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Imaging the ADHD brain: Disorder-specificity, medication effects and clinical

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Article  in  Expert Review of Neurotherapeutics · April 2014

DOI: 10.1586/14737175.2014.907526 · Source: PubMed

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 Review

Imaging the ADHD brain:

disorder-specificity,
medication effects and
clinical translation
Expert Review of Neurotherapeutics Downloaded from informahealthcare.com by Nandini Loganathan on 04/25/14

Expert Rev. Neurother. 14(5), 519–538 (2014)

Katya Rubia*,
Analucia Alegria and
Helen Brinson
Department of Child and Adolescent
Psychiatry, Institute of Psychiatry,
King’s College London, London, UK
*Author for correspondence:
Tel.: +44 207 848 0463
Fax: +44 207 848 0866
For personal use only.
A plethora of magnetic resonance imaging studies have shown that ADHD is characterized by
multiple functional and structural neural network abnormalities beyond the classical fronto-striatal
model, including fronto-parieto-temporal, fronto-cerebellar and even fronto-limbic networks.
There is evidence for a maturational delay in brain structure development which likely extends to
brain function and structural and functional connectivity, but this needs corroboration by
longitudinal imaging studies. Dysfunction of the ventrolateral prefrontal cortex seems to be more
pronounced relative to other pediatric disorders and is also the most consistent target of acute
psychostimulant medication. Future studies are likely to focus on using neuroimaging for clinical

katya.rubia@kcl.ac.uk translation such as for individual diagnostic and prognostic classification and as a neurotherapy to
reverse brain function abnormalities.

KEYWORDS: atomoxetine • attention deficit hyperactivity disorder • autism spectrum disorder • bipolar disorder
• conduct disorder • diffusion tensor imaging • functional magnetic resonance imaging • methylphenidate • MRI
• obsessive-compulsive disorder • psychostimulants

Attention deficit hyperactivity disorder (ADHD)
is characterized by symptoms of age-inappropriate
inattention, hyperactivity and impulsivity [1].
ADHD is one of the most common childhood
psychiatric disorders affecting 3–8% of school-age
children with 65% of cases persisting into adult-
hood [2]. Throughout the lifetime, ADHD has
been associated with adverse outcomes including
academic failure, psychosocial impairment, addi-
tional psychiatric comorbidities [2] and lower qual-
ity of life [3]. ADHD patients have deficits
in higher level cognitive functions necessary for
goal-directed behaviors, the so-called ‘executive
functions’ (EFs), which are known to be mediated
by late developing fronto-striato-parietal and
fronto-cerebellar networks [4]. The most consistent
deficits are in the so-called ‘cool’ EF such as motor
response inhibition, working memory, sustained
attention and cognitive switching [5–7]. However,
there is also consistent evidence for deficits in tem-
poral processing (e.g., motor timing, time estima-
tion and temporal foresight), with most consistent
deficits in tasks of time discrimination and estima-
tion [8,9]. More recently, deficits have also been
observed in the so-called ‘hot’ EF such as reward-
related decision making, as measured in temporal
discounting and gambling tasks [7,9,10]. These
tasks, however, measure both motivation control
and temporal foresight and could reflect problems
in either or both functional domains.
Cross-sectional structural MRI studies
Region of interest studies
ADHD is the most imaged childhood disorder
with a large number of published structural
MRI (sMRI) studies. The vast majority of
sMRI studies, however, have used region of
interest (ROI) analyses, focusing on a priori
hypothesized regions, some of them using
uncorrected thresholds. Consequently, a large
array of not always replicated dysmorphology
findings have been reported, most typically of
reduced volumes, grey matter (GM) and/or
cortical thickness in the basal ganglia, the cere-
bellum, the frontal lobes (most prominently
the dorsolateral prefrontal cortex [DLPFC],
orbitofrontal [OFC], inferior frontal cortex
[IFC], medial prefrontal [MFC] and premotor
regions), anterior cingulate cortex (ACC), corpus
callosum, parieto-temporal and somatosensory

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 Review Rubia, Alegria & Brinson
areas (e.g., [11–13], for review, see [14]). A relatively older meta-
analyses of ROI sMRI studies in children with ADHD found
that relative to healthy controls, ADHD children had the most
consistent reductions in total and right cerebral volumes, in
the posterior inferior cerebellar vermis, the splenium and the
corpus callosum, right caudate and several prefrontal regions
[15]. These ROI-based meta-analytic findings by and large con-
firmed the notion that ADHD patients have deficits in fronto-
striatal and fronto-cerebellar regions that form the networks
that mediate the late developing EFs that are impaired in the
disorder [16]. While the majority of studies have tested for ROI
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deficits in frontal, striatal, corpus callosum and cerebellar
regions, a few recent ROI sMRI studies also found GM abnor-
malities in subcortical and limbic regions such as the insula [17],
amygdala [18] and thalamus [19].
Fewer sMRI studies have been published in adult ADHD
patients. These studies have reported more inconsistent, some-
times negative and overall more moderate structural abnormali-
ties in, however, relatively similar regions in prefrontal (IFC,
DLPFC, OFC), ACC and posterior cingulate cortex (PCC),
temporo-parietal and cerebellar regions, as well as in subcortical
limbic structures (e.g., [13,20–22]). The exceptions, however, are
in the basal ganglia, where the majority of adult ADHD studies
did not show dysmorphology findings (for review, see [14,23]).
For personal use only.
Whole-brain image analyses
Meta-analyses of whole-brain imaging studies have found the
most consistent abnormalities in the basal ganglia. While ROI
studies have their merits, they restrict the search to a priori
hypothesized regions that have been argued to be an unneces-
sarily restricted and biased approach [24]. Whole-brain imaging
analyses have the advantage that they do not bias the search
toward a priori hypothesized regions. Three meta-analyses are
published on the remarkably few whole-brain voxel-based mor-
phometry (VBM) MRI studies of ADHD that compared every
voxel in the brain between groups. The earliest VBM meta-
analysis in pediatric populations found the most consistent
reductions across 7 studies in 114 ADHD and 143 controls in
the GM of the right putamen and globus pallidus [25]. The
second meta-analysis of 14 VBM studies on a total of
378 ADHD children and adults and 344 controls showed that
the most significant volumetric reduction in ADHD was in the
right basal ganglia including putamen, globus pallidus and cau-
date [26]. The same GM dysmorphology in right putamen and
globus pallidus was also observed in the third meta-analysis of
11 VBM studies [27]. Both studies found age effects. The first
study found a linear meta-regression effect of age on GM vol-
umes that became progressively more normal with age, so that
the adult studies showed no significant differences [26]. The sec-
ond tested for a categorical age effect and found that only
ADHD children showed striatal deficits, while the ADHD
adults showed smaller ACC GM volumes [27]. These three
meta-analyses suggest that structural abnormalities in the basal
ganglia rather than the frontal lobes are the most consistent
deficits in ADHD. Given the extensive connections between
520
the basal ganglia and frontal regions [16], a primary deficit in
the basal ganglia, however, still would imply fronto-striatal cir-
cuit abnormalities in ADHD. The studies are paralleled by a
PET meta-analysis that showed reduced striatal dopamine
transporter levels in medication-naı̈ve ADHD patients [28]. The
only enhanced GM volume in the meta-analysis of Nakao
et al. [26] in ADHD patients relative to controls was in the pre-
cuneus, which is part of the default mode network (DMN).
The DMN consists of intercorrelated coactivation of medial
frontal lobe, anterior and posterior cingulate and inferior tem-
poral and parietal areas during rest that are parametrically attenu-
ated during cognitive load, presumably reflecting increases in
attentional and computational resources that impinge upon
task-unrelated thoughts and processes. The DMN is therefore
thought to reflect self-referential and stimulus-independent
thought processes that need to be switched off for successful cog-
nitive functioning, which is shown by increased attentional lapses
being associated with failure to inhibit the DMN [29]. ADHD
patients have shown to have more attentional lapses and attenu-
ated deactivation of the DMN during attention tasks [30–32].
The enlarged volume size may hence potentially be a plastic
consequence of enhanced DMN activation (i.e., diminished
deactivation).
Studies of cortical thickness, a brain morphometric measure
used to describe the combined thickness of the layers of the
cerebral cortex, have also observed abnormalities, most promi-
nently in frontal and parieto-temporal brain regions [33–37].
In conclusion, the most consistent abnormality in ADHD
patients based on whole-brain cross-sectional studies is reduced
GM in the basal ganglia, with additional evidence for abnormal
GM and cortical thickness abnormalities in frontal, temporal and
cerebellar regions based on ROI studies, with some evidence that
basal ganglia deficits may be normal in adult ADHD.
Longitudinal studies: developmental delay of brain
maturation
It has been argued since the 1970s that ADHD children may
be suffering from a delayed brain maturation due to their rela-
tively immature behaviors in behavioral features that diminish
naturally with age such as impulsiveness and inattention and
their deficits in late developing cognitive functions that are
mediated by late developing fronto-striatal and fronto-cerebellar
systems [4]. The first direct evidence for a developmental delay
in ADHD was provided by the seminal longitudinal imaging
studies from the National Institute for Mental Health, which
showed that 232 ADHD patients relative to 232 healthy con-
trols, both of which were scanned up to 4 times between
10 and 17 years, have a delay in the peak of cortical thickness
and surface area. Both cortical thickness and surface area
increase between childhood and adolescence due to synaptic
and axonal branching but then decrease again after a peak of
about age 7 and 13 years, respectively, presumably related to
synaptic pruning and myelination. In children with ADHD,
the peak of cortical thickness and surface area was delayed by
2–5 years, with the most prominent delay in frontal, superior
Expert Rev. Neurother. 14(5), (2014)

temporal and parietal regions [13,38]. The findings showed for
the first time that in ADHD, there is in fact a delayed matura-
tion of structural brain development.
Diffusion tensor imaging studies
Diffusion tensor imaging (DTI) studies allow the mapping of
the diffusion process of molecules, mainly water, in the brain,
which can reflect white matter (WM) fibers, and thus WM
microstructure integrity, by measuring fractional anisotropy
(FA), given that water diffuses more easily alongside fibers than
perpendicular to fiber tracts.
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Pediatric studies
DTI studies have shown that ADHD patients have deficits not
only in isolated brain regions but also in the WM microstruc-
ture integrity between these regions, most prominently in
fronto-striatal, fronto-parietal and fronto-cerebellar WM tracts.
A recent meta-analysis of nine DTI studies using whole-brain
analyses, most of them conducted in children with ADHD
with the exception of one adult study, showed reduced WM
microstructure integrity in a total of 173 ADHD patients rela-
tive to 169 healthy controls, aged 7–49 years, as measured in
FA, in several fronto-striato-cerebellar WM tracts. The affected
WM tracts included the right anterior corona radiata, likely
For personal use only.
containing fibers from the superior longitudinal fasciculus, the
left cerebellar WM, the internal capsule, forceps minor close to
the genu of the corpus callosum and the cingulum [39]. Abnor-
malities in the anterior thalamic radiation, forceps minor and
superior longitudinal fasciculus, furthermore, were also
observed in healthy siblings of ADHD boys, suggesting that
this may be an endophenotype of the disorder [40]. A study
combining DTI and graph theory analysis to investigate the
topological organization of whole-brain WM networks showed
that ADHD boys had decreased connectional properties in the
left parietal, frontal and occipital cortices with decreased FA in
the prefrontal-dominant circuitries and increased FA in OFC–
striatal circuitries, which furthermore correlated with the inat-
tention and hyperactivity/impulsivity symptoms, respectively [41].
The findings suggest abnormalities in several fronto-striatal,
fronto-parieto-temporal and fronto-cerebellar WM tracts. Con-
sistent with the hypothesis that ADHD is associated with a
maturational developmental delay, a slower development of
WM fiber tracts has been observed in the caudate nucleus over
adolescence in ADHD which eventually appeared to catch up
to normal levels by the age of 18 years [42]. In addition, two
studies that tested for microstructure integrity in a range of
WM tracts found almost all WM tracts to be attenuated in
ADHD [43,44] which suggests a possible global delay in WM
tract development in ADHD.
Adult studies
Relatively fewer DTI studies are published in adult ADHD.
Studies found similar abnormalities as in children with ADHD,
most prominently in fronto-striatal and fronto-cingulate WM
tracts [45,46], but also in corpus callosum [47] and temporal WM
informahealthcare.com
Imaging the ADHD brain Review
tracts [48]. A recent larger study in 51 adult ADHD patients, who
had been followed up from childhood ADHD, thus avoiding
recall bias, showed significantly reduced WM connectivity in
similar WM tracts as in the meta-analysis based mostly on pedi-
atric studies [39], that is, in the right superior and posterior corona
radiata, right superior longitudinal fasciculus, in left posterior
thalamic radiation, the retrolenticular part of the internal capsule
and the sagittal striatum [22]. Furthermore, the deficits were inde-
pendent of their remission status with remitters and persisters of
childhood ADHD having the same WM tract abnormalities [22].
Another DTI study has extended these structural findings to
show that the extent of FA abnormality in specific areas was
directly related to behavioral performance with lower FA of the
middle cerebellar peduncle predicting lower global cognitive
scores, lower FA of the internal capsule peduncle predicting
lower EF and lower FA of the posterior corona radiata predicting
lower attention scores [49].
Conclusion
Overall, the DTI findings in children and adults with ADHD
showed abnormalities in the microstructure of the WM in several
longer and shorter distance WM tracts, in particular of fronto-
striatal, fronto-cerebellar and fronto-parieto-temporal connec-
tions, suggesting reduced axonal branching or myelination. Most
of these WM tracts are relatively late developing tracts that
mature well into mid-adulthood [50] so that the ADHD-
associated attenuation in these connections could reflect a matu-
rational delay of WM tract development. This will, however,
have to be corroborated in longitudinal DTI studies.
Functional MRI studies
Functional MRI (fMRI) studies have provided consistent evi-
dence for fronto-striatal, fronto-parietal and fronto-cerebellar
deficits in ADHD during tasks of cognitive control. Further-
more, there is some emerging, but less consistent evidence for
fronto-limbic abnormalities in the context of reward processing.
Several meta-analyses of whole-brain fMRI studies of EF and
timing tasks have been published recently. They showed cogni-
tive domain-specific fronto-striatal, fronto-parietal and fronto-
cerebellar brain dysfunctions in ADHD. Thus, a meta-analysis
of 21 whole-brain fMRI studies of cognitive and motor inhibi-
tion, including 7 adult and 14 pediatric studies, showed that
287 ADHD patients relative to 320 healthy controls had con-
sistently reduced activation in key regions of motor response
inhibition, in right IFC, supplementary motor area (SMA),
ACC, left striatum and right thalamus (FIGURE 1A) [51]. When
inhibition tasks were split into motor response and interference
inhibition, the reduced activations were more prominently right
hemispheric and in the SMA for motor response inhibition,
while for tasks of interference inhibition, left ACC dysfunction
was more prominent in line with the prominent role of the
SMA for motor inhibition and the ACC for interference inhi-
bition, respectively [51]. A meta-analysis on attention tasks
included mostly 13 pediatric whole-brain fMRI studies on a
relatively wide range of attention tasks such as selective, divided
521
 Review Rubia, Alegria & Brinson

A Medial view: B Medial view: C Medial view:

Left Right Left Right

Thalamus Basal
Lateral view: Lateral view: ganglia Lateral view:
Basal ganglia
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Left Right Left Right

Figure 1. Three meta-analyses of functional MRI studies of ADHD patients for different cognitive domains. The meta-analyses
showed reduced activation in ADHD patients in several dissociated fronto-striatal and fronto-cerebellar networks during the respective
cognitive domains. (A) During inhibition functions, ADHD patients have reduced activation relative to healthy controls in the right ventral
inhibition network, in right IFC, ACC/SMA, basal ganglia and thalamus. (B) During attention tasks, ADHD patients have reduced activa-
tion relative to healthy controls in the right dorsal attention network, comprising DLPFC, posterior part of the basal ganglia and thalamus
and parietal regions. (C) During timing tasks, ADHD children have reduced activation in a predominantly left hemispheric timing network,
comprising left inferior frontal cortex, left inferior parietal lobe and right lateral cerebellum. In addition, ADHD patients have enhanced
activation in a default mode region, the posterior cingulate cortex.
ACC/SMA: Anterior cingulate cortex/supplementary motor area; ADHD: Attention deficit hyperactivity disorder; DLPFC: Dorsolateral
prefrontal cortex; IFC: Inferior frontal cortex.
For personal use only.

and sustained attention, as well as alerting and mental rotation
in 171 ADHD patients relative to 178 healthy controls. The
study found reduced activation in the right hemispheric dorsal
attention network, comprising the right DLPFC, right inferior
parietal cortex and caudal parts of the basal ganglia and thala-
mus. In addition, ADHD patients had increased activation rel-
ative to controls in right cerebellum and left cuneus,
presumably compensating for the reduced activation of the
frontal part of the dorsal DLPFC–parieto-cerebellar attention
network (FIGURE 1B) [51]. A meta-analysis of timing functions in
ADHD, including 11 fMRI studies of time discrimination,
time estimation, motor timing and temporal discounting (tem-
poral foresight), showed consistently reduced activation in
150 ADHD patients relative to 145 healthy controls in left
IFC, left inferior parietal lobe and the right lateral cerebel-
lum [31], all key regions of timing functions (FIGURE 1C) [52]. Inter-
estingly, the functional deficits during timing tasks were
predominantly left hemispheric, while the dysfunctions during
attention and inhibition functions were right hemispheric, in
line with the role of the right hemisphere for attention and
inhibition functions [53,54], but a more prominently left hemi-
spheric distribution for timing functions [52]. Also of note is
that the reduced activations in ADHD patients relative to their
age-matched peers were in brain regions that have shown to
increase in activation progressively between childhood and
adulthood during these motor inhibition, attention and timing
tasks [4]. This suggests that the pattern of activation in ADHD
patients is likely that of a younger relative to an older child,
which may be reflective of a delay in brain function matura-
tion, which would parallel a maturational delay in brain struc-
ture. Longitudinal fMRI studies, however, are needed to
corroborate this hypothesis. The timing meta-analysis in addi-
tion also showed increased activation in ADHD patients in
default mode regions, the PCC and precuneus (FIGURE 1C) [31].
This was also found in a parametric task design fMRI study
where ADHD adolescents, unlike controls, did not progres-
sively deactivate the precuneus with increasing attention load;
and furthermore, this was inversely associated with performance
and decreased fronto-striatal activation [30]. Problems to deacti-
vate the DMN have been associated with more attention lapses,
both in normal development and in ADHD [32] and could also
reflect a developmentally delayed stage in attention process-
ing [4]. Both the problematic deactivation of the DMN con-
comitant with poor activation of task relevant and age-
correlated brain activation may hence reflect a developmental
delay of brain function and both are likely underlying the poor
performance in ADHD on attention-demanding higher level
cognitive tasks.
Another recent meta-analysis across a range of EF, attention
and reward tasks was conducted on 55 whole-brain fMRI stud-
ies, including cognitive control and reward tasks, in 16 adult
and 39 pediatric studies and a total of 741 ADHD and
801 control subjects. No significant differences survived correc-
tions when findings were contrasted between adult and pediat-
ric samples, comorbid and noncomorbid or stimulant naı̈ve
and medicated ADHD children or between different tasks. The
meta-analysis showed significant reduced activation in ADHD
relative to controls in bilateral ventral attention (IFC, basal
ganglia) and predominantly right hemispheric fronto-temporo-
parietal networks including DLPFC/IFC, basal ganglia, thala-
mus, ACC and SMA. In addition, enhanced activation was
observed predominantly in default mode regions as well as in

522 Expert Rev. Neurother. 14(5), (2014)


visual and somatomotor regions [55]. The findings by and large
overlap with the above reviewed task domain-specific meta-
analyses [31,51]. Interestingly, the adult submeta-analysis showed
predominant abnormalities in the fronto-parietal attention sys-
tem in line with the behavioral persistence of attention deficits
in adult ADHD [55].
In addition to deficits in fronto-striatal and fronto-cerebellar
regions that mediate the so-called ‘cool’ EF, ADHD children
have also shown reduced activation in OFC–limbic regions
during tasks that tap into ‘hot’ EF such as reward processing or
reward-related decision making such as temporal discounting
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tasks. One of the most consistent findings has been that of
reduced ventral striatum activation in ADHD patients during
the anticipation of rewards. A recent meta-analysis of 8 ROI
fMRI studies of reward anticipation in 340 ADHD patients
and healthy controls, most of which used the same monetary
reward anticipation task, showed consistent reduced activation
of the ventral striatum in ADHD adults and children relative
to healthy controls with a medium effect size [10]. Other studies
have found abnormal activation in OFC in addition to ventral
striatum during temporal discounting [8,56] and during rewarded
trials within attention and inhibition tasks [57,58]. However,
some studies found abnormally enhanced [57,59] and others
reduced OFC activation during reward processing [8,14,58]. The
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inconsistent results are likely due to typical confounds in
ADHD imaging studies such as small sample sizes, previous
medication history and the presence of comorbidities, in partic-
ular conduct disorder (CD). CD has consistently been associ-
ated with OFC–limbic dysfunctions [5] that have been shown
to disappear in ADHD when comorbid CD patients were
excluded from the analysis [14]. Another important caveat is
that deficits in ventral striatum and most findings in OFC
have only been observed in ROI studies. Future large-scale
fMRI studies will have to confirm the presence of abnormalities
in these OFC–limbic–ventral striatal systems in whole-brain
image analyses.
Very few fMRI studies have tested for neurofunctional defi-
cits during emotion processing in ADHD, finding relatively
inconsistent results. During fearful facial expression processing,
children with ADHD compared with healthy controls showed
enhanced activation in the amygdala [60] as well as enhanced
functional connectivity (i.e., increased time series correlations
between the activation of both regions) between the amygdala
and left lateral prefrontal cortex, suggesting emotional hyperres-
ponsivity to negative emotions [61]. However, other studies
found no differences in brain activation to fearful faces [62] and
others found reduced activation in limbic regions during nega-
tive arousing pictures in the insula, basal ganglia and thala-
mus [63]. Medication-naı̈ve adults with ADHD had reduced
activation compared with healthy controls in the ventral stria-
tum in response to unexpected positive versus neutral pictures
and in subgenual cingulate in response to unexpected negative
versus neutral pictures [64].
In conclusion, there is relatively consistent evidence from
several meta-analyses of fMRI studies of ‘cool’ cognitive tasks
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Imaging the ADHD brain Review
that ADHD patients have cognitive domain-dissociated deficits
in several neural networks that mediate higher level cognitive
functions including different right and left hemispheric fronto-
striato-thalamic and fronto-parieto-cerebellar networks such as
IFC–ACC–striato-thalamic networks for inhibitory control
functions, right DLPFC–parieto-striato-cerebellar networks for
attention functions and left IFC–parieto-cerebellar networks for
timing functions (FIGURE 1) [31,51,55]. In addition, poor task-related
activation appears to be concomitant with poor deactivation of
the DMN and both are likely to underlie compromised perfor-
mance in ADHD. The findings point toward complex multi-
system impairments in several dorsal and ventral fronto-striato-
parietal and fronto-cerebellar networks that are likely underly-
ing the problems these patients have in several different cogni-
tive domains such as inhibition, attention and timing. In
addition, there is meta-analytic evidence for deficits in the
DMN, suggesting an abnormal interrelationship between hypo-
engaged task-positive cognitive networks and poorly ‘switched
off’ task-negative DMNs [31,51,55]. There is also some meta-
analytic evidence to suggest compensatory over-regulatory mech-
anisms in visual and somatomotor regions [31,51,55]. Finally, a
ROI meta-analysis of fMRI studies of reward processing tasks
suggests abnormalities in the ventral striatum in line with some
emerging evidence for abnormal OFC–limbic networks for
reward and emotion processing [10]. These ROI analysis-based
deficits, however, will need to be confirmed in future larger sam-
pled studies and whole-brain meta-analyses controlling for CD.
Functional connectivity studies
In addition to ADHD being characterized by deficits in the
function of specific frontal, striatal, temporo-parietal and cere-
bellar regions, a host of functional connectivity studies have
demonstrated that ADHD patients also have abnormalities in
the functional interregional connectivity between these brain
regions both during rest and during cognitive tasks [65]. Func-
tional connectivity measures the way in which brain activations
are related to each other. The simplest method is an analysis of
time series correlation between activated regions as it is
assumed that when regions are activated at the same time, and
hence their activation is intercorrelated, they are working
together and form part of a functional neural network.
Resting state functional connectivity
Functional connectivity is defined as the temporal correlation
or coherence of the activation of spatially remote brain regions.
It is assumed that areas that are activated at the same time, and
hence their time course of activation is synchronous and inter-
correlated, are working together and form part of the same
neurofunctional network. Resting state functional connectivity
fMRI methods, based on low frequency BOLD fluctuations,
measure intrinsic, spontaneous networks that are highly corre-
lated in the absence of external stimuli. The majority of
ADHD resting state functional connectivity studies have used
seed-based ROI correlation approaches that extract the time
series of specific ROIs and correlate these with all other voxels
523
 Review Rubia, Alegria & Brinson
of the brain. However, data-driven analyses that consider all
voxels simultaneously, such as independent component analysis,
graph theory and multivariate pattern recognition analyses, are
considered to be superior in sensitivity and specificity and thus
become more prevalent with the more recent resting state
fMRI studies in ADHD employing these methods.
During the resting state, several studies in ADHD children
have found reduced functional connectivity in the DMN,
mostly between ACC and PCC [66–68], as well as in fronto-
striato-thalamic, fronto-temporal and sensorimotor circuitries
[69,70]. A recent large-scale resting state fMRI study on data
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pooled across five institutions including 455 typically develop-
ing children and 193 ADHD children, of which 112 had
ADHD-combined type and 80 ADHD-inattentive type, showed
atypical functional connectivity patterns relative to controls in
sensorimotor regions in both groups, in line with the motor
deficits associated with the disorder [71]. However, subtype-
specific atypical patterns were also revealed with atypical
connectivity in the DMN being most predictive of the
ADHD-combined type, whereas atypical connectivity in bilat-
eral DLPFC and cerebellum was most predictive of the ADHD-
inattentive type [71]. Increased thalamic–putamen connectivity,
however, has also been observed, which furthermore was corre-
lated with worse performance on a spatial working memory
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task [72]. The findings from these functional connectivity studies
extend task-based fMRI studies by implicating abnormal DMN
and cortico-striatal–thalamic functional networks rather than iso-
lated regions in ADHD, which appear to contribute to the cog-
nitive and behavioral symptoms of ADHD.
In line with the pediatric findings, resting state functional
connectivity studies in adults with ADHD have also consis-
tently found reduced connectivity in the DMN [73,74] as well as
in task-relevant fronto-striatal, fronto-limbic and fronto-
temporal networks [75]. Furthermore, there is evidence for
stronger coherence of the DLPFC with DMN and reduced
anticorrelation between both, which is associated with attention
performance, suggesting a more diffuse connectivity between
functional networks in ADHD where both DMN intrudes dur-
ing attention-demanding contexts, and DLPFC signaling is
insufficiently suppressed in relation to DMN activity [76]. An
interesting recent study found a double dissociation between
attenuated OFC–ventral striatum–limbic functional connectiv-
ity and emotion dysregulation and DLPFC–striato-cingulo-
parietal functional connectivity abnormalities and poor EF [77].
Given that DMN mature progressively with increasing age
between childhood and adulthood [78] and are likely associated
with progressive cognitive maturation [4], it is possible that the
more immature functional connectivity in the DMN reflects
immature functional brain maturation. This hypothesis was
supported by a recent study that used multivariate pattern rec-
ognition analysis, specifically support vector machine (SVM)
learning, combined with resting state data and showed that the
resting state functional connectivity abnormalities that classified
ADHD adults relative to controls were similar to the pattern
observed in younger typically developing subjects, reinforcing
524
the notion of a maturational delay of DMN connectivity in
ADHD [79].
Functional connectivity during cognitive tasks
Task-specific functional connectivity fMRI studies in ADHD
have used either seed-based task-specific correlations of prede-
fined ROIs and independent component analysis methods or
effective connectivity methods, such as psychophysiological
interaction, structural equation modeling and Granger causal
modeling, which are hypothesis driven and measure changes in
interactions across brain activations in relation to different psy-
chological tasks and address questions of directional influences
of one activation cluster over another.
In children with ADHD, reduced functional connectivity
during motor response inhibition and working memory tasks
has been reported relative to healthy controls between the right
IFC and basal ganglia, parietal lobes and cerebellum, and
between cerebellum, parietal and striatal brain regions during
sustained attention [57], interference inhibition and time estima-
tion [80]. Consistent with the above evidence for DMN abnor-
malities during rest, task-related functional connectivity studies
have also found attenuated DMN deactivation during cognitive
tasks involving inhibitory control and working memory [81–83].
Interestingly, this reduced deactivation of the DMN on task
has been shown to be normalized by increasing the motiva-
tional level (i.e., high incentives) [83] or by treatment with
methylphenidate and atomoxetine [83,84].
In adults with ADHD, reduced functional connectivity rela-
tive to healthy controls was observed during motor response
inhibition and working memory tasks between bilateral IFC
and between the right IFC and other areas including basal gan-
glia, cingulate, parieto-temporal and cerebellar regions [85,86].
A reduction of thalamocortical connectivity was also observed
during a simpler task of response preparation [87]. In adults,
however, there is also additional evidence for presumably com-
pensatory increased connectivity between ACC, superior frontal
lobe and cerebellum [86].
To summarize, functional connectivity studies suggest that
abnormalities in brain function in ADHD children and adults
are not simply associated with dysfunction of independent brain
regions but a disturbance in widespread functional neural net-
works, observed both at rest and during cognitive functions.
Given that functional interregional connectivity of both the
DMN and of task-relevant neural networks is progressively more
refined and strengthened over development [4], future longitudi-
nal fMRI studies will have to test whether the attenuated interre-
gional functional network connectivity in ADHD patients is an
expression of a delayed brain function maturation.
Persistence of brain deficits into adulthood
An important question is whether the delayed brain maturation
in ADHD normalizes with age or whether functional and
structural brain abnormalities persist into adulthood in ADHD
persisters. As mentioned above, two whole-brain sMRI meta-
analyses tested for linear [26] and nonlinear age effects [27] and
Expert Rev. Neurother. 14(5), (2014)

found that the basal ganglia GM reductions appear to normal-
ize with age, so that deficits are only significantly abnormal in
children but not in adults with ADHD [26,27]. Adult ADHD
patients, on the other hand, had more deficits in ACC [27].
The findings suggest that basal ganglia deficits normalize with
age. This is in line with an earlier longitudinal imaging study,
where basal ganglia volumes normalized in early adulthood but
not frontal and other cortical deficits [88].
Frontal and other cortical deficits, however, appear to
persist into adulthood. A cross-sectional ROI study in three
medication-naı̈ve groups of 21 children, 18 adolescents and
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20 adults with ADHD showed that reduced frontal cortical
thickness in superior and medial frontal regions were present in
all three age groups relative to matched controls [20]. Another
study testing cortical thickness, however, found that only chil-
dren but not adults with ADHD had reduced laminar cortical
thickness in attention regions of bilateral inferior and superior
parietal and superior frontal and OFC regions [11]. Adult
ADHD studies, however, suffer from recall and ascertainment
bias. Clinically referred adult ADHD patients are those
ADHD children grown up who persist with the disorder and
are hence not directly comparable to pediatric groups where at
least 30–40% of children will grow out of the disorder. Longi-
tudinal studies that followed up from childhood ADHD
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patients are more suitable to address the issue of brain abnor-
malities in persisters and nonpersisters of pediatric ADHD.
A study of 59 adults with ADHD who were followed up from
childhood ADHD found reduced cortical thickness in bilateral
frontal poles, parietal and temporal regions, insula, precentral
gyri and right precuneus and decreased GM in right precentral,
bilateral parietal, right occipital and left temporal regions in
addition to subcortical areas such as the caudate, thalamus and
cerebellar hemispheres [21]. Interestingly, deficits were not dif-
ferent between persisters and remitters, suggesting stable disrup-
tions in large-scale neural systems involved in the regulation of
both attention and emotion in adults with childhood
ADHD [21]. However, the findings of stable deficits across per-
sisters and remitters were not confirmed in a recent large-
sampled mixed cross-sectional and longitudinal sMRI study in
95 children with ADHD who were scanned between 2 and
5 times into adulthood. Persistence of ADD symptoms (i.e.,
ADD symptom count) was predicted by abnormally lower, but
parallel slopes in cortical thinning relative to controls in MFC,
anterior and PCC, premotor cortex and relatively smaller loci
in DLPFC and IFC [13]. Interestingly, no cortical changes were
associated with hyperactivity symptoms that, however, were low
in the adult sample in line with the evidence for remittance of
hyperactivity with age. Remitters, on the other hand, had less
steep slopes of cortical thinning than the healthy controls
which led to a normalization in their cortical thickness in the
same regions [13]. Unlike the cross-sectional study of Proal, the
longitudinal study suggests that ADHD remitters normalize in
their developmentally delayed cortical thickness slopes to typi-
cal dimensions, whereas the persisters showed fixed nonprogres-
sive (delayed) deficits in cortical thickness slopes [13]. The
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Imaging the ADHD brain Review
findings illustrate the importance of using longitudinal imaging
designs to elucidate the neural substrates of persistence and
remittance in ADHD.
Very few cross-sectional fMRI studies have conducted the
same fMRI paradigm in children and adults, making compari-
sons between brain function deficits in pediatric and adult
groups difficult. Furthermore, no longitudinal fMRI studies
have tested for persistence of brain function abnormalities. We
conducted a series of cross-sectional fMRI studies in
medication-naı̈ve adult persisters with ADHD who had been
followed up from childhood using the same paradigms that we
had previously tested in medication-naı̈ve children with
ADHD. We found strikingly similar reduced activations in
IFC and DLPFC–fronto-striatal regions during motor and
interference inhibition, task switching and sustained and selec-
tive attention [14,85,89] including even strikingly similar cere-
bello-occipital-enhanced activation that was anticorrelated with
and hence presumably compensatory for the fronto-striatal
attention network dysfunctions [14], for review, see [23]. An anal-
ysis of age effects in our fMRI meta-analysis of inhibition tasks
showed that basal ganglia and thalamus deficits were only sig-
nificant in children with ADHD, while the medial frontal defi-
cits in the SMA were only significant for adult ADHD [51].
The findings are parallel to the structural meta-analyses find-
ings of VBM studies of exclusive deficits in the GM of the
basal ganglia in pediatric ADHD [26,27] and exclusive medial
frontal (ACC) GM deficits in adult ADHD [27]. The findings
are also in line with theories of prominently subcortical deficits
in pediatric ADHD, which may lead to consequential frontal
abnormalities later on in adult ADHD [90]. However, alterna-
tive interpretations are possible such that ascertainment biases
lead to more severe adult ADHD patients from clinics being
recruited for fMRI studies who have persisted with their
ADHD symptoms and hence have developed more severe or
secondary comorbidities, which may then translate into addi-
tional frontal deficits relative to pediatric samples that typically
include children who will grow out of the disorder in adult
life. Future longitudinal fMRI studies following up ADHD
persisters and remitters will be crucial to define the functional
developmental trajectories of ADHD.
Disorder specificity of ADHD brain abnormalities
compared with other childhood disorders
For neuroimaging to be clinically relevant, it is crucial to estab-
lish disorder-specific biomarkers, that is, brain abnormalities that
are specific to ADHD and not shared with other childhood
disorders. Finding disorder-specific biomarkers can help with
differential diagnosis and differential treatment decisions.
Comparison with CD
The childhood pathology that is most commonly comorbid
with ADHD is CD and oppositional defiant disorder (ODD).
There are hardly any sMRI or fMRI studies that have con-
trolled for CD and/or ODD, and hence the ADHD imaging
literature is confounded by this comorbidity. Also, very few
525
 Review Rubia, Alegria & Brinson
imaging studies have compared noncomorbid ADHD and non-
comorbid CD. The first sMRI study found no disorder-specific
differences between children with ADHD with and without
comorbid CD/ODD, but shared volume reductions in the pos-
terior and inferior cerebellar vermis [91]. A later comparison
study found that only 24 noncomorbid CD children had 13%
reduced GM volumes relative to controls, while the 24 nonco-
morbid ADHD patients had a nonsignificant 3% change com-
pared with controls. CD patients showed reduced GM in
several frontal and parieto-temporal regions relative to ADHD
and controls, while ADHD patients had only reduced regional
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GM deficit in a left DLPFC/precentral region relative to con-
trols. Also there was a shared GM deficit between both disor-
ders in left DLPFC/precentral gyri [92]. However, all analyses
were conducted at uncorrected thresholds, and the ADHD
findings are not consistent with the prior literature.
A series of fMRI studies compared well-differentiated medi-
cation naı̈ve and IQ-matched groups of children with nonco-
morbid CD, some of which also had ODD, and noncomorbid
ADHD during five disorder-relevant EF tasks of response and
interference inhibition, sustained attention, saliency detection
and cognitive switching. Despite no performance differences, in
four of the five tasks, patients with ADHD had disorder-
specific reduced activation compared with both healthy controls
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and CD patients in the IFC/DLPFC [93–96]. During the sus-
tained attention condition, a disorder-dissociated effect was
observed in a large posterior activation cluster comprising the
cerebellum, hippocampus and inferior temporal lobe, which
was enhanced in activation in children with ADHD, presum-
ably compensatory for their frontal activation deficits, but
reduced in children with CD compared with each other and
healthy controls [93]. CD children, on the other hand, showed
reduced activation in the ventromedial prefrontal cortex during
rewarded attention [93] and in paralimbic regions during sus-
tained attention and temporal areas during performance moni-
toring [96], which is in line with consistent evidence for
structural and function deficits in CD in the paralimbic system,
comprising ventromedial OFC and interconnected limbic struc-
tures that mediate motivation and affect control [5]. Two stud-
ies compared ADHD children with and without CD and
psychopathy traits and found that the comorbid group only
had reduced amygdala activation and reduced connectivity
between amygdala and vmPFC in relation to fear [62], but
enhanced activation in vmPFC during punished reversal errors,
both of which furthermore correlated with their antisocial and
psychopathy traits [97]. The findings confirmed the association
between antisocial and psychopathy traits with paralimbic acti-
vation abnormalities relative to ADHD.
In conclusion, it appears that there are disorder specific and
process-related dissociations in prefrontal lobe deficits between
both disorders, with ADHD children having consistent problems
with the recruitment of lateral IFC/DLPFC systems in the con-
text of ‘cool’ executive inhibitory and attention control, whereas
CD children have problems with the recruitment of ‘hot’ ventro-
medial OFC–limbic systems that mediate motivation [5].
526
Comparison with obsessive–compulsive disorder
Disorder-specific reductions in IFC activation in children with
ADHD were also observed compared to children with obses-
sive–compulsive disorder (OCD) during two tasks of motor
response inhibition and switching [98,99]. OCD patients, in
turn, had shared abnormalities with ADHD patients in other
prefrontal regions including the ventromedial OFC and
DLPFC [98,99]. Interestingly, PCC and basal ganglia were also
disorder specifically underactivated in ADHD relative to OCD
that had increased activation in these regions relative to con-
trols and ADHD during a saliency task, which furthermore
correlated inversely with their respective symptom severity [99].
Reduced activation in regions of saliency processing is consis-
tent with the catecholamine deficiency hypothesis of ADHD,
given that catecholamine deficiency diminishes and catechol-
amine agonists enhance the salience of stimuli [100], while
enhanced activation of saliency processing regions in OCD is
in line with the enhanced saliency processing theory of OCD,
presumably related to evidence of enhanced dopamine in the
basal ganglia of OCD patients [101]. In fact, methylphenidate,
the treatment of choice and an indirect catecholamine agonist,
has been shown to upregulate the activation of the basal ganglia
and PCC in children with ADHD, leading to better attention
performance [57]. Structural studies also point toward basal gan-
glia differences in both disorders. While no structural studies
have been directly compared between OCD and ADHD, two
meta-analyses of VBM studies in each disorder using the same
meta-analytic procedure showed differential abnormalities in
the basal ganglia, which were reduced in GM in ADHD [26],
but enhanced in GM in OCD [102]. In conclusion, there is
some evidence to suggest that the basal ganglia structure and
function may differ between disorders and that IFC deficits
may be more pronounced in ADHD relative to OCD.
Comparison with autism spectrum disorder
Two sMRI and two fMRI studies have compared adolescents
with ADHD and autism spectrum disorder (ASD). The first
sMRI study found shared abnormalities in limbic and parietal
regions which, however, did not survive correction for multiple
testing [103]. A study using multivariate pattern recognition analy-
sis found relatively high specificity of about 80% of classifying
ADHD patients relative to both controls and ASD patients based
on brain patterns of later developing lateral fronto-striato-cerebel-
lar networks for the classification of healthy controls and of earlier
developing ventromedial fronto-limbic regions for the classifica-
tion of ADHD patients relative to both controls and ASD
patients [104]. The fMRI study showed shared dysfunction in
DLPFC–striato-thalamic regions and shared problems with the
deactivation of the DMN in both disorders during a parametric
sustained attention task. ASD patients, however, had increased –
presumably compensatory – cerebellar activation and less pro-
nounced DLPFC underfunction relative to ADHD, which may
have underlined their spared task performance deficits that were
only observed in ADHD [30]. The resting state fMRI study tested
for network centrality, which is a measure of whole-brain
Expert Rev. Neurother. 14(5), (2014)

connectivity. This graph-based measure of network organization
captures the functional relationships of a given voxel (node)
within the entire connectivity matrix of the brain (connectome)
rather than with specific nodes or networks. The study reported
shared network centrality abnormalities in precuneus for both dis-
orders in line with the above reported task-based findings of pre-
cuneus dysfunction. ADHD-specific increases, however, were
observed in network centrality in right striatum/pallidum relative
to controls and ASD, while ASD-specific increases in network
centrality were observed in predominantly left temporo-limbic
areas, which are typical areas for socio-emotion processing that
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has consistently been found to be abnormal in ASD [105]. In con-
clusion, the sparse evidence suggests that temporo-limbic regions
may be more prominently affected in ASD.
Comparison with bipolar disorder
ADHD is highly prevalent in children and adults with bipolar
disorder (BD) [106]. While the disorders share several EF defi-
cits, most prominently poor inhibitory control and sustained
attention, there is growing evidence to suggest that both disor-
ders are underpinned by distinct neural abnormalities [107].
Two sMRI studies tested for basal ganglia differences between
pediatric ADHD and BD patient groups and found contrasting
abnormalities of decreased volumes of caudate and putamen
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being associated with ADHD and increased volumes of cau-
date, putamen, globus pallidus and ventral striatum with addi-
tional limbic abnormalities being associated with the BD
group [108,109]. The comorbid group was nonimpaired in one
study [108] and is more like the pure BD group in the other
study [109]. Three adult sMRI studies also observed disorder-
specific abnormalities. One study found that pure ADHD was
associated with smaller GM in superior prefrontal cortex, ACC
and cerebellum, while pure BD was associated with smaller left
orbital prefrontal and larger right thalamic volumes, with the
comorbid disorder having combined deficits from both pure
disorders [110]. Another ROI-based linear regression model anal-
ysis on brain structure in adult patient groups showed that BD
in adults independently from ADHD was associated with sig-
nificantly thicker cortices in parieto-temporal regions, while
ADHD independently of BD was associated with significantly
reduced cortical thickness in frontal, cingulate, SMA and
temporo-parietal regions with the comorbid disorder showing a
combinatorial effect of deficits in both disorder-related
regions [111]. A study on cortical thickness showed that BD
alone was associated with thinning in middle and ventral PFC
and ACC, while an interaction effect between both disorders
was observed in the thinning of left OFC and subgenual
ACC [112]. Last, a DTI study testing for differences in eight
fiber tracts including the corona radiata, anterior limb of the
internal capsule, superior region of the internal capsule, poste-
rior limb of the internal capsule, superior and inferior longitu-
dinal fasciculus, cingulum and splenium reported reduction in
FA in seven WM tracts in ADHD, while BD had shared
abnormalities with ADHD in the anterior corona radiata, a
frontal WM tract and in the splenium, connecting posterior
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Imaging the ADHD brain Review
attention regions [43]. The findings suggest a global dysmatura-
tion of WM tracts in ADHD, with more specific abnormalities
in frontal and parietal WM tracts in BD. Overall, the structural
imaging studies showed more prominent OFC–limbic abnor-
malities for BD and more prominent lateral fronto-striato-pari-
eto-temporal deficits in ADHD.
A few fMRI studies have also compared the two disorders.
For example, during an inhibition task, ADHD children
showed decreased activation relative to BD in typical inhibition
regions of right IFC/VLPFC and bilateral DLPFC, as well as
right superior frontal gyrus, right middle temporal cortex and
left posterior cingulate gyrus, whereas BD had reduced occipital
and postcentral activation relative to ADHD. BD only relative
to controls showed more localized dysfunction in VLPFC and
ventral ACC, suggesting a dysfunctional ventral frontostriatal–
limbic circuit [113]. Studies employing affective challenge have
implicated similar disorder-specific dysfunctional neural areas.
Thus, during an emotional valence Stroop task, BD relative to
healthy controls and ADHD showed increased activation of the
VLPFC and ACC while ADHD patients had reduced VLPFC
activation relative to healthy controls [114]. During an affective
two-back working memory task, BD patients had increased
activation in bilateral caudate relative to ADHD for happy
faces, while for angry faces, the BD group showed increased
activation relative to the ADHD group in emotion regulation
areas of left medial OFC and left subgenual ACC, whereas the
ADHD group showed increased activation in ‘cool’ EF work-
ing memory regions of DLPFC and SMA [115].
Overall, both the structural and functional comparisons sug-
gest that the emotional impulsiveness of noncomorbid BD is
more consistently associated with bottom-up OFC–limbic
abnormalities, while the more cognitive impulsivity of ADHD
appears to be associated with ‘cool’ top-down abnormalities in
cognitive VLPFC/IFC–striatal circuits [107].
Conclusion
In conclusion, the research on disorder specificity of brain bio-
markers of ADHD is relatively sparse and based on relatively
small-sampled comparisons. Some emerging evidence, however,
suggests that ADHD patients may have more pronounced dys-
functions in lateral frontal regions, most prominently in IFC
and DLPFC relative to CD and OCD [5], BD [107] and possi-
bly ASD [30]. In addition, there is some evidence that the basal
ganglia structure and function may be different between
ADHD and both BD and OCD [26,99,102,108,109,115]. Future
larger sampled comparisons in groups of noncomorbid and
comorbid patients, however, will be necessary to establish
disorder-specific structural and functional biomarkers that
could be used to differentiate ADHD from other disorders
with an objective neuroimaging method.
Effects of stimulant & nonstimulant medications on the
ADHD brain
Stimulant medications (e.g., methylphenidate or dexamfet-
amines) and Atomoxetine have been shown to reduce the severity
527
 Review Rubia, Alegria & Brinson
of ADHD core symptoms in up to 70% of patients and are con-
sidered first-line pharmacological treatment for ADHD [116].
However, their mechanisms of action are still relatively poorly
understood. Several fMRI studies have sought to further our
understanding on the acute and chronic effects of stimulant med-
ications on the function of the ADHD brain. Very few studies,
however, have tested acute and chronic effects of atomoxetine.
Nothing is known about stimulant or nonstimulant medication
effects on brain structure as no prospective randomized con-
trolled trial studies have been conducted, presumably due to ethi-
cal constraints of withholding medication for ADHD children
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by placing them in a placebo arm for years. However, several
studies have retrospectively compared the brain structure of med-
icated and medication-naı̈ve ADHD children, which, while
biased by self-selection, may potentially give some indirect indi-
cations on possible structural medication effects.
Effects of stimulant medication on brain function &
structure
Several well-designed (e.g., randomised placebo-controlled, case–
control crossover) whole brain and ROI fMRI studies have exam-
ined the acute effects of methylphenidate on brain function
during a series of cognitive tasks in medication-naı̈ve ADHD
patients. ROI-based studies found that an acute dose of methyl-
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phenidate in medication-naı̈ve ADHD youth increased the
reduced activation in right and left IFC during a stop task [117,118]
and in right IFC during time discrimination [118,119], but had no
effect during a working memory task [84,118]. The studies also
showed that a single dose of methylphenidate normalized the
reduced activation that was observed in ADHD patients under
the placebo condition [117–119]. Whole-brain analyses showed
somewhat wider upregulation and normalization effects of meth-
ylphenidate in predominantly right but also left IFC during tasks
of sustained attention [57], motor inhibition [118,120] and time dis-
crimination [8,118]; in parietal regions during sustained atten-
tion [57], error processing [120] motor and interference inhibition
and time discrimination [118,120]; in the cerebellum during time
discrimination [8], interference and motor inhibition [118,120,121]
and attention tasks [57]; and in the striatum during reward [57]
and response inhibition [118,120] tasks. In chronically medicated
ADHD youth, relative to the off-medication condition, stimu-
lants have shown to increase activation in the striatum [122,123],
IFC, MFC, ACC and the cerebellum [123] during a go/no go
task, in bilateral medial frontal regions during an emotional
Stroop task [124], and to decrease activation in the ACC DMN
region during a cognitive Stroop task [82] but had no effect during
working memory [125].
A meta-analysis of all published 14 whole-brain fMRI stud-
ies that tested the effects of stimulants on brain function in
ADHD showed that the most consistent acute effect is the
increased activation of right IFC/insula, with additional effects
in the putamen at a more lenient threshold [118]. The findings
showed that the most consistent effects of acute stimulant med-
ication is the upregulation of a key area of dysfunction in
ADHD, in right IFC, which furthermore may be a disorder-
528
specific neurofunctional biomarker for ADHD relative to other
childhood disorders (see above). Furthermore, studies that
tested for normalization effects of placebo-related reduced acti-
vations relative to controls after the single dose found that this
region is also most commonly normalized during motor inhibi-
tion [117,120], interference inhibition [121] and time discrimina-
tion [119]. Likewise, basal ganglia underfunctioning has been
found to be normalized during inhibitory control [121,122,126]
and time discrimination [8].
A few studies investigated the acute effects of stimulants on
functional connectivity and found that an acute dose of meth-
ylphenidate normalized almost all functional connectivity defi-
cits in fronto-striatal, fronto-parietal and fronto-cerebellar
networks, as measured using time series correlations of coacti-
vated regions during vigilant attention [57], in fronto-parietal
networks during working memory [86], in ventral ACC and lat-
eral PFC connectivity during a cognitive Stroop task [82] and
between the amygdala and lateral PFC [124] during an emo-
tional Stroop task.
While acute stimulant effects on brain function have been
relatively well studied in ADHD, relatively little is known
about chronic effects. A 12 months trial of stimulant adminis-
tration in children with ADHD appeared to normalize the
enhanced (potentially compensatory) activation in insula and
putamen during a reorienting attention process. Also, there was
a trend for ACC dysfunction to be more pronounced in five
unmedicated relative to nine chronically medicated patients,
suggesting some long-term amelioration [127]. However, given
the small subject numbers, the generalizability of the findings is
limited. A recent study found that methylphenidate over
3 months normalized reduced ventral striatum and thalamus
activation during the processing of low but not high reward
outcomes [128]. In adult ADHD, a 6-week trial of stimulant
medication compared with placebo was associated with
increased activation in the dorsal ACC, DLPFC, premotor and
parietal cortices, caudate, thalamus and cerebellum during
interference inhibition, but only the dorsal ACC upregulation
was associated with treatment response [129]. A meta-regression
analyses within the meta-analyses of fMRI studies found that
long-term (between 6 months to 3 years) stimulant administra-
tion was associated with normalization of right caudate activity
during attention [51] and of right DLPFC activity during tim-
ing tasks [31], but had no effect on brain activations during
inhibition tasks [51].
In conclusion, the meta-analytic findings, together with sev-
eral studies on normalization effects, appear to suggest that
acute and longer term stimulant medication treatment is most
consistently associated with an upregulation and normalization
of a key dysfunctional area in ADHD in the IFC, followed by
upregulation and normalization effects in the striatum.
As mentioned, there are no prospective longitudinal imaging
studies of long-term stimulant effects on brain structure. How-
ever, several studies have retrospectively compared medicated and
nonmedicated ADHD patients in their brain structure measures.
These studies are hampered by the retrospective analysis,
Expert Rev. Neurother. 14(5), (2014)

relatively small sample sizes (fewer than 20 subjects in most stud-
ies) and the use of an ROI approach in their analyses. Interest-
ingly, however, the results of these studies are in the same
positive direction, suggesting that medicated patients with
ADHD have more normal size, volumes, cortical thickness and/
or morphology than unmedicated patients in several ADHD-
relevant brain regions including the right ACC [130], the anterior
pulvinar nucleus of the thalamus [19]; the posterior inferior vermis
of the cerebellum [131]; the left lateral cerebellar surface [132]; the
basal ganglia [133]; and the corpus callosum [134]. Two studies of
retrospective comparisons included longitudinal data. One study
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found comparable WM volumes relative to controls only in
long-term medicated ADHD patients, but smaller WM volumes
in medication-naı̈ve ADHD patients [88], and the other study
showed that 24 ADHD children on long-term stimulant medica-
tion had a less rapid cortical thinning development than 19 non-
medicated children, in the left IFC, premotor and parietal
regions, so that their developmental curves were like those of
controls, while those of the unmedicated groups were devi-
ant [135]. Some other studies, however, found no differences
between medicated and nonmedicated patients in fronto-parietal
[11] or ACC cortical thickness [136], but the samples were very
small below 20.
Two VBM meta-analyses tested for long-term medication
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effects. The study of Nakao conducted a meta-regression analy-
sis with medication status to test for linear effects of the per-
centage of patients with long-term stimulation in each study on
GM volumes. The study found that the percentage of patients
on long-term stimulant medication was correlated with more
normal (i.e., increased) GM volume in the basal ganglia, so
that the basal ganglia were normal in studies that included
more than 75% medicated patients, while studies that included
medication-naı̈ve patients showed the most pronounced GM
decrease [26]. The meta-analysis of Frodl [27] used a covariance
analysis and found that when the number of treated children
were included as a covariate, there was a significant effect of
treatment in left and right caudate, indicating that structural
differences were smaller in studies with higher percentage of
treated children.
In conclusion, overall sMRI and fMRI studies appear to sug-
gest that stimulant medication may potentially be neuroprotec-
tive on brain structure and function. We hypothesized that the
findings of more normal brain structure volumes, morphology
or cortical thickness in long-term treated ADHD patients rela-
tive to medication-naı̈ve ADHD patients could potentially
reflect a plastic effect of chronic upregulation of these brain
regions as demonstrated in fMRI with long-term stimulant
medication [118]. It has been shown that functional activation,
for example, in the form of 4 weeks of learning to juggle, can
lead to structural changes in the relevant brain regions that
have been modulated functionally through practice [137]. How-
ever, this needs to be tested in longitudinal imaging studies.
Studies that have tested for neurochemical effects, on the other
hand, have been less promising. A meta-analysis of PET stud-
ies, mostly in adult ADHD patients, showed that long-term
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Imaging the ADHD brain Review
stimulant medication was associated with an abnormally
increased level of striatal dopamine transporters, which were
reduced relative to healthy controls in medication-naı̈ve
patients, suggesting potential brain adaptation to stimulants [28].
This was also observed in a within-subject study design after a
1-year follow-up of chronic stimulant medication treatment in
a small group of adults with ADHD [138]. These findings of
plastic long-term upregulation of dopamine transporter with
chronic stimulant medication could explain why meta-analysis
and multicenter studies have shown relatively poor long-term
efficacy of stimulant medication [139,140]. A multicenter study,
for example, found that medication is superior to behavioral
treatment after the first but not after 3 years [139,140]. However,
prospective longitudinal imaging studies within a randomized
placebo-controlled design are crucial to confirm these findings
based on cross-sectional comparisons, of plastic effects on brain
structure, function and biochemistry.
Effects of atomoxetine on ADHD brain function
A study from our lab compared the acute effects of methylphe-
nidate and atomoxetine on the brain function in ADHD. We
applied a placebo-controlled randomized within-patient fMRI
study design to compare atomoxetine, methylphenidate and
placebo in medication-naı̈ve ADHD patients during several
disorder-relevant tasks. We found both shared and drug-specific
effects. Both drugs upregulated right IFC activation during
time discrimination and bilateral IFC during inhibition. Fur-
thermore, the reduced activation that was observed in ADHD
patients under placebo relative to healthy controls was normal-
ized with both drugs [117,119]. Both drugs also elicited presum-
ably compensatory fronto-striato-thalamic enhanced activation
and deactivated DMN regions during working memory [84].
Drug-specific effects were also observed: Atomoxetine upregu-
lated and normalized right DLPFC reduced activation, which
was significantly underactivated during working memory [84].
Methylphenidate, on the other hand, increased presumably
compensatory activation in left IFC and the basal ganglia but
only during one of the working memory conditions [84] and
during motor response execution [117]. Furthermore, methylphe-
nidate had drug-specific effects on the upregulation of the acti-
vation of the dopaminergically innervated SMA during motor
response execution and time discrimination [117,119]. Interest-
ingly, while brain function effects were relatively comparable
for both drugs for inhibition and timing, only methylphenidate
improved task performance [84,117,119], in line with the relatively
slow behavioral effects of atomoxetine that typically are only
observable after many weeks of treatment [141].
A few recent fMRI studies tested chronic effects of atomoxe-
tine. The only pilot study in adult ADHD showed that atom-
oxetine treatment over 6 weeks increased activation in ROIs of
DLPFC, parietal cortex and cerebellum but not in dorsal
ACC [142].
A key relevant clinical question, however, is whether clinical
response to medication is associated with medication-elicited
brain function changes in ADHD patients. A comparative
529
 Review Rubia, Alegria & Brinson
fMRI study used a parallel group design in 36 ADHD patients
to address this question and found a shared association between
clinical improvement after 6–8 weeks of both drugs and reduc-
tions in bilateral primary motor cortex activation. There was,
however, also a drug-dissociated association in right IFC, left
ACC/SMA and bilateral PCC cortex that were all enhanced in
activation in relation to clinical response to Atomoxetine but
decreased in activation in relation to clinical response to meth-
ylphenidate [143]. Last, a preliminary analysis in relatively small
subject numbers found that chronic methylphenidate response
in seven ADHD adolescents was associated with acute stimu-
Expert Review of Neurotherapeutics Downloaded from informahealthcare.com by Nandini Loganathan on 04/25/14
lant reduction effects in parietal regional homogeneity during
rest [144]. Future larger powered imaging studies using multivar-
iate pattern recognition methodology are needed, however, to
provide better estimates of whether baseline imaging deficits
can predict medication response.
In conclusion, the relatively sparse evidence indicates that
acute stimulant and nonstimulant medications have shared
effects in key ADHD brain dysfunction in IFC, but may also
have drug-specific effects in other frontal and subcortical
regions. Further studies are needed to disentangle the shared
and specific drug effects of Atomoxetine relative to stimulant
medication on ADHD brain function.
For personal use only.
Clinical application of neuroimaging in ADHD
Despite the fact that ADHD is a neurodevelopmental disorder
with consistent evidence for brain structure and function deficits
as reviewed above, currently ADHD is diagnosed solely on the
basis of subjective clinical and self-rating measures, which are
often unreliable, leading to diagnostic variability between clini-
cians, cultures and countries [145]. Sensitivity of classification of
ADHD children with clinical measures based on DSM-IV crite-
ria, which is the gold standard behavioral measure for ADHD
diagnosis, has been shown to be 70–90% [146], thus misdiagnoses
are around 10–30%. It is thus highly desirable to develop addi-
tional and more reliable diagnostic methods for ADHD patients
based on objectively measurable neuroimaging data. Attempts to
find objective neuroimaging biomarkers for ADHD, however,
have been limited by the fact that in traditional univariate group
statistical analyses, subjects in both groups tend to overlap in
measures that showed group differences, and effect sizes have
been relatively small, which have made diagnostic predictions at
the level of individual subjects difficult.
In contrast, multivariate pattern analyses for imaging data
take into account interactions between regions (i.e., brain struc-
ture or function patterns) and can make predictions (e.g., of
class membership) for individual subjects as opposed to group-
level inferences. These methods have been shown to provide
sensitive and specific diagnostic indicators for individual
patients with other pathologies such as autism, depression and
Alzheimer’s disease (for review, see [147]).
To date, few imaging studies have used multivariate pattern
recognition analyses techniques to classify ADHD patients.
A recent competition to apply multivariate methods on a mul-
ticenter resting state functional and anatomical imaging data
530
set of 285 children and adolescents with ADHD and
491 healthy controls (ADHD-200 Consortium; [148]) was met
by a range of classification approaches including random for-
ests, gradient boosting, multikernel learning and SVMs [149–152].
Accuracies derived by internal cross-validation ranged from
55 to 78% although the accuracies reported on an external test
data set for which diagnostic labels were withheld to be sub-
stantially lower (61% for the winning team [152]). This differ-
ence was attributed to a lack of standardization between sites,
leading to multiple confounds including missing data, site-
specific differences in behavioral measurements, imaging acqui-
sition, processing and protocols, scanner quality and other
unmeasured confounding and mediating variables. Further-
more, the competition data set was highly unbalanced with
more control subjects than ADHD patients (63 and 37%,
respectively) and balanced accuracy measures, calculated as the
mean of sensitivity and specificity, which accommodate that
this imbalance is consistently lower than the figures reported
(e.g., 57.5% for the winning team). In addition, the competi-
tion scoring rewarded specificity more than sensitivity so that
all teams reported high specificity, but poor sensitivity (21%
for the winning team).
A few recent studies used probabilistic classification models
such as Gaussian Process Classifiers (GPCs). GPCs are kernel
classifiers used in machine learning, similar to SVMs, which
have good performance for fMRI [153]. Their main advantage
over alternative methods is that they provide estimates of pre-
dictive uncertainty and can accommodate unbalanced diagnos-
tic settings or variations in disease prevalence, which are crucial
for clinical applications where patients are typically less preva-
lent than controls [154]. Three studies used GPC in structural
and functional imaging data in adolescents with ADHD and
showed a relatively high overall classification accuracy of
between 75 and 80% with relatively small numbers between
20 and 33 patients [104,155]. Interestingly, across all studies, the
brain structure and function patterns that classified controls
were in later developing lateral fronto-striato-parieto-cerebellar
networks, while patterns that classified ADHD were in earlier
developing ventromedial prefrontal and limbic regions [104,156].
Importantly, one of the studies showed that the classification
accuracy was disorder-specific compared with a group of ado-
lescents with ASD [104] that is crucial for the potential future
use of neuroimaging as an aid for differential diagnosis.
Another recent study used a semi-supervised clustering algo-
rithm based on the spatial patterns of variation across the mor-
phological surfaces of numerous cortical and subcortical brain
regions to disorder specifically diagnose, with relatively high
accuracy of almost 90%, youth with ADHD relative to Tour-
ette Syndrome [157]. These studies are a first step toward the
translational use of neuroimaging as a potential differential
diagnostic aid. Future studies will have to test whether classifi-
cation algorithms are stable across patient population, countries
and scanners, as well as their ability to classify ADHD sub-
groups and to determine high clinically useful disorder-specific
classification.
Expert Rev. Neurother. 14(5), (2014)

While imaging-based classification algorithms are unlikely to
replace clinical assessment and diagnosis, they may be a useful
objective, automated and reliable complementary diagnostic
tool that could reduce variability in clinical practice and, ulti-
mately, help to improve diagnostic accuracy or revise clinical
diagnosis through biomarker classification of uncertain diagnos-
tic cases. Furthermore, these methods are likely to be more use-
ful for prognostic rather than diagnostic classification, such as
predicting the disease progression and/or adult outcome of
ADHD or medication response, given that currently no predic-
tors are available for these and that brain mechanisms are likely
Expert Review of Neurotherapeutics Downloaded from informahealthcare.com by Nandini Loganathan on 04/25/14
to be better predictors of disease progression or medication
response than behavioral measures. There is hence a potential
that these methods could revolutionize clinical practice and
personalized medicine.
Expert commentary & five-year view
The last decades of neuroimaging have significantly broadened
our understanding of the underlying neurobiology of ADHD.
They have shown that ADHD is most prominently associated
with the dysmorphology, dysfunction and underconnectivity of
multiple fronto-striatal, fronto-parietal and fronto-cerebellar
networks that mediate ‘cool’ EF including the ventral fronto-
ACC/SMA-striato-thalamic cognitive control system, the dorsal
For personal use only.
and ventral fronto-striato-thalamo-parietal attention systems
and ventral fronto-parieto-cerebellar timing networks. In addi-
tion, ADHD children have structural, functional and connec-
tivity deficits in DMN systems that appear to be poorly
deactivated during task performance and hence intruding upon
task-positive cognitive systems. Both the poor activation of
task-relevant networks and the poor deactivation of the DMN
likely underlie their poor performance on EF (FIGURE 2). There is
evidence for a delay in normal brain maturation from structural
imaging studies. A developmental delay is likely for brain func-
tion with functional patterns of deficits being in late developing
brain regions that progressively mature in their activations with
age, suggesting an immature functional activation profile. Fur-
thermore, there is emerging evidence for OFC–limbic abnor-
malities in the context of reward processing and possibly
emotion processing, with particular implication for the ventral
striatum. However, given that this evidence relies on ROI stud-
ies and does not seem to be observed in whole-brain imaging
studies, this will need to be confirmed in future larger scale
imaging studies. Furthermore, OFC–limbic abnormalities are
typical for antisocial behaviors and have shown to disappear
when controlling for comorbidity with CD [14], which is a
strong confound in ADHD imaging studies [5]. Studies on the
clinically relevant question of disorder specificity of imaging
biomarkers for ADHD are only just emerging, but point
toward potential disorder specificity of ventral prefrontal
under-recruitment relative to CD, OCD and BD [5,107], as well
as of basal ganglia deficits relative to OCD and BD [26,102,107].
Several confounds limit the sMRI and fMRI literature of
ADHD. In particular, structural MRI studies have been con-
ducted in relatively small number of often nonrepresentative
informahealthcare.com
Imaging the ADHD brain Review
Task-related activation Default mode network
DLPFC IFC dACC SMA MFC ACC
Caudate/putamen/ Inferior parieto-
globus pallidus temporal
PCC
Thalamus
Parieto-temporal
Superior
temporal
Cerebellum
Figure 2. Schematic representation of the most consistent
abnormality findings in ADHD. Reduced structure, function
and structural and functional connectivity have been observed in
several dorsal and ventral fronto-striato-thalamo-parietal and
fronto-striato-thalamo-cerebellar networks. Furthermore, there is
evidence for abnormally enhanced gray matter and function in
posterior regions of the default mode network. Evidence for
reduced anticorrelation between task-positive fronto-striatal/
fronto-cerebellar networks and the default mode network
suggests that both poor task-positive activation and reduced
deactivation of the default mode network underlie poor cognitive
functioning in ADHD.
ACC: Anterior cingulate cortex; ADHD: Attention deficit
hyperactivity disorder; dACC: Dorsal anterior cingulate cortex;
IFC: Inferior frontal cortex; MFC: Medial prefrontal;
SMA: Supplementary motor area; PCC: Posterior cingulate cortex.
participant samples of convenience using ROI analyses and
sometimes using liberal uncorrected thresholds. Whole-brain
image meta-analyses of structural studies, hence, have shown
far more limited abnormalities in the basal ganglia only.
Comorbidity with CD/ODD is rarely addressed in pediatric
studies, while adult studies suffer from comorbidity confounds
with secondary affective conditions that may explain the higher
prevalence of limbic abnormalities in the adult ADHD imaging
literature. Adult ADHD imaging studies also suffer from recall
and ascertainment bias from clinical populations which do not
capture remitted cases. The majority of imaging studies have
been conducted in long-term medicated patients. Given the
reviewed effects of stimulant medication on brain structure and
function, future studies will have to focus on medication-naı̈ve
patient populations to assess pure pathology effects uncon-
founded by long-term medication effects.
Given that cross-sectional imaging studies are confounded by
cohort effects and ascertainment bias, there is an urgent need
for longitudinal imaging studies, in particular following up
children with ADHD into mid and late adulthood, to under-
stand the underlying brain mechanisms of remittance and per-
sistence of deficits into adult ADHD. Furthermore, relatively
few studies have combined several imaging technologies. Also,
more sophisticated novel neuroimaging analysis techniques,
such as newer connectivity metrics or pattern recognition
531
 Review Rubia, Alegria & Brinson
analyses, are likely to advance the field. Future studies will
need to focus on multimodal imaging in representative popula-
tions to enhance our holistic understanding on the relationship
between structural, functional, connectivity and blood flow, as
well as brain chemistry abnormalities within the same patient
groups. Also, so far, the majority of studies have prominently
focused on the hyperactive–inattentive combined ADHD sub-
type. Future studies will need to focus on understanding the
(differential) neurobiological basis of different ADHD subtypes
such as children with ADD without hyperactivity, children
with ADHD and emotional dysregulation, as well as comorbid
Expert Review of Neurotherapeutics Downloaded from informahealthcare.com by Nandini Loganathan on 04/25/14
cases with anxiety and affective disorders. Future studies, there-
fore, ideally should be longitudinal, multimodal and tied to
epidemiological samples.
Medication studies on the acute effects of stimulant medi-
cation on brain function have reinforced the pathology find-
ings of ventral fronto-striatal systems in ADHD, showing
that the most consistent mechanism of action across studies
is the upregulation and normalization of the activation of the
IFC and the basal ganglia. Studies on Atomoxetine effects on
brain function have only just emerged, but direct compari-
sons suggest similar acute effects on ventral prefrontal sys-
tems, with potential drug-specific effects on DLPFC
(Atomoxetine) and medial frontal systems and the basal gan-
For personal use only.
glia (methylphenidate). Some evidence from cross-sectional
studies suggests potential long-term plastic medication effects
on brain structure, function and neurochemistry. However,
no longitudinal imaging studies have assessed long-term med-
ication effects in a prospective randomized controlled design.
PET studies will need to investigate the underlying neuro-
transmitter abnormalities in ADHD other than the DA sys-
tem, such as serotonin, noradrenaline, glutamate and GABA
with a particular emphasis on how they interact with the dys-
functional DA system.
Clinical translation of neuroimaging is still in its childhood
and will be the challenge over the next decade. Several pioneering
machine-learning approaches using GPC have been promising,
showing relatively high accuracy of up to 80% in classifying
ADHD patients relative to controls and ASD patients based on
structural or functional imaging scans. Multimodal multivariate
approaches including several imaging modalities, as well as noni-
maging data such as cognitive and genetic measures, have been
shown to achieve higher classification accuracy in other disorders
than univariate approaches [147] and should be applied to
ADHD. These multivariate classification methods have far
higher promise for clinical translation than traditional univariate
methods due to their ability to make individual diagnostic and
predictive assessments. These approaches, if successful and repli-
cated across different representative patient groups, scanners and
demographic populations, may well be able to help with future
imaging-based diagnosis or prognosis of individual patients and
thus build the path for brain-based patient stratification and
personalized medicine.
Last, but by no means least, there is high potential for thera-
peutic neuroimaging. The last two decades have established the
532
neural basis of ADHD. Over the next decade, there are likely to
be more directly translational neuroimaging studies that apply
fMRI or near-infrared spectroscopy as a neurotherapy for
ADHD in the form of neurofeedback (NF) to upregulate the
activation of ADHD-specific dysfunctional brain regions such as
IFC, DLPFC and the basal ganglia. EEG-based NF has been
shown to be very promising in reducing ADHD behaviors with
similar effect sizes to stimulant medication and similar efficacy
when compared directly against stimulant medication [158–160].
A few placebo-controlled EEG NF studies, however, showed no
superior effects of NF over placebo [161–163]. However, these stud-
ies were conducted in relatively small subject numbers, did not
use standardized protocols for EEG NF and showed no learning
effect of the NF itself, so that the placebo control has been ques-
tioned when the NF training was not effective in the first place
(for review, see [159,160]). EEG-NF treatment has the disadvantage
that it requires as many as 40–50 sessions. fMRI-NF has a better
spatial resolution and can target key ADHD regions such as IFC
and basal ganglia. Studies have shown that healthy adults and
adults with psychiatric disorders can upregulate disorder-relevant
regions in a few sessions of 5 min [164]. Likewise, other neuro-
therapies such as regional electrical stimulation using repetitive
transcranial magnetic stimulation and transcranial direct current
stimulation have found successful applications to other psychiat-
ric disorders and are promising for ADHD. Direct current stim-
ulation techniques are relatively noninvasive and can stimulate
brain regions that are underfunctioning in ADHD such as IFC
or DLPFC. These stimulation techniques affect cellular and
molecular mechanisms involved in use-dependent local and dis-
tant synaptic plasticity, that is, GABA and glutamate-mediated
long-term potentiation, which may lead to longer term
effects [165]. So far, only one pilot study tested TMS over right
DLPFC in a single session in 13 ADHD adults and found
increases in behavioral attention scores [166].
In conclusion, we have acquired substantial knowledge on
the underlying neurobiological mechanisms of ADHD. How-
ever, more studies are needed to integrate different imaging
modalities to assess longitudinal trajectories of the disorder to
understand the association between abnormal and potentially
delayed development of brain structure, brain function and
structural and functional connectivity in ADHD. The next
decade will likely focus on using neuroimaging techniques in a
more clinically applied fashion in the form of individual diag-
nosis, prognosis of disease progression and of treatment success
or as a neurotherapy to normalize abnormally functioning
brain regions.
Acknowledgements
We thank Joaquim Radua for help with one of the Figures.
Financial & competing interests disclosure
KR has received research support from Lilly Pharmaceuticals and speaker’ s
honoraria from Lilly, Medice and Novartis. KR received support from the
National Institute of Health Research (NIHR) Biomedical Research Centre
(BRC) for Mental Health at South London and Maudsley NHS
Expert Rev. Neurother. 14(5), (2014)
 Imaging the ADHD brain Review

Foundation Trust and Institute of Psychiatry, Kings College London and
Lilly Pharmaceuticals. Dr Helen Brinson received post-doctoral support
from Action Medical Research. Ms Alegria was supported by an Institute
of Psychiatry PhD excellence award. The authors have no other relevant
affiliations or financial involvement with any organization or entity with
a financial interest in or financial conflict with the subject matter or
materials discussed in the manuscript. This includes employment, consul-
tancies, honoraria, stock ownership or options, expert testimony, grants or
patents received or pending or royalties.
No writing assistance was utilized in the production of this manuscript.

Key issues
• Attention deficit hyperactivity disorder (ADHD) is characterized by a delay in brain structure maturation which possibly extends to brain
function and structural and functional connectivity.
• ADHD is most prominently associated with the dysmorphology, dysfunction and underconnectivity of multiple fronto-striatal, fronto-
Expert Review of Neurotherapeutics Downloaded from informahealthcare.com by Nandini Loganathan on 04/25/14

parietal and fronto-cerebellar networks that mediate ‘cool’ executive functions.

• Executive function deficits appear to be associated with both poor activation of task-relevant fronto-striato-cerebellar systems and with
poor deactivation of the default mode network.
• There is evidence that inferior prefrontal activation deficits may be more pronounced in ADHD relative to other childhood disorders such
as conduct, obsessive–compulsive and bipolar disorder.
• A meta-analysis shows that acute stimulant medication most consistently increases the activation of the right inferior frontal cortex and
the striatum in ADHD which it also normalizes in their underfunctioning relative to controls.
• Meta-regression analyses and retrospective comparisons between medicated and nonmedicated ADHD patients showed that long-term
stimulant medication appears to be associated with abnormally high dopamine transporter levels, but with more normal brain structure,
which need to be corroborated in longitudinal prospective studies.
• Future studies will focus on using neuroimaging for clinical translation, for example, to predict individual diagnostic or prognostic
classification or as a neurotherapy to remediate the brain function abnormalities via neurofeedback or neurostimulation.
For personal use only.

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