Functional Cortical and Subcortical Abnormalities in Pedophilia: A Combined Study Using a Choice Reaction Time Task and fMRI

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ORIGINAL RESEARCH—ANATOMY/PHYSIOLOGY Functional Cortical and Subcortical Abnormalities in Pedophilia: A Combined Study Using a Choice Reaction Time Task and fMRI

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Timm B. Poeppl,*†a Joachim Nitschke, MD,*‡a Beate Dombert, MA,* Pekka Santtila, PhD,§ Mark W. Greenlee, PhD,¶ Michael Osterheider, MD,*† and Andreas Mokros, PhD* *University of Regensburg, Department of Forensic Psychiatry and Psychotherapy, Regensburg, Germany; †University of Regensburg, Department of General Psychiatry, Regensburg, Germany; ‡District Hospital, Forensic Psychiatry Hospital, Ansbach, Germany; §Åbo Akademi University, Department of Psychology and Logopedics, Turku, Finland; ¶University of Regensburg, Department of Experimental Psychology, Regensburg, Germany DOI: 10.1111/j.1743-6109.2011.02248.x

ABSTRACT

Introduction. Pedophiles show sexual interest in prepubescent children but not in adults. Research into the neurofunctional mechanisms of paraphilias has gathered momentum over the last years. Aim. To elucidate the underlying neural processing of sexual interest among pedophiles and to highlight the differences in comparison with nonparaphilic sexual interest in adults. Methods. Nine pedophilic patients and 11 nonpedophilic control subjects underwent functional magnetic resonance imaging (fMRI) while viewing pictures of nude (prepubescents, pubescents, and adults) and neutral content, as well as performing a concomitant choice reaction time task (CRTT). Main Outcome Measures. Brain blood oxygen level-dependent (BOLD) signals and response latencies in the CRTT during exposure to each picture category. Results. Analysis of behavioral data showed group differences in reaction times regarding prepubescent and adult but not pubescent stimuli. During stimulation with pictures displaying nude prepubescents, pedophiles showed increased BOLD response in brain areas known to be involved in processing of visual sexual stimuli. Comparison of pedophilic patients with the control group discovered differences in BOLD responses with respect to prepubescent and adult but not to pubescent stimuli. Differential effects in particular occurred in the cingulate gyrus and insular region. Conclusions. The brain response of pedophiles to visual sexual stimulation by images of nude prepubescents is comparable with previously described neural patterns of sexual processing in nonpedophilic human males evoked by visual stimuli depicting nude adults. Nevertheless, group differences found in the cingulate gyrus and the insular region suggest an important role of these brain areas in pedophilic sexual interest. Furthermore, combining attention-based methods like CRTT with fMRI may be a viable option for future diagnostic procedures regarding pedophilia. Poeppl TB, Nitschke J, Dombert B, Santtila P, Greenlee MW, Osterheider M, and Mokros A. Functional cortical and subcortical abnormalities in pedophilia: A combined study using a choice reaction time task and fMRI. J Sex Med 2011;8:1660–1674. Key Words. Pedophilia; fMRI; Neurofunctional Mechanisms of Paraphilias; Sexual Interest; Insula; Cingulate Gyrus; Choice Reaction Time Task

Introduction

A

s a phenomenon related to sexual activity between adults and children, pedophilia has been described since at least the ancient Greek era a

These authors contributed equally to this work.

J Sex Med 2011;8:1660–1674

[1]. Moreover, it has seemingly occurred in various societies and cultures [2,3]—even though often appraised differently [4]—and has also been reported for nonhuman primates [5]. In the present article, pedophilia is referred to as defined in the Diagnostic and Statistical Manual of Mental Disorders [6]: a paraphilia characterized by recurrent, © 2011 International Society for Sexual Medicine

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Functional Brain Abnormalities in Pedophilia intense sexually arousing fantasies, sexual urges, or behaviors involving sexual activity with a prepubescent child or children (generally age 13 years or younger) over a period of at least 6 months. Findings of neuropsychological impairment in pedophiles have been interpreted as evidence that pedophilia was linked to early neurodevelopmental perturbations [7,8]. Consistent with this assumption, studies using voxel-based morphometry to assess possible structural brain abnormalities in pedophiles showed decreased gray matter volumes in the ventral striatum, the orbitofrontal cortex and the cerebellum [9], lower right amygdalar volume and reduced gray matter in the right amygdala, hypothalamus (bilaterally), septal regions, substantia innominata, and bed nucleus of the stria terminalis [10], as well as white matter deficiencies in the superior frontooccipital fasciculus and the right arcuate fasciculus [11]. This neuroanatomical approach has also been supported by case reports describing latelife pedophilia related to temporal lobe disturbances [12] and impulsive sexual behavior including pedophilia associated with an orbitofrontal lesion [13]. As structural and functional components of the brain are not simply concordant, investigations addressing the neurofunctional aspects of pedophilia are indispensable. While the relationships between brain activation and sexual response in healthy humans seem to be well-defined, relatively little is known about pedophilia in this regard. Studies addressing sexual arousal (SA) among nonparaphilic individuals varied in experimental design and stimulus material, while some employed long blocks of visual sexual stimulation by erotic video clips [14–19], others implemented short presentations of erotic pictures [15,20,21]. In contrast to the use of subjective rating scales as an indicator of SA [16–18,21], also penile turgidity served as a more objective corresponding reference [14,15,18,22]. However, results within similar experimental designs seem to be largely consistent and overlapping. Paradigms coinciding with the design applied in the present study revealed the following cerebral structures whose activation is elicited by visual sexual stimuli (VSS): temporooccipital visual areas, the inferior and superior parietal lobules, the post- and precentral gyri, the cingulate gyrus, prefrontal cortex, amygdala, thalamus, hypothalamus, caudate, and putamen [18,23–26]. Reports on studies of pedophilia that applied functional magnetic resonance imaging (fMRI) are

more heterogeneous. When viewing erotic pictures of adults, significantly lower signal intensities were observed for pedophilic patients compared with healthy control subjects in the hypothalamus, the dorsal midbrain, the insula, the occipital, lateral parietal and lateral prefrontal cortex [27], the caudate nucleus [28], and the cingulate gyrus, fusiform gyrus, precuneus, as well as temporal and occipital cortices [29]. By contrast, during visual stimulation with pictures of nude children, pedophilic patients showed higher blood oxygen leveldependent (BOLD) signals than healthy controls in the anterior cingulate cortex (ACC), ventromedial prefrontal cortex [28], hippocampus, fusiform gyrus, and thalamus [29]. Finally, it has also been reported that relative to stimuli depicting adults, a healthy control group showed less, and pedophiles more, amygdala activation while viewing images of children [30]. Aims

The present study sought to further explore the underlying neural processing of sexual interest of pedophiles. Furthermore, it intended to highlight differences in comparison with nonpedophilic sexual interest, under the hypothesis that these differences would be located in regions known to be involved in SA. Using a similar paradigm (with relatively short blocks of visual sexual stimulation), following Mouras et al., [25] we propose to activate the neural correlates of rather the cognitive, emotional, and motivational (as early responses) than the autonomic (i.e., genital response) components of Redouté’s four-component neurobehavioral model of SA [18]. Yet, given the capability of short (10 seconds) erotic (film) stimuli to induce penile tumescence [31], we would not exclude such a possibility a priori for this experiment. However, our main objective was to reveal the neural correlates of (pedophilic) sexual interest as part of the appraisal stage of SA according to the conceptual model of SA by Janssen et al. [32]. Therefore, fMRI was employed, combined with a choice reaction time task (CRTT) to induce cognitive engagement with potentially erotic images. In the CRTT, a stimulus picture is overlaid with a dot in one of several prescribed locations. The participant is requested to press a corresponding button as quickly as possible. The difference between response latencies for different kinds of stimuli is regarded as an indication of selective attention. By applying fMRI and CRTT (using the same paradigm) to the same group of patients, we J Sex Med 2011;8:1660–1674

1662 aimed to test congruency of both methods and their usability as potential future diagnostic tools. In addition, given the limited number of stimuli (eight per condition) provided by the standardized and rated picture set, which was used for visual stimulation in this experiment, performing fMRI and CRTT in one session meant reducing possible habituation and memory effects because of numerous stimulus repetitions. Combining both methods, also participants’ compliance could be guaranteed, i.e., it was ensured that all subjects were viewing all stimuli without any longer opportunity to turn off their attention. In contrast to previous fMRI-based studies on pedophilia, the control group was composed of nonsexual offenders to control for possible cerebral changes as a result of internment-related stress or general criminality, an issue already acknowledged by Cantor et al. [11].

Methods and Main Outcome Measures

Subjects Nine pedophilic patients and 11 nonsexual offenders were recruited from three high-security forensic hospitals and matched as closely as possible for intelligence quotient (IQ) (mean [M] = 92 ⫾ 18 standard deviation [SD] vs. M = 100 ⫾ 19 SD, t[18 d.f.] = .92, P = .37) and handedness (nonright-handed 22% vs. 27%; P = 1.00 in a twosided Fisher exact test). IQ was determined by the Wiener Matrizen-Test, a Rasch-scaled nonverbal intelligence test [33]. Handedness was ascertained using the Edinburgh Handedness Inventory [34]. Participant groups differed significantly with regard to age, however, with pedophilic subjects on average being older (M = 45 years ⫾ 8 SD) than controls (M = 29 years ⫾ 6 SD): t(18 d.f.) = 5.01, P < 0.001. Out of these 20 participants, seven had taken part in a prior (non-fMRI) study using the CRTT [35]. All pedophilic patients met the DSM-IV-TR criteria for pedophilia [6] and had high scores on the Screening Scale for Pedophilic Interests [36,37] based on sexual offense history variables: M = 4.22 ⫾ 0.83 SD, median (Md) = 4, range: 3–5. Exclusion criteria were psychiatric medication, alcohol or drug abuse, schizophrenia, bipolar disorder, obsessive–compulsive disorder (OCD), and attention deficits. Participants’ sexual orientation was self-reported using the Sell Assessment of Sexual Orientation [38]; the gender of victims was additionally taken into account for pedophiles. J Sex Med 2011;8:1660–1674

Poeppl et al. All subjects provided written informed consent, and the study had been approved by the ethics committee of the School of Medicine at the University of Regensburg.

Paradigm As the stages of sexual maturity may be more informative than chronological age as a predictor of pedophilic attraction to children [39], participants were asked to view 144 pictures of nude males and females at different Tanner stages (i.e., stages of physical development [40]) from the Not Real People (NRP) stimulus set [41] and 24 neutral stimuli during one fMRI session. Tanner stages included I (prepubescent), III (pubescent), and V (adult). Individuals tend to perceive the NRP picture categories of sexual maturity as distinct and well-ordered on a ratio scale of age appearance [42]. Neutral pictures had been generated from the same Tanner pictures with a Fourier transformation, scrambling the figural shapes but keeping the amplitude spectrum and the overall color appearance of the images [43]. Pictures showing individuals at Tanner stages II and IV were not included in the design for two reasons. First, intermediate categories of pubertal development are more difficult to discern. Second, limiting the independent variable to three levels (Tanner stages I, III, and V) affords a reasonable trade-off between endurable time requirements for the measurement within the magnetic resonance (MR) scanner and necessary overall length of the block design. Stimuli were presented in a block design, each block lasting 18 seconds and consisting of four pictures from a single stimulus category (e.g., nude female at Tanner stage III). A fixation cross in the middle of the screen was shown for 500 milliseconds prior to appearance of every picture and for 12 seconds between blocks. The order of pictures and blocks was randomized. Because of the exploratory purpose of our experiment, we employed a block design, which affords superior detectability of activated brain areas [44]. However, research on design-dependent brain activity induced by VSS found differences between block and event-related design in only 10% of the voxels showing taskrelated brain response [23]. Thus, we advance the view that event-related design would have been a potential alternative for our endeavor. In terms of block length (and choice of stimuli), we regard Bühler’s, Hamann’s, Mouras’ and to some extent also Redouté’s and Stark’s studies as templates [18,23–26]. We could not use long erotic (child

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Functional Brain Abnormalities in Pedophilia pornographic) video clips because of ethical and legal reasons. Applying video clips or longer blocks of stimuli would also have precluded the combination of fMRI with CRTT and run the risk of considerable contingency and habituation effects in CRTT, respectively. It has to be noted clearly that the paradigm used in this experiment has not been designed to primarily induce full SA but foremost reveals the neural correlates of processing of VSS and its effect on a concomitant CRTT. The CRTT capitalizes upon an interference effect in selective attention: the participant tries to focus on an ostensible location task while his attention is drawn toward the content of a background picture [45]. Differences in response latencies depending on stimulus content have been shown to be indicative of general sexual orientation [46,47] as well as of sexual preference disorder, specifically pedophilia [35]. In the current experiment, a dot that would vanish upon pressing a response button was superimposed on each picture in one of 12 possible positions (four rows by three columns). These positions were counterbalanced and randomized for each stimulus category. Subjects had been instructed to press a button as fast as possible according to the position of the dot (left, middle, or right column). Reaction times of button presses were recorded during the fMRI session. Responses to the stimuli were analyzed according to each participant’s sexual orientation. That is, only overt responses and BOLD activity for female stimuli were considered for heterosexual subjects, whereas the analysis was restricted to male stimuli for homosexual participants. This approach is concomitant with the comparison of child vs. adult stimuli, irrespective of gender, as practiced within research on penile plethysmography [48].

Imaging Data collection was carried out on a 1.5 Tesla MR scanner (MAGNETOM Sonata, Siemens Medical Solutions, Erlangen, Germany) with an 8-channel, phase-array head coil. Functional images of the whole brain were acquired using an echo-planar imaging sequence (422 volumes consisting of 35 transaxial T2* weighted slices, interleaved acquisition order, field of view 192 mm ¥ 192 mm, matrix size 64 ¥ 64, in-plane resolution 3 mm ¥ 3 mm, slice thickness 3 mm, 15% gap, echo time 50 milliseconds, repetition time 3 seconds, flip angle 90°). Subsequently, a high resolution T1-weighted scan adopting a 3D magnetization-prepared rapid acquisition with gradient echo sequence was performed as a structural reference.

Data were preprocessed [49] and analyzed by means of the SPM5 software (Wellcome Trust Centre for Neuroimaging, London, UK) [50]. Functional images were realigned to the first volume and were coregistered with the structural scan, followed by normalization of both into standard stereotactic space of the Montreal Neurological Institute [51]. Echo-planar images were spatially smoothed with an 8 mm full-width at half maximum Gaussian kernel. Individual statistical activation maps were obtained using the general linear model (GLM) [52]. Single-subject contrast images were entered into a random effects model for both within-group and between-group comparisons applying onesample t-tests and two-sample t-tests, respectively. Age was included for the between-group contrasts as a covariate in the GLM. Initially, the resulting maps of the whole brain analyses (within- and between-group contrasts) were thresholded at P < 0.001, uncorrected, with a cluster size of k ⱖ 10 adjacent voxels. In the within-group contrasts, only regions surpassing an uncorrected cluster-wise threshold of P < 0.05 (please see Tables 1–3 for the corresponding cluster sizes k in voxels) with an uncorrected cluster defining threshold of a voxelwise P < 0.001 were considered as significant. Additionally, voxels surviving correction for multiple comparisons using the family-wise error or false discovery rate method are marked in the tables. Results

Sexual Orientation The majority of participants (N = 13) were categorized as primarily heterosexual. All of the subjects who were categorized as primarily homosexual (N = 7) were from the pedophilic group. Behavioral Data Response latencies in the CRTT were averaged within categories, using reactions toward neutral stimuli as a reference. Figure 1 displays the groupspecific Md of these average increments over neutral stimuli for images from the prepubescent (Tanner I), pubescent (Tanner III), and adult (Tanner V) categories. Clearly, pedophilic participants had higher incremental changes in reaction time in response to Tanner I (Md = 63 milliseconds) and Tanner III stimuli (Md = 68 milliseconds) than with respect to Tanner V images (Md = 9 milliseconds). Control participants, in contrast, showed an increase from the least to the J Sex Med 2011;8:1660–1674

1664 Table 1

Poeppl et al. Active brain regions in pedophiles during stimulation with pictures of nude prepubescent children MNI coordinates

Brain region

Hemisphere

BA

x

y

z

t value

Middle frontal gyrus Inferior temporal/middle occipital/fusiform gyrus Posterior cingulate gyrus Middle occipital gyrus Hippocampus-amygdala complex Postcentral gyrus Posterior cingulate gyrus Precentral gyrus Parahippocampal gyrus/hippocampus Superior parietal lobule (precuneus)/superior temporal gyrus Posterior cingulate gyrus Calcarine

R R R L R R L R L R L R

46 19/37 23/31 19/37

42 52 4 -44 34 46 -4 48 -18 32 -20 22

16 -74 -38 -78 -16 -22 -54 -4 -16 -68 -24 -94

24 -6 26 0 -18 48 24 52 -18 34 32 -4

19.95** 15.47** 13.04* 13.03* 11.72* 10.60* 7.00* 6.84* 6.20* 5.63* 5.55* 5.17*

2/3 23/31 6 28/35 39 17

*P < 0.05, FDR corrected; **P < 0.05, FWE corrected. Peak voxel x, y, z in standard MNI space. Thresholded at voxel-wise P < 0.001, uncorrected, together with cluster-wise P < 0.05, uncorrected (corresponding to a cluster size k ⱖ 22 voxels). R = right; L = left; BA = Brodmann area; MNI = Montreal Neurological Institute.

most mature categories, with incremental changes in reaction time of Md = 27 milliseconds for Tanner I, Md = 74 milliseconds for Tanner III, and Md = 79 milliseconds for Tanner V, respectively. A two-sample generalization of the Friedman ranksums test [53] was employed to test the null hypothesis of equal response profiles across both groups of participants. Overall, the difference in response profiles approached statistical significance (c2(2) = 4.87, P < 0.10), with the most pronounced difference at Tanner V (V = 2.12, P = 0.05, one-sided). At Tanner stages I (V = 1.64, P = 0.14) and III (V = 1.00, P = 0.41), the differences in response latencies between groups did not reach statistical significance. Separate within-group comparisons indicated that the differences in response latencies between stimulus age categories were not significant (using the Friedman rank-sums test). The data revealed a trend in the expected direction for nonpedophilic controls (c2(2) = 4.55, P = 0.10), but the results did not approach significance for the pedophilic subjects (c2(2) = 2.89, P = 0.24). Subsequently, we calculated follow-up tests for the pairwise comparison of picture categories within each of the experimental groups separately: prepubescent– pubescent, prepubescent–adult, and pubescent– adult. A distribution-free multiple comparison test [54] using an exact critical value [55] indicated that the response latencies did not differ significantly between the three categories of pictures in either group. Subtracting mean response latencies for adult (Tanner V) stimuli from those for prepubescent (Tanner I) stimuli yielded an index of pedophilic preference with average values of Md = 58 milliJ Sex Med 2011;8:1660–1674

seconds for the pedophilic subjects and Md = -39 milliseconds for the nonpedophilic control subjects. Consequently, a value > 0 milliseconds on this subtractive index implied that the participant in question on average had longer reaction times toward child (Tanner I) than toward adult stimuli (Tanner V). As expected, the values on the pedophilic preference index (PPI) were higher among the pedophilic subjects than among controls (Mann–Whitney U = 27, P < 0.05, one-sided). The mean difference between groups on the PPI represented a large effect size of about one standard deviation unit (Cohen’s d = 0.99). In terms of overall discriminatory power, the area under a receiver-operating characteristic curve (area under the curve [AUC]) for the PPI was AUC = 0.73 (P = 0.087). Adopting a threshold level for the PPI of > 0 milliseconds maximized the total number of correct allocations to 15 out of 20 participants or 75% (with a sensitivity of 67% and a specificity of 82%). That is, six out of nine individuals would be correctly assigned to the pedophilic group, whereas two out of 11 nonpedophilic controls would be erroneously regarded as pedophilic. Clearly, the majority (i.e., two-thirds) of pedophilic subjects showed the expected pattern of longer reaction times for child than for adult stimuli. Similarly, most of the nonpedophilic controls (i.e., four-fifths) displayed the opposite pattern of longer reaction times for adult than for child stimuli.

Brain Imaging Data To address the question whether sexual interest of pedophiles is basically related to the same brain

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Functional Brain Abnormalities in Pedophilia Table 2 Pedophiles’ and controls’ brain response to pictures of nude prepubescent children (Tanner I) relative to pictures of nude adults (Tanner V)

Group/contrast

Brain region

Hemisphere

BA

x

y

z

t value

% signal change in cluster

Pedophiles Tanner I > Tanner V

Fusiform gyrus Middle occipital/inferior occipital/lingual gyrus Fusiform gyrus Inferior frontal gyrus Middle occipital/middle temporal gyrus Middle temporal/middle occipital gyrus Superior temporal gyrus Middle temporal gyrus/hippocampus/insula Culmen (cerebellum)/parahippocampal gyrus Middle frontal gyrus Precuneus Inferior frontal gyrus (orbital) Putamen Thalamus (pulvinar/LP) Putamen/pallidum (nucleus lentiformis)/ caudate Midbrain Medial frontal gyrus Declive (cerebellum)/fusiform gyrus Middle temporal gyrus Fusiform/inferior occipital gyrus Superior temporal gyrus/insula Middle occipital gyrus Middle occipital gyrus Cerebellum/fusiform gyrus Lingual gyrus Cuneus Paracentral lobule

L L

37 19/18

-30 -28

-48 -92

-16 4

13.88* 12.69*

1.039 1.105

L L R L R R R

37 47 19/18

-40 -40 56 -34 66 42 16

-44 26 -72 -80 -20 -26 -32

-24 -10 4 20 6 -16 -16

10.22 9.42 9.16 9.06 8.93 8.70 8.48

1.254 0.923 1.081 0.858 0.977 0.892 1.416

-32 22 24 -18 26 18

50 -56 38 12 -30 8

-2 50 -6 -2 10 4

8.42 8.18 7.98 7.49 7.43 7.39

0.676 0.762 0.741 0.851 0.787 1.034

37 17/18 18 4/5

0 4 24 42 38 -42 -40 30 28 -16 6 8

-22 58 -64 -58 -66 -24 -70 -74 -48 -62 -86 -42

-12 -2 -20 0 -20 10 -2 22 -20 2 22 64

6.93 6.84 6.78 6.48 6.24 6.23 5.86 5.67 5.47 5.38 5.36 5.32

0.866 1.297 1.527 0.887 1.777 0.640 0.956 1.094 0.966 0.772 0.858 0.740

MNI coordinates

L R R L R R R R R R R L L R R L R R

35

7

10

37/19 41/13/22

Pedophiles Tanner I < Tanner V

No suprathreshold clusters

Controls Tanner I > Tanner V

Putamen Supramarginal gyrus/inferior parietal lobule

L R

40

-28 64

6 -46

-6 40

9.21 5.93

0.597 0.830

Controls Tanner I < Tanner V

Inferior occipital/middle occipital gyrus Inferior occipital gyrus/cuneus/middle occipital gyrus Fusiform gyrus

R L

19/18 18/19

46 -42

-80 -82

-6 -6

9.56 7.89

1.500 1.445

R

37

40

-42

-14

5.90

0.797

Entire Sample

Thalamus (VA/AN [L + R])/putamen/lateral pallidum Insula/inferior parietal lobule Putamen Caudate/putamen/lateral pallidum Supramarginal gyrus/inferior parietal lobule/angular gyrus

L

2

-2

8

5.44

0.911

38 -20 16 64

-24 12 10 -44

28 -2 0 32

5.25 5.03 4.91 4.77

0.492 0.551 0.592 0.617

Tanner I > Tanner V

R L R R

13

40

*P < 0.05, FDR corrected. Peak voxel x, y, z in standard MNI space. Thresholded at voxel-wise P < 0.001, uncorrected, together with cluster-wise P < 0.05, uncorrected (corresponding to a cluster size k ⱖ 16 voxels within the pedophiles, k ⱖ 20 voxels within the controls, and k ⱖ 40 voxels within the entire sample, respectively). R = right, L = left, BA = Brodmann area, MNI = Montreal Neurological Institute, LP = lateral posterior nucleus, VA = ventral anterior nucleus, AN = anterior nucleus.

regions as in healthy males, the first comparison contrasted BOLD responses to stimuli depicting nude children at Tanner stage I against BOLD responses to neutral stimuli (Tanner I > neutral) within the pedophilic group. Table 1 lists significantly active brain regions for this contrast. During stimulation with pictures of nude adults, pedophiles showed increased activity only in

temporo-occipital visual areas bilaterally and the left fusiform gyrus (Tanner V > neutral contrast). Contrasting images depicting Tanner stages against neutral, i.e., scrambled images, however, induces unspecific activations (e.g., in brain areas involved in facial recognition). Then, a review of sexual offender literature indicates that relative response to children—apart from being a powerful J Sex Med 2011;8:1660–1674

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Poeppl et al. Regression analysis with the pedophilic preference index (PPI) as the covariate of interest MNI coordinates

Contrast

Brain region

Hemisphere

BA

x

y

Positive correlation

Middle frontal gyrus Putamen Postcentral/precentral gyrus

L L L

10

-38 -20 -54

56 -6 -18

6 16 44

9.37 6.82 6.81

Negative correlation

Corpus callosum Middle temporal gyrus Corpus callosum Superior temporal gyrus Middle temporal gyrus Precuneus/superior occipital gyrus Angular gyrus Calcarine/posterior cingulate Dentate (cerebellum) Posterior cingulate/precuneus

L+R L R L R R L R R R

-2 -60 16 -36 42 26 -30 18 16 20

-22 -2 10 0 -42 -82 -52 -68 -46 -44

24 -24 28 -26 2 42 36 10 -30 28

23.94** 10.41 9.38 9.03 8.62 7.84 7.08 6.91 6.76 6.75

3/4 21

7/19 30 31

z

t value

**P < 0.05, FWE corrected. Peak voxel x, y, z in standard MNI space. Thresholded at voxel-wise P < 0.001, uncorrected, together with cluster-wise P < 0.05, uncorrected (corresponding to a cluster size k ⱖ 13 voxels). R = right, L = left, BA = Brodmann area, MNI = Montreal Neurological Institute.

predictor of recidivism—offers a more precise differentiation of pedophilic from nonpedophilic individuals than absolute arousal to children on its own [56]. Therefore, we computed within-group

Figure 1 Response latency differences (nude vs. neutral stimuli) in the CRTT, measured in msec. Data points represent group medians of individual averages after subtraction of individual mean values of trials with neutral pictures. The median values thus reflect the incremental changes in reaction time for three categories of nude images (prepubescent, pubescent, and adult) over reaction times for neutral stimuli. Vertical bars indicate median absolute deviation (MAD).

J Sex Med 2011;8:1660–1674

contrasts comparing neural responses to prepubescent stimuli with those to adult stimuli. For the Tanner I > Tanner V contrast, pedophilic patients showed increased responses in several cortical visual areas including the inferior and middle occipital cortices, fusiform and middle temporal gyrus as well as in the superior parietal lobule, superior temporal gyrus, insular region, medial frontal gyrus, midbrain, and cerebellum. Signal changes also comprised subcortical structures, namely the hippocampus, thalamus, lentiform nucleus, and caudate. No brain activations in pedophiles were observed for the opposite contrast (Tanner V > Tanner I). In the same vein, we explored relative brain response to images of children also in the nonsexual offenders group. The Tanner V > Tanner I contrast revealed differential effects in the inferior and middle occipital cortices, cuneus, and fusiform gyrus, while the opposite contrast showed increased activity in the supramarginal gyrus, inferior parietal lobule, and putamen. An overall comparison within the entire sample including Tanner I > Tanner V contrast images indicated a neural pattern consisting of regions that exhibited higher activity in the pedophilic and/or the nonpedophilic subjects for the corresponding contrast. Table 2 provides more detailed information on the above results. To examine associations between behavioral data and brain responses, we subsequently performed a regression analysis using the PPI as the covariate of interest. This addresses the question regarding the extent to which the variance of functional brain activity can be explained by the CRTT as an index of selective attention and/or emotional

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Functional Brain Abnormalities in Pedophilia Table 4

Differences in brain activity between the pedophilic and the control group during visual sexual stimulation MNI coordinates

Contrast

Brain region

Hemisphere

Pedophiles > controls Tanner I > neutral

Middle temporal gyrus Posterior cingulate gyrus Thalamus (MD/VA/LP) Medial frontal lobe Hippocampus Medial temporal lobe (periamygdalar/-insular) Culmen (cerebellum)

R R L R R R R

Pedophiles > controls/ pedophiles < controls Tanner III > neutral

No suprathreshold clusters

Pedophiles < controls Tanner V > neutral

Insula

R

Pedophiles > controls Preferred > neutral

Postcentral gyrus Anterior midcingulate gyrus Insula/inferior parietal lobule Insula (operculo-insular) Middle temporal gyrus

R R L R R

Pedophiles < controls Preferred > neutral

No suprathreshold clusters

BA 31

2/3 24 13 13

x

y

z

t value

44 12 -8 22 34 42 28

-40 -42 -16 12 -20 -4 -44

-2 30 14 26 -16 -24 -24

5.15 4.93 4.82 4.73 4.61 4.55 4.39

32

12

16

5.16

48 8 -40 42 46

-22 -12 -44 8 -42

48 36 22 16 -2

5.49 4.99 4.69 4.59 4.21

R = right, L = left, BA = Brodmann area, MNI = Montreal Neurological Institute. MD = medial dorsal nucleus, VA = ventral anterior nucleus, LP = lateral posterior nucleus. Peak voxel x, y, z in standard MNI space. P < 0.001, uncorrected; cluster size k ⱖ 10 voxels.

interference. The simple regression of PPI scores and the Tanner I > Tanner V pictures contrast on the second level revealed more significant negative than positive relationships between response latencies to prepubescent stimuli in the CRTT and BOLD signals within the pedophilic group (cf. Table 3). The next step in analysis focused on differences in brain activity during the three Tanner conditions between the pedophilic and the control group (between-group comparisons; cf. Table 4). For the Tanner I > neutral pictures contrast, pedophilic patients revealed significantly higher signal intensities in the right middle temporal gyrus, the right medial temporal lobe, the hippocampus, the posterior cingulate cortex, the thalamus, the medial frontal lobe, and the culmen of the cerebellum. No differential neural activity was observed between both groups when viewing pictures of pubescent children (Tanner III > neutral pictures contrast). Subtraction of activation maps of pedophiles from those of forensic controls obtained with the Tanner V > neutral picture contrast resulted in a lone significant deactivation for pedophiles in the right insula. Finally, to investigate group differences in neural activation patterns elicited by visual sexual attraction, pedophilic patients were compared with control subjects during stimulation with their preferred picture material, respectively (i.e.,

Tanner I > neutral picture contrast for the former and Tanner V > neutral picture contrast for the latter). Brain regions with significantly higher signal intensities in pedophiles included the postcentral gyrus, the right middle temporal gyrus, the anterior midcingulate cortex, and the left as well as the right insula. Compared with the activity exhibited by the pedophile subjects, control subjects did not show higher activity in any brain areas for this contrast. Figures 2 and 3 summarize these findings: Figure 2 shows the results concerning Tanner I stimuli for both groups. Figure 3 displays altered insular response to preferred stimuli specific for each group (i.e., Tanner I for pedophilic participants and Tanner V for controls). Discussion

The functional brain imaging data reinforce the results from the behavioral CRTT such that group differences occurred with respect to images from Tanner stages I (prepubescents) and V (adults). In this regard, the present reaction time data support earlier research showing a child-induced attentional bias in pedophiles [35]. More decisively, the outcome of the CRTT conducted in the scanner indicates that the participants did focus on the stimulus material. Otherwise, no group-specific response profiles would have been observed. As a J Sex Med 2011;8:1660–1674

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Poeppl et al. employed paradigms comparable with the present [18,23–26]. Regions comprised associative visual areas in the temporo-occipital cortices, the superior parietal lobule, parts of the limbic system (hippocampus-amygdala complex, posterior cingulate gyrus), the premotor and somatosensory area, and the lateral prefrontal cortex. Application of a more specific contrast (Tanner I > Tanner V) revealed a more distinct neural activation profile. Additional effects could be observed in the cerebellum, midbrain, thalamus, basal ganglia, and insula, activation of the latter being shown to correlate with penile tumescence [14,15,57]. The lack of hypothalamic activation in pedophiles in response to visual sexual child stimuli is in line with previous studies [28–30]. These findings suggest that our paradigm was suitable for exploring brain processing of VSS in pedophiles, and that pedophiles’ brain processing of VSS depicting prepubescents is comparable with brain response elicited by VSS depicting adults in healthy human males. Inspecting the corresponding contrast (Tanner V > Tanner I) in the nonparaphilic offender group, the activations in only temporo-occipital visual

Figure 2 Functional magnetic resonance imaging (fMRI) findings when participants were stimulated with pictures of nude prepubescent children (Tanner I > neutral pictures contrast). Brain areas of higher activity in pedophiles as compared with nonparaphilic offenders (between-group comparison) included (BA; x, y, z) the posterior cingulate cortex (BA 31; 12, -42, 30), thalamus (-8, -16, 14), hippocampus (34, -20, -16), and cerebellum (28, -44, -24). BA = Brodmann area. Peak voxel coordinates (x, y, z) in standard Montreal Neurological Institute (MNI) space.

consequence, the results from the functional brain imaging data may be interpreted as reflecting the subjects’ response to the particular stimulus category (i.e., images of nude children or adults). The fact that sensitivity and specificity were lower than in a previous study using the CRTT to identify pedophilic sexual interest [35] is likely a result of the use of a simplified version of the paradigm given the limitations of available response devices for the MR scanner. Pedophilic patients’ brain response to VSS corresponding with their sexual preference (i.e., prepubescent children; Tanner I > neutral pictures contrast) showed increased BOLD signals in areas that have repeatedly been reported to be involved in SA among human males by studies having J Sex Med 2011;8:1660–1674

Figure 3 Higher neural activity in the left posterior (L) and right anterior (R) insular region of pedophiles compared with nonparaphilic offenders. The activation map was obtained from a between-group comparison for visual sexual stimulation with participants’ preferred picture material, respectively (i.e., Tanner I [prepubescent children] > neutral pictures contrast for pedophiles and Tanner V [adults] > neutral pictures contrast for nonparaphilic control subjects). Peak voxel coordinates in standard Montreal Neurological Institute (MNI) space: x = -40, y = -44, z = 22 (L) and x = 42, y = 8, z = 16 (R).

Functional Brain Abnormalities in Pedophilia areas might seem surprising at first glance, yet could reflect an easier sexual excitability of pedophiles as compared with nonparaphilic subjects when stimulated with non-pornographic and nonerotic material corresponding with their preference. In a similar vein, the results of the opposite contrast (Tanner I > Tanner V) in the control group may seem controversial. However, evidence of the putamen, supramarginal gyrus, and inferior parietal lobule responding not only to pleasant (sexual) but also aversive (sexual) stimuli [17,58–60] may resolve the contradiction. Besides, it also seems reasonable to assume that these neural activations in the control group correlate with pleasant feelings and non-erotic interest induced by pictures of children. The regression analysis on PPI scores addresses effects related to individual performance in the CRTT. Overlaps between the regression analysis and the group differences as shown in Table 4 could be observed in the right middle temporal and right posterior cingulate gyrus (Brodmann area [BA] 31). This suggests that between-group effects in these regions might be associated with the behavioral task, while other regions do not show such a relationship. Surprisingly, activity in both brain areas showed a reverse relationship with PPI scores. Interestingly, however, brain activations negatively correlating with PPI scores in the middle temporal gyrus (BA 21), superior temporal gyrus, calcarine, and posterior cingulate (BA 30) have been demonstrated to negatively correlate in regional cerebral blood flow (rCBF) with markers of SA among human males [18]. When inspecting the group comparisons, it must be acknowledged that the pedophilic subjects and the control group differed systematically with respect to sexual orientation, with the majority of pedophilic participants being homosexual, whereas the participants from the control group were exclusively heterosexual. Research on this topic suggests functional variability in response to VSS between heterosexual and homosexual males in the hypothalamus and in the orbitofrontal as well as the parietal cortex [17]. In the present study, direct group comparisons did not reveal functional differences in these particular brain regions—an outcome that casts doubt on attributing any other between-group effects to heterogeneity with respect to sexual orientation. Nevertheless, given that previous psychological and neuroimaging research demonstrated differences related to sexual orientation in healthy and pedophilic subjects, the group differ-

1669 ences in sexual orientation within the study sample cannot be excluded as contributing to the observed differential effects at this point. Larger sample sizes and systematic comparisons among pedophiles, controlling for sexual orientation in a factorial design, are needed to finally resolve this issue. There were no group differences regarding the viewing of pictures of pubescent children, which may reflect the exclusive attraction of the pedophilic participants to prepubescent children and control subjects’ sexual interest in adults, at least a similarity of both groups in brain response to pubescent stimuli by all means. However, some caution is generally indicated when interpreting comparisons of pedophiles’ cerebral functional networks with those of control groups as a result of possible basic differences in cerebral blood flow [61] and in the present study regarding the differences in age and overall statistical power. Limited statistical power might be an explanation for the surprising finding of differential effects solely in the right insula for the Tanner V > neutral between-group contrast. Besides, the absence of further differential responses may be because of other reasons: first, the control group consisted of nonsexual offenders and not—as in previous studies of pedophilia applying fMRI—of healthy nonoffenders; second, the employment of a standardized and rated set of images depicting nude but generally non-erotic and non-pornographic content in contrast to some previous studies using nonstandardized pictures or pictures of a more erotic character. Third, the inclusion of age as a covariate in the between-group analyses as both groups differed in age. This runs the risk of removing variation that might also be related to pedophilia effects. When performing the betweengroup comparisons without age-modeling, for example, additional effects were observed in clusters located in the right caudate, left thalamus, and visual association cortex (both hemispheres) for the Tanner V > neutral contrast as well as in the right pallidum, right insula, and left hippocampus for the Tanner I > neutral contrast. Further, for the preferred > neutral pictures contrast, we also found altered brain activity in pedophiles, e.g., in the right pallidum, left paracentral lobule, and hippocampus (cf. Table 4 for the analysis with age-modeling). Despite these limitations and differences to previous fMRI studies investigating pedophilia, respectively, our results suggest alterations of the functionality of cortical and subcortical structures in pedophilia. J Sex Med 2011;8:1660–1674

1670 Mental motor imagery seems to be a constant feature of SA [17,18,25] and belongs to the cognitive component of the neurobehavioral model of SA proposed by Redouté [18,25]. The pre- and postcentral gyri have been shown to be active during motor imagery [62] and are likely to be related to the motor imagery processes induced by SA together with the inferior parietal lobules and the cerebellum [17,18,25]. The relatively higher activity of the respective regions in the betweengroup contrasts may reflect an increased tendency of pedophiles toward motor imagery during SA, even in response to visual stimulation with nonpornographic and non-erotic pictures (of children) as used in our study. Besides, effects in the pre- and postcentral gyri could also be a result of differences in pressing the button (slow, hesitant vs. fast) in the CRTT. However, considering the results of the regression analysis, this seems to be unlikely. It nevertheless has to be noted that trial-by-trial reaction times might possibly have influenced individual brain activation maps, eventually also affecting neural activation patterns at group level. As reaction times effects on brain activity were only assessed at the second level but not modeled at first level, some interference may go unnoticed. Moreover, the online combination of a visual distraction task (i.e., CRTT) with fMRI of a possibly sexual arousing condition might also induce brain activations associated with selective attention and/or emotional interference. It is well-known that the anterior cingulate and the lateral prefrontal cortex show activations related to conflict monitoring and selective attention [63,64]. Recent research on this topic suggests that also the postcentral gyrus, the middle temporal gyrus, the midcingulate, the inferior parietal lobule, and the insula are involved in the underlying neural processes [65,66]. With respect to our study and to the between-group contrast of individually preferred vs. neutral stimuli in particular, one could assume that pedophilic patients got more distracted by stimuli depicting nude children than did nonsexual offenders by stimuli depicting nude adults. Neural activity in the postcentral gyrus as well as in the insula and anterior midcingulate has been shown to positively correlate with penile tumescence during SA [14,15,18,57,67]. With respect to the last between-group comparison between pedophiles and nonparaphilic offenders, both watching their preferred sexual content, the corresponding results could reflect an early autonomic response (i.e., penile erection) in pedophiles, whereas the J Sex Med 2011;8:1660–1674

Poeppl et al. control group did not show an analogous response. This seems to possibly reproduce Schiffer’s observation of a higher SA level in pedophiles compared with the control group [28]. Pedophilic subjects also showed altered BOLD response in the thalamus, the caudate, and the pallidum (cf. Tanner I > Tanner V within-group contrast), which were found to be related to general emotional arousal during SA [16,21] and to play a crucial role in human reward circuitries in conjunction with the insula [68]. As neural responses in these areas seem to be specific to high reward levels occurring in the context of increasing reward [68], our results seem to suggest higher/lower reward levels and increasing/ decreasing reward in pedophiles when viewing nude prepubescent children (Tanner I)/nude adults (Tanner V), but therefore also dysfunction in this reward circuit with respect to sexual stimuli compared with nonparaphilic subjects. In terms of altered BOLD responses in the pallidum and associated altered reward processing, however, an altered “lovemap” [69] also has to be considered as a causative factor and might explain activations in this neural circuit, which seems to mediate romantic love [70] and partner preference [71]. The thalamus has extensive connections with the insula [72], which in turn has connections with a wide range of paralimbic areas such as the cingulate areas [73]. Electrical stimulation to BA 24 of the cingulate cortex evokes erection in monkeys [74], and activity in the ACC, posterior cingulate cortex (PCC), and the insula (as well as in the caudate) is correlated with the intensity of miscellaneously provoked OCD symptoms [75,76]. More specifically, McGuire and colleagues hypothesized that increases in rCBF in the pallidum and the thalamus occur in response to the urge to perform compulsive movements, while increased neural activity in the hippocampus and PCC relates to the associated anxiety [76]. For the Tanner I > neutral betweengroup contrast, pedophiles showed higher activity than controls in the PCC, hippocampus, and thalamus, which may mirror their need for acting on their (child) stimuli-induced urges, analogous to OCD patients. In addition, increased activity in the ACC, PCC, and also particularly in the insula during various cue-induced craving scenarios has been revealed by functional imaging of human drug abusers [77,78], whereas a disruption of addiction was reported after insular lesions [79]. Hence, the insula is supposed to play a crucial part in conscious drug urges and in translating interoceptive signals into behavioral

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Functional Brain Abnormalities in Pedophilia biases during decision making that involves uncertain risk and reward [80]. Altered insular functionality associated with stimuli depicting children, especially as revealed by the last between-group contrast of individually preferred against neutral stimuli, seems to underline the notion of addictive behavior in pedophilia [81], which might also explain to some extent the considerable recidivism rates [37] in this form of paraphilia. A previous study reported that pedophilic patients showed significantly lower signal intensities in the left insula than healthy control subjects when viewing erotic pictures depicting adults [27]. Two earlier studies found significantly increased activation for pedophiles compared with healthy controls in the ACC (BA 24, 32) in response to child-related stimuli [28] and less activation in the ACC (BA 24, 32, 33) and PCC (BA 30, 31) when stimulated with erotic pictures of adults [29]. Consistent with these results and integrating them, we observed higher activity in the right PCC (BA 31) in pedophilic patients compared with nonpedophilic control subjects when viewing prepubescent children, a deactivation of the right insula when viewing adults, and increased signal intensities in BA 24 of the anterior midcingulate cortex and the insula bilaterally when both groups were viewing their preferred pictures. These congruent findings in the light of cingulate gyrus and insula playing a crucial role in obsessive–compulsive and addictive behavior might indicate potential relationships and similarities of pedophilia with OCD [82] and addiction [81]. In fact, the notion of “compulsive–aggression” in pedophilia has been proposed by psychological research [83]. Moreover, similarities in personality traits between pedophiles and opiate addicts suggest the consideration of pedophilia as a behavioral addiction [81]. Although cingulate gyrus and insula respond to a variety of stimuli and reverse inference must therefore be made with caution, the results of our study may represent the neural correlates of this model of pedophilia.

previous neuroimaging and psychological research on pedophilia. Despite these consistencies, further investigations are needed. For future research, we strongly recommend the use of non-incarcerated community controls and—if possible—the recruitment of self-identified, non-incarcerated pedophiles (either drawn from groups seeking treatment anonymously or attracted through an Internet survey). However, in consideration of the rich receptor architecture of the cingulate gyrus [84] and the insula [80] as well as reports of successful pharmacological manipulation [85–87], our findings contribute to a better understanding and possibly improved treatment of pedophilia. In addition, both CRTT and functional imaging revealed group differences in response to prepubescent and adult stimuli but not to pubescent stimuli. Therefore, in analogy to the assessment of sexual orientation using the BOLD effect [88], fMRI might also become a prospective complementary tool for diagnosing pedophilia. This assertion is especially likely to hold when fMRI is combined with attention-based techniques such as the choice reaction time method, as implemented in the present study.

Acknowledgements

This study was supported by an Academy of Finland grant (121232) to the fourth (P. Santtila) and last authors (A. Mokros). We thank Matthias Dinnbier, M.Sc., for important suggestions and technical assistance. Corresponding Author: Andreas Mokros, PhD, University of Regensburg, School of Medicine, Department of Forensic Psychiatry and Psychotherapy, District Hospital, Universitaetsstrasse 84, D-93053 Regensburg, Germany. Tel: +49-941-941-1083; Fax: +49-941941-1085; E-mail: [email protected] Conflict of Interest: None.

Statement of Authorship

Category 1 Conclusion

The brain response of pedophiles to visual stimulation by images of nude prepubescents is comparable with nonpedophilic neural processing of VSS depicting nude adults. Both cingulate gyrus and insular regions seem to play an important role in pedophilic sexual interest. In this regard, the results of this study add to and are in line with

(a) Conception and Design Timm B. Poeppl; Joachim Nitschke; Pekka Santtila; Andreas Mokros (b) Acquisition of Data Timm B. Poeppl; Joachim Nitschke; Michael Osterheider; Andreas Mokros (c) Analysis and Interpretation of Data Timm B. Poeppl; Beate Dombert; Mark W. Greenlee; Andreas Mokros J Sex Med 2011;8:1660–1674

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Category 2 (a) Drafting the Manuscript Timm B. Poeppl; Andreas Mokros (b) Revising It for Intellectual Content Joachim Nitschke; Beate Dombert; Pekka Santtila; Mark W. Greenlee; Michael Osterheider

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Supporting Information Additional Supporting Information may be found in the online version of this article: Table S1 Active brain regions in nonpedophilic offenders during stimulation with pictures of nude adults Please note: Wiley-Blackwell are not responsible for the content or functionality of any supporting materials supplied by the authors. Any queries (other than missing material) should be directed to the corresponding author for the article.