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Association of adult attention deficit hyperactivity disorder subtypes and response to methylphenidate HCL treatment: A magnetic resonance spectroscopy study
Neuroscience Letters 604 (2015) 188–192
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Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet
Research paper
Association of adult attention deficit hyperactivity disorder subtypes and response to methylphenidate HCL treatment: A magnetic resonance spectroscopy study Gonca Ayse Unal a , Ayse Nur Inci Kenar b,∗ , Hasan Herken b , Yilmaz Kiroglu c a
Psychiatry Clinic, Kozan State Hospital, Adana, Turkey Dept. of Psychiatry, School of Medicine, Pamukkale University, Denizli, Turkey c Dept. of Radiology, School of Medicine, Pamukkale University, Denizli, Turkey b
h i g h l i g h t s • The effects of MPH on NAA, Cho, and Cr are examined in different subtypes of ADHD. • No significant change was determined in brain metabolite levels after MPH between the subtypes. • Choline levels increased after MPH in striatum in combined type.
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Article history: Received 14 March 2015 Received in revised form 2 August 2015 Accepted 3 August 2015 Available online 6 August 2015 Keywords: Adult ADHD Subtype Methylphenidate Magnetic resonance spectroscopy
a b s t r a c t The effects of methylphenidate (MPH) treatment on N-acetyl aspartate (NAA), choline and creatine are being examined in individuals with different subtypes of attention deficit hyperactivity disorder (ADHD). Sixty ADHD subjects were included into the study aging between 18 and 60 years. Levels of NAA, creatine and choline in anterior cingulate cortex, cerebellum, striatum and dorsolateral prefrontal cortex were measured with magnetic resonance spectroscopy. Then, 10 mg oral MPH was given to the subjects and the same metabolite levels were measured after an interval of 30 min. Distribution of the patients according to the ADHD subtypes was as follows: 21 of them (35.0%) were in the inattentive type, 11 of them (18.3%) were in the hyperactive type and 28 of them were (46.7%) in the combined type. Changes of brain metabolite levels after MPH were found not to be statistically significantly different between the subtypes. The increase of choline levels after MPH compared to the levels of choline before MPH in striatum in the combined type patients were statistically significant. No clear association was found between ADHD subtypes and changes of brain metabolites with use of MPH in adult ADHD. © 2015 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Neuroimaging techniques have an important place to understand the structural and functional changes in attention deficit hyperactivity disorder (ADHD) related brain areas. Recent advances in these techniques also provide such further investigations on brain structures and functions in response to psychostimulant drug treatments. In structural neuroimaging studies; it was reported that there was reduction in brain regions including frontal lobe, cerebellum, corpus callosum, total and right brain and caudate nucleus
∗ Corresponding author at: Psychiatry Dept., School of Medicine, Pamukkale University, 20070 Denizli, Turkey. Fax: +90 258 2131034. E-mail address: [email protected] (A.N.I. Kenar). http://dx.doi.org/10.1016/j.neulet.2015.08.006 0304-3940/© 2015 Elsevier Ireland Ltd. All rights reserved.
by volume [1]. In functional neuroimaging studies; the regional bloodstream and glucose metabolism were reported to decrease in prefrontal and cerebellar areas but to increase in parietooccipital cortex in resting state, and the symptoms to remit after psychostimulant drug treatment [2]. Magnetic resonance spectroscopy (MRS) is used in the differential diagnosis of diseases that have neurodegenerative activity. Since N-acetyl aspartate (NAA) is a marker of neuronal integrity, low NAA/ creatine (Cr) ratio is associated with neuronal loss or damage. Choline (Cho) reflects the membrane integrity and higher choline levels or Cho/Cr ratio results in higher cellular destruction, myelin destruction, gliosis and inflammation. Creatine is a relatively constant member of cellular energy metabolism [3]. In neuroimaging studies performed on patients with MRS in ADHD, it is reported that there were increases in the ratio of
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glutamate + glutamine/creatine (Glx/Cr) and in choline levels in anterior cingulate cortex (ACC) [4]. Jin et al. [5] found a decrease in the ratio of NAA/Cr and increase in the ratio of Cho/Cr and reported no significant changes in these ratios after single dose of methylphenidate (MPH). In a MRS study comparing the subtypes of adult ADHD, it was reported that there was a significant group difference in NAA concentration in the left dorsolateral prefrontal cortex (DLPFC) of patients with pure ADHD and that of healthy controls. Also, absolute concentration of NAA was reported to be significantly decreased only in the ADHD group. The authors speculated that since decrease of NAA reflects a state of neuronal dysfunction, these results indicated an evidence of subtle left prefrontal neuropathology in ADHD of adults [6]. Most of the neuroimaging studies supported impairment in frontostriatalcerebellar circuit [7]. It was demonstrated that MPH effects the functions of frontostriato-thalamic circuit, which is related with the pathophysiology of ADHD. It was reported that increased blood flow rate was determined in bilateral prefrontal, caudate and thalamic areas after MPH administration [2]. Methylphenidate is effective to provide sufficient attention via dopamine and serotonin system in neocortex and to filter unnecessary sensorial stimuli by normalising the excessive excitability in somatosensory cortex [2]. It is aimed to investigate the relation between ADHD subtypes and MPH treatment in adult ADHD patients and the changes in NAA, creatine and choline levels in ACC, cerebellum, striatum and DLPFC measured by MRS. 2. Materials and methods Magnetic resonance spectroscopy studies were obtained and commented in Department of Radiodiagnostics, School of Medicine, Pamukkale University, Denizli. The protocol for the research project has been approved by Ethics Committee of Faculty of Medicine, Pamukkale University that conforms to the provisions of the Declaration of Helsinki (as revised in Edinburgh 2000). 2.1. Subjects A total of 60 patients between ages 18 and 60, meeting DSMIV criteria for adult ADHD were admitted to the study. Written inform consent has been obtained from all the subjects. All patients were recruited from the research center and were of Turkish origin. Patients were evaluated with Wender–Utah rating scale (WURS) and adult attention deficit hyperactivity disorder diagnosis and evaluation scale. Patients, who scored 36 points or more on the WURS and answered at least 6 of the 9 questions as 2 or 3 points in the first and/or second parts of adult attention deficit hyperactivity disorder diagnosis and evaluation scale were diagnosed as ADHD. The patients accompanying neurologic/chronic disease, mental retardation, psychotic disorder, psychiatric disorder due to organic reasons and who were illiterate were discarded from the study. 2.2. Instruments 2.2.1. Social demographic data form A data sheet developed by the researchers for studying sociodemographic characteristics of study groups. 2.2.2. Wender–Utah rating scale (WURS) This scale can be used to assess adults for attention deficit hyperactivity disorder with a subset of 25 questions associated with that diagnosis. WURS was developed by Ward and Wender in 1993 [8].
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Turkish validity and reliability of WURS was established by Oncu and colleagues and the cut-off score point was 36 [9]. 2.2.3. Adult ADD/ADHD DSM IV—based diagnostic screening and rating scale Adult attention deficit hyperactivity disorder diagnosis and evaluation scale were developed by Turgay in 1995 [10]. It is a self assessment scale and patients can complete the questionnaire after being duly informed. When developing adult ADD/ADHD Scale, 18 symptoms of the diagnostic criteria in DSM-IV were reframed, so patients can understand them. The first part of this scale had 9 inattention questions and the second part had 9 hyperactivity/impulsivity questions. The third part of the scale consisted of the most frequently associated symptoms in ADHD that were not in DSM-IV ADHD diagnostic criteria. Turkish validity and reliability was established by Gunay et al. [11]. 2.3. Magnetic resonance spectroscopy (MRS) The study was performed by 1.5 Tesla magnetic resonance device (GE Medical System, Milwaukee, WI, USA) with using a standart head coil. Magnetic resonance protocol was as follows: horizontal plane, 10 mm thickness, TR/TE: 3000/88.2, FOV: 10, Matrix: 512 × 512, Next:1. T2 weighted fast spin echo (FSE) sequences were obtained by using aforementioned parameters. MRS was performed by using single voxel (1H-voxel) technique that were placed in each ACC, striatum, cerebellum, and DLPFC areas. Volume of interest (VOI) was placed on the related areas manually and visually with surely aware of containing the related brain tissue and on predominantly determined areas. Chemical shift selective pulse (CHESS) process was used to inhibit water derived signals. Following CHESS, point-resolved spectroscopy (PRESS) technique was used (TR/TE: 3000-35). Consequently, short-time TE spectrums were obtained from the VOI of ACC, striatum, cerebellum and DLPFC areas and the metabolite ratios obtained by “General Electric Software Spectral Analysis Programme” were evaluated. H1 MRS analysis were performed by an expert radiologist and NAA, Cho, Cr values were measured at the ACC, striatum, cerebellum and DLPFC areas. Oral MPH (10 mg) was given to the patients and NAA, Cho, Cr values were measured again after an interval of 30 min. 2.3.1. Statistical analysis SPSS (statistical package for social sciences) version 16.0 for Windows computing program was used for statistical analysis of the data. Kolmogorov–Smirnov test was used for normality. Twoway ANOVA for repeated measures test was performed to compare the effects of MPH on brain metabolite levels between the subtypes of ADHD. A p value of <0.05 was accepted statistically significant. To determine the effects of MPH on brain metabolite levels in each subtype, the study group was divided into three groups according to the subtypes of ADHD. So far, a p value of <0.017 (0.05/3) was accepted statistically significant. For each subtype, the change in brain metabolite levels after MPH was analyzed by paired t test. 3. Results Mean age of the patients was 28.98 ± 7.66 (18–59) and 12 (20.0%) of them were female (ADHD subtypes: 6 inattentive type, 6 combined type) and 48 (80.0%) of them were male (ADHD subtypes: 15 inattentive type, 11 hyperactive type, 22 combined type). Distribution of the patients according to the ADHD subtypes was as follows: 21 of them (35.0%) were in the inattentive type, 11 of them (18.3%) were in the hyperactive type and 28 of them were (46.7%) in the combined type.
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Table 1 Distribution of NAA levels according to the ADHD subtypes before and after MPH. F*
p*
9.705 12.970
0.207
0.813
63.036 64.500 0.478
8.809 8.094
0.719
0.492
14.471 9.823
58.179 62.393 0.058
13.050 11.206
0.183
0.833
10.992 11.440
62.071 61.357 0.626
9.301 9.162
2.390
0.101
Inattention type (n = 21)
Hyperactive type (n = 11)
Combined type (n = 28)
Mean
SD
Mean
SD
Mean
SD
NAA levels in prefrontal cortex before MPH NAA levels in prefrontal cortex after MPH (within groups) p**
69.333 70.143 0.793
19.004 19.200
69.182 68.727 0.929
13.212 10.574
66.750 68.000 0.593
NAA levels in anterior cingulate cortex before MPH NAA levels in anterior cingulate cortex after MPH (within groups) p**
66.048 69.810 0.176
20.458 15.161
64.273 66.364 0.624
12.681 14.417
NAA levels in cerebellum before MPH NAA levels in cerebellum after MPH (within groups) p**
62.619 61.857 0.699
12.472 12.076
59.727 62.909 0.164
NAA levels in striatum before MPH NAA levels in striatum after MPH (within groups) p**
65.714 68.238 0.292
12.630 14.748
61.727 57.545 0.293
* **
Two-way ANOVA for repeated measures was performed. A p value of <0.05 was accepted statistically significant. Paired t test was performed. A p value of <0.017 was accepted statistically significant.
Table 2 Distribution of creatine levels according to the ADHD subtypes before and after MPH. Inattention type (n = 21)
Hyperactive type (n = 11)
Combined type (n = 28)
F*
p*
Mean
SD
Mean
SD
Mean
Creatine levels in prefrontal cortex before MPH Creatine levels in prefrontal cortex after MPH (within groups) p**
43.190 43.143 0.979
9.673 10.091
40,091 40,909 0.773
5.262 7.463
38.929 40.429 0.296
4.127 6.752
1.873
0.163
Creatine levels in anterior cingulate cortex before MPH Creatine levels in anterior cingulate cortex after MPH (within groups) p**
42.524 45.905 0.056
10.539 8.396
43.545 39.545 0.046
6.593 5.556
41.536 42.929 0.238
6.137 5.571
0.784
0.462
Creatine levels in cerebellum before MPH Creatine levels in cerebellum after MPH (within groups) p**
48.810 52.429 0.077
11.647 10.058
53.000 55.636 0.199
7.550 7.659
50.250 51.929 0.293
10.377 9.899
0.648
0.527
Creatine levels in striatum before MPH Creatine levels in striatum after MPH (within groups) p**
45.714 47.190 0.500
10.257 10.177
44.636 41.636 0.123
7.145 5.537
44.750 43.679 0.387
6.473 6.068
1.026
0.365
* **
SD
Two-way ANOVA for repeated measures was performed. A p value of <0.05 was accepted statistically significant. Paired t test was performed. A p value of <0.017 was accepted statistically significant.
Table 3 Distribution of choline levels according to the ADHD subtypes before and after MPH. Inattention type (n = 21)
Hyperactive type (n = 11)
Combined type (n = 28)
F*
p*
Mean
SD
Mean
SD
Mean
SD
Choline levels in prefrontal cortex before MPH Choline levels in prefrontal cortex after MPH (within groups)p**
41.619 39.667 0.340
9.014 10.850
43.000 41.727 0.512
10.129 10.412
40.714 41.321 0.710
9.181 7.931
0.156
0.856
Choline levels in anterior cingulate cortex before MPH Choline levels in anterior cingulate cortex after MPH (within groups) p**
36.619 38.619 0.376
10.943 7.978
40.636 36.455 0.086
9.190 8.430
38.464 37.571 0.511
7.834 6.669
0.059
0.943
Choline levels in cerebellum before MPH Choline levels in cerebellum after MPH (within groups) p**
42.476 41.762 0.636
8.807 9.818
41.182 41.818 0.770
8.085 9.621
40.571 43.571 0.023
7.791 9.135
0.024
0.977
Choline levels in striatum before MPH Choline levels in striatum after MPH (within groups) p**
36.952 39.333 0.310
7.736 8.404
34.273 32.909 0.549
4.541 7.463
34.179 37.250 0.015**
6.794 6.878
2.284
0.111
* **
Two-way ANOVA for repeated measures was performed. A p value of <0.05 was accepted statistically significant. Paired t test was performed. A p value of <0.017 was accepted statistically significant.
The difference between ADHD subtypes in terms of the changes of NAA, creatine and choline levels before and after MPH was not statistically significant (p > 0.05) (Tables 1, 2 and 3). The increase of choline levels after MPH compared to the levels of choline before MPH in striatum in the combined type patients
were statistically significant (p = 0.015) (Table 3). No difference was determined in terms of the changes of choline levels after MPH compared to the levels of choline before MPH in other brain areas in combined type (p > 0.05). There was no difference in terms of the changes of NAA and creatine levels after MPH compared to the
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levels of these metabolites before MPH in any brain areas in the combined type (p > 0.05) (Tables 1, 2 and 3). No difference was determined in terms of the changes of NAA, choline and creatine levels after MPH compared to the levels of these metabolites before MPH in any brain areas in the inattentive and hyperactive types (p > 0.05) (Tables 1, 2 and 3).
4. Discussion In the present study, changes of brain metabolite levels after MPH was found not to be significantly different between the subtypes. But, there was a significant increase of choline levels after MPH compared to the levels of choline before MPH in striatum in the combined type patients. Wiguna et al. [12] have found an increase of NAA/Cr ratio in the prefrontal cortices of ADHD patients who have used MPH 20 mg/day in their study and have suggested that these changes have occurred by functional amelioration and increase of neuroplasticity. Hesslinger et al. [6] have found decreased NAA levels in the left DLPF cortices of hyperactive subtypes compared to inattentive subtypes in a MRS study that was performed with adult ADHD patients. Decreased NAA levels were associated with neuronal loss or neuronal function impairment [6]. Different from the literature, no significant change was determined in NAA levels after single dose of MPH compared to MPH levels in prefrontal cortices of patients between ADHD subtypes. Most (65%) of our patients were getting MPH treatment for a long time. Due to the fact that NAA levels have returned to normal levels because of neurotrophic effects of drugs, it can be thought that no difference was determined after and before the single dose MPH. If this study was performed with the patients who were diagnosed and given MPH for the first time, the probable effect of MPH should be determined. When studies involving ACC were evaluated; Perlov et al. [13] did not find any difference at NAA/Cr ratio in their study consisting of 28 adult ADHD and 28 healthy controls. In another study, adult ADHD patients were compared with controls and no significant difference at NAA levels in ACC was reported [14]. Despite the study group was divided into ADHD subtypes in the present study, our NAA results involving ACC are similar to the literature. We speculate that the pathology in ACC in ADHD may not be functional but may be structural. No difference was reported at left striatum NAA levels of adult ADHD patients in a study which striatum was analyzed by MRS [6]. NAA/Cr ratio was found significantly low in bilateral striatum in a study performed with children. It was reported that single dose of oral 10 mg MPH have not influenced these ratios. As a result, they have suggested that 20–25% of neurons on average might die or might be seriously dysfunctional [5]. Sun et al. [15] have reported low NAA/Cr ratios in bilateral lenticular nucleus in combined type of ADHD and no significant difference between inattentive type of ADHD and the control group. When they have compared the combined type group with inattentive type group, they have found lower NAA/Cr ratios in right and partially left lenticular nucleus. Consequently, it was suggested that combined type of ADHD have more neuronal dysfunction and low NAA levels in lenticular nucleus may be related with basal ganglia dysfunction and impairment in executive functions [15]. In the present study, no significant change was determined in NAA levels after single dose of MPH compared to MPH levels in cerebellum and striatum of patients between ADHD subtypes, consistent with the studies performed in the children and adults. It can be thought that neuronal death may be related with non-response to treatment beyond neuronal dysfunction. When studies involving creatine levels were evaluated; it was reported that Glx/Cr ratio was decreased in right cingulate cortex in a study investigating the glutamatergic system and the
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pathophysiology of the adult ADHD, and Glx/Cr ratio in ACC was increased in a study performed with the children with ADHD [13,4]. These findings, discrepant with the results of the study of Perlov et al. [13] led us to think that brain metabolites can change by age and results can differ between children and adults [16]. In another study, it was reported that basal levels of striatal glutamate, Glx and creatine in children with ADHD were increased compared to the controls, and also after MPH treatment for 8 weeks, only striatal creatine levels were increased and glutamate or Glx ratios have not changed [17]. In the present study, no statistically significant difference was determined in creatine levels in any brain area between ADHD subtypes after and before MPH treatment. While the study reporting increased basal creatine levels compared to the controls was performed with children, the present study was performed with adults [17]. Differences in results may be associated with the changes of levels of brain metabolites by age. Furthermore, the studies evaluating MRS findings have implied that results about creatine levels were conflicting and have shown less confidence [18]. When studies involving choline levels in ADHD were evaluated; in ACC of ADHD subjects, Perlov et al. [13] reported that Cho/Cr ratio have not changed and Colla et al. [14] reported that Cho levels have increased. It was reported that there was no difference at Cho levels in striatum and left DLPFC in a study performed with adult ADHD [6]. Yeo et al. [19] reported that there was no significant difference at Cho levels in right frontal lobe in ADHD. Wiguna et al. [12] determined a decrease at Cho/Cr ratio in prefrontal cortices of ADHD subjects after long acting MPH treatment for 12 weeks in a study which they investigated the effects of pharmacotherapy on brain metabolites. Jin et al. [5] reported an unilateral slightly increase at Cho/Cr ratio in a study which they reported a significant decrease at NAA/Cr ratio in bilateral striatum with children. Single dose of 10 mg oral MPH have not effected Cho/Cr ratios [5]. In the present study, no significant difference was determined at choline levels after MPH treatment compared to before MPH in prefrontal cortices, ACC, cerebellum and striatum between ADHD subtypes consistent with the literature. However, when the study group was divided into ADHD subtypes, significant increase was determined at choline levels after MPH treatment compared to before MPH in striatum in combined type of ADHD subjects. Low NAA/Cr ratio was determined in bilateral lenticular nucleus only in the combined type of ADHD in a study performed by Sun et al. [15]. No significant difference was reported between the combined type of ADHD and the control group. Lower NAA/Cr ratios were reported in the right and partially left lenticular nucleus in combined type of ADHD when it was compared with the inattentive type of ADHD. These results show that combined type of ADHD has much more neuronal dysfunction. In the study performed by Jin et al. [5], it was suggested that use of single dose of 10 mg oral MPH have not effected Cho/Cr ratios in striatum, because 20–25% of neurons on average have died or might be seriously dysfunctional. Due to the fact that the study was performed with male children by Jin et al. [5], it should be noted that hyperactivity was present in most of the subjects and it might result from that they were of combined type of ADHD. Yet, basal ganglia (striatum) have roles in the auditing of actions and cerebellum have roles in coordinating the voluntary and the complex actions [20]. As a result, when it is considered that cerebellum and striatum are relevant with motor coordination and increase of choline is associated with neuronal death, neuronal damage and death is much more seen in combined type of ADHD, and related with this, we can speculate that increase of choline was determined in striatum in combined type of ADHD. As a result, when it is considered that cerebellum and striatum are relevant with motor coordination, we can speculate that
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neuronal damage and death is much more seen in combined type of ADHD. About 20–30% of ADHD patients do not respond to MPH treatment [2]. In a study investigating the response of MPH treatment in adult ADHD patients and relation of dopamine transporter (DAT) linking, it was reported that none of the patients having low DAT levels siginificantly respond to treatment. Thus, it was suggested that DAT linking can be used as a preliminary marker in terms of response to MPH in non-treated patients [21]. It was reported that non smokers have higher DAT density in a study which relation of cigarette use and DAT density was investigated [22]. When it was considered that 65% of the patients were using cigarette in the present study, it should be noted that most of them have probably low DAT density and were non-responsive to MPH. Limitations of the study were as follows: possibility of effecting MRS metabolite levels due to long term treatment of most of the patients, cigarette that was effecting the response to MPH was not excluded, absence of control group, use of magnetic resonance brain imaging technique with low Tesla value and evaluation of unilateral area. Consequently, no clear association was found between ADHD subtypes and changes of brain metabolites with use of MPH in adult ADHD. It can be thougt that there can be structural and/or metabolic abnormalities in frontal-striatal-cerebellar circuit in subtypes of ADHD. Subtypes of ADHD differ in terms of the underlying neuropathology and may clarify the different effects of drug treatment in the subtypes. Further studies which will be performed with larger sample size and neuroimaging techniques with higher resolution, and accompanying control group are needed. The present study forms a base to the forthcoming ones.
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Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet
Research paper
Association of adult attention deficit hyperactivity disorder subtypes and response to methylphenidate HCL treatment: A magnetic resonance spectroscopy study Gonca Ayse Unal a , Ayse Nur Inci Kenar b,∗ , Hasan Herken b , Yilmaz Kiroglu c a
Psychiatry Clinic, Kozan State Hospital, Adana, Turkey Dept. of Psychiatry, School of Medicine, Pamukkale University, Denizli, Turkey c Dept. of Radiology, School of Medicine, Pamukkale University, Denizli, Turkey b
h i g h l i g h t s • The effects of MPH on NAA, Cho, and Cr are examined in different subtypes of ADHD. • No significant change was determined in brain metabolite levels after MPH between the subtypes. • Choline levels increased after MPH in striatum in combined type.
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Article history: Received 14 March 2015 Received in revised form 2 August 2015 Accepted 3 August 2015 Available online 6 August 2015 Keywords: Adult ADHD Subtype Methylphenidate Magnetic resonance spectroscopy
a b s t r a c t The effects of methylphenidate (MPH) treatment on N-acetyl aspartate (NAA), choline and creatine are being examined in individuals with different subtypes of attention deficit hyperactivity disorder (ADHD). Sixty ADHD subjects were included into the study aging between 18 and 60 years. Levels of NAA, creatine and choline in anterior cingulate cortex, cerebellum, striatum and dorsolateral prefrontal cortex were measured with magnetic resonance spectroscopy. Then, 10 mg oral MPH was given to the subjects and the same metabolite levels were measured after an interval of 30 min. Distribution of the patients according to the ADHD subtypes was as follows: 21 of them (35.0%) were in the inattentive type, 11 of them (18.3%) were in the hyperactive type and 28 of them were (46.7%) in the combined type. Changes of brain metabolite levels after MPH were found not to be statistically significantly different between the subtypes. The increase of choline levels after MPH compared to the levels of choline before MPH in striatum in the combined type patients were statistically significant. No clear association was found between ADHD subtypes and changes of brain metabolites with use of MPH in adult ADHD. © 2015 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Neuroimaging techniques have an important place to understand the structural and functional changes in attention deficit hyperactivity disorder (ADHD) related brain areas. Recent advances in these techniques also provide such further investigations on brain structures and functions in response to psychostimulant drug treatments. In structural neuroimaging studies; it was reported that there was reduction in brain regions including frontal lobe, cerebellum, corpus callosum, total and right brain and caudate nucleus
∗ Corresponding author at: Psychiatry Dept., School of Medicine, Pamukkale University, 20070 Denizli, Turkey. Fax: +90 258 2131034. E-mail address: [email protected] (A.N.I. Kenar). http://dx.doi.org/10.1016/j.neulet.2015.08.006 0304-3940/© 2015 Elsevier Ireland Ltd. All rights reserved.
by volume [1]. In functional neuroimaging studies; the regional bloodstream and glucose metabolism were reported to decrease in prefrontal and cerebellar areas but to increase in parietooccipital cortex in resting state, and the symptoms to remit after psychostimulant drug treatment [2]. Magnetic resonance spectroscopy (MRS) is used in the differential diagnosis of diseases that have neurodegenerative activity. Since N-acetyl aspartate (NAA) is a marker of neuronal integrity, low NAA/ creatine (Cr) ratio is associated with neuronal loss or damage. Choline (Cho) reflects the membrane integrity and higher choline levels or Cho/Cr ratio results in higher cellular destruction, myelin destruction, gliosis and inflammation. Creatine is a relatively constant member of cellular energy metabolism [3]. In neuroimaging studies performed on patients with MRS in ADHD, it is reported that there were increases in the ratio of
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glutamate + glutamine/creatine (Glx/Cr) and in choline levels in anterior cingulate cortex (ACC) [4]. Jin et al. [5] found a decrease in the ratio of NAA/Cr and increase in the ratio of Cho/Cr and reported no significant changes in these ratios after single dose of methylphenidate (MPH). In a MRS study comparing the subtypes of adult ADHD, it was reported that there was a significant group difference in NAA concentration in the left dorsolateral prefrontal cortex (DLPFC) of patients with pure ADHD and that of healthy controls. Also, absolute concentration of NAA was reported to be significantly decreased only in the ADHD group. The authors speculated that since decrease of NAA reflects a state of neuronal dysfunction, these results indicated an evidence of subtle left prefrontal neuropathology in ADHD of adults [6]. Most of the neuroimaging studies supported impairment in frontostriatalcerebellar circuit [7]. It was demonstrated that MPH effects the functions of frontostriato-thalamic circuit, which is related with the pathophysiology of ADHD. It was reported that increased blood flow rate was determined in bilateral prefrontal, caudate and thalamic areas after MPH administration [2]. Methylphenidate is effective to provide sufficient attention via dopamine and serotonin system in neocortex and to filter unnecessary sensorial stimuli by normalising the excessive excitability in somatosensory cortex [2]. It is aimed to investigate the relation between ADHD subtypes and MPH treatment in adult ADHD patients and the changes in NAA, creatine and choline levels in ACC, cerebellum, striatum and DLPFC measured by MRS. 2. Materials and methods Magnetic resonance spectroscopy studies were obtained and commented in Department of Radiodiagnostics, School of Medicine, Pamukkale University, Denizli. The protocol for the research project has been approved by Ethics Committee of Faculty of Medicine, Pamukkale University that conforms to the provisions of the Declaration of Helsinki (as revised in Edinburgh 2000). 2.1. Subjects A total of 60 patients between ages 18 and 60, meeting DSMIV criteria for adult ADHD were admitted to the study. Written inform consent has been obtained from all the subjects. All patients were recruited from the research center and were of Turkish origin. Patients were evaluated with Wender–Utah rating scale (WURS) and adult attention deficit hyperactivity disorder diagnosis and evaluation scale. Patients, who scored 36 points or more on the WURS and answered at least 6 of the 9 questions as 2 or 3 points in the first and/or second parts of adult attention deficit hyperactivity disorder diagnosis and evaluation scale were diagnosed as ADHD. The patients accompanying neurologic/chronic disease, mental retardation, psychotic disorder, psychiatric disorder due to organic reasons and who were illiterate were discarded from the study. 2.2. Instruments 2.2.1. Social demographic data form A data sheet developed by the researchers for studying sociodemographic characteristics of study groups. 2.2.2. Wender–Utah rating scale (WURS) This scale can be used to assess adults for attention deficit hyperactivity disorder with a subset of 25 questions associated with that diagnosis. WURS was developed by Ward and Wender in 1993 [8].
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Turkish validity and reliability of WURS was established by Oncu and colleagues and the cut-off score point was 36 [9]. 2.2.3. Adult ADD/ADHD DSM IV—based diagnostic screening and rating scale Adult attention deficit hyperactivity disorder diagnosis and evaluation scale were developed by Turgay in 1995 [10]. It is a self assessment scale and patients can complete the questionnaire after being duly informed. When developing adult ADD/ADHD Scale, 18 symptoms of the diagnostic criteria in DSM-IV were reframed, so patients can understand them. The first part of this scale had 9 inattention questions and the second part had 9 hyperactivity/impulsivity questions. The third part of the scale consisted of the most frequently associated symptoms in ADHD that were not in DSM-IV ADHD diagnostic criteria. Turkish validity and reliability was established by Gunay et al. [11]. 2.3. Magnetic resonance spectroscopy (MRS) The study was performed by 1.5 Tesla magnetic resonance device (GE Medical System, Milwaukee, WI, USA) with using a standart head coil. Magnetic resonance protocol was as follows: horizontal plane, 10 mm thickness, TR/TE: 3000/88.2, FOV: 10, Matrix: 512 × 512, Next:1. T2 weighted fast spin echo (FSE) sequences were obtained by using aforementioned parameters. MRS was performed by using single voxel (1H-voxel) technique that were placed in each ACC, striatum, cerebellum, and DLPFC areas. Volume of interest (VOI) was placed on the related areas manually and visually with surely aware of containing the related brain tissue and on predominantly determined areas. Chemical shift selective pulse (CHESS) process was used to inhibit water derived signals. Following CHESS, point-resolved spectroscopy (PRESS) technique was used (TR/TE: 3000-35). Consequently, short-time TE spectrums were obtained from the VOI of ACC, striatum, cerebellum and DLPFC areas and the metabolite ratios obtained by “General Electric Software Spectral Analysis Programme” were evaluated. H1 MRS analysis were performed by an expert radiologist and NAA, Cho, Cr values were measured at the ACC, striatum, cerebellum and DLPFC areas. Oral MPH (10 mg) was given to the patients and NAA, Cho, Cr values were measured again after an interval of 30 min. 2.3.1. Statistical analysis SPSS (statistical package for social sciences) version 16.0 for Windows computing program was used for statistical analysis of the data. Kolmogorov–Smirnov test was used for normality. Twoway ANOVA for repeated measures test was performed to compare the effects of MPH on brain metabolite levels between the subtypes of ADHD. A p value of <0.05 was accepted statistically significant. To determine the effects of MPH on brain metabolite levels in each subtype, the study group was divided into three groups according to the subtypes of ADHD. So far, a p value of <0.017 (0.05/3) was accepted statistically significant. For each subtype, the change in brain metabolite levels after MPH was analyzed by paired t test. 3. Results Mean age of the patients was 28.98 ± 7.66 (18–59) and 12 (20.0%) of them were female (ADHD subtypes: 6 inattentive type, 6 combined type) and 48 (80.0%) of them were male (ADHD subtypes: 15 inattentive type, 11 hyperactive type, 22 combined type). Distribution of the patients according to the ADHD subtypes was as follows: 21 of them (35.0%) were in the inattentive type, 11 of them (18.3%) were in the hyperactive type and 28 of them were (46.7%) in the combined type.
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Table 1 Distribution of NAA levels according to the ADHD subtypes before and after MPH. F*
p*
9.705 12.970
0.207
0.813
63.036 64.500 0.478
8.809 8.094
0.719
0.492
14.471 9.823
58.179 62.393 0.058
13.050 11.206
0.183
0.833
10.992 11.440
62.071 61.357 0.626
9.301 9.162
2.390
0.101
Inattention type (n = 21)
Hyperactive type (n = 11)
Combined type (n = 28)
Mean
SD
Mean
SD
Mean
SD
NAA levels in prefrontal cortex before MPH NAA levels in prefrontal cortex after MPH (within groups) p**
69.333 70.143 0.793
19.004 19.200
69.182 68.727 0.929
13.212 10.574
66.750 68.000 0.593
NAA levels in anterior cingulate cortex before MPH NAA levels in anterior cingulate cortex after MPH (within groups) p**
66.048 69.810 0.176
20.458 15.161
64.273 66.364 0.624
12.681 14.417
NAA levels in cerebellum before MPH NAA levels in cerebellum after MPH (within groups) p**
62.619 61.857 0.699
12.472 12.076
59.727 62.909 0.164
NAA levels in striatum before MPH NAA levels in striatum after MPH (within groups) p**
65.714 68.238 0.292
12.630 14.748
61.727 57.545 0.293
* **
Two-way ANOVA for repeated measures was performed. A p value of <0.05 was accepted statistically significant. Paired t test was performed. A p value of <0.017 was accepted statistically significant.
Table 2 Distribution of creatine levels according to the ADHD subtypes before and after MPH. Inattention type (n = 21)
Hyperactive type (n = 11)
Combined type (n = 28)
F*
p*
Mean
SD
Mean
SD
Mean
Creatine levels in prefrontal cortex before MPH Creatine levels in prefrontal cortex after MPH (within groups) p**
43.190 43.143 0.979
9.673 10.091
40,091 40,909 0.773
5.262 7.463
38.929 40.429 0.296
4.127 6.752
1.873
0.163
Creatine levels in anterior cingulate cortex before MPH Creatine levels in anterior cingulate cortex after MPH (within groups) p**
42.524 45.905 0.056
10.539 8.396
43.545 39.545 0.046
6.593 5.556
41.536 42.929 0.238
6.137 5.571
0.784
0.462
Creatine levels in cerebellum before MPH Creatine levels in cerebellum after MPH (within groups) p**
48.810 52.429 0.077
11.647 10.058
53.000 55.636 0.199
7.550 7.659
50.250 51.929 0.293
10.377 9.899
0.648
0.527
Creatine levels in striatum before MPH Creatine levels in striatum after MPH (within groups) p**
45.714 47.190 0.500
10.257 10.177
44.636 41.636 0.123
7.145 5.537
44.750 43.679 0.387
6.473 6.068
1.026
0.365
* **
SD
Two-way ANOVA for repeated measures was performed. A p value of <0.05 was accepted statistically significant. Paired t test was performed. A p value of <0.017 was accepted statistically significant.
Table 3 Distribution of choline levels according to the ADHD subtypes before and after MPH. Inattention type (n = 21)
Hyperactive type (n = 11)
Combined type (n = 28)
F*
p*
Mean
SD
Mean
SD
Mean
SD
Choline levels in prefrontal cortex before MPH Choline levels in prefrontal cortex after MPH (within groups)p**
41.619 39.667 0.340
9.014 10.850
43.000 41.727 0.512
10.129 10.412
40.714 41.321 0.710
9.181 7.931
0.156
0.856
Choline levels in anterior cingulate cortex before MPH Choline levels in anterior cingulate cortex after MPH (within groups) p**
36.619 38.619 0.376
10.943 7.978
40.636 36.455 0.086
9.190 8.430
38.464 37.571 0.511
7.834 6.669
0.059
0.943
Choline levels in cerebellum before MPH Choline levels in cerebellum after MPH (within groups) p**
42.476 41.762 0.636
8.807 9.818
41.182 41.818 0.770
8.085 9.621
40.571 43.571 0.023
7.791 9.135
0.024
0.977
Choline levels in striatum before MPH Choline levels in striatum after MPH (within groups) p**
36.952 39.333 0.310
7.736 8.404
34.273 32.909 0.549
4.541 7.463
34.179 37.250 0.015**
6.794 6.878
2.284
0.111
* **
Two-way ANOVA for repeated measures was performed. A p value of <0.05 was accepted statistically significant. Paired t test was performed. A p value of <0.017 was accepted statistically significant.
The difference between ADHD subtypes in terms of the changes of NAA, creatine and choline levels before and after MPH was not statistically significant (p > 0.05) (Tables 1, 2 and 3). The increase of choline levels after MPH compared to the levels of choline before MPH in striatum in the combined type patients
were statistically significant (p = 0.015) (Table 3). No difference was determined in terms of the changes of choline levels after MPH compared to the levels of choline before MPH in other brain areas in combined type (p > 0.05). There was no difference in terms of the changes of NAA and creatine levels after MPH compared to the
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levels of these metabolites before MPH in any brain areas in the combined type (p > 0.05) (Tables 1, 2 and 3). No difference was determined in terms of the changes of NAA, choline and creatine levels after MPH compared to the levels of these metabolites before MPH in any brain areas in the inattentive and hyperactive types (p > 0.05) (Tables 1, 2 and 3).
4. Discussion In the present study, changes of brain metabolite levels after MPH was found not to be significantly different between the subtypes. But, there was a significant increase of choline levels after MPH compared to the levels of choline before MPH in striatum in the combined type patients. Wiguna et al. [12] have found an increase of NAA/Cr ratio in the prefrontal cortices of ADHD patients who have used MPH 20 mg/day in their study and have suggested that these changes have occurred by functional amelioration and increase of neuroplasticity. Hesslinger et al. [6] have found decreased NAA levels in the left DLPF cortices of hyperactive subtypes compared to inattentive subtypes in a MRS study that was performed with adult ADHD patients. Decreased NAA levels were associated with neuronal loss or neuronal function impairment [6]. Different from the literature, no significant change was determined in NAA levels after single dose of MPH compared to MPH levels in prefrontal cortices of patients between ADHD subtypes. Most (65%) of our patients were getting MPH treatment for a long time. Due to the fact that NAA levels have returned to normal levels because of neurotrophic effects of drugs, it can be thought that no difference was determined after and before the single dose MPH. If this study was performed with the patients who were diagnosed and given MPH for the first time, the probable effect of MPH should be determined. When studies involving ACC were evaluated; Perlov et al. [13] did not find any difference at NAA/Cr ratio in their study consisting of 28 adult ADHD and 28 healthy controls. In another study, adult ADHD patients were compared with controls and no significant difference at NAA levels in ACC was reported [14]. Despite the study group was divided into ADHD subtypes in the present study, our NAA results involving ACC are similar to the literature. We speculate that the pathology in ACC in ADHD may not be functional but may be structural. No difference was reported at left striatum NAA levels of adult ADHD patients in a study which striatum was analyzed by MRS [6]. NAA/Cr ratio was found significantly low in bilateral striatum in a study performed with children. It was reported that single dose of oral 10 mg MPH have not influenced these ratios. As a result, they have suggested that 20–25% of neurons on average might die or might be seriously dysfunctional [5]. Sun et al. [15] have reported low NAA/Cr ratios in bilateral lenticular nucleus in combined type of ADHD and no significant difference between inattentive type of ADHD and the control group. When they have compared the combined type group with inattentive type group, they have found lower NAA/Cr ratios in right and partially left lenticular nucleus. Consequently, it was suggested that combined type of ADHD have more neuronal dysfunction and low NAA levels in lenticular nucleus may be related with basal ganglia dysfunction and impairment in executive functions [15]. In the present study, no significant change was determined in NAA levels after single dose of MPH compared to MPH levels in cerebellum and striatum of patients between ADHD subtypes, consistent with the studies performed in the children and adults. It can be thought that neuronal death may be related with non-response to treatment beyond neuronal dysfunction. When studies involving creatine levels were evaluated; it was reported that Glx/Cr ratio was decreased in right cingulate cortex in a study investigating the glutamatergic system and the
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pathophysiology of the adult ADHD, and Glx/Cr ratio in ACC was increased in a study performed with the children with ADHD [13,4]. These findings, discrepant with the results of the study of Perlov et al. [13] led us to think that brain metabolites can change by age and results can differ between children and adults [16]. In another study, it was reported that basal levels of striatal glutamate, Glx and creatine in children with ADHD were increased compared to the controls, and also after MPH treatment for 8 weeks, only striatal creatine levels were increased and glutamate or Glx ratios have not changed [17]. In the present study, no statistically significant difference was determined in creatine levels in any brain area between ADHD subtypes after and before MPH treatment. While the study reporting increased basal creatine levels compared to the controls was performed with children, the present study was performed with adults [17]. Differences in results may be associated with the changes of levels of brain metabolites by age. Furthermore, the studies evaluating MRS findings have implied that results about creatine levels were conflicting and have shown less confidence [18]. When studies involving choline levels in ADHD were evaluated; in ACC of ADHD subjects, Perlov et al. [13] reported that Cho/Cr ratio have not changed and Colla et al. [14] reported that Cho levels have increased. It was reported that there was no difference at Cho levels in striatum and left DLPFC in a study performed with adult ADHD [6]. Yeo et al. [19] reported that there was no significant difference at Cho levels in right frontal lobe in ADHD. Wiguna et al. [12] determined a decrease at Cho/Cr ratio in prefrontal cortices of ADHD subjects after long acting MPH treatment for 12 weeks in a study which they investigated the effects of pharmacotherapy on brain metabolites. Jin et al. [5] reported an unilateral slightly increase at Cho/Cr ratio in a study which they reported a significant decrease at NAA/Cr ratio in bilateral striatum with children. Single dose of 10 mg oral MPH have not effected Cho/Cr ratios [5]. In the present study, no significant difference was determined at choline levels after MPH treatment compared to before MPH in prefrontal cortices, ACC, cerebellum and striatum between ADHD subtypes consistent with the literature. However, when the study group was divided into ADHD subtypes, significant increase was determined at choline levels after MPH treatment compared to before MPH in striatum in combined type of ADHD subjects. Low NAA/Cr ratio was determined in bilateral lenticular nucleus only in the combined type of ADHD in a study performed by Sun et al. [15]. No significant difference was reported between the combined type of ADHD and the control group. Lower NAA/Cr ratios were reported in the right and partially left lenticular nucleus in combined type of ADHD when it was compared with the inattentive type of ADHD. These results show that combined type of ADHD has much more neuronal dysfunction. In the study performed by Jin et al. [5], it was suggested that use of single dose of 10 mg oral MPH have not effected Cho/Cr ratios in striatum, because 20–25% of neurons on average have died or might be seriously dysfunctional. Due to the fact that the study was performed with male children by Jin et al. [5], it should be noted that hyperactivity was present in most of the subjects and it might result from that they were of combined type of ADHD. Yet, basal ganglia (striatum) have roles in the auditing of actions and cerebellum have roles in coordinating the voluntary and the complex actions [20]. As a result, when it is considered that cerebellum and striatum are relevant with motor coordination and increase of choline is associated with neuronal death, neuronal damage and death is much more seen in combined type of ADHD, and related with this, we can speculate that increase of choline was determined in striatum in combined type of ADHD. As a result, when it is considered that cerebellum and striatum are relevant with motor coordination, we can speculate that
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neuronal damage and death is much more seen in combined type of ADHD. About 20–30% of ADHD patients do not respond to MPH treatment [2]. In a study investigating the response of MPH treatment in adult ADHD patients and relation of dopamine transporter (DAT) linking, it was reported that none of the patients having low DAT levels siginificantly respond to treatment. Thus, it was suggested that DAT linking can be used as a preliminary marker in terms of response to MPH in non-treated patients [21]. It was reported that non smokers have higher DAT density in a study which relation of cigarette use and DAT density was investigated [22]. When it was considered that 65% of the patients were using cigarette in the present study, it should be noted that most of them have probably low DAT density and were non-responsive to MPH. Limitations of the study were as follows: possibility of effecting MRS metabolite levels due to long term treatment of most of the patients, cigarette that was effecting the response to MPH was not excluded, absence of control group, use of magnetic resonance brain imaging technique with low Tesla value and evaluation of unilateral area. Consequently, no clear association was found between ADHD subtypes and changes of brain metabolites with use of MPH in adult ADHD. It can be thougt that there can be structural and/or metabolic abnormalities in frontal-striatal-cerebellar circuit in subtypes of ADHD. Subtypes of ADHD differ in terms of the underlying neuropathology and may clarify the different effects of drug treatment in the subtypes. Further studies which will be performed with larger sample size and neuroimaging techniques with higher resolution, and accompanying control group are needed. The present study forms a base to the forthcoming ones.
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