with both
(Table 1). The location of disorder-specific abnormality was more
dorsolateral for the stop and oddball tasks and more ventrolateral
for the sustained attention and switching tasks. Furthermore, the
tasks (107,109) but left hemispheric for the stop and oddball tasks
(96,102) (Figure 1A, Table 1). During the sustained attention condi-
tion, we also observed a disorder-dissociated effect in a large pos-
terior activation cluster comprising the cerebellum, hippocampus,
and inferior temporal lobe, which was enhanced in activation in
children with ADHD but reduced in children with CD compared
1). The cerebellum is an essential part of frontocerebellar networks
been shown to be crucially implicated in attention functions
(154,155). We hypothesized that the disorder-specific enhanced
satory for the reduced IFC activation during the task, corroborated
by the finding of a negative correlation between these two brain
regions in ADHD children but not the other two groups.
e74 BIOL PSYCHIATRY 2011;69:e69–e87
The disorder-specific reduced IFC activation in ADHD patients
across four different tasks is a consistent finding that may suggest
that IFC dysfunction is a disorder-specific neurofunctional bio-
marker for ADHD, at least when compared with CD. This is in line
with the fact that we also found disorder-specific reduction in IFC
inhibition and switching, when compared with healthy children
and children with obsessive-compulsive disorder (156). Obsessive-
compulsive disorder patients, in turn, had shared abnormalities
with ADHD patients in other prefrontal regions, including the OFC
and dorsolateral prefrontal cortex (106,156) (Figure 2). The IFC has
not exclusively in the right hemisphere, as demonstrated by fMRI
studies of children and adults during motor inhibition tasks
(22,52,53,157), as well as lesion (158) and transcranial magnetic
resonance imaging studies (159). The IFC, however, is also a key
itory control, such as interference inhibition, which has more com-
monly been found to be mediated by left hemispheric inferior
Figure 1. (A) Disorder-specific underactivation in inferior prefrontal cortex in attention-deficit/hyperactivity disorder (ADHD) children compared with
conduct disorder (CD) and healthy children. Disorder-specific underactivation in inferior prefrontal cortex in children with ADHD (n ? 20) compared with
age-matched healthy control children (n ? 20) and children with conduct disorder (n ? 14) during tasks of motor inhibition (stop task), sustained attention
(continuous performance task), attention allocation (oddball task), and cognitive switching. The cerebellum activation was increased in activation in ADHD
but decreased in CD children relative to control subjects and each other. In ADHD patients, the cerebellum activation correlated negatively with the inferior
with healthy children and children with ADHD in areas of the paralimbic system, including the temporal lobe (inhibition failures in the stop task; sustained
anterior cingulate, insula and hippocampus (sustained attention task). For more details, see Rubia et al. (96,102,107,109).
BIOL PSYCHIATRY 2011;69:e69–e87 e75
frontal cortex (51,53,160–162). It is also involved in cognitive
switching, in a typically bilateral location, presumably mediating
the inhibition of previously valid but no longer relevant stimulus-
response associations (right IFC) and the re-engagement of novel
stimulus-response associations (left IFC) (51,53,163). It has also
for the update of information in tasks of cognitive control, which
could explain its ubiquitous activation across cognitive control
tasks (160). Furthermore, the bilateral IFC is also consistently acti-
attention (108,164) and attention allocation in oddball tasks
tional biomarker of ADHD, when compared with CD, is in line with
neuropsychological findings. Attention-deficit/hyperactivity disor-
by IFC (21,23,113) and this is more prominent than in children with
CD (24). Furthermore, children with CD or ODD are often not im-
parallel to regression analyses that show that ADHD, but not CD,
traits account for poor performance in these IFC mediated cool
executive function tasks (50).
For the reward contrast, however, it was the CD children who
regions (109). Children with CD, relative to control subjects and
children with ADHD, showed reduced activation in ventromedial
OFC, which is known to be crucial for executive reward processing
and the mediation of motivation (51,165,166) (Figure 1B, Table 1).
The orbitofrontal cortex is thought to be important for holding
information 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 with
reward as opposed to punishment-driven processes (168–170).
The disorder-specific abnormality in ventromedial PFC for CD is in
Furthermore, the lateral and ventromedial orbitofrontal cortex
also plays a crucial role in the modulation of paralimbic brain re-
frontal cortex, together with temporal areas including amygdala
and hippocampus, was reduced in gray matter in adolescent boys
with CD (135). It has been hypothesized that abnormalities in re-
ward computations mediated by orbitofrontal cortex leading to
enhanced frustration could trigger reactive aggression, which
reward system, and orbitofrontal abnormalities (174). The disorder
specificity of the dysfunction of the ventromedial frontal cortex in
relation to reward compared with ADHD is also in line with evi-
dence of reduced autonomic response in patients with CD com-
pared with ADHD and healthy control subjects during emotional
It thus seems that there is a disorder-specific and process-re-
lated dissociation in prefrontal lobe deficits, where ADHD children
context of cool executive inhibitory and attention control across
several cognitive domains, while CD children have problems with
the recruitment of hot ventromedial OFC systems that mediate
motivation in the context of reward processing (109) (Figure 1B,
Attention-deficit/hyperactivity disorder children, during the re-
to control and CD children in the posterior cingulate and precu-
neus, brain regions known to mediate visual-spatial attention pro-
cessing of saliency (176,177). The posterior cingulate and precu-
neus are reciprocally connected with the anterior cingulate cortex
(ACC) (178), which monitors action outcomes to support learning
the value of actions (179), and the parietal cortex, which directs
cingulate and precuneus are typically reduced in activation in chil-
dren with ADHD during salient stimuli such as errors (95,96) and
Figure 2. Disorder-specific underactivation in attention-deficit/hyperactivity disorder children compared with obsessive-compulsive disorder and healthy
and cognitive switching (switch task). For more details, see Rubia et al. (156).
e76 BIOL PSYCHIATRY 2011;69:e69–e87
deficiency hypothesis of ADHD, given that catecholamine defi-
ciency diminishes and catecholamine agonists enhance the sa-
lience of stimuli (182). In fact, methylphenidate, the treatment of
choice and an indirect catecholamine agonist, has been shown to
upregulate the activation of posterior cingulate in children with
ADHD, leading to better attention performance (108). Abnormal
cingulate activation in ADHD children may thus be the neurobio-
logical substrate of catecholamine deficiency-related abnormal sa-
disorder patients demonstrated disorder-specific reductions of ac-
tivation compared with control subjects in several other regions of
the paralimbic system during all tasks. During the sustained atten-
tion task, where ADHD children showed disorder-specific inferior
frontal underactivation relative to control and CD children, that
furthermore correlated with the main performance indicator (i.e.,
omission errors), children with CD showed reduced activation rela-
have been shown to contribute to sustained attention through
their mediation of motivation, such as hippocampus, the insula,
a cluster comprising the cerebellum, the hippocampus, and the
inferior temporal lobes (109) (Figure 1B, Table 1). These regions of
the paralimbic system lie at the interface between emotion and
cognition. The dorsal anterior cingulate is connected to frontal-
parietal attentional networks but is also crucial for motivation and
arousal (183,184). Hippocampus and insula form part of the limbic
system and visuomotor pathways and are an interface between
the 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 hemispheres
form part of frontocerebellar attention systems (72,154,155,187).
The superior and inferior temporal lobes are closely connected to
the limbic system and contribute to cognitive functions such as
perceptual selective attention (188). Together, it thus appears that
CD children show disorder-specific underactivation in subcortical
and 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 and
subjects, which reached significance for ADHD. This suggests that
the underrecruitment of cool IFC networks, as well as the reduced
recruitment of motivational paralimbic brain regions, can lead to
similar performance underachievement.
In addition, CD children showed disorder-specific underactiva-
tion of the superior temporal lobes during failures in the stop task
compared with both ADHD children and healthy control subjects
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 negative
feedback than healthy children (39,47). Disorder-specific reduced
compared with control subjects, but not ADHD patients, during
cognitive switching (107) and sustained attention (109) (Figure 1B,
Dysfunction of the temporal lobes during attention and perfor-
mance monitoring in patients with CD is in line with evidence for
structural abnormalities in this brain region (134,135,137). Fur-
thermore, temporal lobe lesions have been associated with ag-
In conclusion, the findings of disorder-specific deficits in these
two clinically overlapping disorders suggest distinct underlying
neurofunctional abnormalities, both of which may be related to
overlapping behavioral features. Attention-deficit/hyperactivity
disorder appears to be associated with disorder-specific cool top-
late cognitive control/attention networks, presumably causing re-
duced top-down executive inhibitory and attention control.
Conduct disorder, by contrast, appears to be associated with neu-
ventromedial OFC and underlying bottom-up limbic and paralim-
bic structures (anterior cingulate, superior temporal lobes insula,
known to feed into attention systems (164,183,184,186).
The findings of disorder-specific abnormalities in areas of the
paralimbic system in CD are in line with neuropsychological evi-
dence that shows specific impairment in these children in tasks of
hyposensitivity to punishment in reward-related paradigms
(39,45–47,192). Furthermore, symptom-regression analyses show
that CD/ODD symptoms account for the deficits in hot reward-
in cool executive function tasks (50). This neuropsychological evi-
dence, combined with our imaging findings of disorder-specific
the motivational limbic system—that is different from that of
ADHD—that disturbs the normal interaction between motivation
cool executive system, necessary for normal optimal performance.
Given that motivation and reward upregulate cognitive processes
(185,193,194), both a dysfunction of the hot motivation system, as
appears to be the case in CD, as well as a dysfunction of the cool
executive system directly, as observed in ADHD, would lead to
cognitive impairment. The difference is that the neurobiological
deficit in ADHD is directly affecting the cool cognitive control sys-
tems, while the deficit in CD affects these systems indirectly, via a
dysregulation of the neuronal interplay between motivation and
tional imaging is more sensitive than performance to differentiate
between behaviorally and cognitively overlapping patient groups.
This is illustrated, in particular, for the sustained attention task,
where both disorders shared the same number of omission errors
but the underlying disorder-specific dysfunctions were in perfor-
mance correlated cool IFC frontocerebellar activation in patients
with ADHD and in hot paralimbic motivation regions in CD that
were not directly related to task performance.
We also observed shared abnormalities in the two disorders.
compared with control subjects, presumably reflecting shared re-
duced activation to salience, given that both errors and incongru-
ent trials are salient stimuli (96,102). Another brain region that was
jects was the right medial frontal lobe during visual-spatial atten-
tion to oddball stimuli (102) (Table 1). It thus appears that a shared
abnormality in both disorders is the recruitment of dorsolateral
prefrontal and posterior parietal brain regions that mediate visual-
spatial attention to salient events.
BIOL PSYCHIATRY 2011;69:e69–e87 e77
Comparisons Between Children with CD-CU and Comorbid
ADHD with Noncomorbid Children with ADHD
Two fMRI studies from within the same research group com-
pared children with callous-unemotional traits and either CD or
ODD with children with noncomorbid ADHD as well as control
subjects (148,195). The groups were not well separated in clinical
symptomatology because the group with CD/ODD-CU also had
Mood and anxiety disorders were excluded. Furthermore, the ma-
jority of children with ADHD in either group were medicated with
psychostimulants. In the study of Marsh et al. (148), reduced right
amygdala activation was found to fearful compared with neutral
faces in the group with CD/ODD-CU and ADHD relative to control
subjects and relative to noncomorbid ADHD, while the latter
groups did not differ from each other (148). No group effects were
jects and ADHD patients without CD/ODD-CU had a higher degree
of 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 the
severity of the psychopathy symptom scores (Table 1). The
amygdala plays an important role in fear processing and socializa-
tion (140), and its abnormal response may be the neural substrate
for reduced distress cue processing and socialization problems in
psychopathy (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) are
crucial to affect control (198). Together, they mediate appropriate
behavioral decision making based on positive and negative feed-
back (51,199) and moral decision making (200–202). These two
The second study by Finger et al. (195), on the same sample,
compared 14 children with CD/ODD-CU, allowing for ADHD symp-
antisocial traits and 14 healthy control subjects in a reversal task.
While healthy and ADHD children showed reduced activation in
bilateral 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 showed
enhanced activation in this region during punished reversal errors
relative to the other two groups. The disorder-specific abnormali-
ties in ventromedial prefrontal activation in the CD-CU and ADHD
group were furthermore correlated with total scores on antisocial
and callous-unemotional traits (Table 1). Although some of the
patients were medicated, the findings remained when these were
excluded from the analysis (195). Both the ADHD only group and
the group with psychopathy and CD/ODD/ADHD showed en-
group of ADHD without comorbid CD-CU compared with control
line with the underactivation findings of the majority of fMRI stud-
ies of ADHD during tasks of cognitive flexibility (100,107) or error
processing (95,96,156). The negative findings may potentially be
related to the fact that the children in this group had a higher IQ
compared with the other two groups. While at first the findings of
enhanced ventromedial frontal activation may seem in the oppo-
in children with CD during rewarded attention trials (109), they
are, in fact, consistent with each other. The children with psychop-
medial PFC activation during rewarded correct trials, even though
this did not reach significance, but showed enhanced activation in
this region during punished error trials relative to control subjects
and ADHD patients. It thus may be that reward and punishment
result in patients with CD in dissociated abnormal response pat-
terns in ventromedial and orbitofrontal brain regions, showing hy-
posensitive activation in the context of reward and hypersensitive
activation during punishment, suggesting a contingency-sensitive
orbitofrontal dysregulation. Alternatively, it is also possible that
substrates, as demonstrated with evidence with respect to
amygdala hyperactivation in CD (139,144) and hypoactivation in
CD-CU (148). The disorder-specific abnormality findings in ventro-
medial prefrontal and amygdala activation in the children with
with evidence for dysfunction and dysmorphology of these two
structures in adults with psychopathy (29,138,145,204–206).
thy compared with control subjects and ADHD patients for pun-
ished reversal errors compared with correct rewarded trials, the
opposite pattern as in control subjects. However, the caudate hy-
caudate is a key region of typically reduced activation in children
with ADHD during tasks of cognitive control (94,97,113,207), in-
cluding tasks of cognitive flexibility (100,156,208). The finding of
enhanced caudate activation in antisocial pathologies compared
in these disorders.
In summary, the disorder-specific functional imaging findings
suggest that CD and CD-CU compared with ADHD are associated
with disorder-specific abnormalities of the paralimbic system of
amygdala, hippocampus, and the superior temporal lobes, known
to regulate affect and motivation. The disorder-specific dysfunc-
tions in children with ADHD, by contrast, appear to be in brain
and attention control, most prominently in IFC-striatal circuitries.
The findings of disorder-specific cool IFC dysfunction in ADHD
and disorder-specific hot ventromedial-paralimbic dysfunction in
CD is further interesting with respect to the genotypes that have
been associated most prominently with each of the two disorders.
In ADHD, dopamine dysregulation is thought to play a crucial role
and the dopamine genotypes of DAT1 and dopamine receptor D4
(DRD4) 7-repeat allele are most commonly associated with the
disorder (209). The DRD4-7-7 genotype has been associated with
reduced volume and cortical thickness of the right IFC in normal
development, which was, furthermore, particularly pronounced in
been associated with abnormal caudate volume, as well as activa-
tion in patients with ADHD (211,212). Antisocial behaviors, includ-
ing psychopathy and CD, have more commonly been associated
with serotonin genotypes. Thus, the short allele of the serotonin
transporter has been associated with impulsive and antisocial be-
adults. In children, the short variant has been associated with anti-
social and aggressive behavioral features in adoptees (216) and
with childhood aggression (217). Furthermore, the short allele
behavior (218). In healthy adults, the short allele of the serotonin
e78 BIOL PSYCHIATRY 2011;69:e69–e87
transporter has consistently been associated with the brain struc-
tures that have been associated with CD. It has been related to a
dysmorphology and dysregulation of the ventromedial prefrontal
cortex, including anterior cingulate and medial frontal cortex, and
the amygdala, as well as the functional connectivity between both
impulsive aggression (171). Genetic predisposition, hence, may
play a role in the development of the disorder-specific dysregula-
tion of IFC-striatal and ventromedial-limbic neural networks in
ADHD and antisocial-aggressive behaviors, respectively.
Conclusion and Future Directions
This review shows that ADHD is most prominently associated
with the dysmorphology, dysfunction, and the underconnectivity
that regulate cognition and attention. Furthermore, these regions,
most prominently the IFC, are disorder-specific underfunctioning
when compared with CD. Antisocial and aggressive behaviors in
the 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 frontolimbic
underconnectivity. Furthermore, compared with ADHD, this para-
cific (Figure 3).
Comorbidity Between Disorders
There are several potential caveats, however, that need to be
taken into account. All structural studies have tested children with
CD with over 50% comorbidity with ADHD. Consequently, struc-
tural abnormality findings apply mostly to the comorbid presenta-
studies, except for those conducted in my laboratory, where we
compared noncomorbid patient groups. Although in the majority
of studies, brain structure and function abnormalities correlated
not be excluded that the comorbid ADHD features may have con-
tributed to the abnormalities. The fact that the studies from our
laboratory, however, were conducted in noncomorbid groups and
showed disorder-specific functional brain abnormalities in nonco-
morbid CD relative to noncomorbid ADHD in paralimbic regions,
including superior temporal lobes, orbitofrontal cortex, insula, an-
terior cingulate, and hippocampus, reinforces the association be-
tween these paralimbic functional deficits, also observed in the
studies of comorbid cases and antisocial behaviors. However, non-
comorbid patient groups may be less representative of the typical
CD or ADHD population. According to epidemiological studies,
children with noncomorbid CD or noncomorbid ADHD are rela-
tively rare (19,78,149). An epidemiological prevalence study in
without CD can be relatively high (30%), CD without ADHD is rela-
tively uncommon (1.5%) (223). Epidemiological data from the Brit-
ish Child Mental Health Survey, however, using diagnostic criteria
that elicit a relatively conservative ADHD prevalence of 1.5%,
showed that only 23% of children with CD had ADHD comorbidity,
while 50% of ADHD children had CD comorbidity (224). In US sam-
ples, this ratio appears to be higher, however, with odds ratios of
41.3 for concurrent comorbidity of ADHD given CD and of 79 for
Figure 3. Schematic representation of the magnetic resonance imaging evidence for disorder-specific structural and functional brain abnormalities in
children with attention-deficit/hyperactivity disorder and those with conduct disorder. The figure is based on evidence for disorder-specific abnormalities
conduct disorder. ADHD, attention-deficit/hyperactivity disorder; CD, conduct disorder; PFC, prefrontal cortex.
BIOL PSYCHIATRY 2011;69:e69–e87 e79
from a dysregulation of both cool fronto-striato-parieto-cerebellar
as well as hot ventromedial fronto-temporo-limbic neural net-
works. Future studies will need to compare 100% comorbid cases
with 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 a
more complex disorder, characterized by a qualitatively different
Furthermore, although most studies in ADHD and CD have ex-
sive symptoms, it cannot be completely excluded that underlying
problems of anxiety and depression may have contributed to the
observed brain abnormalities. Future studies are needed to assess
the contribution of affective symptomatology on brain abnormali-
ties in these disorders, by comparing children with noncomorbid
CD, as well as comorbid presentations of these disorders.
Bias in Structural and Functional Imaging Studies
There has been a bias in structural studies, where regions of
brain regions, while areas of the paralimbic motivation circuitries
have more commonly been selected as regions of interest in struc-
that have selected limbic areas as regions of interest have, in fact,
Plessen et al. (225) found enhanced volumes in the head of the
hippocampus in 51 children with the combined type of ADHD
compared with 63 healthy control subjects. This structural abnor-
mality, however, was associated with fewer ADHD symptoms and
hence interpreted as a compensatory plastic hypertrophic re-
sponse, possibly for reduced prefrontal parts of frontal-hippocam-
pal circuitries. Surface morphology analyses also showed reduced
tal cortex size, suggesting reduced frontal-amygdala connectivity.
The amygdala surface morphology was negatively associated with
suggesting distinct associations between amygdala neurobiology
and 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 not
associated with the findings. Abnormalities in medial frontal re-
gions and their connections to amygdala and hippocampus could
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 mnemonic
the pulvinar of the thalamus in 46 children with ADHD compared
with healthy control subjects. A dissociation of thalamic volumes
with ADHD symptoms was observed, with hyperactivity being as-
sociated with smaller left ventrolateral and pulvinar regions and
inattention with larger right pulvinar and medial dorsal thalamic
regions (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 limbic
system, including the amygdala (229,230), and hence part of an
emotional regulation network (228). Moreover, recent positron
relative to healthy adults in areas of the limbic system including
nucleus accumbens and midbrain, amygdala, and hippocampus
that furthermore correlated with inattention but not hyperactivity
In fMRI studies of both disorders, there has also been a bias in
paradigm selection, where cool cognitive paradigms have been
applied in the majority of fMRI studies of ADHD to test the hypoth-
esis of frontostriatal deficits, while hot motivational paradigms
have been more commonly chosen for fMRI research of CD. In fact,
more recent fMRI studies that have tested for deficits in motiva-
reward-related functions have, indeed, found underfunctioning in
children and adults with ADHD in limbic brain regions, including
orbital and ventromedial prefrontal cortex, amygdala, and ventral
the results. This, however, also applies to the majority of fMRI stud-
ies that observed frontostriatal dysfunctions during cool executive
CD. In support of an association with ADHD, however, is the fact
in limbic regions, such as ventral striatum and amygdala, with hy-
conclusion, given the bias in the neuroimaging literature of ADHD
and CD in the selection of regions of interest in structural imaging
studies and paradigm selection for fMRI studies, future imaging
studies should combine structural and functional analyses in large
patient numbers to conduct head-to-head comparisons between
children with noncomorbid CD, noncomorbid ADHD, and comor-
bid cases using whole-brain structural imaging analyses and using
fMRI tasks that tap into both hot and cool executive functions.
Potential Overlap Between Disorders in Brain Structure and
Ventromedial-limbic circuitries and mesolimbic dopamine re-
ward pathways may potentially be a shared abnormality between
both ADHD and CD. The nucleus accumbens is located between
limbic areas and is thought to be a key mediator between motiva-
tion and attention functions (64). It is ideally placed to integrate
emotional salience and contextual constraints, processed in
amygdala and hippocampus, respectively, and goal-directed exec-
utive plans from the PFC. The mesolimbic dopamine system main-
tains the balance between limbic and cortical drive within this
region (64). This region is closely interconnected with anterior cin-
gulate, ventromedial frontal cortex, and amygdala, which, in con-
cert, mediate reward-related decision making (67,236,237). Fur-
thermore, abnormalities in these circuitries have been associated
with impulsiveness and behavioral disinhibition (67,238), overlap-
medial frontal cortices, anterior cingulate, amygdala, and hip-
or functional MRI study, however, has as yet tested for structural
abnormalities of nucleus accumbens in children with CD or for
potential activation abnormalities in reward-related paradigms
be tested in future studies.
Another area of potential overlap could be the anterior cingu-
late. This paralimbic area lies at the interface between the frontal
lobes and the limbic system and has been associated with several
functions, depending on exact location, including performance
monitoring, error detection, arousal, motivation, and outcome
e80 BIOL PSYCHIATRY 2011;69:e69–e87
Both rostral and dorsal anterior cingulate have consistently been
found to be abnormal in structural and functional imaging studies
of CD (see above). This brain region has also been found to be
abnormal in brain structure and function in ADHD children
sons between ADHD and CD, however, point toward more severe
abnormalities in this region in CD. Functional MRI comparisons
with 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 CU
symptoms (144). Structural studies found ACC to be specifically
The ACC abnormality may thus be more strongly associated with
antisocial behavioral features than ADHD symptoms and abnor-
mality findings in ACC in ADHD patients—more commonly ob-
served in adult than childhood ADHD (for review, see 125])—may
potentially be associated with underlying, and mostly uncon-
trolled, antisocial features.
Lastly, we found that in children with ADHD and emotional
dysregulation, both the DRD4 7-repeat allele as well as the short
allele of the serotonin transporter have been associated with emo-
common in ADHD children and associated with CD and/or ODD
behavior, may be mediated by the abnormality of both top-down
PFC control systems, the cool executive lateral PFC-striatal control
network as well as the hot ventromedial PFC-limbic pathway that
controls affect and motivation (243).
In conclusion, there is evidence that some brain regions that
may be affected in both disorders, but this needs to be further
tested in head-to-head comparisons between noncomorbid and
comorbid patient groups.
Heterogeneity Within ADHD and CD
Both 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, children
ical abnormalities than children with the combined type ADHD.
subtype of ADHD and CD, in particular the impulsive-aggressive
ADHD may be associated with deficits in frontostriatal mediated
cool EF, whereas hyperactivity/impulsivity symptoms may reflect
hot executive function deficits, mediated by paralimbic brain re-
may be mediated by different brain abnormalities, with the impul-
with this theory, limbic brain abnormalities in orbitofrontal,
tive but not inattentive symptoms (117,233,235). Symptoms of in-
been shown to correlate with limbic abnormalities in children with
studies (136,231). By contrast, hyperactivity/impulsiveness symp-
toms and not inattention symptoms correlated inversely with gray
matter reductions in cool fronto-temporo-parietal brain regions
with inattention and sluggish cognitive tempo have more anxiety
by contrast, point toward abnormalities in orbitofrontal-limbic
that overlap substantially with the observed brain abnormalities in
are needed to clarify potential differences in the underlying neural
substrates of each of the subtypes.
subtypes of CD because there are likely to be differences in the
underlying neurobiological substrates of CD children with and
mental aggression. Lastly, there are likely to be neurophysiological
aging substrates of ODD, independent from CD, or compared be-
tween different subtypes of CD.
Need for Longitudinal and Combined Structure-Function
sectional. Longitudinal imaging studies will be needed to assess
differences in the developmental trajectories of the disorders.
While in ADHD there is evidence for a maturational delay (93,247),
brain abnormalities, i.e., in the onset of their deviance from normal
development and/or in their developmental trajectories, rather
than at any chosen cross-sectional time point.
Furthermore, no studies have combined structural and func-
tional information. Future, large-scale multimodal imaging studies
should compare ADHD and CD in brain structure, brain function,
and structural and functional connectivity. Modern multivariate
pattern recognition analysis classification systems applied to MRI
data, which differentiate cases and control subjects on the basis of
quantitative, spatially distributed neural networks rather than iso-
(248–250), could potentially be of clinical use by providing a more
objective, neuroimaging-based differential diagnosis. A successful
neurobiological abnormalities would not only provide a more ob-
jective differential diagnosis but also deliver a target for disorder-
specific preventions and interventions aimed at normalizing disor-
der-specific abnormal brain and neurotransmitter systems and
their abnormal development.
KR has received funding from Eli Lilly for another research project
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