International Journal of Impotence Research (2015), 1–6 © 2015 Macmillan Publishers Limited All rights reserved 0955-9930/15 www.nature.com/ijir
ORIGINAL ARTICLE
Sex differences in interactions between nucleus accumbens and visual cortex by explicit visual erotic stimuli: an fMRI study SW Lee1, BS Jeong1, J Choi2 and J-W Kim3 Men tend to have greater positive responses than women to explicit visual erotic stimuli (EVES). However, it remains unclear, which brain network makes men more sensitive to EVES and which factors contribute to the brain network activity. In this study, we aimed to assess the effect of sex difference on brain connectivity patterns by EVES. We also investigated the association of testosterone with brain connection that showed the effects of sex difference. During functional magnetic resonance imaging scans, 14 males and 14 females were asked to see alternating blocks of pictures that were either erotic or non-erotic. Psychophysiological interaction analysis was performed to investigate the functional connectivity of the nucleus accumbens (NA) as it related to EVES. Men showed significantly greater EVES-specific functional connection between the right NA and the right lateral occipital cortex (LOC). In addition, the right NA and the right LOC network activity was positively correlated with the plasma testosterone level in men. Our results suggest that the reason men are sensitive to EVES is the increased interaction in the visual reward networks, which is modulated by their plasma testosterone level. International Journal of Impotence Research advance online publication, 14 May 2015; doi:10.1038/ijir.2015.8 INTRODUCTION Sex is related to differences in the brain. Sex differences are found in brain structure,1 development2 and functional connectivity.3 It is a phenomenological representation of the brain that these differences can determine behavior.4,5 Among the various behaviors, sexual behavior and the differences between the sexes are among those that are interesting, and many studies have been conducted to understand the biological mechanisms of sexual behavior. Animal studies have revealed that specific brain regions are related to appetitive behavior and to gonadal hormone effects on sexual behavior.6 For example, the nucleus accumbens (NA), which receives dopamine signals from the ventral tegmental area, is important to appetitive behaviors. In male rats, ventral tegmental area stimulation enhances mating behaviors, and sexual behavior induces dopamine release in the NA.7,8 Furthermore, NA/ventral tegmental area activity is enhanced or modulated by gonadal hormones.9,10 In addition, some human functional neuroimaging studies have been conducted to find sex differences in brain activity related to visual sexual stimuli. The ventral striatal region, which includes the NA and is involved in the conditioning of sexual arousal, showed hyperactivity in men.11 The amygdala and hypothalamus, which has a high correlation with sexual arousal, was more activated in men than in women by visual erotic stimuli.12 Differences in the visual processing regions, including lateral occipital cortex (LOC), were also reported.13 In addition, studies showed that the level of sex hormones affect the activities of several brain regions, including the amygdala,14 thalamus and cingulate gyrus,15 in men who were given visual erotic stimuli. To summarize, previous animal and human neuroimaging studies suggested that sex differences in sexual responses are caused by
interactions of various brain regions. In particular, the reward network from the NA, and the visual and emotional network involving the amygdala and LOC were commonly reported and could be key brain network responsible for sex differences in response to erotic stimuli. In addition, modulatory effects of sex hormones, such as testosterone, could also have major roles in determining sexual responses. Although much research has been conducted and has revealed sex differences in brain networks, it remains unclear how the activity and modulation of these brain networks may be connected with sex-based differences in response to explicit visual erotic stimuli (EVES). Therefore, in our study, we searched for a clue to connect the activities of brain networks with sexual response to EVES using context-specific, functional connectivity analysis. The NA, the pivotal center for regulating motivation and reward,16,17 was chosen as the seed region. The brain networks from the seed region that is specifically activated during EVES were verified using psychophysiological interaction (PPI) analysis.18 This study had three goals: (1) delineate the visual reward networks active during EVES, (2) explain the sex differences in emotional response to EVES according to the connectivity patterns of the networks, and (3) explore the modulatory effect of plasma testosterone on these brain networks. Our study provides background necessary for understanding the sex differences in response to EVES regarding brain networks, and may give clues for the understanding of pathological sexual behaviors. MATERIALS AND METHODS Subjects Twenty-eight subjects participated in the study, 14 males (mean age 28.8 ± 7.1 years; range 22–47) and 14 females (mean age 29.1 ± 8.9 years;
1 Korea Advanced Institute of Science and Technology (KAIST), Laboratory of Clinical Neuroscience and Development, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea; 2Department of Psychiatry, Daejeon St Mary's Hospital, The Catholic University of Korea, College of Medicine, Daejeon, Republic of Korea and 3 Department of Psychiatry, College of Medical Science, Kongyang University, Daejeon, Republic of Korea. Correspondence: Professor BS Jeong, Laboratory of Clinical Neuroscience and Development, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Yuseong-gu, Daejeon 305-701, Republic of Korea. E-mail: [email protected] Received 8 May 2014; revised 8 January 2015; accepted 18 April 2015
Sex effects on erotic stimuli processing SW Lee et al
2 range 18–49). Seven subjects (3 males and 4 females) were in a marital relationship, while the others were single. There were no significant differences between the two sex groups both in age (T = − 0.10, P = 0.924) and in marital status (χ2 = 0.19, P = 0.663). All subjects voluntarily participated for this study and provided written informed consent before enrolling in the study. Two psychiatrists interviewed all subjects using Diagnostic and Statistical Mental Disorder, Fourth Edition (DSM-IV) criteria to exclude any patients with psychiatric disorders in axis-I. Subjects were requested to abstain from any sexual activities, including masturbation, for 1 day before undergoing the functional magnetic resonance imaging (fMRI) procedures. This study was approved by the Institutional Review Board of Eulji University Hospital.
Experimental design During the fMRI sessions, subjects were asked to passively view alternating 24-s blocks of pictures that represented four different conditions. The conditions consisted of three blocks, and each block had four different pictures, which changed every 6 s. Pictures of naked couples in erotic poses of sexual activity were presented as EVES, and pictures of people with no overt sexual context (PEOPLE) were used to induce positive emotions related to interaction between people (for example, a couple with happy faces staring at each other). Pictures of NATURE (trees, stone, flowers and shrubs) and FOOD (ice cream, oriental noodles, chocolate and spaghetti) were included to confirm whether other non-erotic stimuli related to reward may show sex differences (Supplementary Text S1). Most of the pictures, including all those of erotic stimulation and of nature, were selected from the International Affective Picture System (IAPS),19 whereas some pictures of non-erotic stimuli and food were produced for this study. Pictures were matched for standard values of arousal, pleasantness and dominance as provided by the IAPS and for sexual intensity as described before.20 In this study, three consecutive blocks of the same condition were applied because the erotic block could affect responses to its following blocks. For example, if a PEOPLE block came after an EVES block, subjects may recall the erotic pictures, while they see the people pictures. Therefore, the stimuli blocks were presented in this consecutive order: NATURE, FOOD, PEOPLE and EVES. Each block was followed by a fixation block of the same length. This experimental paradigm was successfully used to lead EVES in previous work21 for which the data of the male subjects in this study had been used previously. After the fMRI, to evaluate the emotional response to EVES, the subjects were asked to evaluate the subjective intensity of sexual arousal, disgust and interest in the erotic pictures provided during the fMRI scan using an eight-point Likert scale (1–8, with 8 indicating highest intensity of feeling). The questions and the method of how the survey was administrated to the subjects are described in Supplementary Text S2.
Data acquisition and preprocessing A total of 255 blood oxygen level dependent-based functional MRI images were acquired on a 3.0 T whole-body MRI Echospeed system (ISOL, Daejeon, Korea) using T2*–weighted gradient echo, echo-planar imaging pulse sequence (repetition time (TR) = 2400 ms, echo time (TE) = 35 ms, flip angle = 70°, field of view (FOV) = 192 × 220 mm, slice thickness = 5 mm, inter-slice gap = 2 mm, acquisition matrix = 64 × 64). The data were preprocessed with the FMRI Expert Analysis Tool (FEAT) of the FMRIB Software Library (FSL),22 and Analysis of Functional Neuroimages (AFNI) software was also used for de-spiking the images.23 After de-spiking, motion correction was performed using the linear interpolation method (MCFLIRT). Skull stripping of functional images was conducted by a brain extraction tool in the FSL. Spatial smoothing using a 6 mm full-width/half-maximum Gaussian Kernel was applied to the images. The images were filtered with a high pass filter (cutoff frequency 0.01 Hz) to remove low-frequency drift and with a low pass filter (cutoff frequency 0.1 Hz) to reduce highfrequency noises. Spatial registration of images was conducted to register images from the echo-planar imaging sequence into standard Montreal Neurological Institute (MNI) space with 12 degrees of freedom using FMRIB’s Linear Image Registration Tool (FLIRT).
Functional region of interest (ROI) selection using a group activation map 22
Data analyses for post-processing were performed with the FEAT. A general linear model was applied to a single subject level analysis. Images of each subject were analyzed using contrasts to evaluate differences in the effects of functional activations in the brain by two different International Journal of Impotence Research (2015), 1 – 6
conditions, EVES vs PEOPLE. A block-shaped matrix was designed using a three-column format of the general linear model in the FEAT. A temporal derivative was used to convolve the canonical hemodynamic response function. Pre-whitening was conducted to solve an autocorrelation problem before estimation. To select EVES-specific functional NA ROI, the group mean activation map in EVES vs PEOPLE was assessed. A one sample and unpaired t-test using the mixed effects model (FLAME 1) was performed using the Z-static image of each subject, and age was included as a covariate to control the age effects of erotic stimuli.21 Age was also controlled in other group comparison analyses and correlation analyses described below. Gaussian random field theory was used to correct for multiple comparisons at the cluster level. The voxels within the cluster were Z42.3. The threshold for statistical significance was a corrected cluster threshold Po 0.05. This cluster level threshold was applied to all the other analyses in our study. Using a group mean activation map of each sex, the NA ROI was defined when it satisfied two criteria: (1) the voxels with 25% or greater probability of being labeled as the NA from the probability maps of the HarvardOxford Subcortical Structural Atlas were selected, and (2) within these voxels, both sexes showed an activation in EVES vs PEOPLE contrast (Figure 1c).
Group comparisons of the context-based interaction map Context-based functional connectivity patterns were evaluated by PPI analysis using the FSL software.22 PPI analysis measures the interaction between the psychological context (the task) and the physiological input (the time course of a ROI) to assess the functional connectivity for a given task.18 The selected NA ROI in standard-space was transformed to fMRIspace using a FLIRT, and the time-series of each ROI was extracted by the ‘fslmeants’ command in the FSL. The PPI regressor was obtained by multiplying the demeaned time-series of the ROIs with a zero-centered task variable of the convolved three-column format. Then, the general linear model was applied to find functionally related regions from the ROI of single subjects. Each subject’s context-based functional connectivity maps from NA ROI were obtained under two different contrasts, EVES and PEOPLE. Using individual PPI maps, the functional connectivity patterns of men were compared with those of women. Functional connectivity can be affected by two independent variables, sex and condition. Thus, a two-way analysis of variance, which has been commonly used for analyzing a 2 × 2 factorial design, was used to measure the effects of interactions between sex (men vs women) and condition (EVES vs PEOPLE), on functional connectivity from the NA. In addition, within brain regions that showed statistically significant interaction in the two-way analysis of variance, we extracted the mean of parameter estimates using the 10 mm sphere around the peak coordinate of each brain region to measure sex-based interaction patterns by conditions.
Correlation analysis between PPI results and the testosterone level before exposure to EVES The plasma concentration of testosterone was evaluated 30 min before an fMRI session to verify the hormonal effects on the EVES-related brain network, and 12 male subjects finished the test. The chemiluminescence immunoassay was used to measure the testosterone concentration. Correlations between plasma concentrations of testosterone and parameter estimates in individual PPI maps of the NA were estimated during EVES to infer the hormonal effects on the brain network. All correlation analyses were conducted using simple linear regression analysis with the FEAT.
Correlation analysis between the PPI results and a subject’s feeling score Using simple linear regression analysis with the FEAT, the relationships between the feeling score of a subject and degrees of functional connectivity were evaluated.
RESULTS Functional ROI selection using a group activation map (EVES vs PEOPLE) Both male and female subjects showed numerous activated brain regions when they received sexual stimuli, including the bilateral © 2015 Macmillan Publishers Limited
Sex effects on erotic stimuli processing SW Lee et al
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Figure 1. Brain activity patterns stimulated by explicit visual erotic stimuli (EVES) and functional region of interest (ROI) selection. The figure shows the activity patterns of men (a) and women (b). Both genders had similar regional activations (c). The region with brain activity within 25% of the probability map of the Harvard-Oxford Subcortical Structural Atlas represent the right nucleus accumbens (NA): male (blue) and female (red). Purple represents the areas that overlap between men and women, and these regions were used as the ROI in the psychophysiological interaction (PPI) analysis. Signals present in the external MNI space were excluded in this figure. The numbers on each image indicate the z-coordinates in the space. MNI, Montreal Neurological Institute. *Po0.05.
LOC, anterior cingulate cortex, right orbitofrontal cortex, bilateral thalamus and right NA (Figures 1a and b). The right NA was selected for the ROI PPI analysis (Figure 1c). No sex differences were found in the activated regions.
Sex differences in context-based functional connectivity from the right NA to the whole brain As a result of two-way analysis of variance, the interaction effects between sex and condition determined the functional connectivity from the right NA to several brain regions. The functional connectivity from the right NA in men was greater in the right LOC during EVES than in women (Figure 2). © 2015 Macmillan Publishers Limited
Relationship between PPI results and the testosterone level before exposure to EVES Twelve male subjects were measured for plasma concentration of testosterone. The mean testosterone level was 426.8 ± 144.3 ng dl–1 (normal range is 241–827). The testosterone level was positively correlated with the activity of the right NA–right LOC network (Figure 3). Relationship between PPI results and feeling scores of subjects Twenty-three subjects (13 males and 10 females) completed the survey regarding their subjective feelings after the experiment. Group differences in the scores of the survey were analyzed using an unpaired t-test. The scores of subjective sexual arousal were International Journal of Impotence Research (2015), 1 – 6
Sex effects on erotic stimuli processing SW Lee et al
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Figure 2. Psychophysiological interaction (PPI) results from the right nucleus accumbens (NA). Sex-based stimulation interaction maps, during explicit visual erotic stimuli (EVES), from the right NA (a). The sex difference in the right NA–right lateral occipital cortex (LOC) network activity was evaluated by mean parameter estimates in each region of interest (ROI) using a 10 mm mask (MNI coordinates of center of ROI: 32/-84/32). Durning EVES, the right NA-right LOC connectivits was greater in men than in women (P o0.05) (b) Signals present in the external MNI space were excluded from this figure. MNI, Montreal Neurological Institute.
Figure 3. The relationship between psychophysiological interaction (PPI) results during the explicit visual erotic stimuli (EVES) and individual testosterone level. Regions associated with plasma concentration levels of testosterone (a). The degree of functional connectivity between the right nucleus accumbens (NA) and right lateral occipital cortex (LOC) showed a significant correlation with baseline testosterone (b). The parameter estimates of the right NA–right LOC network was measured at MNI coordinates x = 52, y = − 70 and z = 28 (one of the peak voxels in the cluster within orange circle). MNI, Montreal Neurological Institute.
higher in men than in women (mean of men 5.1 ± 2.0; mean of women 2.8 ± 2.3; T = 2.55, P = 0.016). However, there were no significant differences between the sexes for subjective disgust (mean of men 2.8 ± 1.6; mean of women 4.1 ± 2.8; T = − 1.36; P = 0.188) and interest (mean of men = 5.3 ± 2.1, mean of women = 3.5 ± 2.2, T = 2.04, P = 0.054). In men, the right NA–right LOC network during EVES had a statistically significant negative correlation to feelings of disgust (Supplementary Figure S1). DISCUSSION In our study, the EVES we provided induced moderate, but not intense, sexual arousal in men (mean sexual arousal score: 5.1 out of 8), and the arousal level of men was higher than that of women. International Journal of Impotence Research (2015), 1 – 6
Koukounas et al.24 demonstrated that men felt more positive emotion and had greater physiological and subjective sexual arousal in response to visual erotic stimuli. This was mirrored in the survey that was administered to the subjects after the fMRI scan. In contrast to sexual arousal level, both sexes showed similar brain regions activated by EVES; no sex differences in the activated regions were found in our study. These results may have been influenced by the moderate intensity of the erotic stimuli we provided. In our study, EVES pictures were selected from IAPS, and these stimuli can be less sexually stimulating than pornographic video clips or tactile simulations. Previous studies using sexual pictures as stimuli also reported no significant differences between the sexes in brain activation.25,26 To explain this discordance between subjective arousal and brain activity, functional connectivity from the NA, which is closely © 2015 Macmillan Publishers Limited
Sex effects on erotic stimuli processing SW Lee et al
related to human sexual response including sexual arousal11 and sexual desire,17 was evaluated. The right NA that was used in our study was activated both in men and women during EVES processing and reflected the anatomical region well. In the PPI analysis, the responses of the functional network involving the LOC and the right NA during EVES was greater for men than for women. This result may suggest that the visual reward functional network has an important role in processing EVES in men. In the previous studies, LOC activity was reported to be associated with visual stimuli that induced sexual arousal.26 It is still unclear how EVES induces activation in the LOC; however, there is a possible basis for understanding the relationship between LOC activation and sexual responses in men. The LOC has an important role in object recognition, especially regarding information about the shapes of objects.27,28 Men tend to perceive the bodies of women not as a whole but only by the sexual parts according to objectification theory.29 For men, such objectification of the actors is important in order to achieve sexual arousal by watching erotic movies.30 Therefore, recognizing attractive women for objectification in erotic pictures may place a heavy load on the LOC, thus making LOC in need for positive modulation from other brain regions, like the NA. In addition, the right-side visual cortex activation can be related to interpreting pleasant stimuli,31 and the fact that ratings of disgust were negatively correlated with activity of the right NA–right LOC network is parallel to this hypothesis. Although direct anatomical connections between the NA and visual processing areas were not clearly demonstrated,32 there were several clues that proved functional connections between reward responses and visual area activation. The primary visual cortex of adult rats can detect subsequent rewards,33 and Serences et al.34 demonstrated value-related modulations on the visual areas in human. Recently, a MEG study reported that reward enhanced the activity of the visual system, including the LOC during visual category processing.35 Therefore, reward may have tuning effects on sensory processing, concepts of the reward system have been extended to integrate the sensory system.36 Furthermore, the NA and visual cortex network was highly activated when subjects were exposed to anything visually attractive other than EVES. Attractive faces generate high activation in the NA,37 as well as the LOC.38 Binge-eating symptoms have a correlation with the NA and visual cortex connectivity when obese subjects were given high calorie food cues.39 Compared with pictures of small cars, those of sports cars induce more activation of the NA and LOC.40 Therefore, the visual reward processing network may take part in allowing the eye to catch on to visually attractive things. Moreover, the activity of the right NA–right LOC network was positively correlated with the baseline testosterone level in men. In the previous study, injecting testosterone into the NA induced a reward response in rats.41 The visual cortex has many testosterone receptors, and sex differences in visual perceptual processing have been reported.42 Our results may suggest that testosterone has an effect on processing EVES by modulating the visual reward processing network, thus the level of testosterone in individuals can create differences in sexual responses to EVES with a moderate intensity. These modulatory effects of testosterone need to be confirmed with further studies using large samples with a wide testosterone range. In addition, it is important to note that steroid hormones including testosterone has dichomatized effects: activating and organizing effects.43 In our results, response patterns to EVES in the visual reward network showed differences between males and females. These sex differences in response patterns of EVES may be programmed during sensitive periods of growth and development, such as prenatal/perinatal period44,45 and adolescence46,47 by organizing effects of steroid hormones. However, on the contrary, baseline testosterone levels of males showed a positive correlation with the activity of the right © 2015 Macmillan Publishers Limited
5 NA–right LOC network. This means that the enhancement of the right NA–right LOC network can be modified using the levels of sex hormones. This result can imply the activating effects of steroid hormones (for example, testosterone). We believe longitudinal study with participants in critical periods of brain development (for example, adolescence) can be valuable to clarify the interaction between organizing and activating effects of steroid hormones in processing EVES stimuli. There are several limitations in our study. First of all, the right NA–right LOC network did not show any correlations with the ratings of the sexual arousal of the subjects. This may reduce the explanatory power of our results. One possible explanation is that the lack of correlation may be induced by a ceiling effect. In our study, men showed a generally moderate mean and low variance of sexual arousal scores; thus limiting the variability of the data may reduce the statistical power of the results. Second, regarding the contrast between EVES and PEOPLE, several confounding factors may have existed, such as using a stimulus type (for example, visual vs audiovisual or tactile, or naked vs dressed), inter-stimulus variation in evoked intensity or sex differences in preference to stimulus. Cultural difference may be considered as a confounding factor because only Korean subjects were included in the study. Further studies are needed to explore sex differences in brain network connectivity using various intensities of sexual stimuli, such as video clips and using stimuli of a detailed story for female arousal.48 Future studies should also incorporate various subjects from diverse ethnic backgrounds. Third, in our experimental paradigm, PEOPLE stimuli were followed by EVES stimuli because we considered the effects of EVES stimuli on subsequent stimuli to be more problematic than order effects. However, brain activity can be influenced by stimulation order through habituation or anticipation effects. Fourth, menstrual cycles and sexual hormones in women, including estrogen, progesterone and testosterone, can affect brain activity related to erotic stimuli.49,50 In spite of these limitations, this study has important clinical implications. Our results suggest that the increased interaction in visual reward networks, rather than the activation of a specific brain region, is the reason why men are sensitive to EVES with moderate intensity, and is modulated by testosterone level. These results can provide a possible explanation for normal sexual behavior and an opportunity to comprehend pathological sexual behaviors more accurately. CONFLICT OF INTEREST The authors declare no conflict of interest.
ACKNOWLEDGMENTS This work was supported by grants (NRF-2012R1A1A2001 and NRF-2006-2005372 to B Jeong) from National Research Foundation and in part by the KAIST Future Systems Healthcare Project from the Ministry of Science, ICT and Future Planning (N01130009, N01130010, G04110085 to B Jeong).
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Supplementary Information accompanies the paper on International Journal of Impotence Research website (http://www.nature.com/ijir)
International Journal of Impotence Research (2015), 1 – 6
© 2015 Macmillan Publishers Limited
ORIGINAL ARTICLE
Sex differences in interactions between nucleus accumbens and visual cortex by explicit visual erotic stimuli: an fMRI study SW Lee1, BS Jeong1, J Choi2 and J-W Kim3 Men tend to have greater positive responses than women to explicit visual erotic stimuli (EVES). However, it remains unclear, which brain network makes men more sensitive to EVES and which factors contribute to the brain network activity. In this study, we aimed to assess the effect of sex difference on brain connectivity patterns by EVES. We also investigated the association of testosterone with brain connection that showed the effects of sex difference. During functional magnetic resonance imaging scans, 14 males and 14 females were asked to see alternating blocks of pictures that were either erotic or non-erotic. Psychophysiological interaction analysis was performed to investigate the functional connectivity of the nucleus accumbens (NA) as it related to EVES. Men showed significantly greater EVES-specific functional connection between the right NA and the right lateral occipital cortex (LOC). In addition, the right NA and the right LOC network activity was positively correlated with the plasma testosterone level in men. Our results suggest that the reason men are sensitive to EVES is the increased interaction in the visual reward networks, which is modulated by their plasma testosterone level. International Journal of Impotence Research advance online publication, 14 May 2015; doi:10.1038/ijir.2015.8 INTRODUCTION Sex is related to differences in the brain. Sex differences are found in brain structure,1 development2 and functional connectivity.3 It is a phenomenological representation of the brain that these differences can determine behavior.4,5 Among the various behaviors, sexual behavior and the differences between the sexes are among those that are interesting, and many studies have been conducted to understand the biological mechanisms of sexual behavior. Animal studies have revealed that specific brain regions are related to appetitive behavior and to gonadal hormone effects on sexual behavior.6 For example, the nucleus accumbens (NA), which receives dopamine signals from the ventral tegmental area, is important to appetitive behaviors. In male rats, ventral tegmental area stimulation enhances mating behaviors, and sexual behavior induces dopamine release in the NA.7,8 Furthermore, NA/ventral tegmental area activity is enhanced or modulated by gonadal hormones.9,10 In addition, some human functional neuroimaging studies have been conducted to find sex differences in brain activity related to visual sexual stimuli. The ventral striatal region, which includes the NA and is involved in the conditioning of sexual arousal, showed hyperactivity in men.11 The amygdala and hypothalamus, which has a high correlation with sexual arousal, was more activated in men than in women by visual erotic stimuli.12 Differences in the visual processing regions, including lateral occipital cortex (LOC), were also reported.13 In addition, studies showed that the level of sex hormones affect the activities of several brain regions, including the amygdala,14 thalamus and cingulate gyrus,15 in men who were given visual erotic stimuli. To summarize, previous animal and human neuroimaging studies suggested that sex differences in sexual responses are caused by
interactions of various brain regions. In particular, the reward network from the NA, and the visual and emotional network involving the amygdala and LOC were commonly reported and could be key brain network responsible for sex differences in response to erotic stimuli. In addition, modulatory effects of sex hormones, such as testosterone, could also have major roles in determining sexual responses. Although much research has been conducted and has revealed sex differences in brain networks, it remains unclear how the activity and modulation of these brain networks may be connected with sex-based differences in response to explicit visual erotic stimuli (EVES). Therefore, in our study, we searched for a clue to connect the activities of brain networks with sexual response to EVES using context-specific, functional connectivity analysis. The NA, the pivotal center for regulating motivation and reward,16,17 was chosen as the seed region. The brain networks from the seed region that is specifically activated during EVES were verified using psychophysiological interaction (PPI) analysis.18 This study had three goals: (1) delineate the visual reward networks active during EVES, (2) explain the sex differences in emotional response to EVES according to the connectivity patterns of the networks, and (3) explore the modulatory effect of plasma testosterone on these brain networks. Our study provides background necessary for understanding the sex differences in response to EVES regarding brain networks, and may give clues for the understanding of pathological sexual behaviors. MATERIALS AND METHODS Subjects Twenty-eight subjects participated in the study, 14 males (mean age 28.8 ± 7.1 years; range 22–47) and 14 females (mean age 29.1 ± 8.9 years;
1 Korea Advanced Institute of Science and Technology (KAIST), Laboratory of Clinical Neuroscience and Development, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea; 2Department of Psychiatry, Daejeon St Mary's Hospital, The Catholic University of Korea, College of Medicine, Daejeon, Republic of Korea and 3 Department of Psychiatry, College of Medical Science, Kongyang University, Daejeon, Republic of Korea. Correspondence: Professor BS Jeong, Laboratory of Clinical Neuroscience and Development, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Yuseong-gu, Daejeon 305-701, Republic of Korea. E-mail: [email protected] Received 8 May 2014; revised 8 January 2015; accepted 18 April 2015
Sex effects on erotic stimuli processing SW Lee et al
2 range 18–49). Seven subjects (3 males and 4 females) were in a marital relationship, while the others were single. There were no significant differences between the two sex groups both in age (T = − 0.10, P = 0.924) and in marital status (χ2 = 0.19, P = 0.663). All subjects voluntarily participated for this study and provided written informed consent before enrolling in the study. Two psychiatrists interviewed all subjects using Diagnostic and Statistical Mental Disorder, Fourth Edition (DSM-IV) criteria to exclude any patients with psychiatric disorders in axis-I. Subjects were requested to abstain from any sexual activities, including masturbation, for 1 day before undergoing the functional magnetic resonance imaging (fMRI) procedures. This study was approved by the Institutional Review Board of Eulji University Hospital.
Experimental design During the fMRI sessions, subjects were asked to passively view alternating 24-s blocks of pictures that represented four different conditions. The conditions consisted of three blocks, and each block had four different pictures, which changed every 6 s. Pictures of naked couples in erotic poses of sexual activity were presented as EVES, and pictures of people with no overt sexual context (PEOPLE) were used to induce positive emotions related to interaction between people (for example, a couple with happy faces staring at each other). Pictures of NATURE (trees, stone, flowers and shrubs) and FOOD (ice cream, oriental noodles, chocolate and spaghetti) were included to confirm whether other non-erotic stimuli related to reward may show sex differences (Supplementary Text S1). Most of the pictures, including all those of erotic stimulation and of nature, were selected from the International Affective Picture System (IAPS),19 whereas some pictures of non-erotic stimuli and food were produced for this study. Pictures were matched for standard values of arousal, pleasantness and dominance as provided by the IAPS and for sexual intensity as described before.20 In this study, three consecutive blocks of the same condition were applied because the erotic block could affect responses to its following blocks. For example, if a PEOPLE block came after an EVES block, subjects may recall the erotic pictures, while they see the people pictures. Therefore, the stimuli blocks were presented in this consecutive order: NATURE, FOOD, PEOPLE and EVES. Each block was followed by a fixation block of the same length. This experimental paradigm was successfully used to lead EVES in previous work21 for which the data of the male subjects in this study had been used previously. After the fMRI, to evaluate the emotional response to EVES, the subjects were asked to evaluate the subjective intensity of sexual arousal, disgust and interest in the erotic pictures provided during the fMRI scan using an eight-point Likert scale (1–8, with 8 indicating highest intensity of feeling). The questions and the method of how the survey was administrated to the subjects are described in Supplementary Text S2.
Data acquisition and preprocessing A total of 255 blood oxygen level dependent-based functional MRI images were acquired on a 3.0 T whole-body MRI Echospeed system (ISOL, Daejeon, Korea) using T2*–weighted gradient echo, echo-planar imaging pulse sequence (repetition time (TR) = 2400 ms, echo time (TE) = 35 ms, flip angle = 70°, field of view (FOV) = 192 × 220 mm, slice thickness = 5 mm, inter-slice gap = 2 mm, acquisition matrix = 64 × 64). The data were preprocessed with the FMRI Expert Analysis Tool (FEAT) of the FMRIB Software Library (FSL),22 and Analysis of Functional Neuroimages (AFNI) software was also used for de-spiking the images.23 After de-spiking, motion correction was performed using the linear interpolation method (MCFLIRT). Skull stripping of functional images was conducted by a brain extraction tool in the FSL. Spatial smoothing using a 6 mm full-width/half-maximum Gaussian Kernel was applied to the images. The images were filtered with a high pass filter (cutoff frequency 0.01 Hz) to remove low-frequency drift and with a low pass filter (cutoff frequency 0.1 Hz) to reduce highfrequency noises. Spatial registration of images was conducted to register images from the echo-planar imaging sequence into standard Montreal Neurological Institute (MNI) space with 12 degrees of freedom using FMRIB’s Linear Image Registration Tool (FLIRT).
Functional region of interest (ROI) selection using a group activation map 22
Data analyses for post-processing were performed with the FEAT. A general linear model was applied to a single subject level analysis. Images of each subject were analyzed using contrasts to evaluate differences in the effects of functional activations in the brain by two different International Journal of Impotence Research (2015), 1 – 6
conditions, EVES vs PEOPLE. A block-shaped matrix was designed using a three-column format of the general linear model in the FEAT. A temporal derivative was used to convolve the canonical hemodynamic response function. Pre-whitening was conducted to solve an autocorrelation problem before estimation. To select EVES-specific functional NA ROI, the group mean activation map in EVES vs PEOPLE was assessed. A one sample and unpaired t-test using the mixed effects model (FLAME 1) was performed using the Z-static image of each subject, and age was included as a covariate to control the age effects of erotic stimuli.21 Age was also controlled in other group comparison analyses and correlation analyses described below. Gaussian random field theory was used to correct for multiple comparisons at the cluster level. The voxels within the cluster were Z42.3. The threshold for statistical significance was a corrected cluster threshold Po 0.05. This cluster level threshold was applied to all the other analyses in our study. Using a group mean activation map of each sex, the NA ROI was defined when it satisfied two criteria: (1) the voxels with 25% or greater probability of being labeled as the NA from the probability maps of the HarvardOxford Subcortical Structural Atlas were selected, and (2) within these voxels, both sexes showed an activation in EVES vs PEOPLE contrast (Figure 1c).
Group comparisons of the context-based interaction map Context-based functional connectivity patterns were evaluated by PPI analysis using the FSL software.22 PPI analysis measures the interaction between the psychological context (the task) and the physiological input (the time course of a ROI) to assess the functional connectivity for a given task.18 The selected NA ROI in standard-space was transformed to fMRIspace using a FLIRT, and the time-series of each ROI was extracted by the ‘fslmeants’ command in the FSL. The PPI regressor was obtained by multiplying the demeaned time-series of the ROIs with a zero-centered task variable of the convolved three-column format. Then, the general linear model was applied to find functionally related regions from the ROI of single subjects. Each subject’s context-based functional connectivity maps from NA ROI were obtained under two different contrasts, EVES and PEOPLE. Using individual PPI maps, the functional connectivity patterns of men were compared with those of women. Functional connectivity can be affected by two independent variables, sex and condition. Thus, a two-way analysis of variance, which has been commonly used for analyzing a 2 × 2 factorial design, was used to measure the effects of interactions between sex (men vs women) and condition (EVES vs PEOPLE), on functional connectivity from the NA. In addition, within brain regions that showed statistically significant interaction in the two-way analysis of variance, we extracted the mean of parameter estimates using the 10 mm sphere around the peak coordinate of each brain region to measure sex-based interaction patterns by conditions.
Correlation analysis between PPI results and the testosterone level before exposure to EVES The plasma concentration of testosterone was evaluated 30 min before an fMRI session to verify the hormonal effects on the EVES-related brain network, and 12 male subjects finished the test. The chemiluminescence immunoassay was used to measure the testosterone concentration. Correlations between plasma concentrations of testosterone and parameter estimates in individual PPI maps of the NA were estimated during EVES to infer the hormonal effects on the brain network. All correlation analyses were conducted using simple linear regression analysis with the FEAT.
Correlation analysis between the PPI results and a subject’s feeling score Using simple linear regression analysis with the FEAT, the relationships between the feeling score of a subject and degrees of functional connectivity were evaluated.
RESULTS Functional ROI selection using a group activation map (EVES vs PEOPLE) Both male and female subjects showed numerous activated brain regions when they received sexual stimuli, including the bilateral © 2015 Macmillan Publishers Limited
Sex effects on erotic stimuli processing SW Lee et al
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Figure 1. Brain activity patterns stimulated by explicit visual erotic stimuli (EVES) and functional region of interest (ROI) selection. The figure shows the activity patterns of men (a) and women (b). Both genders had similar regional activations (c). The region with brain activity within 25% of the probability map of the Harvard-Oxford Subcortical Structural Atlas represent the right nucleus accumbens (NA): male (blue) and female (red). Purple represents the areas that overlap between men and women, and these regions were used as the ROI in the psychophysiological interaction (PPI) analysis. Signals present in the external MNI space were excluded in this figure. The numbers on each image indicate the z-coordinates in the space. MNI, Montreal Neurological Institute. *Po0.05.
LOC, anterior cingulate cortex, right orbitofrontal cortex, bilateral thalamus and right NA (Figures 1a and b). The right NA was selected for the ROI PPI analysis (Figure 1c). No sex differences were found in the activated regions.
Sex differences in context-based functional connectivity from the right NA to the whole brain As a result of two-way analysis of variance, the interaction effects between sex and condition determined the functional connectivity from the right NA to several brain regions. The functional connectivity from the right NA in men was greater in the right LOC during EVES than in women (Figure 2). © 2015 Macmillan Publishers Limited
Relationship between PPI results and the testosterone level before exposure to EVES Twelve male subjects were measured for plasma concentration of testosterone. The mean testosterone level was 426.8 ± 144.3 ng dl–1 (normal range is 241–827). The testosterone level was positively correlated with the activity of the right NA–right LOC network (Figure 3). Relationship between PPI results and feeling scores of subjects Twenty-three subjects (13 males and 10 females) completed the survey regarding their subjective feelings after the experiment. Group differences in the scores of the survey were analyzed using an unpaired t-test. The scores of subjective sexual arousal were International Journal of Impotence Research (2015), 1 – 6
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Figure 2. Psychophysiological interaction (PPI) results from the right nucleus accumbens (NA). Sex-based stimulation interaction maps, during explicit visual erotic stimuli (EVES), from the right NA (a). The sex difference in the right NA–right lateral occipital cortex (LOC) network activity was evaluated by mean parameter estimates in each region of interest (ROI) using a 10 mm mask (MNI coordinates of center of ROI: 32/-84/32). Durning EVES, the right NA-right LOC connectivits was greater in men than in women (P o0.05) (b) Signals present in the external MNI space were excluded from this figure. MNI, Montreal Neurological Institute.
Figure 3. The relationship between psychophysiological interaction (PPI) results during the explicit visual erotic stimuli (EVES) and individual testosterone level. Regions associated with plasma concentration levels of testosterone (a). The degree of functional connectivity between the right nucleus accumbens (NA) and right lateral occipital cortex (LOC) showed a significant correlation with baseline testosterone (b). The parameter estimates of the right NA–right LOC network was measured at MNI coordinates x = 52, y = − 70 and z = 28 (one of the peak voxels in the cluster within orange circle). MNI, Montreal Neurological Institute.
higher in men than in women (mean of men 5.1 ± 2.0; mean of women 2.8 ± 2.3; T = 2.55, P = 0.016). However, there were no significant differences between the sexes for subjective disgust (mean of men 2.8 ± 1.6; mean of women 4.1 ± 2.8; T = − 1.36; P = 0.188) and interest (mean of men = 5.3 ± 2.1, mean of women = 3.5 ± 2.2, T = 2.04, P = 0.054). In men, the right NA–right LOC network during EVES had a statistically significant negative correlation to feelings of disgust (Supplementary Figure S1). DISCUSSION In our study, the EVES we provided induced moderate, but not intense, sexual arousal in men (mean sexual arousal score: 5.1 out of 8), and the arousal level of men was higher than that of women. International Journal of Impotence Research (2015), 1 – 6
Koukounas et al.24 demonstrated that men felt more positive emotion and had greater physiological and subjective sexual arousal in response to visual erotic stimuli. This was mirrored in the survey that was administered to the subjects after the fMRI scan. In contrast to sexual arousal level, both sexes showed similar brain regions activated by EVES; no sex differences in the activated regions were found in our study. These results may have been influenced by the moderate intensity of the erotic stimuli we provided. In our study, EVES pictures were selected from IAPS, and these stimuli can be less sexually stimulating than pornographic video clips or tactile simulations. Previous studies using sexual pictures as stimuli also reported no significant differences between the sexes in brain activation.25,26 To explain this discordance between subjective arousal and brain activity, functional connectivity from the NA, which is closely © 2015 Macmillan Publishers Limited
Sex effects on erotic stimuli processing SW Lee et al
related to human sexual response including sexual arousal11 and sexual desire,17 was evaluated. The right NA that was used in our study was activated both in men and women during EVES processing and reflected the anatomical region well. In the PPI analysis, the responses of the functional network involving the LOC and the right NA during EVES was greater for men than for women. This result may suggest that the visual reward functional network has an important role in processing EVES in men. In the previous studies, LOC activity was reported to be associated with visual stimuli that induced sexual arousal.26 It is still unclear how EVES induces activation in the LOC; however, there is a possible basis for understanding the relationship between LOC activation and sexual responses in men. The LOC has an important role in object recognition, especially regarding information about the shapes of objects.27,28 Men tend to perceive the bodies of women not as a whole but only by the sexual parts according to objectification theory.29 For men, such objectification of the actors is important in order to achieve sexual arousal by watching erotic movies.30 Therefore, recognizing attractive women for objectification in erotic pictures may place a heavy load on the LOC, thus making LOC in need for positive modulation from other brain regions, like the NA. In addition, the right-side visual cortex activation can be related to interpreting pleasant stimuli,31 and the fact that ratings of disgust were negatively correlated with activity of the right NA–right LOC network is parallel to this hypothesis. Although direct anatomical connections between the NA and visual processing areas were not clearly demonstrated,32 there were several clues that proved functional connections between reward responses and visual area activation. The primary visual cortex of adult rats can detect subsequent rewards,33 and Serences et al.34 demonstrated value-related modulations on the visual areas in human. Recently, a MEG study reported that reward enhanced the activity of the visual system, including the LOC during visual category processing.35 Therefore, reward may have tuning effects on sensory processing, concepts of the reward system have been extended to integrate the sensory system.36 Furthermore, the NA and visual cortex network was highly activated when subjects were exposed to anything visually attractive other than EVES. Attractive faces generate high activation in the NA,37 as well as the LOC.38 Binge-eating symptoms have a correlation with the NA and visual cortex connectivity when obese subjects were given high calorie food cues.39 Compared with pictures of small cars, those of sports cars induce more activation of the NA and LOC.40 Therefore, the visual reward processing network may take part in allowing the eye to catch on to visually attractive things. Moreover, the activity of the right NA–right LOC network was positively correlated with the baseline testosterone level in men. In the previous study, injecting testosterone into the NA induced a reward response in rats.41 The visual cortex has many testosterone receptors, and sex differences in visual perceptual processing have been reported.42 Our results may suggest that testosterone has an effect on processing EVES by modulating the visual reward processing network, thus the level of testosterone in individuals can create differences in sexual responses to EVES with a moderate intensity. These modulatory effects of testosterone need to be confirmed with further studies using large samples with a wide testosterone range. In addition, it is important to note that steroid hormones including testosterone has dichomatized effects: activating and organizing effects.43 In our results, response patterns to EVES in the visual reward network showed differences between males and females. These sex differences in response patterns of EVES may be programmed during sensitive periods of growth and development, such as prenatal/perinatal period44,45 and adolescence46,47 by organizing effects of steroid hormones. However, on the contrary, baseline testosterone levels of males showed a positive correlation with the activity of the right © 2015 Macmillan Publishers Limited
5 NA–right LOC network. This means that the enhancement of the right NA–right LOC network can be modified using the levels of sex hormones. This result can imply the activating effects of steroid hormones (for example, testosterone). We believe longitudinal study with participants in critical periods of brain development (for example, adolescence) can be valuable to clarify the interaction between organizing and activating effects of steroid hormones in processing EVES stimuli. There are several limitations in our study. First of all, the right NA–right LOC network did not show any correlations with the ratings of the sexual arousal of the subjects. This may reduce the explanatory power of our results. One possible explanation is that the lack of correlation may be induced by a ceiling effect. In our study, men showed a generally moderate mean and low variance of sexual arousal scores; thus limiting the variability of the data may reduce the statistical power of the results. Second, regarding the contrast between EVES and PEOPLE, several confounding factors may have existed, such as using a stimulus type (for example, visual vs audiovisual or tactile, or naked vs dressed), inter-stimulus variation in evoked intensity or sex differences in preference to stimulus. Cultural difference may be considered as a confounding factor because only Korean subjects were included in the study. Further studies are needed to explore sex differences in brain network connectivity using various intensities of sexual stimuli, such as video clips and using stimuli of a detailed story for female arousal.48 Future studies should also incorporate various subjects from diverse ethnic backgrounds. Third, in our experimental paradigm, PEOPLE stimuli were followed by EVES stimuli because we considered the effects of EVES stimuli on subsequent stimuli to be more problematic than order effects. However, brain activity can be influenced by stimulation order through habituation or anticipation effects. Fourth, menstrual cycles and sexual hormones in women, including estrogen, progesterone and testosterone, can affect brain activity related to erotic stimuli.49,50 In spite of these limitations, this study has important clinical implications. Our results suggest that the increased interaction in visual reward networks, rather than the activation of a specific brain region, is the reason why men are sensitive to EVES with moderate intensity, and is modulated by testosterone level. These results can provide a possible explanation for normal sexual behavior and an opportunity to comprehend pathological sexual behaviors more accurately. CONFLICT OF INTEREST The authors declare no conflict of interest.
ACKNOWLEDGMENTS This work was supported by grants (NRF-2012R1A1A2001 and NRF-2006-2005372 to B Jeong) from National Research Foundation and in part by the KAIST Future Systems Healthcare Project from the Ministry of Science, ICT and Future Planning (N01130009, N01130010, G04110085 to B Jeong).
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Supplementary Information accompanies the paper on International Journal of Impotence Research website (http://www.nature.com/ijir)
International Journal of Impotence Research (2015), 1 – 6
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