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The Journal of Neuroscience, August 1, 1998, 18(15):5901-5907
DOPA Decarboxylase Activity in Attention Deficit Hyperactivity
Disorder Adults. A [Fluorine-18]Fluorodopa Positron Emission
Tomographic Study
Monique
Ernst,
Alan J.
Zametkin,
John A.
Matochik,
Peter H.
Jons, and
Robert M.
Cohen
Laboratory of Cerebral Metabolism, National Institute of Mental
Health, Bethesda, Maryland 20892
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ABSTRACT |
Converging evidence implicates the dopaminergic system and the
prefrontal and nigrostriatal regions in the pathophysiology of
attention deficit hyperactivity disorder (ADHD). Using positron emission tomography (PET) with [fluorine-18]fluorodopa
(F18-DOPA), we compared the integrity of the presynaptic
dopaminergic function between 17 ADHD adults and 23 healthy controls.
The ratio of the isotope concentration of specific regions to that of
nonspecific regions reflects DOPA decarboxylase activity and dopamine
storage processes. Of three composite regions (prefrontal cortex,
striatum, and midbrain), only the prefrontal cortex showed
significantly different F18-DOPA ratios in ADHD as compared with
control adults (p < 0.01). The medial and
left prefrontal areas were the most altered (lower F18-DOPA ratios by
52 and 51% in ADHD as compared with controls). Similarly, the
interaction [sex × diagnosis] was significant only in the
prefrontal cortex (p < 0.02): lower ratios in men than in women in ADHD and vice versa in controls. These findings
suggest that a prefrontal dopaminergic dysfunction mediates ADHD
symptoms in adults and that gender influences this abnormality. On the
basis of previous neuroimaging findings in ADHD showing discrepant
findings in adults and adolescents and on evidence for midbrain
dopaminergic defect in adolescents, we hypothesize that the prefrontal
dopaminergic abnormality in ADHD adults is secondary and results from
an interaction of the primary subcortical dopaminergic deficit with
processes of neural maturation and neural adaptation.
Key words:
prefrontal cortex; nigrostriatal pathways; presynaptic
dopaminergic function; attention deficit hyperactivity disorder; gender; neurodevelopment; PET; (F18)fluorodopa
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INTRODUCTION |
Attention deficit hyperactivity
disorder (ADHD), a highly prevalent neurodevelopmental disorder, has
been ascribed to prefrontal (Mattes, 1980 ; Benton, 1991; Heilman et
al., 1991) and striatonigral dysfunction (Castellanos, 1997; Ernst,
1998). These assumptions are based primarily on the nature of ADHD
symptoms, i.e., impaired executive function (Denckla, 1994) and
excessive motor activity, traditionally associated with damage in the
frontal lobes (Clark et al., 1986; Goldman-Rakic, 1992) and basal
ganglia (Graybiel, 1991), respectively. The time course of ADHD
(childhood onset and variable outcome into adulthood) and its gender
distribution (approximately four boys to one girl) (Barkley, 1996)
implicate neural maturation, adaptive neural changes, and sexual
genetic or hormonal influences on the frontal- striatal-thalamic
network. This network, organized into parallel, segregated circuits
(Alexander et al., 1986; DeLong et al., 1990), is modulated mainly by
dopamine. Although dysfunction in these areas and associated circuits
is proposed as the cause of ADHD, the exact pathophysiological
mechanism remains unclear.
Up to 60% of children with ADHD continue to present impairing symptoms
in adulthood (Gittelman et al., 1985; Weiss and Hechtman, 1986;
Barkley, 1990). Although recent, the recognition of this disorder later
in life has gained considerable importance, notably because of the high
rate of comorbidity with antisocial personality disorder and substance
abuse disorder (Downey et al., 1997; Bellak and Black, 1992; Mannuzza
et al., 1993), which worsen severity and outcome. Although stimulant
treatment appears as effective in adults as in children (Matochik et
al., 1994; Spencer et al., 1995; Wilens et al., 1995), substance abuse
liability is a concern. A better understanding of the pathophysiology
of this disorder is needed for the development of highly specific
therapeutic pharmacological agents. Furthermore, the investigation of
ADHD may further our understanding of those neural systems,
particularly dopamine, that subserve the cognitive and social behavior
that are altered in this disorder.
Converging evidence from genetic and neuroimaging studies has supported
the dopaminergic hypothesis of ADHD. Most exciting are the reports of
linkages between ADHD and genetic markers of dopaminergic genes (Cook
et al., 1995; LaHoste et al., 1996; Gill et al., 1997). In addition,
abnormal laterality and function have been reported in dopaminergic
structures by MRI (Caparulo et al., 1981; Hynd et al., 1993; Aylward et
al., 1996; Castellanos et al., 1996) and SPECT/PET
(single-photon emission computed tomography/positron emission
tomography), respectively (Lou et al., 1989; Zametkin et al., 1990;
Lou, 1991; Zametkin et al., 1993; Ernst et al., 1994, 1997a). Although
conceptual models of the neuropathophysiology of ADHD have been
proposed (Heilman et al., 1991; Castellanos, 1997; Solanto, 1998), no
human studies have yet examined directly, in vivo, the
function of specific neurochemical systems implicated in this
disorder.
We elected to assess the integrity of the dopaminergic presynaptic
function in ADHD, using PET with [fluorine-18]fluorodopa ([F18]FDOPA). The tracer [F18]FDOPA, an analog of DOPA, is
transported into presynaptic neurons. There, it is converted by the
enzyme DOPA decarboxylase to [F18]FDOPA and stored in storage
vesicles. Therefore, data obtained by using [F18]FDOPA and PET
reflect DOPA decarboxylase activity and dopamine storage processes.
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MATERIALS AND METHODS |
Subjects. This study was approved by the Human
Subjects Protection Committee of the National Institute of Mental
Health, and written informed consents were obtained from all subjects
after they received a complete description of the study.
Volunteers with ADHD were recruited via advertisement in local
newspapers and with the help of an ADHD advocacy and support organization. Screening included a complete physical and laboratory medical work-up. Subjects were evaluated psychiatrically by
means of a semi-structured diagnostic interview (Schedule for Affective Disorders and Schizophrenia, life-long version) (Endicott and Spitzer,
1978). Exclusion criteria were any axis I or axis II DSM-III-R
psychiatric disorders (American Psychiatric Association, 1987) or any
medical problems, including neurological deficits, history of head
trauma with loss of consciousness, and cardiac or blood pressure
abnormalities. Behavioral ratings included the 10 item Conners
abbreviated teacher's rating scale (Conners-ATRS) (Conners, 1969;
Goyette et al., 1978) adapted for adults self-rating. Only four ADHD
individuals had a history of treatment with stimulants. None was
currently receiving medical treatment. Psychiatric family history in
both ADHD and control groups was obtained by structured interviews
(Gershon et al., 1988).
Procedures. The study consisted of a 2 hr [F18]FDOPA PET
session, including a 90 min uptake period and a 32 min acquisition period. The tracer [F18]FDOPA was administered in a 1 min intravenous infusion at a dose of 5.0 mCi. The sensitivity of the method was improved significantly by the following strategy. To increase the
availability of [F18]FDOPA in plasma to the brain, we blocked the
peripheral decarboxylation of [F18]FDOPA by the administration of 150 mg of carbidopa (L-aromatic amino acid decarboxylase
inhibitor) 1 hr before injection of the tracer (McLellan et al., 1991).
In addition, to minimize the accumulation of nonspecific cerebral radioactivity, which originates mostly from the peripheral metabolite 3-O-methyl-6-[F18]FDOPA, we saturated the blood-brain barrier transport system for large neutral amino acids by the intravenous infusion of a solution of unlabeled large neutral amino acids (Travasol 5%), starting 60 min after injection of the tracer
and maintained at a rate of 40 mg/kg per hour throughout the scanning period (Doudet et al., 1992b). During the first 90 min of tracer uptake, the subjects were watching a videotape. A custom-fitted plastic
head holder was used to immobilize the head during the next 30 min of
scanning time (90-120 min after injection of the tracer).
A seven-slice brain PET (Scanditronix PC-1024-7B, Uppsala, Sweden) was
used. The in-plane and axial resolutions were 5.2 and 11.8 mm,
respectively. Four transverse levels of seven slices each were
collected, i.e., a total of 28 slices, at 3.5 mm intervals. Transmission scans were used to correct for attenuation at all four
transverse levels, using a rotating germanium (68Ge) pin.
Thirty-two circular regions of interest (ROIs) of 37 pixels each (pixel
size = 4 mm2) were placed onto PET images so as
to match a standard template based on the atlas of Matsui and Hirano
(1978). The placement of ROIs was performed by a single rater who was
unaware of the identity and diagnosis of the subjects. A template of
the ROIs reported in this manuscript is provided in Figure
1. A high level of interrater reliability
was achieved with this procedure (Semple et al., 1993).
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Figure 1.
Template of regions of interest (ROIs). The ROIs
were placed according to a predetermined algorithm. The slice with the
highest striatal FDOPA signal was the "slice of reference" (at
approximately the level of the canthomeatal line) and is the one
presented in this figure. Striatal ROIs first were placed on the slice
of reference and then on both slices directly above and below,
respectively. The occipital ROIs were placed on the same slices as
those containing the striatal ROIs. The frontal ROIs were placed on the
4th (presented here) and 5th slice above the slice of reference
(~15-20 mm above the striatal plane, at the level of Brodmann area
10). The midbrain ROIs were placed on the 2nd (presented here)
and 3rd slice below the slice of reference (~7 and 10 mm below the
striatum).
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The ratio of specific to nonspecific radioactivity was chosen as the
method of analysis. This method has been shown to provide accurate and
reliable data and to be sensitive to changes in dopaminergic function
(Doudet et al., 1992a; Ernst et al., 1996). Presynaptic accumulation of
[F18]fluorodopamine was measured in anatomical ROIs drawn on five
brain areas rich in dopamine (four lateralized pairs: head of caudate
nucleus, putamen, midbrain, and lateral prefrontal cortex; one medial:
medial prefrontal cortex) and one region poor in dopamine (occipital
cortex) (Fig. 1). To reduce variability, we measured each regional F-18
signal in two (for the frontal, midbrain, and occipital regions) or
three consecutive planes (for the caudate and putamen regions) that
included the plane with the highest signal; the mean of these measures
was used for analysis. The midbrain region included the mesencephalic dopamine-rich cell bodies of the substantia nigra and of the ventral tegmentum. So that the effects of differences in input tracer and
measurement errors could be minimized, the [F18] activity from the
occipital cortex served as the measure of nonspecific activity and was
used to normalize [F18] activity of the dopamine-rich areas. These
normalized values or ratios, obtained from the formula [(region of
interest [F18]  occipital [F18])/occipital [F18]], were the
variables used for analysis and are referred to as the F18-ratio.
Statistical analysis. Three multivariate ANOVA
(MANOVA) tested the interactions and main effects of two between-group
factors (diagnosis, sex) and two within-subjects factors (region and
side) on the F18-ratios of the prefrontal cortex (medial, left, and right prefrontal areas), the striatum (left and right: caudate, anterior putamen, and posterior putamen), and the midbrain (left and
right). Statistically significant results were investigated further by
Student's t tests.
The potential influences of age and history of smoking on the
F18-ratios of the composite four regions, prefrontal (medial, and left
and right), caudate nucleus (left and right), putamen (left and right),
and midbrain (left and right), were tested by analyses of Pearson
product-moment correlation coefficients and a MANOVA, respectively.
Age was not correlated with F18-ratios in any of the four composite
regions in either the ADHD (0.04 < r < 0.42;
n = 17; 0.09 < p < 0.87) or the
control group (0.11 < r < 0.38;
n = 23; 0.22 < p < 0.61). Similarly,
a history of smoking did not influence F18-ratios (diagnosis × smoking: F(1,35) = 0.01, p = 0.94; smoking: F(1,35) = 0.00, p = 0.98). Thus, age and history of smoking were not controlled for in
the analysis of the results.
The association of clinical measures with regional F18-ratios was
assessed by means of Pearson product-moment correlation coefficients.
Only those measures that significantly differed between groups were
entered in the analysis. Clinical measures of severity of ADHD symptoms
were the overall scores on the 10 item Conners rating scale, the number
of DSM-III-R criteria for ADHD met currently and in childhood, and the
number of Utah criteria for ADHD met for past and current
symptomatology.
Statistical significance was set at p < 0.05 and
statistical trend at p < 0.10. All tests were
two-tailed.
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RESULTS |
Seventeen adults with ADHD (8 males and 9 females; 39.3 ± 6.2 years old) and 23 control adults (13 males and 10 females;
33.7 ± 10.5 years old) completed the study. Demographic and
behavioral characteristics are described in Table
1. Mean age tended to be higher in the
ADHD than in the control group (t = 1.94; df = 38;
p = 0.06), yet because age did not correlate
significantly with the F18-ratios of the four large regions analyzed
(frontal, caudate nucleus, putamen, and midbrain), it was not entered
as a covariate in subsequent analyses.
Interactions and main effects of diagnosis, laterality, and gender are
summarized in Table 2. Diagnosis
influenced F18-ratios only in the prefrontal cortex: F18-ratios were
lower in ADHD than in controls (see Tables
3 and 4).
Post hoc simple comparisons showed that both F18-ratios in
the medial and left lateral prefrontal areas were, respectively, 52 and
51% significantly lower in ADHD than in controls (medial prefrontal:
t = 2.90, df = 38, p = 0.006; left
lateral prefrontal: t = 2.09, df = 38, p = 0.04) (Figs. 2, 3). In addition, the prefrontal cortex
was the only region in which the relative male-to-female F18-ratios
values were different as a function of diagnosis: in ADHD, F18-ratios
were lower in men as compared with women; the opposite was found in
controls. Of interest, women had higher striatal F18-ratios than men in both ADHD and control groups. Finally, laterality was not affected by
diagnosis in any of the regions sampled.
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Table 2.
Interactions and main effects of diagnosis, gender, and
laterality on F18-ratios of three composite brain regions (frontal
cortex, striatum, and midbrain) (df = 1, 36 in all cases)
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Figure 2.
Scatter plot of individual F18-ratio values of the
medial prefrontal cortex (F18-ratio = [ROI-occipital]/occipital;
nCi/cc, nCi/cc). The horizontal line in each
diamond represents the group mean (for both women and
men); its length represents the group size, and its height represents
the 95% confidence interval.
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Figure 3.
Scatter plot of individual F18-ratio values of the
left prefrontal cortex (F18-ratio = [ROI-occipital]/occipital;
nCi/cc, nCi/cc). The horizontal line in each
diamond represents the group mean (for both women and
men); its length represents the group size, and its height represents
the 95% confidence interval.
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In the ADHD group the F18-ratios of the medial prefrontal cortex did
not correlate with any measures of severity of ADHD, whereas F18-ratios
of the left prefrontal cortex were correlated negatively with Utah
criteria of childhood ADHD (r = 0.54;
n = 17; p = 0.03) (Fig.
4).
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Figure 4.
Regression line of F18-ratios of the left
prefrontal cortex with the number of Utah criteria met for the presence
of ADHD in childhood in the ADHD group.
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DISCUSSION |
Adults with ADHD have abnormally low DOPA decarboxylase activity
in the prefrontal cortex, particularly in the medial and left lateral
areas.
Two caveats need to preamble the discussion of these findings: the
variability of the F18-ratios is increased in regions with relatively
low dopaminergic neural density (e.g., prefrontal cortex) or of small
sizes (e.g., dopaminergic cell body nuclei of the midbrain), which
weakens the power to detect significant differences between groups. For
example, a mean difference of 33% in the F18-ratios of the right
prefrontal cortex does not reach statistical significance. Furthermore,
the frontal signal is not quite dopamine-specific, because it arises
from both dopaminergic and noradrenergic nerve terminals. Thus, the
involvement of other monoamines and areas cannot be ruled out.
Although not the limiting factor in the rate of dopamine synthesis,
DOPA decarboxylase is the limiting step for F-dopamine synthesis from
F-DOPA (Gjedde et al., 1991, 1993). Therefore, a lower F18 signal
reflects reduction in the activity of the enzyme, either
structurally, i.e., decreased number of synapses, or
functionally, i.e., inhibition of the enzymatic activity
(decreased concentration or affinity). Structurally, a fewer
number of synapses would be consistent with a reduction of dopaminergic
terminals, which may result from a toxic effect or from an adaptive
response to an imbalance in the dopaminergic network.
Functionally, the inhibition of the enzyme could reflect
deficits in other functional units of the dopaminergic system. Indeed,
low extracellular dopamine concentration and blockade of D1 or D2
dopamine receptors have been associated with upregulation of DOPA
decarboxylase (Abercrombie et al., 1990; Hadjiconstantinou et al.,
1993; Zhu et al., 1993; Torstenson et al., 1997), whereas activation of
these receptors has been shown to downregulate DOPA decarboxylase
(Hadjiconstantinou et al., 1993; Zhu et al., 1993). The exact mechanism
leading to lower DOPA decarboxylase cannot be identified in this study
and neither can the role of this abnormality as a primary or secondary effect in ADHD. However, findings from the literature can suggest the
most likely mechanisms.
Because clinical and biological findings in ADHD differ between adults
and children, we propose that the prefrontal dopaminergic deficits in
ADHD adults are not the primary pathological defect but, rather, result
from an interaction of the primary neural deficit with maturation and
aging processes. Clinically, adults who continue to meet criteria for
ADHD present less hyperactivity but unchanged impairment in attention
as compared with their childhood symptoms (American Academy of Child
and Adolescent Psychiatry, 1997). This clinical evolution suggests that
a functional normalization of the structures that control motor
activity (mainly basal ganglia) may occur either via compensatory
neural mechanisms or a combination of learned and age-related
changes.
Consistent with this hypothesis, a functional normalization of
subcortical dopaminergic structures has been observed indirectly. CSF or blood concentrations of the dopaminergic metabolite
homovanillic acid (HVA) have been found abnormal in ADHD children
(Shaywitz et al., 1977; Castellanos et al., 1994), but not in ADHD
adults (Reimherr et al., 1984; Ernst et al., 1997b). The primary site of origin for HVA in the CSF has been ascribed to the structures of
densest dopaminergic innervation (nigrostriatum) (Amin et al., 1992).
Conversely, the failure to detect plasma or CSF dopaminergic aberrations would be expected were the dopaminergic abnormality in ADHD
circumscribed to areas receiving moderate dopaminergic input, such as
the prefrontal cortex. These findings suggest that the subcortical
dopaminergic nuclei are affected in children more than in adults.
Further evidence comes from neuroimaging studies, which have the
advantage of directly assessing defined localized areas of structural
or functional neurochemical specificity. PET studies of ADHD have
revealed different patterns of cerebral metabolic rates of glucose
(CMRglc) in adolescents and adults (Zametkin et al., 1990; Ernst et
al., 1994). Although abnormally low in adults (Zametkin et al., 1990),
global CMRglc was unaltered in adolescents (Zametkin et al., 1993;
Ernst et al., 1994). However, when regional CMRglc were normalized
(regional/global), the left prefrontal cortex was the region most
affected in adults (Zametkin et al., 1990) and adolescents (Ernst et
al., 1994). Furthermore, because CMRglc seemed to be more deviant in
girls than in boys in a small subsample of 11 girls (Ernst et al.,
1994), an independent larger sample of 21 girls was studied and
revealed dysfunction in the anterior putamen (Ernst et al., 1997a).
Taken together, these neuroimaging data suggest a more extensive
cortical involvement in ADHD adults than in ADHD adolescents.
The findings of different patterns of abnormalities in ADHD girls than
in ADHD boys need to be assessed more carefully with larger samples,
yet the role of the putamen in ADHD girls is consistent with hypotheses
of nigrostriatal dysfunction (Castellanos, 1997; Ernst, 1998). The
gender-related difference seems to hold true for both adolescents and
adults. However, whereas girls may have CMRglc more deviant than boys,
women seem to show less dopaminergic dysfunction than men (lower
F18-ratios in ADHD men than in ADHD women). The protective effect of
estrogen on the dopaminergic system (Thompson and Moss, 1997) and the
physiological dopamine loss with age (Roth and Joseph, 1994) will need
to be considered in the working model of the pathophysiology of
ADHD.
Finally, our laboratory recently completed a study of PET and
[F18]FDOPA comparing 10 ADHD adolescents with 10 age-matched controls
(our unpublished data) and found a significantly higher F18-ratio of
the right midbrain in the ADHD group than in the control group.
Although lower by 15% in ADHD, F18-ratios in the medial prefrontal
cortex did not differ significantly between ADHD and control
adolescents. The discrepancy between the adult and the adolescent
[F18]FDOPA findings may have reflected the inadvertent selection of
two different populations. For example, the adolescents may not
continue to present ADHD symptoms in adulthood, whereas the adults have
a form of ADHD that remains into adulthood. This hypothesis based on
the heterogeneity of ADHD may be of use for genetic studies. The
reports of an association between the seven-repeat allele of D4 gene
and ADHD (LaHoste et al., 1996) may be a better marker for the type of
ADHD that continues into adulthood, because this dopamine receptor is
found in the frontal cortex, but not in the nigrostriatum, in humans
(Matsumoto et al., 1995). The association of ADHD with markers of the
dopamine transporter gene (Cook et al., 1995; Gill et al., 1997) may be more central to the initial functional deficit that seems to involve the dopaminergic nuclei where dopamine transporters are highly concentrated.
Another hypothesis involves the developmental trajectory of the neural
substrates of ADHD. Dopamine has been shown to play an important role
in neurogenesis (Schmidt et al., 1996; Levitt et al., 1997), and an
early disruption of the dopamine system is likely to affect brain
maturation. Significant brain maturational changes occur during
adolescence; notwithstanding, the age-related decline of dopaminergic
innervation seems to be steepest between 10 and 20 years of age (Seeman
et al., 1987). In addition, although based on a limited number of
adolescents studied (n = 3), cortical and subcortical
synaptic activity indexed by PET assay of CMRglc was reported to
plateau in early adolescence (10-15 years) before decreasing to adult
levels (Chugani et al., 1987). Parallel to these maturational changes
that reflect neuronal pruning (Changeux and Danchin, 1976;
Huttenlocher, 1979; Cowan et al., 1984; Bourgeois et al., 1994), a
functionally specific refinement of the prefrontal neural circuitry has
been demonstrated in nonhuman primates during the peripubertal period
(Woo et al., 1997). This reorganization affects the superficial layers
of the prefrontal cortex where the density of dopamine axons is the
greatest (Lewis et al., 1998). Because developmentally the density of
dopaminergic synapses appears to peak before this peripubertal
reorganization (Lewis et al., 1998), dopamine is likely to influence
this neural maturation. With respect to ADHD, these maturational
changes may contribute to the shift of the dopaminergic abnormality
from midbrain in children to prefrontal cortex in adults; synaptic
pruning in the basal ganglia may compensate for the increased
presynaptic level of DOPA decarboxylase in midbrain of ADHD children
and unmask functional dopaminergic deficit in the prefrontal cortex of
ADHD adults. Alternatively, the reduction in dopamine function in the prefrontal cortex may serve to compensate for the dopaminergic abnormality in midbrain. Deafferentation of prefrontal dopamine projections has been shown to upregulate dopamine function in the basal
ganglia (Pycock et al., 1980; King and Finlay, 1995). It is also
possible that the prefrontal dopaminergic deficit is secondary to a
neurotoxic effect of dopamine (Alagarsamy et al., 1997) that could be
released in abnormal concentrations in the prefrontal terminal
field because of subcortical dopaminergic dysregulation.
In conclusion, the present work sets the direction for the
investigation of the neural mechanisms that mediate ADHD. Future studies need to examine systematically each of the functional units of
the dopamine system to identify the exact nature of the dopaminergic
dysfunction in ADHD. Furthermore, research in ADHD is ripe for
combining both brain imaging and genetics approaches. Proposed
strategies include the examination of the effects of susceptibility
genes on neuroimaging findings and, reciprocally, the exploitation of
homogenous brain imaging phenotypes in the search of candidate
genes.
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FOOTNOTES |
Received March 2, 1998; revised May 7, 1998; accepted May 13, 1998.
We thank the PET technologists and Chemistry Department of Nuclear
Medicine, National Institutes of Health Clinical Center, for their
assistance in performing this study.
Correspondence should be addressed to Dr. Monique Ernst or Dr. Robert
Cohen, National Institutes of Health, Building 36, Room 1A05, 36 Convent Drive, MSC 4030, Bethesda, MD 20892-4030.
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REFERENCES |
-
Abercrombie ED,
Bonatz AE,
Zigmond MJ
(1990)
Effects of L-dopa on extracellular dopamine in striatum of normal and 6-hydroxydopamine-treated rats.
Brain Res
525:36-44[Web of Science][Medline].
-
Alagarsamy S,
Phillips M,
Pappas T,
Johnson KM
(1997)
Dopamine neurotoxicity in cortical neurons.
Drug Alcohol Depend
48:105-111[Web of Science][Medline].
-
Alexander GE,
DeLong MR,
Strick PL
(1986)
Parallel organization of functionally segregated circuits linking basal ganglia and cortex.
Annu Rev Neurosci
9:357-381[Web of Science][Medline].
-
American Academy of Child and Adolescent Psychiatry
(1997)
Practice parameters for the assessment and treatment of children, adolescents, and adults with attention-deficit/hyperactivity disorder.
J Am Acad Child Adolesc Psychiatry
36:85S-121S[Medline].
-
American Psychiatric Association
(1987)
In: Diagnostic and statistical manual of mental disorders (DSM-III-R), 3rd ed, Revised. Washington, DC: American Psychiatric Association.
-
Amin F,
Davidson M,
Davis KL
(1992)
Homovanillic acid measurement in clinical research: a review of methodology.
Schizophr Bull
18:123-148.
-
Aylward EH,
Reiss AL,
Reader MJ
(1996)
Basal ganglia volumes in children with attention-deficit hyperactivity disorder.
J Child Neurol
11:112-115[Abstract/Free Full Text].
-
Barkley R
(1990)
Developmental course and adult outcome.
In: Attention deficit hyperactivity disorder. A handbook for diagnosis and treatment, pp 114-129. New York: Guilford.
-
Barkley RA
(1996)
Attention-deficit hyperactivity disorder.
In: Child psychopathology (Mash EJ,
Barkley RA,
eds), pp 63-112. New York: Guilford.
-
Bellak L,
Black RB
(1992)
Attention-deficit hyperactivity disorder in adults.
Clin Ther
14:138-147[Web of Science][Medline].
-
Benton A
(1991)
Prefrontal injury and behavior in children.
Dev Neuropsychol
7:275-282.
-
Bourgeois JP,
Goldman-Rakic PS,
Rakic P
(1994)
Synaptogenesis in the prefrontal cortex of rhesus monkeys.
Cereb Cortex
4:78-96[Abstract/Free Full Text].
-
Caparulo BK,
Cohen DJ,
Rothman SL,
Young JG,
Katz JD,
Shaywitz SE,
Shaywitz BA
(1981)
Computed tomographic brain scanning in children with developmental neuropsychiatric disorders.
J Am Acad Child Adolesc Psychiatry
20:338-357[Web of Science].
-
Castellanos FX
(1997)
Toward a pathophysiology of attention-deficit hyperactivity disorder.
Clin Pediatr (Phila)
36:381-393[Abstract/Free Full Text].
-
Castellanos FX,
Elia J,
Kruesi MJP,
Gulotta CS,
Mefford IN,
Potter WZ,
Ritchie GF,
Rapoport JL
(1994)
Cerebrospinal fluid monoamine metabolites in boys with attention deficit hyperactivity disorder.
Psychiatry Res
52:305-316[Web of Science][Medline].
-
Castellanos FX,
Giedd JN,
Marsh WL
(1996)
Quantitative brain magnetic resonance imaging in attention-deficit/hyperactivity disorder.
Arch Gen Psychiatry
53:607-616[Abstract/Free Full Text].
-
Changeux JP,
Danchin A
(1976)
Selective stabilization of developing synapses as a mechanism for the specification of neuronal networks.
Nature
264:705-712[Medline].
-
Chugani HT,
Phelps ME,
Mazziotta JC
(1987)
Positron emission tomography study of human brain functional development.
Ann Neurol
22:487-497[Web of Science][Medline].
-
Clark CR,
Geffen GM,
Geffen LB
(1986)
Role of monoamine pathways in the control of attention: effects of droperidol and methylphenidate in normal adult humans.
Psychopharmacology
90:28-34[Medline].
-
Conners CK
(1969)
A teacher rating scale for use in drug studies with children.
Am J Psychiatry
126:884-888[Abstract/Free Full Text].
-
Cook EH,
Stein MA,
Krasowski MD
(1995)
Association of attention deficit disorder and the dopamine transporter gene.
Am J Hum Genet
56:993-998[Web of Science][Medline].
-
Cowan WM,
Fawcett JW,
O'Leary DD,
Stanfield BB
(1984)
Regressive events in neurogenesis.
Science
225:1258-1265[Abstract/Free Full Text].
-
DeLong MR,
Alexander GE,
Miller WC,
Crutcher MD
(1990)
Anatomical and functional aspects of basal ganglia-thalamocortical circuits.
In: Function and dysfunction in the basal ganglia (Franks AJ,
Ironside JW,
Mindham RHS,
Smith RJ,
Spokes EGS,
Winlow W,
eds), pp 3-32. Manchester, UK: Manchester UP.
-
Denckla MB
(1994)
Measurement of executive function.
In: Frames of reference for the assessment of learning disabilities: new views on measurement issues (Lyon GR,
ed), pp 117-142. Baltimore: Brookes.
-
Doudet DJ,
Aigner TG,
McLellan CA,
Cohen RM
(1992a)
Positron emission tomography with 18-F-dopa: interpretation and biological correlates in non-human primates.
Psychiatry Res
45:153-168[Web of Science][Medline].
-
Doudet DJ,
McLellan CA,
Aigner TG,
Wyatt RJ,
Cohen RM
(1992b)
Delayed L-phenylalanine infusion allows for simultaneous kinetic analysis and improved evaluation of specific-to-nonspecific fluorine-18-dopa uptake in brain.
J Nucl Med
33:1383-1389[Abstract/Free Full Text].
-
Downey KK,
Stelson FW,
Pomerleau OF,
Giordani B
(1997)
Adult attention deficit hyperactivity disorder: psychological test profiles in a clinical population.
J Nerv Ment Dis
185:32-38[Web of Science][Medline].
-
Endicott J,
Spitzer RL
(1978)
A diagnostic interview: the schedule for affective disorders and schizophrenia.
Arch Gen Psychiatry
35:837-844[Abstract/Free Full Text].
-
Ernst M
(1998)
Dopaminergic function in ADHD.
In: Dopaminergic disorders: novel approaches for drug discovery and development, pp 235-260. Southborough, MA: IBC.
-
Ernst M,
Liebenauer LL,
King AC,
Fitzgerald GA,
Cohen RM,
Zametkin AJ
(1994)
Reduced brain metabolism in hyperactive girls.
J Am Acad Child Adolesc Psychiatry
33:858-868[Web of Science][Medline].
-
Ernst M,
Zametkin A,
Matochik J,
Pascualvaca D,
Jons P,
Hardy K,
Hankerson J,
Doudet D,
Cohen R
(1996)
Presynaptic dopaminergic deficits in Lesch-Nyhan disease.
N Engl J Med
334:1568-1604[Abstract/Free Full Text].
-
Ernst M,
Cohen RM,
Liebenauer LL,
Jons PH,
Zametkin AJ
(1997a)
Cerebral glucose metabolism in adolescent girls with attention-deficit/hyperactivity disorder.
J Am Acad Child Adolesc Psychiatry
36:1399-1406[Web of Science][Medline].
-
Ernst M,
Liebenauer LL,
Tebeka D,
Jons PH,
Eisenhofer G,
Murphy DL,
Zametkin AJ
(1997b)
Selegiline in ADHD adults. II. Plasma monoamines and monoamine metabolite.
Neuropsychopharmacology
16:276-284[Web of Science][Medline].
-
Gershon ES,
DeLisi LE,
Hamovit J,
Nurnberger JIJ,
Maxell ME,
Schreiber J,
Dauphinais D,
Dingman CWI,
Guroff JJ
(1988)
A controlled family study of chronic psychosis.
Arch Gen Psychiatry
45:328-336[Abstract/Free Full Text].
-
Gill M,
Daly G,
Heron S,
Hawi Z,
Fitzgerald M
(1997)
Confirmation of association between attention deficit hyperactivity disorder and a dopamine transporter polymorphism.
Mol Psychiatry
2:311-313[Web of Science][Medline].
-
Gittelman R,
Mannuzza S,
Shenker R,
Bonagura N
(1985)
Hyperactive boys almost grown up. I. Psychiatric status.
Arch Gen Psychiatry
42:937-947[Abstract/Free Full Text].
-
Gjedde A,
Reith J,
Dyve S,
Léger G,
Guttman M,
Diksic M,
Evans A,
Kuwabara H
(1991)
Dopa decarboxylase activity of the living human brain.
Proc Natl Acad Sci USA
88:2721-2725[Abstract/Free Full Text].
-
Gjedde A,
Léger GC,
Cumming P,
Yasuhara Y,
Evans AC,
Guttman M,
Kuwabara H
(1993)
Striatal L-dopa decarboxylase activity in Parkinson's disease in vivo: implications for the regulation of dopamine synthesis.
J Neurochem
61:1538-1541[Web of Science][Medline].
-
Goldman-Rakic PS
(1992)
Dopamine-mediated mechanisms of the prefrontal cortex.
Semin Neurosci
4:149-159.
-
Goyette CH,
Conners CK,
Ulrich RF
(1978)
Normative data on revised Conners parent and teacher rating scales.
J Abnorm Child Psychol
6:221-236[Web of Science][Medline].
-
Graybiel AM
(1991)
Basal ganglia
 input, neural activity, and relation to the cortex.
Curr Opin Neurobiol
1:644-651[Medline]. -
Hadjiconstantinou M,
Wemlinger TA,
Sylvia CP,
Hubble JP,
Neff NH
(1993)
Aromatic L-amino acid decarboxylase activity of mouse striatum is modulated via dopamine receptors.
J Neurochem
60:2175-2180[Web of Science][Medline].
-
Heilman KM,
Voeller KKS,
Nadeau SE
(1991)
A possible pathophysiologic substrate of attention deficit hyperactivity disorder.
J Child Neurol
6:S76-S81.
-
Huttenlocher PR
(1979)
Synaptic density in human frontal cortexdevelopmental changes and effects of aging.
Brain Res
163:195-205[Web of Science][Medline].
-
Hynd GW,
Hern KL,
Novey ES
(1993)
Attention deficit hyperactivity disorder and asymmetry of the caudate nucleus.
J Child Neurol
8:339-347[Abstract/Free Full Text].
-
King D,
Finlay J
(1995)
Effects of selective dopamine depletion in medial prefrontal cortex on basal and evoked extracellular dopamine in neostriatum.
Brain Res
685:117-128[Web of Science][Medline].
-
LaHoste GJ,
Swanson JM,
Wigal SB
(1996)
Dopamine D4 receptor gene polymorphisms associated with attention deficit hyperactivity disorder.
Mol Psychiatry
1:121-124[Web of Science][Medline].
-
Levitt P,
Harvey JA,
Friedman E,
Simansky K,
Murphy EH
(1997)
New evidence for neurotransmitter influences on brain development.
Trends Neurosci
20:269-274[Web of Science][Medline].
-
Lewis DA,
Sesack SR,
Levey AI,
Rosenberg DR
(1998)
Dopamine axons in primate prefrontal cortex: specificity of distribution, synaptic targets, and development.
Adv Pharmacol
42:703-706.
-
Lou HC
(1991)
Cerebral glucose metabolism in hyperactivity.
N Engl J Med
324:1216-1217[Medline].
-
Lou HC,
Henriksen L,
Bruhn P,
Borner H,
Nielsen JB
(1989)
Striatal dysfunction in attention deficit and hyperkinetic disorder.
Arch Neurol
46:48-52[Abstract/Free Full Text].
-
Mannuzza S,
Klein RG,
Bessler A,
Malloy P,
LaPadula M
(1993)
Adult outcome of hyperactive boys: educational achievement, occupational rank, and psychiatric status.
Arch Gen Psychiatry
50:565-576[Abstract/Free Full Text].
-
Matochik JA,
Liebenauer LL,
King C,
Szymanski HV,
Cohen RM,
Zametkin AJ
(1994)
Cerebral glucose metabolism in adults with attention deficit hyperactivity disorder after chronic stimulant treatment.
Am J Psychiatry
151:658-664[Abstract/Free Full Text].
-
Matsui T,
Hirano A
(1978)
In: An atlas of the human brain for computerized tomography. New York: Igaku-Shoin.
-
Matsumoto M,
Hidaka K,
Tada S,
Tasaki Y,
Yamaguchi T
(1995)
Full-length cDNA cloning and distribution of human dopamine D4 receptor.
Brain Res Mol Brain Res
29:157-162[Medline].
-
Mattes JA
(1980)
The role of frontal lobe dysfunction in childhood hyperkinesis.
Compr Psychiatry
21:358-369[Web of Science][Medline].
-
McLellan C,
Doudet D,
Brucke T,
Aigner T,
Cohen R
(1991)
New rapid analysis method demonstrates differences in 6-[18-F]Fluoro-L-dopa plasma input curves with and without carbidopa in hemi-MPTP lesioned monkeys.
Int J Rad Appl Instrum [A]
42:847-854.
-
Pycock CJ,
Kerwin RW,
Carter CJ
(1980)
Effect of lesion of cortical dopamine terminals on subcortical dopamine receptors in rats.
Nature
286:74-76[Medline].
-
Reimherr FW,
Wender PH,
Ebert MH,
Wood DR
(1984)
Cerebrospinal fluid homovanillic acid and 5-hydroxyindolacetic acid in adults with attention deficit hyperactivity disorder, residual type.
Psychiatry Res
11:71-78[Web of Science][Medline].
-
Roth GS,
Joseph JA
(1994)
Cellular and molecular mechanisms of impaired dopaminergic function during aging.
Ann NY Acad Sci
719:129-135[Web of Science][Medline].
-
Schmidt U,
Beyer C,
Oestreicher AB,
Reisert I,
Schilling K
(1996)
Pilgrim C activation of dopaminergic D1 receptors promotes morphogenesis of developing striatal neurons.
Neuroscience
74:453-460[Web of Science][Medline].
-
Seeman P,
Bzowej NH,
Guan HC,
Bergeron C,
Becker LE,
Reynolds GP,
Bird ED,
Riederer P,
Jellinger K,
Watanabe S
(1987)
Human brain dopamine receptors in children and aging adults.
Synapse
1:399-404[Web of Science][Medline].
-
Semple WE,
Johnson JL,
Cohen RM
(1993)
Reliability in positron emission tomography.
In: Imaging drug action in the brain (London ED,
ed), pp 297-316. Boca Raton, FL: CRC.
-
Shaywitz BA,
Cohen DJ,
Bowers MB
(1977)
CSF amine metabolites in children with minimal brain dysfunction: evidence for alteration of brain dopamine.
J Pediatr
90:67-71[Web of Science][Medline].
-
Solanto MV (1998) Neuropsychopharmacological mechanisms of
stimulant drug action in attention deficit/hyperactivity disorder: a
review and integration. Behav Brain Res, in press.
-
Spencer T,
Wilens T,
Biederman J,
Faraone SV,
Ablon S,
Lapey K
(1995)
A double-blind, cross-over comparison of methylphenidate and placebo in adults with childhood onset attention deficit hyperactivity disorder.
Arch Gen Psychiatry
52:434-443[Abstract/Free Full Text].
-
Thompson TL,
Moss RL
(1997)
Modulation of mesolimbic dopaminergic activity over the rat estrous cycle.
Neurosci Lett
229:145-148[Web of Science][Medline].
-
Torstenson R,
Hartvig P,
Langstrom B,
Westerberg G,
Tedroff J
(1997)
Differential effects of levodopa on dopaminergic function in early and advanced Parkinson's disease.
Ann Neurol
41:334-440[Web of Science][Medline].
-
Weiss G,
Hechtman LT
(1986)
In: Hyperactive children grown up. New York: Guilford.
-
Wilens TE,
Biederman J,
Spencer TJ,
Prince J
(1995)
Pharmacotherapy of adult attention deficit/hyperactivity disorder: a review.
J Clin Psychopharmacol
15:270-279[Web of Science][Medline].
-
Woo TU,
Pucak ML,
Kye CH,
Matus CV,
Lewis DA
(1997)
Peripubertal refinement of the intrinsic and associational circuitry in monkey prefrontal cortex.
Neuroscience
80:1149-1158[Web of Science][Medline].
-
Zametkin AJ,
Nordahl TE,
Gross M,
King AC,
Semple WE,
Rumsey J,
Hamburger S,
Cohen RM
(1990)
Cerebral glucose metabolism in adults with hyperactivity of childhood onset.
N Engl J Med
323:1361-1366[Abstract].
-
Zametkin AJ,
Liebenauer LL,
Fitzgerald GA,
King AC,
Minkunas DV,
Herscovitch P,
Yamada EM,
Cohen RM
(1993)
Brain metabolism in teenagers with attention deficit hyperactivity disorder.
Arch Gen Psychiatry
50:333-340[Abstract/Free Full Text].
-
Zhu MY,
Jurio AV,
Paterson I,
Boulton AA
(1993)
Regulation of striatal L-amino acid decarboxylase: effects of blockade or activation of dopamine receptors.
Eur J Pharmacol
238:157-164[Web of Science][Medline].
Copyright © 1998 Society for Neuroscience 0270-6474/98/18155901-07$05.00/0
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Abstract
Introduction
