Positron emission tomography neuroimaging for a better understanding of the biology of ADHD.
ABSTRACT Attention-deficit/hyperactivity disorder (ADHD) is a neurobehavioral disorder characterized by inappropriate symptoms of inattention, impulsivity and motor restlessness. Converging data from neuropsychological, genetic, neurochemical and pharmacological studies have implicated fronto-striatal network abnormalities as the likely cause of ADHD. The functional imaging field has evolved rapidly providing unprecedented tools to examine questions regarding the pathophysiology of ADHD and the biological effects of medications used to treat it. Positron emission tomography (PET) provides unique quantitative information on the spatial resolution of radiolabelled molecules in the brain of patients or healthy subjects allowing the longitudinal assessment of physiological parameters such as binding potential over extended periods of time. The main goal of this review is to provide an overview of PET studies performed in ADHD patients, discuss their relative strengths and weaknesses and show how they can complement one another to enable a better understanding of the neurobiology and the neuropharmacology of this disease.
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ABSTRACT: Attention-deficit/hyperactivity disorder (ADHD) is a complex and heterogeneous disorder that is characterized not only by cognitive deficits but also by affective dysfunctions, both motivational and emotional. Nevertheless, the neural bases of affective dysfunctions have barely been explored in relation to this disorder, in contrast to extensive research that examined the neural correlates of its main cognitive deficits (attention, response inhibition and working memory). This article reviews the available data regarding the neurobiological substrates of motivational and emotional alterations showed by children, adolescents and adults with ADHD. Practical implications derived from these data are discussed and future research directions from affective neuroscience are suggested.Escritos de Psicología (Internet). 04/2010; 3(2):17-29.
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ABSTRACT: The origin of ADHD is multifactorial and both the aetiology and pathophysiology of ADHD are as yet incompletely understood. The monoamine deficit hypothesis of ADHD postulates a dysbalance in the interaction of the neurotransmitters dopamine, noradrenaline and serotonin. Pathophysiological mechanisms involved in ADHD include alterations in fronto-striatal circuits. The currently proposed animal models of ADHD are heterogeneous with regard to their pathophysiological alterations and their ability to mimic behavioural symptoms and to predict response to medication. Some evidence points to a genetic basis for ADHD which is likely to involve many genes of small individual effects. In summary, specific neurobiological substrates of ADHD are unknown and multiple genetic and environmental factors appear to act together to create a spectrum of neurobiological liability.Fortschritte der Neurologie · Psychiatrie 01/2014; 82(1):9-29. · 0.85 Impact Factor
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ABSTRACT: Attention deficit/hyperactivity disorder (ADHD) is present in 8% to 12% of children, and 4% of adults worldwide. Children with ADHD can have learning impairments, poor selfesteem, social dysfunction, and an increased risk of substance abuse, including cigarette smoking. Overall, the rate of treatment with medication for patients with ADHD has been increasing since 2008, with ≥ 2 million children now being treated with stimulants. The rise of adolescent prescription ADHD medication abuse has occurred along with a concomitant increase of stimulant medication availability. Of adults presenting with a substance use disorder (SUD), 20% to 30% have concurrent ADHD, and 20% to 40% of adults with ADHD have a history of SUD. Following a brief review of the etiology of ADHD, its diagnosis and treatment, we focus on the benefits of early and appropriate testing for a predisposition to ADHD. We suggest that by genotyping patients for a number of known, associated dopaminergic polymorphisms, especially at an early age, misdiagnoses and/or over-diagnosis can be reduced. Ethical and legal issues of early genotyping are considered. As many as 30% of individuals with ADHD are estimated to either have secondary side-effects or are not responsive to stimulant medication. We also consider the benefits of non-stimulant medication and alternative treatment modalities, which include diet, herbal medications, iron supplementation, and neurofeedback. With the goals of improving treatment of patients with ADHD and SUD prevention, we encourage further work in both genetic diagnosis and novel treatment approaches.Postgraduate Medicine 01/2014; 126(1):153-77. · 1.97 Impact Factor
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Positron emission tomography neuroimaging for a better understanding
of the biology of ADHD
aLaboratory of Neuropharmacology, EAC CNRS 5006, University of Lyon 1, Lyon, France
bPET Department, CERMEP–Imagerie du Vivant, 69003 Lyon, France
a r t i c l e i n f o
Received 13 May 2009
Received in revised form
29 July 2009
Accepted 4 August 2009
a b s t r a c t
Attention-deficit/hyperactivity disorder (ADHD) is a neurobehavioral disorder characterized by inappro-
priate symptoms of inattention, impulsivity and motor restlessness. Converging data from neuro-
psychological, genetic, neurochemical and pharmacological studies have implicated fronto-striatal
network abnormalities as the likely cause of ADHD. The functional imaging field has evolved rapidly
providing unprecedented tools to examine questions regarding the pathophysiology of ADHD and the
biological effects of medications used to treat it. Positron emission tomography (PET) provides unique
quantitative information on the spatial resolution of radiolabelled molecules in the brain of patients or
healthy subjects allowing the longitudinal assessment of physiological parameters such as binding
potential over extended periods of time. The main goal of this review is to provide an overview of PET
studies performed in ADHD patients, discuss their relative strengths and weaknesses and show how they
can complement one another to enable a better understanding of the neurobiology and the neurophar-
macology of this disease.
? 2009 Elsevier Ltd. All rights reserved.
Attention-deficit/hyperactivity disorder (ADHD) is a heteroge-
neous neurobehavioral disorder affecting approximately 5% of
school-age children and frequently persisting into adulthood. It is
most prevalent among boys and typically manifests by the age of
7 years. The three main clinical symptoms defining ADHD are:
inattentiveness, hyperactivity and impulsiveness.
come from positron emission tomography (PET) studies in humans.
PET provides a powerful and non-invasive way of measuring the
spatial distribution of radiolabelled compounds in the body and
can be used, for example, to monitor neuronal activity indirectly via
measurements of blood flow or metabolism, or the ligand–receptor
interactions of particular neurotransmitter systems. These methods
are used to investigate the functional localisation of activity to
specific brain networks and its modulation by chemical neuro-
This review is an overview of the contribution that PET has
made tothe studyof ADHD and discusses, inparticular, the utilityof
PET in identifying patterns of chemical changes among patients.
2. Biological basis of ADHD
The biological origins of ADHD are complicated by a variety of
clinical symptoms, comorbidity (approximately 65%) with other
disorders (conduct, mood, bipolar and anxiety disorders, Tourette’s),
and the exacerbation by environment and psychological events
(Solanto et al., 2001). Nevertheless, neuroanatomic, genetic, and
neurobiological data strongly support a pathophysiologic basis for
initially by magnetic resonance imaging (MRI), converge on the
catecholamine-rich frontal cortex and subcortical neural networks.
Moreover, studies in twins have estimated that genetic factors
account for more than 70% of cases (Durston, 2008). At present,
a majority of specific genes implicated in ADHD encode components
of catecholamine signalling systems and include the dopamine
transporter (DAT), noradrenaline transporter (NAT), D4 and D5
dopamine receptors and dopamine b-hydroxylase (Faraone, 2007).
The positive correlation between levels of the dopamine metabolite
homovanillic acid in cerebrospinal fluid and ADHD symptoms
supports the hypothesis that an excess of dopamine in the brain
might contribute to hyperactivity, although a more elaborate mech-
anism is likely involved than suggested here (Gonon, 2009). Dysre-
gulation in catecholamine neurotransmission is implicated in the
and noradrenaline transporters. Accordingly, psychostimulants
* CERMEP-Imagerie du Vivant, Groupement Hospitalier Est, Boulevard Pinel,
F-69003 Lyon, France. Tel.: þ33 4 72 68 86 09; fax: þ33 4 72 68 86 10.
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Contents lists available at ScienceDirect
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Neuropharmacology 57 (2009) 601–607
Author's personal copy
treatments for ADHD (Kollins, 2008).
Genetic studies have concentrated on catecholaminergic candi-
dates but have failedto reveal anintegrated modelto explainhow the
that ADHD could be heritable, there is no obvious link between risk
genes and the clinical phenotype (Durston, 2008). However, deter-
mining andunderstandingtheunderlyingneurobiologyofADHDis of
tomography (PET) imaging could potentially be useful in this regard.
D-amphetamine) are the most common
3. Principles of PET imaging
or biochemically active compounds labelled with short-lived posi-
tron-emitting radionuclides. This functional imaging technique is
useful for improving our understanding of disease pathophysiology,
studying treatment effects and in clinical diagnosis. The first step in
a PETstudy is the production of positron-emitting radionuclides and
their incorporation into molecules during radiochemical synthesis
(giving the PET radiotracer). Briefly, the radionuclides are produced
18 as the main radioisotopes. With a physical half-life of 110 min,
fluorine-18 is the most attractive PET radioisotope, allowing imaging
durations of several hours. Despite the shorter half-life of carbon-11
(11C, 20.4 min), the majority of PET pharmacokinetic experiments
have relied on11C-labelled tracer molecules. After pharmaceutical
controls, the labelled compound (named ‘‘radiopharmaceutical’’) is
administered to the subject (a volunteer, a patient or a research
animal model) via intravenous injection. The injected radiotracer
reaches the targeted organ where the emitted positrons travel a few
millimetres until they combine with an electron (‘‘annihilation
event’’), generating two photons each with energy of 511 keV. These
photons are recorded simultaneously by the camera consisting of
a gantry with multiple rings of scintillation crystals, the detectors.
distribution as a function of time with a maximum temporal reso-
The obtained images are then analysed and quantified by tracer
kinetic modelling aimed at simplifying biological complexities. In
principle, there are two different ways in which PET can be used in
clinical studies. The first and most employed approach involves the
interaction of a drug molecule with its target (e.g., receptor, trans-
porters, enzymes etc.). This method allows the quantification of
parameters related to binding site density (Fowler et al., 1999). To
date, a variety of radiotracers for specific receptor subtypes, partic-
ularly those implicated in neuropsychiatric disorders, have been
validated (Lee and Farde, 2006). The second way inwhich PETcan be
employed involves direct radiolabelling of drug molecules to study
their tissue distribution and pharmacokinetics. This approach, called
‘‘PET microdosing’’, is of particular interest in drug development. In
the following chapters, we will see how PETcan be used to improve
our understanding of the biology of ADHD.
4. PET brain activation studies
which brain region(s) is implicated in the pathophysiology of the
disease, independently of a neurotransmission system. In the case of
ADHD, and on the basis of cognitive neuroscience literature, func-
tional imaging has focused on brain regions that are normally
involved in attention, cognition, working memory, response inhibi-
tion and reward motivation i.e. dorsolateral prefrontal cortex,
ventrolateralprefrontal cortex,dorsal anteriorcingulated cortex and
striatum (Bush et al., 2005).
4.1. Glucose metabolism
As glucose metabolic activity represents a common pathway of
neurochemical activity in the brain, the
in terms of different neurochemical mechanisms, they do initiate
subsequent studies using selective neuroreceptor radiotracers. In
this way, a variety of studies over the last decade have revealed
a perturbation of neuronal energy metabolism in ADHD patients.
The first large-scale functional imaging study using FDG PET was
carried out by Zametkin et al. (1990). Studying 75 adult subjects
(25 treatment-naive ADHD patients, 50 control subjects), they
reported that global cerebral glucose metabolism was 8.1% lower in
the ADHD group and that regional metabolism remained lower in
the premotor cortex and in the superior prefrontal cortex after
normalization for global decreases. The fact that the studied control
group contained a high percentage of women compared with the
ADHD group, coupled with the fact that the female control subjects
had a higher global metabolism, has led to some debate over the
conclusion of a reduced glucose metabolism (Baumeister and
Hawkins, 2001). In fact, two subsequent studies (in adolescents) by
the same group (Ernst et al., 1994; Zametkin et al., 1993) failed to
find the same global or regional deficits. Globally, the studies of
in ADHD but highlight that gender effects should be taken into
account in future studies. It has been suggested that some of the
inconsistencies in studies of regional brain metabolism in ADHD
may be due to age-, gender, and diagnostic-related variables (Ernst
et al., 1998; Todd and Botteron, 2001). For example, the brain size
depends on age and gender (Castellanos, 2002) and brain glucose
metabolism is influenced both bygender differences and by normal
aging (Kawachi et al., 2002). Moreover, reduced glucose metabolic
rates are associated with increased age in ADHD women but not in
ADHD men (Ernst et al., 1998). Finally, PET studies by Schweitzer
et al. (2000) and Ernst et al. (2003), although based on small
samples and different paradigms (working memory and gambling
tasks, respectively), were consistent with the conclusion that
fronto-striatal abnormalities might be associated with ADHD.
4.2. Flow metabolism
Cerebral blood flow can be assessed in nuclear medicine by
either SPECT (Single Photon Emission Computerized Tomography)
or PET (Matochik et al., 1993, 1994) The lower cost associated with
SPECT explain why there are more SPECT studies, using
HMPAO as an indirect marker of cerebral blood flow (Andersen,
1989), than PET studies, using15O-H2O as a direct radiotracer of
cerebral blood flow (Ito et al., 2005). Initial studies using99mTc-
HMPAO found reduced blood flow in right frontal regions of chil-
dren with ADHD (Gustafsson et al., 2000). In a large SPECT study
using the same radiotracer, Kim et al. (2001) showed a significant
cerebral blood flow increase following treatment with the psy-
chostimulant methylphenidate in the bilateral prefrontal cortex,
caudate, and thalamus of boys. Unfortunately, PET studies per-
formed since have not confirmed these results. In a 2003 study, ten
adult subjects had cerebral blood flow assessed by PET before and
after a three week methylphenidate trial (Schweitzer et al., 2003).
Methylphenidate induced increases in blood flow in the cerebellar
vermis, but decreases in the precentral gyri and the left caudate
nucleus. In contrast, Szobot et al. (2003) found a decreased left
parietal blood flow with methylphenidate relative to placebo in
a relatively large cohort of children and adolescents with ADHD
(n ¼ 36). Finally, Castellanos (2002) questioned the utility of PET
cerebral blood flow studies and suggested that fMRI and the
L. Zimmer / Neuropharmacology 57 (2009) 601–607 602
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assessment of catecholamine transporters would more likely result
in increasing our understanding of the pharmacodynamics of
treatments for ADHD. A relatively poor spatial resolution is often
of15O. More precisely, the higher energy of this positron emitter
in comparison to11C or18F, allows a longer trajectory before anni-
hilation event and photon emission (see Section 3). Thus, although
important uses still exist for PET, particularly for the study of
neurotransmission (as will be discussed in the following sections),
for flow metabolism this technique has now be replaced by fMRI for
functional studies in ADHD patients.
5. PET studies on dopaminergic neurotransmission
There is considerable evidence that both dopamine (DA) and
noradrenaline (NA) contribute to the pathophysiology of ADHD, as
well as to the mechanism of therapeutic action of stimulant drugs
such as methylphenidate, amphetamine and pemoline (Kollins,
2008). In addition, structural MRI studies showing reduced regional
brain volumes in the caudate nucleus of children with ADHD are in
favour of the involvement of the striatal dopaminergic pathway
(Castellanos et al., 2001).
5.1. Dopamine transporter
The dopamine transporter (DAT) is responsible for the presynaptic
reuptake of dopamine and is therefore considered as central in the
regulation of dopamine. On the basis of several lines of evidence, the
DAT is currently one of the major candidates implicated in the path-
ophysiology of ADHD and in anti-ADHD drug mechanisms. Firstly,
dopamine transport inhibitors indirectly activate dopamine receptor
activity which enhances attention and engenders stimulation.
medications (amphetamine and methylphenidate). Thirdly, the
DAT gene is associated with ADHD. Altogether, these results suggest
medications (Madras et al., 2005). In this context, nuclear medicine
imaging is a fruitful approach in measuring levels of DA transporter
occupancy by the use of specific radioligands (Spencer et al., 2005).
Several radioligands are available which bind to the dopamine trans-
porter and give a measure of its binding potential. These, include
11C-altropane or11C-PE2I forPET(Elsingaet al., 2006) and123I-IPTand
99mTc-TRODAT for SPECT (Booij and Knol, 2007).
As the majority of studies have been performed using SPECT
radiotracers, PET and SPECT studies will be reviewed together. The
in the striatum of ADHD patients. Measuring the DAT density with
123I-altropan Doughertyet al. (1999) showed a 70% increase in all six
adult patients with ADHD studied compared with healthy controls.
Concordantly, Dresel et al. (2000) reported that 17 untreated ADHD
patients presented with a significantly increased specific binding of
99mTc-TRODAT-1 to the DAT as compared with normal controls
(þ17%). Using the same radiotracer, Krause et al. (2000) found
a similar increase of DAT binding in all ten adults with ADHD
a significant increase in DAT binding in the nine drug-naive children
with ADHD studied compared to the six control children, with no
correlation between theseverityscores of ADHD andthe radiotracer
binding. More recently, in a large cohort (21 ADHD patients and 26
control subjects), Spencer et al. (2007) showed significantly
increased DAT binding in the adults with ADHD compared with
subjects without the disorder using the PET radiotracer
123I-IPT, Cheon et al. (2003) then showed
However, others teams, although less numerous, have reported
no change in DAT density. Van Dyck et al. (2002) used123I-b CITand
found no difference in the binding between nine adult patients
with ADHD and nine healthy subjects. Another team studied 12
adolescents with ADHD and ten young control adults using the
selective PET radioligand11C-PE2I and reported a similar binding
potential value for the radiotracer in the striatum of both groups
(Jucaite et al., 2005).
(2006, 2009) were the first to describe a decrease in DAT binding
The group of Nora Volkow studied the DAT using11C-cocaine (Vol-
kow et al., 2007) andfound lowerlevels in the left striatum in ADHD
patientscompared to controls (20 patientsversus 25 control adults).
The reasons for these discrepancies are unclear and may be due
to several factors. First, the clinical heterogeneity of the ADHD
phenotype could be involved (Castellanos and Tannock, 2002)
highlighting the need forhomogeneity in theselected studiedgroup
of patients. Another explanation could be previous exposure to
stimulants or other drugs, smoking status (Krause et al., 2002, 2003;
Spencer et al., 2005), as well as age and possibly gender (Best et al.,
2005). When such potentially confounding factors are taken into
lower in the left caudate nucleus and left nucleus accumbens of
treatment-naive adults with ADHD (Volkow et al., 2007). Method-
ological aspects may also contribute to the variation in the results.
Several teams quantified their results using the cerebellum or the
occipital cortex as the reference tissue, explaining variability in the
results. Another relevant reason could be the use of different radi-
oligands and the interpretation of their binding phenomena (Bush,
2008). Indeed, while measures of DAT by PET or SPECT may reflect
the densityofdopamine terminals,they mayalsoreflect adaptations
inresponse to extracellulardopamine levels.Forexample,lowlevels
of DAT measured could either reflect decreased dopamine innerva-
tions to thecaudate ordown-regulationof thetransporters. Another
point concerns the different binding characteristics of the radio-
specificity. Although these methodological limitations are to be
taken into account, it appears that a majority of available studies
describe an increase of the DAT density in ADHD patients.
5.2. Dopamine D2receptors
Since dopamine transport function indirectly influences dopa-
mine receptor activity, several teams wished to image dopamine
receptors and more particularly the D2/D3receptors (Nikolaus et al.,
2007). To this end, the dopamine D2/D3receptor antagonist11C-
raclopride has become a widely utilised radioligand for PET studies
in the human brain. Moreover, because it competes with dopamine
measure of dopamine release or reuptake inhibition in humans.
One of the first studies relating to the D2receptor in ADHD was
published by Ilgin et al. (2001) in which non-drug treated children
with ADHD, presented higher D2receptor availability (measured
made with a control group. This result was confirmed however by
another team in a more robust study in which children with
symptoms of ADHD showed a higher binding potential of
raclopride than that observed in adults (Lou et al., 2004). The same
group later showed other results evoking a reduction of
raclopride binding in the brain of nine patients with ADHD after an
acute challengewith methylphenidate (Rosa-Neto et al., 2005). This
binding decrease was interpreted as the consequence of the accu-
mulation of extracellular dopamine evoked by pharmacological
123I-IBZM) at baseline, though no direct comparison was
L. Zimmer / Neuropharmacology 57 (2009) 601–607603
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blockade of DAT. In the context of previously mentioned imaging
studies showing increased DAT concentration in ADHD patients,
these results suggest that an increase of extracellular DA is a key
factor in the efficacy of methylphenidate in the treatment of ADHD
(Rosa-Neto et al., 2005).
These initial studies regarding the effect of stimulant medication
on the D2receptor are in accordance with previous PET and SPECT
studies showing D2receptor down-regulation in healthy volunteers
following an increase in extracellular dopamine induced by meth-
ylphenidate administration (Booij et al., 1997; Montgomery et al.,
2007). Therefore, it is proposed that the high D2levels frequently
dopamine level, supporting the dopamine-deficiency hypothesis
associated with this disease (Montgomeryet al., 2007). Interestingly,
methylphenidate seems to be more efficacious in reducing impul-
sivity and hyperactivity when baseline dopamine D2/D3receptor
availability was shown to be high using PET or SPECT, suggesting
a potential interest in imaging to predict the therapeutic response in
patients suffering ADHD. However, it should be noted that one
published study does not confirm this hypothesis. Indeed, in this
study, binding potential values for11C-raclopride in the striatum of
adolescents with ADHD were found to be no different from those of
young adult control subjects (Jucaite et al., 2005). However, dopa-
mine D2/D3receptorbinding inthe right caudate nucleuswasshown
to positively correlate with measures of hyperactivity.
5.3. Dopamine metabolism
Previous PET studies implicate dopamine inputs to prefrontal
cortical areas in the pathophysiology of ADHD. In this context, it was
evaluated and quantified using PET imaging. FluoroDOPA (18F-DOPA)
is a fluorinated analogue of DOPA and is transported into presynaptic
neurons where it is converted to18F-fluorodopamine by the enzyme
DOPA-decarboxylase and then stored in catecholamine storage vesi-
cles. Brain incorporation of fluoroDOPA therefore reflects the whole
dopamine metabolism from DOPA incorporation, to dopamine
synthesis, storage and transformation into metabolites.
A first study revealed that presynaptic dopamine function, as
assessed by18F-DOPAuptake, was reportedly lower in sub-regions of
the prefrontal cortex of adults with ADHD compared with healthy
controls (Ernst et al., 1998). In a later study, however, the same
group found increased18F-DOPA utilisation in the right midbrain of
adolescents with ADHD (Ernst et al., 1999). These apparent discrep-
ancies can be explained by demographic differences between both
groups (mean age of 39.3 versus 13.8) and by the fact that different
brain regions were studied.
in a number of brain regions of adolescents with ADHD, especially
the midbrain, nucleus accumbens and putamen, with smaller
decreases in some prefrontal areas (Forssberg et al., 2006). A more
recent study investigated alterations in dopamine metabolism in
young males with ADHD who had never been pharmacologically
treated in comparison with methylphenidate-treated patients and
healthy subjects (Ludolph et al., 2008). In this study, fluoroDOPA
PETscans were carried out on 20 male patients with ADHD
(8 without psychostimulant and 12 with treatment) versus 18
healthy men. Compared to controls, ADHD patients as a group
(irrespective of treatment status) showed lower radiotracer
incorporation in bilateral putamen, amygdala and dorsal midbrain.
A lower fluoroDOPA incorporation in the left putamen, right
amygdala and right dorsal midbrain was observed in untreated
patients compared to controls together with a relatively higher
influx in the left amygdala and right anterior cingulate cortex.
Methylphenidate treatment was associated with a significantly
18F-DOPA utilisation was found to be lower
lower fluoroDOPA incorporation in the striatum and amygdala
bilaterally. To summarize, this study indicates local dopamine
metabolism modifications in young male adults with ADHD
affecting particularly the mesolimibic, mesocortical and nigros-
triatal tracts of the dopaminergic system. To summarize, it
is hypothesized that these reduced prefrontal activities of DOPA-
decarboxylase, as measured by fluoroDOPA incorporation, may be
secondary to a subcortical dopaminergic deficit in ADHD patients,
as previously proposed by Krause et al. (2000).
6. Psychostimulant and PET microdosing studies
The term microdose is defined as ‘‘less than 1/100th the dose
on primary pharmacodynamic data obtained in vitro or in vivo and
with a maximum dose of 100 mg’’ (Combes et al., 2003). With a sensi-
tivity for the detection of mass in the lower femtomole range
where only limited toxicological information is available (Bergstro ¨m
et al., 2003). In this context, a general interest in the recent concept of
PET microdosing has grown with the advent of new synthesis
methods,allowing the majorityof new drug candidates to be labelled.
The labelling of compounds with positron-emitting radionuclides
results in high specific radioactivity, i.e. a very high amount of radio-
activity per unit of cold compound. The purpose of a PET microdosing
study is to provide information on a drug’s distribution pattern and
kinetics and allow the modelling of this relationship.
In this context, theinvivo pharmacokinetics of methylphenidate,
one of the most frequently prescribed treatments for ADHD, was
investigated using PET microdosing (Volkow et al., 1995, 2005).
Labelling methylphenidate with carbon-11 enables the determina-
tion of its concentration in the human brain without changing the
pharmacological properties of the drug. When administered intra-
and fast reaching a peak concentration in less than 10 min. The
pharmacokinetics of orally administered methylphenidate however
led to a peak concentration in brain that did not occur until 60 min
after administration. Finally, the distribution of methylphenidate in
brain was found to be heterogeneous with a maximum concentra-
tion occurring in the striatum, with lower levels in the thalamus,
cortex, and cerebellum, in accordance with the distribution of DAT
(Volkow et al., 1995).
It is interesting to note that although11C-methylphenidate and
11C-cocaine compete with each other for DAT, these two drugs
differ markedly in their pharmacokinetics. Clearance of11C-meth-
ylphenidate from striatum (90 min) was significantly longer than
that of11C-cocaine (20 min). According to these PET microdosing
results, the authors proposed that the slow clearance of methyl-
phenidate from the brain may serve as a factor which would limit
its frequent self-administration (Volkow et al., 1995).
To our knowledge, although clinical trials are in the design phase
for new anti-ADHD treatments, no other studies have yet been
published in this new field of PET microdosing. In addition to
a restriction to specialised centres (mainly within pharmaceutical
studies supplying new drug approvals are rarely published.
7. Towards other neurotransmitter system PET studies
7.1. Noradrenaline system
It is clear that in order to achieve a precise understanding of the
pathophysiology of ADHD PET neurotransmission studies should
investigate beyond the dopamine system. Indeed, while the
L. Zimmer / Neuropharmacology 57 (2009) 601–607604
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effectiveness of psychostimulant drugs is considered at least partly
due to increasing dopamine neurotransmission, there is growing
recognition of the role of noradrenalinein the aetiologyof ADHD. In
particular, it is known that the noradrenaline transporter is the
other target of the stimulants like methylphenidate and amphet-
amine (Arnsten, 2006). Recently, the selective noradrenaline
reuptake inhibitor atomoxetine has been introduced as the first
non-stimulant-based medication in the treatment of ADHD with
proven efficacy in both children and adults (Caballero and Nahata,
2003; Thomason and Michelson, 2004). Moreover, the selective
alpha-2 adrenergic receptoragonist guanfacine has also been found
to be effective in the treatment of ADHD (Scahill et al., 2001).
However it should be noted that few clinical PET studies have been
performed on the brain noradrenaline systems in relation to ADHD,
mainly due to the lack of suitable PET radioligands. Thus, only a few
PET radiotracers developed for imaging alpha2-adrenoceptors
show promise for use in humans (Jakobsen et al., 2006; Van der
Mey et al., 2006). Concerning PET radioligands to image the
noradrenaline transporter (NET), several candidates have been
evaluated in animal models and are currently being evaluated in
healthy human subjects (Arakawa et al., 2008; Takano et al., 2008).
This explains why, although an undoubted interest surrounds the
noradrenaline system in relation to ADHD, no clinical PETstudy has
yet been performed in ADHD patients.
7.2. Other neurotransmitter systems
Several epidemiological studies show that ADHD patients are at
higher risk of nicotine addiction (Milberger et al., 1997). Since
nicotine is a cholinergic agonist, these data are in favour of a role of
the cholinergic system in ADHD. An indirect cholinergic agonist
ABT-418 was shown to reduce ADHD symptoms in adults (Wilens
et al., 1999). Several authors propose that cholinergic agonists may
work through catecholamine systems by increasing levels of
dopamine in the ventral striatum (Brody et al., 2004). Currently,
while two radiotracers (2-18F-FA and 6-18F-FA) are available for
studying nicotinic acetylcholine receptors in human brain using
PET (Horti et al., 2009), to our knowledge, no studies have yet been
performed in ADHD patients.
The sigma receptors are another potent target for ADHD treat-
ment. They represent a new and different avenue in the possible
pharmacological treatment of several brain-related disorders
including ADHD (Guitart et al., 2004). PET could therefore be of
special interest for the development of drugs relating to sigma-
receptor function and pathophysiological studies in ADHD patients.
A first sigma PET radiotracer (11C-SA5845) was recently developed
and evaluated in primates (Kortekaas et al., 2008) however it has
not yet been administered to ADHD patients.
Finally, the importance of other neurotransmitters may be
highlighted through genetic studies. Since twin studies have indi-
cated that ADHD has a genetic component (Durston, 2008), the
search for genes conveying a risk for this disease is ongoing. A large
number of genes have been investigated, particularly in relation to
the catecholamine systems. A recent meta-analysis concluded that
alleles in catecholamine genes (dopamine D4receptor, D5receptor,
dopamine transporter, dopamine beta-hydroxylase) and seroto-
ninergic genes (serotonin transporter and serotonin1B receptor)
are overtransmitted in ADHD (Biederman and Faraone, 2002). The
serotonin system has some theoretical relevance to ADHD, accord-
ing to its implication in impulsivity, aggression and behaviour in
preclinical and clinical studies (Popova, 2008). Therefore, a genetic
approach could open up new avenues for PET investigation, under
the condition to have additional pharmacological or neurobiological
data and, of course, under the condition that a corresponding PET
radiotracer is available.
PET is a powerful non-invasive imaging technique allowing the
extrapolation of findings from animal models to human cases of
neuropsychiatric disorders like ADHD. A clear advantage of PET is
the ability to repeatedly assess brain function in longitudinal studies.
However, PET presents several limitations. The first is the generally
restricted use of radioactive compounds in children and adolescents
due to legitimate concerns over radiation exposure. This presents
a major obstacle to ADHD-based research on juvenile and adolescent
individuals. PET functional imaging studies are also relatively expen-
sive, and as such typically use small sample sizes. Often the control
group is a homogeneous sample matched to an often less homoge-
nous patient group, making it impossible to generalize findings. In
particular, medication status is an issue requiring increased attention.
Although wash-out procedures ensure complete elimination of any
medication, the long-term effects of medications are not yet known
and might represent a potential confounding variable.
Other limitations are specific to particular imaging modalities.
For example, PET offers inferior spatial resolution compared with
fMRI, particularlyconcerning15O-H2O blood flow studies. Although
the main strength of PET imaging is the ability to directly visualize
the brain neurotransmission in vivo, a large number of factors
which influence neurotransmission imaging results are still under-
studied and often ignored. Some examples would be the effects
of age, gender, caffeine use, alcohol use, intelligence quotient,
receptor availability, or the reproducibility of binding data. There-
fore, researchers investigating ADHD should share guidelines for
their patient inclusion in future PET protocols.
In the future, particular attention should be paid to increasing
the rigour of proposed mechanistic hypotheses. Initial work can
start with simplistic models of dysfunction within a single region,
a predetermined neurotransmission system ora simplified network,
however follow-up studies must then test more complex alternative
models. Since it is highly likely that the pathophysiology of ADHD
involves a dysfunctional interaction among components of fronto-
striatal circuitry, future studies should specifically test for dysfunc-
In this more integrated context, multimodality PET imaging
implying complementary studies with fMRI will be helpful.
Using PET imaging to study the pathophysiology of ADHD is
important for a more thorough understanding of the perturbation of
brain chemistry and for the longitudinal follow-up of treatments,
however there are no current plans for its clinical use as a diagnostic
of ADHD for example). This said, there are many reasons to develop
a diagnostic imaging test in terms of reducing levels of overdiagnosis
and underdiagnosis. Therefore, used wisely, PET functional imaging
should continue to be one of the strongest tools available for
a complete understanding of the neurochemistry of ADHD.
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