European Neuropsychopharmacology (2013) 23, 1151–1164

www.elsevier.com/locate/euroneuro

REVIEW

MR imaging of the effects of methylphenidate

on brain structure and function in
Attention-Deficit/Hyperactivity Disorder
Lizanne J.S. Schwerenn, Patrick de Zeeuw, Sarah Durston

Neuroimaging Lab, Department of Psychiatry, Rudolf Magnus Institute of Neurosciences, University

Medical Centre Utrecht, The Netherlands

Received 18 April 2012; received in revised form 4 September 2012; accepted 26 October 2012

KEYWORDS Abstract
Childhood ADHD; Methylphenidate is the first-choice pharmacological intervention for the treatment of Attention-
Methylphenidate; Deficit/Hyperactivity Disorder (ADHD). The pharmacological and behavioral effects of methylpheni-
Structural MRI; date are well described, but less is known about neurochemical brain changes induced by
Functional MRI methylphenidate. This level of analysis may be informative on how the behavioral effects of
methylphenidate are established. This paper reviews structural and functional MRI studies that have
investigated effects of methylphenidate in children with ADHD. Structural MRI studies provide
evidence that long-term stimulant treatment may normalize structural brain changes found in the
white matter, the anterior cingulate cortex, the thalamus, and the cerebellum in ADHD. Moreover,
preliminary evidence suggests that methylphenidate treatment may normalize the trajectory of
cortical development in ADHD. Functional MRI has provided evidence that methylphenidate
administration has acute effects on brain functioning, and even suggests that methylphenidate
may normalize brain activation patterns as well as functional connectivity in children with ADHD
during cognitive control, attention, and during rest. The effects of methylphenidate on the
developing brain appear highly specific and dependent on numerous factors, including biological
factors such as genetic predispositions, subject-related factors such as age and symptom severity, and
task-related factors such as task difficulty. Future studies on structural and functional brain changes
in ADHD may benefit from inclusion strategies guided by current medication status and medication
history. Further studies on the effects of methylphenidate treatment on structural and functional MRI
parameters are needed to address unresolved issues of the long-term effects of treatment, as well as
the mechanism through which medication-induced brain changes bring about clinical improvement.
& 2012 Elsevier B.V. and ECNP. All rights reserved.

n
Correspondence to: University Medical Centre Groningen, Department of Child and Adolescent Psychiatry, Room: 0.N.14, Huispostcode
CC10, Hanzeplein 1, 9700 RB Groningen, The Netherlands. Tel.: +31 6 5375 2270.
E-mail address: l.j.s.schweren@umcg.nl (L.J.S. Schweren).

0924-977X/$ - see front matter & 2012 Elsevier B.V. and ECNP. All rights reserved.
http://dx.doi.org/10.1016/j.euroneuro.2012.10.014
1152
1. Introduction
Attention-Deficit/Hyperactivity Disorder (ADHD) is the most
common developmental disorder in childhood, estimated to
affect three to seven percent of school-age children and
2.5 percent of adults globally (Polanczyk et al., 2007; Simon
et al., 2009). ADHD is characterized by age-inappropriate
attention problems, and/or impulsivity and hyperactivity
(American Psychiatric Association, 2000). The clinical presen-
tation of ADHD is heterogeneous and comorbidity with opposi-
tional defiant disorder (ODD), conduct disorder (CD), other
neurodevelopmental disorders, mood and anxiety disorders is
frequent (Pliszka, 2000). ADHD is regarded as an etiologically
multi-factorial disorder, with most likely both genetic and
environmental factors influencing the clinical presentation
(American Psychiatric Association, 2000; Plomp et al., 2009).
Treatment with psycho-stimulants remains the most
common pharmacological intervention in ADHD and is
effective for the majority of affected individuals
(e.g. Barbaresi et al., 2006). Methylphenidate, available in
various forms of delivery, is commonly regarded as the first-
choice stimulant intervention (Meijer et al., 2009). Treat-
ment is generally well tolerated and side-effects are
typically mild (Greenhill et al., 2002; Wilens et al., 2006).
Robust behavioral effects of stimulants have been reported,
and include reduced symptoms of hyperactivity and inatten-
tion (Conners, 2002; MTA Cooperative Group, 1999; Spencer
et al., 1996; Swanson et al., 1993).
The pharmacological properties of methylphenidate have
been well investigated (Heal et al., 2009). Changes in the
levels of dopamine and norepinephrine in the brain have
frequently been associated with ADHD (Del Campo et al.,
2011). A growing body of evidence suggests that methylphe-
nidate increases the levels of dopamine and norepinephrine
in the synaptic cleft, thereby stimulating their receptors
(e.g. Arnsten, 2006; Kuczenski and Segal, 1997; Volkow
et al., 2001). However, the question remains how these
neurochemical methylphenidate-induced changes in the
synapse result in the clinical and behavioral effects of
methylphenidate treatment (Winstanley et al., 2006). More-
over, much remains unknown about the manifestation of such
neurochemical effects in structural brain development, and
its behavioral correlates. One approach to addressing these
questions is to make use of modern neuroimaging techniques
such as magnetic resonance imaging (MRI). Neuroimaging has
the potential to provide researchers with relevant biomar-
kers, or clinically relevant characteristics that may be
objectively measured as an indicator of pharmacological
responses to therapeutic intervention (Minzenberg, 2012).
In recent years, structural and functional neuroimaging
has been used to investigate the effects of medication on
macroscopic brain measures in a variety of psychiatric
disorders, including depression and schizophrenia (Honey
and Bullmore, 2004). Not only have these studies contrib-
uted to our understanding of the brain mechanisms which
may drive the clinical effect of pharmacological treatments
for these psychiatric disorders, but they have also advanced
our understanding of the mechanisms underlying these
disorders themselves (Doyle et al., 2005). Whereas direct
pharmacological effects of methylphenidate have been
investigated using the more invasive methods of positron
emission tomography (PET) and SPECT, magnetic resonance
L.J.S. Schweren et al.
imaging (MRI) is a tool more apt to studying macroscopic
brain effects of methylphenidate. MRI has undergone rapid
technological progression in recent years, allowing for the
investigation of both structural and functional correlates of
pharmacological treatment. In addition, MRI is a noninvasive
tool, permitting its use in children, and is available in many
research institutions (Honey and Bullmore, 2004).
Since the advent of MRI, several reports have appeared
on the effects of methylphenidate on brain measures
derived from MRI. Recent extensive and high-quality studies
of methylphenidate effects (e.g. Rubia et al. 2009, 2011a,
2011b) have shown significant effects of methylphenidate.
Owing to the high degree of specialization of such investiga-
tions, an increasingly detailed and complex picture emerges
of the effects of methylphenidate on the developing brain.
In an attempt to integrate such detailed descriptions of
methylphenidate effects, this paper reviews the effects of
childhood methylphenidate treatment on structural and
functional MRI measures. Both acute and long-term effects
of psycho-stimulant treatment will be addressed.
2. Method
This paper provides a systematic narrative review of the currently
available MRI studies addressing the macroscopic effects of methyl-
phenidate on the developing brain. The online databases of the US
National Library of Medicine and the National Institutes of Health
(PubMed), of the American Psychological Association (PsychInfo),
and Web of Science were searched for relevant articles. In addition,
reference lists of relevant articles were searched. Keywords for the
search included ADHD, methylphenidate, MRI, fMRI, and neuroima-
ging. All abstracts that met these search criteria were read, and we
selected those articles that (1) were written in English,
(2) addressed the effects of methylphenidate administration during
childhood (as opposed to drug administration during adulthood) in
individuals with ADHD (as opposed to in other diagnostic groups),
and (3) used magnetic resonance imaging (MRI) as a neuroimaging
tool. When eligibility for inclusion in the review was doubted, the
authors discussed and included the paper only upon consensus. Our
search resulted in a total of 27 articles published between
November 1998 and March 2012, including 26 original research
articles and one meta-analysis/review article.
3. The effects of methylphenidate on brain
structure in children with ADHD
A large and growing number of structural MRI studies
document neuroanatomical changes between children with
ADHD and typically developing controls (Seidman et al.,
2005; Valera et al., 2007; Durston et al., 2009). A decrease
in global brain volume has been reported in children and
adolescents with ADHD compared to typically developing
children, as well as local volume reductions in the frontal
cortex, caudate nucleus, the cerebellum, and the corpus
callosum, among other brain regions (Seidman et al., 2005;
Valera et al., 2007). However, the long-term effects of
stimulant treatment on these structural changes have
received little attention. Studies that have specifically
targeted such analyses are summarized in Table 1. Impor-
tantly, all studies investigating the effects of stimulant
treatment on structural MRI measures are naturalistic in
nature, and all except one (Shaw et al., 2009) employ a
MRI in ADHD
cross-sectional design (Table 1). Although this approach may
be the most feasible approach to studying long-term treat-
ment effects in children, the limitations of naturalistic,
cross-sectional study designs need to be kept in mind when
interpreting the results.
A small number of volumetric studies have compared
volumes of specific brain regions (usually gray matter)
between children with ADHD who were medication-naı̈ve,
children with ADHD who had been using medication, and
typically developing children. An early study investigated
total cerebral and cerebellar gray matter volume, as well as
gray matter volume in the four major lobes, in these three
groups. Compared to typically developing children, both
medicated and medication-naı̈ve subjects with ADHD
showed reduced gray matter volumes, suggesting that gray
matter volumes may not be affected by methylphenidate
treatment (Castellanos et al., 2002). More recently, the
majority of studies have turned to a hypothesis-driven
region of interest (ROI) approach, where the volume of an
a priori defined brain region was compared between groups.
With this approach, medication effects have been found in
the anterior cingulate cortex (ACC) (Semrud-Clikeman
et al., 2006), the pulvinar nucleus of the thalamus (Ivanov
et al., 2010), and in the posterior inferior cerebellum
(Bledsoe et al., 2009). Compared to typically developing
children, children with ADHD who had not been treated with
stimulants had significant volume reductions in these
regions. These ADHD-related volume reductions did not
occur, or were attenuated, in children who had been
medicated with psycho-stimulants. No such effect of stimu-
lant treatment was found in the caudate nucleus
(Castellanos et al., 2002), although one study investigating
a small sample of children with ADHD, the majority of them
diagnosed with co-morbid CD, suggested smaller caudate
nucleus volumes in previously medicated children with
ADHD compared to medication-naı̈ve children with ADHD
(Bussing et al., 2002).
Another approach to investigating structural changes in
the brain involves data-driven methods, where large brain
areas are investigated without an a-priori hypothesis, such
as with voxel-based morphometry (VBM) or cortical thick-
ness measurements. In VBM, individual scans are normalized
to a template brain, effectively comparing gray and white
matter volume between groups in each voxel of the brain,
rather than in specific anatomical brain regions of interest
(Ashburner and Friston, 2000). In a meta-analysis of VBM
studies in ADHD, a medication effect was found in the right
basal ganglia (Nakao et al., 2011). Across individuals with
ADHD, gray matter volume in the right caudate nucleus was
decreased. However, the percentage of medicated subjects
in the studies included in this meta-analysis correlated
positively with gray matter volume in the right caudate
nucleus. In studies with a larger percentage of medicated
children, right caudate nucleus volume was larger, thus
more normal, compared to in studies including a smaller
percentage of medicated children. No such medication
effect was found in the left precuneus that showed
increased volume in children with ADHD compared to
controls (Nakao et al., 2011). Cortical thickness analyses
provide a more direct measure of the thickness of the outer
gray matter layer of the cerebrum than volumetric analyses
can provide. Shaw et al. (2009) applied such analyses in a
1153
unique longitudinal study, and found that unmedicated
children with ADHD showed excessive cortical thinning
compared to typically developing children during adoles-
cence, whereas children with ADHD receiving stimulant
medication during the period of study did not. This study
suggests that stimulant treatment may reduce the rate of
cortical thinning in frontal and parieto-occipital regions
during adolescence.
Methylphenidate treatment may also affect measures of
white matter structure (Table 1). For example, cerebral
white matter volume was found to be reduced in medica-
tion-naı̈ve children with ADHD compared to typically devel-
oping children, but also compared to previously medicated
children with ADHD. In fact, children with ADHD with a
history of psycho-stimulant use showed no changes in total
white matter volume, or in white matter volume in any of
the four major lobes, suggesting that methylphenidate
treatment may normalize white matter volume reductions
in children with ADHD (Castellanos et al., 2002). In line with
this, two studies investigating white matter volume that
included previously medicated subjects with ADHD only,
reported no evidence for white matter volume reduction
(Batty et al., 2010; Carmona et al., 2005). Unfortunately, in
a meta-analysis of volumetric studies, Valera et al. (2007)
were unable to assess possible effects of stimulant medica-
tion on white matter volume, due to a lack of information
regarding medication status and history. A recent study that
investigated the microstructure of frontal-striatal white
matter tracts in children with ADHD using diffusion tensor
imaging (DTI) found decreased structural connectivity
within these tracts (De Zeeuw et al., 2012). An exploratory
analysis of the effects of stimulant medication compared
subjects that had been medicated for a relatively long
period with subjects that had been medicated for a shorter
period. No significant effect of treatment duration on
microstructural abnormalities was found (De Zeeuw et al.,
2012). Thus, white matter volume may be affected by the
use of stimulant medication, but the exact nature of these
changes requires further investigation.
In conclusion, structural MRI studies have provided evi-
dence that stimulant treatment may normalize specific, but
not all, structural brain abnormalities found in children with
ADHD, in both gray and white matter.
4. The effects of methylphenidate on
patterns of brain activation in children with
ADHD
In contrast to the few structural MRI studies investigating
the effects of methylphenidate, there have been numerous
functional MRI (fMRI) studies on the acute effects of
methylphenidate (Table 2). Such studies can be divided into
those investigating spontaneous brain activation while at
rest (resting-state fMRI), and those investigating task-
related brain activation. Two resting-state fMRI studies,
employing T2 relaxometry as an indirect measure of cere-
bral blood volume, suggested that methylphenidate may
have an acute normalizing effect on striatal (Teicher et al.,
2000) and cerebellar (Anderson et al., 2002) activation in
boys with ADHD during rest. Task-related fMRI studies on the
effects of methylphenidate have been more numerous and
1154 L.J.S. Schweren et al.

Table 1 Structural magnetic resonance imaging studies investigating the effects of methylphenidate treatment in children
with ADHDa.

Study Year Main findings Comments

Castellanos 2002 Design TDC vs. ADHDon vs. ADHDoff. Volumetric study of the gray and white matter in frontal,
et al. temporal, parietal and occipital lobes, basal ganglia and cerebellum
Subjects NTDC = 139, NADHD-off = 103, NADHD-on = 49; age range 5–19
Findings Children with ADHD had smaller cerebral volumes, smaller cerebellar volumes, and
smaller temporal gray matter volumes than TDC. MPH affected WM but not GM volumes.
WM volumes in non-medicated children with ADHD were smaller than in TDC, while
medicated children with ADHD did not show WM volume reductions
Limitations 4, 5

Bussing et al. 2002 Design ADHDoff vs. ADHDon

Subjects NTDC = 19, NADHD-off = 7, NADHD-on =5; age range 8–12
Findings Caudate nucleus volumes were smaller in medicated children with ADHD when
compared to medication-naı̈ve children with ADHD
Limitations 1, 2, 4, 5, 6

Semrud- 2006 Design TDC vs. ADHDoff vs. ADHDon

Clikeman
et al.
Subjects NTDC = 21, NADHD-off = 14, NADHD-on = 16; age range 9–15
Findings Caudate nucleus and ACC volume were investigated. MPH did not affect caudate
nucleus volume. Compared to in TDC, right ACC volume was decreased in medication-
naı̈ve children with ADHD, but not in medicated children with ADHD. A similar trend was
found in the left ACC
Limitations 4, 5, 6

Bledsoe et al. 2009 Design TDC vs. ADHDoff vs. ADHDon

Subjects NTDC = 15, NADHD-off = 14, NADHD-on = 18; mean age =11.5(2.5)
Findings Overall cerebellar volume was the same in all three groups. There were no volumetric
group differences in the anterior or posterior superior vermis of the cerebellum. The
inferior vermis of the cerebellum was smaller in non-medicated children with ADHD
compared to both medicated children with ADHD and TDC
Limitations 4, 5, 6

Shaw et al. 2009 Design ADHDoff vs. ADHDon vs. template of cortical development based on TDC participants
Subjects NTDC = 294, NADHD-off = 19, NADHD-on = 24, age range 9–20
Findings At baseline, no group differences in cortical thickness were found between the three
groups, but both ADHD groups contained children with a history of stimulant medication. At
follow-up, cortical thickness did not differ between controls and medicated children with
ADHD, while non-medicated children with ADHD showed a higher rate of cortical thinning
in the IFG, the right precentral gyrus, and right parieto-occipital gyrus
Limitations 3, 5, 7

Ivanov et al. 2010 Design TDC vs. ADHDoff vs. ADHDon

Subjects NTDC = 59, NADHD-off = 15, NADHD-on = 31, age range 8–18
Findings Children with ADHD had reduced regional volumes of thalamic surfaces, including the
pulvinar nucleus. Medicated children with ADHD had larger pulvinar volumes than their
non-medicated peers
Limitations 4, 5, 6, 7

De Zeeuw et al. 2012 Design TDC vs. ADHD, and ADHDlong-medication vs. ADHDshort-medication
Subjects NTDC = 34, NADHD = 30, NADHD-long-medication = 13, NADHD-short-medication = 13, age range 6–16
Findings Microstructural abnormalities were observed in frontostriatal WM in children with
ADHD. Medication duration (long vs. short) was calculated relative to the children’s
age. Exploratory analyses showed no effect of treatment duration on these
abnormalities
Limitations 4, 5, 6

Nakao et al. 2011 Design TDC vs. ADHD, meta-regression of 9 pediatric VBM datasets
Subjects NTDC = 198, NADHD = 202
MRI in ADHD 1155

Table 1 (continued )

Study Year Main findings Comments

Findings In a VBM meta-analysis of regional GM volumes, children with ADHD showed GM volume
decrease in the right caudate nucleus, and GM volume increase in the left precuneus
cortex. In studies including a larger percentage of medicated children with ADHD, right
caudate nucleus volume was larger, thus more normal, compared to in studies including
a smaller percentage of medicated children with ADHD. No medication effect was found
in the precuneus cortex
Limitations 4, 5, 7

ADHDon, children with ADHD receiving stimulant treatment; ADHDoff, children with ADHD not receiving stimulant treatment; TDC,
typically developing controls; MPH, methylphenidate; CD, conduct disorder; GM, gray matter; WM, white matter; ACC, anterior
cingulate cortex; IFG, inferior frontal gyrus; VBM, voxel-based morphometry. Study limitations are coded as follows: 1=small sample
size (No45 or n per group/conditiono15); 2=no direct between-group comparison between TDC, ADHDmedicated and ADHDnon-medicated
is reported; 3=medication history prior to study participation is unknown/not reported; 4= cross-sectional study design: no within-
subject analysis of medication effects; 5=naturalistic study design: no randomized clinical trial; 6 =selective analyses of brain regions;
7=medication group/condition includes pharmacological treatment other than MPH.
a
ADHD, Attention-Deficit/Hyperactivity Disorder.

have often focused on cognitive domains implicated in
ADHD, and where performance is known to improve with
methylphenidate administration. A fairly consistent overall
picture of the acute effects of methylphenidate adminis-
tration emerges across various experimental designs:
During tasks tapping cognitive control, the ability to inhibit
inappropriate responses in favor of more appropriate ones,
methylphenidate appeared to normalize brain activation pat-
terns in children with ADHD by enhancing activation in
frontostriatal circuits (Epstein et al., 2007; Lee et al., 2010;
Rubia et al., 2011b; Vaidya et al., 1998). A similar upregulation
of activation towards activation levels of typically developing
children was found in parietal brain regions (Rubia et al.,
2011a). Furthermore, methylphenidate administration was
found to overcome deficits in the suppression of default mode
network (DMN) activity, or activity within a network of brain
regions typically deactivated during goal-directed behavior:
during cognitive control tasks, children with ADHD were shown
to fail to suppress activation within this network, and methyl-
phenidate was found to restore DMN suppression towards the
levels of typically developing children (Peterson et al., 2009).
The effects of methylphenidate on behavioral measures
of attention problems are well established (e.g. MTA
Cooperative Group, 1999). Cognitive tasks measuring
aspects of attention, such as the ability to sustain attention
over time, or to divide attentional resources amongst
subtasks, are frequently used in fMRI studies of ADHD.
Methylphenidate appeared to at least partially normalize
brain activation patterns in children with ADHD during
divided attention (Rubia et al., 2009; Shafritz et al.,
2004). In addition, methylphenidate has been shown to
restore functional connectivity, or synchronized activity, in
disparate but functionally related brain regions, in networks
involved in attention in children with ADHD (Rubia et al.,
2009). Interestingly, methylphenidate administration may
also elicit non-normalizing, additional activity in the brain.
During vigilance, a basic form of sustained attention,
methylphenidate administration was found to elicit com-
pensatory activation in the prefrontal cortex of children
with ADHD that was not evident in typically developing
children (Rubia et al., 2009).
By contrast, studies investigating the effects of methyl-
phenidate on activation patterns during working memory
tasks have yielded inconsistent results. During working
memory, stimulant administration elicited increases of
activation in the frontal cortex (Prehn-Kristensen et al.,
2011) and in frontal-parietal networks (Wong and Stevens,
2012), but not in the striatum (Prehn-Kristensen et al.,
2011). However, opposing findings of reduction of prefrontal
cortex activity by methylphenidate administration
(Sheridan et al., 2010) or no effect of medication on
frontal-striatal activation (Kobel et al., 2009) have also
been reported. The lack of a control group in some of these
studies (Sheridan et al., 2010; Wong and Stevens, 2012) and
the absence of a placebo condition in others (Kobel et al.,
2009; Prehn-Kristensen et al., 2011), may contribute to the
conflicting findings, and limits the interpretation of the
results. Studies investigating stimulant effects on regional
functional connectivity during working memory tasks have
similarly yielded inconsistent results. In a pilot study in
adolescent girls with ADHD, stimulant medication decreased
functional connectivity during a working memory task
(Sheridan et al., 2010). By contrast, Wong and Stevens
(2012) found that stimulant medication increased functional
connectivity between frontostriatal brain structures and
other brain regions in children with ADHD during a working
memory task. However, since both studies did not include a
control group, it is unclear how these methylphenidate-
induced changes compare to functional brain connectivity
during working memory in typically developing children.
In contrast to the numerous studies investigating the
acute effects of methylphenidate administration, only two
studies have investigated the effects of long-term methyl-
phenidate treatment on brain activation patterns in chil-
dren with ADHD. Overall, after wash-out, methylphenidate
treatment appeared not to translate into long-lasting
alterations of brain activation patterns, nor into normal-
ization of functional brain development. During tasks tap-
ping aspects of cognitive control (Konrad et al., 2007; Pliszka
1156 L.J.S. Schweren et al.

Table 2 Functional magnetic resonance imaging studies investigating the effects of methylphenidate administration in
childhood ADHDa.

Domain Study Subjects Main findings Comments

Resting state Teicher et al. NTDC =6 ADHD vs. TDC Children with ADHD showed lower bilateral putamen activation, but normal
(2000) NADHD = 11 thalamic and caudate activation
Age range MPH effects MPH increased putamen activation in hyperactive children with ADHD, but
6–12 decreased putamen activation in non-hyperactive children with ADHD. MPH did
not affect thalamic or caudate activation
Limitations 1, 4, 5, 7
Anderson et al. NTDC =6 ADHD vs. TDC No analyses
(2002)
NADHD = 10 MPH effects MPH decreased activity of the cerebellar vermis, but not the cerebellar
Mean age hemispheres, in hyperactive children with ADHD. MPH increased activity of the
9.6(1.6) cerebellar vermis in non-hyperactive children with ADHD
Limitations 1, 3, 4, 5, 7

Response inhibition Vaidya et al. NTDC =6 ADHD vs. TDC Children with ADHD showed decreased striatal activation, and increased frontal
(1998) NADHD = 10 activation
Age range MPH effects MPH increased striatal activation in children with ADHD, but decreased striatal
8–13 activation in typically developing subjects. MPH increased frontal activation in
both children with ADHD and typically developing children
Limitations 1, 4, 7
Zang et al. NTDC =9 ADHD vs. TDC Typically developing children showed a ‘neuronal Stroop effect’ in brain
(2005) NADHD = 9 activation patterns, in which brain activation during non-congruent Stroop-trials
Age range was larger than during congruent Stroop-trials. Children with ADHD showed the
9–15 opposite pattern, congruent trials eliciting more brain activation than non-
congruent trials
MPH effects MPH tended to restore the neuronal Stroop effect in children with ADHD towards
the pattern seen in typically developing children
Limitations 1, 3, 7, 9
Pliszka et al. NTDC =15 ADHD vs. TDC Overall, comparable activation was found in the ACC, dorsolateral PFC, and
(2006) NADHD = 17 ventrolateral PFC, in typically developing children, medication-naı̈ve children
Age range with ADHD, and previously medicated children with ADHD. During incorrect
9–15 responses, typically developing children showed increased ACC activation
compared to during correct responses, while medication-naı̈ve children with
ADHD showed the opposite pattern
MPH effects One year MPH treatment increased ACC activation during incorrect responses,
but not to TDC levels
Limitations 1, 5, 6, 7
Epstein et al. NTDC =9 ADHD vs. TDC Children with ADHD showed decreased activation in the frontal lobe, the ACC,
(2007) NADHD = 20 the inferior parietal cortex, and caudate nucleus
Age range
7–9
MPH effects MPH increased activation in the frontal lobe, the ACC, the inferior parietal
cortex, the caudate nucleus and the cerebellum
Limitations 1, 3, 7
Peterson et al. NTDC =20 ADHD vs. TDC During a Stroop task, children with ADHD showed less prominent task-related
(2009) NADHD = 16 deactivation of the DMN than typically developing subjects. Functional
Age range connectivity between the Lateral PFC and the ACC was reduced in children with
7–18 ADHD
MPH effects MPH restored task-related deactivations in the DMN, and increased functional
connectivity between the LPFC and the ACC
Limitations 4
Lee et al. (2010) NADHD = 8 MPH effects During interference suppression, MPH increased activation in the right PFC.
Age range There were no effects of MPH during response inhibition
9–11
Limitations 1, 2, 3, 4, 9
Rubia et al. NTDC =13 ADHD vs. TDC During interference inhibition, boys with ADHD showed reduced activity in the
(2011a) NADHD = 12 right inferior PFC, left striatum and thalamus, mid-cingulate/SMA region, and
Age range left superior temporal lobe
10–16
MPH effects MPH administration resulted in an upregulation of activity in the right inferior
prefrontal cortex and in premotor areas in children with ADHD. While on MPH,
children with ADHD no longer showed activity reduction in the right PFC or
striato-thalamic areas
Limitations 1

Working memory Kobel et al. NTDC =12 ADHD vs. TDC

(2009) NADHD = 14
MRI in ADHD 1157

Table 2 (continued )

Domain Study Subjects Main findings Comments

Children with ADHD showed less activation in the frontal and parietal regions,
and failed to recruit the cerebellum. Left sided frontal and parietal activation
was more reduced than right sided activation
Age range MPH effects No effects of MPH were found
9–13 Limitations 1, 4, 10
Sheridan et al. NADHD =5 MPH effects MPH decreased PFC activation and functional connectivity between frontal and
(2010) Age range subcortical regions. MPH increased connectivity between the MFG and the
11–17 cerebellar vermis
Limitations 1, 2, 3, 4, 7, 8, 10
Prehn-Kristensen NTDC = 12 ADHD vs. TDC In the non-distracted task, children with ADHD showed reduced frontal
et al. (2011) NADHD =12 activation compared to typically developing children. In the distracted task,
Age range children with ADHD showed a lack of caudate nucleus activation
10–17
MPH effects MPH restored frontal activation during the non-distracted task to normal levels.
MPH did not restore caudate nucleus activation during the distracted task
Limitations 1, 4, 10
Wong and NADHD =18 MPH effects Stimulant medication increased the magnitude of frontoparietal network
Stevens (2012) Age range activation during a working memory task. Moreover, stimulant medication
11–17 increased regional functional connectivity between frontoparietal network
structures and other brain regions
Limitations 2, 3, 4

Attention Shafritz et al. NTDC = 14 ADHD vs. TDC During tasks of selective and divided attention, children with ADHD showed less
(2004) NADHD =27 activation in the left basal ganglia and the middle temporal gyrus
Age range
12–20
MPH effects MPH increased activation in the left basal ganglia, but not in the middle
temporal gyrus
Limitations –
Konrad et al. NTDC = 14 ADHD vs. TDC Whereas typically developing children showed increase in ACC and TPJ
(2007) NADHD =16 activation during attention processes over the course of one year, children with
Mean age ADHD (regardless of medication status) did not
11.3(1.3)
MPH effects MPH did not elicit developmentally appropriate increases in ACC and TPJ
activation. However, whereas non-medicated children showed developmentally
inappropriate activation of the insula and striatum during reorienting of
attention, this possibly compensatory activation was not present in children that
received one year of stimulant treatment
Limitations 1, 3, 6
Rubia et al. NTDC = 13 ADHD vs. TDC During selective attention, children with ADHD showed reduced activation and
(2009) NADHD =13 functional connectivity in fronto-striato-parieto-cerebellar networks

Age range MPH effects MPH increased fronto-striato-cerebellar and parieto-temporal activation, as well
10–16 as fronto-striatal and fronto-cerebellar connectivity
Limitations 1

Reward processing Rubia et al. NTDC = 13 ADHD vs. TDC During reward processing, children with ADHD showed increased orbito-frontal
(2009) NADHD =13 and superior temporal activation
Age range
10–16
MPH effects MPH decreased orbito-frontal activation
Limitations 1
Stoy et al. (2011) NTDC = 12 ADHD vs. TDC Activation in the ventral striatum and OFC were equal in TDC adults, adults with
NADHD- ADHD who had been treated during childhood, and adults with ADHD who had not
untreated =12
NADHD-
treated =11
Mean age MPH effects During loss avoidance, insula activation was lower in drug-naı̈ve subjects in
27.5(4.6) comparison to both TDC and previously treated groups
Limitations 1, 5, 6, 7

Error Rubia et al. NTDC = 13 ADHD During failed response inhibition, or error monitoring, boys with ADHD showed
processing (2011b) NADHD =12 vs. TDC reduced brain activation in the dorsomedial and left ventrolateral PFC, the
Age range thalamus, cingulate, and parietal areas. During successful response inhibition,
10–16 boys with ADHD showed underactivation in the right medial temporal and
inferior parietal lobe, the precuneus and the cerebellum
MPH effects During both failed and successful inhibition, MPH restored activation patterns to
the levels of typically developing children. No differences between brain
1158 L.J.S. Schweren et al.

Table 2 (continued )

Domain Study Subjects Main findings Comments

activation patterns of children with ADHD on MPH and typically developing

children were observed
Limitations 1

Emotional Schlochtermeier NTDC =10 ADHD vs. TDC No analyses

et al. (2011)

Processing NADHD- MPH effects MPH-naı̈ve adults with childhood ADHD, but not adults with ADHD who had been
untreated = 10 treated with MPH during childhood, showed decreased activation in the
NADHD- subgenual cingulate and the ventral striatum compared to TDC
treated =10
Mean age
28.4(5.2)
Limitations 1, 5, 6, 7

ADHDon, subjects with ADHD receiving stimulant treatment; ADHDoff, subjects with ADHD not receiving stimulant treatment; TDC,
typically developing control subjects; MPH, methylphenidate; ACC, anterior cingulate cortex; VBM, voxel-based morphometry; TPJ,
temporo-parietal junction; PFC, prefrontal cortex; DMN, default mode network; RI, response inhibition; MFG, medial frontal gyrus.
Study limitations are coded as follows: 1=small sample size (n per group/conditiono15); 2=absence of control group/condition; 3=no
direct between-group comparison between TDC, ADHDon-medication and ADHDoff-medication is reported; 4=medication history prior to
study participation is unknown/not reported; 5=cross-sectional study design: no within-subject analysis of medication effects;
6=naturalistic study design: no randomized clinical trial; 7=selective analyses of brain regions; 8=medication group/condition
includes pharmacological treatment other than MPH; 9=statistical testing is not reported for all contrasts of interest; 10=absence of
placebo group/condition.
a
ADHD, Attention-Deficit/Hyperactivity Disorder.

et al., 2006), no changes were found in overall brain activation
patterns between children who had previously received long-
term methylphenidate treatment, and children who had not.
Observed long-term methylphenidate treatment effects were
restricted to highly specific tasks and brain regions. By
contrast, two recent fMRI studies in currently un-medicated
adults with ADHD that specifically investigated the effect of
stimulant treatment history during childhood did find evidence
of lasting medication effects on brain activation patterns.
Methylphenidate-naı̈ve adult subjects with ADHD showed
changes in brain activation during emotional processing
(Schlochtermeier et al., 2011) and during reward processing
(Stoy et al., 2011) compared to typical control subjects,
whereas adult subjects with ADHD who had received methyl-
phenidate treatment during childhood did not. This suggests
that childhood methylphenidate treatment may result in
normalization of brain activation patterns in adulthood, similar
to the acute functional normalization after methylphenidate
administration in children with ADHD. However, opposing
findings of larger functional brain abnormalities in adult ADHD
subjects with a history of stimulant treatment, compared to
subjects without a history of stimulant treatment, have also
been reported (Ludolph et al., 2008).
Importantly, these studies have limitations (Table 2). First,
for many cognitive domains, the effects of methylphenidate
have only been investigated once or twice. As such, replica-
tion is clearly needed. Second, sample sizes are typically
small, with the majority of studies investigating fewer than
fifteen subjects per group or condition. Third, only a small
minority of these studies are randomized, double-blind,
placebo-controlled trials (Rubia et al., 2011a, 2011b; Wong
and Stevens, 2012), limiting the inferences that can be drawn
from the literature currently available. Fourth, studies tend
to range widely in terms of inclusion criteria and the
selection of cognitive tasks, further complicating direct
comparison of their results and this may well contribute to
the discrepant outcomes between studies. For instance, a
subject’s medication history (medication-naı̈ve vs. previously
medicated, as well as medication duration and dosage in the
past) may influence the effects of acute methylphenidate
administration on the brain, but remains undisclosed in
several of the fMRI studies (e.g. Vaidya et al., 1998;
Teicher et al., 2000; Peterson et al., 2009). Finally, although
all studies investigating acute effects of methylphenidate
administration ensured a wash-out period prior to study
participation, acute rebound effects after sudden cessation
of medication cannot be controlled for.
5. Methylphenidate effects are likely to be
highly specific and rate-dependent
Based on the literature to date, methylphenidate administra-
tion appears to elicit functional and structural changes
throughout the brain. The results of the studies reported in
Tables 1 and 2 suggest that the direction of methylphenidate
effects may be related to the specific neural changes in ADHD.
Different cognitive paradigms elicit different brain activation
patterns, and therefore are associated with differing changes
in brain activity with methylphenidate administration. Func-
tional neuroimaging studies have suggested that methylphe-
nidate induces acute normalization of activation patterns in
wide-spread regions of the brain, including brain regions that
have been associated with structural and functional changes in
ADHD. However, the direction of these methylphenidate-
induced functional changes varied. For example, reduced
MRI in ADHD
ACC activity was found in children with ADHD during a
cognitive control task, which increased with methylphenidate
administration (Epstein et al., 2007), while another study
found that methylphenidate enhanced task-related deactiva-
tion in the ACC in children with ADHD (Peterson et al., 2009). A
third study, by contrast, has found that typically developing
children, but not children with ADHD, showed increased ACC
activity during incongruent Stroop-trials compared to during
neutral trials, and that this lack of increase in ACC activity in
ADHD was restored by methylphenidate administration (Zang
et al., 2005). Thus, whereas all three studies report acute
normalization of ACC activation after methylphenidate admin-
istration, the effects of methylphenidate on the ACC differed
between studies. The consistency of the normalization of brain
activity patterns by methylphenidate suggests that its see-
mingly discrepant acute effects on brain activation patterns
across studies do not merely represent conflicting findings.
Rather, the effects of methylphenidate may be highly specific,
depending on the presence or absence of ADHD-related
functional changes in specific brain regions during the perfor-
mance of specific cognitive tasks. Since unmedicated children
with ADHD show regionally specific and task-dependent deficits
in brain activation, the modulating effects of methylphenidate
treatment on these functional changes may also be specific. In
sum, the studies to date suggest that methylphenidate mod-
ulates activity levels towards the levels of typically developing
children, regardless of whether the ADHD-related changes (i.e.
without medication) constituted decreased or increased activ-
ity compared to typically developing controls.
The rate-dependency hypothesis suggests that the effects
of methylphenidate treatment on brain activation may be
dependent on the amount of ‘baseline’ activation (or
activation while not on stimulant medication) in a particular
brain region (Andersen, 2005). Thereby, methylphenidate
may have a different effect on the brain of subjects with
ADHD than in typical controls. This issue is subject to
intense debate, and is hard to address as ethical constraints
disallow the administration of drugs to typically developing
children. In the only study to address methylphenidate
effects in both children with ADHD and typically developing
children, Vaidya et al. (1998) used a cognitive control
paradigm. Children with ADHD showed decreased striatal
activation compared to typically developing children with-
out methylphenidate, but showed an increase in striatal
activation after methylphenidate administration. By con-
trast, typically developing children showed decreased acti-
vation of the striatum after methylphenidate administration
(Vaidya et al., 1998). In typical adults, methylphenidate
administration has been found to change brain activation
patterns during a variety of cognitive functions, including
working memory, attention and reversal learning (e.g.
Tomasi et al., 2011; Dodds et al., 2008), but such changes
have not been compared directly to methylphenidate-
induced brain changes in adult subjects with ADHD.
6. Methylphenidate effects may be
influenced by various biological, subject-
related and task-related factors
Adding to the complexity of the rate-dependency hypothesis
are numerous other factors, including biological, subject-
1159
related demographic, and task-related ones. All may affect
baseline brain activation. By affecting brain activation
patterns, these factors may also influence the effect of
methylphenidate administration on these patterns. First,
several biological factors may be at play. For example,
neural activity levels while not on medication may be
modulated by the density of neuronal dopamine receptors,
which, in turn, seems to be genetically determined, at least

partially (e.g. Bedard et al., 2010; Durston et al., 2008;
Heinz et al., 2000). In typical adults, regional D2 receptor
availability was found to be correlated to metabolic changes
in the cerebellum, frontal and temporal regions induced by
methylphenidate administration (Volkow et al., 1997).
Thus, biological factors including genetic predispositions
may determine, at least to some extent, how the brain
responds to methylphenidate administration, via modula-
tion of dopamine neurotransmission characteristics in an
unmedicated state.
In addition to biological factors, subject-related demo-
graphic factors such as age and gender may contribute to
regional brain activation patterns. Such factors could in turn
influence the neural effects of methylphenidate treatment
in a highly specific manner. Animal studies suggest that age
at initiation of stimulant treatment is of particular impor-
tance (e.g. Canese et al., 2009). The brain undergoes
drastic changes in structural and functional organization
during development. Although the mechanism of stimulant
action is likely to be similar in the immature and mature
brain, the substrate that stimulants act on, i.e. the
catecholaminergic system, develops with age (Andersen,
2005). This may result in different patterns of brain
response to methylphenidate administration at different
ages. For example, methylphenidate was found to increase
frontostriatal and cerebellar activation in children with
ADHD, whereas it increased striatal activation but
decreased prefrontal and right parietal activation in adults
with ADHD (Epstein et al., 2007). The effects of methyl-
phenidate administration may differ not only between
children and adults, but also over childhood. Moreover,
each brain region has a unique developmental trajectory,
which leads to a complex picture of brain regions each being
more or less sensitive to stimulant treatment at different
time points in development (Rapoport and Gogtay, 2008).
Finally, task-related factors may influence the effect of
methylphenidate on the brain through the brain activation
patterns they evoke. For example, a working memory task
elicits different patterns of brain activation than a cognitive
control task, and will therefore show functional changes in
ADHD that are specific to that cognitive task or domain. As a
result, possible methylphenidate-induced functional
changes during a working memory task will differ from
methylphenidate-induced changes during a cognitive con-
trol task. The same principle may apply to task difficulty. It
has been suggested that functional brain changes in children
with ADHD are more pronounced during cognitively demand-
ing tasks than during less demanding tasks (e.g. Kobel et al.,
2009; Vaidya et al., 1998; Zang et al., 2005). Consequently,
the rate-dependency hypothesis implies larger methylphe-
nidate effects during more difficult cognitive challenges.
Indeed, normalization of brain activation patterns with
methylphenidate appears more pronounced in cognitively
more demanding tasks than in less demanding tasks (Shafritz
1160
et al., 2004; Vaidya et al., 1998). Interestingly, a recent
study suggests that the effects of methylphenidate across
cognitive tasks of increasing difficulty are finite (Prehn-
Kristensen et al., 2011). In a relatively non-demanding
working memory task, children with ADHD showed a lack
of predominantly frontal activation compared to typically
developing children, which was resolved by the administra-
tion of methylphenidate. When task difficulty was increased
by adding distractors, typically developing children, but not
children with ADHD, recruited the caudate nucleus.
Whereas increasing task difficulty resulted in the additional
recruitment of the caudate nucleus in typically developing
children, this strategy was not brought about by methyl-
phenidate administration in children with ADHD (Prehn-
Kristensen et al., 2011). Thus, task characteristics, includ-
ing task difficulty, may affect the detection of methylphe-
nidate effects on the brain.
In sum, methylphenidate-induced changes in brain acti-
vation patterns may be dependent on the level of ‘baseline’
activation in the brain, which in turn is determined by a
multitude of factors. As such, biological factors, subject-
related factors and task-related factors, amongst many,
may influence methylphenidate-induced changes in the
brain of children with ADHD. Thus, the available evidence
suggests that methylphenidate treatment does not neces-
sarily affect brain activity in the same way for all children
with ADHD, similar to the way methylphenidate treatment
also affects behavior differentially between children with
ADHD (e.g. MTA Cooperative Group, 1999).
7. Behavioral correlates of methylphenidate-
induced neural changes
This paper aimed to decrease the gap between the well-
described physiological effects of methylphenidate in the
synapse, and the beneficial effects of methylphenidate on
ADHD symptoms. A growing body of work shows that
methylphenidate affects MRI-based brain measures in chil-
dren with ADHD, by normalizing both structural and func-
tional changes observed in unmedicated subjects with
ADHD. However, to investigate the mechanisms by which
methylphenidate changes behavior it is important to relate
these brain changes to behavioral outcome measures, such
as ADHD symptom severity or task performance during
functional MRI experiments.
The important issue of whether methylphenidate-induced
brain changes in children with ADHD are accompanied by
behavioral changes has rarely been addressed directly, and
results have been inconsistent. Ivanov et al. (2010) found an
association between behavioral ratings of hyperactivity and
thalamus volume reduction in ADHD. Both ADHD symptoms
and volume reductions were less severe in children who had
been treated with psycho-stimulants. By contrast, Shaw
et al. (2009) found that the excessive cortical thinning that
occurred in children with ADHD that stopped taking psycho-
stimulant medication, but not in children with ADHD that
continued taking psycho-stimulant medication, was not
associated with differences in clinical outcome between
these two groups. Several methodological differences
between studies, such as age of the studied sample, make
these results hard to interpret. In their meta-analysis,
L.J.S. Schweren et al.
Nakao et al. (2011) were unable to assess whether
methylphenidate-induced structural changes were related
to behavioral changes in children with ADHD, due to
methodological discrepancies between studies. Diverse
results also emerge from functional MRI studies. Whereas
in some studies functional normalization was accompanied
by symptom reduction or improved task performance (e.g.
Peterson et al., 2009; Anderson et al., 2002; Lee et al.,
2010; Prehn-Kristensen et al., 2011; Rubia et al., 2009;
Teicher et al., 2000; Vaidya et al., 1998), others did not find
such a relation (e.g. Epstein et al., 2007; Kobel et al., 2009;
Rubia et al., 2011a; Shafritz et al., 2004).
Alternatively, one could regard behavioral measures
while not on medication, such as symptom severity, as a
subject-related factor associated with ‘baseline’ brain
activity. Subjects with ADHD who are more severely beha-
viorally affected could present with more functional
changes in the brain (Depue et al., 2010), which could
hypothetically result in more pronounced changes in brain
activation patterns after methylphenidate administration.
As such, behavioral or clinical measures may be a possible
predictor of methylphenidate-induced changes in brain
activation patterns. Indeed, differential effects of methyl-
phenidate administration on resting-state brain activity
have been found for behaviorally hyperactive vs. non-
hyperactive children with ADHD. More hyperactive children
with ADHD showed larger effects of methylphenidate
administration on resting-state activity in the striatum and
cerebellum than less hyperactive children with ADHD
(Anderson et al., 2002; Teicher et al., 2000). Clearly, more
evidence is needed in order to understand the association
between the structural and functional brain changes after
methylphenidate administration on the one hand, and the
clinical effects of psycho-stimulant treatment on the other.
8. Implications for neurobiological research
into ADHD
A large proportion of children with ADHD receive stimulant
treatment at some point in their life. As a result, research-
ers investigating the neural correlates of ADHD face a major
methodological challenge: whereas including children with
a history of stimulant treatment introduces a potential
biasing effect of methylphenidate treatment into the study
sample, excluding children with a history of stimulant
treatment would greatly reduce the number of potential
study participants, and would reduce generalizability of
study results to the population of all individuals affected
with ADHD. In practice, neuroimaging studies include sub-
jects with or without a history of stimulant treatment, or a
mixture of these groups.
The effects of methylphenidate on structural and func-
tional MRI highlight the importance of monitoring medica-
tion status and medication history of study participants.
Including medicated subjects with ADHD in structural MRI
studies may result in reduced power to find structural brain
changes that are relevant to the phenotype, given that
treatment with methylphenidate appears to normalize brain
development to some extent. Therefore, studies investigat-
ing neuroanatomical changes between subjects with ADHD
and typically developing subjects may benefit from the
MRI in ADHD
inclusion of medication-naı̈ve children with ADHD only.
Alternatively, addressing the possible confounding effects
of treatment history in a sample including participants with
variable medication histories (e.g. De Zeeuw et al., 2012),
may further our understanding of long-term methylpheni-
date effects. The acute normalizing effects of methylphe-
nidate on fMRI measures imply that functional deficits
underlying ADHD symptoms may be less pronounced in an
ADHD sample including medicated individuals, emphasizing
the importance of medication wash-out prior to functional
MRI scanning. Until today, no conclusive evidence of lasting
functional alterations after methylphenidate treatment has
been reported in children with ADHD. The long-term effects
of stimulant treatment on functional MRI measures thus
need further investigation.
Several hypotheses have been proposed on mechanisms
underlying the brain effects of long-term methylphenidate
treatment. It has been suggested that the effects of
methylphenidate treatment on structural MRI measures
could be an example of activity-induced neuronal plasticity
(Ivanov et al., 2010; Semrud-Clikeman et al., 2006; Shaw
et al., 2009). Stimulants are thought to increase catecho-
laminergic neurotransmission, which may influence cellular
morphology (Robinson and Kolb, 2004). In addition, the
increased catecholaminergic neurotransmission may lower
the threshold for learning, or plasticity, allowing the brain
to form new connections during cognitive tasks, resulting in
volumetric changes. However, such hypotheses regarding
possible biological mechanisms for long-term structural
changes remain speculative. More direct measures of cate-
cholaminergic neurotransmission, such as SPECT and PET,
may be more informative than MRI in this regard (e.g. Fusar-
Poli et al., 2012).
9. Limitations and future perspectives
This paper reviews the currently available studies on the
effects of stimulant treatment on brain structure and
functioning as assessed using MRI-based techniques, in
children with ADHD. Although a meta-analytic review has
benefits over a narrative review such as this one, the
methods applied in the different studies vary strongly at
this time. As such, the descriptive nature of this review
reflects the current state of the literature. Any conclusions
regarding the specificity of the effects of stimulant treat-
ment on the developing brain therefore remain speculative,
and are limited by the caveats inherent to the original
research articles presented in Tables 1 and 2.
Each of the reported studies has their own methodologi-
cal drawbacks, but some of these are common across the
literature. We mention five main issues. First, the majority
of structural MRI studies have (of necessity) adopted a
naturalistic, cross-sectional design. This does not allow for
any conclusions on cause and effect or a more informative
within-subject evaluation of stimulant treatment effects.
Second, a major concern that applies to all but two
functional MRI studies is small sample size, with sometimes
less than fifteen subjects per group or condition. Third,
several functional MRI studies have not provided informa-
tion on the type or duration of stimulant treatment. Fourth,
a less common limitation, which is more common to
1161
structural MRI studies, has been the inclusion of children
(albeit a small percentage of participants) who were being
treated with non-stimulant medication, such as atomoxe-
tine (e.g. Ivanov et al., 2010; Shaw et al., 2009). Fifth, both
structural and, to a lesser extent, functional MRI studies
have often investigated specific brain regions of interest,
and as such could have failed to detect effects of stimulant
treatment on other regions. Finally, signs of considerable
publication bias have been reported in clinical treatment
literature, where null-findings or conflicting findings are less
likely to be published (Dwan et al., 2008; McGauran et al.,
2010). We cannot exclude the possibility that a similar issue
may be at play in the literature on brain changes induced by
methylphenidate and as such may limit our understanding of
its effects.
A number of issues are of great importance for future
work. First, an unresolved issue is the link between struc-
tural and functional brain changes induced by methylphe-
nidate treatment on the one hand, and clinical response to
methylphenidate treatment on the other. Not all children
with ADHD respond to stimulant treatment in the same way,
both at the neural and behavioral level. One promising
approach would be to compare responders to non-
responders. This could provide researchers with valuable
clues as to which regions or processes in the brain are
related to the beneficial effects to stimulant treatment.
Secondly, the long-term effects of stimulant treatment
on the brain functioning are largely unknown. The long-term
normalizing effects of stimulant treatment on brain struc-
ture in children with ADHD, appear paradoxical to the rapid
return of ADHD symptoms after stimulant treatment is
ceased, and do not correspond with the putative evidence
of the absence of long-term functional brain changes with
stimulant treatment. In future studies, a developmental
perspective will be critical, since brain development may
well add to the existing variability in methylphenidate-
induced brain changes in children with ADHD. Moreover,
long-term methylphenidate effects may become apparent
only after adolescence or young adulthood, when neurode-
velopment enters a more stable phase (Andersen, 2005).
Long-term effects of methylphenidate treatment on the
developing brain should ideally be investigated in a large
prospective cohort of children with ADHD as well as
typically developing control subjects, with both structural
and functional neuroimaging sessions before stimulant
treatment is initiated, and follow-up continuing into
adulthood.
MR imaging of methylphenidate effects could benefit from
adding genetic markers to relate to individual differences in
treatment response. Neuroimaging of the effects of methyl-
phenidate could serve as an endophenotype between genetic
predisposition and clinical amelioration with methylpheni-
date treatment, by comparing methylphenidate-induced
alterations in brain functioning and behavior between groups
that differed in genotype for genetic polymorphisms relevant
to ADHD. Such an approach may relate the molecular basis of
the clinical effects of the treatment, to neurobiological
substrate of ADHD. In addition, such studies may provide
geneticists with valuable biological markers in pursuit of
identifying genes involved in brain structure and function in
ADHD (Wood and Neale, 2010). Several promising papers have
appeared combining pharmacogenetics with neuroimaging
1162
methods other than MRI, such as SPECT and EEG (e.g. Rohde
et al., 2003; Loo et al., 2003).
In sum, a modest literature suggests that the effects of
methylphenidate treatment on brain development in ADHD
are highly specific and dependent on numerous factors,
including biological factors such as genetic predispositions,
subject-related factors such as age and symptom severity,
and task-related factors such as task difficulty. Future
studies on structural and functional brain changes in ADHD
would benefit from inclusion strategies guided by current
medication status and medication history and will need to
address unresolved issues including the effects of the long-
term treatment, and the mechanism underlying its ther-
apeutic effects.
Role of the funding source
None to declare.
Contributors
LS and PdZ designed the study and review procedure. LS performed
the literature search and wrote the first draft of the manuscript.
All authors contributed text and ideas to the subsequent and final
versions of the manuscript and approved of the final version
submitted.
Conflict of interest
Prof. Dr. Durston has received a research grant from Unilever Foods.
The other authors declare no biomedical or financial interests, or
conflicts of interest.
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