c o r t e x 4 8 ( 2 0 1 2 ) 1 9 4 e2 1 5

Available online at www.sciencedirect.com

Journal homepage: www.elsevier.com/locate/cortex

Special issue: Research report

A review of fronto-striatal and fronto-cortical brain

abnormalities in children and adults with Attention Deficit
Hyperactivity Disorder (ADHD) and new evidence for
dysfunction in adults with ADHD during motivation and
attention

Ana Cubillo, Rozmin Halari, Anna Smith, Eric Taylor and Katya Rubia*
Department of Child Psychiatry, Institute of Psychiatry, King’s College London, UK

article info abstract

Article history: Attention Deficit Hyperactivity Disorder (ADHD) has long been associated with abnor-
Received 14 October 2010 malities in frontal brain regions. In this paper we review the current structural and
Revised 12 January 2011 functional imaging evidence for abnormalities in children and adults with ADHD in fronto-
Accepted 11 April 2011 striatal, fronto-parieto-temporal, fronto-cerebellar and fronto-limbic regions and
Published online 27 April 2011 networks. While the imaging studies in children with ADHD are more numerous and
consistent, an increasing number of studies suggests that these structural and functional
Keywords: abnormalities in fronto-cortical and fronto-subcortical networks persist into adulthood,
Adult ADHD despite a relative symptomatic improvement in the adult form of the disorder.
fMRI We furthermore present new data that support the notion of a persistence of neurofunc-
Reward tional deficits in adults with ADHD during attention and motivation functions. We show
Sustained attention that a group of medication-naı̈ve young adults with ADHD behaviours who were followed
Review up 20 years from a childhood ADHD diagnosis show dysfunctions in lateral fronto-striato-
parietal regions relative to controls during sustained attention, as well as in ventromedial
orbitofrontal regions during reward, suggesting dysfunctions in cognitive-attentional as
well as motivational neural networks. The lateral fronto-striatal deficit findings, further-
more, were strikingly similar to those we have previously observed in children with ADHD
during the same task, reinforcing the notion of persistence of fronto-striatal dysfunctions
in adult ADHD. The ventromedial orbitofrontal deficits, however, were associated with
comorbid conduct disorder (CD), highlighting the potential confound of comorbid antiso-
cial conditions on paralimbic brain deficits in ADHD.
Our review supported by the new data therefore suggest that both adult and childhood
ADHD are associated with brain abnormalities in fronto-cortical and fronto-subcortical
systems that mediate the control of cognition and motivation. The brain deficits in
ADHD therefore appear to be multi-systemic and to persist throughout the lifespan.
ª 2011 Elsevier Srl. All rights reserved.

* Corresponding author. Department of Child Psychiatry/SGDP, P046, King’s College London, Institute of Psychiatry, 16 De Crespigny Park,
London SE5 8AF, UK.
E-mail address: katya.rubia@kcl.ac.uk (K. Rubia).
0010-9452/$ e see front matter ª 2011 Elsevier Srl. All rights reserved.
doi:10.1016/j.cortex.2011.04.007
 c o r t e x 4 8 ( 2 0 1 2 ) 1 9 4 e2 1 5
1. Introduction
Attention Deficit Hyperactivity Disorder (ADHD) is charac-
terised by age-inappropriate symptoms of inattention,
impulsiveness and hyperactivity (Diagnostic Standard
manual-IV – DSM-IV)(American Psychiatric Association, 1994).
It disrupts academic and social development, and is associated
with significant psychiatric comorbidities and mental health
problems in adult life (Faraone et al., 2007; Spencer et al., 2007;
Taylor et al., 1996). ADHD affects 3e8% school-aged children
(American Psychiatric Association, 1994; Froehlich et al., 2007)
and persists into adulthood in 65% of cases (Barkley et al., 2002;
Biederman et al., 2006), affecting 4% of the adult population
(Faraone and Biederman, 2005; Kessler et al., 2006).
2. Neuropsychological deficits in children
and adults with ADHD
Executive functions (EF) are defined as functions that are
necessary for mature adult goal-directed behaviour, such as
set-shifting and set maintenance, higher level and selective
attention, interference control, motor inhibition, integration
across space and time, planning, decision making, temporal
foresight and working memory (Stuss and Alexander, 2000). It
should be noted that we use the wider definition of EF that
includes attention functions as well as specific aspects of
temporal processing such as temporal foresight since they are
underlying basic functions for all goal-directed behaviours.
“Cool” EF are mediated by ventrolateral and dorsolateral
(DLPFC) fronto-striatal, fronto-cerebellar and fronto-parietal
neural networks. More recently, a differentiation has been
made between “cool” cognitive EF, typically elicited by rela-
tively abstract and descontextualized problems, and “hot”
motivation and reward-related EF, which involve the regulation
of affect and motivation (Zelazo and Muller, 2002). Thus, “hot”
EF consist of tasks of reward-related decision making, reversal
of rewarded stimuluseresponse associations, temporal dis-
counting and other EF that are dependent on motivation and
reward. “Hot” EF are mediated by mesolimbic ventromedial
(VMPFC) and orbitofrontal (OFC)-striatal and limbic circuits
(Zelazo and Muller, 2002). In neuropsychological studies, as
a group, child and adult patients with ADHD have shown defi-
cits both in “cool” EF (Marchetta et al., 2008; Martinussen et al.,
2005; Rubia et al., 2001, 2007a; Sergeant et al., 2002; Valko et al.,
2010; Willcutt et al., 2005) and “hot” EF (Antrop et al., 2006;
Bitsakou et al., 2009; Dalen et al., 2004; Luman et al., 2005;
Marco et al., 2009; Sagvolden et al., 1998), for review see
(Rubia, 2010). Deficits have furthermore been observed in
temporal (for review see Rubia et al., 2009a) and perceptual
processes (Banaschewski et al., 2006; Boonstra et al., 2005).
However, while as a group ADHD children show impairments
in these functions, a proportion of ADHD children is not
impaired in any of these functions (Nigg et al., 2005; Sonuga-
Barke et al., 2010) and there are subgroups of children with
ADHD who are impaired in either “cool” EF, “hot” EF or temporal
processes with only some of them having overlapping deficits
(Nigg et al., 2005; Sonuga-Barke et al., 2010). Different theoret-
ical approaches have attempted to explain this heterogeneity
195
suggesting multiple developmental pathways for ADHD
(Makris et al., 2009; Nigg and Casey, 2005; Sonuga-Barke et al.,
2010; Willcutt et al., 2005), with structural and functional
abnormalities in shared but dissociable functional networks
underlying the observed deficits (Makris et al., 2009).
3. Structural and functional neuroimaging of
childhood and adult ADHD
3.1. Structural studies
Using structural magnetic resonance imaging (sMRI), children
with ADHD relative to controls have shown consistent abnor-
malities in late developing fronto-striatal, fronto-temporo-
parietal and fronto-cerebellar networks. These brain regions
are known to mediate the above mentioned cognitive control
functions that are impaired in the disorder. Thus, reduced
volume and cortical thickness have been observed in several
frontal brain regions, in parieto-temporal areas, the basal
ganglia, posterior cingulate (PCC), the cerebellum and the
splenium of the corpus callosum (Batty et al., 2010; Carmona
et al., 2005, 2009; Castellanos et al., 2002; Mackie et al., 2007;
Shaw et al., 2006; for reviews see Krain and Castellanos, 2006;
Rubia, 2010). A meta-analysis of structural studies using
region of interest analyses showed that the largest volume
reductions in ADHD children relative to controls were in
several frontal brain regions, total and right cerebral volumes,
the posterior inferior vermis of the cerebellum, the splenium of
the corpus callosum and right caudate (Valera et al., 2007). A
subsequent meta-analysis of whole-brain voxel-based
morphometry studies in children with ADHD found that the
most consistent regional gray matter reduction in ADHD
patients compared to controls was in right putamen and globus
pallidus (Ellison-Wright et al., 2008). Longitudinal imaging
studies have provided some evidence that the structural
abnormalities observed in children with ADHD compared to
healthy peers in frontal, striatal, parietal and cerebellar regions
may be due to a delay in structural maturation (Castellanos
et al., 2002; Shaw et al., 2007). The peak of cortical thickness
maturation was found to be delayed in ADHD children relative
to typical controls by an average of 3 years across all cortical
regions, with up to 4e5 years delay in frontal and temporal
areas, respectively (Shaw et al., 2007). This was further rein-
forced by findings that the rate of cortical thinning in these
regions, which is thought to mirror synaptic pruning and
reflect structural and cognitive maturation, has been shown to
be inversely associated with the severity of hyperactivity and
impulsiveness in normal development (Shaw et al., 2011).
Structural MRI studies in adult ADHD have observed
abnormalities in similar cortical brain regions, including
deficits in overall cortical gray matter, volumes and cortical
thickness of superior frontal and OFC, anterior cingulate
(ACC), Inferior frontal cortex (IFC), DLPFC, PCC, temporo-
parietal, cerebellar and occipital regions (Amico et al., 2010;
Biederman et al., 2008; Hesslinger et al., 2002; Makris et al.,
2010; Seidman et al., 2006), as well as in subcortical brain
areas including the caudate, nucleus accumbens and the
amygdala (Almeida Montes et al., 2010; Frodl et al., 2009;
196 c o r t e x 4 8 ( 2 0 1 2 ) 1 9 4 e2 1 5
Seidman et al., 2006). However, there have also been negative
findings with respect to structural differences in frontal lobes,
basal ganglia, amygdala and hippocampus (Ahrendts et al., in
press; Amico et al., 2010; Depue et al., 2010b; Perlov et al.,
2008).
Diffusion tensor imaging studies furthermore have
demonstrated abnormalities at the neural network level. Thus,
children and adults with ADHD compared to controls have
shown reduced white matter connectivity in fronto-striatal,
cingulate, as well as fronto-parietal, fronto-cerebellar and
parieto-occipital white matter tracts (Ashtari et al., 2005;
Davenport et al., 2010; Konrad et al., 2010; Makris et al., 2008;
Pavuluri et al., 2009; for a review see Konrad and Eickhoff, 2010).
Our recent meta-analysis of 14 whole-brain voxel-based
morphometry studies in children and adults with ADHD,
including in total 378 ADHD and 344 controls, showed that the
most consistent regional gray matter reduction in ADHD
patients compared to controls was in right lenticular nucleus,
including the caudate. A meta-regression analysis, however,
showed that the grey matter volume size was associated with
age, with volumes becoming progressively more normal in
older patients, resulting in a normalisation in the adult
subgroup. A meta-regression analysis on the effect of psy-
chostimulants showed that the morphological deficit was
associated with medication status, so that studies that included
a high proportion of stimulant-medicated patients no longer
showed the basal ganglia abnormalities (Nakao et al., in press).
3.2. Functional imaging studies
Functional magnetic resonance imaging (fMRI) studies have
provided evidence for the fronto-striatal deficit hypothesis of
ADHD in addition to providing evidence for wider deficits.
Thus, children with ADHD have shown underactivation rela-
tive to controls in the DLPFC/IFC, ACC, caudate, supplemen-
tary motor area (SMA) as well as in temporo-parietal cortices
during motor response inhibition (Booth et al., 2005; Durston
et al., 2003, 2006; Epstein et al., 2007; Pliszka et al., 2006;
Rubia et al., 1999, 2005, 2008, 2010b; Smith et al., 2006;
Suskauer et al., 2008a, 2008b), interference inhibition
(Konrad et al., 2006; Rubia et al., 2009b, 2011; Vaidya et al.,
2005) as well as during vigilant, selective and flexible atten-
tion (Rubia et al., 2009b, 2009c, 2009d, 2010a, 2010b, 2011, in
press; Smith et al., 2006; Stevens et al., 2007; Tamm et al.,
2004, 2006; for meta-analysis and review see Dickstein et al.,
2006; and Rubia, 2010, respectively). Furthermore, during
tasks involving temporal processing, children with ADHD
have shown reduced activation compared to controls in dorsal
and ventrolateral prefrontal cortex, SMA, ACC and cerebellum
(Durston et al., 2007; Rubia et al., 1999, 2001, 2009a; Smith
et al., 2008; Vloet et al., 2010). Using “hot” EF tasks, abnormal
activation has been observed in children with ADHD relative
to healthy controls in ventral striatum (VS) during reward
anticipation (Scheres et al., 2007), in ventrolateral
fronto-striato-thalamo-parieto-cerebellar network during
a temporal discounting task (Rubia et al., 2009a), in precuneus,
PCC (Rubia et al., 2009c) and in OFC, temporal regions and
cerebellum during rewarded trials within a Continuous
Performance Task (CPT) (Rubia et al., 2009d). Very few fMRI
studies have tested for neurofunctional deficits during
emotion processing in ADHD. During fearful facial expression
processing, children with ADHD compared to healthy controls
have shown either no differences in brain activation (Marsh
et al., 2008) or enhanced activation in the amygdala
(Brotman et al., 2010), and during visualisation of negative
arousing pictures reduced activation was observed in insula,
basal ganglia and thalamus (Herpertz et al., 2008).
Fewer fMRI studies have been conducted in adult ADHD,
and findings are more inconsistent. This is likely due to the
impact of confounding factors, more pronounced in adult
compared to childhood ADHD imaging studies, such as small
sample sizes, high rates of comorbidity, long-term medication
history and the need for a retrospective diagnosis of ADHD in
childhood (Cubillo and Rubia, 2010). Adults with ADHD have
shown underactivation compared to controls in OFC, IFC,
DLPFC, ACC, striatal, premotor, parietal and cerebellar brain
regions during motor and interference inhibition (Banich et al.,
2009; Burgess et al., 2010; Bush et al., 1999; Cubillo et al., 2010, in
press; Epstein et al., 2007; Schneider et al., 2010), inhibition of
memories (Depue et al., 2010a), working memory (Hale et al.,
2007; Valera et al., 2005, 2010a; Wolf et al., 2009), cognitive
switching (Cubillo et al., 2010; Dibbets et al., 2010) and senso-
rimotor timing (Valera et al., 2010b). Other studies, however,
observed increased activation in medial frontal, DLPFC, pre-
motor, parietal and occipital cortices during inhibitory and
working memory tasks (Banich et al., 2009; Dibbets et al., 2009,
2010; Epstein et al., 2007; Hale et al., 2007; Schneider et al., 2010;
for a review see Cubillo and Rubia, 2010). Functional abnor-
malities during reward-related tasks have been observed in
adults with ADHD in OFC and limbic regions. Thus, patients
compared to controls showed underactivation in VS during
gain anticipation in a monetary incentive delay task, but
increased activation in IFC, OFC, DLPFC and striatum during
gain outcome (Ströhle et al., 2008). During temporal discount-
ing, reduced activation was found in VS and amygdala during
immediate choices whereas increased striatal and amygdala
activations were observed during delayed choices (Plichta
et al., 2009). During emotion processing tasks, medication-
naı̈ve adults with ADHD compared to healthy controls showed
underactivation in VS in response to unexpected positive
versus neutral pictures, and in subgenual cingulate in
response to unexpected negative versus neutral pictures
(Schlochtermeier et al., in press). Furthermore, symptom
severity has been found to be negatively correlated with key
fronto-striato-thalamic, temporo-parietal and cerebellar
regions, thus overlapping with areas observed to be under-
activated during motor and interference inhibition, switching
and working memory tasks (Cubillo et al., 2010, in press; Depue
et al., 2010b; Valera et al., 2010a).
3.3. Functional connectivity
Recent evidence from functional connectivity fMRI studies
demonstrates that the functional abnormalities in ADHD not
only affect isolated brain regions but also the functional inter-
regional interconnectivity between these regions. Thus,
during the resting state, children and adults with ADHD
showed reduced functional connectivity relative to healthy
controls in fronto-striatal, cingulate, fronto-parietal, temporo-
parietal and fronto-cerebellar networks (Cao et al., 2006, 2009;
 c o r t e x 4 8 ( 2 0 1 2 ) 1 9 4 e2 1 5
Castellanos et al., 2008; Konrad et al., 2010; Uddin et al., 2008;
Zang et al., 2007; for review see Konrad and Eickhoff, 2010).
Some studies, however, also reported increased inter-regional
connectivity between ACC, striatum and temporo-cerebellar
regions (Tian et al., 2006; Wang et al., 2009; Zang et al., 2007;
Zhu et al., 2005). Reduced functional connectivity has been
observed in the context of cognitive tasks in children with
ADHD relative to controls between IFC and the basal ganglia,
parietal lobes and cerebellum, and between cerebellum,
parietal and striatal brain regions during sustained attention
(Rubia et al., 2009d), interference inhibition and time estima-
tion (Vloet et al., 2010).
In adults with ADHD, deficits in functional inter-regional
connectivity relative to healthy controls were observed
between right and left IFC, and between the right IFC and
other areas including basal ganglia, cingulate, parieto-
temporal and cerebellar regions during motor response inhi-
bition and working memory (Cubillo et al., 2010; Wolf et al.,
2009). In adults, however, there is also additional evidence
for compensatory increased connectivity between ACC,
superior frontal lobe and cerebellum (Wolf et al., 2009).
3.4. Conclusions
Neuropsychological evidence shows that children and adults
with ADHD are impaired in “cool” as well as “hot” EF. Struc-
tural and functional imaging studies show that these abnor-
malities in cognitive control are mediated by abnormalities in
lateral inferior and dorsolateral prefrontal as well as some
medial frontal regions such as rostral ACC and SMA and their
regional interconnections with striatal, cerebellar, and
parieto-temporal areas. Weaknesses in motivation control as
measured in “hot” EF appear to be related to lateral orbito-
frontal and ventromedial prefrontal regions and their associ-
ated ventral striatal and limbic areas. While studies in
children with ADHD are more numerous and consistent, the
emerging evidence from imaging studies in adult ADHD
suggests that the structural and functional brain abnormali-
ties observed in children with ADHD persist into adult ADHD
in those who do not grow out of the disorder.
4. New data: lateral inferior fronto-striatal
and orbitofrontal-ventromedial brain
dysfunction in adults with childhood ADHD and
persistent hyperactive/inattentive behaviours
during sustained attention and reward
Despite the reported persistence of inattention problems in
adult ADHD (Biederman et al., 2000), and consistent evidence
for deficits in adult ADHD in tasks of sustained and selective
attention such as the CPT (Hervey et al., 2004; Marchetta et al.,
2008), few studies in adults with ADHD have focused on the
neuroimaging correlates of sustained and selective attention
functions. A few fMRI studies in adult ADHD have
co-measured higher executive selective attention functions
embedded within cognitive control tasks such as conflict
detection tasks or flexible attention during tasks of cognitive
flexibility. These studies show that adults with ADHD
compared to healthy controls have underactivation in
197
IFC/DLPFC, caudate (Cubillo et al., in press) and ACC (Burgess
et al., 2010; Bush et al., 1999) during selective attention/
conflict inhibition in interference inhibition tasks, and
decreased inferior fronto-striatal and parietal activation
during flexible attention in cognitive switching tasks (Cubillo
et al., 2010; Dibbets et al., 2010). However, hardly any studies
have tested for neurofunctional deficits during tasks that are
purposely designed to measure selective and sustained
attention such as continuous performance or target detection
tasks. Given that deficits in sustained attention as measured
in the CPT are one of the most consistent findings of the child
and adult ADHD literature (Epstein et al., 2001; Hervey et al.,
2004; Marchetta et al., 2008; Willcutt et al., 2005), it is
surprising that no fMRI study in adult ADHD has tested the
neurofunctional correlates of this function. Furthermore, the
findings between fMRI studies of the reward system in adults
with ADHD are inconsistent. While functional abnormalities
in ADHD adults relative to controls were observed in similar
regions across studies, in particular in VS, amygdala and
VMPFC/OFC cortex, the direction of some of these dysfunc-
tions have been different. For example, some studies observed
OFC underactivation (Dibbets et al., 2009) while others
observed OFC overactivation (Ströhle et al., 2008). The incon-
sistent results are likely due to typical confounds in adult
ADHD imaging studies, such as small sample sizes, previous
medication history, presence of comorbidities and retrospec-
tive diagnosis of ADHD in childhood (Cubillo and Rubia, 2010).
To avoid these confounds, we recruited medication-naı̈ve
adults from an ongoing longitudinal study, with a confirmed
diagnosis of childhood ADHD, who were followed up 20 years
into adulthood, where they showed persistent symptoms of
inattention/hyperactivity. We aimed to investigate the neural
correlates of the interaction between “hot”, motivational and
“cool” cognitive processes within a rewarded CPT task that
measured the effect of reward upon sustained attention.
Furthermore, we aimed to investigate whether these adult
patients present similar functional abnormalities as those
observed previously in children with ADHD during the same
task (Rubia et al., 2009c, 2009d). Motivation is particularly
relevant for attention processes and motivation and attention
are hence closely interrelated. Reward and enhanced arousal
states have shown to potentiate selective (Engelmann and
Pessoa, 2007; Krawczyk et al., 2007; Lang et al., 1990;
Rothermund et al., 2001) and sustained attention functions
(Tomporowski and Tinsley, 1996). Functional MRI studies have
demonstrated that motivation in the form of reward can
enhance activation within brain regions that mediate arousal
and selective attention such as ventrolateral prefrontal, pari-
etal and PCC cortices (Lang et al., 1990; Mohanty et al., 2008;
Pochon et al., 2002; Rothermund et al., 2001; Small et al.,
2005). Furthermore, we have shown that in healthy adoles-
cents and adults, reward within the CPT task further upre-
gulates the same inferior fronto-striatal and temporo-parietal
regions that mediate sustained attention under the non-
rewarded condition (Smith et al., 2011). In healthy children
and adults, sustained attention in the same and similar tasks
activates inferior frontal, striatal, temporal and parietal
regions and cerebellum (Lawrence et al., 2003; Smith et al.,
2011; Tana et al., 2010; Voisin et al., 2006) and elicits under-
activation in these regions in children with ADHD (Rubia et al.,
198 c o r t e x 4 8 ( 2 0 1 2 ) 1 9 4 e2 1 5

2009c, 2009d). During the rewarded condition, healthy adults
activate VMPFC/OFC, ACC, striatal and temporo-parietal
regions (Smith et al., 2011), while children with ADHD show
abnormal activation relative to controls in PCC and precuneus
(Rubia et al., 2009c), cerebellum, OFC and temporal regions
(Rubia et al., 2009d).
We hypothesised that medication-naı̈ve adults with
a confirmed childhood diagnosis of ADHD and persistent
hyperactive/inattentive behaviours in adulthood would show
reduced activation relative to healthy controls in lateral IFC,
striatal, temporo-parietal and cerebellar brain regions during
sustained attention, and abnormal function in OFC, VMPFC
and VS during reward, similar to the dysfunctions previously
observed in children with ADHD during the same task and in
adult ADHD during similar tasks.
4.1. Methods
4.1.1. Subjects
The patient group and the diagnostic procedures have been
described previously (Cubillo et al., 2010, in press). In brief,
patients were 11 male right-handed adults (mean age
(years) ¼ 29, standard deviation (SD) ¼ 1, age range ¼ 26e30),
recruited from a 20-year prospective longitudinal epidemio-
logical study (Taylor et al., 1991). Six and 7 years old school
children were initially assessed (Taylor et al., 1991). Those
who met criteria for hyperactive/inattentive behaviour
according to both teacher and parent rating scales were fol-
lowed up, and re-assessed at age 16e18 years (Danckaerts
et al., 2000; Taylor et al., 1996) and 26e30 years (Stringaris
et al., in press). The subjects for this paper had also met
criteria for ADDH, which the DSM-III diagnosis was at the time
corresponding to the contemporary ADHD.
The assessment in this 20 years follow-up included (i)
Schedule for Affective Disorders and Schizophrenia (SADS)
(Endicott and Spitzer, 1978), (ii) Adult Personality Functioning
Assessment (APFA) (Hill et al., 1989), (iii) Self-reported check-
list of the DSM-IV items comprising the criteria for ADHD, (iv)
Adult Hyperactivity Interview (AHI) (Stringaris et al., in press),
developed for this project which defines symptoms in terms
appropriate to adulthood. The scale ranges from 0 to 24. A
score >10 is associated with poor social functioning (Stringaris
et al., in press). A diagnostic conference was held for each
case, chaired by an experienced child psychiatrist (ET). All
relevant DSM-IV diagnoses were reviewed, including ADHD
(Table 1), which required four of the DSM-IV criteria for inat-
tentiveness, hyperactivity-impulsiveness or both, significant
functional impairment, and a score >10 on the AHI. As the
diagnostic process was blind to childhood status, the age of
onset (before age 7) criteria was not included. All subjects met
DSM-IV diagnostic criteria for ADHD, except for three who had
subthreshold symptoms, coded in DSM-IV as “ADHD in partial
remission”. Like previous studies in adults with ADHD (i.e.,
Valera et al., 2010b), we decided to include these subjects,
taking into account the age-related decrease in hyperactivity/
impulsivity symptoms (Biederman et al., 2000), and the fact
that remission defined in DSM-IV refers to fewer symptoms
than required and not to functional improvement, which has
been criticised not to reflect adult characteristics of ADHD
(Faraone et al., 2000). There was no evidence for a selection
bias, since the scanned adults did not differ from the rest of
the group in their childhood measures of IQ, classroom or
home hyperactivity symptoms, conduct disturbance or
emotional problems [F(7,82)<1, p ¼ n.s.].
Several patients presented a current Axis I comorbid
diagnosis: Anxiety (n ¼ 1), Mood (n ¼ 3), Conduct (n ¼ 1) and
non-stimulant Substance Related Disorders (n ¼ 2; Cannabis,
Alcohol), although only one subject had suffered enough
impairment to attend specialists services.
Controls were 15 adult right-handed age-matched males of
average intellectual ability, recruited through advertisement
in the community (mean age ¼ 28, SD ¼ 3). Exclusion criteria
for controls were present or past history of any mental
disorder, substance abuse or psychotropic medication.
Neurological abnormalities were exclusion criteria for all
subjects. All participants scored above cut-off on the Raven’s
Standard Progressive Matrices Intelligence Questionnaire
(Raven, 1960) (i.e., over 75; fifth percentile) (Converted IQ
estimate: Controls: mean IQ ¼ 108, SD ¼ 12, Patients: mean
IQ ¼ 92, SD ¼ 10). One-way analyses of variance (ANOVAs)
showed that the groups did not differ significantly in age
[F (1,23) ¼ 1.67, p ¼ n.s.], but in IQ estimate [F(1,23) ¼ 13.18,
p ¼ .001]. Since low IQ is associated with ADHD both in
children and adults (Bridgett and Walker, 2006; Crosbie and

Table 1 e Description of symptoms for adults with childhood ADHD and persistent hyperactivity/inattention symptoms.

Childhood diagnosis AHI scores Hyperactivity symptomsa Inattention symptomsa ADHD DSM-IV criteria

ADHD hyp þ CD 19 3 3 YES-combined

ADHD combined 24 3 3 YES-combined
ADHD hyp þ CD 24 3 3 YES-combined
ADHD combined 10 0 1 NO-inattentive symptoms
ADHD hyp þ CD 13 0 1 NO-inattentive symptoms
ADHD hyp 16 0 1 NO-inattentive symptoms
ADHD combined þ CD 10 2 1 YES-predominantly Hyperactive
CD þ ADHD hyp 18 2 3 YES-combined
ADHD combined 14 3 3 YES-combined
ADHD combined 25 3 1 YES-predominantly Hyperactive
ADHD hyp þ CD 14 2 2 YES-combined

Note: ADHD hyp ¼ ADHD hyperactive subtype.

a 3 ¼ level of problem impairing function and deserving diagnosis; 2 ¼ definite problem; 1 ¼ moderate problem; 0 ¼ no problem.
 c o r t e x 4 8 ( 2 0 1 2 ) 1 9 4 e2 1 5
Schachar, 2001), covarying for IQ would not be appropriate
(Miller and Chapman, 2001), while matching groups for IQ
would create unrepresentative groups (Dennis et al., 2009).
Therefore, as suggested by some authors (Bridgett and
Walker, 2006), fMRI data were analysed with and without IQ
as a covariate to assess the impact of IQ.
The study was approved by the local ethics committee and
written informed consent was obtained from all participants.
4.1.2. fMRI paradigm: rewarded CPT
A rapid, mixed trial, event related fMRI design was used with
jittered inter-trial-intervals (ITI) and randomised presentation
to optimise statistical efficiency. Subjects practised the task
once prior to scanning.
In the CPT task, subjects have to detect and respond with
a button press to infrequent targets that are embedded in
highly frequent non-targets that require no action and can
therefore be simply being ignored. The difficulty of the task
therefore consists in detecting the rare targets. The task
measures selective and sustained attention and target detec-
tion (Conners, 1993). The computerised fMRI adaptation of the
rewarded CPT (Rubia et al., 2009c, 2009d; Schmitz et al., 2008;
Smith et al., 2011) consists of a stream of 416 stimuli (letters) of
300 milliseconds (msec) presentation time each (mean ITI:
900 msec), including 48 target stimuli, the letters “X” (24) and
“O” (24) and 368 non-target letters (A, B, C, D, E, F, G, H, K, L, M,
N) (30 or 31 each). There are hence 11.5% target letters that are
randomly interspersed with 88.5% non-target letters. Each
letter had a presentation time of 300 msec and each of the 24
target letters ‘X’ and ‘O’ were separated in the stream by at
least 5400 msec and at most 9000 msec to allow for separa-
bility of haemodynamic response. Subjects have to respond
with the right hand button box to target letters only (X and O)
and ignore all other letters. One of the target letters was
rewarded (£1 for every three correct responses) and the
amount of money earned during the task (£8 for 100% correct
responses) was displayed throughout the task on the right
screen side by one of two differently coloured rising score-
bars (red/blue). Which target letter was rewarded and which
was not rewarded was counterbalanced across subjects.
Next to the letter frame two feedback bars appeared on
screen at all times with ascending panels numbered from 1 to
8, one of which indicated the accumulation of correct
responses to X (coloured red) and the other, the number of
correct responses to O (coloured blue). These feedback bars
would flash for each correct response to their associated letter
and on every third successful hit would move upwards to fill
a panel with colour. In the case of the rewarded feedback bar
each filled panel signalled to the participant that they had
made three successful responses to a rewarded letter and had
won a £1; in the case of the non-rewarded feedback bar this
signalled to the participant that they had made three
successful responses to the non-rewarded letter with no
associated winnings. It was emphasised to the subject which
feedback panel informed them of the accumulation of their
monetary reward (as well as providing feedback) and which
bar gave them feedback about the number of successful non-
rewarded targets. Since there were 24 rewarded target trials
there was a maximum of £8 to win. Regardless of their ex-
pected winnings, all participants were given this sum at the
199
end of the scanning session. Single letters were chosen as
targets rather than complex letter combinations (CPT-AX) to
reduce the load on working memory (Rubia et al., 2009c;
Schmitz et al., 2008) (Fig. 1).
For the fMRI analysis the contrast between non-rewarded
target trials and non-target trials measures the brain
response to sustained attention and will be labelled “sus-
tained attention contrast”. The contrast between rewarded
and non-rewarded target trials measures the effect of reward
upon sustained attention functions and will be labelled
“reward contrast”.
4.1.3. Analysis of performance data
Repeated measures multiple two-way ANOVAs were per-
formed with group (adult ADHD; healthy controls) as
a between subjects factor and trial type (non-rewarded;
rewarded) as within subjects factor for the dependent vari-
ables of omission errors and reaction time (RT). Commission
errors (responses to non-targets) were compared using
a t-test.
4.1.4. fMRI image acquisition and analyses
Gradient-echo echoplanar MR imaging (EPI) data were
acquired on a GE Signa 1.5T Horizon LX System (General Elec-
tric, Milwaukee, WI, USA) at the Maudsley Hospital, London.
Consistent image quality was ensured by a semi-automated
quality control procedure. A quadrature birdcage head coil
was used for RF transmission and reception. In each of 16 non-
contiguous planes parallel to the anterioreposterior commis-
sural, 208 T2*-weighted MR images depicting Blood Oxygen
Fig. 1 e Schematic illustration of the Rewarded Continuous
Performance Test. Response required to “X” or “O”, not to
any other letters. Reward is given for each response to one
of the two target letters (which letter was rewarded was
randomised across subjects). Red/blue bars indicate correct
responses to targets (X/O). Three correct responses make
one score on the bar for the rewarded and non-rewarded
targets, but only the rewarded target scores are
remunerated with £1. Up to £8 can be won on the task.
200 c o r t e x 4 8 ( 2 0 1 2 ) 1 9 4 e2 1 5
Level Dependent (BOLD) contrast covering the whole brain
were acquired with TE ¼ 40 msec, TR ¼ 1.8 sec, flip angle ¼ 90 ,
in-plane resolution ¼ 3.1 mm, slice thickness ¼ 7 mm, slice-
skip ¼ .7 mm. This EPI dataset provided complete brain
coverage.
For fMRI analysis, the software package of XBAM was used
(www.brainmap.co.uk, Brammer et al., 1997) that uses median
statistics to control outlier effects and permutation rather
than normal theory based inference, recommended for fMRI
(Thirion et al., 2007).
fMRI data were realigned to minimise motion-related
artefacts (Bullmore et al., 1999) and smoothed using
a Gaussian filter (full-width half maximum, 7.2 mm). Time-
series analysis of individual subject activation was per-
formed using XBAM, with a wavelet-based re-sampling
method previously described (Bullmore et al., 2001). Briefly, we
first convolved each experimental condition (i.e., rewarded
and non-rewarded target trials vs the implicit baseline of non-
target trials) with two Poisson model functions (delays of 4
and 8 sec). Only correct trials were included in the analyses.
We then calculated the weighted sum of these two convolu-
tions that gave the best fit (least-squares) to the time series at
each voxel. A goodness-of-fit statistic (the SSQ-ratio) was then
computed at each voxel consisting of the ratio of the sum of
squares of deviations from the mean intensity value due to
the model (fitted time series) divided by the sum of squares
due to the residuals (original time series minus model time
series). The appropriate null distribution for assessing signif-
icance of any given SSQ-ratio was established using the
wavelet-based data re-sampling method (Bullmore et al., 2001)
and applying the model-fitting process to the re-sampled data.
This process was repeated 20 times at each voxel and the data
combined over all voxels, resulting in 20 null parametric maps
of SSQ-ratio for each subject, which were combined to give the
overall null distribution of SSQ-ratio. The same permutation
strategy was applied at each voxel to preserve spatial corre-
lation structure in the data. Activated voxels, at a <1 level of
Type I error, were identified through the appropriate critical
value of the SSQ-ratio from the null distribution. The first
contrast involved subtracting activation associated with non-
target trials (implicit baseline) from the non-rewarded target
trials (non-rewarded target trials- non-target trials),
measuring sustained attention. The second contrast sub-
tracted activation from non-rewarded target trials from
rewarded target trials (rewarded e non-rewarded target
trials), measuring effects of reward upon sustained attention.
A group activation map was then produced for the exper-
imental conditions by calculating the median observed
SSQ-ratio over all subjects at each voxel in standard space and
testing them against the null distribution of median
SSQ-ratios computed from the identically transformed
wavelet re-sampled data (Brammer et al., 1997). The voxel-
level threshold was first set to p < .05 to give maximum
sensitivity and to avoid type II errors. Next, a cluster-level
threshold was computed for the resulting 3D voxel clusters
such that the final expected number of type I error clusters
was <1 per whole brain. Cluster mass rather than a cluster
extent threshold was used, to minimise discrimination
against possible small, strongly responding foci of activation
(Bullmore et al., 1999). For the group activation analyses, less
than one false positive activation locus was expected for
p < .05 at voxel level and p < .01 at cluster level. ANOVA
analysis for between-group differences was conducted using
randomisation-based test for voxel or cluster-wise differences
(Bullmore et al., 1999). Less than 1 false activated cluster was
expected at a p-value of p < .05 for voxel and p < .01 for cluster
comparisons. Thus, an expected cluster-level type I error rate
of <1 per brain was achieved by first applying a voxel-level
threshold of p < .05 followed by thresholding the 3D clusters
formed from the voxels that survived this initial step at
a cluster-level threshold of p < .01. The cluster-level threshold
of p < .01, was therefore not applied to the whole brain (which
would be lenient) but rather to the data previously thresh-
olded at a voxel-wise level of p < .05. The necessary combi-
nation of voxel and cluster-level thresholds is not assumed
from theory but rather determined by direct permutation for
each data set. White matter regions were extracted from
analyses using the BET tool from the FSL software package
(Smith, 2002). This creates a grey matter mask of the Talairach
template used for normalisation. This mask was subsequently
used to restrict the analysis to those voxels lying within grey
matter.
In order to test whether the between-group differences in
brain activation were related to performance differences,
statistical measures of BOLD response for each participant
were extracted in each of the clusters of between-group
differences for the sustained attention and reward contrasts.
These BOLD measures were then correlated within each group
with RT using Pearson correlations, and with commission
errors using Spearman’s rho, given the non-parametric nature
of these.
4.2. Results
4.2.1. Task performance
Repeated measures ANOVA showed that there was no effect
of reward on omission errors or RT within each group or
reward by group interactions (see Table 2). However, patients
showed significantly reduced mean RT to targets (whether
rewarded or not) [F(1,23) ¼ 6, p ¼ .01], and a trend for an
increased number of commission errors [t(23) ¼ 2, p ¼ .08],
suggesting a different speed-accuracy trade-off, favouring
speed.
Table 2 e Performance data for adults with childhood
ADHD and persistent hyperactivity/inattention
symptoms and healthy comparison adults.
Performance variable Controls ADHD
(N ¼ 14) (N ¼ 11)
Mean (SD) Mean (SD)
a
Rewarded trials MRT (msec) 420 (48) 382 (42)
Non-rewarded trials MRT (msec)a 422 (39) 388 (43)
Rewarded trials omission errors 0 (1) 0 (0)
Non-rewarded trials omission errors 0 (1) 0 (0)
Commission errors 1(1) 2 (2)
MRT ¼ Mean Reaction Time.
a Significant between-groups differences.
 c o r t e x 4 8 ( 2 0 1 2 ) 1 9 4 e2 1 5 201

4.2.2. Brain activation
4.2.2.1. MOTION. Multivariate Analyses of Variance (MANOVA)
showed no between-group differences in any of the x, y, z
translation and rotation motion parameters [F(6, 18) ¼ 1,
p ¼ .44].
4.2.2.2. SUSTAINED ATTENTION: NON-REWARDED TARGET TRIALS
COMPARED TO NON-TARGET TRIALS. Within-group activation maps
for each group are shown in Fig. 2a and Supplementary Table
1a. Healthy control adults showed activation in IFC, ACC,
putamen and globus pallidus, PCC, primary motor cortex and
SMA, thalamus, temporal, parietal, and occipital cortices and
cerebellum. Adults with childhood ADHD showed activation
in IFC, medial and superior frontal cortices, ACC and PCC,
striatum, thalamus, temporal, parietal, and occipital cortices
and cerebellum.
The ANOVA comparison showed increased activation in
the control group during non-rewarded target compared to
non-target trials compared to adults with childhood ADHD in
three clusters, the largest in the left hemisphere including
IFC/insula reaching into pre-SMA and ACC, as well as deep
into caudate, putamen, globus pallidus, and thalamus, one
comprising right premotor and postcentral gyri, extending to
insula, putamen and thalamus, and one including right PCC,
precuneus, and parahippocampal gyrus (Fig. 3a, Table 3a). In
all these clusters, controls showed increased activation during
non-rewarded target trials relative to non-target trials, while
patients with ADHD showed decreased activation for this
contrast or increased activation during non-target trials rela-
tive to non-rewarded target trials. Effect sizes were large for all
these clusters, with Cohen’s d values between .77 and 1.09
(see Table 3a).
Patients compared to controls showed increased activation
in bilateral posterior brain regions comprising cerebellum,
PCC, precuneus, inferior and superior parietal cortices, and
occipital regions (Fig. 3a, Table 3a). This increased activation
was due to patients showing more activation than control
subjects in these regions during non-rewarded targets
compared non-target trials while controls showed either less
activation or deactivation for this contrast. Effect sizes were
large for all these clusters, with Cohen’s d values between 1.05
and 1.81 (see Table 3a).
Given evidence for inferior fronto-cerebellar neural
networks that mediate selective and sustained attention
(Arnsten and Rubia, in press; Smith et al., 2011; Tana et al.,
2010), we tested whether the increased cerebellar activation

Fig. 2 e Within group activation maps for controls and adults with childhood ADHD and persistent hyperactivity/inattention
symptoms. Axial sections showing within-group brain activation for the healthy comparison group and the adults with
childhood ADHD and persistent hyperactivity/inattention symptoms for the contrasts (a) Sustained attention:
non-rewarded target e non-target trials, (b) Reward: rewarded e non-rewarded target trials. Tailarach z-coordinates are
indicated for slice distance (in mm) from the intercommissural line.
202 c o r t e x 4 8 ( 2 0 1 2 ) 1 9 4 e2 1 5

Fig. 3 e Results of the ANOVA between-group difference analyses. Axial sections showing the ANOVA between-group
difference effects in brain activation between adults with persistent hyperactive/inattentive behaviours and childhood
ADHD for (a) Sustained attention: non-rewarded target e non-target trials contrast, and (b) Reward: rewarded e
non-rewarded target trials contrast. Tailarach z-coordinates are indicated for slice distance (in mm) from the
intercommissural line. Section (b) includes axial sections showing the ANOVA between-group difference effects in brain
activation for the Reward contrast between healthy controls and only those six adults with persistent hyperactive/
inattentive behaviours and childhood ADHD who also had comorbid childhood CD (N [ 6). Adults with persistent symptoms
in adulthood and with childhood ADHD without comorbid childhood CD showed no brain differences when compared to
controls. Tailarach z-coordinates are indicated for slice distance (in mm) from the intercommissural line.

observed in ADHD patients relative to controls was
a compensatory effect related to the reduced inferior fronto-
striatal activation. For this purpose, average scalar measures
of the BOLD response was extracted for each subject in three
of the clusters that differed between groups: in the large left
inferior fronto-striatal activation cluster and in the two cere-
bellar clusters in left lateral cerebellum and right cerebellar
vermis (see Table 3). Then Pearson correlations were calcu-
lated between the scalar measures of the BOLD response in
the left inferior frontal cluster and each of the two cerebellar
clusters, separately within ADHD and control patients. In the
group of adults with ADHD, significant negative correlations
were observed between the activation in left inferior frontal
cortex and in right cerebellar vermis (r ¼ .71, p < .01), as well
as between the activation in left inferior frontal cortex and left
lateral cerebellum (r ¼ .81, p < .01) (see Supplementary Fig. 1).
In healthy control subjects, there was a significant correlation
between activation in left inferior frontal cortex and left
lateral cerebellum (r ¼ .51, p < .03) (Supplementary Fig. 1),
whereas the correlation between the activation in left inferior
frontal cortex and right cerebellar vermis was not significant
(r ¼ .04, p ¼ n.s.).
When IQ was used as a covariate, the main findings
remained, at the same p-value of p < .05 for voxel and p < .01
for cluster comparisons, but with slightly smaller cluster
sizes.
In order to correlate clusters of between-group differences
with performance measures we also extracted average scalar
measures of the BOLD response for each cluster that differed
between groups and then conducted two-tailed Pearson
 c o r t e x 4 8 ( 2 0 1 2 ) 1 9 4 e2 1 5 203

Table 3 e Differences in brain activation between adults with childhood ADHD and healthy comparison adults.

Brain regions of activation Brodman Peak Talairach N of p Effect Sizes

area (BA) coordinates (x; y; z) voxels values (Cohen’s d )

(a) Sustained attention: non-rewarded target e non-target trials

C > ADHD
L inferior frontal/insula/premotor/putamen/globus pallidus/ 6/44/9/24/32 29; 4; 26 136 >.001 1.09
caudate/thalamus/insula/ACC/pre-SMA
R premotor/postcentral gyrus/insula/putamen 4/6/43 58; 4; 15 43 .004 .93
R PCC/precuneus/parahippocampal gyrus 18/19/31/7 11; 33; 20 64 .01 .77
ADHD > C
L inferior/superior parietal gyrus 40/7 43; 37; 42 28 .001 1.05
R inferior/superior parietal gyrus 40/7 47; 41; 42 109 .002 1.08
R þ L cuneus/precuneus/PCC 18/19/7/29/30 7; 74; 26 408 >.001 1.43
R vermis cerebellum/occipital/PCC 18/23/30/31 4; 67; 13 244 .003 1.43
L cerebellum/occipital/inferior temporal 19/18/37 25; 63; 13 309 >.001 1.81
(b) Reward: rewarded target e non-rewarded target trials
C > ADHD
R medial/superior frontal gyrus 10/46/9/8 36; 52; 15 140 .014 1.35
R ventromedial orbitofrontal 11/9/10 25; 48; 13 105 .011 1.24

N voxels ¼ number of voxels. L ¼ left; R ¼ right. The maps are thresholded to give less than 1 Type I error cluster per map.

correlations between those measures and performance vari-
ables within each group. There was a significant negative
correlation within the ADHD group between commission
errors (that were trend-wise increased in ADHD compared to
controls) and activation in the right PCC/precuneus activation
difference cluster (r ¼ .63, p < .03) (that was reduced in ADHD
patients relative to control). No significant correlation was
observed between activation in this cluster and commission
errors in the healthy adults group (r ¼ .06, p ¼ n.s.). However,
within the control subject group there was a positive corre-
lation between activation in this PCC/precuneus cluster and
RT (that was increased relative to patients) (r ¼ .65, p < .01),
whereas this correlation was not significant within the ADHD
group (r ¼ .03, p ¼ n.s.). RT also correlated negatively within
the healthy adults group with activation in right inferior
parietal lobe (that was decreased in controls relative to ADHD
patients) (r ¼ .65, p < .01). No significant correlation was
observed between RT and parietal activation within the ADHD
group (r ¼ .21, p ¼ n.s.). Differences between the correlations
observed within the two groups were only significant for the
correlation between RT and activation in parietal cortex
(z ¼ 2.16, p < .03) (Supplementary Fig. 1).
4.2.2.3. EFFECTS OF REWARD: REWARDED TARGETS COMPARED TO NON-
REWARDED TARGET TRIALS. Within-group activation maps for
each group are shown in Fig. 2b and Supplementary Table 1b.
Healthy adults showed activation in OFC, IFC, medial frontal
lobe, striatum, ACC, SMA, insula, thalamus, amygdala,
temporal, parietal and occipital cortices and cerebellum.
Adults with childhood ADHD showed activation in IFC, medial
frontal regions, ACC and PCC, SMA, striatum, thalamus,
insula, temporal, parietal, occipital cortices and cerebellum.
The ANOVA comparison showed increased activation in
the control group compared to adults with childhood ADHD in
two clusters, one comprising right OFC and VMPFC and
a second one including right medial and superior frontal
cortices (Fig. 3b, Table 3b). No areas of increased activation
were detected for the patient group when compared to
controls. The group differences were due to an increased
activation in these clusters for controls during the rewar-
dedenon-rewarded target contrast, while ADHD patients
showed increased activation in these regions during non-
rewarded target compared to rewarded target trials. No
brain regions were increased in adults with childhood ADHD
compared to controls. The effect sizes were large (Cohen’s
d ¼ 1.35 and 1.24) (see Table 3b).
When covarying for IQ at a p-value of p < .05 for voxel and
at a more lenient p < .03 for cluster comparisons, the findings
remained essentially unchanged. No significant correlations
were observed between brain activation in these clusters and
performance measures.
Given that patients with CD have been shown to have
consistent functional and structural abnormalities in ventro-
medial and orbitofrontal cortices (Rubia, 2010); and, further-
more, that ventromedial orbitofrontal activation (in a similar
location to this one) has been shown to be disorder-
specifically underactivated in children with CD compared to
children with ADHD during the same reward contrast of this
CPT task (Rubia et al., 2009c), we tested for the potential
impact of the presence of comorbid CD in childhood on the
functional brain activation abnormalities. For this purpose,
two exploratory between-group ANOVAs were conducted,
comparing brain activation during the reward condition in
controls (N ¼ 14) with activation in the subsample of patients
with additional comorbid CD in childhood (N ¼ 6), and with
the activation observed in patients without comorbid CD in
childhood (N ¼ 5). Less than 1 false activated cluster was ex-
pected at a p-value of p < .05 for voxel and p < .01 for cluster
comparisons.
The subgroup of patients with comorbid CD in childhood
when compared to controls showed underactivation in one
large cluster, comprising the same regions as previously
observed in the whole group, in bilateral OFC/VMPFC and
superior frontal cortices, including ACC and reaching deep
into left caudate (Fig. 3b). Despite the small sample size, the
effect size was large (Cohen’s d ¼ 2.8). No areas of increased
204 c o r t e x 4 8 ( 2 0 1 2 ) 1 9 4 e2 1 5
activation in ADHD patients with comorbid CD compared to
controls were observed. The subgroup of ADHD patients
without comorbid CD, however, showed no differences in
brain activation when compared to controls.
4.3. Discussion
Medication-naı̈ve adults with a confirmed diagnosis of child-
hood hyperactivity who displayed persistent ADHD symp-
toms in adulthood showed reduced activation compared to
healthy controls in lateral fronto-striatal and superior parietal
regions during “cool” sustained attention processes and in
paralimbic VMPFC/OFC areas during “hot” reward-associated
functions. Subsequent exploratory analyses furthermore
showed that the VMPFC/OFC underactivation was observed
only in those adults who had comorbid CD in childhood.
During sustained attention, adults with ADHD seemed to
compensate with cerebellar overactivation, which correlated
negatively with the underactivation observed in IFC. The
reduced activation in PCC, furthermore, appeared to be asso-
ciated with a more impulsive performance style, as it was
negatively associated with commission errors in patients but
positively with slower RTs in controls.
For the sustained attention contrast, ADHD patients
showed reduced activation in key areas of sustained atten-
tion, in IFC, striatum, thalamus, anterior insula and PCC
(Lawrence et al., 2003; Tana et al., 2010; Voisin et al., 2006). IFC-
striatal underactivation has previously been observed in adult
ADHD during inhibitory and attention processes (Banich et al.,
2009; Cubillo et al., 2010, in press; Depue et al., 2010a; Dibbets
et al., 2010; Epstein et al., 2007; for review see Cubillo and
Rubia, 2010). IFC dysfunction during cognitive tasks is one of
the most consistent fMRI findings in children with ADHD
(Booth et al., 2005; Durston et al., 2006; Konrad et al., 2006;
Pliszka et al., 2006; Rubia et al., 1999, 2001, 2005, 2008; Smith
et al., 2006; Vaidya et al., 2005; for review see Rubia, 2010),
and has been shown to be disorder-specific compared to
children with CD (Rubia et al., 2008, 2009b, 2009c, 2010a) and
OCD (Rubia et al., 2010b, 2011; for review see Rubia, 2010). The
findings thus show that the key abnormality of IFC dysfunc-
tion in childhood ADHD, which may potentially be a disorder-
specific neurofunctional biomarker, persists into adulthood.
The underactivation findings in ACC is in line with
previous fMRI findings in adults with ADHD during tasks of
interference inhibition (Banich et al., 2009; Burgess et al., 2010;
Bush et al., 1999; Cubillo et al., in press), motor response
inhibition (Cubillo et al., 2010) and working memory (Valera
et al., 2010a) and may be associated with the generic role of
this area in output related attention functions (MacDonald
et al., 2000; Ridderinkhof et al., 2003).
The observed underactivation in the group of adults with
ADHD extended to pre-SMA. Reduced activation in SMA and
pre-SMA has previously observed in children with ADHD
during tasks of cognitive control such as sustained (Rubia et al.,
2009d) and selective attention in conflict tasks (Rubia et al.,
2011, in press), attentional switching (Rubia et al., 2010b), as
well as motor response inhibition (Suskauer et al., 2008a, 2008b;
Tamm et al., 2004). It has also been found to be underactivated
during motor and perceptual temporal processes (Rubia et al.,
1999; Smith et al., 2008). In the same group of adults with
ADHD studied here, we observed underactivation in the SMA
during motor response inhibition (Cubillo et al., 2010).
However, increased activation in the SMA has also been
observed in children with ADHD after failed motor response
inhibition (Spinelli et al., in press) and in adults with ADHD
during an attentional switching task (Dibbets et al., 2010). The
pre-SMA has been shown to be involved in sustained attention
in healthy adults (Lawrence et al., 2003; Tana et al., 2010) and to
have a role in motor response preparation and selection as well
as motor response inhibition (Mostofsky and Simmonds, 2008;
Sharp et al., 2010; Simmonds et al., 2008; Tabu et al., in press).
The pre-SMA in particular has been associated with free
response selection as well as attention processes such as
attention to intention and attention to action (Lau et al., 2004a,
2004b). The abnormal activation in ADHD adults during this
target detection task may hence reflect abnormalities in exec-
utive attention and response selection networks.
ADHD patients, on the other hand, showed increased
activation in several posterior brain regions, comprising
lateral and medial cerebellum, PCC, parietal and occipital
areas. The enhanced activation in cerebellar regions is likely
to be compensatory, as it correlated negatively with the
(reduced) activation in inferior frontal regions in both patients
and controls. The cerebellum as part of fronto-cerebellar
neural networks (Arnsten and Rubia, in press) is involved in
higher cognitive processes (Steinlin, 2007), including sus-
tained attention (Lawrence et al., 2003; Voisin et al., 2006). The
underactivation in the frontal parts of this network in patients
may hence have triggered a compensatory activation increase
in the cerebellum. Functional abnormalities in the cerebellum
have previously been observed in adults with ADHD during
other functions that involve attention such as working
memory and timing (Valera et al., 2005, 2010a, 2010b; Wolf
et al., 2009). The PCC together with the ACC forms part of
the midline attention network, and mediates visualespatial
attention to saliency (Mesulam et al., 2001; Mohanty et al.,
2008; Small et al., 2003), whereas precuneus has been
predominantly associated with voluntary attention shifting
and directed spatial attention (Cavanna and Trimble, 2006).
The PCC and precuneus are typically reduced in activation in
children with ADHD during salient stimuli such as stop errors
(Rubia et al., 2005, 2008), oddball or incongruent targets (Rubia
et al., 2007b, 2009b, 2011; Tamm et al., 2006), rare targets in
sustained attention tasks (Rubia et al., 2009c) as well as during
a motor delay task (Rubia et al., 1999).
The pattern of underactivation in IFC and striatum
together with enhanced activation in cerebellar and occipital
brain regions are strikingly similar to that we have previously
observed in children with ADHD relative to the healthy
controls during the same rewarded sustained attention task
(Rubia et al., 2009c, 2009d) (see Fig. 4). These findings of similar
brain under- and overactivation during the same task in
children and adults with ADHD relative to their respective
age-matched controls support the notion of a continuity of
dysfunctions that are typically observed in children with
ADHD into adult ADHD.
During the rewarded relative to the non-rewarded sus-
tained attention condition, adults with ADHD showed reduced
activation in paralimbic VMPFC and OFC regions, key areas of
reward processing, which are typically activated in this task
 c o r t e x 4 8 ( 2 0 1 2 ) 1 9 4 e2 1 5 205

Fig. 4 e Similarities in reduced and increased brain activation in medication-naı̈ve adults with childhood ADHD and
persistent hyperactivity/inattention symptoms relative to their age-matched controls and in medication-naı̈ve children
with ADHD during the Sustained Attention condition compared to their respective age-matched healthy comparison
subjects.

(Smith et al., 2011). The lateral OFC mediates stimulus-
reinforcement learning (Baxter and Murray, 2002;
Schoenbaum et al., 2006). The VMPFC is associated specifi-
cally with reward as opposed to punishmentedriven
processes (Christakou et al., 2009; Knutson et al., 2003;
O’Doherty, 2004; Windmann et al., 2006). Furthermore, the
lateral and VMPFC/OFC modulate interconnected paralimbic
brain regions and mediate topedown affect regulation that is
typically weak in disorders of impulsiveness and aggression
(Davidson et al., 2000a, 2000b; Haber, 2008; Haber et al., 2006;
Catani et al., 2012; Thiebaut de Schotten et al., 2012). These
networks of affect regulation and motivation are
typically involved in “hot” EF (Zelazo and Muller, 2002).
The underactivation in OFC cortex during the reward
contrast in adult ADHD is in line with the underactivation
finding by Dibbets et al. (2009) in adults with ADHD in bilateral
IFC/OFC during positive feedback during a motor inhibition
task. However, it is not in line with finding of increased acti-
vation in OFC in adults with ADHD during reward outcome
(Ströhle et al., 2008). We argue that underactivation in OFC may
potentially be associated with the presence of CD comorbidity,
given that children with CD relative to healthy controls typi-
cally show underactivation in VMPFC/OFC (Rubia, 2010).
Furthermore, this region has been shown to be disorder-
specifically underactivated in children with pure CD relative
to pure ADHD and control children during the reward compo-
nent of the same task (Rubia et al., 2009c). In this sample, six
subjects had comorbid CD in childhood, although it only per-
sisted into adulthood in one case. Our exploratory analysis
supported this hypothesis of an association between CD and
206 c o r t e x 4 8 ( 2 0 1 2 ) 1 9 4 e2 1 5
OFC dysfunction. Only those patients with ADHD with comor-
bid CD in childhood showed underactivation in VMPFC/OFC
regions compared to healthy controls during the reward aspect
of the task, while patients without comorbid CD in childhood
showed no abnormalities in this condition (Fig. 3). The findings
hence suggest that comorbid CD in childhood may have
accounted for the OFC/VMPFC abnormalities, despite the
symptomatic improvement of CD symptoms in adulthood.
Previous studies of ADHD in adulthood did not assess or report
the presence of comorbid CD in childhood. Presence or absence
of comorbid CD thus could potentially explain the differences
in OFC findings across studies (Sundram et al., 2012). Our
findings of a significant impact of childhood CD on reward-
associated functional brain activation in OFC/VMPFC stresses
the importance of assessing childhood CD in addition to
childhood ADHD in studies of adult ADHD.
The data thus provide additional evidence for dysfunctions
in overlapping “cool” attention and “hot” motivation brain
networks in a group of adult patients with ADHD who were
followed up from childhood. However, potential caveats of
a relatively small sample size, of IQ differences and of the
potential impact of CD comorbidity on the OFC deficit findings
need to be taken into consideration. The findings of lateral
fronto-striatal deficits during “cool” EF, however, are in line
with previous fronto-striatal deficit findings in the same group
of patients during other “cool” EF, including motor and inter-
ference inhibition, cognitive switching and oddball detection
(Cubillo et al., 2010, in press). Across all tasks, these adults
with childhood ADHD showed underactivation in inferior
Fig. 5 e Reduced brain activation in adults with childhood ADHD relative to healthy controls across a series of cognitive
tasks in fMRI. For details on images a, b, eeg see Cubillo et al., 2010, in press.
prefrontal cortex and the basal ganglia (Fig. 5). However, the
exact location of the inferior prefrontal location differed
between tasks and task conditions. During motor inhibition,
switching and sustained attention, the location was in
predominantly right hemispheric or bilateral deep inferior
prefrontal junction reaching into insula, in line with the
known role of the right IFC in inhibitory control and sustained
attention processes (Derrfuss et al., 2005; Rubia et al., 2003,
2007c; Voisin et al., 2006). During an interference inhibition
and oddball tasks, the location was exclusively left hemi-
spheric and in a more superior, dorsolateral prefrontal loca-
tion and included also ACC, in line with evidence implicating
left DLPFC and ACC in conflict monitoring (MacDonald et al.,
2000). In line with the role of ventromedial orbitofrontal
cortex with emotional-driven action selection and reward
processing (Bechara et al., 2000; Kringelbach, 2005), this loca-
tion was underactivated in adult ADHD patients during the
only “hot” EF, the reward contrast in the sustained attention
task. Furthermore, this activation may have been due to
comorbid childhood CD rather than ADHD. With respect to the
basal ganglia deficits, the inhibition tasks (motor and inter-
ference inhibition) elicited reduced activation in the caudate
in the group of ADHD adults, while during sustained and
flexible attention the putamen was also underactivated, in
line with fronto-caudate implications in cognitive control
(Aron et al., 2007; Rubia et al., 2007c) and putamen involve-
ment in attention functions (Adler et al., 2001).
The underactivation observed in caudate and putamen
across tasks (Cubillo et al., 2010, in press) suggests persistent
 c o r t e x 4 8 ( 2 0 1 2 ) 1 9 4 e2 1 5
striatal dysfunctions in adults with symptoms of ADHD. This is
neither in line with longitudinal findings of structural caudate
normalisation in young ADHD adulthood (Castellanos et al.,
2002) nor with our meta-regression analysis showing that the
caudate normalises with age (Nakao et al., in press). However, it
is in line with caudate and putamen abnormality findings from
recent cross-sectional structural (Almeida Montes et al., 2010;
Seidman et al., 2011) and functional (Epstein et al., 2007;
Schneider et al., 2010) imaging studies in adults with ADHD.
As discussed above, the SMA was underactivated during both
sustained attention and successful inhibition (Cubillo et al.,
2010), in line with the role of this region in both motor
response inhibition and attention to response (Lau et al., 2004a,
2004b; Mostofsky and Simmonds, 2008; Sharp et al., 2010;
Simmonds et al., 2008; Tabu et al., in press). Overall, the find-
ings show that across tasks, including “cool” and “hot” EF as well
as simple (oddball task) and higher level executive attention
functions (interference inhibition and sustained attention
tasks), adults with childhood ADHD have deficits in their acti-
vation of fronto-striatal neural networks. However, the exact
location of frontal and striatal dysfunctions is task-dependent,
with dorsolateral fronto-striatal deficits during cognitive
control and selective attention, inferior fronto-striatal
dysfunctions during inhibitory control and sustained atten-
tion and ventromedial orbitofrontal deficits during reward
processing. The findings suggest that overlapping fronto-
striatal neural networks, mediating both “cool” attentional
and cognitive control as well “hot” motivation processes may be
dysfunctional in ADHD, in line with models of multisystem
dysfunctions in ADHD (Makris et al., 2009; Nigg and Casey, 2005).
The findings have to be interpreted in light of some limi-
tations. One is the small sample size. Large numbers were
difficult to obtain due to factors inherent to long-term follow-
up studies: many patients grew out of the disorder, changed
their geographic area, making contact impossible, or refused
to participate in the scanning study. Despite the small sample
size, however, we observed significant differences in brain
activation between cases and controls, which are consistent
with previous findings. Furthermore, the effect sizes for the
between-group findings were relatively large.
The presence of comorbid conditions constitutes another
limitation. However, comorbidity is extremely common with
up to 87% both in children (Blackman et al., 2005; Kadesjo and
Gillberg, 2001; Spencer, 2006) and in adults with ADHD
(Biederman et al., 2006; Kessler et al., 2006; Sobanski et al.,
2007), most commonly mood (40e61%), substance related
(15e70%), and anxiety disorders (30e47%) (Kessler et al., 2006;
Miller et al., 2007; Sobanski et al., 2007, 2008; Wilens et al.,
2009). Pure cases are therefore the rare exception, and the
selection of an ADHD group without any psychiatric comor-
bidities would not be representative for ADHD in adulthood
(Biederman et al., 2006), since it would only include subjects
with milder forms of the disorder, or of higher functioning.
That is also the reason why most previous fMRI studies of
adult ADHD have typically included samples with comorbid
psychiatric disorders (Dibbets et al., 2009; Epstein et al., 2007;
Hale et al., 2007; Valera et al., 2010a).
The groups differed significantly in IQ. However, given the
association between low IQ and ADHD, matching for IQ would
create unrepresentative groups. The similarity in the findings
207
with and without IQ as covariate, however, suggests that the
observed dysfunctions are associated with the disorder and
not IQ.
A common problem with fMRI adaptations of CPT tasks is
that motor responses to targets are not controlled for since
a motor response to non-targets would place unwanted atten-
tion demands. While this does not affect the reward contrast
that was well controlled, this could have affected the sustained
attention contrast. Thus, some activation differences between
groups for this contrast could potentially be motor- rather than
purely attention-related, such as the differences in premotor
and SMA regions. The majority of ANOVA findings, however,
were not in motor regions. Inferior prefrontal, cingulate and
striato-thalamic activation for example that was reduced in
activation in ADHD adults, is known to mediate sustaining
attention in motor-controlled vigilance and parametric sus-
tained attention tasks (Lawrence et al., 2003; Voisin et al., 2006).
A key strength of this study is the medication-naivety of
patients, which allowed us to avoid the common confound of
the long-term effects of stimulant medication history on brain
function. This, together with the clearly established presence
of hyperactivity during childhood, which avoids the potential
recall bias present in retrospective diagnosis (Mannuzza et al.,
2002), make this a valuable sample. Additionally, the
enhanced homogeneity of the sample by the inclusion of
males only, and a restricted age range, helped us to avoid the
confounding effects of gender and age.
In conclusion, we observed that medication-naı̈ve adults
who were known to have ADHD symptoms in childhood and
persistent inattention/hyperactivity symptoms in adult life
showed “cool” attention-related inferior fronto-striatal brain
dysfunctions as well as presumably compensatory hyper-
activation in cerebellum, strikingly similar to previous find-
ings in adolescents with ADHD. We also observed abnormal
brain function in “hot” reward-related EF, with reduced par-
alimbic VMPFC/OFC activation during rewarded sustained
attention trials. However, these lateral OFC and VMPFC acti-
vation dysfunctions were only present in those subjects with
comorbid CD during childhood, suggesting that childhood CD
problems may have accounted for these. The findings stress
the importance for assessing CD in childhood and for testing
their impact on brain deficits. Overall, the findings therefore
suggest that attention and motivation-related lateral and
ventromedial fronto-striatal brain abnormalities observed in
children with ADHD may persist into adulthood, despite
a relative symptomatic improvement.
5. Overall conclusions
We show in this review that structural and functional imaging
studies provide evidence for abnormalities in children and
adults with ADHD both in lateral inferior/dorsolateral and
dorsomedial fronto-striatal, fronto-parietal and fronto-
cerebellar neural networks that mediate “cool” abstract-
cognitive EF, including higher level motor, attention, and
temporal processes, as well as in lateral orbitofrontal and
ventromedial networks that mediate “hot” motivation control
functions, all of which are behaviourally and cognitively
compromised in the disorder. We furthermore provide new
208 c o r t e x 4 8 ( 2 0 1 2 ) 1 9 4 e2 1 5

functional imaging evidence in support of the notion of the
adult persistence of dysfunctions previously observed in chil-
dren with ADHD. Medication-naı̈ve adults with hyperactive/
inattentive behaviours, followed up from a confirmed presence
of ADHD symptoms in childhood, showed underactivation in
both “cool” and “hot” lateral inferior fronto-striatal and
ventromedial fronto-striatal networks involved in sustained
attention and motivation, respectively, in association with
a more impulsive performance style. The findings were similar
to those previously observed in the same group of adults during
other cognitive functions. They were furthermore strikingly
similar to those findings previously observed in childhood
ADHD during the same tasks and hence are in support of our
reviewed evidence that adults with ADHD continue to show the
same abnormalities in lateral fronto-striato-parietal and
fronto-cerebellar cognitive control networks as well as in
ventromedial fronto-striatal and fronto-temporo-limbic
networks during motivation control as children with ADHD.
The review together with the new data therefore suggest that
childhood and adult ADHD, as a group, are characterised by the
impairment of several overlapping neural networks, affecting
fronto-subcortical, fronto-cortical and fronto-cerebellar neural
circuitries that mediate “cool” attention and cognitive control
functions as well as fronto-temporo-limbic neural networks of
affect and motivation control (see schematic Fig. 6). The “cool”
neural circuitries furthermore are known to interact closely
with the “hot” neural circuitries (Goel and Dolan, 2003; Krain
et al., 2006). The findings are therefore in line with previously
suggested concepts of multiple neural system impairment in
ADHD associated with the different motor, attention, cognitive
control and motivational processes that are impaired in the
disorder (Makris et al., 2009; Nigg and Casey, 2005).
There are, however, several potential caveats in the imaging
literature of ADHD that need to be considered. The majority of
structural and functional imaging studies in children and adults
with ADHD have not excluded comorbidity with conduct
disorder (CD)/antisocial personality disorder. We have shown
in a previous review that antisocial behaviours are associated
with abnormalities in neural networks of the paralimbic system
that mediate affect and motivation (i.e., “hot” EF), comprising
ventromedial frontal cortex, superior temporal lobe and
underlying limbic structures (Rubia, 2010). Furthermore,
abnormalities in these paralimbic regions appear to be
disorder-specific when compared with non-comorbid ADHD
patients, while “cool” EF lateral inferior fronto-cortical and
fronto-subcortical networks appear to be disorder-specific in
non-comorbid ADHD patients relative to pure CD cases (Rubia,
2010). While some ADHD patients, in particular those with
emotion dysregulation or irritability, or comorbid emotional
and antisocial problems, are likely to suffer from abnormalities
in both “cool” and “hot” EF neurocircuitries, it is possible that
pure, non-comorbid ADHD groups may only be impaired in
“cool” EF brain systems. In adult ADHD, the majority of imaging
studies have included high rates of comorbid cases with

Fig. 6 e Schematic representation of the MRI evidence for structural and functional brain abnormalities in children and
adults with ADHD in overlapping neural networks that mediate “cool” cognitive-abstract and “hot” reward-associated
executive and cognitive functions. “Cool” cognitive networks of dysfunction in ADHD include inferior, dorsolateral and
medial fronto-striatal, fronto-parieto-temporal and fronto-cerebellar regions and networks that mediate functions such
as motor response and interference inhibition, cognitive flexibility, temporal foresight, selective and sustained attention,
working memory, motor and timing processes. “Hot” EF network dysfunctions in ADHD patients have been observed in
the context of temporal discounting, reward processing and reward anticipation. IFG [ inferior frontal gyrus;
OFC [ orbitofrontal cortex; DLPFC [ dorsolateral prefrontal cortex; vmOFC [ ventromedial orbitofrontal cortex;
d/vACC [ dorsal/ventral ACC cortex; SMA [ Supplementary Motor Area.
 c o r t e x 4 8 ( 2 0 1 2 ) 1 9 4 e2 1 5
emotional and affective problems. Our findings of no orbito-
frontal deficits in adults with ADHD without antisocial prob-
lems in the reward condition would be in line with the notion
that some ADHD patients, who have no association with anti-
social or affective behaviours, may not share affective circuit
impairment. This would also be in line with meta-analysis
studies of whole brain structural imaging studies that do not
find fronto-limbic but predominantly basal ganglia impair-
ments both in children with ADHD (Ellison-Wright et al., 2008)
and across the lifespan (Nakao et al., in press). On the other
hand, however, there has been a bias in structural MRI studies
of ADHD towards the selection of regions of interest that
mediate “cool” cognitive functions or fMRI paradigms of
abstractecognitive control. Only relatively recent structural
and functional imaging studies have focussed their interest on
limbic regions and on fMRI tasks of motivation and affect
control. More imaging studies of ADHD are needed that focus on
limbic regions and limbic white matter networks as well as
emotional fMRI paradigms to assess more thoroughly to what
degree these systems are affected in ADHD and their subgroups.
A limitation of the field is furthermore the fact that most
imaging studies are based on group statistics on relatively
small numbers. This applies particularly to the adult imaging
literature. There are as yet few studies that tested for neural
networks in subgroups of ADHD patients. There is likely to be
heterogeneity in neural network impairments between ADHD
patients and subgroups, similar to the observed heterogeneity
in neuropsychological impairments (Nigg et al., 2005; Sonuga-
Barke et al., 2010). Thus, some children may have no brain
abnormalities, while others may have abnormalities in
specific fronto-striatal circuitries of specific “cool” EF, timing,
motor and/or attention functions, and yet others may suffer
from dysfunctions in fronto-limbic emotion/motivation
circuits or in both, overlapping cognitive and affective neu-
rocircuitries. This would be in line with the notion of ADHD as
a multisystem developmental disorder, where the clinical
expression is based on the degree and heterogeneity of the
neural system dysfunction (Makris et al., 2009).
An important confound in the majority of adult ADHD
imaging studies is long-term medication history. Our recent
meta-regression analysis showed that basal ganglia abnor-
malities were correlated with the percentage of medication-
naı̈ve patients included in the studies (Nakao et al., in press).
This would suggest that the current literature, mostly con-
ducted in adult ADHD patients with a medication history,
shows a more lenient deficit picture from what would be
observed in untreated patients. The findings of striking simi-
larities in functional deficits between our previously scanned
medication-naı̈ve ADHD children and the here presented
medication-naı̈ve adults with ADHD are in line with this and
suggest that deficit findings may be more similar when
medication-naı̈ve patients are being compared.
It also remains to be investigated to what degree ADHD is
a delay of normal brain structure or function maturation.
Overall, the cross-sectional findings from the different imaging
modalities suggest that ADHD children have deficits in the very
brain regions, functions and functional and structural neural
networks that develop late between childhood and adulthood
(Geier and Luna, 2009; Giedd et al., 2001; Konrad and Eickhoff,
2010; Makris et al., 2009). Longitudinal imaging studies have
209
demonstrated a delay in cortical thickness maturation in
children with ADHD (Shaw et al., 2007). Unfortunately, these
studies have not scanned ADHD patients beyond the age of 20.
If a delay is defined as a maturational lag that normalises
eventually with age (i.e., catches up), then this seems not to
apply to ADHD, given that similar brain structure, function and
structural and functional interconnectivity deficits are still
observed in adults with ADHD in cross-sectional imaging
studies. One possible exception may be basal ganglia struc-
tures, where there is some evidence for normalisation from
longitudinal (Castellanos et al., 2002) and meta-regression
studies (Nakao et al., in press). The findings of persisting
brain abnormalities in adult ADHD seem to suggest that the
maturational “delay”, if it is a “delay” persists throughout adult
life. Also, to our knowledge, no imaging studies have been
conducted in elderly patients with ADHD, but there may well be
differences in normal ageing processes too. Future longitudinal
structural and functional imaging studies will be needed to
elucidate whether there is a structural and functional matu-
rational delay in ADHD patients that persists throughout the
lifespan or whether this normalises at any given age. Such
studies should also test for different factors that may influence
a potential normalisation process, including symptom
severity, environmental factors, cognitive faculties, genetic
predisposition or pharmacological and behavioural treatment.
Acknowledgements
The research was supported by grants from the Medical
Research Council (G9900839) and The Wellcome Trust (053272/
Z/98/Z/JRS/JP/JAT). AC and ABS were supported by PHD
studentship/post-doctoral fellowships by the National Insti-
tute for Health Research (NIHR) Biomedical Research Centre
(BRC) for Mental Health at the South London and Maudsley
NHS Foundation Trust (SLaM) and the Institute of Psychiatry
at King’s College, London.
Supplementary data
Supplementary data related to this article can be found online
at doi:10.1016/j.cortex.2011.04.007.
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