Available online at www.sciencedirect.

com

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Brain development in ADHD
Lisa A Friedman and Judith L Rapoport
Attention-deficit/hyperactivity disorder (ADHD) is a common
neurodevelopmental disorder with underlying brain anatomical
and functional measures, as well as familial/genetic factors that
are major foci of neuropsychiatric research. Advances in
imaging technology have shown structural and functional brain
differences between individuals with and without ADHD.
Longitudinal studies have enabled the elucidation of
differences in developmental course. Studies comparing
persisting and remitting cases of ADHD are particularly
promising. Therapeutic doses of psychostimulants normalize
many measures of brain anatomy and function.
Addresses
Child Psychiatry Branch, National Institutes of Mental Health, National
Institutes of Health, Bethesda, MD, United States
Corresponding authors: Friedman, Lisa A (Lisa.Friedman@nih.gov) and
Rapoport, Judith L (Judy.Rapoport@nih.gov)

Current Opinion in Neurobiology 2015, 30:106111

This review comes from a themed issue on Neuropsychiatry
Edited by Steven Hyman and Raquel Gur
For a complete overview see the Issue
Available online 9th December 2014
http://dx.doi.org/10.1016/j.conb.2014.11.007
0959-4388/# Published by Elsevier Ltd.

Introduction

brain development remain the dominant perspective

today.
Magnetic resonance imaging (MRI) has been a critical
tool for examining brain development in ADHD. MRI is a
safe, noninvasive method for gathering detailed data, as it
does not rely on ionizing radiation [8]. This enables
imaging of young children, as well as prospective longitudinal studies. While differences were also documented
with positron emission tomography [9], the technique
relies on radioactive tracers making health risks prohibitive in children.
This highly selective review focuses on two key areas:
neurodevelopmental trajectories and the effects of psychostimulants on brain development and function in
individuals with ADHD.

Anatomic studies of brain development in

ADHD
There is consensus regarding atypical brain structure in
ADHD, implicating multiple neural systems including
attention, cognitive control, and working memory [10,11].
Volumetric analyses have shown global reductions in total
brain volume, most prominent in the prefrontal cortex,
basal ganglia, cerebellum, and parieto-temporal regions
[8,1113]. Volume loss in the right striatum has been
highlighted as a central feature of ADHD in voxel-based
studies, which are agnostic, that is, not limited to preplanned analyses [12].

Attention-deficit/hyperactivity disorder (ADHD) is a

neurodevelopmental disorder characterized by inattentiveness, hyperactivity, and/or impulsivity [1]. Symptoms
of ADHD emerge before the age of 12 and are present in
at least two different settings. So defined, ADHD affects
about 5% of children [2]. While some outgrow the
disorder, symptoms persist beyond adolescence in as
many as 65% of individuals [3]. This highly variable
course has allowed researchers to examine brain development in relation to symptomology, treatment, and
outcome [4]. Stimulant medication remains the treatment
of choice, although questions remain regarding the influence of psychostimulants on neurodevelopment [5,6].

Most brain MRI studies have been cross-sectional, but

prospective longitudinal studies have enabled detection
of abnormalities in developmental trajectories in
ADHD. In a large prospective study in children, Shaw
and colleagues showed that in young subjects, prefrontal
cortical development was delayed in ADHD compared
to typical individuals [14,15]. This held true for both
cortical thickness and surface area, and was most evident in executive cortical regions controlling cognitive
processes, including motor and attention planning.
Cross-sectional studies have subsequently leant support, indicating symptomatic correlations with developmental trajectories in gray matter volume and cortical
thickness [16,17].

Advances in technology have enabled researchers to

elucidate neuroanatomical and neurophysiological underpinnings of ADHD that were previously undetectable.
Indeed, in the 1970s, ADHD was termed Minimal Brain
Dysfunction owing to its strong association with neurologic disorders [7]. Presumed subtle abnormalities in

Cross-sectional studies have found neuroanatomical

abnormalities in adults with ADHD that resemble those
seen in studies of pediatric patients. For example, Makris
and colleagues found that ADHD adults had a thinner
cortex in regions supporting attention and executive
function, namely the right dorsolateral prefrontal cortex,

Current Opinion in Neurobiology 2015, 30:106111

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Brain development in ADHD Friedman and Rapoport 107

the anterior cingulate cortex, and inferior parietal lobule

[18]. Only one study has used longitudinal data to link
developmental trajectories with adult outcome [19].
Shaw and colleagues compared ninety-two ADHD subjects, primarily with combined type at baseline, with
184 typically developing controls. Participants were
imaged both as children (mean age 10.7) and adults (mean
age 23.8), uniquely showing change in relation to clinical
course. At follow-up in adulthood, inattentive symptoms
were more persistently present than hyperactive and
impulsive symptoms; 60% of patients no longer met
criteria for ADHD. Rates of cortical thinning were associated with ADHD symptoms in posterior portions of the
cingulate gyrus, dorsolateral and medial prefrontal cortices, and precuneus. Among those who remitted, cortical
thickness converged toward typical dimensions
(Figure 1). By contrast, those with persisting ADHD
showed a fixed thinning of the cortex. The smaller cortical
thickness in Shaws population compared to controls
aligns with findings by Makris et al. of cortical thinning
in adults with continuing ADHD symptoms [18,19].
Other studies have implicated cerebellar developmental
trajectories and hippocampal volumes in the outcome
severity of ADHD symptoms [20,21].
The delineation of neurodevelopment trajectories and
continuous nature of ADHD symptoms raises the question of whether these anatomical trajectories are continuous across typical development. It appears that, in fact,
decreased regional cortical thickness and slowing of cortical development are associated with inattention symptoms in healthy children [22]. Ducharme and colleagues
prospectively followed 357 children (672 MRI scans total)

and examined 257 children cross-sectionally [22]. In

younger children, greater inattentive symptoms were
associated with a thinner right lateral and left medial
prefrontal cortex; this link was absent in the adolescent
group. Longitudinal analyses indicated that children with
higher levels of inattentive symptoms had a slower rate of
cortical thinning, reaching trend levels in the right ventrolateral cortex and regions of the lateral and medial prefrontal cortex. This is consonant with a study by Shaw and
colleagues, where children with higher levels of hyperactivity/impulsivity had a slower rate of cortical thinning,
particularly in prefrontal, frontal premotor, medial prefrontal, and cingulate regions [23].

Functional magnetic resonance imaging

(fMRI) studies and brain development in ADHD
Perspectives on etiological brain models of ADHD have
broadened in recent years, as the focus moves from
anatomically anomalous regions to network dysfunction
[24,25]. In the absence of longitudinal imaging studies,
only tentative developmental inferences can be drawn
from comparison of separate childhood and adult studies.
The default mode network (DMN), encompassing the
precuneus/posterior cingulate cortex, medial prefrontal
cortex, and dorsal anterior cingulate cortex, has drawn
particular interest in resting-state studies. Interestingly,
both child and adult ADHD studies indicate mixed
findings, with some reports of increased [26] and others
of decreased [24,27,28] synchronous activity within this
network. Future research needs to examine the link
between ADHD course and disruptions to typical developmental patterns, including shifts from diffuse to more

Figure 1

Right hemisphere

(a)

Cortical thickness (mm)

Typical

Persisters

Left hemisphere

(b)

Remitters

Typical

3.85

3.75

3.75

3.65

3.65

3.55

3.55

3.45

3.45

3.35

Persisters

Remitters

3.25

3.35
8

10 12 14 16 18 20 22
Age (years)

10 12 14 16 18 20 22
Age (years)
Current Opinion in Neurobiology

Trajectory of cortical thickness in right and left medial/cingulate cortices [19]. Typically developing subjects (healthy controls) and persisting subjects
(those with continuing ADHD) followed the same developmental course (P > 0.1), while remitting subjects (those who no longer met criteria for ADHD)
had significantly different slopes from both of these groups (all P < 0.01), suggesting compensatory changes. Adapted from Shaw et al., 2013 [19].
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Current Opinion in Neurobiology 2015, 30:106111

108 Neuropsychiatry

focal activation and a bolstering of long-range over shortrange connectivity [29].

We have been struck by the range of experimental
approaches in task-related fMRI studies, and for a
detailed examination of task-based studies we refer the
reader elsewhere (see Cortese et al. [30]) [30]. A comprehensive review by Rubia and colleagues notes that
anomalies have been found in the left IFC, left inferior
parietal lobe, and right lateral cerebellum in timing tasks,
SMA in motor response inhibition tasks, left ACC in
interference inhibition tasks, and ventral striatum in
reward tasks [31]. From a developmental perspective,
adults with persisting ADHD have anomalies in frontoparietal circuits associated with attention. It is important
to note the heterogeneity of symptomology within
ADHD, and recent neuropsychological findings indicate
differences in cognitive and temporal control among
individuals with ADHD [32]. We concur with Rubias
speculation that structural developmental delay in
ADHD is associated with functional delay, but longitudinal studies are needed to provide additional support [31].

Diffusion tensor imaging (DTI) in ADHD

DTI enables visualization of white matter tracts in the
brain by measuring the diffusion of water molecules, and
deriving global measures of directionality, such as fractional anisotropy (FA) [33]. Meta-analyses of childhood
ADHD studies find decreased FA mainly within association tracts linking cognitive control and attentional cortical networks (e.g. the right superior longitudinal
fasciculus, linking the inferior parietal lobule and lateral
prefrontal cortex) as well as projection tracts integrating
cortical and lower brain processing centers (e.g. the corticospinal tract) [34]. A similar picture emerges from
cross-sectional studies of adult ADHD [35,36]. A recent
study found that decreased FA within multiple association and projection tracts emerged when data were
analyzed based on childhood diagnosis, suggesting these
differences represent a trait marker [37]. The group with
persisting ADHD also tended to have more pronounced
white matter anomalies than those in the remitted group,
consonant with gray matter thickness and volume findings in the same subjects. While limited knowledge of
underlying tissue differences complicates the interpretation of decreased FA, DTI remains a promising for
investigating connectivity development in ADHD.

Stimulant treatment and neurodevelopment in

ADHD
Stimulant drugs are the treatment of choice for ADHD
and have a high success rate, with positive patient outcomes in almost all who try both methylphenidate and
dextroamphetamine at various doses [38,39]. There have
been concerns regarding potential neurodevelopmental
effects of maintaining long-term stimulant treatments in
children and adolescents with ADHD [6]. Here, we
Current Opinion in Neurobiology 2015, 30:106111

review evidence indicating that psychostimulants have

normalizing effects on both brain function and structure.
It is critical to note that all studies conducted to date are
observational, and that we refer to normalization only as
inferred from observational studies with nonrandom
medication assignment.
Psychostimulants appear to normalize brain activity both
during resting state and task-based studies [5,4042]. In
a study of resting state activity, Peterson and colleagues
found that psychostimulants brought the DMN activity in
ADHD youth closer to control levels, and boosted the
synchronicity of activity between the DMN and the
lateral prefrontal cortex [40]. A recent meta-analysis of
task-based fMRI studies indicated that chronic psychostimulant treatment of ADHD did not affect activation in
regions involved in task inhibition but did affect the right
caudate, which is active during attentional tasks [42]. In
another meta-analysis, right dorsolateral prefrontal cortical activity during timing tasks was found to occur at the
same levels in controls and ADHD patients on psychostimulants compared to unmedicated ADHD patients
[41]. The patients receiving stimulants were tested after
a medication-free period lasting at least 18 hours. A metaanalysis by Rubia and colleagues found that activity in the
right inferior frontal cortex increased after an acute dose
of methylphenidate in ADHD children [5].
Several reports find that stimulants, in the low doses
prescribed for ADHD, also normalize neuroanatomy.
Anterior cingulate and cerebellar vermis dimensions were
closer to control levels in ADHD youth taking psychostimulants compared to their medication-nave counterparts
[43,44]. A meta-analysis of voxel-based morphometric
studies found the magnitude of volume loss in the right
striatum to be greater in cohorts with higher proportions of
psychostimulant-nave participants [12]. In one study,
Shaw and colleagues examined change in cortical thickness
for 43 children and adolescents with ADHD, 24 who were
treated with psychostimulants and 19 who were not [45].
The medicated and unmedicated groups did not differ in
rate of cortical change across most of the cerebral cortex,
demonstrating that psychostimulants were not associated
with lagging cortical development. However, trajectory
differences did emerge in the left dorsolateral prefrontal
cortex, where those on psychostimulants had more typical
rates of cortical change. Importantly, however, this was not
associated with clinical outcome.
There are several possible explanations for the impact of
psychostimulants on neurodevelopment in ADHD:
either the stimulant itself acts directly to make brain
development more typical or, more likely, the drug
enables function-driven anatomic normalization. Future
studies should examine the effects of psychostimulants
on structure, function, and connectivity over a wide timeframe, as there is a dearth of knowledge in this area [5].
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Brain development in ADHD Friedman and Rapoport 109

Longitudinal imaging components in future clinical trials

could address this, but long-term randomized studies are
likely to be infeasible.

Familial/genetic impact on neurodevelopment

in ADHD
Childhood and adult ADHD are known to be highly
heritable, with estimates around 40%, and it is unsurprising
that twin studies suggest that the course of symptoms is
also heritable [4649]. Indeed, family studies indicate
greater risk for ADHD among first-degree relatives of
probands with persisting ADHD compared to remitting
[50,51]. Identifying genes conferring this heritability has
been challenging, and it is hoped that intermediate imaging of phenotypic traits linking clinical diagnosis and
familial etiology might help accelerate gene discovery
[49]. In one task-based study, boys with ADHD and their
unaffected siblings had less activity in the ventral prefrontal and inferior parietal cortices during inhibitory tasks
compared to controls [52]. These findings were particularly
interesting given the lack of performance differences between groups. Structurally, an earlier study found
decreased gray and white matter in the left occipital cortex
and decreased gray matter in the right prefrontal cortex in
ADHD boys and in their unaffected siblings compared to

controls [13]. In contrast, the ADHD group had smaller

cerebellar volume compared to the unaffected sibling and
control groups, suggesting that gray and white matter
findings were heritable, while the cerebellar volume difference was related to disease state.
A recent study conducted by Pironti and colleagues found
anatomic intermediate phenotypes in adult ADHD, as
both adults with ADHD and their unaffected first-degree
relatives had decreased gray matter volume in the right
inferior frontal gyrus and greater white matter volume in
the posterior region of the right inferior fronto-occipital
fasciculus compared to controls [53]. ADHD subjects and
their unaffected first-degree relatives also both performed
poorer than controls on sustained attention tasks. Reproducibility of results remains crucial for the emerging and
promising area of genetic neuroimaging.

Future directions
Recent advances in ADHD research have been exciting,
opening new avenues of study (Figure 2). This is particularly true for structural and functional imaging as they
relate to disease phenotype, progression, treatment, and
heritability. Sadly, practitioners remain far from being
able to use research data in the clinic. Although modern

Figure 2

Persisting ADHD
Fixed cortical thinning in the
cingulate gyrus, precuneus,
and dorsolateral and medial
prefrontal cortices
Cerebellar and hippocampal
developmental trajectories are
linked with symptom severity

Childhood-onset disorder
Delayed prefrontal cortical development
Cortical thickness trajectories correlate
with symptom severity
Stimulants can normalize anatomic and
functional measures, independent of
clinical outcome

Remitting ADHD
Normalization of cortical thinning
integrity of white matter tracts
compared to persisting cases
Current Opinion in Neurobiology

Overview of recent research examining brain development in ADHD.

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Current Opinion in Neurobiology 2015, 30:106111

110 Neuropsychiatry

technologies prove excellent for elucidating differences

on a population level, current tools and approaches to data
analysis do not provide results that can be used diagnostically. It will be exciting to see how advances in science
and medicine address these issues in the coming years.

Conflict of interest statement

Nothing declared.

Acknowledgement
The authors would like to thank Philip Shaw, MD, PhD, for helpful
discussions of this manuscript.

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