European Psychiatry 30 (2015) 193–197
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Original article
The correlation between mid-brain serotonin transporter availability and intelligence quotient in healthy volunteers P.Y. Tseng a, I.H. Lee a,b, K.C. Chen a,b,c, P.S. Chen a,b,c, N.T. Chiu d, W.J. Yao d, C.L. Chu a, T.L. Yeh a,b, Y.K. Yang a,b,* a
Department of Psychiatry, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan Addiction Research Center, National Cheng Kung University, Tainan, Taiwan Department of Psychiatry, National Cheng Kung University, Dou-Liou Branch, Yunlin, Taiwan d Department of Nuclear Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 28 April 2014 Received in revised form 29 August 2014 Accepted 9 September 2014 Available online 28 October 2014
Purpose: This study was performed to investigate the association between the mid-brain serotonin transporter (SERT) availability and intelligence quotient (IQ). Methods: One hundred and thirteen healthy participants, including 52 male and 61 female subjects, were recruited. We used SPECT with [123I]ADAM images to determine the SERT availability in the mid-brain, and measured the subjects’ IQ using the WAIS-R. Results: We found a significant positive correlation between the mid-brain SERT availability and the IQ of the participants. Even when controlling for age and sex, the significant association still existed. Conclusion: This result implied that the higher the SERT binding in the mid-brain, the better the IQ in healthy participants. ß 2014 Elsevier Masson SAS. All rights reserved.
Keywords: Serotonin transporter availability Intelligence quotient Cognitive function [123I]ADAM SPECT
1. Introduction Since the 19th century, when Broca [6] and Wernicke [54] noted that specific cognitive functions are located in certain brain regions, it has been found that the cortex is highly associated with intelligence [11,20]. With improvements in technology, we have been able to discover what specific site of our cortex takes charge of what specific cognitive function, and realized that the cortex is highly associated with intelligence [11,20]. Meanwhile, probing the mechanism and molecules that mediate cognitive function and intelligence has become an issue of increasing importance [33,39]. Molecular imaging, such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT), has been applied as a tool for in vivo analysis and quantification of biochemical reactions [31]. Neuroimaging studies have indicated that dopamine is associated with variations in memory performance and verbal organization [10,13,16,32], which implies that dopamine is correlated with cognitive function. Meanwhile, * Corresponding author. Department of Psychiatry, National Cheng Kung University Hospital, 138, Shen Li Road, 704 Tainan, Taiwan. Tel.: +886 6 2353535x5213; fax: +886 6 2084767. E-mail address: [email protected] (Y.K. Yang). http://dx.doi.org/10.1016/j.eurpsy.2014.09.001 0924-9338/ß 2014 Elsevier Masson SAS. All rights reserved.
serotonin is also one of the most important neurotransmitters in the brain [49]. It has been shown that the serotonergic system is not only associated with emotions but also with a wide range of cognition and behaviors such as sleep, aggression, personality and hostility [3,19,22,26,38,43,44,47,58,59]. The serotonin transporter (SERT), which controls the reuptake of serotonin through the synaptic cleft to presynaptic neurons, plays a critical role in the serotonergic system. Serotonergic neurons originate from the raphe nucleus in the brain stem and are projected to the mid-brain, hypothalamus, thalamus, amygdala, striatum and prefrontal cortex [49]. SPECT image studies have shown that the highest SERT availability is in the mid-brain [12]. The dorsal raphe nucleus, the largest serotonergic nucleus, is located in the mid-brain [1]. It projects serotonergic neurons to other parts of the brain [14]. In studies of the treatment of obsessive compulsive disorder and depression, the mid-brain SERT occupancy was used to evaluate the response to and effects of medication [28,50,61,62]. Thus, SERT binding in the mid-brain may generally reflect the serotonergic neuron activity. The SERT density might reflect the activity of serotonergic neurons. McCann et al. [29] showed better verbal memory and a greater SERT density in the dorsal lateral prefrontal cortex in a healthy control group than in ecstasy users through PET study. Madsen et al. found that higher frontal-striatal cortex SERT binding is correlated with better executive function [27]. Therefore,
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some studies have used the availability of SERT to evaluate the neurotoxicity of substances to serotonergic neurons [37]. Non-neuroimaging studies have implied that lower serotonergic activity is associated with a lower performance in cognitive tests [38,43,44]. Schmitt et al. [44] concluded that reduced serotonin turnover is consistently associated with impaired long-term memory functioning. With a supplement of serotonin, participants achieved a better performance in the tests. Therefore, serotonergic activity might be related to intelligence. McCann et al. [29] showed a positive association between verbal memory and SERT binding at the dorsolateral prefrontal cortex and parietal cortex in a healthy control group through PET study. Lower verbal memory and lower SERT binding have been found in ecstasy users. Madsen et al. [27] found that high SERT binding in the fronto-striatal regions is related to better performance in terms of executive function and logical reasoning. Kish et al. [21] found that performances in some tests of memory and mental flexibility are correlated with SERT binding in the hippocampus and insular cortex. This raises the possibility that serotonergic disturbance related to low SERT might lead to subtle problems in memory, self-awareness and insight, which could lead to functional difficulty. However, the results regarding the relationship between cognitive function and SERT availability remain inconsistent. Burke et al. [7] showed that neuropsychological measurements in young healthy people cannot be based on the subcortical SERT availabilities in the brain. Currently, studies investigating the relationship between SERT availability, global cognitive function and intelligence quotient (IQ) are scarce. The aim of this study was to investigate the relationship between SERT availability and IQ, using SPECT with the [123I]-labeled 2-((2-((dimethylamino)methyl) phenyl)thio)-5-iodophenylamine ([123I]ADAM) ligand to evaluate SERT availability [24,35].
2. Materials and methods 2.1. Ethics statement The research protocol was approved by the Ethical Committee for Human Research at the National Cheng Kung University, and written informed consent was obtained from each subject before any procedures were performed. 2.2. Participants The participants were enrolled from the community through advertisement. They were recruited as healthy controls in our previous studies, which focused on major depressive disorder, heroin use and other mental problems [15,16,51,58–60]. The individuals were excluded if they were found to have a mental illness after a diagnostic interview, the Chinese version of the Mini International Neuropsychiatry Interview (MINI) [45]. Meanwhile, participants with a history of physical disease, alcohol abuse or other substance abuse were omitted from our study. Finally, 113 healthy participants, of which 52 were male and 61 female, with a mean age of 32.94 years (SD = 12.08) were recruited. The mean educational years was 14.01 years (SD = 3.45). 2.3. Imaging ADAM, a selective radioligand that can bind SERT specifically in the central nervous system, was used for quantification of SERT under SPECT imaging [23,35,48]. This radioligand was synthesized using the iododestannylation reaction from the tributyltin precursor, which was oxidized by hydrogen peroxide. The purity of that compound was found to be 96.8 1.8% by high-pressure liquid chromatography (HPLC).
Before the [123I]ADAM SPECT examination was initiated, all of the participants were administered 9 mL of Lugol’s solution in order to prevent [123I]ADAM being absorbed into the thyroid gland. We see that 185 MBq (5 mCi) of [123I]ADAM was then administered to the participants through an intravenous catheter. This procedure was performed in a quiet place. The catheter was removed after [123I]ADAM injection. A triple-headed rotating gamma camera (Siemens Medical Systems; Hoffman Estates, IL, USA) with fan-beam collimators was used to produce the images, with a resolution of around 8.5 mm FWHM. A 20% energy window at 159 KeV was placed symmetrically in the machine. SPECT images were obtained over a circular 3608 rotation of 120 steps (50 seconds per step) in a 128 128 16 matrix. Butterworth and Ramp filters (cut-off frequency: 0.3 Nyquist; power factor: 7) attenuated by Chang’s method were used to reconstruct the SPECT images. The slice thickness of each reconstructed image was 2.89 mm. The transverse images were aligned parallel to the canthomeatal line. Six continuous transverse slices on which the mid-brain was best visualized were combined to obtain a slice of a thickness of 17.34 mm for semi-quantitative analysis. SPECT images were obtained 10 minutes and 6 hours after 185 MBq [123I]ADAM injection. The images taken 10 minutes after [123I]ADAM administration were regarded as the early-phase images, which illustrated blood–brain barrier transition and mimicked cerebral blood flow images. The late-phase images were taken 6 hours after injection of [123I]ADAM, and showed the distribution of SERT. To obtain a better depiction of the mid-brain and cerebellum, a senior nuclear medicine specialist who was blind to the clinical data of the participants identified the regions of interest (ROIs) of the mid-brain (a specific SERT binding site) and cerebellum (a nonspecific site because of the lack of SERT). The volume of the midbrain ROI (covering the mid-brain raphe nuclei) was about 8.6 cm3. Magnetic resonance imaging (MRI) (Signa CV/i, 1.5 tesla; GE Medical Systems, Milwaukee, WI, USA) was used to determine the mid-brain and cerebellum on the SPECT images. The late-phase SPECT images were coregistered with the early-phase images. The optimal time for [123I]ADAM SPECT quantification was around 4– 6 hours after administration [8]; therefore, we determined the SERT availability from the late-phase images. SERT availability was calculated as the average mid-brain ROI minus the cerebellum ROI divided by the cerebellum ROI [(mid-brain–cerebellum)/cerebellum, (Mb–Cb)/Cb ratio]. A higher serotonergic activity was ascribed to the position with higher SERT availability [12]. For a more detailed description of the method, see Huang et al. [17]. 2.4. Wechsler Adult Intelligence Scale-Revised (WAIS-R) The WAIS-R [53], designed by David Wechsler, was used to evaluate individual intelligence. Such a test gives a full-scale IQ (FIQ) and 2 different dimensions of IQ. Due to the lack of a Chinese WAIS-R version and the norm of Taiwan (e.g., the differences in political background, etc.), subtests with cultural or language factors [42] were not administered. The six-subtest short-form combination was composed of digit symbol, block design, object assembly, digit span, similarity, and arithmetic tests. We used the former three to obtain an estimated performance IQ (PIQ), while the latter three were used to obtain an estimated verbal IQ (VIQ). The mean FIQ score in this test is 100 (the standard deviation is 15). 2.5. Statistical analysis Means and standard deviations (SDs) were calculated for descriptive analysis of the participants’ age, SERT availability, and WAIS-R score. Because the WAIS-R score was not of a normal distribution, the Mann-Whitney U test was used to examine the
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Table 1 Demographic data of the total, male, and female subjects. Total (n = 113)
Male (n = 52)
Female (n = 61)
Statistic analysis between males and females
Mean SD
Mean SD
Mean SD
Mann-Whitney U
P
Effect size
0.36 2.27 0.29
0.72 0.02 0.77
0.03 0.21 0.03
2.62 0.40 3.66 2.29 2.15 1.95 0.27 3.28 2.44
0.01 0.69 < 0.001 0.02 0.03 0.052 0.79 0.001 0.01
0.25 0.04 0.34 0.22 0.20 0.18 0.03 0.31 0.23
32.94 12.08 14.01 3.45 1.39 0.44
Age Educational years SERT availability WAIS-R PIQ Digit symbol Block design Object assembly VIQ Digit span Similarity Arithmetic FIQ
107.33 11.91 11.56 8.13 110.73 13.14 10.35 10.69 110.42
31.84 10.60 14.94 2.69 1.39 0.47
13.19 2.78 2.70 2.58 16.89 3.08 2.91 2.96 14.96
111.12 12.17 12.62 8.75 114.21 13.73 10.42 11.77 114.1
10.70 2.52 2.09 2.22 16.73 2.88 3.00 2.99 13.48
33.87 13.23 13.21 3.83 1.39 0.41 104.1 11.69 10.66 7.61 107.75 12.64 10.30 9.77 107.28
14.29 2.99 2.85 2.76 16.58 3.18 2.86 2.61 15.54
SERT: serotonin transporter; WAIS-R: Wechsler Adult Intelligence Scale-Revised; PIQ: performance IQ; VIQ: verbal IQ; FIQ: full-scale IQ.
differences between the male and female subjects. Pearson’s r and Spearman’s r correlation analyses (two-tailed) were carried out to examine the association between SERT availability and WAIS-R score. Furthermore, partial correlations to control for age and sex were also performed. The threshold for statistical significance was 0.05. The data were analyzed using SPSS software 17 (SPSS Inc., Chicago, IL, USA).
between SERT availability and FIQ was significant (r = 0.31, P = 0.02), but this was not the case in the male participants (r = 0.10, P = 0.49) (Fig. 1). This pattern was confirmed by Pearson correlation analysis, before and after controlling the effect of age. Similar results were also found for the PIQ and VIQ.
3. Results
The results revealed a significant correlation between SERT availability and FIQ score in healthy participants. This might reflect that the higher the density of SERT, the higher the IQ of the participant. It is currently unclear as to why there was no correlation with VIQ before controlling the effects of age and sex. The discrepancy could be due to the influences of age and sex. Other PET imaging studies regarding VIQ and SERT availability have also demonstrated that there is a positive correlation [27,29]. In previous studies, it has been shown that increasing age results in impairment in cognitive function [9,34,36,40,41]. The effect of aging also influences the SERT availability. A decline in
The mean of the SERT availability was 1.39 0.44. The FIQ, VIQ, and PIQ scores were 110.42 14.96 (range: 75141), 110.73 16.89 (range: 74150), and 107.33 13.19 (range: 74134), respectively. Sex differences were found in several domains of the IQ test, but not in the SERT availability (Table 1). Pearson’s r and Spearman’s rho revealed significant correlations between SERT availability and FIQ (r = 0.19, P = 0.04; r = 0.21, P = 0.03) and PIQ scores (r = 0.20, P = 0.03; r = 0.20, P = 0.03). After controlling for age and sex, the significant correlations between SERT availability and FIQ (r = 0.25, P = 0.01) and PIQ (r = 0.24, P = 0.01) remained robust, and the association between SERT availability and VIQ also reached a significant level (r = 0.20, P = 0.04). However, the associations between SERT availability and subtests were not significant, with the exception of the similarity subtest, as shown in Table 2. Although the associations of SERT availability with PIQ and FIQ were found to be independent of sex, we conducted a supplemental stratified analysis. In the female participants, the correlation
4. Discussion
Table 2 Correlation between SERT availability and WAIS-R.
PIQ Digit symbol Block design Object assembly VIQ Digit span Similarity Arithmetic FIQ
Parametric correlation
Non-parametric correlation
Partial correlation
r
P
r
P
r
P
0.20 0.10 0.11 0.08 0.14 0.04 0.23 0.07 0.19
0.03 0.31 0.26 0.42 0.14 0.71 0.01 0.46 0.04
0.20 0.17 0.12 0.06 0.15 0.04 0.23 0.08 0.21
0.03 0.07 0.21 0.52 0.12 0.67 0.01 0.42 0.03
0.24 0.17 0.18 0.11 0.20 0.09 0.27 0.11 0.25
0.01 0.08 0.05 0.25 0.04 0.35 < 0.005 0.23 0.01
The effects of age and sex were controlled in the partial correlation. SERT: serotonin transporter; WAIS-R: Wechsler Adult Intelligence Scale-Revised; PIQ: performance IQ; VIQ: verbal IQ; FIQ: full-scale IQ.
Fig. 1. Scatter plot of SERT availability and FIQ in male and female subjects. FIQ: fullscale intelligence quotient; SERT: serotonin transporter; Female: Spearman’s r correlation = 0.31, P = 0.02; partial correlation = 0.32, P = 0.01; Male: Spearman’s r correlation = 0.10, P = 0.49; partial correlation = 0.14, P = 0.33.
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SERT density was found in elderly participants [52,57]. In this study, the correlation between SERT availability and all of the IQ items (PIQ, VIQ, and FIQ) was still robust following adjustment for age. The present finding supports that the correlation between SERT and IQ is independent of the effect of age. McCann et al. [29] found a positive association between verbal memory and SERT binding in the dorsal lateral prefrontal cortex (DLPFC) and parietal cortex in healthy controls. Madsen et al. [27] found that high SERT binding in the frontal-striatal regions is related to better executive function and logical reasoning. Therefore, the SERT availability in cortex might be related to performance in terms of cognitive function. These studies supported the present findings [25,29]. However, Burke et al. [7], using SPECT with [123I]b-CIT, showed that the measurement of neuropsychological function could not be based on the subcortical SERT availabilities. The inconsistencies in the results might be due to the different characteristics of the radio-ligands. McCann et al. [29] and Madsen et al. [27] used [11C]DASB in a PET study, which can bind to SERT more specifically and could offer better evaluation of the SERT availability. Burke et al. [7] showed no significant differences in the results through SPECT with [123I]b-CIT, which can bind with both SERT and the dopamine transporter. Another possible reason for the differences in the results is differences in the regions of the brain studied. McCann et al. [29] and Madsen et al. [27] showed a positive association between cognitive function and SERT binding in the dorsal lateral prefrontal cortex (DLPFC), parietal cortex and frontal-striatal regions. However, Burke et al. [7] found no significant relationship between SERT availability and cognitive function in subcortical areas (mid-brain and thalamus). Burke et al. used the Dutch adult reading test, rather than a traditional IQ test, to estimate verbal IQ. There was a positive correlation between SERT availability and FIQ in the female participants. However, this was not the case in the male participants. Additionally, correlations between SERT availability and the results of the similarity and digit symbol subtests were found only in the female participants. Currently, we are unable to explain these sex differences. In studies on the treatment of dementia and neuroendocrine studies, estrogen modulates serotonin neurons through indirect or direct pathways. It could also affect cognitive function directly [4,5,46,55]. One of the possible reasons could be due to the fact that estrogen or other sex hormones could play important roles in cognitive enhancement. However, in the aforementioned studies about cognitive function and SERT, no gender differences were mentioned [27,29,37,38,43,44]. The present study had several limitations. First, it was an association study. As changes in IQ were not dependent on experimental manipulation of serotonergic tone, the causal relationships between the mid-brain serotonergic activities and IQ could not be confirmed. Second, different phases of the menstrual cycle may influence serotonin transmission [56]. In an animal study, estradiol increased the serotonin MRNA expression and SERT density [30]. Estradiol could therefore increase the clearance of serotonin [2]. Thus, the effect of the menstrual cycle should be considered in the future. Third, the changes in central serotonin might not be fully accounted for by the single-site model used in this study [25]. Because of the high heterogeneity in human intelligence, the association found between SERT and IQ score provides a potential direction for future studies in this area. Fourth, the resolution of [123I]ADAM SPECT isn’t as good as that of PET images such as [11C]DASB. Moreover, the binding affinity of [11C]DASB is better than that of [123I]ADAM [18]. The instruments used for neuroimaging cannot assess the exact binding potential in detailed regions. Whether or not IQ is associated with exact regions (i.e., convergent versus discriminate validity) is unclear. Finally, the primary aim of the present study was to probe the association
between SERT availability and IQ (full, verbal, and performance). The role of type I error was small (1–0.96 0.99 0.99 = 0.006); however, this cannot be omitted from the analyses of subgroups and the subtest results. In conclusion, we found a positive association between SERT availability and IQ. This result implies that the higher the SERT availability in the mid-brain, the better the performance in cognitive tasks. Although the results still need to be explored and replicated, this could indicate that clinicians should pay more attention to the relationship between serotonin and cognitive function when they prescribe serotonin-related medication to patients. The association found between SERT and IQ score in this study may offer a potential direction for future studies on human intelligence. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. Acknowledgements The authors wish to thank Dr. Shih-Hsien Lin, Ms. Tsai Hua Chang, Mr. Chien Ting Lin, and all of the research participants. This study was supported in part by grants from the National Science Council of Taiwan (NSC 93-NU-7-006-004, NSC 93-2314-B-006107, NSC 97-2314-B-006-006-MY3) and the Atomic Energy Council of Taiwan (NSC 99-NU-E-006-003). This research also received funding (D102-35001 and D103-35A09) from the Headquarters of University Advancement at the National Cheng Kung University, which is sponsored by the Ministry of Education, Taiwan, ROC. References [1] Baker KG, Halliday GM, Hornung JP, Geffen LB, Cotton RG, Tork I. Distribution, morphology and number of monoamine-synthesizing and substance P-containing neurons in the human dorsal raphe nucleus. Neuroscience 1991;42:757–75. [2] Benmansour S, Piotrowski JP, Altamirano AV, Frazer A. Impact of ovarian hormones on the modulation of the serotonin transporter by fluvoxamine. Neuropsychopharmacology 2009;34:555–64. [3] Bennett AJ, Lesch KP, Heils A, Long JC, Lorenz JG, Shoaf SE, et al. Early experience and serotonin transporter gene variation interact to influence primate CNS function. Mol Psychiatry 2002;7:118–22. [4] Bethea CL, Lu NZ, Gundlah C, Streicher JM. Diverse actions of ovarian steroids in the serotonin neural system. Front Neuroendocrinol 2002;23:41–100. [5] Bethea CL, Pecins-Thompson M, Schutzer WE, Gundlah C, Lu ZN. Ovarian steroids and serotonin neural function. Mol Neurobiol 1998;18:87–123. [6] Broca P. New finding of aphasia following a lesion of the posterior part of the second and third frontal convolutions. Bull Soc Anatomique 1861;6:398–407. [7] Burke SM, van de Giessen E, de Win M, Schilt T, van Herk M, van den Brink W, et al. Serotonin and dopamine transporters in relation to neuropsychological functioning, personality traits and mood in young adult healthy subjects. Psychol Med 2011;41:419–29. [8] Catafau AM, Perez V, Penengo MM, Bullich S, Danus M, Puigdemont D, et al. SPECT of serotonin transporters using 123I-ADAM: optimal imaging time after bolus injection and long-term test-retest in healthy volunteers. J Nucl Med 2005;46:1301–9. [9] Charlton RA, Barrick TR, McIntyre DJ, Shen Y, O’Sullivan M, Howe FA, et al. White matter damage on diffusion tensor imaging correlates with age-related cognitive decline. Neurology 2006;66:217–22. [10] Chen PS, Yang YK, Lee YS, Yeh TL, Lee IH, Chiu NT, et al. Correlation between different memory systems and striatal dopamine D2/D3 receptor density: a single photon emission computed tomography study. Psychol Med 2005;35: 197–204. [11] Deary IJ, Penke L, Johnson W. The neuroscience of human intelligence differences. Nat Rev Neurosci 2010;11:201–11. [12] Erlandsson K, Sivananthan T, Lui D, Spezzi A, Townsend CE, Mu S, et al. Measuring SSRI occupancy of SERT using the novel tracer [123I]ADAM: a SPECT validation study. Eur J Nucl Med Mol Imaging 2005;32:1329–36. [13] Guo JF, Yang YK, Chiu NT, Yeh TL, Chen PS, Lee IH, et al. The correlation between striatal dopamine D2/D3 receptor availability and verbal intelligence quotient in healthy volunteers. Psychol Med 2006;36:547–54.
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Original article
The correlation between mid-brain serotonin transporter availability and intelligence quotient in healthy volunteers P.Y. Tseng a, I.H. Lee a,b, K.C. Chen a,b,c, P.S. Chen a,b,c, N.T. Chiu d, W.J. Yao d, C.L. Chu a, T.L. Yeh a,b, Y.K. Yang a,b,* a
Department of Psychiatry, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan Addiction Research Center, National Cheng Kung University, Tainan, Taiwan Department of Psychiatry, National Cheng Kung University, Dou-Liou Branch, Yunlin, Taiwan d Department of Nuclear Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 28 April 2014 Received in revised form 29 August 2014 Accepted 9 September 2014 Available online 28 October 2014
Purpose: This study was performed to investigate the association between the mid-brain serotonin transporter (SERT) availability and intelligence quotient (IQ). Methods: One hundred and thirteen healthy participants, including 52 male and 61 female subjects, were recruited. We used SPECT with [123I]ADAM images to determine the SERT availability in the mid-brain, and measured the subjects’ IQ using the WAIS-R. Results: We found a significant positive correlation between the mid-brain SERT availability and the IQ of the participants. Even when controlling for age and sex, the significant association still existed. Conclusion: This result implied that the higher the SERT binding in the mid-brain, the better the IQ in healthy participants. ß 2014 Elsevier Masson SAS. All rights reserved.
Keywords: Serotonin transporter availability Intelligence quotient Cognitive function [123I]ADAM SPECT
1. Introduction Since the 19th century, when Broca [6] and Wernicke [54] noted that specific cognitive functions are located in certain brain regions, it has been found that the cortex is highly associated with intelligence [11,20]. With improvements in technology, we have been able to discover what specific site of our cortex takes charge of what specific cognitive function, and realized that the cortex is highly associated with intelligence [11,20]. Meanwhile, probing the mechanism and molecules that mediate cognitive function and intelligence has become an issue of increasing importance [33,39]. Molecular imaging, such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT), has been applied as a tool for in vivo analysis and quantification of biochemical reactions [31]. Neuroimaging studies have indicated that dopamine is associated with variations in memory performance and verbal organization [10,13,16,32], which implies that dopamine is correlated with cognitive function. Meanwhile, * Corresponding author. Department of Psychiatry, National Cheng Kung University Hospital, 138, Shen Li Road, 704 Tainan, Taiwan. Tel.: +886 6 2353535x5213; fax: +886 6 2084767. E-mail address: [email protected] (Y.K. Yang). http://dx.doi.org/10.1016/j.eurpsy.2014.09.001 0924-9338/ß 2014 Elsevier Masson SAS. All rights reserved.
serotonin is also one of the most important neurotransmitters in the brain [49]. It has been shown that the serotonergic system is not only associated with emotions but also with a wide range of cognition and behaviors such as sleep, aggression, personality and hostility [3,19,22,26,38,43,44,47,58,59]. The serotonin transporter (SERT), which controls the reuptake of serotonin through the synaptic cleft to presynaptic neurons, plays a critical role in the serotonergic system. Serotonergic neurons originate from the raphe nucleus in the brain stem and are projected to the mid-brain, hypothalamus, thalamus, amygdala, striatum and prefrontal cortex [49]. SPECT image studies have shown that the highest SERT availability is in the mid-brain [12]. The dorsal raphe nucleus, the largest serotonergic nucleus, is located in the mid-brain [1]. It projects serotonergic neurons to other parts of the brain [14]. In studies of the treatment of obsessive compulsive disorder and depression, the mid-brain SERT occupancy was used to evaluate the response to and effects of medication [28,50,61,62]. Thus, SERT binding in the mid-brain may generally reflect the serotonergic neuron activity. The SERT density might reflect the activity of serotonergic neurons. McCann et al. [29] showed better verbal memory and a greater SERT density in the dorsal lateral prefrontal cortex in a healthy control group than in ecstasy users through PET study. Madsen et al. found that higher frontal-striatal cortex SERT binding is correlated with better executive function [27]. Therefore,
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some studies have used the availability of SERT to evaluate the neurotoxicity of substances to serotonergic neurons [37]. Non-neuroimaging studies have implied that lower serotonergic activity is associated with a lower performance in cognitive tests [38,43,44]. Schmitt et al. [44] concluded that reduced serotonin turnover is consistently associated with impaired long-term memory functioning. With a supplement of serotonin, participants achieved a better performance in the tests. Therefore, serotonergic activity might be related to intelligence. McCann et al. [29] showed a positive association between verbal memory and SERT binding at the dorsolateral prefrontal cortex and parietal cortex in a healthy control group through PET study. Lower verbal memory and lower SERT binding have been found in ecstasy users. Madsen et al. [27] found that high SERT binding in the fronto-striatal regions is related to better performance in terms of executive function and logical reasoning. Kish et al. [21] found that performances in some tests of memory and mental flexibility are correlated with SERT binding in the hippocampus and insular cortex. This raises the possibility that serotonergic disturbance related to low SERT might lead to subtle problems in memory, self-awareness and insight, which could lead to functional difficulty. However, the results regarding the relationship between cognitive function and SERT availability remain inconsistent. Burke et al. [7] showed that neuropsychological measurements in young healthy people cannot be based on the subcortical SERT availabilities in the brain. Currently, studies investigating the relationship between SERT availability, global cognitive function and intelligence quotient (IQ) are scarce. The aim of this study was to investigate the relationship between SERT availability and IQ, using SPECT with the [123I]-labeled 2-((2-((dimethylamino)methyl) phenyl)thio)-5-iodophenylamine ([123I]ADAM) ligand to evaluate SERT availability [24,35].
2. Materials and methods 2.1. Ethics statement The research protocol was approved by the Ethical Committee for Human Research at the National Cheng Kung University, and written informed consent was obtained from each subject before any procedures were performed. 2.2. Participants The participants were enrolled from the community through advertisement. They were recruited as healthy controls in our previous studies, which focused on major depressive disorder, heroin use and other mental problems [15,16,51,58–60]. The individuals were excluded if they were found to have a mental illness after a diagnostic interview, the Chinese version of the Mini International Neuropsychiatry Interview (MINI) [45]. Meanwhile, participants with a history of physical disease, alcohol abuse or other substance abuse were omitted from our study. Finally, 113 healthy participants, of which 52 were male and 61 female, with a mean age of 32.94 years (SD = 12.08) were recruited. The mean educational years was 14.01 years (SD = 3.45). 2.3. Imaging ADAM, a selective radioligand that can bind SERT specifically in the central nervous system, was used for quantification of SERT under SPECT imaging [23,35,48]. This radioligand was synthesized using the iododestannylation reaction from the tributyltin precursor, which was oxidized by hydrogen peroxide. The purity of that compound was found to be 96.8 1.8% by high-pressure liquid chromatography (HPLC).
Before the [123I]ADAM SPECT examination was initiated, all of the participants were administered 9 mL of Lugol’s solution in order to prevent [123I]ADAM being absorbed into the thyroid gland. We see that 185 MBq (5 mCi) of [123I]ADAM was then administered to the participants through an intravenous catheter. This procedure was performed in a quiet place. The catheter was removed after [123I]ADAM injection. A triple-headed rotating gamma camera (Siemens Medical Systems; Hoffman Estates, IL, USA) with fan-beam collimators was used to produce the images, with a resolution of around 8.5 mm FWHM. A 20% energy window at 159 KeV was placed symmetrically in the machine. SPECT images were obtained over a circular 3608 rotation of 120 steps (50 seconds per step) in a 128 128 16 matrix. Butterworth and Ramp filters (cut-off frequency: 0.3 Nyquist; power factor: 7) attenuated by Chang’s method were used to reconstruct the SPECT images. The slice thickness of each reconstructed image was 2.89 mm. The transverse images were aligned parallel to the canthomeatal line. Six continuous transverse slices on which the mid-brain was best visualized were combined to obtain a slice of a thickness of 17.34 mm for semi-quantitative analysis. SPECT images were obtained 10 minutes and 6 hours after 185 MBq [123I]ADAM injection. The images taken 10 minutes after [123I]ADAM administration were regarded as the early-phase images, which illustrated blood–brain barrier transition and mimicked cerebral blood flow images. The late-phase images were taken 6 hours after injection of [123I]ADAM, and showed the distribution of SERT. To obtain a better depiction of the mid-brain and cerebellum, a senior nuclear medicine specialist who was blind to the clinical data of the participants identified the regions of interest (ROIs) of the mid-brain (a specific SERT binding site) and cerebellum (a nonspecific site because of the lack of SERT). The volume of the midbrain ROI (covering the mid-brain raphe nuclei) was about 8.6 cm3. Magnetic resonance imaging (MRI) (Signa CV/i, 1.5 tesla; GE Medical Systems, Milwaukee, WI, USA) was used to determine the mid-brain and cerebellum on the SPECT images. The late-phase SPECT images were coregistered with the early-phase images. The optimal time for [123I]ADAM SPECT quantification was around 4– 6 hours after administration [8]; therefore, we determined the SERT availability from the late-phase images. SERT availability was calculated as the average mid-brain ROI minus the cerebellum ROI divided by the cerebellum ROI [(mid-brain–cerebellum)/cerebellum, (Mb–Cb)/Cb ratio]. A higher serotonergic activity was ascribed to the position with higher SERT availability [12]. For a more detailed description of the method, see Huang et al. [17]. 2.4. Wechsler Adult Intelligence Scale-Revised (WAIS-R) The WAIS-R [53], designed by David Wechsler, was used to evaluate individual intelligence. Such a test gives a full-scale IQ (FIQ) and 2 different dimensions of IQ. Due to the lack of a Chinese WAIS-R version and the norm of Taiwan (e.g., the differences in political background, etc.), subtests with cultural or language factors [42] were not administered. The six-subtest short-form combination was composed of digit symbol, block design, object assembly, digit span, similarity, and arithmetic tests. We used the former three to obtain an estimated performance IQ (PIQ), while the latter three were used to obtain an estimated verbal IQ (VIQ). The mean FIQ score in this test is 100 (the standard deviation is 15). 2.5. Statistical analysis Means and standard deviations (SDs) were calculated for descriptive analysis of the participants’ age, SERT availability, and WAIS-R score. Because the WAIS-R score was not of a normal distribution, the Mann-Whitney U test was used to examine the
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Table 1 Demographic data of the total, male, and female subjects. Total (n = 113)
Male (n = 52)
Female (n = 61)
Statistic analysis between males and females
Mean SD
Mean SD
Mean SD
Mann-Whitney U
P
Effect size
0.36 2.27 0.29
0.72 0.02 0.77
0.03 0.21 0.03
2.62 0.40 3.66 2.29 2.15 1.95 0.27 3.28 2.44
0.01 0.69 < 0.001 0.02 0.03 0.052 0.79 0.001 0.01
0.25 0.04 0.34 0.22 0.20 0.18 0.03 0.31 0.23
32.94 12.08 14.01 3.45 1.39 0.44
Age Educational years SERT availability WAIS-R PIQ Digit symbol Block design Object assembly VIQ Digit span Similarity Arithmetic FIQ
107.33 11.91 11.56 8.13 110.73 13.14 10.35 10.69 110.42
31.84 10.60 14.94 2.69 1.39 0.47
13.19 2.78 2.70 2.58 16.89 3.08 2.91 2.96 14.96
111.12 12.17 12.62 8.75 114.21 13.73 10.42 11.77 114.1
10.70 2.52 2.09 2.22 16.73 2.88 3.00 2.99 13.48
33.87 13.23 13.21 3.83 1.39 0.41 104.1 11.69 10.66 7.61 107.75 12.64 10.30 9.77 107.28
14.29 2.99 2.85 2.76 16.58 3.18 2.86 2.61 15.54
SERT: serotonin transporter; WAIS-R: Wechsler Adult Intelligence Scale-Revised; PIQ: performance IQ; VIQ: verbal IQ; FIQ: full-scale IQ.
differences between the male and female subjects. Pearson’s r and Spearman’s r correlation analyses (two-tailed) were carried out to examine the association between SERT availability and WAIS-R score. Furthermore, partial correlations to control for age and sex were also performed. The threshold for statistical significance was 0.05. The data were analyzed using SPSS software 17 (SPSS Inc., Chicago, IL, USA).
between SERT availability and FIQ was significant (r = 0.31, P = 0.02), but this was not the case in the male participants (r = 0.10, P = 0.49) (Fig. 1). This pattern was confirmed by Pearson correlation analysis, before and after controlling the effect of age. Similar results were also found for the PIQ and VIQ.
3. Results
The results revealed a significant correlation between SERT availability and FIQ score in healthy participants. This might reflect that the higher the density of SERT, the higher the IQ of the participant. It is currently unclear as to why there was no correlation with VIQ before controlling the effects of age and sex. The discrepancy could be due to the influences of age and sex. Other PET imaging studies regarding VIQ and SERT availability have also demonstrated that there is a positive correlation [27,29]. In previous studies, it has been shown that increasing age results in impairment in cognitive function [9,34,36,40,41]. The effect of aging also influences the SERT availability. A decline in
The mean of the SERT availability was 1.39 0.44. The FIQ, VIQ, and PIQ scores were 110.42 14.96 (range: 75141), 110.73 16.89 (range: 74150), and 107.33 13.19 (range: 74134), respectively. Sex differences were found in several domains of the IQ test, but not in the SERT availability (Table 1). Pearson’s r and Spearman’s rho revealed significant correlations between SERT availability and FIQ (r = 0.19, P = 0.04; r = 0.21, P = 0.03) and PIQ scores (r = 0.20, P = 0.03; r = 0.20, P = 0.03). After controlling for age and sex, the significant correlations between SERT availability and FIQ (r = 0.25, P = 0.01) and PIQ (r = 0.24, P = 0.01) remained robust, and the association between SERT availability and VIQ also reached a significant level (r = 0.20, P = 0.04). However, the associations between SERT availability and subtests were not significant, with the exception of the similarity subtest, as shown in Table 2. Although the associations of SERT availability with PIQ and FIQ were found to be independent of sex, we conducted a supplemental stratified analysis. In the female participants, the correlation
4. Discussion
Table 2 Correlation between SERT availability and WAIS-R.
PIQ Digit symbol Block design Object assembly VIQ Digit span Similarity Arithmetic FIQ
Parametric correlation
Non-parametric correlation
Partial correlation
r
P
r
P
r
P
0.20 0.10 0.11 0.08 0.14 0.04 0.23 0.07 0.19
0.03 0.31 0.26 0.42 0.14 0.71 0.01 0.46 0.04
0.20 0.17 0.12 0.06 0.15 0.04 0.23 0.08 0.21
0.03 0.07 0.21 0.52 0.12 0.67 0.01 0.42 0.03
0.24 0.17 0.18 0.11 0.20 0.09 0.27 0.11 0.25
0.01 0.08 0.05 0.25 0.04 0.35 < 0.005 0.23 0.01
The effects of age and sex were controlled in the partial correlation. SERT: serotonin transporter; WAIS-R: Wechsler Adult Intelligence Scale-Revised; PIQ: performance IQ; VIQ: verbal IQ; FIQ: full-scale IQ.
Fig. 1. Scatter plot of SERT availability and FIQ in male and female subjects. FIQ: fullscale intelligence quotient; SERT: serotonin transporter; Female: Spearman’s r correlation = 0.31, P = 0.02; partial correlation = 0.32, P = 0.01; Male: Spearman’s r correlation = 0.10, P = 0.49; partial correlation = 0.14, P = 0.33.
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SERT density was found in elderly participants [52,57]. In this study, the correlation between SERT availability and all of the IQ items (PIQ, VIQ, and FIQ) was still robust following adjustment for age. The present finding supports that the correlation between SERT and IQ is independent of the effect of age. McCann et al. [29] found a positive association between verbal memory and SERT binding in the dorsal lateral prefrontal cortex (DLPFC) and parietal cortex in healthy controls. Madsen et al. [27] found that high SERT binding in the frontal-striatal regions is related to better executive function and logical reasoning. Therefore, the SERT availability in cortex might be related to performance in terms of cognitive function. These studies supported the present findings [25,29]. However, Burke et al. [7], using SPECT with [123I]b-CIT, showed that the measurement of neuropsychological function could not be based on the subcortical SERT availabilities. The inconsistencies in the results might be due to the different characteristics of the radio-ligands. McCann et al. [29] and Madsen et al. [27] used [11C]DASB in a PET study, which can bind to SERT more specifically and could offer better evaluation of the SERT availability. Burke et al. [7] showed no significant differences in the results through SPECT with [123I]b-CIT, which can bind with both SERT and the dopamine transporter. Another possible reason for the differences in the results is differences in the regions of the brain studied. McCann et al. [29] and Madsen et al. [27] showed a positive association between cognitive function and SERT binding in the dorsal lateral prefrontal cortex (DLPFC), parietal cortex and frontal-striatal regions. However, Burke et al. [7] found no significant relationship between SERT availability and cognitive function in subcortical areas (mid-brain and thalamus). Burke et al. used the Dutch adult reading test, rather than a traditional IQ test, to estimate verbal IQ. There was a positive correlation between SERT availability and FIQ in the female participants. However, this was not the case in the male participants. Additionally, correlations between SERT availability and the results of the similarity and digit symbol subtests were found only in the female participants. Currently, we are unable to explain these sex differences. In studies on the treatment of dementia and neuroendocrine studies, estrogen modulates serotonin neurons through indirect or direct pathways. It could also affect cognitive function directly [4,5,46,55]. One of the possible reasons could be due to the fact that estrogen or other sex hormones could play important roles in cognitive enhancement. However, in the aforementioned studies about cognitive function and SERT, no gender differences were mentioned [27,29,37,38,43,44]. The present study had several limitations. First, it was an association study. As changes in IQ were not dependent on experimental manipulation of serotonergic tone, the causal relationships between the mid-brain serotonergic activities and IQ could not be confirmed. Second, different phases of the menstrual cycle may influence serotonin transmission [56]. In an animal study, estradiol increased the serotonin MRNA expression and SERT density [30]. Estradiol could therefore increase the clearance of serotonin [2]. Thus, the effect of the menstrual cycle should be considered in the future. Third, the changes in central serotonin might not be fully accounted for by the single-site model used in this study [25]. Because of the high heterogeneity in human intelligence, the association found between SERT and IQ score provides a potential direction for future studies in this area. Fourth, the resolution of [123I]ADAM SPECT isn’t as good as that of PET images such as [11C]DASB. Moreover, the binding affinity of [11C]DASB is better than that of [123I]ADAM [18]. The instruments used for neuroimaging cannot assess the exact binding potential in detailed regions. Whether or not IQ is associated with exact regions (i.e., convergent versus discriminate validity) is unclear. Finally, the primary aim of the present study was to probe the association
between SERT availability and IQ (full, verbal, and performance). The role of type I error was small (1–0.96 0.99 0.99 = 0.006); however, this cannot be omitted from the analyses of subgroups and the subtest results. In conclusion, we found a positive association between SERT availability and IQ. This result implies that the higher the SERT availability in the mid-brain, the better the performance in cognitive tasks. Although the results still need to be explored and replicated, this could indicate that clinicians should pay more attention to the relationship between serotonin and cognitive function when they prescribe serotonin-related medication to patients. The association found between SERT and IQ score in this study may offer a potential direction for future studies on human intelligence. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. Acknowledgements The authors wish to thank Dr. Shih-Hsien Lin, Ms. Tsai Hua Chang, Mr. Chien Ting Lin, and all of the research participants. This study was supported in part by grants from the National Science Council of Taiwan (NSC 93-NU-7-006-004, NSC 93-2314-B-006107, NSC 97-2314-B-006-006-MY3) and the Atomic Energy Council of Taiwan (NSC 99-NU-E-006-003). This research also received funding (D102-35001 and D103-35A09) from the Headquarters of University Advancement at the National Cheng Kung University, which is sponsored by the Ministry of Education, Taiwan, ROC. References [1] Baker KG, Halliday GM, Hornung JP, Geffen LB, Cotton RG, Tork I. Distribution, morphology and number of monoamine-synthesizing and substance P-containing neurons in the human dorsal raphe nucleus. Neuroscience 1991;42:757–75. [2] Benmansour S, Piotrowski JP, Altamirano AV, Frazer A. Impact of ovarian hormones on the modulation of the serotonin transporter by fluvoxamine. Neuropsychopharmacology 2009;34:555–64. [3] Bennett AJ, Lesch KP, Heils A, Long JC, Lorenz JG, Shoaf SE, et al. Early experience and serotonin transporter gene variation interact to influence primate CNS function. Mol Psychiatry 2002;7:118–22. [4] Bethea CL, Lu NZ, Gundlah C, Streicher JM. Diverse actions of ovarian steroids in the serotonin neural system. Front Neuroendocrinol 2002;23:41–100. [5] Bethea CL, Pecins-Thompson M, Schutzer WE, Gundlah C, Lu ZN. Ovarian steroids and serotonin neural function. Mol Neurobiol 1998;18:87–123. [6] Broca P. New finding of aphasia following a lesion of the posterior part of the second and third frontal convolutions. Bull Soc Anatomique 1861;6:398–407. [7] Burke SM, van de Giessen E, de Win M, Schilt T, van Herk M, van den Brink W, et al. Serotonin and dopamine transporters in relation to neuropsychological functioning, personality traits and mood in young adult healthy subjects. Psychol Med 2011;41:419–29. [8] Catafau AM, Perez V, Penengo MM, Bullich S, Danus M, Puigdemont D, et al. SPECT of serotonin transporters using 123I-ADAM: optimal imaging time after bolus injection and long-term test-retest in healthy volunteers. J Nucl Med 2005;46:1301–9. [9] Charlton RA, Barrick TR, McIntyre DJ, Shen Y, O’Sullivan M, Howe FA, et al. White matter damage on diffusion tensor imaging correlates with age-related cognitive decline. Neurology 2006;66:217–22. [10] Chen PS, Yang YK, Lee YS, Yeh TL, Lee IH, Chiu NT, et al. Correlation between different memory systems and striatal dopamine D2/D3 receptor density: a single photon emission computed tomography study. Psychol Med 2005;35: 197–204. [11] Deary IJ, Penke L, Johnson W. The neuroscience of human intelligence differences. Nat Rev Neurosci 2010;11:201–11. [12] Erlandsson K, Sivananthan T, Lui D, Spezzi A, Townsend CE, Mu S, et al. Measuring SSRI occupancy of SERT using the novel tracer [123I]ADAM: a SPECT validation study. Eur J Nucl Med Mol Imaging 2005;32:1329–36. [13] Guo JF, Yang YK, Chiu NT, Yeh TL, Chen PS, Lee IH, et al. The correlation between striatal dopamine D2/D3 receptor availability and verbal intelligence quotient in healthy volunteers. Psychol Med 2006;36:547–54.
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