Relationship Between Neuroticism Personality Trait and Serotonin Transporter Binding

Relationship Between Neuroticism Personality Trait and Serotonin Transporter Binding

Relationship Between Neuroticism Personality Trait and Serotonin Transporter Binding Akihiro Takano, Ryosuke Arakawa, Mika Hayashi, Hidehiko Takahashi...

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Relationship Between Neuroticism Personality Trait and Serotonin Transporter Binding Akihiro Takano, Ryosuke Arakawa, Mika Hayashi, Hidehiko Takahashi, Hiroshi Ito, and Tetsuya Suhara Background: Personality trait is thought to be one of the important factors for vulnerability to depression. The relation between serotonin transporter (5-HTT) polymorphism and anxiety-related personality has been investigated in genetic research. In this study, we investigated the relation between in vivo regional 5-HTT binding in the brain and personality inventory measures in normal male volunteers. Methods: Thirty-one healthy male volunteers underwent positron emission tomography scans with 11C-labeled 3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl) benzonitrile ([11C]DASB) to measure 5-HTT and completed revised NEO Personality Inventory. Correlation of [11C]DASB binding potentials (BP) with personality inventory measures was calculated using region-of-interest analysis and statistical parametric mapping based on the BP images. Results: Neuroticism was positively correlated with 5-HTT binding in the thalamus (p ⫽ .004). No significant correlation was observed in any other brain region. Within the neuroticism dimension, the facet of depression was positively correlated with 5-HTT binding in the thalamus (p ⫽ .001). Conclusions: Subjects with higher thalamic 5-HTT binding are more likely to express higher levels of neuroticism and depressive feeling. Serotonin transporter binding in the thalamus might be a marker of vulnerability to depression. Key Words: [11C]DASB, depression, neuroticism, positron emission tomography, serotonin transporter, thalamus


ersonality trait is thought to be one of the key factors contributing to the vulnerability to depression and outcome of treatment (Cloninger et al. 2006; Coyne and Whiffen 1995; Duggan et al. 1995; Matsudaira and Kitamura 2006; Mulder et al. 2006; Smith et al. 2005). Several studies have indicated that personality traits such as harm avoidance and neuroticism were related to vulnerability to depression (Cloninger et al. 2006; Coyne and Whiffen 1995; Duggan et al. 1995; Matsudaira and Kitamura 2006; Smith et al. 2005). The factors predicting poor outcome for depression were reported to include a high score for harm avoidance (Mulder et al. 2006). As personality trait is suggested to be, in part, heritable (Cloninger 1987), relationships between personality trait and genetic factors have been extensively investigated, and several associations have been reported with factors related to neurotransmissions (Ebstein et al. 1996; Lesch et al. 1996). Lesch et al. (1996) reported that subjects with short variant of serotonin transporter (5-HTT) gene-linked promoter region (5-HTTLPR) gene polymorphism have lower 5-HTT in lymphoblasts and have higher neuroticism personality, and a number of studies have reported on the relationship between 5-HTTLPR and personality (Murakami et al. 1999; Ricketts et al. 1998; Sen et al. 2004b). Neuroticism is a term introduced by Eysenck (1967) to describe a major factor in analyses of self-rated or observer-rated measures of personality, characterized by dysphoria, anxiety, tension, and emotional reactivity (Costa and McCrae 1992; De-

From the Department of Molecular Neuroimaging, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan. Address reprint requests to Tetsuya Suhara, M.D., Ph.D., Department of Molecular Neuroimaging, Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1, Anagawa, Inage-ku, Chiba 263-8555, Japan; E-mail: [email protected] Received August 4, 2006; revised November 3, 2006; accepted November 9, 2006.

0006-3223/07/$32.00 doi:10.1016/j.biopsych.2006.11.007

Neve and Cooper 1998). High neuroticism scores are associated with people who tend to experience various negative affective states. High premorbid neuroticism scores are reported to be a predictor of future onset of depression (Bienvenu et al. 2001; Clark et al. 1994; Kendler et al. 1993; Khan et al. 2005). Using positron emission tomography (PET), the relationships between neuroreceptor bindings and personality traits have been investigated (Farde et al. 1997; Kestler et al. 2000; Suhara et al. 2001). Using [11C]raclopride, striatal dopamine D2 receptor was reported to be associated with emotional detachment in Karolinska Scales of Personality (Farde et al. 1997) or Revised NEO Personality Inventory (NEO PI-R) personality facet of depression (Kestler et al. 2000). In extrastriatal regions using carbon-11labelled(S)-5-bromo-N-((1-ethyl-2-pyrrolidinyl)methyl)-2,3-dimethooxybenzamide ([11C]FLB457), insular dopamine D2 receptor and novelty seeking in the Temperament and Character Inventory (TCI) were correlated (Kaasinen et al. 2004; Suhara et al. 2001). Regarding serotonin (5-HT) receptors, 5-HT1A receptor in the neocortex, hippocampus, and raphe was associated with scores for self-transcendence (Borg et al. 2003) and 5-HT2A receptor in the cerebral cortex was correlated with harm avoidance personality (Moresco et al. 2002). To visualize and quantify 5-HTT in the living human brain, carbon-11-labelled trans-1,2,3,5,6,10-␤-hyxahydro-6-[4-(methylthio)phenyl]pyrrolo [2,1-a] isoquinoline ([11C](⫹)McN5652) (Suehiro et al. 1993), 11C-labeled 3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl) benzonitrile ([11C]DASB) (Houle et al. 2000), and carbon-11-labelled N,N-dimethyl-2-(2-amino-4-methyphenylthio)-benzylamine ([11C]MADAM) (Halldin et al. 2005) have been used. The [11C](⫹)McN5652 has disadvantage over other two radioligands because of higher nonspecific binding. Positron emission tomography studies have reported 5-HTT alterations in mood disorder (Ichimiya et al. 2002; Meyer et al. 2004; Parsey et al. 2006). These studies suggested that the change of 5-HTT in the brain might be relevant in the pathophysiology of depression. Although the serotonin neurotransmission system may be associated with vulnerability to depression, the relationship between regional 5-HTT bindings and personality traits in healthy subjects has not been fully investigated. BIOL PSYCHIATRY 2007;62:588 –592 © 2007 Society of Biological Psychiatry

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A. Takano et al. In this study, we examined the relationship between in vivo regional 5-HTT binding and the personality trait of neuroticism in healthy male subjects using PET.

Methods and Materials Subjects Thirty-one healthy male volunteers aged 20 to 30 years (mean ⫾ SD, 23.6 ⫾ 2.8) participated in the study. They were recruited mainly from university campuses. None had a history of psychiatric or neurological illness, brain injury, chronic somatic illness, or substance abuse. They were all nonsmokers. They were examined by T1-weighted magnetic resonance imaging (MRI) using 1.5 tesla Philips Gyroscan NT (Philips Medical Systems, Best, The Netherlands) to rule out organic brain diseases. This study was approved by the Ethics and Radiation Safety Committee of the National Institute of Radiological Sciences, Chiba, Japan. Written informed consent was obtained from all subjects. PET Measurement The [11C]DASB was synthesized by methylation of the corresponding desmethyl precursor with methyl iodine ([11C]CH3I) (Wilson et al. 2000). Radiochemical purities were over 95%. After a 10-min transmission scan, a bolus of 444 to 803 MBq (mean ⫾ SD, 688 ⫾ 90) of [11C]DASB with high specific radioactivities (67.8 –217.8 GBq/␮mol; mean ⫾ SD, 111.4 ⫾ 37.3 GBq/␮mol) was injected into the antecubital vein with a 10-mL saline flush. Radioactivity was measured for 90 min using Siemens ECAT47 (Siemens, Knoxville, Tennessee) in two-dimensional (2-D) mode. PET Data Analysis All emission scans were reconstructed with a ramp filter cutoff frequency of .5. Six regions of interest (prefrontal cortex, thalamus, striatum, amygdala, hippocampus, and anterior cingulate cortex) and one reference region (cerebellum) were drawn on the coregistered PET/MRI images. The cerebellar vermis was excluded for the cerebellum. Multilinear reference tissue model 2 (MRTM 2) was used for quantification (Ichise et al. 2003), and was expressed by C (T ) ⫽ ⫺

V V'b



兰C ' (t)dt ⫹ k ' C ' (T ) 0



兰C (t)dt


where C (t) andC =(t) are the regional or voxel time-radioactivity concentrations in the tissue and reference regions, respectively (kBq/mL), V and V = are the corresponding total distribution volumes (mL/mL), k 2(min-1) is the clearance rate constant from the reference region to plasma, and b is the intercept term, which becomes constant for T⬎ t *. The cerebellum was used as the reference tissue because of its negligible density of 5-HTT (Cortes et al. 1988; Backstrom et al. 1989). These models allow the estimation of binding potentials (BP) (⫽ f2 Bmax/Kd), which is proportional to the transporter density (Bmax) where Kd and f2 are the dissociation constant and free tissue fraction, respectively. Personality Assessment Personality traits were assessed with the Japanese version of the Revised NEO Personality Inventory (Costa and McCrae 1992; Shimonaka et al. 1997; Yoshimura et al. 2001) on the same day as the performance of PET scans. This test is composed of 240 items and contains five dimensional scales (neuroticism, extraversion, openness to experience, agreeableness, and conscien-

tiousness) that correspond to a five-factor model of personality trait. Within the neuroticism dimension there are six underlying personality trait facets: anxiety, anger-hostility, depression, selfconsciousness, impulsiveness, and vulnerability. Revised NEO Personality Inventory results are presented as T scores with a mean of 50 and a standard deviation of 10. In this study, we focused on neuroticism, based on the priori hypothesis for the relationship between serotonin neurotransmission and neuroticism personality trait (Lesch et al. 1996). Statistics Pearson correlation coefficients (r) were calculated to explore the relation between regional 5-HTT BP and neuroticism dimensional scales. After the relations were found to be statistically significant in the dimension, the relations between regional 5-HTT binding and each facet within the dimension were investigated to determine which facet had the greatest influence on the results. To avoid type I errors in the multiplicity of statistical analysis, p ⬍ .008 ⫽ .05/6 was considered significant. To confirm the findings of region of interest (ROI) analysis, parametric images of BP calculated from MRTM 2 were made using PMOD software (PMOD Technoligie Ltd., Zurich, Switzerland) (Ichise et al. 2003). With SPM2 (Wellcome Department of Imaging Neuroscience, London, United Kingdom), each of the PET parametric images was coregistered to each of the MRI images. Then, with the parameters for each MRI image to be normalized, PET parametric images were normalized and smoothed. Correlation between [11C]DASB parametric images and parameters in NEO PI-R scales was analyzed using simple regression (correlation) in SPM2. As this was a hypothesis-led analysis, the threshold of the p value was ⬍ .001, uncorrected.

Results Serotonin transporter BPs in the thalamus were positively correlated with the neuroticism personality trait (Table 1, Figure 1A). There were no significant correlations between the other five regions and the neuroticism personality trait. Within the neuroticism dimension, only the depression facet was correlated with 5-HTT binding in the thalamus (Table 2, Figure 1B). The result obtained using a hypothesis-led SPM2 analysis of BP images of [11C]DASB indicated a significant correlation with neuroticism in the right thalamus (p ⬍ .001, uncorrected), and at a lower threshold (p ⬍ .01), the areas extended into the opposite side of the central part of the thalamus (Figure 2). The result obtained using a hypothesis-led SPM2 analysis of BP images of [11C]DASB indicated a significant correlation with depression in the right thalamus (p ⬍ .001, uncorrected), and at a lower threshold (p ⬍ .01), the areas extended into the opposite side of Table 1. Correlation Between Regional 5-HTT Binding Potential Values and Neuroticism from the Revised NEO Personality Inventory Region Prefrontal Cortex Thalamus Striatum Hipppocampus Amygdala Anterior Cingulate Cortex

r (p) ⫺.05 (.79) .51 (.004)a .15 (.42) .19 (.30) .03 (.88) ⫺.02 (.94)

5-HTT, serotonin transporter. a p ⬍ .05/6 ⫽ .0083.

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Figure 1. The relationship between [11C]DASB binding potentials in the thalamus and neuroticism (A) and a facet of neuroticism, depression, on NEO PI-R (B). [11C]DASB, 11C-labeled 3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)benzonitrile; NEO PI-R, Revised NEO Personality Inventory.

the thalamus (Figure 3). At the same low threshold, no significant correlation was observed in any other region.

Discussion In this study, we found a positive relationship between 5-HTT binding in the thalamus and neuroticism, a dimension of the Revised NEO Personality Inventory, in normal male subjects. In the dimension, the facet of depression was correlated positively with 5-HTT binding in the thalamus. No other region except the thalamus was correlated with neuroticism or depression in the NEO PI-R scale. Twice as large variations of 5-HTT binding potentials in the thalamus (from 1.31 to 2.56) were observed in the present study among normal subjects, which was consistent with other reports on 5-HTT using PET (Ichimiya et al. 2002; Meyer et al. 2004). Previously, higher 5-HTT bindings with [11C]McN(⫹)5652 were reported to be seen in mood disorder (Ichimiya et al. 2002). Higher 5-HTT binding with [11C]DASB were also reported in brain regions including thalamus, anterior cingulate, prefrontal cortex, caudate, and putamen of depressive patients with highly negativistic dysfunctional attitudes (Meyer et al. 2004). Recently, Cannon et al. (2006) reported also the elevation of 5-HTT binding in the cortex, thalamus, and striatum with patients with bipolar disorder. The patients in the study were all in a current major depressive episode. The positive correlation between 5-HTT binding in the thalamus and neuroticism personality and the depression facet in the present study indicated that the thalamus is a region that is related to the vulnerability to depression. Although the correlation with personality scores might be indistinct in the cortex

because of low signal to noise ratio (S/N) compared with the thalamus, this would not apply to the striatum. The thalamus could be important for its connection since neurons arising from the thalamus innervate most of the cortical and limbic regions (Alexander et al. 1986). The thalamus is thought to filter or regulate sensory input, and the anterior and mediodorsal thalamus play an important role in the expression and experience of emotion (LeDoux 2000; Preuss and Goldman-Rakic 1987; Price 1999). The thalamus integrates and redistributes emotionally relevant stimuli to the frontal cortex in connection with the anterior cingulate cortex and insular cortex (Denicoff et al. 1999; Phillips et al. 2003; Price 1999; Sax et al. 1999). The thalamus is also a major target for output from the amygdala, which mediates the emotional responses (LeDoux 2000). The thalamus forms a critical link in the corticolimbic circuitry including the amygdala,

Table 2. Correlation Between Thalamic 5-HTT Binding Potential Values and Facets of Neuroticism from the Revised NEO Personality Inventory Facet of Neuroticism Anxiety Angry Hostility Depression Self-Consciousness Impulsiveness Vulnerability 5-HTT, serotonin transporter. a p ⬍ .05/6 ⫽ .0083.

r (p) .41 (.021) .44 (.015) .58 (.001)a .23 (.21) .26 (.16) .45 (.012)

Figure 2. Brain regions showing a trend of correlation between binding potentials of [11C]DASB and neuroticism on NEO PI-R: SPM2 projections superimposed on representative transaxial, sagittal, and coronal magnetic resonance images (threshold for display: p ⬍ .01, uncorrected). [11C]DASB, 11 C-labeled 3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)benzonitrile; NEO PI-R, Revised NEO Personality Inventory.

A. Takano et al.

BIOL PSYCHIATRY 2007;62:588 –592 591 al. 2006). Ichise et al. (2003) showed that the reference tissue model using the cerebellar cortex as the reference tissue provides valid and reliable measure of the 5-HTT BP using [11C]DASB. It was also reported that even a complete blockade of 5-HTT would have a minimal effect on [11C]DASB binding in the cerebellum and the underestimation of BPs in the target regions would not exceed 7% (Kish et al. 2005). In conclusion, the present study showed that the variation of 5-HTT binding in the thalamus was related to the neuroticism personality trait and the facet of depression. Considering that high neuroticism personality is one of the risk factors for depression, the present study indicated that 5-HTT binding in the thalamus could be a possible marker for the vulnerability to depression. This study was supported by a consignment expense for Molecular Imaging Program on “Research Base for PET Diagnosis” from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japanese Government. We thank Jun Kosaka, Miho Ota, Shoko Nozaki, Chikako Hirai, and Yoshiko Fukushima for their help with the positron emission tomography (PET) study.

Figure 3. Brain regions showing a trend of correlation between binding potentials of [11C]DASB and depression, a facet of neuroticism, on NEO PI-R: SPM2 projections superimposed on representative transaxial, sagittal, and coronal magnetic resonance images (threshold for display: p ⬍ .01, uncorrected). [11C]DASB, 11C-labeled 3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)benzonitrile; NEO PI-R, Revised NEO Personality Inventory.

anterior cingulate, and the prefrontal cortex, which regulates mood and various cognitive processes (Denicoff et al. 1999; Mialet et al. 1996; Sax et al. 1999). There have been several discussions about the role of 5HTTLPR polymorphism in personality dimensions (Lesch et al. 1996; Munafo et al. 2003, 2005; Schinka et al. 2004; Sen et al. 2004a). Although we did not investigate gene polymorphism of the subjects in this study, there seemed to be a potential discrepancy from a previous genetic study (Lesch et al. 1996). Lesch et al. (1996) reported that subjects with short variant of 5-HTTLPR have higher neuroticism personality and lower 5-HTT in lymphoblasts. However, 5-HTT binding in the brain measured by PET (Shioe et al. 2003) and single-photon emission computed tomography (SPECT) (Willeit et al. 2001) showed no significant difference among 5-HTTLPR gene polymorphisms. There could be several factors affecting the expression of 5-HTT in the brain. In this study, we only investigated normal male subjects. Because female subjects are known to be vulnerable to depression (Amenson and Lewinsohn 1981; Kessler et al. 1994; Myers et al. 1984) and female subjects were reported to have lower 5-HTT binding than male subjects (Nordström et al. 2006), it would also be important to investigate female subjects in further study, and further long-term follow-up studies on the vulnerability for depression will be needed. The subjects in this study were 20 to 30 years old. Although the 5-HTT binding was reported to decrease with age (Cannon et al. 2006; Yamamoto et al 2002), the average rates of decrease were less than 10% per decade and the variability in young ages was large enough to avoid the age correction in this age range. Regarding the reference region, there are some arguments about the use of the cerebellum as a reference region (Szabo et al. 2002). However, the cerebellar cortex has been reported to be the optimal reference region for modeling with [11C]DASB refering postmortem and in vivo neuroimaging assessments (Parsey et

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