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Serotonin transporter in attention-deficit hyperactivity disorder – preliminary results from a positron emission tomography study
Psychiatry Research: Neuroimaging 212 (2013) 164–165
Contents lists available at SciVerse ScienceDirect
Psychiatry Research: Neuroimaging journal homepage: www.elsevier.com/locate/psychresns
Brief report
Serotonin transporter in attention-deficit hyperactivity disorder – preliminary results from a positron emission tomography study ¨ aki ¨ f, Elina Sihvola f, Linnea Karlsson a,b,n, Lauri Tuominen c,d, Antti Huotarinen e, Sami Leppam c c f c,g c,d Semi Helin , Maria Sipila¨ , Pekka Tani , Jussi Hirvonen , Jarmo Hietala , Hasse Karlsson c,d,h a
Turku University Hospital, Department of Child Psychiatry, P.O. Box 52, 20521 Turku, Finland National Institute for Health and Welfare, Department of Mental Health and Substance Abuse Services, Peltolantie 3, 20720 Turku, Finland c Turku PET Centre, University of Turku and Turku University Hospital, 20014 Turku, Finland d University of Turku, Department of Psychiatry, 20700 Turku, Finland e Helsinki University Central Hospital, Department of Neurosurgery, P.O. Box 266, 00029 HUS, Finland f Helsinki-Uusimaa Hospital District, Department of Psychiatry, P.O. Box 590, 00029 HUS, Finland g University of Turku, Department of Radiology, Kiinamyllynkatu 4-8, 20520 Turku, Finland h Turku University Hospital, Department of Psychiatry, 20520 Turku, Finland b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 29 August 2012 Received in revised form 12 December 2012 Accepted 7 February 2013
The serotonin transporter (SERT) in attention-deficit hyperactivity disorder (ADHD) patients has not been explored by earlier positron emission tomography (PET) studies. We measured SERT availability in female ADHD patients (n ¼ 8) and healthy controls (n ¼14) with PET and [11C]MADAM as a tracer. No significant group differences in [11C]MADAM binding potential were noted. & 2013 Elsevier Ireland Ltd. All rights reserved.
Keywords: ADHD SERT PET
1. Introduction
2. Method
Previous studies using positron emission tomography (PET) in attention-deficit hyperactivity disorder (ADHD) patients have focused on blood flow, glucose metabolism or dopaminergic neurotransmission (Zimmer, 2009; Bush, 2011). Dysfunctions in dopaminergic neurotransmission in fronto-striatal, cerebellar (Bush, 2011), and mesoaccumbens pathways (Volkow et al., 2011) have been consistently identified. Yet, some of the core symptoms of ADHD (e.g. impaired impulse control, emotional dysregulation) (Soloff et al., 2010) and data from molecular genetic studies (Archer et al., 2011) motivate research on the serotonin system in ADHD. The serotonin transporter (SERT) has a central role on terminating synaptic serotonergic transmission (Bengel 1998). We used [11C]MADAM and PET to assess SERT density (binding potential, BPND) in female ADHD patients and healthy controls.
2.1. Subjects
n Corresponding author at: Turku University Hospital, Department of Child Psychiatry, Lehmustie 12 b, P.O. Box 52, 20720 Turku, Finland. Tel.: þ358 40 7445052; fax: þ358 2 313 2412. E-mail address: linnea.karlsson@utu.fi (L. Karlsson).
0925-4927/$ - see front matter & 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.pscychresns.2013.02.001
Eight (n¼8) female ADHD outpatients, who provided written informed consent, were recruited from the neuropsychiatric clinic of Helsinki University Central Hospital in Southern Finland. The control scans (n¼14) comprised all comparable scans of healthy females available in the Turku PET Centre. Females between 20 and 40 years were included. The mean age was 27.6 years (range 19–39, S.D.¼8.84) in ADHD patients and 34.8 years (range 20–46, S.D. 8.31) in controls (t¼ 1.91, p¼0.07, S.D.¼ 3.77). ADHD diagnosis was assessed with CAADID (Conners’ Adult ADHD Diagnostic Interview) (Epstein et al., 2001) by clinicians trained in ADHD diagnostics. Parent interview and lifetime medical record data were included. Exclusion criteria of ongoing psychiatric or somatic comorbidity, other neurodevelopmental disorders or regular medication were assessed with the Structured Clinical Interviews for DSM-IV (SCID); (First et al., 2002). Two ADHD patients had two recovered episodes of major depressive disorder each (4 to 6 months of duration). Three subjects had used serotonin selective reuptake inhibitors (SSRIs) for 4 and 6 months in duration in years 2000, 2001, and 2005. Short-acting methylphenidate (Ritalin&) use was reported by two subjects in years 2004–2007. The duration of medication-free time varied from several months to several years. The Joint Ethics Committee of the University of Turku and the Turku University Central Hospital approved the protocol. 2.2. Imaging procedures PET scans were carried out in years 2008–2010 with a brain-dedicated highresolution PET scanner (ECAT HRRT, Siemens Medical Solutions). The imaging
L. Karlsson et al. / Psychiatry Research: Neuroimaging 212 (2013) 164–165
Table 1 Comparison of mean serotonin transporter (SERT) [11C]MADAM binding potential (BPND ) in preselected brain regions in female attention deficit hyperactivity disorder (ADHD) patients (n¼ 8) and controls (n¼14).
dACC vlpfc dlpfc tha vst put dnr
Mean (S.D.), ADHD patients
Mean (S.D.), controls
t value p value 95% CI*
0.45 0.30 0.32 1.32 1.30 1.19 2.66
0.47 0.30 0.37 1.39 1.34 1.21 2.40
0.28 0.15 1.33 0.73 0.35 0.28 1.08
(0.11) (0.07) (0.09) (0.27) (0.25) (0.18) (0.64)
(0.08) (0.09) (0.08) (0.20) (0.20) (0.13) (0.46)
0.78 0.88 0.20 0.48 0.73 0.78 0.29
0.09, 0.07, 0.12, 0.28, 0.23, 0.16, 0.24,
0.07 0.08 0.03 0.13 0.17 0.12 0.74
dACC ¼dorsal anterior cingulate cortex, vlpfc ¼ventrolateral prefrontal cortex, dlpfc¼ dorsolateral prefrontal cortex, tha ¼thalamus, vst ¼ventral striatum, put¼ putamen, dnr ¼ dorsal raphe nucleus, 95% CI* ¼95% confidence interval of the difference in means procedure was performed as described earlier by our group (Hirvonen et al., 2008; Tuominen et al., 2012). Magnetic resonance imaging (MRI) was performed using a Philips Gyroscan Intera 1.5T CV Nova Dual MRI scanner. Each subject was scanned once using [11C]MADAM according to a standard procedure to measure SERT BPND in the brain (Lundberg et al., 2006; Tuominen et al., 2012). The injected dose and mass of [11C]MADAM were 481.9 7 49.3 MBq and 0.78 70.7 mg (ADHD patients) and 472.3 7 58.9 MBq and 0.467 0.16 mg (controls). 2.3. Estimation of regional BPND In all, 23 cortical and subcortical regions of interest (ROIs) were manually drawn as described by Tuominen et al. (2012). Time-activity curves were derived from ROIs and regional BPND was estimated with a simplified reference tissue model with cerebellar grey matter as the reference region (Lammertsma and Hume, 1996). 2.4. Statistical procedures Statistical Package for the Social Sciences-19 for MAC (copyright SPSS, Inc., 1989–2010) was used for statistical analyses for ROI-based data. Group differences in BPND were analysed with independent samples t-test separately for each brain region, and P-values o 0.05 were considered statistically significant. Spearman’s correlation was used for correlation analyses. In the confirmatory whole brain voxel-wise analysis, a cluster-level family-wise error (FWE) corrected p-value o 0.05 was considered statistically significant. No corrections for multiple comparisons were performed in these preliminary analyses.
3. Results The ADHD diagnostic subtypes comprised pure or predominantly inattentive type (n¼4) and combined inattentive and hyperactive type (n¼4). No statistically significant differences in [11C]MADAM BPND between ADHD patients and healthy controls were detected in any of the brain regions either in t-test comparisons or in the confirmatory whole brain voxel-wise analysis. Inclusion of age as a covariate did not alter the results (data not shown). Data illustrating SERT BPND in preselected ROIs are presented in Table 1. No correlation between the total symptom counts of inattentive or hyperactivity/impulsivity dimensions and SERT BPND was observed.
4. Discussion No main effects of SERT density being linked with ADHD were observed. Comparisons with earlier studies are hampered by the lack of prior PET studies on SERT in ADHD. It remains unknown if a particular feature, such as inattention, results from similar neurocircuitry pathways in all ADHD patients (Bush, 2011). The roles of other parts of the 5-HT system and possible modulating effects of SERT on other neurotransmitter
165
systems need to be investigated separately. In this study, only females were included as both the serotonin system (Soloff et al., 2010) and ADHD-related neural networks (Valera et al., 2010) show sex differences. The patients went through comprehensive diagnostic assessment, they were currently unmedicated, and their lifetime use of psychotropic medication was limited. Menstruation cycle (Jovanovic et al., 2009), recovered depression (Bhagwagar et al., 2007), or smoking (Erritzoe et al., 2010) should not affect SERT availability or MADAM BPND. SERT density was measured with a state-of-the-art HRRT PET scanner with a ligand highly specific for SERT. The group difference in mean age should not bias the results as age-related decline in SERT availability per year is very small (Reimold et al., 2008). Small sample size is reflected, for example, in wide 95% confidence intervals. Thus, the results should be considered as preliminary. Further research in larger samples, in males and in subjects with hyperactive/impulsive phenotype are necessary. References Archer, T., Oscar-Berman, M., Blum, K., 2011. Epigenetics in developmental disorder: ADHD and endophenotypes. Journal of Genetic Syndromes and Gene Therapy 30 (2(104)), doi:pii: 1000104.. Bengel, D., 1998. Altered brain serotonin homeostasis and locomotor insensitivity to 3, 4-methylenedioxymethamphetamine (‘‘Ecstasy’’) in serotonin transporterdeficient mice. Molecular Pharmacology 53, 649–655. Bhagwagar, Z., Murthy, N., Selvaraj, S., Hinz, R., Taylor, M., Fancy, S., Grasby, P., Cowen, P., 2007. 5-HTT binding in recovered depressed patients and healthy volunteers: a positron emission tomography study with [11C]DASB. American Journal of Psychiatry 164, 1858–1865. Bush, G., 2011. Cingulate, frontal, and parietal cortical dysfunction in attention deficit/hyperactivity disorder. Biological Psychiatry 69, 1160–1167. Erritzoe, D., Frokjaer, V.G., Haahr, M.T., Kalbitzer, J., Svarer, C., Holst, K.K., Hansen, D.L., Jernigan, T.L., Lehel, S., Knudsen, G.M., 2010. Cerebral serotonin transporter binding is inversely related to body mass index. Neuroimage 52, 284–289. Epstein, J., Johnson, D.E., Conners, C.K., 2001. Conners’ Adult ADHD Diagnostic Interview for DSM-IVT. Multi-Health Systems, Inc., Cheektowaga, NY. First, M.B., Spitzer, R.L., Gibbon, M., Williams, J.B.W., 2002. Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Patient Edition. (SCID-I/P). Biometrics Research, New York State Psychiatric Institute, New York. Hirvonen, J., Johansson, J., Teras, M., Oikonen, V., Lumme, V., Virsu, P., Roivainen, A., Nagren, K., Halldin, C., Farde, L., Hietala, J., 2008. Measurement of striatal and extrastriatal dopamine transporter binding with high-resolution PET and [11C]PE2I: quantitative modeling and test-retest reproducibility. Journal of Cerebral Blood Flow and Metabolism 28, 1059–1069. ¨ Jovanovic, H., Karlsson, P., Cerin, A., Halldin, C., Nordstrom, A.L., 2009. 5-HT(1A) receptor and 5-HTT binding during the menstrual cycle in healthy women 11 11 examined with[ C]WAY100635 and [ C]MADAM PET. Psychiatry Research: Neuroimaging 172, 31–37. Lammertsma, A.A., Hume, S.P., 1996. Simplified reference tissue model for PET receptor studies. Neuroimage 4, 153–158. Lundberg, J., Halldin, C., Farde, L., 2006. Measurement of serotonin transporter binding with PET and [11C]MADAM: a test-retest reproducibility study. Synapse 60, 256–263. Reimold, M., Batra, A., Knobel, A., Smolka, M.N., Zimmer, A., Mann, K., Solbach, C., ¨ ¨ Reischl, G., Schwarzler, F., Grunder, G., Machulla, H.J., Bares, R., Heinz, A., 2008. Anxiety is associated with reduced central serotonin transporter availability in unmedicated patients with unipolar major depression: a [11C]DASB PET study. Molecular Psychiatry 13, 606–613. Soloff, P.H., Price, J.C., Mason, N.S., Becker, C., Meltzer, C.C., 2010. Gender, personality, and serotonin-2A receptor binding in healthy subjects. Psychiatry Research: Neuroimaging 181, 77–84. ˚ ¨ E., Tuominen, L., Salo, J., Hirvonen, J., Nagren, K., Laine, P., Melartin, T., Isometsa, ¨ Viikari, J., Cloninger, C.R., Raitakari, O., Hietala, J., Keltikangas-Jarvinen, L., 2012. Temperament, character and serotonin activity in the human brain: a positron emission tomography study based on a general population cohort. Psychological Medicine 31, 1–14. Valera, E.M., Brown, A., Biederman, J., Faraone, S.V., Makris, N., Monuteaux, M.C., Whitfiled-Gabrieli, S., Vitulano, M., Schiller, M., Seidman, L.J., 2010. Sex differences in the functional neuroanatomy of working memory in adults with ADHD. American Journal of Psychiatry 167, 86–94. Volkow, N.D., Wang, G.J., Newcorn, J.H., Kollins, S.H., Wigal, T.L., Telang, F., Fowler, J.S., Goldstein, R.Z., Klein, N., Logan, J., Wong, C., Swanson, J.M., 2011. Motivation deficit in ADHD is associated with dysfunction of the dopamine reward pathway. Molecular Psychiatry 16, 1147–1154. Zimmer, L., 2009. Positron emission tomography neuroimaging for a better understanding of the biology of ADHD. Neuropharmacology 57, 601–607.
Contents lists available at SciVerse ScienceDirect
Psychiatry Research: Neuroimaging journal homepage: www.elsevier.com/locate/psychresns
Brief report
Serotonin transporter in attention-deficit hyperactivity disorder – preliminary results from a positron emission tomography study ¨ aki ¨ f, Elina Sihvola f, Linnea Karlsson a,b,n, Lauri Tuominen c,d, Antti Huotarinen e, Sami Leppam c c f c,g c,d Semi Helin , Maria Sipila¨ , Pekka Tani , Jussi Hirvonen , Jarmo Hietala , Hasse Karlsson c,d,h a
Turku University Hospital, Department of Child Psychiatry, P.O. Box 52, 20521 Turku, Finland National Institute for Health and Welfare, Department of Mental Health and Substance Abuse Services, Peltolantie 3, 20720 Turku, Finland c Turku PET Centre, University of Turku and Turku University Hospital, 20014 Turku, Finland d University of Turku, Department of Psychiatry, 20700 Turku, Finland e Helsinki University Central Hospital, Department of Neurosurgery, P.O. Box 266, 00029 HUS, Finland f Helsinki-Uusimaa Hospital District, Department of Psychiatry, P.O. Box 590, 00029 HUS, Finland g University of Turku, Department of Radiology, Kiinamyllynkatu 4-8, 20520 Turku, Finland h Turku University Hospital, Department of Psychiatry, 20520 Turku, Finland b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 29 August 2012 Received in revised form 12 December 2012 Accepted 7 February 2013
The serotonin transporter (SERT) in attention-deficit hyperactivity disorder (ADHD) patients has not been explored by earlier positron emission tomography (PET) studies. We measured SERT availability in female ADHD patients (n ¼ 8) and healthy controls (n ¼14) with PET and [11C]MADAM as a tracer. No significant group differences in [11C]MADAM binding potential were noted. & 2013 Elsevier Ireland Ltd. All rights reserved.
Keywords: ADHD SERT PET
1. Introduction
2. Method
Previous studies using positron emission tomography (PET) in attention-deficit hyperactivity disorder (ADHD) patients have focused on blood flow, glucose metabolism or dopaminergic neurotransmission (Zimmer, 2009; Bush, 2011). Dysfunctions in dopaminergic neurotransmission in fronto-striatal, cerebellar (Bush, 2011), and mesoaccumbens pathways (Volkow et al., 2011) have been consistently identified. Yet, some of the core symptoms of ADHD (e.g. impaired impulse control, emotional dysregulation) (Soloff et al., 2010) and data from molecular genetic studies (Archer et al., 2011) motivate research on the serotonin system in ADHD. The serotonin transporter (SERT) has a central role on terminating synaptic serotonergic transmission (Bengel 1998). We used [11C]MADAM and PET to assess SERT density (binding potential, BPND) in female ADHD patients and healthy controls.
2.1. Subjects
n Corresponding author at: Turku University Hospital, Department of Child Psychiatry, Lehmustie 12 b, P.O. Box 52, 20720 Turku, Finland. Tel.: þ358 40 7445052; fax: þ358 2 313 2412. E-mail address: linnea.karlsson@utu.fi (L. Karlsson).
0925-4927/$ - see front matter & 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.pscychresns.2013.02.001
Eight (n¼8) female ADHD outpatients, who provided written informed consent, were recruited from the neuropsychiatric clinic of Helsinki University Central Hospital in Southern Finland. The control scans (n¼14) comprised all comparable scans of healthy females available in the Turku PET Centre. Females between 20 and 40 years were included. The mean age was 27.6 years (range 19–39, S.D.¼8.84) in ADHD patients and 34.8 years (range 20–46, S.D. 8.31) in controls (t¼ 1.91, p¼0.07, S.D.¼ 3.77). ADHD diagnosis was assessed with CAADID (Conners’ Adult ADHD Diagnostic Interview) (Epstein et al., 2001) by clinicians trained in ADHD diagnostics. Parent interview and lifetime medical record data were included. Exclusion criteria of ongoing psychiatric or somatic comorbidity, other neurodevelopmental disorders or regular medication were assessed with the Structured Clinical Interviews for DSM-IV (SCID); (First et al., 2002). Two ADHD patients had two recovered episodes of major depressive disorder each (4 to 6 months of duration). Three subjects had used serotonin selective reuptake inhibitors (SSRIs) for 4 and 6 months in duration in years 2000, 2001, and 2005. Short-acting methylphenidate (Ritalin&) use was reported by two subjects in years 2004–2007. The duration of medication-free time varied from several months to several years. The Joint Ethics Committee of the University of Turku and the Turku University Central Hospital approved the protocol. 2.2. Imaging procedures PET scans were carried out in years 2008–2010 with a brain-dedicated highresolution PET scanner (ECAT HRRT, Siemens Medical Solutions). The imaging
L. Karlsson et al. / Psychiatry Research: Neuroimaging 212 (2013) 164–165
Table 1 Comparison of mean serotonin transporter (SERT) [11C]MADAM binding potential (BPND ) in preselected brain regions in female attention deficit hyperactivity disorder (ADHD) patients (n¼ 8) and controls (n¼14).
dACC vlpfc dlpfc tha vst put dnr
Mean (S.D.), ADHD patients
Mean (S.D.), controls
t value p value 95% CI*
0.45 0.30 0.32 1.32 1.30 1.19 2.66
0.47 0.30 0.37 1.39 1.34 1.21 2.40
0.28 0.15 1.33 0.73 0.35 0.28 1.08
(0.11) (0.07) (0.09) (0.27) (0.25) (0.18) (0.64)
(0.08) (0.09) (0.08) (0.20) (0.20) (0.13) (0.46)
0.78 0.88 0.20 0.48 0.73 0.78 0.29
0.09, 0.07, 0.12, 0.28, 0.23, 0.16, 0.24,
0.07 0.08 0.03 0.13 0.17 0.12 0.74
dACC ¼dorsal anterior cingulate cortex, vlpfc ¼ventrolateral prefrontal cortex, dlpfc¼ dorsolateral prefrontal cortex, tha ¼thalamus, vst ¼ventral striatum, put¼ putamen, dnr ¼ dorsal raphe nucleus, 95% CI* ¼95% confidence interval of the difference in means procedure was performed as described earlier by our group (Hirvonen et al., 2008; Tuominen et al., 2012). Magnetic resonance imaging (MRI) was performed using a Philips Gyroscan Intera 1.5T CV Nova Dual MRI scanner. Each subject was scanned once using [11C]MADAM according to a standard procedure to measure SERT BPND in the brain (Lundberg et al., 2006; Tuominen et al., 2012). The injected dose and mass of [11C]MADAM were 481.9 7 49.3 MBq and 0.78 70.7 mg (ADHD patients) and 472.3 7 58.9 MBq and 0.467 0.16 mg (controls). 2.3. Estimation of regional BPND In all, 23 cortical and subcortical regions of interest (ROIs) were manually drawn as described by Tuominen et al. (2012). Time-activity curves were derived from ROIs and regional BPND was estimated with a simplified reference tissue model with cerebellar grey matter as the reference region (Lammertsma and Hume, 1996). 2.4. Statistical procedures Statistical Package for the Social Sciences-19 for MAC (copyright SPSS, Inc., 1989–2010) was used for statistical analyses for ROI-based data. Group differences in BPND were analysed with independent samples t-test separately for each brain region, and P-values o 0.05 were considered statistically significant. Spearman’s correlation was used for correlation analyses. In the confirmatory whole brain voxel-wise analysis, a cluster-level family-wise error (FWE) corrected p-value o 0.05 was considered statistically significant. No corrections for multiple comparisons were performed in these preliminary analyses.
3. Results The ADHD diagnostic subtypes comprised pure or predominantly inattentive type (n¼4) and combined inattentive and hyperactive type (n¼4). No statistically significant differences in [11C]MADAM BPND between ADHD patients and healthy controls were detected in any of the brain regions either in t-test comparisons or in the confirmatory whole brain voxel-wise analysis. Inclusion of age as a covariate did not alter the results (data not shown). Data illustrating SERT BPND in preselected ROIs are presented in Table 1. No correlation between the total symptom counts of inattentive or hyperactivity/impulsivity dimensions and SERT BPND was observed.
4. Discussion No main effects of SERT density being linked with ADHD were observed. Comparisons with earlier studies are hampered by the lack of prior PET studies on SERT in ADHD. It remains unknown if a particular feature, such as inattention, results from similar neurocircuitry pathways in all ADHD patients (Bush, 2011). The roles of other parts of the 5-HT system and possible modulating effects of SERT on other neurotransmitter
165
systems need to be investigated separately. In this study, only females were included as both the serotonin system (Soloff et al., 2010) and ADHD-related neural networks (Valera et al., 2010) show sex differences. The patients went through comprehensive diagnostic assessment, they were currently unmedicated, and their lifetime use of psychotropic medication was limited. Menstruation cycle (Jovanovic et al., 2009), recovered depression (Bhagwagar et al., 2007), or smoking (Erritzoe et al., 2010) should not affect SERT availability or MADAM BPND. SERT density was measured with a state-of-the-art HRRT PET scanner with a ligand highly specific for SERT. The group difference in mean age should not bias the results as age-related decline in SERT availability per year is very small (Reimold et al., 2008). Small sample size is reflected, for example, in wide 95% confidence intervals. Thus, the results should be considered as preliminary. Further research in larger samples, in males and in subjects with hyperactive/impulsive phenotype are necessary. References Archer, T., Oscar-Berman, M., Blum, K., 2011. Epigenetics in developmental disorder: ADHD and endophenotypes. Journal of Genetic Syndromes and Gene Therapy 30 (2(104)), doi:pii: 1000104.. Bengel, D., 1998. Altered brain serotonin homeostasis and locomotor insensitivity to 3, 4-methylenedioxymethamphetamine (‘‘Ecstasy’’) in serotonin transporterdeficient mice. Molecular Pharmacology 53, 649–655. Bhagwagar, Z., Murthy, N., Selvaraj, S., Hinz, R., Taylor, M., Fancy, S., Grasby, P., Cowen, P., 2007. 5-HTT binding in recovered depressed patients and healthy volunteers: a positron emission tomography study with [11C]DASB. American Journal of Psychiatry 164, 1858–1865. Bush, G., 2011. Cingulate, frontal, and parietal cortical dysfunction in attention deficit/hyperactivity disorder. Biological Psychiatry 69, 1160–1167. Erritzoe, D., Frokjaer, V.G., Haahr, M.T., Kalbitzer, J., Svarer, C., Holst, K.K., Hansen, D.L., Jernigan, T.L., Lehel, S., Knudsen, G.M., 2010. Cerebral serotonin transporter binding is inversely related to body mass index. Neuroimage 52, 284–289. Epstein, J., Johnson, D.E., Conners, C.K., 2001. Conners’ Adult ADHD Diagnostic Interview for DSM-IVT. Multi-Health Systems, Inc., Cheektowaga, NY. First, M.B., Spitzer, R.L., Gibbon, M., Williams, J.B.W., 2002. Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Patient Edition. (SCID-I/P). Biometrics Research, New York State Psychiatric Institute, New York. Hirvonen, J., Johansson, J., Teras, M., Oikonen, V., Lumme, V., Virsu, P., Roivainen, A., Nagren, K., Halldin, C., Farde, L., Hietala, J., 2008. Measurement of striatal and extrastriatal dopamine transporter binding with high-resolution PET and [11C]PE2I: quantitative modeling and test-retest reproducibility. Journal of Cerebral Blood Flow and Metabolism 28, 1059–1069. ¨ Jovanovic, H., Karlsson, P., Cerin, A., Halldin, C., Nordstrom, A.L., 2009. 5-HT(1A) receptor and 5-HTT binding during the menstrual cycle in healthy women 11 11 examined with[ C]WAY100635 and [ C]MADAM PET. Psychiatry Research: Neuroimaging 172, 31–37. Lammertsma, A.A., Hume, S.P., 1996. Simplified reference tissue model for PET receptor studies. Neuroimage 4, 153–158. Lundberg, J., Halldin, C., Farde, L., 2006. Measurement of serotonin transporter binding with PET and [11C]MADAM: a test-retest reproducibility study. Synapse 60, 256–263. Reimold, M., Batra, A., Knobel, A., Smolka, M.N., Zimmer, A., Mann, K., Solbach, C., ¨ ¨ Reischl, G., Schwarzler, F., Grunder, G., Machulla, H.J., Bares, R., Heinz, A., 2008. Anxiety is associated with reduced central serotonin transporter availability in unmedicated patients with unipolar major depression: a [11C]DASB PET study. Molecular Psychiatry 13, 606–613. Soloff, P.H., Price, J.C., Mason, N.S., Becker, C., Meltzer, C.C., 2010. Gender, personality, and serotonin-2A receptor binding in healthy subjects. Psychiatry Research: Neuroimaging 181, 77–84. ˚ ¨ E., Tuominen, L., Salo, J., Hirvonen, J., Nagren, K., Laine, P., Melartin, T., Isometsa, ¨ Viikari, J., Cloninger, C.R., Raitakari, O., Hietala, J., Keltikangas-Jarvinen, L., 2012. Temperament, character and serotonin activity in the human brain: a positron emission tomography study based on a general population cohort. Psychological Medicine 31, 1–14. Valera, E.M., Brown, A., Biederman, J., Faraone, S.V., Makris, N., Monuteaux, M.C., Whitfiled-Gabrieli, S., Vitulano, M., Schiller, M., Seidman, L.J., 2010. Sex differences in the functional neuroanatomy of working memory in adults with ADHD. American Journal of Psychiatry 167, 86–94. Volkow, N.D., Wang, G.J., Newcorn, J.H., Kollins, S.H., Wigal, T.L., Telang, F., Fowler, J.S., Goldstein, R.Z., Klein, N., Logan, J., Wong, C., Swanson, J.M., 2011. Motivation deficit in ADHD is associated with dysfunction of the dopamine reward pathway. Molecular Psychiatry 16, 1147–1154. Zimmer, L., 2009. Positron emission tomography neuroimaging for a better understanding of the biology of ADHD. Neuropharmacology 57, 601–607.