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Abnormal white matter integrity in rapists as indicated by diffusion tensor imaging

Abnormal white matter integrity in rapists as indicated by diffusion tensor imaging Background: Recent research has documented structural brain abnormalities in various criminal offenders. However, there have been few brain imaging studies of sex offenders, and none on white matter integrity. The current study tested the hypothesis that rapists, when compared to matched controls, would show abnormal cortical and subcorti‑ cal white matter integrity. Results: Rapists showed significantly increased fractional anisotropy in the internal capsule in the thalamus, caudate, and globus pallidus, and also in white matter tracts near the angular gyrus, posterior cingulate, frontal pole, lateral occipital cortex, and genu compared to controls matched for age, gender, and educational status. Reduced fractional anisotropy was observed in rapists in the posterior cingulum and in the inferior fronto‑ occipital fasciculus. Conclusions: To our knowledge, this is the first study indicating white matter abnormalities in rapists. Findings indi‑ cate abnormalities in white matter connectivity in brain regions involved in reward/motivation and moral judgment, which may predispose rapists to be both over‑ responsive to sexual reward stimuli and also to make inappropriate moral decisions. Keywords: Rapist, Reward, Moral judgment, Diffusion tensor imaging, White matter Background globus pallidus and striatum, which correspond to In 2011, The National Center for Missing and Exploited key brain areas involved in sexual arousal and behav- Children estimated that there were over 747,000 regis- ior, showed significant activation in pedophiles, but not tered sex offenders in the United States. As the rate of in controls. Research on moral decision-making has sex crimes and number of sexual offenders continue to also documented abnormalities in the neural circuitry grow, much effort has been devoted to understanding involved in moral decision-making in antisocial individu- the nature of these crimes, as well as the characteristics als, specifically, the medial polar prefrontal cortex, the of the offenders. Some have proposed that heterosexual angular gyrus, the amygdala, and the posterior cingulate rapists may be over-responsive to sexual stimuli [1]. Oth- [5, 6]. ers have hypothesized an association between the con- Despite the increased utilization of imaging technology, struct of moral judgment and sexual offenses [e.g., 2, 3]. few studies have examined the integrity of white matter, In recent years, such investigations have benefited from as opposed to functional or structural imaging. Though advances in neuroimaging technologies, which con- several studies have documented reduced fractional ani- tribute to better understanding of the brain areas that sotropy (FA) in association with increased aggression in may be involved with the commission of sexual crimes. schizophrenics [7–9], we are currently not aware of any For example, Schiffer et  al. [ 4] found that the thalamus, study that has investigated FA in sex offenders. The cur - rent study examined white matter integrity in sex offend - ers using diffusion tensor imaging (DTI) to assess FA in *Correspondence: cplin@ym.edu.tw the brains of 15 adult males who had raped one or more Brain Research Center, National Yang‑ Ming University, Taipei 112, Taiwan Full list of author information is available at the end of the article © 2016 The Author(s). This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Chen et al. BMC Neurosci (2016) 17:45 Page 2 of 8 adult females, and 15 matched controls. Based on the DTI scans were acquired using a single-shot spin-echo aforementioned research findings, we hypothesized that echo-planar imaging (EPI) sequence with diffusion sensi - abnormality would be observed in some of the brain tization gradients applied in thirteen non-collinear direc- structures involved in sexual arousal and behavior among tions at a b-value of 900 s/mm . Additional null (b = 0 s/ rapists, including those constituting the basal ganglia. mm ) images were acquired as reference images for signal In addition, we hypothesized that sex offenders would attenuation measurement. The following parameters were also show abnormality in the white matter circuitry con- used: TR = 17,000 ms, TE = 68.9 ms, number of excita- nected with the medial polar prefrontal cortex, the angu- tions (NEX) = 6, number of slices = 70 in the axial orien- lar gyrus, the amygdala, and the posterior cingulate. tation for whole brain coverage, slice thickness = 2.2 mm without slice spacing, FOV = 260 × 260 mm , and matrix Methods size  =  128  ×  128. Total scanning time for each subject Subjects was approximately 32 min. Participants consisted of 15 male sex offenders and 15 controls, matched for age and gender. There were Image processing no differences between the sex offender (mean age DTI preprocessing, including eddy current correction 33.1 ± 6.5 years) and control (mean age 33.0 ± 6.8 years) and brain tissue extraction using the Brain Extraction groups in age (t (14) = 0.04, p = 0.968). Tool (BET v2.1) [10], was performed with FSL v4.1.7 Sex offenders were recruited from Taipei Prison in Tai - (Functional Magnetic Resonance Imaging of the Brain wan. In an effort to delineate a relatively homogenous Software Library; http://www.fmrib.ox.au.uk/fsl). The group of sex offenders, offenders had to be male adults eddy current correction involved registering the diffu - who had raped an adult female stranger. They were serv - sion-weighted images to the null image through affine ing sentences ranging from 5 to 10  years. Exclusion cri- transformations not only to minimize the image dis- teria for this study were a history of psychiatric illness, tortions due to the eddy currents induced by the fast- neurological illness, prior and current psychiatric treat- switching gradient coils, but also to reduce the simple ment, and commission of rape while under the influence head motion. The Brain Extraction Tool was applied to of alcohol or drugs. The non-offender control subjects remove the non-brain tissue and background noise from were recruited from the Center of Health Examination the images. Voxel-wise calculation of fractional anisot- in Taipei Veterans General Hospital, Taiwan. None of ropy images were derived based on Basser’s model [11] the control participants had any history of psychiatric or using in-house software. neurological illness, previous or current psychiatric treat- ment, or history of drug or alcohol abuse. All participants Statistical analysis provided written informed consent before participating The Tract-Based Spatial Statistics (TBSS) tool in FSL was in the study, which was approved by the Ethics Commit- used to calculate differences in FA values between the sex tee of Taipei Prison, Taiwan and the Institutional Review offender group and controls. TBSS is described in greater Board of National Yang Ming University (ref: 970003). detail elsewhere [12]. In general, the strengths of voxel- based-analyses (VBA) are that they are fully automated, Data acquisition and do not require pre-specifying features or region-of- The magnetic resonance imaging (MRI) scans were interest. However, errors and concerns may be raised due performed on a 1.5 T MR system (Excite II; GE Medi- to alignment inaccuracies and  the lack of a principled cal Systems, Milwaukee, Wis., USA) equipped with an way for choosing a smoothing extent. In Tract-Based 8-channel head coil in Taipei Veterans General Hospi- Spatial Statistics (TBSS), the idea of projection of FA data tal. All subjects underwent the same imaging protocol onto a WM skeleton is to avoid the partial volume effect using T1-weighted (T1  W) and diffusion-tensor imag - (PVE) and gain statistical power since this approach does ing. Images were acquired parallel to the anterior–pos- not require data smoothing. Meanwhile, TBSS keeps the terior commissure line. High resolution T1 W structural features of a fully automated method [13]. images covering the entire brain were acquired using Like all methods, this approach also has some draw- three dimensional fluid-attenuated inversion-recovery, backs that should be recognized when considering analy- fast spoiled gradient recalled echo (FLAIR-FSPGR) sis outcomes. TBSS discards the orientation information sequence with following parameters: repetition time captured in the diffusion data since it only makes use of (TR)  =  8.548  ms, echo time (TE)  =  1.836  ms, inver- FA maps. The extent of anatomical inaccuracies, which sion time (TI)  =  400  ms, flip angle  =  15°, field of is inherent in the FA skeleton projection, can potentially view =  260 ×  260  mm , matrix size =  256 × 256, num- introduce biases in the data outcomes. Additionally, ber of slice = 124 and slice thickness = 1.5 mm. TBSS is known to be purely FA-based and it has been Chen et al. BMC Neurosci (2016) 17:45 Page 3 of 8 previously reported that adjacent WM tracts can be not Mean diffusivity (MD) was also analyzed but did not necessarily separable based only on their FA [14, 15]. show significant differences in sexual offenders compared For the analysis, briefly, a cross-subject mean FA skel - to the control group. eton, which was previously aligned to the MNI-152 template, was created to represent the centers of all Discussion fiber tracts common to the entire group. All other FA As predicted, results from this study revealed that male maps were transformed to the MNI-152 space by con- rapists show abnormalities in white matter integrity. Sig- catenating the FNIRT nonlinear transformation to the nificant FA increases were found in: (a) white matter near representative FA image with the transformation to the the angular gyrus, posterior cingulate, and the medial MNI-152 template. Each subject’s aligned FA map was frontal pole, and (b) the internal capsule at the level of projected onto the mean FA skeleton by filling the skele - the thalamus, caudate, and globus pallidus. Significantly ton with FA values from the nearest relevant tract center. reduced FA was observed in: (i) the posterior cingulum This ensured that each subject’s skeleton was in the and (ii) the inferior fronto-occipital fasciculus within the group space, yet represented the center of that subject’s middle occipital gyrus. To our knowledge, these con- own unique fiber tracts. The skeletonized FA data were stitute the first DTI findings on any sex offender group. fed into the following voxel-wise cross-subjects statistics These findings may be interpreted within the theoreti - which were based on non-parametric permutation test- cal contexts of abnormalities in moral decision-making, ing (Randomise v2.1, a part of the FSL tool; http://www. sexual over-arousal, reward sensitivity, fear conditioning, fmrib.ox.ac.uk/fsl/randomise/index.html). and distorted social cognition in rapists. Analysis of between-group difference in FA values were Significant group differences were observed in white conducted in a non-parametric analysis of covariance matter near the angular gyrus, the posterior cingulate, design [16] using a cluster-extent threshold to account and the medial frontal pole. Previous studies using func- for the multiple comparison (corrected-p  <  0.05). Age tional imaging have reported these regions to be involved was entered into the analysis as a potential confound to in moral decision-making [18, 19]. These same regions ensure that any observed difference in FA between the have also been found to be dysfunctional in violent and two groups was independent of age-related changes. psychopathic criminals [5]. It has also been argued that Each possible contrast (normal control  >  sex offenders the rule-breaking behavior that is common in antiso- and sex offenders  >  normal controls) was tested with cial, violent, and psychopathic individuals, is in part due 5000 random permutations. Effect sizes were calculated to impairments in these structures that underlie moral using Cohen’s d [17]. The most probable anatomic locali - cognition and emotion [5]. Consequently, abnormal- zation of each cluster was determined by means of the ity in white matter connectivity involving these regions FSL atlas tool (http://www.fmrib.ox.ac.uk/fsl/fslview/ could contribute to the antisocial, rule-breaking behavior atlas-descriptions.html). All reported brain images were found in rapists. While we found increased as opposed to acquired using the “tbss_fill” script from the FSL package. decreased FA in rapists in these regions, it is conceivable that this increase could imply some dysfunction in the Results circuits associated with moral decision-making in this Direct group comparisons group. Deteriorated functions of these cortical regions Compared to the matched controls, sex offenders had could, for example, result in increased white matter con- smaller FA in several clusters. These include the left nectivity, in an effort to compensate for this cortical dys - inferior fronto-occipital fasciculus of the occipital gyrus function [20]. (p < 0.001), the right posterior cingulum of the parahip- As indicated in Table  1, four of the 10 areas showing pocampal gyrus (p < 0.001), and the right superior longi- increased FA in rapists involved the internal capsule at tudinal fasciculus of the supramarginal gyrus (p < 0.001) the level of the thalamus, caudate, and globus pallidus. (see Table 1; Fig. 1). Activation of both the thalamus and caudate has been Some regions showed greater FA in sex offenders com - observed in normal men in response to viewing sexual pared to controls. These include clusters of the left supe - material [21, 22]. Furthermore, at least one functional rior longitudinal fasciculus adjacent to the angular gyrus imaging study has shown that sex offenders registered (p  <  0.001), the right posterior cingulate (p  <  0.003), over-activation of the thalamus, caudate, and globus pal- the forceps minor adjacent to the medial frontal pole lidus during visual sexual stimulation [4]. Consequently, (p  <  0.001), and the right internal capsule at the level of increased FA found in white matter tracts located near the thalamus (p < 0.001), caudate (p < 0.001), and globus the thalamus, caudate, and globus pallidus may contrib- pallidus (p < 0.001) (see Table 1; Fig. 2). ute to over-activation of brain areas related to sexual arousal. This over-activation could contribute to sexual Chen et al. BMC Neurosci (2016) 17:45 Page 4 of 8 Table 1 Brain regions showing significant differences between  rapist and  control subjects, illustrating clusters in  which rapists had reduced and increased white matter fractional anisotropy compared with control subjects Cluster MNI coordi- Anatomical location FA (Mean ± SD) T score p value Cohen’s d size (mm ) nates (mm) x y z White matter tract Brain region Control Oender ff Decreased FA in sex offenders versus controls 18 −35 −82 16 Inferior fronto‑ occipital Lateral occipital lobe, 0.42 ± 0.06 0.32 ± 0.03 5.55 0.0000 2.11 fasciculus Middle occipital gyrus 13 21 −43 0 Posterior cingulum Parahippocampul gyrus 0.59 ± 0.05 0.50 ± 0.04 5.05 0.0001 1.99 10 52 −39 23 Superior longitudinal Inferior parietal lobule, 0.54 ± 0.05 0.45 ± 0.05 4.26 0.0001 1.80 fasciculus or Supramarginal gyrus 10 25 −35 −10 Posterior cingulum Parahippocampul gyrus 0.60 ± 0.07 0.52 ± 0.05 3.39 0.0071 1.32 Increased FA in sex offenders versus controls 29 −16 33 11 Genu 0.55 ± 0.05 0.63 ± 0.06 4.08 0.0001 1.45 17 12 8 1 Internal capsule (anterior Caudate 0.62 ± 0.05 0.71 ± 0.04 4.45 0.0002 1.99 thalamic radiation) 16 −25 −69 26 Lateral occipital lobe 0.48 ± 0.05 0.56 ± 0.05 4.11 0.0002 1.60 (superior division) 16 18 −10 −3 Poterior limb of internal Globus pallidus 0.70 ± 0.05 0.76 ± 0.04 4.16 0.0003 1.33 capsule 14 24 −46 3 Posterior cingulate Posterior cingulate 0.34 ± 0.09 0.46 ± 0.07 3.88 0.0028 1.49 14 −6 51 −18 Forceps minor Medial frontal pole 0.23 ± 0.03 0.32 ± 0.07 4.06 0.0001 1.67 12 −7 −81 29 Forceps major Cunerus 0.24 ± 0.04 0.33 ± 0.06 4.47 0.0002 1.77 11 42 −51 37 Superior longitudinal Supramarginal, or Angu‑ 0.38 ± 0.09 0.51 ± 0.07 4.18 0.0006 1.61 fasciculus lar gyrus 10 −13 0 4 Internal capsule (anterior Caudate 0.63 ± 0.05 0.71 ± 0.06 3.83 0.0025 1.45 thalamic radiation) 10 −11 −5 −10 Posterior limb of internal Lower thalamus 0.69 ± 0.04 0.76 ± 0.05 3.37 0.0013 1.55 capsule Covariate: age Fig. 1 Regions with significantly reduced fractional anisotropy (FA) in rapists versus controls. The group mean FA skeleton (black) was overlaid on the MNI‑152 T1 volume. The regions with significantly lower FA in rapists are highlighted with colored voxels (blue to light blue) corresponding to the t‑scores. Significantly reduced FA was observed in the posterior cingulum (A), the inferior fronto ‑ occipital fasciculus within the middle occipital gyrus (B), and the superior longitudinal fasciculus near the inferior parietal lobule (C) Chen et al. BMC Neurosci (2016) 17:45 Page 5 of 8 Fig. 2 Regions with significantly increased fractional anisotropy (FA) in rapists versus controls. The group mean FA skeleton (black) was superim‑ posed on the MNI‑152 T1 image. The regions in color (red to yellow) represent the areas with significantly higher FA in rapists, including: white mat ‑ ter near the angular gyrus (F), the posterior cingulate (G), the medial frontal pole (I), and the internal capsule at the level of the thalamus (E), caudate (B, C), and globus pallidus (D) over-arousal in offenders, which then acts as a trigger for striatum. Similar to OCD patients, rapists have been actions leading to rape. hypothesized to have obsessive sexual thoughts [27]. In this study, we observed increased FA in rapists in Furthermore, OCD patients have been found to have brain areas involved in the reward system, including increased FA in the internal capsule adjacent to the cau- the caudate, globus pallidus, and thalamus. Enlarge- date, as well as reduced FA in the cingulum [28], a pat- ment of the caudate has been associated with inter- tern also observed in rapists. It is conceivable therefore personal and affective features of psychopathy, as well that abnormal FA in the internal capsule and cingulum as impulsivity and stimulation seeking behavior [23]. could contribute to obsessive thinking on sexual themes, Amongst sex offenders, rapists have been found to be which may lead to a compulsion to rape. more psychopathic than incest and pedophile offend - When compared to controls, rapists also showed ers [24]. Heightened sensitivity to reward in rapists may, reduced FA in a number of white matter tracts in this therefore, contribute to a heightened desire to pursue study. First, they had reduced FA in the posterior cin- sexual rewards, and thus lead to rape in certain social gulum. The posterior cingulum connects the cingulate circumstances. and parahippocampal gyri to the septal cortex. As such, Results from the current study showed that the sex reduced FA may reflect an abnormality in septal func - offender group had increased FA in several regions of the tioning in sex offenders. Positioned alongside the hip - internal capsule, when compared with the control group. pocampus, the parahippocampal gyrus and the septum Previous research on obsessive–compulsive disorder have been thought to play important roles in condi- (OCD) has also indicated structural volumetric abnor- tioning [29]. The reduced FA in the posterior cingulum malities of the internal capsule in patients with OCD shown in this study, that connects these structures, may [25], in addition to increased FA in this same region [26]. suggest impairments in fear conditioning. Fear condi- As a result, deep brain stimulation treatment of OCD has tioning impairments as early as age 3  years have been targeted the area of the internal capsule and the adjacent found to predispose individuals to criminal behavior at Chen et al. BMC Neurosci (2016) 17:45 Page 6 of 8 age 23 [30]. Likewise, poor fear conditioning could pre- Alternatively, replacing the TBSS registration step with a dispose men to rape, because they do not experience tensor-based, group-wise registration, e.g. using DTI-TK, anticipatory fear, and hence are less concerned about the may be an alternative, particularly given that reliability consequences of their illegal behavior. for low-FA structures like the fornix or the external cap- Abnormal posterior cingulum circuitry may result in sule can be quite low [39]. Additionally, a combination reduced activation of the septum and a predisposition of approaches using fMRI (both active and resting) and towards aggressive behavior. The same condition may be VBM may provide information for selection of areas for associated with increased activation of the anterior hypo- specific-tract tractography, and so extend the range of thalamus, and hence increased sexual arousal [31]. Recent the current findings. It is important to remember, how - research has documented abnormality in the septum in ever, that the TBSS analysis employed here required no aggressive and psychopathic individuals, as indicated by assumptions to be made regarding regions that may be cavum septum pellucidum [32], a neurological abnormal- affected, whereas a more specific hypothesis would be ity reflecting abnormal growth of limbic structures that required for tractography analysis. include the septal nuclei, corpus callosum, hippocampus, Despite these limitations, however, this study provides amygdala, and other midline structures [33, 34]. In ani- the first demonstration of abnormalities in the structural mals, the septum is critically involved in the regulation integrity of white matter in the brains of rapists. Inclu- of aggression [35, 36]. Reduced FA in the posterior cin- sion criteria that restricted participants to adult males gulum could therefore result in reduced activation of the perpetrating their offense on a female stranger resulted in septum and a predisposition towards aggressive behavior, a relatively homogenous group in contrast to some other as well as increased activation of the anterior hypothala- neurobiological studies that examined more heterogene- mus and hence increased sexual arousal [31]. ous groups of sex offenders [e.g. 40]. Results from this Finally, we found that rapists, when compared to con- study encourage future research investigating white mat- trols, had decreased FA in the inferior fronto-occipital ter integrity among sexual offenders. fasciculus within the middle occipital gyrus. This fiber tract has been found to be critically involved in the Conclusion semantic processing and conceptualizing of visual stimuli In this study, significant differences in FA between male [37, 38]. Distortions in social cognition have been found rapists and the control group were seen in a number of in rapists, which may serve as a basis and justification areas including white matter near the angular gyrus, for their inappropriate sexual acts. An abnormality in posterior cingulate, the medial frontal pole, the internal the way rapists semantically process visual stimuli of a capsule at the level of the thalamus, caudate, and glo- sexual nature in females (e.g. how they are dressed) could bus pallidus, the posterior cingulum, and the inferior contribute to how they inappropriately mis-attribute the fronto-occipital fasciculus within the middle occipital intentions of the women they meet. gyrus. A subset of these areas (the angular gyrus, pos- Several limitations of the current study should be rec- terior cingulate, and the medial frontal pole) have pre- ognized. First, given the relatively modest sample size, viously been found to be dysfunctional in violent and replications involving larger sample sizes are recom- psychopathic criminals, consistent with the functional mended in order to confirm results from this study. relevance of these areas to criminal behavior. Differ - Second, findings from adult male rapists cannot be gen - ences in the remaining areas may relate to, for example, eralized to other sexual offending groups, including a tendency for sexual over-arousal, heightened sensi- pedophiles and homosexual rapists. Third, while results tivity to reward, obsessive thinking on sexual themes, indicated a number of significant abnormalities in white and poor fear conditioning, all of which may potentially matter integrity in rapists, our study cannot delineate the contribute to the nature of the criminal behavior per- cause of these abnormalities. Fourth, the hypothesis that petrated by these individuals. Future work to investigate increased FA in the internal capsule in rapists may con- potential causes of these differences, as well as contrast - tribute to obsessive sexual thinking must be regarded as ing rapists with different criminal populations, would be preliminary and requiring further substantiation. beneficial. Additionally, like any analytical method, there is poten- tial for improvement in future investigations, based both Abbreviations on the findings from the study here, and refinement FA: fractional anisotropy; DTI: diffusion tensor imaging; MRI: magnetic reso ‑ using data collected employing additional or alternative nance imaging; T1W: T1‑ weighted; FLAIR‑FSPGR: fast spoiled gradient recalled echo; TR: repetition time; TE: echo time; TI: inversion time; EPI: echo‑planar methods. For the TBSS analysis, an approach using reg- imaging; BET: brain extraction tool; FSL: functional magnetic resonance istration to either the FMRIB58 template or to the most imaging of the brain software library; TBSS: tract‑based spatial statistics; OCD: representative subject of the group may be beneficial. obsessive–compulsive disorder. Chen et al. BMC Neurosci (2016) 17:45 Page 7 of 8 Authors’ contributions 10. Smith SM. Fast robust automated brain extraction. 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Abnormal white matter integrity in rapists as indicated by diffusion tensor imaging

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Springer Journals
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Copyright © 2016 by The Author(s)
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Biomedicine; Neurosciences; Neurobiology; Animal Models
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1471-2202
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10.1186/s12868-016-0278-3
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Abstract

Background: Recent research has documented structural brain abnormalities in various criminal offenders. However, there have been few brain imaging studies of sex offenders, and none on white matter integrity. The current study tested the hypothesis that rapists, when compared to matched controls, would show abnormal cortical and subcorti‑ cal white matter integrity. Results: Rapists showed significantly increased fractional anisotropy in the internal capsule in the thalamus, caudate, and globus pallidus, and also in white matter tracts near the angular gyrus, posterior cingulate, frontal pole, lateral occipital cortex, and genu compared to controls matched for age, gender, and educational status. Reduced fractional anisotropy was observed in rapists in the posterior cingulum and in the inferior fronto‑ occipital fasciculus. Conclusions: To our knowledge, this is the first study indicating white matter abnormalities in rapists. Findings indi‑ cate abnormalities in white matter connectivity in brain regions involved in reward/motivation and moral judgment, which may predispose rapists to be both over‑ responsive to sexual reward stimuli and also to make inappropriate moral decisions. Keywords: Rapist, Reward, Moral judgment, Diffusion tensor imaging, White matter Background globus pallidus and striatum, which correspond to In 2011, The National Center for Missing and Exploited key brain areas involved in sexual arousal and behav- Children estimated that there were over 747,000 regis- ior, showed significant activation in pedophiles, but not tered sex offenders in the United States. As the rate of in controls. Research on moral decision-making has sex crimes and number of sexual offenders continue to also documented abnormalities in the neural circuitry grow, much effort has been devoted to understanding involved in moral decision-making in antisocial individu- the nature of these crimes, as well as the characteristics als, specifically, the medial polar prefrontal cortex, the of the offenders. Some have proposed that heterosexual angular gyrus, the amygdala, and the posterior cingulate rapists may be over-responsive to sexual stimuli [1]. Oth- [5, 6]. ers have hypothesized an association between the con- Despite the increased utilization of imaging technology, struct of moral judgment and sexual offenses [e.g., 2, 3]. few studies have examined the integrity of white matter, In recent years, such investigations have benefited from as opposed to functional or structural imaging. Though advances in neuroimaging technologies, which con- several studies have documented reduced fractional ani- tribute to better understanding of the brain areas that sotropy (FA) in association with increased aggression in may be involved with the commission of sexual crimes. schizophrenics [7–9], we are currently not aware of any For example, Schiffer et  al. [ 4] found that the thalamus, study that has investigated FA in sex offenders. The cur - rent study examined white matter integrity in sex offend - ers using diffusion tensor imaging (DTI) to assess FA in *Correspondence: cplin@ym.edu.tw the brains of 15 adult males who had raped one or more Brain Research Center, National Yang‑ Ming University, Taipei 112, Taiwan Full list of author information is available at the end of the article © 2016 The Author(s). This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Chen et al. BMC Neurosci (2016) 17:45 Page 2 of 8 adult females, and 15 matched controls. Based on the DTI scans were acquired using a single-shot spin-echo aforementioned research findings, we hypothesized that echo-planar imaging (EPI) sequence with diffusion sensi - abnormality would be observed in some of the brain tization gradients applied in thirteen non-collinear direc- structures involved in sexual arousal and behavior among tions at a b-value of 900 s/mm . Additional null (b = 0 s/ rapists, including those constituting the basal ganglia. mm ) images were acquired as reference images for signal In addition, we hypothesized that sex offenders would attenuation measurement. The following parameters were also show abnormality in the white matter circuitry con- used: TR = 17,000 ms, TE = 68.9 ms, number of excita- nected with the medial polar prefrontal cortex, the angu- tions (NEX) = 6, number of slices = 70 in the axial orien- lar gyrus, the amygdala, and the posterior cingulate. tation for whole brain coverage, slice thickness = 2.2 mm without slice spacing, FOV = 260 × 260 mm , and matrix Methods size  =  128  ×  128. Total scanning time for each subject Subjects was approximately 32 min. Participants consisted of 15 male sex offenders and 15 controls, matched for age and gender. There were Image processing no differences between the sex offender (mean age DTI preprocessing, including eddy current correction 33.1 ± 6.5 years) and control (mean age 33.0 ± 6.8 years) and brain tissue extraction using the Brain Extraction groups in age (t (14) = 0.04, p = 0.968). Tool (BET v2.1) [10], was performed with FSL v4.1.7 Sex offenders were recruited from Taipei Prison in Tai - (Functional Magnetic Resonance Imaging of the Brain wan. In an effort to delineate a relatively homogenous Software Library; http://www.fmrib.ox.au.uk/fsl). The group of sex offenders, offenders had to be male adults eddy current correction involved registering the diffu - who had raped an adult female stranger. They were serv - sion-weighted images to the null image through affine ing sentences ranging from 5 to 10  years. Exclusion cri- transformations not only to minimize the image dis- teria for this study were a history of psychiatric illness, tortions due to the eddy currents induced by the fast- neurological illness, prior and current psychiatric treat- switching gradient coils, but also to reduce the simple ment, and commission of rape while under the influence head motion. The Brain Extraction Tool was applied to of alcohol or drugs. The non-offender control subjects remove the non-brain tissue and background noise from were recruited from the Center of Health Examination the images. Voxel-wise calculation of fractional anisot- in Taipei Veterans General Hospital, Taiwan. None of ropy images were derived based on Basser’s model [11] the control participants had any history of psychiatric or using in-house software. neurological illness, previous or current psychiatric treat- ment, or history of drug or alcohol abuse. All participants Statistical analysis provided written informed consent before participating The Tract-Based Spatial Statistics (TBSS) tool in FSL was in the study, which was approved by the Ethics Commit- used to calculate differences in FA values between the sex tee of Taipei Prison, Taiwan and the Institutional Review offender group and controls. TBSS is described in greater Board of National Yang Ming University (ref: 970003). detail elsewhere [12]. In general, the strengths of voxel- based-analyses (VBA) are that they are fully automated, Data acquisition and do not require pre-specifying features or region-of- The magnetic resonance imaging (MRI) scans were interest. However, errors and concerns may be raised due performed on a 1.5 T MR system (Excite II; GE Medi- to alignment inaccuracies and  the lack of a principled cal Systems, Milwaukee, Wis., USA) equipped with an way for choosing a smoothing extent. In Tract-Based 8-channel head coil in Taipei Veterans General Hospi- Spatial Statistics (TBSS), the idea of projection of FA data tal. All subjects underwent the same imaging protocol onto a WM skeleton is to avoid the partial volume effect using T1-weighted (T1  W) and diffusion-tensor imag - (PVE) and gain statistical power since this approach does ing. Images were acquired parallel to the anterior–pos- not require data smoothing. Meanwhile, TBSS keeps the terior commissure line. High resolution T1 W structural features of a fully automated method [13]. images covering the entire brain were acquired using Like all methods, this approach also has some draw- three dimensional fluid-attenuated inversion-recovery, backs that should be recognized when considering analy- fast spoiled gradient recalled echo (FLAIR-FSPGR) sis outcomes. TBSS discards the orientation information sequence with following parameters: repetition time captured in the diffusion data since it only makes use of (TR)  =  8.548  ms, echo time (TE)  =  1.836  ms, inver- FA maps. The extent of anatomical inaccuracies, which sion time (TI)  =  400  ms, flip angle  =  15°, field of is inherent in the FA skeleton projection, can potentially view =  260 ×  260  mm , matrix size =  256 × 256, num- introduce biases in the data outcomes. Additionally, ber of slice = 124 and slice thickness = 1.5 mm. TBSS is known to be purely FA-based and it has been Chen et al. BMC Neurosci (2016) 17:45 Page 3 of 8 previously reported that adjacent WM tracts can be not Mean diffusivity (MD) was also analyzed but did not necessarily separable based only on their FA [14, 15]. show significant differences in sexual offenders compared For the analysis, briefly, a cross-subject mean FA skel - to the control group. eton, which was previously aligned to the MNI-152 template, was created to represent the centers of all Discussion fiber tracts common to the entire group. All other FA As predicted, results from this study revealed that male maps were transformed to the MNI-152 space by con- rapists show abnormalities in white matter integrity. Sig- catenating the FNIRT nonlinear transformation to the nificant FA increases were found in: (a) white matter near representative FA image with the transformation to the the angular gyrus, posterior cingulate, and the medial MNI-152 template. Each subject’s aligned FA map was frontal pole, and (b) the internal capsule at the level of projected onto the mean FA skeleton by filling the skele - the thalamus, caudate, and globus pallidus. Significantly ton with FA values from the nearest relevant tract center. reduced FA was observed in: (i) the posterior cingulum This ensured that each subject’s skeleton was in the and (ii) the inferior fronto-occipital fasciculus within the group space, yet represented the center of that subject’s middle occipital gyrus. To our knowledge, these con- own unique fiber tracts. The skeletonized FA data were stitute the first DTI findings on any sex offender group. fed into the following voxel-wise cross-subjects statistics These findings may be interpreted within the theoreti - which were based on non-parametric permutation test- cal contexts of abnormalities in moral decision-making, ing (Randomise v2.1, a part of the FSL tool; http://www. sexual over-arousal, reward sensitivity, fear conditioning, fmrib.ox.ac.uk/fsl/randomise/index.html). and distorted social cognition in rapists. Analysis of between-group difference in FA values were Significant group differences were observed in white conducted in a non-parametric analysis of covariance matter near the angular gyrus, the posterior cingulate, design [16] using a cluster-extent threshold to account and the medial frontal pole. Previous studies using func- for the multiple comparison (corrected-p  <  0.05). Age tional imaging have reported these regions to be involved was entered into the analysis as a potential confound to in moral decision-making [18, 19]. These same regions ensure that any observed difference in FA between the have also been found to be dysfunctional in violent and two groups was independent of age-related changes. psychopathic criminals [5]. It has also been argued that Each possible contrast (normal control  >  sex offenders the rule-breaking behavior that is common in antiso- and sex offenders  >  normal controls) was tested with cial, violent, and psychopathic individuals, is in part due 5000 random permutations. Effect sizes were calculated to impairments in these structures that underlie moral using Cohen’s d [17]. The most probable anatomic locali - cognition and emotion [5]. Consequently, abnormal- zation of each cluster was determined by means of the ity in white matter connectivity involving these regions FSL atlas tool (http://www.fmrib.ox.ac.uk/fsl/fslview/ could contribute to the antisocial, rule-breaking behavior atlas-descriptions.html). All reported brain images were found in rapists. While we found increased as opposed to acquired using the “tbss_fill” script from the FSL package. decreased FA in rapists in these regions, it is conceivable that this increase could imply some dysfunction in the Results circuits associated with moral decision-making in this Direct group comparisons group. Deteriorated functions of these cortical regions Compared to the matched controls, sex offenders had could, for example, result in increased white matter con- smaller FA in several clusters. These include the left nectivity, in an effort to compensate for this cortical dys - inferior fronto-occipital fasciculus of the occipital gyrus function [20]. (p < 0.001), the right posterior cingulum of the parahip- As indicated in Table  1, four of the 10 areas showing pocampal gyrus (p < 0.001), and the right superior longi- increased FA in rapists involved the internal capsule at tudinal fasciculus of the supramarginal gyrus (p < 0.001) the level of the thalamus, caudate, and globus pallidus. (see Table 1; Fig. 1). Activation of both the thalamus and caudate has been Some regions showed greater FA in sex offenders com - observed in normal men in response to viewing sexual pared to controls. These include clusters of the left supe - material [21, 22]. Furthermore, at least one functional rior longitudinal fasciculus adjacent to the angular gyrus imaging study has shown that sex offenders registered (p  <  0.001), the right posterior cingulate (p  <  0.003), over-activation of the thalamus, caudate, and globus pal- the forceps minor adjacent to the medial frontal pole lidus during visual sexual stimulation [4]. Consequently, (p  <  0.001), and the right internal capsule at the level of increased FA found in white matter tracts located near the thalamus (p < 0.001), caudate (p < 0.001), and globus the thalamus, caudate, and globus pallidus may contrib- pallidus (p < 0.001) (see Table 1; Fig. 2). ute to over-activation of brain areas related to sexual arousal. This over-activation could contribute to sexual Chen et al. BMC Neurosci (2016) 17:45 Page 4 of 8 Table 1 Brain regions showing significant differences between  rapist and  control subjects, illustrating clusters in  which rapists had reduced and increased white matter fractional anisotropy compared with control subjects Cluster MNI coordi- Anatomical location FA (Mean ± SD) T score p value Cohen’s d size (mm ) nates (mm) x y z White matter tract Brain region Control Oender ff Decreased FA in sex offenders versus controls 18 −35 −82 16 Inferior fronto‑ occipital Lateral occipital lobe, 0.42 ± 0.06 0.32 ± 0.03 5.55 0.0000 2.11 fasciculus Middle occipital gyrus 13 21 −43 0 Posterior cingulum Parahippocampul gyrus 0.59 ± 0.05 0.50 ± 0.04 5.05 0.0001 1.99 10 52 −39 23 Superior longitudinal Inferior parietal lobule, 0.54 ± 0.05 0.45 ± 0.05 4.26 0.0001 1.80 fasciculus or Supramarginal gyrus 10 25 −35 −10 Posterior cingulum Parahippocampul gyrus 0.60 ± 0.07 0.52 ± 0.05 3.39 0.0071 1.32 Increased FA in sex offenders versus controls 29 −16 33 11 Genu 0.55 ± 0.05 0.63 ± 0.06 4.08 0.0001 1.45 17 12 8 1 Internal capsule (anterior Caudate 0.62 ± 0.05 0.71 ± 0.04 4.45 0.0002 1.99 thalamic radiation) 16 −25 −69 26 Lateral occipital lobe 0.48 ± 0.05 0.56 ± 0.05 4.11 0.0002 1.60 (superior division) 16 18 −10 −3 Poterior limb of internal Globus pallidus 0.70 ± 0.05 0.76 ± 0.04 4.16 0.0003 1.33 capsule 14 24 −46 3 Posterior cingulate Posterior cingulate 0.34 ± 0.09 0.46 ± 0.07 3.88 0.0028 1.49 14 −6 51 −18 Forceps minor Medial frontal pole 0.23 ± 0.03 0.32 ± 0.07 4.06 0.0001 1.67 12 −7 −81 29 Forceps major Cunerus 0.24 ± 0.04 0.33 ± 0.06 4.47 0.0002 1.77 11 42 −51 37 Superior longitudinal Supramarginal, or Angu‑ 0.38 ± 0.09 0.51 ± 0.07 4.18 0.0006 1.61 fasciculus lar gyrus 10 −13 0 4 Internal capsule (anterior Caudate 0.63 ± 0.05 0.71 ± 0.06 3.83 0.0025 1.45 thalamic radiation) 10 −11 −5 −10 Posterior limb of internal Lower thalamus 0.69 ± 0.04 0.76 ± 0.05 3.37 0.0013 1.55 capsule Covariate: age Fig. 1 Regions with significantly reduced fractional anisotropy (FA) in rapists versus controls. The group mean FA skeleton (black) was overlaid on the MNI‑152 T1 volume. The regions with significantly lower FA in rapists are highlighted with colored voxels (blue to light blue) corresponding to the t‑scores. Significantly reduced FA was observed in the posterior cingulum (A), the inferior fronto ‑ occipital fasciculus within the middle occipital gyrus (B), and the superior longitudinal fasciculus near the inferior parietal lobule (C) Chen et al. BMC Neurosci (2016) 17:45 Page 5 of 8 Fig. 2 Regions with significantly increased fractional anisotropy (FA) in rapists versus controls. The group mean FA skeleton (black) was superim‑ posed on the MNI‑152 T1 image. The regions in color (red to yellow) represent the areas with significantly higher FA in rapists, including: white mat ‑ ter near the angular gyrus (F), the posterior cingulate (G), the medial frontal pole (I), and the internal capsule at the level of the thalamus (E), caudate (B, C), and globus pallidus (D) over-arousal in offenders, which then acts as a trigger for striatum. Similar to OCD patients, rapists have been actions leading to rape. hypothesized to have obsessive sexual thoughts [27]. In this study, we observed increased FA in rapists in Furthermore, OCD patients have been found to have brain areas involved in the reward system, including increased FA in the internal capsule adjacent to the cau- the caudate, globus pallidus, and thalamus. Enlarge- date, as well as reduced FA in the cingulum [28], a pat- ment of the caudate has been associated with inter- tern also observed in rapists. It is conceivable therefore personal and affective features of psychopathy, as well that abnormal FA in the internal capsule and cingulum as impulsivity and stimulation seeking behavior [23]. could contribute to obsessive thinking on sexual themes, Amongst sex offenders, rapists have been found to be which may lead to a compulsion to rape. more psychopathic than incest and pedophile offend - When compared to controls, rapists also showed ers [24]. Heightened sensitivity to reward in rapists may, reduced FA in a number of white matter tracts in this therefore, contribute to a heightened desire to pursue study. First, they had reduced FA in the posterior cin- sexual rewards, and thus lead to rape in certain social gulum. The posterior cingulum connects the cingulate circumstances. and parahippocampal gyri to the septal cortex. As such, Results from the current study showed that the sex reduced FA may reflect an abnormality in septal func - offender group had increased FA in several regions of the tioning in sex offenders. Positioned alongside the hip - internal capsule, when compared with the control group. pocampus, the parahippocampal gyrus and the septum Previous research on obsessive–compulsive disorder have been thought to play important roles in condi- (OCD) has also indicated structural volumetric abnor- tioning [29]. The reduced FA in the posterior cingulum malities of the internal capsule in patients with OCD shown in this study, that connects these structures, may [25], in addition to increased FA in this same region [26]. suggest impairments in fear conditioning. Fear condi- As a result, deep brain stimulation treatment of OCD has tioning impairments as early as age 3  years have been targeted the area of the internal capsule and the adjacent found to predispose individuals to criminal behavior at Chen et al. BMC Neurosci (2016) 17:45 Page 6 of 8 age 23 [30]. Likewise, poor fear conditioning could pre- Alternatively, replacing the TBSS registration step with a dispose men to rape, because they do not experience tensor-based, group-wise registration, e.g. using DTI-TK, anticipatory fear, and hence are less concerned about the may be an alternative, particularly given that reliability consequences of their illegal behavior. for low-FA structures like the fornix or the external cap- Abnormal posterior cingulum circuitry may result in sule can be quite low [39]. Additionally, a combination reduced activation of the septum and a predisposition of approaches using fMRI (both active and resting) and towards aggressive behavior. The same condition may be VBM may provide information for selection of areas for associated with increased activation of the anterior hypo- specific-tract tractography, and so extend the range of thalamus, and hence increased sexual arousal [31]. Recent the current findings. It is important to remember, how - research has documented abnormality in the septum in ever, that the TBSS analysis employed here required no aggressive and psychopathic individuals, as indicated by assumptions to be made regarding regions that may be cavum septum pellucidum [32], a neurological abnormal- affected, whereas a more specific hypothesis would be ity reflecting abnormal growth of limbic structures that required for tractography analysis. include the septal nuclei, corpus callosum, hippocampus, Despite these limitations, however, this study provides amygdala, and other midline structures [33, 34]. In ani- the first demonstration of abnormalities in the structural mals, the septum is critically involved in the regulation integrity of white matter in the brains of rapists. Inclu- of aggression [35, 36]. Reduced FA in the posterior cin- sion criteria that restricted participants to adult males gulum could therefore result in reduced activation of the perpetrating their offense on a female stranger resulted in septum and a predisposition towards aggressive behavior, a relatively homogenous group in contrast to some other as well as increased activation of the anterior hypothala- neurobiological studies that examined more heterogene- mus and hence increased sexual arousal [31]. ous groups of sex offenders [e.g. 40]. Results from this Finally, we found that rapists, when compared to con- study encourage future research investigating white mat- trols, had decreased FA in the inferior fronto-occipital ter integrity among sexual offenders. fasciculus within the middle occipital gyrus. This fiber tract has been found to be critically involved in the Conclusion semantic processing and conceptualizing of visual stimuli In this study, significant differences in FA between male [37, 38]. Distortions in social cognition have been found rapists and the control group were seen in a number of in rapists, which may serve as a basis and justification areas including white matter near the angular gyrus, for their inappropriate sexual acts. An abnormality in posterior cingulate, the medial frontal pole, the internal the way rapists semantically process visual stimuli of a capsule at the level of the thalamus, caudate, and glo- sexual nature in females (e.g. how they are dressed) could bus pallidus, the posterior cingulum, and the inferior contribute to how they inappropriately mis-attribute the fronto-occipital fasciculus within the middle occipital intentions of the women they meet. gyrus. A subset of these areas (the angular gyrus, pos- Several limitations of the current study should be rec- terior cingulate, and the medial frontal pole) have pre- ognized. First, given the relatively modest sample size, viously been found to be dysfunctional in violent and replications involving larger sample sizes are recom- psychopathic criminals, consistent with the functional mended in order to confirm results from this study. relevance of these areas to criminal behavior. Differ - Second, findings from adult male rapists cannot be gen - ences in the remaining areas may relate to, for example, eralized to other sexual offending groups, including a tendency for sexual over-arousal, heightened sensi- pedophiles and homosexual rapists. Third, while results tivity to reward, obsessive thinking on sexual themes, indicated a number of significant abnormalities in white and poor fear conditioning, all of which may potentially matter integrity in rapists, our study cannot delineate the contribute to the nature of the criminal behavior per- cause of these abnormalities. Fourth, the hypothesis that petrated by these individuals. Future work to investigate increased FA in the internal capsule in rapists may con- potential causes of these differences, as well as contrast - tribute to obsessive sexual thinking must be regarded as ing rapists with different criminal populations, would be preliminary and requiring further substantiation. beneficial. Additionally, like any analytical method, there is poten- tial for improvement in future investigations, based both Abbreviations on the findings from the study here, and refinement FA: fractional anisotropy; DTI: diffusion tensor imaging; MRI: magnetic reso ‑ using data collected employing additional or alternative nance imaging; T1W: T1‑ weighted; FLAIR‑FSPGR: fast spoiled gradient recalled echo; TR: repetition time; TE: echo time; TI: inversion time; EPI: echo‑planar methods. For the TBSS analysis, an approach using reg- imaging; BET: brain extraction tool; FSL: functional magnetic resonance istration to either the FMRIB58 template or to the most imaging of the brain software library; TBSS: tract‑based spatial statistics; OCD: representative subject of the group may be beneficial. obsessive–compulsive disorder. Chen et al. BMC Neurosci (2016) 17:45 Page 7 of 8 Authors’ contributions 10. Smith SM. Fast robust automated brain extraction. 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The spatial and temporal signatures of word produc‑ tion components. Cognition. 2004;92:101–44. Submit your next manuscript to BioMed Central and we will help you at every step: • We accept pre-submission inquiries • Our selector tool helps you to find the most relevant journal • We provide round the clock customer support • Convenient online submission • Thorough peer review • Inclusion in PubMed and all major indexing services • Maximum visibility for your research Submit your manuscript at www.biomedcentral.com/submit

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BMC Neuroscience – Springer Journals

Published: Jul 7, 2016

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