Effects of Visual Sexual Stimuli and Apomorphine SL on Cerebral Activity in Men with Erectile Dysfunction

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1 European Urology European Urology 43 (2003) Effects of Visual Sexual Stimuli and Apomorphine SL on Cerebral Activity in Men with Erectile Dysfunction Jörn H. Hagemann a, Georg Berding b, Sven Bergh b, Darryl J. Sleep c, Wolfram H. Knapp b, Udo Jonas a, Christian G. Stief a,* a Department of Urology and Pediatric Urology, University School of Medicine, Carl-Neuberg-Strasse 1, D Hannover, Germany b Department of Nuclear Medicine, University School of Medicine, Hannover, Germany c Abbott Laboratories, Abbott Park, IL, USA Accepted 28 December 2002 Abstract Purpose: The present study investigates whether cerebral activation during visually evoked sexual arousal is different in patients with erectile dysfunction (ED) compared to the known pattern observed in healthy men, and additionally how cerebral activity during visual sexual stimulation is modified by treatment with apomorphine SL and whether the observed cerebral activity correlates with penile rigidity. Patients and Methods: Cerebral activity was measured before and after treatment in 12 patients with erectile dysfunction randomised to receive either apomorphine SL or placebo using [ 15 O]H 2 O-PET. Two PET scans were performed prior to administration of the study medication, the first after a neutral audiovisual stimulus and the second following a sexually stimulating audiovisual presentation. After receiving the study medication, patients were subjected to two additional scans each preceded by a sexually stimulating stimulus. Penile rigidity was assessed with the RigiScan 1 device. Evaluation for significant regional cerebral activation was performed using statistical parametric mapping (SPM99). Results: Cerebral activity increased significantly after the sexually stimulating video sequence compared to the neutral one in the inferior frontal cortex (Brodmann areas [BA] 47, 10, 11) and the rostral anterior cingulate (BA 32), and cerebral activity was observed to decrease in both inferior temporal cortices (BA 20). 4 out of 6 patients showed significant penile rigidity after apomorphine SL and in none of those receiving placebo. Apomorphine SL was observed to increase cerebral activity in the right superior prefrontal area (BA 6) that was not seen with placebo, while neither apomorphine SL nor placebo produced decreased cerebral activity. Penile rigidity correlated with increased cerebral activity in the anterior cingulum and right prefrontal cortex, and with decreased activity in the temporal cortex. Conclusions: In patients with erectile dysfunction, the pattern of increased and decreased cerebral activity in response to visual sexual stimuli in this study is similar to that reported in the literature in healthy men. Apomorphine SL appears to induce additional cerebral activity in the right prefrontal cortex, an area previously shown to be associated with sexual arousal in male volunteers during orgasm. This increased cerebral activity was associated with penile rigidity, further supporting the conclusion that apomorphine SL improves erectile function in men with ED by enhancing the natural central erectile signals that normally occur during sexual stimulation. # 2003 Elsevier Science B.V. All rights reserved. Keywords: Erectile dysfunction; Sexual arousal; Apomorphine; Functional imaging 1. Introduction * Corresponding author. Tel. þ ; Fax: þ address: stief.christian@mh-hannover.de (C.G. Stief). Studies of CNS activity during sexual arousal and penile erection in healthy men have provided strong evidence that central neuroanatomical structures are /03/$ see front matter # 2003 Elsevier Science B.V. All rights reserved. doi: /s (03)

2 J.H. Hagemann et al. / European Urology 43 (2003) involved in this state. Modified activation has been particularly reported for the orbitofrontal cortex, the anterior cingulate and the temporal cortex [1 5]. Penile erection can be induced in healthy male volunteers with the dopamine receptor agonist apomorphine [6]. Cortical activation is likely to be part of the mechanism of action, since it has been demonstrated in volunteers that apomorphine increases activity particularly in the anterior cingulate and prefrontal cortex [7,8]. Moreover, it is capable of restoring task related activation of the anterior cingulum and supplementary motor area in patients with schizophrenia and Parkinson s disease [9,10]. Apomorphine has been used therapeutically for many years in Parkinson s disease to compensate the striatal dopaminergic deficit [11]. Experimental data indicates that the dopaminergic system is also important in erectile function. Autonomic innervation of the penis that originates from the paraventricular nucleus (PVN) of the hypothalamus has been identified using pseudorabies virus injection into the penis. Electrical stimulation, as well as microinjection of apomorphine into the PVN, have been shown to induce penile erection in rats [12,13]. Therefore, it is appropriate to use apomorphine in the treatment of erectile dysfunction (ED). The erectogenic effect of subcutaneous apomorphine was demonstrated patients with ED [14,15]. Oral (sublingual) application of apomorphine (apomorphine SL) is an effective treatment for ED and has been proven to have significant erectogenic properties with few side effects [16]. In the context of data set out above, functional imaging studies are of particular interest to demonstrate the central mechanism of action of apomorphine in patients with erectile dysfunction. However, direct imaging of D 2 -receptors in the PVN to identify potential abnormalities is not feasible even with dedicated fullring PET devices, due to the small size of the PVN and the adjacent striatum with it is high D 2 -receptor density. Moreover, D 2 -receptor imaging could theoretically only show displacement of the radioligand used for imaging from the receptor and would not be suitable to trace effects of apomorphine on further CNS structures. Therefore, we employed [ 15 O]H 2 O- PETas a marker of regional cerebral blood flow (rcbf) to assess the effects of apomorphine SL in patients with erectile dysfunction on cerebral activity. The present study investigates in detail: (i) whether visual sexual stimuli induce a distinct pattern of cerebral activity in patients with erectile dysfunction compared to that seen in healthy men, (ii) how cerebral activation is altered in patients with erectile dysfunction responding to apomorphine SL compared to a control group receiving placebo and (iii) if cerebral regions can be identified with activity that correlates to the degree of penile erection (rigidity). 2. Patients and methods 2.1. Patients A total of 12 men with erectile dysfunction were enrolled in the study. The diagnosis of ED was based on the documentation of less than 50% successful attempts to attain and/or maintain an erection firm enough for intercourse with his partner for a minimum of 90 days prior to inclusion in the study, or if no attempts were made in those 90 days, other anamnestic documentation indicating the diagnosis of erectile dysfunction. In all patients, intrinsic penile function was preserved as documented by a history of an ability to attain an erection at some time-point since the onset of erectile dysfunction as evidenced by nocturnal/morning erections, masturbatory erection and/or other sexual activity. The mean age of the patients was 35 years (range 24 41); the mean weight was 82 kg (range 65 93); and mean height was 180 cm (range ). Six of the subjects were smokers and nine consumed alcohol; all subjects were right-handed. There were no clinically significant laboratory serum or urine abnormalities. Upon meeting the enrollment criteria, subjects were assigned a 2-digit Subject Number in ascending numerical order. Based on these numbers, the subjects were randomly assigned in equal proportion to two treatment groups. One group received placebo and the other 4 mg apomorphine SL during the PET procedures described further Methods RigiScan 1 monitoring A RigiScan 1 device, as originally described by Bradley et al. [17], was utilized for continuous real time monitoring of penile rigidity during all PET procedures. Measurements were started 10 minutes before the first PET scan. Measurements were performed continuously during the study procedure and for 10 minutes after the last PET scan. Rigidity (percent of linear displacement of the loops due to the constant force) was determined and charted for the periods during the PET scans. A rigidity of at least 40% after receiving the medication was considered as a positive response, while values below 40% were considered as non-response [18] Positron emission tomography Four PET scans were performed in each patient. Before each PET study, a 30-second video sequence of neutral (before 1st study) or sexually stimulating content (before 2nd, 3rd and 4th PET studies) was presented to the patient via video glasses. The neutral video clip presented the townscape of Toronto, Canada, while a visual auditory pornographic video clip, featuring heterosexual intercourse, was selected for the stimulating sequence. At the end of the second PET study, the patient received either 4 mg apomorphine SL or placebo sublingually. The 3rd and 4th PET studies were performed at 20 minutes and 50 minutes after the study medication was taken. The complete time schedule of the PET procedures is given in Table 1. Patients were placed in comfortable supine position on the scanner bed and the RigiScan 1 device was prepared as described above. Video glasses were applied and the patients head was fixed with a head holder. An initial transmission scan was acquired for 10 minutes. For each PET study, 1.85 GBq [ 15 O]H 2 O was automatically injected intravenously as a bolus over 7 seconds. Simultaneously, a dynamic data acquisition consisting of twelve 5-second, four 15-second, two 30-second and two 60-second frames was started

3 414 J.H. Hagemann et al. / European Urology 43 (2003) Table 1 Time schedule of PET activation studies Min p.i. at a dedicated fullring PET scanner (ECAT EXACT 922/47, Siemens, Erlangen, Germany). Transaxial tomograms of [ 15 O]H 2 O uptake were reconstructed using iterative methods [19]. Uptake was integrated over the first 90 seconds p.i. of the dynamic study. During this period, regional activity was linearly correlated with regional cerebral blood flow (rcbf) over a wide flow range [20]. For statistical analysis, the statistical parametric mapping software (SPM99, Wellcome Department of Cognitive Neurology, London, UK) was used. Three-dimensional [ 15 O]H 2 O uptake was transformed into the stereotaxic standard space according to the Montreal Neurological Institute (MNI) using parameter affine transformations and non-linear iterations. The spatially normalised data was analysed using the following statistical models: (i) populations main effect (paired t-test) to detect differences in rcbf between scans after neutral and sexually stimulating video, (ii) compare populations (unpaired t-test) for the assessment of differences before and after apomorphine SL and (iii) singlesubject covariates only to evaluate correlation between rigidity and rcbf. For statistical inferences, an uncorrected p-value on voxel level of p < 0:001 (Z > 3:09) together with an uncorrected p-value on cluster level of p < 0:05 was used [21]. 3. Results Start of 0 Neutral video sequence 0.5 1st PET study 15 Sexually stimulating video sequence nd PET study 20.5 Administration of apomorphine or placebo 40 Sexually stimulating video sequence rd PET study 70 Sexually stimulating video sequence th PET study 3.1. Clinical results Two subjects reported the adverse event of headache; both were receiving placebo. One headache occurred within 10 minutes and one within 16 minutes after Table 2 Results of RigiScan 1 measurements (average values of percent rigidity measured at tip and base of the penis are given) Medication Rigidity at baseline Rigidity 20 min after medication Rigidity 50 min after medication Placebo No Placebo No Placebo No Placebo No Placebo No Placebo No Apomorphine SL No Apomorphine SL No Apomorphine SL Yes Apomorphine SL Yes Apomorphine SL Yes Apomorphine SL Yes Response receiving placebo. Both events were mild in severity, did not last longer than 2 hours and did not fulfill any criteria of a serious adverse event. No adverse events were observed after administration of apomorphine SL. A positive RigiScan 1 response was seen in 4 out of 6 patients receiving apomorphine SL, while no significant response was observed in any patient receiving the placebo. Details of the RigiScan 1 results are provided in Table Results of positron emission tomography Cerebral activation/deactivation due to sexually stimulating video Increases in regional cerebral blood flow (rcbf) were detected in the cingulated cortex as well as the inferior and anterior frontal cortex after the sexually stimulating video sequence, when compared to the rcbf recorded after the neutral video. Details of the locations of increased rcbf and the degree of significance are demonstrated in Table 3. Significant reductions of rcbf associated with the sexually stimulating Table 3 Regional increases of ½ 15 OŠH 2 O uptake (rcbf) observed in patients with erectile dysfunction after watching a sexually stimulating video compared to rcbf after seeing a neutral video MNI coordinates x,y,z (mm) Localisation (cortex) Brodmann area Cluster level Voxel level Corrected p k voxels Uncorrected p Corrected p Z Frontal inferior Cingulate Frontal anterior Frontal anterior Frontal inferior Frontal inferior Frontal inferior Putamen rcbf: regional cerebral blood flow, MNI: Montreal Neurological Institute, positive x-coordinates indicate right side.

4 J.H. Hagemann et al. / European Urology 43 (2003) Table 4 Regional decreases of ½ 15 OŠH 2 O uptake (rcbf) observed in patients with erectile dysfunction after watching a sexually stimulating video compared to rcbf after seeing a neutral video MNI coordinates x,y,z (mm) Localisation (cortex) Brodmann area Cluster level Voxel level Corrected p k voxels Uncorrected p Corrected p Z Temporal inferior Temporal inferior Temporal inferior Parietal superior Parietal superior Temporal inferior rcbf: regional cerebral blood flow, MNI: Montreal Neurological Institute, positive x-coordinates indicate right side. video sequence were observed bilaterally in the inferior temporal and superior parietal cortecies when compared to the rcbf pattern associated with the neutral sequence (Table 4). Fig. 1 shows overlays of the statistical parametric maps, areas of significantly increased (A) or decreased (B) rcbf to magnetic resonance (MR) images, confirming the stereotaxic standard space according to MNI Cerebral activation following medication Regional cerebral blood flow after viewing the sexually stimulating video sequence was compared before and after receiving a sublingual tablet of either placebo or apomorphine SL for each group independently. No significant changes in rcbf were recorded after patients received placebo compared with the sexually stimulating sequence alone. In contrast, apomorphine SL resulted in a significant increase in rcbf in the right superior prefrontal cortex of patients who recorded a positive erectile response as measured by RigiScan 1. The anatomical localisation of the activated area is shown in Fig. 2, while details of SPM analysis are shown in Table 5. No significant decreases in rcbf were detected after patients received apomorphine SL Correlation between cerebral activation and penile rigidity Results of RigiScan 1 measurements correlated to rcbf measurements at corresponding times (without differentiation whether apomorphine SL or placebo was given): a positive correlation between penile rigidity and rcbf in the superior prefrontal cortex was seen 20 minutes after apomorphine SL was dosed, while a negative correlation between rcbf in the cerebellum and penile rigidity was found. At 50 minutes after apomorphine SL was taken there was a correlation between penile rigidity and increased rcbf in the cingulated and decreased activity in the medial temporal cortex. Areas of positive and negative correlation at the respective times are displayed in Fig. 3. Stereotactic coordinates, extent and significance level of the detected correlations are given in Table Discussion This study investigated cerebral activation recorded as alterations in regional cerebral blood flow measured by PET scanning during sexual arousal with visual sexual stimuli, the effect of apomorphine SL on the rcbf activity pattern, and the correlation between regional cerebral activity and penile rigidity in patients with erectile dysfunction. Increased activity was detected in the inferior (orbito-) frontal cortex (with a right predominance) and the anterior cingulum with visual sexual stimulation. These results are essentially the same compared to literature as sexual induced activity that has been reported in the same brain regions using similar activation paradigms in healthy men [1 5]. Table 5 Regional increase of ½ 15 OŠH 2 O uptake (rcbf) observed in patients with erectile dysfunction responding to apomorphine SL after the drug was given compared to before MNI coordinates x,y,z (mm) Localisation (cortex) Brodmann area Cluster level Voxel level Corrected p k voxels Uncorrected p Corrected p Z Prefrontal superior In this comparison only PET studies after the patient watched a sexually stimulating video were included. rcbf: regional cerebral blood flow, MNI: Montreal Neurological Institute, positive x-coordinate indicates right side.

5 416 J.H. Hagemann et al. / European Urology 43 (2003) Fig. 1. Brain areas in patients with erectile dysfunction showing increased (A) or decreased (B) activity (rcbf) due to the observation of a sexually stimulating video sequence before the PET measurement, compared to activity after watching a neural video (townscape) as reference condition. Displayed are the respective statistical parametric maps overlaid to MR images confirming a sterotaxic standard space (MNI).

6 J.H. Hagemann et al. / European Urology 43 (2003) Fig. 2. Regional increase of activity (rcbf) in the right superior prefrontal cortex of patients responding to apomorphine SL compared to PET studies before medication was given (all investigations included were performed after the patient watched a sexually stimulating video clip). The activation of the orbitofrontal region observed after visual sexual stimulation is plausible because of the known involvement of this region in the regulation of emotional expression and experience. This is supported by the theories of mind reading and mirroring that stress the relevance of the orbitofrontal region for mentally placing oneself in the position of another person (i.e. for patients in this study, in the position of the actor of the stimulating video) [1,22]. There are several indications that sexual stimuli are processed particularly in the right orbitofrontal cortex. By means of functional magnetic resonance (fmri), this area has been demonstrated to represent reward; therefore, activity in this region shown in the present study may be related to pleasant bodily sensations induced by penile tumescence [23]. Moreover, EEG studies showed a right hemispheric preponderance of activation during orgasm in healthy volunteers and in actors generating feelings of sexual arousal [24,25]. The activation recorded in the anterior cingulum after the patient viewed the sexually stimulating video is in accordance with experimental data that demonstrated that electrical stimulation of the anterior cingulate cortex elicits penile erection in monkeys [26]. Furthermore, this region of the brain is known to modulate autonomic responses in man and has been found to be one of the cerebral areas where electrical discharge started in partial seizures with sexual manifestations [27]. With respect to subregions of the anterior cingulum, we found the most significant activation with sexual stimulation occurred in the rostral part (BA 32). This finding is similar to those of other activation studies using PET and fmri, demonstrating that this area may mediate subjective emotional responses [28,29]. Moreover, activation in area BA 32 has been demonstrated during sexual arousal induced by script driven imagery [3]. Conflicting results have been reported with respect to the activity of temporal cortices after visual sexual stimulation. Some studies have reported increased activation of this area with sexual stimulation [1,5]. In these studies, the visual sexual stimulation was continued during the PET acquisition. Redoute et al. [4], however, observed decreased temporal activity with sexual stimulation, as was the case in the present study. In our study, visual stimulation was terminated at Table 6 Regions with correlation between ½ 15 OŠH 2 O uptake (rcbf) and percent of penile rigidity in patients with erectile dysfunction (after watching a sexually stimulating video and having received either placebo or apomorphine SL) MNI coordinates x,y,z (mm) Localisation (cortex) Brodmann area Cluster level Voxel level Corrected p k voxels Uncorrected p Corrected p Z Prefrontal superior Prefrontal superior Prefrontal superior Cerebellum Cingulate Temporal medial Temporal medial rcbf: regional cerebral blood flow, MNI: Montreal Neurological Institute, positive x-coordinates indicate right side, 1: positive, 2: negative correlation 20 minutes after medication; 3: positive, 4: negative correlation 50 minutes after medication.

7 418 J.H. Hagemann et al. / European Urology 43 (2003) Fig. 3. Regions of positive (A) and negative (B) correlation between cerebral activity (rcbf) and penile rigidity measured 20 minutes and 50 minutes after medication (either placebo or apomorphine SL) was given. the beginning of the PET acquisition. Decreased temporal cortical activity was also found (in the inferior temporal cortex) when sexual arousal was induced by script driven imagery rather than visual stimulation [3]. Therefore, temporal cortical activation, particularly in the posterior temporal cortex that has been observed in some of the above studies, might not be related to sexual arousal but rather to the visual stimulation itself.

8 J.H. Hagemann et al. / European Urology 43 (2003) That decreased activity of temporal cortices is the likely characteristic feature of sexual arousal is also supported by the observation of hypersexuality that occurs after removal of the temporal lobes in epilepsy surgery [30]. These observations imply a tonic inhibition of sexual arousal by temporal cortices. In normal controls, apomorphine SL has been demonstrated to increase cerebral activity in the anterior cingulum [7,8]. This supports the rationale of using apomorphine SL for the treatment of erectile dysfunction, since activation of this region appears to be particularly relevant for sexual arousal and penile erection. However, we could not detect any specific increased activity in the anterior cingulate cortex after apomorphine SL dosing. This could be explained by the fact that in this study, only activation that was additional to that caused by the visual sexual stimulation was considered as being due to apomorphine SL. In an earlier preliminary study by Montorsi et al. [31], using fmri to detect cerebral activation caused by apomorphine SL with visual sexual stimulation, activation of the anterior cingulum was also not detected. However, as in the present study, the authors reported increased activity caused by apomorphine SL in the superior prefrontal cortex. These observations are in keeping with the increased activity observed in the prefrontal cortices after apomorphine SL was administered to healthy volunteers with right-sided predominance in another earlier study [7,8]. Furthermore, in a recent SPECT study of rcbf during orgasm in healthy right-handed males, the right prefrontal cortex was found to be the only region activated [32]. We found increased activity, specifically in the right prefrontal cortex with apomorphine SL. The evidence from both normal control subjects as well as patients with erectile dysfunction suggests that apomorphine increases activity in this region of the brain that is obviously involved in sexual arousal. Finally, we observed a correlation between cerebral activity and penile rigidity in a group of patients with erectile dysfunction in which penile erection was achieved in two thirds of those receiving apomorphine SL. Positive correlation (increased activity) was observed in the right superior prefrontal cortex and the anterior cingulum, while a negative correlation (decreased activity) was found in the temporal region. The relevance of the activation/deactivation of these regions in sexual arousal and penile erection has already been emphasised. The observed correlations provide further support that apomorphine contributes to the enhanced cerebral activity observed in those regions of the brain that are involved in erectogenic function. 5. Conclusion Audiovisual sexual stimulation has been shown to result in increased cerebral activity in specific areas and decreased cerebral activity in others of both patients with erectile dysfunction and healthy men. Furthermore, the areas of increased and decreased activity are generally the same for both groups of men. Apomorphine SL has been shown to improve the erectile function of approximately 70% of men with erectile dysfunction. Apomorphine SL has an exclusive central mechanism of action that has been shown to involve the enhancement of dopamine mediated erectogenic signals in the paraventricular nucleus of the hypothalamus. In addition, these results and those of other studies suggest that other central structures may be involved in the erectogenic effect of apomorphine, in particular the right prefrontal cortex, a finding consistent with the known relevance of this area in sexual arousal in healthy men and the known effect of apomorphine on cerebral activity in normal volunteers. The results of this study indicate that apomorphine SL improves erectile function in men with ED by enhancing the natural signals that are normally generated during sexual stimulation. References [1] Bocher M, Chisin R, Parag Y, Freedman N, Meir Weil Y, Lester H, et al. Cerebral activation associated with sexual arousal in response to a pornographic clip: A 15 OH 2 O PET study in heterosexual men. NeuroImage 2001;14: [2] Park K, Seo JJ, Kang HK, Ryu SB, Kim HJ, Jeong GW. A new potential of blood oxygenation level dependent (BOLD) functional MRI for evaluation cerebral centers of penile erection. Int J Impotence Res 2001;13: [3] Rauch SL, Shin LM, Dougerty DD, Alpert NM, Orr SP, Lasko M, et al. Neural activation during sexual and competitive arousal in healthy men. Psychiatry Res 1999;91:1 10. [4] Redoute J, Stoleru S, Gregoire MC, Costes N, Cinotti L, Lavenne F, et al. Brain processing of visual stimuli in human males. Hum Brain Mapp 2000;11: [5] Stoleru S, Gregoire MC, Gerad D, Decety J, Lafarge E, Cinotti L, et al. Neuroanatomical correlates of visually evoked sexual arousal in human males. Arch Sex Behav 1999;28:1 21. [6] Danjou P, Alexandre L, Warot D, LaComblez L, Pvech A. Assessment of erectogenic properties of apomorphine and yohimbine in man. Br J Clin Pharmacol 1988;26: [7] Grasby PM, Friston KJ, Bench CJ, Cowen PJ, Frith CD, Liddle PF, et al. The effect of the dopamine agonist, apomorphine, on regional

9 420 J.H. Hagemann et al. / European Urology 43 (2003) cerebral blood flow in normal volunteers. Psychol Med 1993;23: [8] Kapur S, Meyer J, Wilson AA, Houle S, Brown GM. Activation of specific cortical regions by apomorphine: an [ 15 O]H 2 O positronemission tomography (PET) in humans. Neurosci Lett 1994;176:21 4. [9] Fletcher PC, Frith CD, Grasby PM, Friston KJ, Dolan RJ. Local and distributed effects of apomorphine on fronto-temoral function in acute unmediated schizophrenia. J Neurosci 1996;16: [10] Jenkins IH, Fernandez W, Playford ED, Lees AJ, Frackowiak RS, Passingham RE, et al. Impaired activation of the supplementary motor area in Parkinson s disease is reversed when akinesia is treated with apomorphine. Ann Neurol 1992;32: [11] Tolosa E, Marti MJ, Valldeoriola F, Molinuevo JL. History of levodopa and dopamine agonists in Parkinson s disease treatment. Neurology 1998;50(6 Suppl):S2 10. [12] McKenna KE. Central control of penile erection. Int J Impotence Res 1998;10(Suppl 1):S [13] Melis M, Argiolas A, Gessa G. Apomorphine-induced penile erection and yawning: site of action in brain. Brain Res 1987;415: [14] Lal S, Laryea E, Thavundayil JX, Nair NP, Negrete J, Ackman D, et al. Apomorphine-induced penile tumescence in impotent patients preliminary findings. Prog Neuro-Psychopharmacol Biol Psychiatry 1987;11: [15] Segraves RT, Bari M, Segraves K, Spirnak P. Effect of apomorphine on penile tumescence in men with psychogenic impotence. J Urol 1991;145: [16] Heaton JP, Morales A, Adams MA, Johnston B, el-rashidy R. Recovery of erectile function by the oral administration of apomorphine. Urology 1995;45: [17] Bradley WE, Timm GW, Gallagher JM, Johnson BK. New method for continuous measurement of nocturnal penile tumescence and rigidity. Urology 1985;26:4 9. [18] Kessler WO. Nocturnal penile tumescence. Urol Clin North Am 1988;15:81 6. [19] Hudson HM, Larkin RS. Accelerated image reconstruction using ordered subsets of projection data. IEEE Trans Med Image 1994; 13: [20] Shin LM, Kosslyn SM, McNally RJ, Alpert NM, Thompson WL, Rauch SL, et al. Visual imagery and perception in posttraumatic stress disorder. A positron emission tomograpic investigation. Arch Gen Psychiatry 1997;54: [21] Signorini M, Paulesu E, Friston K, Perani D, Colleluori A, Lucignani G, et al. Rapid assessment of regional cerebral metabolic abnormalities in single subjects with quantitative and nonquantitative [ 18 F]FDG PET: A clinical validation of statistical parametric mapping. NeuroImage 1999;9: [22] Damasio H, Grabowski T, Frank R, Galaburda AM, Damasio AR. The return of Phineas Gage: clues about the brain from the skull of a famous patient. Science 1994;264: [23] Francis S, Rolls ET, Bowtell R, McGlone F, O Doherty J, Browning A, et al. The representation of pleasant touch in the brain and its relationship with taste and olfactory areas. NeuroReport 1999;10: [24] Cohen HD, Rosen RC, Goldstein L. Electroencephalographic laterality changes during human sexual orgasm. Arch Sex Behav 1976;5: [25] Tucker DM, Dawson SL. Asymmetric EEG changes as method actors generated emotions. Biol Psychol 1984;19: [26] Robinson BW, Mishkin M. Penile erection evoked from forebrain structures in Macaca mulatta. Arch Neurol 1968;19: [27] Devinsky O, Morrell MJ, Vogt BA. Contributions of anterior cingulate cortex to behaviour. Brain 1995;118: [28] Lane RD, Reiman EM, Ahern GL, Schwartz GE, Davidson RJ. Neuroanatomical correlates of happiness, sadness, and disgust. Am J Psychiatry 1997;154: [29] Teasdale JD, Howard RJ, Cox SG, Ha Y, Brammer MJ, Williams SC, et al. Functional MRI study of the cognitive generation of affect. Am J Psychiatry 1999;156: [30] Terzian H, Dalle Ore G. Syndrome of Klüver and Bucy reproduced in man by bilateral removal of temporal lobes. Neurology 1955;5: [31] Montorsi F, Salonia A, Scifo P, Anchisi D, Rigiroli P, Zanoni M, et al. Human cerebral activation by apomorphine after neutral and erotic visual stimulation: Results of a double blind, placebo-controlled study with functional MRI of the brain. J Urol 2001;165(Suppl 5):913. [32] Tiihonen J, Kuikka J, Kupila J, Partanen K, Vainio P, Airaksinen J, et al. Increase in cerebral blood flow of right prefrontal cortex in man during orgasm. Neurosci Lett 1994;170:241 3.