Journal of Child Psychology and Psychiatry 47:10 (2006), pp 1051–1062 doi:10.1111/j.1469-7610.2006.01671.

The neural correlates of attention deficit

hyperactivity disorder: an ALE meta-analysis
Steven G. Dickstein, Katie Bannon, F. Xavier Castellanos,
and Michael P. Milham
NYU Child Study Center, USA

Background: Attention deficit/hyperactivity disorder (ADHD) is one of the most prevalent and com-
monly studied forms of psychopathology in children and adolescents. Causal models of ADHD have long
implicated dysfunction in fronto-striatal and frontal-parietal networks supporting executive function, a
hypothesis that can now be examined systematically using functional neuroimaging. The present work
provides an objective, unbiased statistically-based meta-analysis of published functional neuroimaging
studies of ADHD. Methods: A recently developed voxel-wise quantitative meta-analytic technique
known as activation likelihood estimation (ALE) was applied to 16 neuroimaging studies examining and
contrasting patterns of neural activity in patients with ADHD and healthy controls. Voxel-wise results
are reported using a statistical threshold of p < .05, corrected. Given the large number of studies ex-
amining response inhibition, additional meta-analyses focusing specifically on group differences in the
neural correlates of inhibition were included. Results: Across studies, significant patterns of frontal
hypoactivity were detected in patients with ADHD, affecting anterior cingulate, dorsolateral prefrontal,
and inferior prefrontal cortices, as well as related regions including basal ganglia, thalamus, and por-
tions of parietal cortex. When focusing on studies of response inhibition alone, a more limited set of
group differences were observed, including inferior prefrontal cortex, medial wall regions, and the
precentral gyrus. In contrast, analyses focusing on studies of constructs other than response inhibition
revealed a more extensive pattern of hypofunction in patients with ADHD than those of response
inhibition. Conclusions: To date, the most consistent findings in the neuroimaging literature of ADHD
are deficits in neural activity within fronto-striatal and fronto-parietal circuits. The distributed nature of
these results fails to support models emphasizing dysfunction in any one frontal sub-region. While our
findings are suggestive of the primacy of deficits in frontal-based neural circuitry underlying ADHD, we
discuss potential biases in the literature that need to be addressed before such a conclusion can be fully
embraced. Keywords: Attention deficit/hyperactivity disorder (ADHD), meta-analysis, neuroimaging,
functional magnetic resonance imaging (fMRI), positron emission tomography (PET), executive function.

Models of attention-deficit/hyperactivity disorder Given both the strong association between execu-
(ADHD) have long posited that a core deficit in frontal tive function and the frontal lobes, and the sub-
lobe function underlies its various cognitive and stantial literature confirming the presence of
behavioral manifestations. In particular, fronto- executive dysfunction in ADHD (Willcutt et al.,
striatal and fronto-parietal networks supporting an 2005), it is not surprising that nearly all neuro-
array of top-down or executive processes, such as imaging studies have focused on cognitive para-
dorsolateral prefrontal cortices, anterior cingulate digms assessing executive processes. Amongst
cortices, and associated striatal regions, are fre- these, response inhibition has been the most studied
quently cited as loci of dysfunction in ADHD (e.g., of executive top-down functions, reflecting the im-
Barkley, 1997; Castellanos & Tannock, 2002). Until pact of an influential theory which posited inhibitory
recently, such models have relied heavily upon dysfunction as the primary deficit in ADHD (Barkley,
anatomical and neuropsychological studies of ADHD 1997).
(see recent reviews, Willcutt, Doyle, Nigg, Faraone, & Several recent reviews have examined the ADHD
Pennington, 2005; Seidman, Valera, & Makris, 2005) neuroimaging literature. Bush, Valera, and Seidman
as well as inferences based upon functional neuroi- (2005) surveyed over a dozen neuroimaging studies
maging findings from healthy normal adults. How- of ADHD, encompassing a variety of functional
ever, with recent advances in non-invasive imaging techniques (PET, SPECT, fMRI, EEG) and
neuroimaging techniques such as functional mag- cognitive paradigms (e.g., inhibitory control, select-
netic resonance imaging (fMRI), researchers have ive attention, working memory, and vigilance). They
begun examining the neural correlates of ADHD, found a consistent pattern of frontal dysfunction
resulting in a rapidly growing literature. with altered patterns of activity in anterior cingulate,
dorsolateral prefrontal, and ventrolateral prefrontal
cortices, as well as associated parietal, striatal, and
Conflict of interest statement: No conflicts declared. cerebellar regions. Despite broad consistencies,
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Published by Blackwell Publishing, 9600 Garsington Road, Oxford OX4 2DQ, UK and 350 Main Street, Malden, MA 02148, USA
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1052 Steven G. Dickstein et al.

Bush et al. noted multiple challenges in comparing the exception of response inhibition, this is not
results across studies, and cited difficulties in possible, as no individual construct has a sufficient
interpretation due to small sample sizes and meth- number of studies to date. Instead, it is more prac-
odological issues related to statistical correction for tical to study the commonalities across executive
multiple comparisons that impact rates of false function tasks in a systematic statistically driven
positives and false negatives. fashion, with the realization that some regions spe-
Aron and Poldrack (2005) examined the existent cific to an individual executive process may have
literature with a narrower focus on the neural cor- decreased detectability using this method. Support
relates of inhibitory control rather than the broader for this approach comes from the descriptive reviews
construct of executive processes. Their review already discussed (Aron & Poldrack, 2005; Bush et
included imaging, behavioral, and genetic studies in al., 2005), which noted a pattern of ADHD-related
patients with ADHD as well as healthy participants, hypofunction in specific frontal regions (e.g., anterior
along with basic animal studies. Their conclusions cingulate cortex) across studies in the existent lit-
support the hypothesis that dysfunctions in pre- erature, despite the heterogeneity of methods. Given
frontal cortex (specifically the right inferior pre- the large number of studies examining response
frontal cortex), basal ganglia, and the related inhibition in ADHD, we carried out a second meta-
neurotransmitter systems (dopaminergic, noradren- analysis focusing on this construct alone.
ergic, and serotonergic) underlie inhibitory deficits in One potential difficulty for a meta-analysis of
ADHD. neuroimaging in ADHD is that about a third of cur-
Here we build upon these prior efforts by using the rent studies do not provide direct comparisons be-
recently developed activation likelihood estimation tween patients with ADHD and healthy controls.
(ALE) (Lancaster, Laird, Fox, Glahn, & Fox, 2005; Instead, those studies have typically reported acti-
Laird et al., 2005a) technique to carry out a quanti- vations for each group (ADHD, control) individually,
tative voxel-wise meta-analysis of published func- with qualitative assessments about differences in the
tional neuroimaging studies of ADHD. While prior patterns observed for the two individual groups.
reviews have attempted to synthesize the literature, Alternatively, some studies have simply presented
a quantitative meta-analysis can provide a useful region of interest analyses. Furthermore, the small
method to assess the state of the field, and to provide sample sizes included in several of the studies
a plan for future research, for several reasons. First, reporting direct comparisons may limit their ability
quantitative meta-analytic techniques provide an to detect group differences. An important advantage
objective, unbiased, statistically-based approach to of the ALE approach is that we can overcome these
examine findings across studies, as opposed to the obstacles to some degree by carrying out separate
traditional ‘box-score’ or label-based qualitative meta-analyses for each group (ADHD, controls) and
methods (Laird et al., 2005b). Second, a voxel-wise then comparing the two meta-analyses statistically.
approach provides increased spatial resolution,
delineating not only large frontal sub-regions but
specific areas within them by optimally using data Methods
generated across functional imaging studies. The
Study selection
advantages of increased spatial distinction are sub-
stantial in the frontal lobes given the remarkable Neuroimaging studies comparing patterns of activity in
functional heterogeneity that is increasingly being patients with ADHD and healthy comparisons were
mapped at the level of sub-lobar regions (Stuss, found primarily by searching the PUBMED database
(http://www.pubmed.org) and Google Scholar (http://
Murphy, Binns, & Alexander, 2003; Miller & Cohen,
scholar.google.com/schhp?hl¼en&tab¼ws&q¼) using
2001; Wagner, 1999). Finally, a quantitative meta-
the keywords: ADHD, fMRI, PET, Executive Function,
analysis yields specific brain coordinates that are Inhibition, Working Memory, Child, Adolescent, Adult,
confirmed across multiple studies, thus helping to and Imaging. We then reviewed the reference lists of
filter out otherwise unavoidable spurious activations each of these articles to obtain additional papers. Four
representing type I errors. additional articles were included after the initial review
It is important to note that this is a novel appli- process. Three articles currently in press at the Ameri-
cation of the ALE meta-analytic methodology. Typ- can Journal of Psychiatry were provided by the editor
ically, researchers have used ALE to examine a with the permission of the authors, and one article that
particular cognitive construct across a set of studies had not appeared during our database searches was
within a relatively homogenous population (e.g., pointed out by an anonymous reviewer. Only articles
that reported activation foci as 3-D coordinates (x, y, z)
healthy adult volunteers) (Laird et al., 2005a,
in stereotactic space, examined active cognitive con-
2005b). Here, we use ALE to examine differences
structs, and presented results for individual participant
associated with ADHD across a set of studies groups were included. The 16 studies identified using
assessing executive function. Ideally, a separate our criteria are listed in Table 1. These studies yielded a
meta-analysis would be conducted for each indivi- total of 134 foci of activation for patients with ADHD
dual executive process as it relates to ADHD. How- and 180 foci of activation for controls. For the purpose
ever, given the infancy of the current literature, with of analysis, any foci that were reported according to the
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Meta-analysis of neuroimaging in ADHD 1053

Table 1 Data sources

Article Imaging modality N Task(s) Contrast(s)

Booth et al., 2005 fMRI (1.5T) 12 ADHD Visual search; Go-No go Nine stimuli vs. one
12 Controls stimulus; No-go vs. Go
Bush et al., 1999 fMRI (1.5T) 8 ADHD 8 Controls Counting Stroop Interference vs. neutral
(adults)
Durston et al., 2003 fMRI (1.5T) 7 ADHD 7 Controls Go-No go (Modified) No-go vs. Go
Ernst et al., 2003 PET 10 ADHD 12 Controls Decision-making gambling task Choice vs. No choice
(adults)
Pliszka et al., in press FMRI (2.0T) 17 ADHD 15 Controls Stop task Stop vs. Go; Successful stop
vs. Unsuccessful stop
Rubia et al., 2005 FMRI (1.5T) 16 ADHD 21 Controls Stop task Stop vs. Go
Schulz et al., 2004 FMRI (1.5T) 10 ADHD 9 Controls Go-No go No-go vs. Go
Schulz et al., 2005 FMRI (1.5T) 8 ADHD 8 Controls Stimulus and response Stimulus conflict
Conflict tasks vs. control and
location; Response
conflict vs. control; Combined
conflict condition vs. control
and location
Schweitzer et al., 2000 PET 6 ADHD 6 Controls Paced auditory Serial addition vs. Random
(adults) Serial addition task number vocalization
Schweitzer et al., 2004 PET 10 ADHD 11 Controls Paced auditory Serial addition vs. Random
(adults) Serial addition task number vocalization
Silk et al., 2005 FMRI (3.0T) 7 ADHD 7 Controls Mental rotation Mental rotation vs.
Fourier-transformed
noise patch
Smith et al., in press FMRI 19 ADHD 27 Controls Go-No go Motor-Stroop No-go vs. oddball trials;
Switch task Incongruent vs. congruent;
Switch vs. Repeat trials
Tamm et al., 2004 FMRI (1.5T) 10 ADHD 12 Controls Go-No go (modified) No-go vs. Go
Tamm et al., in press FMRI (1.5T) 14 ADHD 12 Controls Oddball task Oddball vs. Standard
stimulus
Vaidya et al., 2005 FMRI (3.0T) 10 ADHD 10 Controls Eriksen Flanker + Go-No go Incongruent vs. Neutral;
No-go vs. Neutral
Valera et al., 2005 FMRI (1.5T) 20 ADHD 20 Controls N-Back 2-back vs. ‘X’ vigilance task
(adults)

These studies contained a total of 134 foci of activation for patients with ADHD and 180 foci for controls. Unless specifically noted
above as ‘adults’, study participants were children and adolescents.

atlas of the Montreal Neurological Institute (MNI two separate meta-analyses were conducted, one using
coordinates) were converted to Talairach coordinates the foci reported for patients with ADHD and one using
using the algorithm implemented by Matt Brett the foci reported for controls. More specifically, for each
(mni2tal.m) (http://www.mrc-cbu.cam.ac.uk/Imaging/ group, activation likelihood estimates were calculated
Common/downloads/MNI2tal/mni2tal.m). Of the ten for each voxel by modeling each coordinate with an
functional neuroimaging studies of ADHD not included equal weighting using a 3-D Gaussian probability
in this meta-analysis, six studies were excluded be- density function with FWHM ¼ 10 mm. We next carried
cause they did not provide stereotactic coordinates out a permutation test to determine the voxel-wise sig-
(Ernst et al., 1994; Vaidya et al., 1998; Sunshine et al., nificance of the resulting ALE values. We made use of a
1997; Zang et al., 2005; Rubia et al., 2001; Teicher non-parametric statistical approach previously des-
et al., 2000), one contained no active cognitive task cribed by Turkeltaub et al. (2002), in which 5000 per-
(Ernst, Cohen, Liebenauer, Jons, & Zametkin, 1997), mutations were generated using the same number of
three examined only effects of medication treatment foci and FWHM as used to generate the ALE map. As
rather than effects of cognitive tasks (Anderson, Polcari, such, no assumptions were made with respect to the
Lowen, Renshaw, & Teicher, 2002; Teicher et al., 2000; distribution or spatial separation of these random foci
Schweitzer et al., 2003), and a final study was excluded (Laird et al., 2005a; Turkeltaub et al., 2002). Resulting
from analyses because results were not reported for statistical maps were corrected for multiple compari-
individual participant groups (Rubia et al., 1999). sons using false discovery rates (FDR), and then
thresholded at p < .05, corrected, with a cluster extent
threshold of 16 voxels. To directly compare patients
Meta-analytic techniques
with ADHD and controls, we used the ALE maps gene-
All meta-analyses were carried out using the activation rated for each group to calculate ALE difference maps,
likelihood estimation (ALE) technique (Turkeltaub, controls – ADHD and ADHD – controls. Each of these
Eden, Jones, & Zeffiro, 2002) implemented in BrainMap difference maps was entered into a permutation ana-
(Laird et al., 2005a). Based on the Talairach stereotactic lysis to generate voxel-wise statistical scores, as was
coordinates reported by the studies listed in Table 1, previously done for the individual meta-analyses.
 2006 The Authors
Journal compilation  2006 Association for Child and Adolescent Mental Health.
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1054 Steven G. Dickstein et al.

Given the existence of a sufficient number of studies ally and in the lentiform nucleus (portions of
to examine response inhibition specifically, we carried a putamen and globus pallidus) only on the right. A
second set of meta-analyses (ADHD only, controls only, significantly elevated probability of activation was
controls – ADHD, ADHD – controls) using the same also noted in the posterior cerebellum on the right
approach, but only included those studies examining which extended to the occipital lobe of patients with
response inhibition (Go No-go and Stop Tasks). To more
ADHD.
fully measure the effect of response inhibition on the
overall meta-analysis, we also created meta-analyses
using those tasks excluded from the response-inhibi- Controls>ADHD
tion meta-analyses.
Finally, to examine other possible sources of hetero- Consistent with models of hypofrontality, when the
geneity, additional separate meta-analyses were carried individual ALE maps for the two groups (ADHD,
out for the studies that included only child and adol- control) were compared statistically, controls dem-
escent participants (11 studies) and the studies that onstrated significantly greater probability of activa-
only included medication-naı̈ve participants (four tion in a variety of regions relative to patients with
studies). ADHD, including bilateral areas of frontal lobe as
well as areas of parietal lobe, and parts of striatum
(see Table 2 and Figure 1). More specifically, areas of
Results left ventral prefrontal cortex and DLPFC (BA 6, BA 8,
Controls only BA 13, BA 44), anterior cingulate cortex (BA 24, BA
32), bilateral parietal lobe (bilateral BA 7, right BA
Consistent with current models of executive function 40), right thalamus, and left middle occipital gyrus
and prior work using the specific tasks selected by (BA 19) showed a significantly greater probability of
ADHD investigators, our meta-analysis detected activation in controls than in patients with ADHD.
significantly elevated probabilities of activation in a There was also a significantly greater probability of
distributed network of brain regions both in frontal activation in controls compared with patients with
and posterior regions (see Table 2 and Figure 1). ADHD in an area centered at the right claustrum,
Frontal regions showed significantly elevated prob- covering 133 voxels, extending from insula (BA 13) to
abilities of activation in areas of anterior cingulate striatum (see Figure 1).
cortex (BA 32, BA 24), left dorsolateral prefrontal
cortices (DLPFC)(BA 6, BA 8), and bilateral inferior
prefrontal cortices (BA 13, BA 45). Additionally, sig- ADHD>Controls
nificantly elevated probabilities of activation were A few regions had a greater probability of activation
identified in right-sided thalamus, claustrum, insu- in patients with ADHD than in controls (see Table 2).
lar cortex (BA 13), and striatum, as well as bilateral Within the left frontal lobe, greater probabilities of
sub-regions of parietal lobe (bilateral BA 7, right BA activation were detected for insular cortex (BA 13)
40). An area of left occipital cortex (BA 19) was also and portions of middle frontal gyrus (BA 9, BA 10).
shown to have a significantly elevated probability of There was also an increased probability of activation
activation. in the left thalamus and the right paracentral lobule
(BA 5).
ADHD only
Medication-naı̈ve patients only
For patients with ADHD, similar to controls, our
meta-analysis demonstrated a distributed pattern of Of the 16 studies included in our meta-analyses,
regions with significantly elevated probabilities of four examined the neural correlates of ADHD in
activation (see Table 2 and Figure 1). With the medication-naı̈ve patients (Pliszka et al., in press;
exception of two large clusters in the left middle Rubia, Smith, Brammer, Toone, & Taylor, 2005; Silk
frontal gyrus, these clusters were generally smaller et al., 2005; Smith, Taylor, Brammer, Toone, & Ru-
and distributed over fewer structures than the bia, in press). Though not uncommon in the study of
clusters identified in the ALE maps from controls. psychiatric illness, the decision to include patients
Frontal regions showed significantly elevated prob- with a history of prior psychotropic medication
abilities of activation in areas of bilateral middle treatment can limit a study’s ability to definitively
frontal gyrus, and left medial frontal lobe (bilateral attribute group-differences to the underlying psycho-
BA 10, left BA 46, and right BA 6). Activations in pathology as opposed to past effects of treatment. In
anterior cingulate were particularly inconsistent, order to gain some insight into the likelihood that
with no cluster reaching significance. Significantly our findings could reflect past treatment with
elevated probabilities of activation in ventral pre- psychotropic medications as opposed to ADHD, we
frontal cortices were much more prominent in the carried out an exploratory meta-analysis limited to
left hemisphere, unlike in controls where they were the four studies examining ADHD in medication-
detected bilaterally. Significantly elevated probabili- naı̈ve patients. Though drastically less robust due to
ties of activation were detected in thalamus bilater- small sample size, we once again noted a pattern of
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Meta-analysis of neuroimaging in ADHD 1055

Table 2 Individual groups and group differences: all studies. Group differences: medication-naı̈ve participants. Regions of signi-
ficant elevated probability of activation

x y z Cluster size (voxels) p*

Controls only
Frontal lobe
Inferior frontal gyrus (BA 45)(L) )48 17 4 143 9.4 · 10)3
Middle frontal gyrus (BA 8)(L) )34 17 46 74 9.4 · 10)3
Insula (BA 13)(L) )34 25 13 65 8.5 · 10)3
Middle frontal gyrus (BA 6)(L) )24 )1 43 44 9.8 · 10)3
Insula (BA 13)(L) )40 )17 )7 34 8.2 · 10)3
Middle frontal gyrus (BA 8)(L) )40 28 38 24 7.7 · 10)3
Insula (BA 13)(R) 42 15 6 19 8.0 · 10)3
Medial wall
Cingulate gyrus (BA 32)(L) )4 22 37 370 9.5 · 10)3
Cingulate gyrus (BA 24)(L) )6 1 47 105 1.1 · 10)3
Parietal lobe
Precuneus (BA 7)(L) )24 )53 51 191 1.0 · 10)3
Parietal lobe (BA 40)(R) 28 )41 54 88 9.3 · 10)3
Postcentral gyrus (BA 40)(R) 60 )21 19 42 8.8 · 10)3
Superior parietal lobule (BA 7)(R) 26 )65 45 25 8.1 · 10)3
Basal ganglia/thalamus
Claustrum(striatum/insula)(R)** 26 19 0 238 9.9 · 10)3
Thalamus (R) 22 )28 1 76 8.8 · 10)3
Occipital lobe
Middle occipital gyrus (BA 19)(L) )46 )60 )6 25 8.1 · 10)3
ADHD only
Frontal lobe
Middle frontal gyrus (BA 46)(L) )40 14 20 827 9.9 · 10)3
Middle frontal gyrus (BA 10)(L) )34 46 12 216 7.7 · 10)3
Middle frontal gyrus (BA 6)(R) 36 3 38 77 8.1 · 10)3
Medial frontal lobe (BA 10)(L) )16 47 )6 23 7.0 · 10)3
Middle frontal gyrus (BA 10)(R) 36 38 5 17 6.9 · 10)3
Parietal lobe
Paracentral lobule (BA 5)(R) 12 )34 48 62 8.6 · 10)3
Precuneus (BA 7)(C) 0 )55 44 37 8.4 · 10)3
Inferior parietal lobule (BA 40)(L) )34 )47 45 24 7.7 · 10)3
Basal ganglia/thalamus
Thalamus (L) )12 )12 14 129 9.2 · 10)3
Thalamus (R) 24 )24 13 63 7.3 · 10)3
Lentiform nucleus (R) 10 3 1 40 7.7 · 10)3
Cerebellum
Cerebellum posterior, declive (R) 36 )64 )15 141 8.1 · 10)3
Controls>ADHD
Frontal lobe
Precentral gyrus (BA 44)(L) )50 15 6 73 9.5 · 10)3
Middle frontal gyrus (BA 8)(L) )34 17 46 65 9.4 · 10)3
Middle frontal gyrus (BA 6)(L) )24 )1 43 54 9.3 · 10)3
Inferior frontal gyrus (BA 13)(L) )34 27 12 18 8.2 · 10)3
Medial wall
Cingulate gyrus (BA 32)(L) )4 24 33 262 9.6 · 10)3
Cingulate gyrus (BA 24)(L) )6 1 47 92 1.0 · 10)2
Parietal lobe
Precuneus (BA 7)(L) )26 )53 53 121 1.0 · 10)2
Parietal lobe (BA 40)(R) 30 )41 54 77 9.2 · 10)3
Postcentral gyrus (BA 40)(R) 58 )21 19 32 8.6 · 10)3
Superior parietal lobule (BA 7)(R) 26 )65 45 21 1.0 · 10)4
Basal ganglia/thalamus
Thalamus (R) 22 )30 )1 37 8.6 · 10)3
Claustrum(striatum/insula)(R)** 26 19 0 133 8.9 · 10)3
Occipital lobe
Middle occipital gyrus (BA 19)(L) )46 )60 )6 26 7.9 · 10)3
ADHD>Controls
Frontal lobe
Insula (BA 13)(L) )40 14 17 293 1.0 · 10)2
Middle frontal gyrus (BA 9)(L) )42 9 35 30 8.6 · 10)3
Middle frontal gyrus (BA 10)(L) )38 42 8 30 8.4 · 10)3
Middle frontal gyrus (BA 9)(L) )32 20 33 21 9.0 · 10)3
Parietal lobe
Paracentral lobule (BA 5)(R) 12 )32 50 38 9.2 · 10)3

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1056 Steven G. Dickstein et al.

Table 2 Continued

x y z Cluster size (voxels) p*

Basal ganglia/thalamus
Thalamus (L) )12 )14 13 35 9.3 · 10)3
Studies of medication-naı̈ve participants only:
Controls>ADHD
Frontal lobe
Insula (BA 13)(R) 42 15 6 73 6.6 · 10)3
Medial frontal gyrus (BA 10)(R) 18 59 )5 18 5.5 · 10)3
Precentral gyrus (BA 4)(L) )54 )11 27 17 5.7 · 10)3
Medial wall
Cingulate gyrus (BA 32)(L) )2 26 27 17 5.5 · 10)3
Medial frontal gyrus (BA 10) 0 59 )7 17 5.5 · 10)3
Parietal lobe
Postcentral gyrus (BA 40)(R) 60 )22 17 83 7.4 · 10)3
Inferior parietal lobule (BA 40)(L) )48 )44 42 18 5.7 · 10)3
ADHD>Controls
Frontal lobe
Middle frontal gyrus (BA 9)(L) )38 16 22 179 6.7 · 10)3
Medial frontal gyrus (BA 10)(L) )16 47 )6 71 6.1 · 10)3
Temporal lobe
Fusiform gyrus (BA 37)(R) 42 )58 )10 20 6.0 · 10)3

BA ¼ Brodmann area, L ¼ left, R ¼ right, cluster threshold ¼ 16 voxels.

*False Discovery Rate (FDR) corrected p values.
**Area centered at claustrum extended from striatum to insula.

(a)
! C on t r o l s O nl y

(b)
!ADHD Only

(c)
Controls vs. ADHD

Controls > ADHD ADHD > Controls

Figure 1 ALE meta-analyses across studies of ADHD and controls (a) Activation likelihood estimation (ALE) meta-
analyses revealed an extensive pattern of significantly elevated probabilities of activation in regions of frontal lobe
(bilaterally), medial wall, and right-sided striatum for Controls. (b) Patients with ADHD show more localized areas of
significantly elevated probabilities of activation, predominantly in left frontal lobe. (c) To better compare the groups, a
difference map of results for Controls vs. patients with ADHD is shown. For all images: x ¼ )6, y ¼ 13, z ¼ 1
respectively, p < .05 corrected

significantly greater likelihood of activation in frontal also noted a pattern of greater likelihood of activation
and parietal regions for controls than patients with in some left prefrontal regions for patients with
ADHD (see Table 2). Similar to our prior analyses, we ADHD relative to controls. As such, the medication-
 2006 The Authors
Journal compilation  2006 Association for Child and Adolescent Mental Health.
 14697610, 2006, 10, Downloaded from https://acamh.onlinelibrary.wiley.com/doi/10.1111/j.1469-7610.2006.01671.x, Wiley Online Library on [27/07/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Meta-analysis of neuroimaging in ADHD 1057

naı̈ve only analysis does not support the notion that tions than controls, the medial frontal gyrus (BA 10)
our findings in the primary meta-analyses reflect the and the right paracentral lobule (BA 5).
impact of medications as opposed to ADHD. Admit-
tedly, caution should be taken in interpreting the
Executive processes excluding response inhibition
findings of the medication-naı̈ve meta-analysis, as
the low number of studies (n ¼ 4) clearly limits our ALE meta-analyses generated by excluding those
ability to detect group differences and potentially studies examining response inhibition specifically
decreases the stability of the findings. revealed a pattern of increased likelihood of activa-
tions seen for controls compared to subjects with
ADHD which mirrored the results from the meta-
Response inhibition only
analyses of the total combined studies except for a
In ALE meta-analyses generated using only studies lack of significantly greater likelihood of activation in
that specifically examined response inhibition, a the right inferior frontal lobe (a complete table of
more restricted pattern of increased likelihood of results for this subset of analyses is available upon
activations was seen for controls compared to sub- request from the corresponding author). Controls
jects with ADHD in the prefrontal cortices bilaterally were significantly more likely to have activations in
(left BA 47 and BA 6, right BA 44), cingulate cortex areas of the left frontal lobe (BA 8, BA 9, BA 13),
(BA 24), left parietal lobe (BA 7), and right caudate cingulate cortex (BA 10, BA 24, BA 32), bilateral
(see Table 3). There were only two areas in which parietal lobe (bilateral BA 7, right BA 5, left BA 3),
ADHD subjects had significantly more likely activa- right lentiform nucleus, right thalamus, as well as

Table 3 Individual groups and group differences: response inhibition only. Regions of significant elevated probability of activation

x y z Cluster size (voxels) p*

Controls only
Frontal lobe
Inferior frontal gyrus (BA 47)(L) )44 19 2 104 6.8 · 10)3
Precentral gyrus (BA 6)(L) )38 1 34 77 6.0 · 10)3
Insula (BA 13)(R) 42 15 6 65 6.7 · 10)3
Insula (BA 13)(L) )42 6 17 53 6.2 · 10)3
Medial wall
Cingulate (BA 32) 0 12 35 18 5.9 · 10)3
Basal ganglia/striatum
Caudate (R) 14 2 23 37 6.0 · 10)3
ADHD only
Frontal lobe
Paracentral lobule (BA 5)(R) 12 )34 49 140 7.2 · 10)3
Insula (BA 13)(L) )38 12 19 57 6.3 · 10)3
Inferior frontal gyrus (BA 47)(R) 34 24 )7 21 5.5 · 10)3
Inferior frontal gyrus (BA 47)(L) )32 25 )2 20 5.8 · 10)3
Insula/Claustrum (L) )30 17 6 20 5.8 · 10)3
Medial wall
Medial frontal gyrus (BA 9)(R) 4 45 15 16 5.6 · 10)3
Temporal lobe
Superior temporal gyrus (BA 39)(R) 40 )58 28 18 5.6 · 10)3
Cerebellum
Cerebellum posterior, declive (R) 34 )68 )19 17 5.6 · 10)3
Controls>ADHD
Frontal lobe
Inferior frontal gyrus (BA 47)(L) )44 19 2 78 6.5 · 10)3
Precentral gyrus (BA 44)(R) 44 15 6 67 6.6 · 10)3
Precentral gyrus (BA 6)(L) )34 )1 38 22 6.0 · 10)3
Medial wall
Cingulate gyrus (BA 24)(R) 2 9 34 36 6.0 · 10)3
Parietal lobe
Superior parietal lobe (BA 7)(L) )42 )61 55 16 1.0 · 10)3
Basal ganglia
Caudate (body) (R) 14 0 23 40 5.9 · 10)3
ADHD>Controls
Frontal lobe
Medial frontal gyrus (BA 10)(L) )14 51 )7 16 1.0 · 10)3
Parietal lobe
Paracentral lobule (BA 5)(R) 12 )34 48 132 7.2 · 10)3

BA ¼ Brodmann area, L ¼ left, R ¼ right, cluster threshold ¼ 16 voxels.

*False Discovery Rate (FDR) corrected p values.

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1058 Steven G. Dickstein et al.

areas of the left occipital cortex (BA 18, BA 19) and While our findings are primarily centered in frontal
sub-cortical areas of the right temporal lobe (BA 37). regions, they should not be over-interpreted as sug-
Subjects with ADHD showed significantly higher gesting that frontal dysfunction alone underlies
probability of activation than controls in areas of left ADHD. All of the tasks from studies included in our
frontal lobe in insula (BA 13) and middle frontal gy- meta-analysis were designed to isolate executive
rus (BA 9, BA 10) and right precentral gyrus (BA 9), processes, which are primarily supported by fronto-
along with bilateral thalamus and right lentiform striatal and fronto-parietal neural networks. Despite
nucleus. differences in the specific executive process being
examined across studies, our findings confirm the
effectiveness of such an approach in detecting group
Children and adolescents only differences in a set of frontal regions common to the
While most studies included in our meta-analyses processes examined. Of course, our findings may be
focused on ADHD in children and adolescents, five an underestimate for some individual processes that
studies examine ADHD in adult populations instead may uniquely activate a broader range of regions.
(Bush et al., 1999; Ernst et al., 2003; Schweitzer et al., Evidence for this comes from our findings of ADHD-
2000, 2004; Valera, Faraone, Biederman, Poldrack, & related caudate hypofunction in the response-inhi-
Seidman, 2005). These studies were included in our bition-only meta-analysis, but not in the larger
analyses in order to maximize our ability to detect combined meta-analysis. To fully establish the pri-
ADHD-related differences across studies. However, macy of frontal dysfunction in ADHD, future studies
one possible risk of this approach is that the neural will need to provide a more comprehensive exam-
correlates of ADHD in adults may differ to some de- ination of executive function, as well as other cog-
gree from the findings in children and adolescents, nitive domains, using tasks known to produce
resulting in the introduction of unintended hetero- consistent patterns of activity in other regions con-
geneity that may decrease our ability to detect ADHD- sidered putative sources of dysfunction (e.g., cere-
related differences. In order to address this concern, bellum, ventral striatum, parietal cortices). In the
all meta-analyses were repeated with the five adult absence of such a literature, we can only conclude
studies excluded (all of which were non-inhibition that robust evidence of frontal hypofunction exists in
studies). Removal of the heterogeneity introduced by ADHD.
the adult studies did not result in detection of addi- Given the prominence of response-inhibition tasks
tional regions reflecting group differences. in the ADHD literature, the present work provided a
Overall, the results of our meta-analyses excluding separate analysis focusing on this subset of studies
adult studies were highly similar to those obtained alone, once again finding evidence of frontal hypo-
when the adult studies were included, though function, albeit less widespread. More specifically, a
markedly less robust. Such reductions in effect size meta-analysis carried out across ten contrasts iso-
were expected due to a smaller sample size (see lating response inhibition revealed relatively small
Table 4 and Figure 2). While most group differences areas of frontal hypofunction within inferior frontal,
remained detectable at p < .05 corrected (see medial wall regions (including anterior cingulate
Table 4), a more lenient threshold of p < .005 un- cortex) and the precentral gyrus. The limited findings
corrected was employed in Figure 2 to demonstrate for the meta-analysis focusing on inhibition alone
the high degree of similarity to overall (adult + child/ may reflect the smaller number of studies included,
adolescent) group differences. While these findings though ten contrasts should be enough to obtain
do not exclude the possibility that the neural corre- relatively robust findings based on prior work.
lates of ADHD may differ in children and adolescents Alternatively, the suggestion that response inhibition
versus adults, they do suggest a reasonable degree of relies on a fairly focal network within the brain (Aron
overlap. et al., 2005) may be responsible for the sparse re-
sults found here. In order to further examine this
possibility, we carried out a meta-analysis of the
non-inhibition studies alone, finding a highly similar
Discussion
pattern to the combined meta-analysis, suggesting
In line with models implicating frontal lobe dys- that the findings for non-inhibition studies tend to
function in ADHD, our meta-analyses provided be more robust than those focusing on response
objective, unbiased evidence of a consistent pattern inhibition.
of frontal hypoactivity in patients with ADHD com- With respect to further examination of frontal
pared to controls across 16 peer-reviewed neuro- dysfunction in ADHD, we believe that a recent dis-
imaging studies. The frontal hypoactivity noted in tinction between types of executive function may be
patients with ADHD is widely distributed, affecting usefully explored in future efforts. Zelazo and col-
anterior cingulate, dorsolateral prefrontal, inferior leagues differentiate between ‘hot’ (i.e., affective) and
prefrontal, and orbitofrontal cortices, as well as ‘cool’ (i.e., non-affective) subtypes of executive func-
related regions, such as portions of the basal ganglia tion, involving orbitofrontal and dorsolateral pre-
and parietal cortices. frontal areas, respectively. As reviewed elsewhere
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Meta-analysis of neuroimaging in ADHD 1059

Table 4 Group differences: child/adolescent participants only. Regions of significant elevated probability of activation

x y z Cluster size (voxels) p*

Controls>ADHD
Frontal lobe
Middle frontal gyrus (BA 9)(R) 50 18 29 34 5.0 · 10)3
Inferior frontal gyrus (BA 47)(L) )24 28 )9 31 5.1 · 10)3
Superior frontal gyrus (BA 6)(R) 20 )3 71 28 5.3 · 10)3
Inferior frontal gyrus (BA 9)(R) 52 4 30 27 5.3 · 10)3
Precentral gyrus (BA 4)(L) )34 )27 56 26 5.3 · 10)3
Middle frontal gyrus (BA 6)(L) )20 )2 56 24 5.3 · 10)3
Middle frontal gyrus (BA 10)(L) )42 41 23 22 5.4 · 10)3
Insula (BA 13)(L) )34 25 9 21 5.5 · 10)3
Superior frontal gyrus (BA 6)(L) )4 12 57 21 5.4 · 10)3
Superior frontal gyrus (BA 8)(L) )2 30 44 21 5.3 · 10)3
Medial wall
Cingulate (BA 31) 0 )24 39 29 5.3 · 10)3
Cingulate gyrus (BA 24)(R) 12 )4 49 24 5.4 · 10)3
Medial frontal gyrus (BA 6)(L) )6 0 49 21 5.5 · 10)3
Parietal lobe
Precuneus (BA 7)(L) )16 )71 50 33 5.1 · 10)3
Postcentral gyrus (BA 3)(R) 38 )28 52 31 5.1 · 10)3
Superior parietal lobule (BA 5)(L) )18 )39 60 28 5.2 · 10)3
Precuneus (BA 7)(L) )8 )63 39 26 5.4 · 10)3
Postcentral gyrus (BA 3)(R) 24 )35 52 25 5.4 · 10)3
Superior parietal lobule (BA7)(R) 26 )65 48 25 5.3 · 10)3
Basal ganglia
Lentiform nucleus (R) 24 15 0 21 5.5 · 10)3
Occipital lobe
Middle occipital gyrus (BA 19)(L) )28 )78 12 76 5.6 · 10)3
Temporal lobe
Superior temporal gyrus (BA 22)(L) )50 )47 14 32 5.3 · 10)3
ADHD>Controls
Frontal lobe
Inferior frontal gyrus (BA 9)(L) )44 16 22 201 5.8 · 10)3
Middle frontal gyrus (BA 10)(L) )38 44 8 109 6.0 · 10)3
Middle frontal gyrus (BA 9)(L) )30 22 33 32 5.1 · 10)3
Middle frontal gyrus (BA 46)(R) 38 40 3 31 5.1 · 10)3
Precentral gyrus (BA 9)(R) 36 5 36 27 5.2 · 10)3
Inferior frontal gyrus (BA 44)(R) 52 10 15 25 5.4 · 10)3
Middle frontal gyrus (BA 6)(L) )26 14 57 21 5.1 · 10)3
Medial wall
Anterior cingulate gyrus (BA 32)(R) 6 35 19 25 5.3 · 10)3
Medial frontal gyrus (BA 8)(L) )2 19 46 25 5.1 · 10)3
Parietal lobe
Postcentral gyrus (BA 2)(R) 40 )25 32 25 5.3 · 10)3
Basal ganglia
Caudate (R) 6 17 15 31 5.2 · 10)3
Lentiform nucleus (R) 10 1 )1 16 5.6 · 10)3
Temporal lobe
Superior temporal gyrus (BA 38)(L) )40 6 )15 18 5.5 · 10)3

BA ¼ Brodmann area, L ¼ left, R ¼ right, cluster threshold ¼ 16 voxels.

*False Discovery Rate (FDR) corrected p values.

(Castellanos, Sonuga-Barke, Milham, & Tannock, target regions associated with ‘hot’ executive func-
2006), despite the emphasis of the current ADHD tion and affectively laden processing, such as the
literature on deficits in ‘cool’ executive function, a orbitofrontal cortices and related ventral striatal
large-scale meta-analysis of behavioral studies areas.
involving executive function found that while statis- Although a consistent theme in the current ADHD
tically significant, effect sizes of these deficits were literature, some caution should be taken in making
modest at best (Willcutt et al., 2005). Of note, group inferences about the significance of ‘frontal hypo-
differences extending in the present meta-analysis activity.’ While typically thought to reflect a decrease
extended into left orbitofrontal cortex, a putative ‘hot’ in the intensity of activation in a particular region, it
area, despite the tendency of most studies to use may also reflect decreases in the spatial extent of
tasks designed to assess the ‘cool’ DLPFC and cin- activations, more spatial dispersion of activations,
gulate regions. These findings support the expansion decreases in functional connectivity, or more statis-
of the scope of experimental paradigms to expressly tical noise (possibly due to factors such as more
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1060 Steven G. Dickstein et al.

ADHD vs. Controls

Controls vs. ADHD ADHD > Controls

Figure 2 ALE meta-analyses for child and adolescent participants only. While similar in distribution to meta-ana-
lyses including both adults and children, results from the child-only analyses were less robust. For all images: x ¼
)5, y ¼ 13, z ¼ 1 respectively, p < .005 uncorrected

variable responses in or greater motion in patients). other related concern is that even studies reporting
Similarly, it is important to note that our analyses stereotactic coordinates focused their results based
suggested that some regions show locally greater on regions of interest rather than on whole brain
activations for patients with ADHD when compared analyses, potentially missing other putative sources
to controls, suggesting that ADHD is not purely of dysfunction, such as cerebellum and ventral stri-
accounted for by hypofunction. These increases may atum.
reflect compensatory recruitment of accessory brain Variability in statistical approaches employed in
regions to accomplish a given cognitive task or the literature is another potential methodological
alternatively an abnormally increased activation that concern, in particular with respect to corrections for
interferes with typically recruited brain regions. multiple comparisons and threshold selection. These
Further work is merited to clarify the nature of both differences impact rates for false positives and false
findings of decreased and increased activity associ- negatives. ALE addresses this issue by weighting the
ated with ADHD. findings of each peer-reviewed study equally and
Despite our success in demonstrating consisten- relying upon patterns of consistency across studies
cies in findings across studies, specific methodo- to overcome this concern. Two notable risks of this
logical limitations should be considered with respect approach are that studies with less stringent
to the current functional neuroimaging literature thresholds can introduce a larger number of foci,
examining ADHD. First, only nine of the studies in- and that higher- and lower-powered studies have
cluded in this meta-analysis reported direct com- equal weighting. In our meta-analyses, such con-
parisons between participants with ADHD and founds are not more likely to impact one group than
healthy controls and those that do provide such di- the other, as we only included studies that provide
rect comparisons tend to use small sample sizes, results for patients with ADHD and controls. In a
thereby limiting their ability to detect subtle be- study with a lenient threshold, both groups will
tween-group differences. By creating a difference benefit and have a greater number of foci, thus
map between ALE estimates of participants with nullifying the effect on group differences. Further-
ADHD and controls we were able to include the seven more, as a test of the possibility that differences in
studies that did not report direct comparisons and number of foci alone may be driving our group dif-
thus create a meta-analysis across all 16 of the ferences, we matched the two groups for number of
studies in the literature that examined cognitive foci by randomly selecting and dropping foci from
constructs reported results for individual participant the control group and reran the meta-analyses (Laird
groups and reported results in stereotactic coordi- et al., 2005a). No marked differences in the pattern
nates. Second, multiple studies in the literature did of results were observed.
not report their results in standard 3-D stereotactic Finally, the presence of substantial heterogeneity
coordinates, and only reported their findings in with regard to study samples is another notable
terms of anatomically determined regions of interest. limitation of the current literature. In particular,
Without the use of standardized 3-D coordinates, differences in the age ranges examined across stud-
comparisons between these studies must rely on ies may be a source of concern. Both age-related
more subjective approaches and cannot be included differences in the expression of ADHD symptoms
in voxel-based, statistical meta-analyses such as the and potential age-related differences in patterns of
present study. Despite exclusion of these studies, functional activity can complicate the integration of
our results are broadly consistent with those of findings across studies. At present, there are not yet
qualitative reviews that included both studies with a sufficient number of studies of ADHD in either
and without stereotactic coordinates. Finally, an- adult or pediatric populations to distinguish age-
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Meta-analysis of neuroimaging in ADHD 1061

related or developmental effects. Other notable Bush, G., Frazier, J.A., Rauch, S.L., Seidman, L.J.,
sources of heterogeneity include medication history, Whalen, P.J., Jenike, M.A., et al. (1999). Anterior
ADHD subtypes, medication status during imaging, cingulate cortex dysfunction in attention-deficit/
and age of onset. Despite these multiple sources of hyperactivity disorder revealed by fMRI and the
heterogeneity, our meta-analyses suggests that counting stroop. Biological Psychiatry, 45, 1542–
1552.
commonalities across patients with ADHD in the
Bush, G., Valera, E.M., & Seidman, L.J. (2005).
range of tasks examined to date are not obliterated Functional neuroimaging of attention-deficit/hyper-
by the undoubted heterogeneity encompassed within activity disorder: A review and suggested future
this diagnostic category. directions. Biological Psychiatry, 57, 1273–1284.
In conclusion, our findings draw attention to the Castellanos, F.X., Sonuga-Barke, E.J., Milham, M.P., &
presence of consistent differences in the neural Tannock, R. (2006). Characterizing cognition in
substrates of cognitive function between partici- ADHD: Beyond executive dysfunction. Trends in
pants with and without a diagnosis of ADHD across Cognitive Sciences, 10, 117–123.
studies. This has significant implications for future Castellanos, F.X., & Tannock, R. (2002). Neuroscience
studies of the neuropathophysiology of ADHD, of attention-deficit/hyperactivity disorder: The
highlighting consistently identified regions across search for endophenotypes. Nature Reviews Neuro-
science, 3, 617–628.
studies. The results of this meta-analysis do not
Durston, S., Tottenham, N.T., Thomas, K.M., Davidson,
support simpler models which posit that ADHD is M.C., Eigsti, I.M., Yang, Y.H., et al. (2003). Differen-
strictly a disorder resulting from deficits of activity in tial patterns of striatal activation in young children
a few isolated brain regions. Thus, a continued with and without ADHD. Biological Psychiatry, 53,
examination of the cognitive substrates of ADHD is 871–878.
needed. Ernst, M., Cohen, R.M., Liebenauer, L.L., Jons, P. H., &
Zametkin, A.J. (1997). Cerebral glucose metabolism
in adolescent girls with attention-deficit/hyperactiv-
Acknowledgements ity disorder. Journal of the American Academy of
Child and Adolescent Psychiatry, 36, 1399–1406.
This work was supported by the National Institute of Ernst, M., Kimes, A.S., London, E.D., Matochik, J.A.,
Mental Health (T32 MH 067763). Eldreth, D., Tata, S., et al. (2003). Neural substrates
The authors would like to thank Dr. Michael Sey- of decision making in adults with attention deficit
ffert, Dr. Amy Krain, Dr. Clare Kelly, and Dr. Manely hyperactivity disorder. American Journal of Psychia-
Ghaffari for their assistance in the preparation of the try, 160, 1061–1070.
manuscript. Ernst, M., Liebenauer, L.L., King, A.C., Fitzgerald, G.A.,
Cohen, R.M., & Zametkin, A. J. (1994). Reduced brain
metabolism in hyperactive girls. Journal of the Amer-
ican Academy of Child and Adolescent Psychiatry, 33,
Correspondence to 858–868.
Michael P. Milham, NYU Child Study Center, 14th Laird, A.R., Fox, P.M., Price, C.J., Glahn, D.C., Uecker,
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USA; E-mail: [email protected] lysis: Controlling the false discovery rate and per-
forming statistical contrasts. Human Brain Mapping,
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 2006 The Authors

Journal compilation  2006 Association for Child and Adolescent Mental Health.