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Brain & Development 27 (2005) 279285

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Original article
Regional cerebral blood flow in children with ADHD: changes with age
Ozgur Onera,*, Pnar Onerb, Ayla Aysevc, Ozlem Kucukd, Erkan Ibisd
a
Advanced Research Fellow, NIMH Fogarty International Mental Health and Developmental Disabilities Program, Istanbul, Turkey
b
Mersin University School of Medicine Psychiatry Department, Turkey
c
Department of Child Psychiatry, University of Ankara Medical School, Ankara, Turkey
d
Department of Nuclear Medicine, University of Ankara Medical School, Ankara, Turkey
Received 4 June 2003; received in revised form 12 July 2004; accepted 22 July 2004

Abstract
The aim of this study was to investigate the changes in regional cerebral blood flow (rCBF) with age in patients with attention deficit
hyperactivity disorder (ADHD). Twenty-nine drug-naive ADHD subjects (24 boys, 5 girls; age 713; meanGSDZage 9.2G2.1) and 12
subjects with epilepsy (all diagnosed as having complex partial seizure, 6 boys, 6 girls; age 714; meanGSDZ8.5G2.1) were included in
the study. All cases of ADHD were diagnosed according to DSM-IV criteria. Cerebral blood flow was evaluated with Tc-99m-
hexamethylpropyleneamine oxime (Tc99m HMPAO) brain single photon emission tomography (SPECT) during standard resting condition
in all of the cases. Asymmetry indices for each region of interest were calculated. Absolute rCBF values were normalized as the absolute
rCBF values divided by the whole brain absolute value. The prefrontal lobe asymmetry indices were significantly negatively correlated with
age in ADHD cases (rZK0.408, PZ0.025), which indicated the increased prefrontal rCBF lateralization from the right to the left side with
age. When ADHD cases older than 7 years of age were compared with those with epilepsy, the ADHD cases had lower right prefrontal and
frontal rCBF and higher left parietal rCBF. The epilepsy group showed no significant correlations between age and asymmetry indices and
showed a different developmental trajectory for prefrontal asymmetry and right prefrontal rCBF values. The results indicated that the left
hemisphere dominance in the prefrontal cortex significantly increases with age in ADHD cases.
q 2004 Elsevier B.V. All rights reserved.

Keywords: Attention deficit hyperactivity disorder; SPECT; Prefrontal cortex

1. Introduction cortex, and the caudate nucleus [816]. Thus, right-sided


abnormalities of the prefrontal cortex-basal ganglia circuit
Attention Deficit Hyperactivity Disorder (ADHD) is a have been implicated in pathophysiology of ADHD [17].
common disorder that affects many children, significantly There have been a number of MRI studies evaluating
impacting their potential for development [1]. There is an structural changes of the brain in normal subjects including
increasing convergence of results demonstrating both children. The findings of those studies are summarized as
structural and functional characteristics of the brains of follows: cerebral volume does not change significantly after
patients with ADHD. Structural MRI studies have shown 5 years of age [1820]; the cortical gray matter volume
abnormalities of the whole brain, the frontal lobes, the basal decreases significantly with age [21]; and the cerebral white
ganglia, the corpus callosum, the parietal lobes, and the matter volume increases throughout childhood [2022]:
cerebellar vermis [27]. The results of functional studies, these changes appear to be region specific [23].
mostly comprised of SPECT and PET, have not been PET studies involving children with neurological con-
entirely consistent, but indicated reduced brain activity in cerns (e.g. seizures, epilepsy, SturgeWeber syndrome)
the prefrontal and the parietal cortices, the anterior cingulate indicate that cerebral glucose metabolic rates follow a
triphasic evolution characterized by rapid increase after
* Corresponding author. Address: Gazi Ethem Pasa Sokak, Atala Apt.
birth, persistent high levels during childhood, possibly a
6/1, Senesenevler, 34742 Istanbul, Turkey. Fax: C90 312 3620809. result of increased energy demand resulting from transient
E-mail address: ozz_oner@yahoo.com (O. Oner). synaptic exuberance, and a subsequent decline to reach
0387-7604/$ - see front matter q 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.braindev.2004.07.010
280 O. Oner et al. / Brain & Development 27 (2005) 279285

the adult levels by the end of adolescence [24,25]. Results of were mentally retarded as judged from their academic and
SPECT studies indicated that the activities of the frontal, social functioning. MRI images of those cases were not
parietal, left temporal and cingulate cortices were signifi- available. The SPECT scans of those subjects with epilepsy
cantly higher in children than in adults [26]. were collected from Ankara University Nuclear Medicine
The aim of the present study was to investigate the age- Department archives and analyzed quantitatively later for
specific changes in regional cerebral blood flow (rCBF) and this research. All of them were judged as unremarkable at
the degree of asymmetry in rCBF in ADHD subjects. There the level of visual inspection. We adopted those subjects as
have been few previous SPECT studies involving ADHD controls in this study because, as in the previous studies
children and none have evaluated the changes in rCBF conducted with children, it was impossible to obtain SPECT
with age. images of children with no neurological problems.

2.2. Image acquisition


2. Method
All children and their parents were informed of the
2.1. Subjects procedure for SPECT. The subjects were asked to lie calmly
at supine with one of his/her parents accompanying them
Subjects were 29 patients with ADHD (24 boys, 5 girls; without talking to him/her, with eyes closed with minimal
age 713; meanGSDZ9.19G2.01). None of the cases were sensory stimulation for 5 min and then received Tc99m
left handed per Pediatric Assessment of Neurological Soft HMPAO intravenously under resting conditions with
Signs [27] handedness items. All of the cases were minimal sensory stimulation (eyes covered in a quiet,
Caucasian. All subjects were recruited from the general dimly lit room). The dose of Tc99m HMPAO was calculated
outpatient clinic at the Child Psychiatry Department, who as [(ageC1)/(ageC7)]!standard adult dose (15 mCi).
fulfilled the inclusion criteria. The same group of patients Patients were asked to lie calmly for an additional period
has been the subjects of the two previous studies by the of 5 min after the injection. The SPECT image acquisition
same investigators: the one on the effects of methylpheni- started 15 min after the injection. The researchers were
date on the rCBF [28] and the other one on the rCBF in present during the scanning in order to control the
juvenile obsessive-compulsive disorders and ADHD [29]. conditions for compliance with the procedure.
Informed consent was obtained from the parents before The radiochemical purity was assessed by instant thin-
enrollment with local ethics committee approval for layer chromatography and was always above 90%. Scans
inclusion in both of the studies. Diagnosis was based on were performed with a SPECT system (GE 4000I) using a
DSM-IV criteria and was established by a consensus of at high resolution collimator and were acquired over 3 min as
least two psychiatrists. ADHD symptom severity was 128 projections into 64!64 matrices (each pixel 4!4 mm).
evaluated in 17 cases using Conners Teacher Rating These data were processed using Meltz filter and were
Scale [31]: inattentiveness score was 11.2G4.9 (meanG reconstructed by filtered back-projection with a Ramp filter.
SD); hyperactivity 13.2G0.4; conduct problems 9.0G0.8; Attenuation correction was applied to the data using the
total score 39.0G10.6. Sorenson method. Oblique reorientation was performed to
All ADHD cases had unremarkable medical history other yield 2-pixel-thick (8 mm) transaxial images parallel to the
than ADHD and were clinically screened for psychosis, orbitomeatal line.
eating disorders, substance use disorders, pervasive devel- Regions of interest (ROIs) were generated manually over
opmental disorders, and mental retardation. In all of the the right cerebral hemisphere in the prefrontal, frontal,
ADHD cases, diagnoses were of combined subtype [30]. All temporal, and parietal cortices. Occipital cortex, basal
patients were diagnosed for the first time and had never been ganglia, and cerebellum could not be evaluated due to data
evaluated for psychiatric disorders or treated with psycho- loss by a computer error for these regions in a substantial
pharmacological medicine. SPECT study was performed proportion of the subjects of the epilepsy group. Analysis
relatively shortly (within 2 weeks) after the diagnosis was was performed by one of the authors who were unaware of
made. the subjects diagnosis. To increase the objectivity of the
The subjects with epilepsy (age range 714 years; findings, a Bayesian approach to interpretation was used,
meanGSDZ8.5G2.11; 6 boys and 6 girls) included with the reading rendered initially without, and then with,
children who were referred for SPECT investigation for the knowledge of the clinical parameters [32]. Double-
epilepsy work-up, as the diagnosis of complex partial reading of scans with third-party adjudication for disputed
seizure (legion related epilepsy) was suspected: the most findings was used to ensure quality control.
common clinical manifestations included altered level of Transaxial slices were selected with a neuroanatomical
consciousness (i.e. aura followed by confusional state, etc.), reference method [33] used as a reference guide, in order to
which were suggestive of complex partial seizures. These encompass the different ROIs. Semiquantitative evaluation
children had been diagnosed as epilepsy for the first time was performed by drawing irregular ROIs in five standar-
and never been on antiepileptic drugs. None of the patients dized 8-mm-thick oblique slices corresponding to
O. Oner et al. / Brain & Development 27 (2005) 279285 281

anatomical levels that define the boundaries of anatomical 3.3. Correlations with the teacher ratings
structures. No attempt was made to compare counts in ROIs
directly. Uptakes of the radioligand in these regions were Right prefrontal and left temporal rCBF were significantly
calculated and expressed as within-subject ratios to the correlated with the inattentiveness score (rZ0.547, PZ0.02;
cortical blood flow (the sum of the rCBF values for the rZK0.528, PZ0.03, respectively). There were no other
bilateral prefrontal, frontal, parietal, and temporal cortices) significant correlations between the teacher ratings and the
to normalize the scans. Right and left hemisphere rCBF SPECT variables (K0.34!r!0.44; 0.08!P!0.99).
asymmetry indices were calculated by the formula (right Regarding the asymmetry indices, the most significant
rCBFKleft rCBF)/(right rCBFCleft rCBF). correlation was between the Total Problems score and the
prefrontal asymmetry values (rZ0.44, PZ0.08). Age of the
2.3. Data analysis patients was not significantly correlated with the teacher
ratings (K0.162!r!0.385; 0.127!P!0.535).
In order to detect rCBF changes with age, we calculated
the correlations of relative perfusions in the right and left
cerebral areas and asymmetry indices with age by using the 4. Discussion
Pearsons correlation coefficient. The gender distribution in
the ADHD group and epilepsy group were different, but Our results indicate that the prefrontal cortex rCBF
did not reach statistically significant levels (x2Z4.64, during resting conditions in ADHD cases shows increased
PZ0.052, Fishers Exact Test). The age distribution in the lateralization from the right to the left with age and that
ADHD cases and epilepsy group were not statistically ADHD cases have lower right prefrontal and frontal and
different (FZ0.91; dfZ1,39; PZ0.34). MannWhitney-U higher parietal relative rCBF values compared with those
test and analysis of variance (ANOVA) were performed in patients with epilepsies. The differences between the groups
order to compare the rCBF between ADHD cases and are more prominent when subjects older than 7 years of age
epilepsy cases. Two-tailed significance tests (P!0.05) are were compared. The decreased right prefrontal and frontal
reported throughout. SPSS 10.0 statistical package (SPSS, rCBF is consistent with previous studies that reported
Inc.) was used for the analysis. greater dysfunction in the right hemisphere [1734]. A loss
of normal asymmetry in the volume of the caudate nucleus
and in the volume of the right striatal and anterior frontal
areas in subjects with ADHD has been demonstrated, which
3. Results is suggestive of a deviation from normal development of
right frontal-subcortical circuits [2,3]. Functional imaging
and electroencephalographic studies have shown a failure of
3.1. Correlations with age right prefrontal activation during response inhibition
paradigms in ADHD [15,35,36]. Normally, there is a
Age was not significantly correlated with any of the coupling of cerebral blood flow and functional activity
relative rCBF values (K0.340!r!0.193; 0.07!P!0.91) [10], and of glucose utilization and the number of neurons
in the ADHD group. However, with increasing age and synapses in a region [25]. The lower prefrontal cortex
prefrontal asymmetry indices decreased significantly volumes reported previously might be related with lower
(rZK0.407, P!0.028) in the ADHD group. In the epilepsy prefrontal rCBF values in ADHD cases. The parietal cortex
group, there were no significant correlations of rCBF was also reported to be effected in ADHD [3]. Overall, our
or asymmetry indices with age (K0.100!r!0.430; results were consistent with these studies, particularly for
0.15!P!0.84). Changes with age in the rCBF values cases older than 7 years of age.
(Fig. 1) and asymmetry indices (Fig. 2) in the prefrontal and Our results have shown a trend as increasing age for
frontal cortices in the two groups were evaluated. lower right and higher left prefrontal and frontal rCBF
values in the ADHD group (Figs. 1 and 2). The correlation
3.2. rCBF in ADHD and epilepsy subjects coefficients become significant when the asymmetry values,
that is the difference between right and left rCBF, are taken
ADHD cases had significantly lower right prefrontal and into account. The epilepsy subjects showed a different
frontal rCBF values (FZ4.99, dfZ1,39, PZ0.03; FZ5.05, developmental trajectory for prefrontal asymmetry and right
dfZ1,39, PZ0.03) and higher left parietal rCBF values prefrontal rCBF values. An intriguing finding of the present
(FZ5.03, dfZ1,39, PZ0.03, ANOVA) compared with study was that the rCBF differences between the ADHD and
epilepsy subjects (Table 1). These differences were more epilepsy groups (lower right prefrontal and frontal rCBF
significant when cases older than 7 years of age (nZ20 for values and higher left parietal rCBF values in ADHD) were
ADHD, nZ7 for epilepsy) were compared (right prefrontal: more prominent in cases older than 7 years of age. From the
zZK2.76, PZ0.004; right frontal: zZK2.21, PZ0.027; regression lines in Fig. 2 (indicating decreasing right
left parietal: zZK2.82, PZ0.003; MannWhitney-U test). relative to left prefrontal and frontal rCBF values with age
282 O. Oner et al. / Brain & Development 27 (2005) 279285

Fig. 1. Right and left prefrontal and frontal rCBF values in ADHD subjects (nZ29) (left side) and those with epilepsy (nZ12) (right side). Regression lines
with 95% confidence intervals. Abscissa: age in years. Ordinate: CBF in percent of total rCBF (the sum of rCBF values for the bilateral prefrontal, frontal,
parietal, and temporal cortices) to the prefrontal and frontal regions.

in ADHD group), we infer that the decrease of relative right Frontal lobes are among the last cortical regions to
prefrontal rCBF with age in ADHD group might account for mature anatomically and functionally and the frontalisation
the more prominent rCBF differences in older subjects. process may not be over until the mid-twenties [25,3739].
However, with the 95% confidence intervals for older Previous studies conducted with normal pediatric popu-
subjects being quite large in the epilepsy group, these results lations have indicated that the rates of glucose metabolism
must be interpreted with caution. in the cerebrum exceed those of adults by 34 years of age,
O. Oner et al. / Brain & Development 27 (2005) 279285 283

Fig. 2. Prefrontal and frontal asymmetry values of ADHD (nZ29) (left side) and epilepsy (nZ12) (right side) groups. Regression lines with 95% confidence
intervals.

maintained until approximately 9 years of age when they fluorodopa ([F18]FDOPA) PET in adult ADHD cases,
begin to decline [25]. A former SPECT study conducted and the variability of F18 ratios may be higher in regions
with 23 normal children indicated that both left and right with low dopaminergic activity like prefrontal cortex, which
cortical rCBF values decreased with age [26]. The decrease makes interpretation of results more difficult. Another
of the relative right prefrontal rCBF with age in the ADHD important point is the ages of the sample. As the authors
group observed in the present study was somehow suggested, due to maturation and aging processes, there
unexpected. It may be accounted for as follows; the might be clinical and biological differences between adult
ADHD cases in our study were diagnosed for the first and child ADHD cases [40].
time and had never been treated for ADHD. Those data The present study has several limitations. Our study
taken together, it may be inferred that the longer period had a methodological disadvantage as compared to PET
before the diagnosis is made might be related with the lower Table 1
prefrontal brain volumes and hence with the lower rCBF rCBF in percent of total CBF (the sum of the CBF values for bilateral
values. However, more data are required to support this prefrontal, frontal, parietal, and temporal cortices)
hypothesis. Region Epilepsy (CPS) ADHD
The symptom severity assessed by teacher reports was
Mean SD Mean SD
correlated positively with right prefrontal rCBF in ADHD
cases. Some of the former studies reported a negative Right prefrontal 12.7 0.81 12.2 0.69
Right frontal 12.7 0.55 12.3 0.45
correlation between symptom severity and prefrontal Right parietal 12.1 0.78 12.5 0.75
dopamine metabolism [40], while others reported that Right temporal 12.7 0.64 13.0 0.98
higher symptom severity was related with higher right Left prefrontal 12.4 0.73 12.2 0.72
perfusion relative to left [41]. These differences might be Left frontal 12.6 0.54 12.4 0.48
Left parietal 11.9 0.72 12.4 0.52
related with the neuroimaging methods and sample
Left temporal 12.7 0.88 13.0 0.98
characteristics. The former study utilized [fluorine-18]
284 O. Oner et al. / Brain & Development 27 (2005) 279285

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