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Differences between attention-deficit disorder with and without hyperactivity: a 1H-magnetic resonance spectroscopy study
Brain & Development 27 (2005) 340–344 www.elsevier.com/locate/braindev
Original article
Differences between attention-deficit disorder with and without hyperactivity: a 1H-magnetic resonance spectroscopy study Li Suna, Zhen Jinb, Yu-feng Zanga, Ya-wei Zengb, Gang Liub, Yang Lia, Larry J. Seidmanc, Stephen V. Faraoned,e, Yu-feng Wanga,* a
Insttitute of Mental Health, Peking University, Huayuanbeilu 51, Haidian District, Beijing 100083, People’s Republic of China b Center of fMRI, Hospital 306, Beijng 100101, People’s Republic of China c Department of Psychiatry, Massachusetts Mental Health Center, Harvard Medical School, Boston, MA, USA d Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA e Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA Received 1 June 2004; received in revised form 26 July 2004; accepted 11 September 2004
Abstract Using proton magnetic resonance spectroscopy (1H-MRS) to investigate possible neurometabolic differences between the predominantly inattentive subtype (ADHD-I), the combined subtype (ADHD-C) and normal controls. Proton spectra were acquired bilaterally on the lenticular nucleus in 20 schoolboys having ADHD and 10 matched controls. The boys with ADHD were divided into ADHD-C subtype (nZ10) and ADHD-I subtype (nZ10) according to DSM-IV criteria. The peaks of N-acetylaspartate (NAA), Choline moieties (Cho), myoinositol (mI), creatine (Cr) and a-Glx were measured and their ratios to Cr were calculated. One-way ANOVA and post-hoc Bonferroni tests were used to detect the difference of the peak–area ratios of NAA, Cho, mI, and a-Glx to Cr among the three groups. There was a significant overall group difference in the NAA/Cr ratio both in the right and left lenticular nucleus (right: PZ0.002; left: PZ0.003). Only the ADHD-C subtype group showed a significant difference with controls (right: PZ0.001; left: PZ0.003) the right lenticular nucleus, the NAA/Cr ratio in the ADHD-C group was significantly lower than that in the ADHD-I group (PZ0.012). In the left lenticular nucleus, the NAA/Cr ratio in the ADHD-C group showed a significant trend compared to the ADHD-I group (PZ0.06). This study demonstrated the existence of measurable difference between children with ADHD-C and ADHD-I using 1H-MRS. q 2004 Elsevier B.V. All rights reserved. Keywords: Attention deficit hyperactivity disorder; Subtype; 1H-magnetic resonance spectroscopy; Lenticular nucleus; N-aceytylaspartate
1. Introduction Attention-deficit hyperactivity disorder (ADHD) is one of the most common psychiatric disorders in childhood and adolescence. The disorder is characterized by developmentally inappropriate symptoms of inattention, impulsivity and hyperactivity, with a prevalence estimated to be between 3 and 5% among school-age children. Problems such as learning disabilities, school failure, peer difficulties, and other disruptive behaviors are commonly associated with
* Corresponding author. Tel.: C86 10 82801969; fax: C86 10 62027314. E-mail addresses: [email protected] (Y.-f. Wang), wangyufengbmu@ hotmail.com (Y.-f. Wang). 0387-7604/$ - see front matter q 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.braindev.2004.09.004
the disorder. The disorder is primarily found in boys, occurring in a ratio of 4–9:1 (boys to girls) [1]. Depending on which symptoms predominate, the Diagnostic and Statistical Manual of Mental Disorder (DSM-IV) recognizes three subtypes of ADHD: the predominantly inattentive subtype (ADHD-I), the predominantly hyperactive-impulsive subtype (ADHD-HI), and the combined subtype (ADHD-C). Each subtype has distinct clinical features: ADHD-I children have short concentration spans and are easily distracted; children with ADHD-HI are often restless, fidgety and impulsive; and children with ADHD-C have both concentration problems and hyperactivity [2]. The DSM-IV field trials indicated that the current subtypes differ significantly on age at onset, gender, and level of social and academic impairment [3]. Several studies
L. Sun et al. / Brain & Development 27 (2005) 340–344
indicated that the ADHD-C children had higher rates of comorbidity compared with the ADHD-HI subtype and the ADHD-I subtype. Regarding clinical features, the combined subtype children tend to show more severe disorder than the other DSM-IV subtypes [4,5]. Morgan et al. [6] reported that the ADHD-C subtype children are perceived by their parents as displaying significantly more externalizing, delinquent, and aggressive behavior than the ADHD-I subtype children. From a neuropsychological view, Houghton et al. compared the executive functions in ADHD subtypes and normal control subjects, they found that the ADHD-C subtype children made the most errors on the Wisconsin Card Sorting Test and performed more poorly than the ADHD-I subtype and the controls for the Stroop Color-Word Test. These results demonstrate that the impairments in executive function are clearly present in ADHD, particularly in the ADHD-C subtype [7]. In addition to the neuropsychological measurements, volumetric neuroimaging [8–13] and functional neuroimaging studies have shown that abnormalities in frontal networks or fronto-striatal dysfunction comprise the disorder’s best identified neural substrate [14–18], but up to the present there have been no studies to identify the different features of ADHD subtypes by these instruments. Proton magnetic resonance spectroscopy (1H-MRS) is a non-invasive technique for evaluating brain chemistry in vivo, which can detect the metabolic changes in the brain and reflects the developmental status of brain. Using MRS we can obtain the spectra of N-acetylaspartate (NAA), Choline moieties (Cho), creatine (Cr) and myo-inositol (mI) [19]. Although the role of NAA in neurons is not yet fully understood, it is found predominantly within neurons, so it serves as a neuronal marker, reflecting neuronal density, neuronal viability, and may undergo reversible changes. NAA reductions have been interpreted as strong evidence for neuron loss or dysfunction in a brain region of interest [20]. Few studies have observed intracerebral neurochemical concentration in ADHD using Proton magnetic resonance spectroscopy (1H-MRS). Hesslinger et al. [21] reported that reduced NAA concentration was found in left dorsolateral prefrontal cortex in adults with ADHD, but there was no significant difference in left global pallidus. MacMaster et al. [22] found that frontal–striatal glutamatergic resonances were elevated in the children with ADHD as compared to normal children. ADHD girls had especially low NAA concentrations in right dorsolateral frontal [23]. Accumulating evidence suggests the basal ganglia is involved in emotional, motivational, and cognitive functions [24–26].We have previously reported that NAA/Cr ratio decreased significantly in bilateral lenticular nucleus (LN) for ADHD children [27]. The primary aim of the current study was to view such changes among ADHD subtypes. As a matter of fact that ADHD-HI is relatively rare, so only ADHD-I and ADHD-C subtypes were included.
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2. Method 2.1. Subjects Thirty right handed boys aging from 10 to 14 years old participated in this study. We compared three groups (nZ10 each), namely ADHD-Combined type (ADHD-C), ADHD Inattentive type (ADHD-I) and a control group. Materials of some subjects, including 10 controls and eight ADHD children (four ADHD-C, four ADHD-I), had been reported in our previous work [27]. Groups were matched for age, gender and handedness. Both groups of ADHD children were recruited from the child psychiatric clinics at Peking University Institute of Mental Health. No subjects had a history of medication use for ADHD. The normal control group came from local schools. Informed consent was obtained from their parents. 2.1.1. ADHD children Inclusion in the ADHD groups was based on a clinical assessment by two psychiatrists separately, one of who was a senior psychiatrist. Diagnostic criteria were collected with the Clinical Diagnostic Interviewing Scales (CDIS) [28], a structured, interviewer-administered interview based on DSM-IV. The CDIS asks questions about behavioral and emotional disorders of childhood, such as ADHD, oppositional defiant disorder (ODD), conduct disorder (CD), tic disorders, emotional disorders, affective disorders, and learning problems. In the ADHD section, the CDIS recognizes three types of ADHD: ADHD inattentive type (ADHD-I), ADHD hyperactive-impulsive type (ADHDHI), and ADHD combined type (ADHD-C). All the parents were interviewed. There were 10 ADHDC boys (mean age: 12.43G1.38 years old) and 10 ADHD-I boys (mean age: 12.64G1.02 years old) included. Assessment was based on a CDIS [28] with a parent, and comorbidities were assessed at the same time. All ADHD boys were assessed using the Chinese-Wechlser Intelligence Scale for Children (C-WISC) [29], they have a full scale IQ no lower than 75 (the ADHD-C group: mean IQ scoresZ 99.50G12.53, the ADHD-I group: mean IQ scoresZ100.7G9.51). In the ADHD-C group, three children were ‘pure’ ADHD without comorbidity, one child had a CD, two children had ODD, three children had tic disorders, and seven children had learning problems. In the ADHD-I group, one child was ‘pure’ ADHD, two children had CD, five children had ODD, and nine children had learning problems. 2.1.2. Normal controls The normal controls (mean age: 12.67G1.15 years) were screened using the Clinical Diagnostic Interview Scale (CDIS) [28] with a parent, and Raven Standard Progressive Matrices [30]. They were free of any psychiatric disorder and had no attention deficit, hyperactivity or learning problem.
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For all groups, subjects were excluded if they had a history of neurological diseases, schizophrenia, pervasive development disorder, affective disorder, epilepsy, and mental retardation (Standard Score from the Raven Standard Progressive Matrices lower than 25 percentile). 2.2. MRS methods Magnetic resonance investigations were performed on a 1.9T Prestige Imaging/MRS scanner, using an Elscint/GE (Haifa) with a circularly polarized head coil suit for MR imaging and Volume selective 1H MRS. Standard-spin echo (SE) T1 and fast-spin echo (FSE) T2 weighted axial images covering the whole brain were acquired first to guide the MRS localizing and screening for brain pathology. The single spectral volume of interest (VOI) was 2!2!2 cm3, which centered at the medial part of the lenticular nucleus (LN) (Fig. 1). The VOI was located at the similar, as far as possible, position across subjects. Right and left LN was scanned in random order. The point resolved spectroscopy (PRESS) scan sequence (TRZ1500 ms; TEZ35.5 ms; NEXZ200; MatrixZ1020) was used for spectral acquisition. Carefully shimming for the magnetic field and chemical-shift selective water suppression scanning were completed before the spectral acquisition. 1 H spectra were analyzed online using the software provided by Elscint/GE. The prominent N-acetylaspartate (NAA) peak at 2.0 ppm was used as an internal chemical shift reference. The spectra exhibited peaks of choline complex (Cho) at 3.2 ppm, and creatine (Cr) at 3.02 ppm, myo-inositol (mI) at 3.5 ppm, and glutamate plus glutamine (a-Glx) at 3.75 ppm. For relative quantification of the metabolites, both the area under the spectral peaks and the amplitude of the peaks were measured. The measurements were given as peak–area ratios of NAA, Cho, mI, and a-Glx to Cr, because the peak of Cr at 3.02 ppm is an accepted internal amplitude reference and it is the metabolite among those visible that has the most stable concentration [20].
Fig. 1. Localizer on the bilateral lenticular nucleus for the 1H-MRS study. Spectra were obtained from an 8-cm3 volume of interest. The N-acetyl aspartate (NAA), creatine (Cr), choline (Cho), myo-inositol (mI) and glutamate and glutamine (a-Glx) on the spectrum.
2.3. Statistical analysis All statistical computations were performed using Statistics Package for Social Science 10.0 (SPSS version 10.0; SPSS Inc., Chicago, IL). One-way analysis of variance (ANOVA) and post-hoc Bonferroni tests were conducted to detect the difference of the peak–area ratios of NAA, Cho, mI, and a-Glx to Cr. Then the symmetry between the bilateral LN of the peak–area ratios of NAA, Cho, mI, and a-Glx to Cr were examined with t-tests for each group, within which the peak–area ratios of NAA, Cho, mI, and a-Glx to Cr in left LN were compared with those in right LN. A two-tailed P level of 0.05 was used as the criterion of statistical significance.
3. Results No significant age differences were found among three groups (FZ0.114, PZ0.893). There was a significant overall group difference in the NAA/Cr ratio both in the right and left LN (DFZ2, right: FZ7.95, PZ0.002; left: FZ7.106, PZ0.003). In the right LN, the ratio of NAA/Cr was significantly decreased in the ADHD-C group as compared to both the ADHD-I (PZ0.012, post-hoc Bonferroni tests) and control subjects (PZ0.001, post-hoc Bonferroni tests). In the left LN, the ratio of NAA/Cr was significantly decreased in the ADHD-C group as compared to the control subjects (PZ0.003, post-hoc Bonferroni tests). And the ratio of NAA/Cr in the ADHD-C group also showed a trend toward significance as compared to the ADHD-I group (PZ0.06, post-hoc Bonferroni tests, and PZ0.02 when no correction was used.) (see Table 1). For the ratios of Cho/Cr, MI/Cr and a-Glx/Cr, there were no significant differences among the three groups. The laterality testing for the peak–area ratios of NAA, Cho, mI, and a-Glx to Cr all showed no difference in each group (PO0.05).
4. Discussion Magnetic resonance spectroscopy (MRS) is a noninvasive functional imaging technique, which measures brain tissue metabolites such as N-acetylaspartate (NAA), choline (Cho), creatine-phosphocreatine (Cr), and myoinositol (mI) metabolites [19]. NAA is thought to be a neuronal/axonal maker, whose concentration provides a measure of both the number and integrity of neurons within a region of the brain. Reductions in NAA may reflect abnormalities of neuronal structure (e.g. reduced neuronal density or viability) or abnormalities of neuronal function [31]. Our previous work had found lower NAA/Cr in ADHD children at bilateral LN [27]. But due to limitation of sample size, two-subtype mixed ADHD children (five ADHD-C, seven ADHD-I) have been included in that study. Here we demonstrated that
L. Sun et al. / Brain & Development 27 (2005) 340–344
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Table 1 Difference (one way ANOVA) between the ratios of NAA/Cr, Cho/Cr, MI/Cr and a-Glx/Cr among three groups Normal controls(nZ10) NAA/Cr Cho/Cr mI/Cr a-Glx/Cr
L R L R L R L R
2.351G0.210 2.343G0.229 0.806G0.071 0.810G0.059 0.615G0.161 0.595G0.102 0.991G0.179 0.932G0.129
ADHD-I (nZ10) 2.172G0.383 2.270G0.347 0.821G0.078 0.860G0.143 0.594G0.161 0.648G0.167 0.893G0.261 0.926G0.236
ADHD-C (nZ10) a,b
1.822G0.339 1.836G0.332c,d 0.841G0.075 0.816G0.089 0.627G0.110 0.596G0.128 0.939G0.094 0.963G0.221
F
P
7.106 7.950 0.552 0.701 0.130 0.474 0.658 0.094
0.003 0.002 0.582 0.505 0.878 0.628 0.526 0.911
NAA, N-acetyl aspartate; Cr, creatine; Cho, choline; mI, myo-inositol; a-Glx, glutamate and glutamine. For the ADHD-C group, the ADHD-I group and normal controls, meanGSD values are tabulate for each of the four MRS ratios: NAA/Cr, Cho/Cr, mI/Cr, and a-Glx/Cr. Data are presented separately for left lenticular nucleus (L) and right (R) LN. a ADHD-C (L) vs normal controls (L) (PZ0.003, after correction). b ADHD-C (L) vs ADHD-I (L) (PZ0.06 after correction and PZ0.02 before correction). c ADHD-C (R) vs normal controls (R) (PZ0.001, after correction). d ADHD-C (R) vs ADHD-I (R) (PZ0.012 after correction).
such lower NAA/Cr was seen in bilateral LN for only ADHD-C children, whereas no significant difference between ADHD-I and control group in either left or right LN. Moreover, ADHD-C children show significant (PZ0.012, Bonferroni corrected) lower NAA/Cr than ADHD-I in right LN and tend-to-significant (PZ0.06, Bonferroni corrected, and PZ0.02 before correction) lower in left LN. Hesslinger et al. compared the NAA/Cr ratio of five ADHD-I male patients, five ADHD-C male patients and that of five normal controls. They also found significant reduction of NAA concentration in ADHD-C other than ADHD-I compared to controls at left dorsolateral prefrontal cortex. However, they did not find a significant difference in the left striatum [21]. Though the authors did not illustrate at which particular part of striatum they had tested, results at basal ganglia from the two studies were difficult to be compared because all of their subjects are adults. At least, both results of Hesslinger et al. and the current study indicate that ADHD-C subtype show more neural dysfunction than ADHD-I subtype do. These results may partly explain the pathogenic mechanism of the clinical features of ADHD-C subtype, such as increased externalizing, delinquent, and aggressive behavior and a general tendency to show more severe symptoms than ADHD-I subtype children [6]. Barkley proposed that the core of ADHD pathology is executive function deficit. The executive control network seems to include the midline frontal areas including the anterior cingulate gyrus, supplementary motor area (SMA), and portions of the basal ganglia. The basal ganglia have extensive connections with diverse regions of the prefrontal cortex that have been considered to be particularly important in mediating executive functions [32]. In this study, significantly lower relative NAA levels were found bilaterally in the lenticular nucleus, suggesting that the decreased NAA is associated with dysfunction of the basal ganglia and perhaps executive function deficit.
Morphological and functional brain studies in ADHD patient have reported reduce volume, functional deficits and low metabolism in the basal ganglia [8,9,11,13,16,17,33]. The accumulated body of evidence is generally consistent with our finding.
5. Conclusion We have used relative quantitative measurement, i.e. the ratio to Cr, rather than concentration as used by Hesslinger et al. [21] due to our scanner limitation. It will be a problem when changes of the numerator and the denominator are correlated [34], though quite a few researchers have been using such ratio in their MRS study [35,36]. Another limitation is the partial volume due the rather large voxel (2!2!2 cm3) covering both putamen and lenticular nucleus. We could not conclude which of the two structures has contributed more to the positive results. In addition, all participants were male. Further studies with larger, welldefined patient populations will better elucidate the pathophysiology of ADHD. In summary, this study demonstrated the existence of measurable differences between children with ADHD-C and ADHD-I using 1H-MRS. The results are in line with previous clinical and psychological differences between the two subtypes of ADHD. These differences between the two subtypes appear to be in the degree of severity of the disorder rather than a different neurological dysfunction, but at present there is no direct evidence to confirm this viewpoint. Further research is needed to investigate this problem.
Acknowledgements This research was supported By National ‘Pandeng’ Project of China (95-09) and the Key Project For Clinical Faculty Foundation, Ministry of Health, China (2004).
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Original article
Differences between attention-deficit disorder with and without hyperactivity: a 1H-magnetic resonance spectroscopy study Li Suna, Zhen Jinb, Yu-feng Zanga, Ya-wei Zengb, Gang Liub, Yang Lia, Larry J. Seidmanc, Stephen V. Faraoned,e, Yu-feng Wanga,* a
Insttitute of Mental Health, Peking University, Huayuanbeilu 51, Haidian District, Beijing 100083, People’s Republic of China b Center of fMRI, Hospital 306, Beijng 100101, People’s Republic of China c Department of Psychiatry, Massachusetts Mental Health Center, Harvard Medical School, Boston, MA, USA d Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA e Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA Received 1 June 2004; received in revised form 26 July 2004; accepted 11 September 2004
Abstract Using proton magnetic resonance spectroscopy (1H-MRS) to investigate possible neurometabolic differences between the predominantly inattentive subtype (ADHD-I), the combined subtype (ADHD-C) and normal controls. Proton spectra were acquired bilaterally on the lenticular nucleus in 20 schoolboys having ADHD and 10 matched controls. The boys with ADHD were divided into ADHD-C subtype (nZ10) and ADHD-I subtype (nZ10) according to DSM-IV criteria. The peaks of N-acetylaspartate (NAA), Choline moieties (Cho), myoinositol (mI), creatine (Cr) and a-Glx were measured and their ratios to Cr were calculated. One-way ANOVA and post-hoc Bonferroni tests were used to detect the difference of the peak–area ratios of NAA, Cho, mI, and a-Glx to Cr among the three groups. There was a significant overall group difference in the NAA/Cr ratio both in the right and left lenticular nucleus (right: PZ0.002; left: PZ0.003). Only the ADHD-C subtype group showed a significant difference with controls (right: PZ0.001; left: PZ0.003) the right lenticular nucleus, the NAA/Cr ratio in the ADHD-C group was significantly lower than that in the ADHD-I group (PZ0.012). In the left lenticular nucleus, the NAA/Cr ratio in the ADHD-C group showed a significant trend compared to the ADHD-I group (PZ0.06). This study demonstrated the existence of measurable difference between children with ADHD-C and ADHD-I using 1H-MRS. q 2004 Elsevier B.V. All rights reserved. Keywords: Attention deficit hyperactivity disorder; Subtype; 1H-magnetic resonance spectroscopy; Lenticular nucleus; N-aceytylaspartate
1. Introduction Attention-deficit hyperactivity disorder (ADHD) is one of the most common psychiatric disorders in childhood and adolescence. The disorder is characterized by developmentally inappropriate symptoms of inattention, impulsivity and hyperactivity, with a prevalence estimated to be between 3 and 5% among school-age children. Problems such as learning disabilities, school failure, peer difficulties, and other disruptive behaviors are commonly associated with
* Corresponding author. Tel.: C86 10 82801969; fax: C86 10 62027314. E-mail addresses: [email protected] (Y.-f. Wang), wangyufengbmu@ hotmail.com (Y.-f. Wang). 0387-7604/$ - see front matter q 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.braindev.2004.09.004
the disorder. The disorder is primarily found in boys, occurring in a ratio of 4–9:1 (boys to girls) [1]. Depending on which symptoms predominate, the Diagnostic and Statistical Manual of Mental Disorder (DSM-IV) recognizes three subtypes of ADHD: the predominantly inattentive subtype (ADHD-I), the predominantly hyperactive-impulsive subtype (ADHD-HI), and the combined subtype (ADHD-C). Each subtype has distinct clinical features: ADHD-I children have short concentration spans and are easily distracted; children with ADHD-HI are often restless, fidgety and impulsive; and children with ADHD-C have both concentration problems and hyperactivity [2]. The DSM-IV field trials indicated that the current subtypes differ significantly on age at onset, gender, and level of social and academic impairment [3]. Several studies
L. Sun et al. / Brain & Development 27 (2005) 340–344
indicated that the ADHD-C children had higher rates of comorbidity compared with the ADHD-HI subtype and the ADHD-I subtype. Regarding clinical features, the combined subtype children tend to show more severe disorder than the other DSM-IV subtypes [4,5]. Morgan et al. [6] reported that the ADHD-C subtype children are perceived by their parents as displaying significantly more externalizing, delinquent, and aggressive behavior than the ADHD-I subtype children. From a neuropsychological view, Houghton et al. compared the executive functions in ADHD subtypes and normal control subjects, they found that the ADHD-C subtype children made the most errors on the Wisconsin Card Sorting Test and performed more poorly than the ADHD-I subtype and the controls for the Stroop Color-Word Test. These results demonstrate that the impairments in executive function are clearly present in ADHD, particularly in the ADHD-C subtype [7]. In addition to the neuropsychological measurements, volumetric neuroimaging [8–13] and functional neuroimaging studies have shown that abnormalities in frontal networks or fronto-striatal dysfunction comprise the disorder’s best identified neural substrate [14–18], but up to the present there have been no studies to identify the different features of ADHD subtypes by these instruments. Proton magnetic resonance spectroscopy (1H-MRS) is a non-invasive technique for evaluating brain chemistry in vivo, which can detect the metabolic changes in the brain and reflects the developmental status of brain. Using MRS we can obtain the spectra of N-acetylaspartate (NAA), Choline moieties (Cho), creatine (Cr) and myo-inositol (mI) [19]. Although the role of NAA in neurons is not yet fully understood, it is found predominantly within neurons, so it serves as a neuronal marker, reflecting neuronal density, neuronal viability, and may undergo reversible changes. NAA reductions have been interpreted as strong evidence for neuron loss or dysfunction in a brain region of interest [20]. Few studies have observed intracerebral neurochemical concentration in ADHD using Proton magnetic resonance spectroscopy (1H-MRS). Hesslinger et al. [21] reported that reduced NAA concentration was found in left dorsolateral prefrontal cortex in adults with ADHD, but there was no significant difference in left global pallidus. MacMaster et al. [22] found that frontal–striatal glutamatergic resonances were elevated in the children with ADHD as compared to normal children. ADHD girls had especially low NAA concentrations in right dorsolateral frontal [23]. Accumulating evidence suggests the basal ganglia is involved in emotional, motivational, and cognitive functions [24–26].We have previously reported that NAA/Cr ratio decreased significantly in bilateral lenticular nucleus (LN) for ADHD children [27]. The primary aim of the current study was to view such changes among ADHD subtypes. As a matter of fact that ADHD-HI is relatively rare, so only ADHD-I and ADHD-C subtypes were included.
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2. Method 2.1. Subjects Thirty right handed boys aging from 10 to 14 years old participated in this study. We compared three groups (nZ10 each), namely ADHD-Combined type (ADHD-C), ADHD Inattentive type (ADHD-I) and a control group. Materials of some subjects, including 10 controls and eight ADHD children (four ADHD-C, four ADHD-I), had been reported in our previous work [27]. Groups were matched for age, gender and handedness. Both groups of ADHD children were recruited from the child psychiatric clinics at Peking University Institute of Mental Health. No subjects had a history of medication use for ADHD. The normal control group came from local schools. Informed consent was obtained from their parents. 2.1.1. ADHD children Inclusion in the ADHD groups was based on a clinical assessment by two psychiatrists separately, one of who was a senior psychiatrist. Diagnostic criteria were collected with the Clinical Diagnostic Interviewing Scales (CDIS) [28], a structured, interviewer-administered interview based on DSM-IV. The CDIS asks questions about behavioral and emotional disorders of childhood, such as ADHD, oppositional defiant disorder (ODD), conduct disorder (CD), tic disorders, emotional disorders, affective disorders, and learning problems. In the ADHD section, the CDIS recognizes three types of ADHD: ADHD inattentive type (ADHD-I), ADHD hyperactive-impulsive type (ADHDHI), and ADHD combined type (ADHD-C). All the parents were interviewed. There were 10 ADHDC boys (mean age: 12.43G1.38 years old) and 10 ADHD-I boys (mean age: 12.64G1.02 years old) included. Assessment was based on a CDIS [28] with a parent, and comorbidities were assessed at the same time. All ADHD boys were assessed using the Chinese-Wechlser Intelligence Scale for Children (C-WISC) [29], they have a full scale IQ no lower than 75 (the ADHD-C group: mean IQ scoresZ 99.50G12.53, the ADHD-I group: mean IQ scoresZ100.7G9.51). In the ADHD-C group, three children were ‘pure’ ADHD without comorbidity, one child had a CD, two children had ODD, three children had tic disorders, and seven children had learning problems. In the ADHD-I group, one child was ‘pure’ ADHD, two children had CD, five children had ODD, and nine children had learning problems. 2.1.2. Normal controls The normal controls (mean age: 12.67G1.15 years) were screened using the Clinical Diagnostic Interview Scale (CDIS) [28] with a parent, and Raven Standard Progressive Matrices [30]. They were free of any psychiatric disorder and had no attention deficit, hyperactivity or learning problem.
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For all groups, subjects were excluded if they had a history of neurological diseases, schizophrenia, pervasive development disorder, affective disorder, epilepsy, and mental retardation (Standard Score from the Raven Standard Progressive Matrices lower than 25 percentile). 2.2. MRS methods Magnetic resonance investigations were performed on a 1.9T Prestige Imaging/MRS scanner, using an Elscint/GE (Haifa) with a circularly polarized head coil suit for MR imaging and Volume selective 1H MRS. Standard-spin echo (SE) T1 and fast-spin echo (FSE) T2 weighted axial images covering the whole brain were acquired first to guide the MRS localizing and screening for brain pathology. The single spectral volume of interest (VOI) was 2!2!2 cm3, which centered at the medial part of the lenticular nucleus (LN) (Fig. 1). The VOI was located at the similar, as far as possible, position across subjects. Right and left LN was scanned in random order. The point resolved spectroscopy (PRESS) scan sequence (TRZ1500 ms; TEZ35.5 ms; NEXZ200; MatrixZ1020) was used for spectral acquisition. Carefully shimming for the magnetic field and chemical-shift selective water suppression scanning were completed before the spectral acquisition. 1 H spectra were analyzed online using the software provided by Elscint/GE. The prominent N-acetylaspartate (NAA) peak at 2.0 ppm was used as an internal chemical shift reference. The spectra exhibited peaks of choline complex (Cho) at 3.2 ppm, and creatine (Cr) at 3.02 ppm, myo-inositol (mI) at 3.5 ppm, and glutamate plus glutamine (a-Glx) at 3.75 ppm. For relative quantification of the metabolites, both the area under the spectral peaks and the amplitude of the peaks were measured. The measurements were given as peak–area ratios of NAA, Cho, mI, and a-Glx to Cr, because the peak of Cr at 3.02 ppm is an accepted internal amplitude reference and it is the metabolite among those visible that has the most stable concentration [20].
Fig. 1. Localizer on the bilateral lenticular nucleus for the 1H-MRS study. Spectra were obtained from an 8-cm3 volume of interest. The N-acetyl aspartate (NAA), creatine (Cr), choline (Cho), myo-inositol (mI) and glutamate and glutamine (a-Glx) on the spectrum.
2.3. Statistical analysis All statistical computations were performed using Statistics Package for Social Science 10.0 (SPSS version 10.0; SPSS Inc., Chicago, IL). One-way analysis of variance (ANOVA) and post-hoc Bonferroni tests were conducted to detect the difference of the peak–area ratios of NAA, Cho, mI, and a-Glx to Cr. Then the symmetry between the bilateral LN of the peak–area ratios of NAA, Cho, mI, and a-Glx to Cr were examined with t-tests for each group, within which the peak–area ratios of NAA, Cho, mI, and a-Glx to Cr in left LN were compared with those in right LN. A two-tailed P level of 0.05 was used as the criterion of statistical significance.
3. Results No significant age differences were found among three groups (FZ0.114, PZ0.893). There was a significant overall group difference in the NAA/Cr ratio both in the right and left LN (DFZ2, right: FZ7.95, PZ0.002; left: FZ7.106, PZ0.003). In the right LN, the ratio of NAA/Cr was significantly decreased in the ADHD-C group as compared to both the ADHD-I (PZ0.012, post-hoc Bonferroni tests) and control subjects (PZ0.001, post-hoc Bonferroni tests). In the left LN, the ratio of NAA/Cr was significantly decreased in the ADHD-C group as compared to the control subjects (PZ0.003, post-hoc Bonferroni tests). And the ratio of NAA/Cr in the ADHD-C group also showed a trend toward significance as compared to the ADHD-I group (PZ0.06, post-hoc Bonferroni tests, and PZ0.02 when no correction was used.) (see Table 1). For the ratios of Cho/Cr, MI/Cr and a-Glx/Cr, there were no significant differences among the three groups. The laterality testing for the peak–area ratios of NAA, Cho, mI, and a-Glx to Cr all showed no difference in each group (PO0.05).
4. Discussion Magnetic resonance spectroscopy (MRS) is a noninvasive functional imaging technique, which measures brain tissue metabolites such as N-acetylaspartate (NAA), choline (Cho), creatine-phosphocreatine (Cr), and myoinositol (mI) metabolites [19]. NAA is thought to be a neuronal/axonal maker, whose concentration provides a measure of both the number and integrity of neurons within a region of the brain. Reductions in NAA may reflect abnormalities of neuronal structure (e.g. reduced neuronal density or viability) or abnormalities of neuronal function [31]. Our previous work had found lower NAA/Cr in ADHD children at bilateral LN [27]. But due to limitation of sample size, two-subtype mixed ADHD children (five ADHD-C, seven ADHD-I) have been included in that study. Here we demonstrated that
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Table 1 Difference (one way ANOVA) between the ratios of NAA/Cr, Cho/Cr, MI/Cr and a-Glx/Cr among three groups Normal controls(nZ10) NAA/Cr Cho/Cr mI/Cr a-Glx/Cr
L R L R L R L R
2.351G0.210 2.343G0.229 0.806G0.071 0.810G0.059 0.615G0.161 0.595G0.102 0.991G0.179 0.932G0.129
ADHD-I (nZ10) 2.172G0.383 2.270G0.347 0.821G0.078 0.860G0.143 0.594G0.161 0.648G0.167 0.893G0.261 0.926G0.236
ADHD-C (nZ10) a,b
1.822G0.339 1.836G0.332c,d 0.841G0.075 0.816G0.089 0.627G0.110 0.596G0.128 0.939G0.094 0.963G0.221
F
P
7.106 7.950 0.552 0.701 0.130 0.474 0.658 0.094
0.003 0.002 0.582 0.505 0.878 0.628 0.526 0.911
NAA, N-acetyl aspartate; Cr, creatine; Cho, choline; mI, myo-inositol; a-Glx, glutamate and glutamine. For the ADHD-C group, the ADHD-I group and normal controls, meanGSD values are tabulate for each of the four MRS ratios: NAA/Cr, Cho/Cr, mI/Cr, and a-Glx/Cr. Data are presented separately for left lenticular nucleus (L) and right (R) LN. a ADHD-C (L) vs normal controls (L) (PZ0.003, after correction). b ADHD-C (L) vs ADHD-I (L) (PZ0.06 after correction and PZ0.02 before correction). c ADHD-C (R) vs normal controls (R) (PZ0.001, after correction). d ADHD-C (R) vs ADHD-I (R) (PZ0.012 after correction).
such lower NAA/Cr was seen in bilateral LN for only ADHD-C children, whereas no significant difference between ADHD-I and control group in either left or right LN. Moreover, ADHD-C children show significant (PZ0.012, Bonferroni corrected) lower NAA/Cr than ADHD-I in right LN and tend-to-significant (PZ0.06, Bonferroni corrected, and PZ0.02 before correction) lower in left LN. Hesslinger et al. compared the NAA/Cr ratio of five ADHD-I male patients, five ADHD-C male patients and that of five normal controls. They also found significant reduction of NAA concentration in ADHD-C other than ADHD-I compared to controls at left dorsolateral prefrontal cortex. However, they did not find a significant difference in the left striatum [21]. Though the authors did not illustrate at which particular part of striatum they had tested, results at basal ganglia from the two studies were difficult to be compared because all of their subjects are adults. At least, both results of Hesslinger et al. and the current study indicate that ADHD-C subtype show more neural dysfunction than ADHD-I subtype do. These results may partly explain the pathogenic mechanism of the clinical features of ADHD-C subtype, such as increased externalizing, delinquent, and aggressive behavior and a general tendency to show more severe symptoms than ADHD-I subtype children [6]. Barkley proposed that the core of ADHD pathology is executive function deficit. The executive control network seems to include the midline frontal areas including the anterior cingulate gyrus, supplementary motor area (SMA), and portions of the basal ganglia. The basal ganglia have extensive connections with diverse regions of the prefrontal cortex that have been considered to be particularly important in mediating executive functions [32]. In this study, significantly lower relative NAA levels were found bilaterally in the lenticular nucleus, suggesting that the decreased NAA is associated with dysfunction of the basal ganglia and perhaps executive function deficit.
Morphological and functional brain studies in ADHD patient have reported reduce volume, functional deficits and low metabolism in the basal ganglia [8,9,11,13,16,17,33]. The accumulated body of evidence is generally consistent with our finding.
5. Conclusion We have used relative quantitative measurement, i.e. the ratio to Cr, rather than concentration as used by Hesslinger et al. [21] due to our scanner limitation. It will be a problem when changes of the numerator and the denominator are correlated [34], though quite a few researchers have been using such ratio in their MRS study [35,36]. Another limitation is the partial volume due the rather large voxel (2!2!2 cm3) covering both putamen and lenticular nucleus. We could not conclude which of the two structures has contributed more to the positive results. In addition, all participants were male. Further studies with larger, welldefined patient populations will better elucidate the pathophysiology of ADHD. In summary, this study demonstrated the existence of measurable differences between children with ADHD-C and ADHD-I using 1H-MRS. The results are in line with previous clinical and psychological differences between the two subtypes of ADHD. These differences between the two subtypes appear to be in the degree of severity of the disorder rather than a different neurological dysfunction, but at present there is no direct evidence to confirm this viewpoint. Further research is needed to investigate this problem.
Acknowledgements This research was supported By National ‘Pandeng’ Project of China (95-09) and the Key Project For Clinical Faculty Foundation, Ministry of Health, China (2004).
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