Dynamics of male sexual arousal: Distinct components of brain

activation revealed by fMRI

Antonio Ferretti,
a,b,
*
Massimo Caulo,
b
Cosimo Del Gratta,
a,b
Rosalia Di Matteo,
b
Arcangelo Merla,
b
Francesco Montorsi,
c
Vittorio Pizzella,
a,b
Paolo Pompa,
d
Patrizio Rigatti,
c
Paolo Maria Rossini,
e,f,g
Andrea Salonia,
c
Armando Tartaro,
a,b
and Gian Luca Romani
a,b
a
Istituto di Tecnologie Avanzate Biomediche-Fondazione Universita` G. DAnnunzio, Chieti, Italy
b
Dipartmento di Scienze Cliniche e Bioimmagini, Universita` G. DAnnunzio, Chieti, Italy
c
Unita` Operativa e Cattedra di Urologia, Universita` Vita e Salute, Ospedale S. Raffaele, Milano, Italy
d
Divisione di Urologia, Ospedale SS. Annunziata, Chieti, Italy
e
Dipartimento di Neurologia, Ospedale Fatebenefratelli-Isola Tiberina, Roma, Italy
f
Universita` Campus Bio-Medico, Roma, Italy
g
IRCCS Centro S. Giovanni di Dio, Brescia, Italy
Received 27 September 2004; revised 9 March 2005; accepted 17 March 2005
Available online 28 April 2005
The peripheral mechanisms of male sexual arousal are well known.
Recently, neuroimaging techniques, such as PET or fMRI, allowed the
investigation of the subjacent cerebral mechanisms. In ten healthy
subjects, we have simultaneously recorded fMRI images of brain
activation elicited by viewing erotic scenes, and the time course of
penile tumescence by means of a custom-built MRI-compatible
pneumatic cuff. We have compared activation elicited by video clips
with a long duration, that led to sexual arousal and penile erection, and
activation elicited by briefly presented still images, that did induce
sexual arousal without erection. This comparison and the use of the
time course of penile tumescence in video clips allowed to perform a
time resolved data analysis and to correlate different patterns of brain
activation with different phases of sexual response. The activation
maps highlighted a complex neural circuit involved in sexual arousal.
Of this circuit, only a few areas (anterior cingulate, insula, amygdala,
hypothalamus, and secondary somatosensory cortices) were specifically
correlated with penile erection. Finally, these areas showed distinct
dynamic relationships with the time course of sexual response. These
differences might correspond to different roles in the development and
appraisal of the sexual response. These findings shed light on the
psychophysiology of male sexuality and open new perspectives for the
diagnosis, therapy, and possible rehabilitation of sexual dysfunction.
D 2005 Elsevier Inc. All rights reserved.
Keywords: Brain mapping; Functional magnetic resonance imaging;
Psychophysiology of sexual behavior
Introduction
Human sexual arousal is a multidimensional experience
comprising physiological and psychological processes. Studies
on sexual behavior have mainly focused on the peripheral
mechanisms of sexual response. The neurovascular, autonomic,
and hormonal mechanisms involved in the sexual response in man
have been for the largest part established (Anderson, 2003; Morrel
et al., 1994; Simonsen et al., 2002). However, relatively little is
known about the brain areas supporting the psychological
mechanisms involved in sexual response and of the hierarchical
organization along with the different stages characterizing sexual
arousal, penile tumescence, and erection.
Modern techniques dealing with mapping procedures of brain
function in time and space allow the in vivo observation of brain
activation correlated with sensory or cognitive processing and
emotional states. Previous studies (Arnow et al., 2002; Beauregard
et al., 2001; Bocher et al., 2001; Hamann et al., 2004; Holstege et
al., 2003; Karama et al., 2002; Mouras et al., 2003; Park et al.,
2001a,b; Redoute et al., 2000, 2005; Stoleru et al., 1999) using
functional magnetic resonance imaging (fMRI) or positron
emission tomography (PET), and remote sexual stimuli such as
visual erotica, have shown increased neural activity in several areas
including the inferior right frontal cortex, the inferior temporal
cortex, the left anterior cingulate cortex, and the right insula,
possibly representing a distributed network.
The aim of this study was to disentangle the spatiotemporal
characteristics of relationships among brain areas during the
various phases of a behavioral response to visual erotic stimuli
leading to a complete erection, and distinguishing them from each
other and from non-sexual arousal and attention. Since there is
1053-8119/$ - see front matter D 2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.neuroimage.2005.03.025
* Corresponding author. Institute for Advanced Biomedical Technologies,
University G. DAnnunzio of Chieti, Via dei Vestini, 33, 66013 Chieti
(CH), Italy. Fax: +39 0871 3556930.
E-mail address: aferretti@itab.unich.it (A. Ferretti).
Available online on ScienceDirect (www.sciencedirect.com).
www.elsevier.com/locate/ynimg
NeuroImage 26 (2005) 1086 1096
general consensus that penile erection in a sexual context is the
best index of sexual arousal, we simultaneously recorded both the
BOLD response and the level of penile tumescence during visual
erotic stimulation in two different fMRI experimental paradigms.
In the first paradigm, participants were presented with prolonged
erotic video clips, while in the second paradigm they were briefly
presented with erotic still images. The on-line continuous measure-
ment of penile tumescence allowed: (1) to identify, in the former
paradigm, the linkage between successive phases of behavioral
response and the hierarchy of the distributed brain network
supporting it; and (2) to verify that the latter paradigm never led
participants to penile erection while the former always did. The
hypothesis was that brain areas activated only in the former
condition should be related to erection rather than to simple sexual
arousal and that in the former condition the relative timing of the
activated areas should reflect the progression from a general sexual
arousal to a sustained sexual response.
Methods
Subjects and stimuli
Ten healthy heterosexual male volunteers ranging in age from
21 to 25 years were enrolled in this study. All subjects received a
detailed explanation of the study design and gave their written
informed consent according to the Declaration of Helsinki (World
Medical Association Declaration of Helsinki, 1997). The protocol
was approved by the local Ethics Committee. Prior to the study,
participants were interviewed in order to assess their motivation to
participate in the study and were asked to complete: (1) a sexual
behavior inventory (SESAMO, Sexuality Evaluation Schedule
Assessment Monitoring; Boccadoro, 1996), identifying back-
ground information such as age, sexual status, availability of a
current partner, and sexual experience, and (2) a battery of
questionnaires (CBA, Cognitive Behavioral Assessment; Berto-
lotti, 1987), providing multidimensional distress indices (State-
Trait Anxiety Inventories, Eysenck Personality Questionnaire,
Depressive Symptoms Assessment Questionnaire, and Maudsley
ObsessiveCompulsive Questionnaire). None of the participants
revealed symptoms of psychological disease or personality
disorders. Finally, the subjects were asked to fill out the Interna-
tional Index of Erectile Dysfunction questionnaire (Rosen et al.,
1997). All subjects underwent two distinct studies in the same
session.
The first study was performed according to a standard block
paradigm, with prolonged visual stimulation using erotic, sport,
and neutral video clips. Erotic video clips showed consensual
sexual interactions between one man and one woman (petting,
vaginal intercourse, and oral sex), following the guidelines of
Koukounas and Over (1997). The video clips were selected from
about 30 segments taken from commercial adult films by 11 male
volunteers (PhD students working in our laboratory). Each
volunteer was asked to view privately the film segments and to
assign a score from 1 to 5 based on his personal feeling of arousal.
The six segments with maximum total score were selected as
stimuli for the fMRI study. This procedure was similar to the one
described by Karama et al. (2002) in a previous study on sexual
arousal, and was adopted in order to select scenes that had greatest
chances to meet the personal preferences of the subjects. Sport
video clips depicted close-up scenes from rugby and football
matches. The neutral video clips showed scenes with an emotion-
ally neutral content (such as ordinary objects, houses, or people).
These scenes were only used as a relaxing pause between different
stimulation conditions and were never used as a baseline for the
calculation of activation maps. The duration of erotic, sport, and
neutral clips was 3 min, 2 min, and 30 s, respectively. A total of 6
erotic, 6 sport, and 12 neutral clips were presented in a single
session (Fig. 1). Video clips were presented alternately, in an
ordered sequence, in which a sport and neutral clips always
preceded an erotic clip, rather than in a randomized order, to avoid
the occurrence of two consecutive erotic clips. In the latter case,
due to the long-lasting mechanism of detumescence, there might
have been a prolongation of the erection phase in the second erotic
clip without the onset phase that would have normally occurred
after a sport video clip. Since, as will be described in detail below,
we wanted to compare activation across different phases of sexual
response, we deliberately avoided the presentation of two consec-
utive erotic video clips. Subjects were asked to report their feeling
of sexual arousal or lack of sexual interest by pressing an MRI
compatible push-button, and the subjective times of beginning and
ending of sexual arousal, respectively, were recorded. We used the
sport video clips as a baseline in order to remove the confounding
effect of non-sexual arousal or attention elicited by the view of
human beings in physical contact with some amount of motion.
The 30-s duration of neutral video clips allowed the emotional
Fig. 1. An example (subject no. 7) of the time course of penile reaction as recorded by the penile tumescence measuring device. The curve is shown against a
schematic of the fMRI acquisition paradigm that consists of six identical epochs, each composed of a sport video clip (light gray), a neutral video clip (white),
an erotic video clip (darker shades of gray), and finally, another neutral video clip (white). The vertical bars represent the times of button depression indicating
the beginning of subjective interest for the erotic content of images (full line) or the lack of interest (dotted line). Different shades of gray in the erotic video clip
sections highlight distinct phases of penile reaction as indicated by the penile tumescence measuring device. Lighter gray: absence of erection (NE); middle
gray: rising erection (OE); and darker gray: sustained erection (SE).
A. Ferretti et al. / NeuroImage 26 (2005) 10861096 1087
disengagement from the content of sport and erotic visual stimuli
(Garret and Maddock, 2001).
The second study was performed according to an event-related
paradigm in which a pseudorandom sequence of sport and erotic
pictures (still images) was used for visual stimulation. The content
of erotic and sport pictures was similar to that used in the study
with video clips. The erotic pictures were selected from about 200
pictures with the same procedure described above for the video
clips. Each picture was shown for 3 s and was followed by a grey
screen for 15 s with approximately the same average luminance of
the pictures. In total, 40 sport and 40 erotic images were
presented.
The presentation of video clips and pictures was controlled by a
MATLAB
\
code running on a PC placed in the scanner console
room. Visual stimuli were projected on a translucent glass placed
on the back of the scanner bore by means of an LCD projector. A
mirror fixed to the head coil inside the magnet allowed the subjects
to view the translucent glass.
Physiological and fMRI data acquisition
In both studies, penile tumescence was recorded continuously,
during visual stimulation and fMRI data acquisition, by means of a
custom-built MRI-compatible pneumatic device. A few days prior
to the experiment, each subject was acquainted with the general
experimental setup and, in particular, with the pneumatic device.
During this trial session, each subject was also presented with sport
and erotic video clips similar to those used during the fMRI session
in order to verify the feasibility of the experiment. The content of
the stimuli was similar in both sessions (i.e., the same kind of
sexual interactions between one man and one woman), but the set
and the actors were different. This solution was adopted to avoid
memory and habituation effects.
Prior to the start of the fMRI acquisition, the pressure cuff was
placed on the penis using a condom and was inflated to an initial
pressure of 80 mm Hg. The cuff was connected by a thin tube to a
pressure transducer placed outside the shielded room. The pressure
transducer was connected to an amplifier and the analog signal
from this device was recorded at a sampling rate of 100 Hz on a PC
for off-line data analysis. A standard head coil was used and the
subjects head was fixed with foam pads to reduce involuntary
movement.
Blood oxygen level dependent (BOLD) contrast functional
images were acquired with a SIEMENS MAGNETOM VISION
scanner at 1.5 T by means of T2*-weighted echo planar imaging
(EPI) free induction decay (FID) sequences with the following
parameters: Study 1: TR 4087 ms, TE 60 ms, matrix size 64 64,
FOV 256 mm, in-plane voxel size 4 mm 4 mm, flip angle 90-,
slice thickness 4 mm and no gap; 535 functional volumes
consisting of 24 transaxial slices were acquired; Study 2: TR
2095 ms, TE 60 ms, matrix size 64 64, FOV 256 mm, in-plane
voxel size 4 mm 4 mm, flip angle 90-, slice thickness 6 mm and
no gap; 715 functional volumes consisting of 16 transaxial slices
were acquired. In order to minimize the susceptibility artifacts in
the deep mesial temporal regions, we oriented the slices in an
oblique-axial fashion to include in the scan volume the smallest
possible portion of the temporal bone. Finally, a high resolution
structural volume was acquired at the end of the session via a 3D
MPRAGE sequence with the following features: sagittal, matrix
256 256, FOV 256 mm, slice thickness 1 mm, no gap, in-plane
voxel size 1 mm 1 mm, flip angle 12-, TR = 9.7 ms, TE = 4 ms.
Image analysis
Data were analyzed by means of the Brain Voyager 4.9
software (Brain Innovation, The Netherlands). Due to the T1
saturation effects, the first 5 scans of each run were discarded
from the analysis. Preprocessing of functional scans included
motion correction and removal of linear trends from voxel time
series. The motion correction was performed by means of a three-
dimensional rigid body transformation to match each functional
volume to the reference volume (the sixth volume). The estimated
translation and rotation parameters for each volume in the time
course were inspected to check that the movement was not larger
than approximately half a voxel for each functional run and that
no stimulus-correlated movement had occurred (Friston et al.,
1996; Hajnal et al., 1994). One of the subjects was discarded from
further analysis due to excessive motion. Inspection of the raw
signal time course in the deep mesial temporal regions and the
hypothalamus in subjects that entered the analysis revealed no
signal dropout due to susceptibility artifacts. Preprocessed func-
tional volumes of a subject were coregistered with the corre-
sponding structural data set. Since the 2D functional and 3D
structural measurements were acquired in the same session, the
coregistration transformation was determined using the Siemens
slice position parameters of the functional images and the position
parameters of the structural volume. Structural and functional
volumes were transformed into Talairach space (Talairach and
Tournoux, 1988) using a piecewise affine and continuous trans-
formation. Functional volumes were resampled at a voxel size of 3
mm 3 mm 3 mm.
The statistical analysis was performed for individual subjects
for the video study using three different approaches: first, statistical
activation maps were obtained using the general linear model
(GLM) (Friston et al., 1995) with correction for temporal
autocorrelation (Bullmore et al., 1996; Woolrich et al., 2001),
considering as predictor of interest the erotic video clip. The sport
video clip was used as baseline and the neutral video clip was
included in the model as a predictor of no interest. A standard
hemodynamic response function was used in order to account for
the hemodynamic delay (Boynton et al., 1996). This analysis was
performed in order to identify brain areas of increased BOLD
signal during viewing of erotic movies with respect to sport
movies.
Second, a regression analysis was performed using penile
turgidity data as the reference time course. This analysis aimed at
identifying brain areas more specifically related to the erection
dynamics.
Third, a GLM analysis was performed by defining three
predictors of interest during the erotic video clip, according to
the penile turgidity data (Fig. 1). For each erotic video clip
presentation, the flat baseline preceding the sharp increase in the
output signal of the pneumatic device was defined as the no
erection (NE) phase. The rising part of the penile tumescence
signal was defined as the onset of erection (OE) phase. Finally,
the plateau following the onset of erection was defined as the
sustained erection (SE) phase. The time window between the
start of the erotic video clips and the button press indicating the
beginning of subjective interest was excluded from the NE phase.
Together, the three phases and the delay time corresponding to the
button press covered the whole erotic video clip presentation
epoch. The mean duration of these phases across subjects is
reported in Results. Contrasts between the three phases were
A. Ferretti et al. / NeuroImage 26 (2005) 10861096 1088
performed. This was done in order to test whether differential
activation was observed in some of the brain areas that were active
in the erotic vs. sport contrast. The advantage of this procedure
over a simple regression with the erectile response is the possibility
to detect areas that show a variation in the activation within the
erotic visual stimulation epoch and across different phases of the
erectile response. In addition, the contrasts OE vs. NE and SE vs.
NE should reveal only brain areas related to aspects of the erection
phenomena. Indeed, the NE condition (viewing an erotic movie
without experiencing erection) is a better matched baseline with
respect to the sport condition (viewing a sport movie) in order to
remove effects due not only to a general arousal but also to the
erotic content of the visual stimuli. This analysis, which was never
tried in previous studies, aimed at identifying brain areas
specifically related to the erection dynamics in a more selective
way with respect to the regression analysis using the penile
tumescence time course.
Statistical analysis for the picture study was performed for
individual subjects using the GLM with two predictors of interest
(erotic pictures, sport pictures). To account for the hemodynamic
delay, the boxcar waveform representing the rest and stimuli
conditions was convolved with the empirically founded hemody-
namic response function described in Boynton et al. (1996).
Statistical activation maps were computed for the contrast erotic vs.
sport pictures.
Statistical activation maps obtained from the above analysis
procedures were thresholded at P < 0.05 (Bonferroni corrected)
and superimposed on the respective (Talairach transformed)
structural scans for the localization of significantly activated areas.
In order to take into account the between-subjects variance of
the BOLD response, regions of interest based on individual
activation maps were first defined. Individual responses in each
activated area were then compared across conditions by means of
analysis of variance, as described in the section below. This
procedure allowed to avoid the problems of a voxel-wise analysis
due to the intrinsic limitations of Talairach spatial normalization, as
described for example in Beauchamp et al. (2004).
Regions of interest (ROIs) for individual data analysis
Regions of interest (ROIs) were determined for each subject,
and for the video and the picture study by considering the mask
obtained from voxels activated in the contrast erotic vs. sport visual
stimulation. The Talairach coordinates of each ROI were deter-
mined considering the centroid of the related cluster of activation.
For the video study, the mean time course of the fMRI signal
from voxels belonging to a given ROI was analyzed to inspect the
effect of the different phases (NE, OE, SE) corresponding to the
erotic epoch. The subjects responses during the three phases were
characterized by evaluating the BOLD signal intensity variation in
each ROI. The relative signal variation between baseline (sport
video clips) and each phase (NE, OE, SE) was calculated from the
fitted parameters of the GLM as: BOLD % change = (beta
i
100)/
baseline, where beta
i
(i = NE, OE, SE ) represents the estimated
amplitude of the variation of the fMRI signal.
The comparison of activation across the three conditions was
undertaken by means of analysis of variance (ANOVA) for
repeated measures. The dependent variable of the ANOVA analysis
was the relative variation of the BOLD signal between each phase
and the baseline condition (sport video clips) and the factor was the
erection condition (NE, OE, SE).
For all the ANOVA calculations, Mauchleys test was used to
evaluate the sphericity assumption. The number of degrees of
freedom was corrected by means of the GreenhouseGeisser
procedure, and the Duncan test was used for post hoc comparisons.
Fixed-effect group analysis
To search for activated areas that were consistent for the whole
group of subjects, a voxel-wise fixed-effect group analysis was
performed as well. In this case, the time series from each subject
were z normalized and concatenated prior to the statistical
computation. The resulting group activation maps were thresh-
olded with the same procedure used for the individual maps and
superimposed on the Talairach transformed structural scan of one
of the subjects.
Results
Physiological and behavioral data
Penile erection was observed for all the subjects in the video
study. An example of the penile tumescence time course recorded
for one of the subjects is shown in Fig. 1. The physiological
conditions (NE, OE, SE), defined according to penile turgidity, are
shown as different shades of grey in the erotic epochs. Finally, the
times of beginning and end of subjective interest (button
depression) are shown as vertical bars below the curve.
The mean delay across subjects between the start of the erotic
video clips and the button depression indicating the beginning of
subjective interest was 12 T 10 s (mean T SD), while the mean
delay between the end of the erotic clips and the button depression
indicating the lack of sexual interest was 6 T 4 s.
The mean number of functional volumes, across subjects,
belonging to each phase was 9, 20, and 12 for NE, OE, and SE,
respectively, corresponding to a mean duration of 37, 82, and 49 s,
respectively. The total mean number of volumes in the three
phases, taking into account that there are six video clip
presentations in a study, was 54, 120, and 72, respectively.
In the study with still image stimulation, penile erection was
never observed.
fMRI datagroup results
Group activation maps obtained with the contrast between
erotic and sport visual stimulation conditions in the video (block
design) and the picture (event related design) studies are shown in
Figs. 2 and 3, respectively, superimposed on the inflated cortex
obtained from an individual, Talairach-transformed, structural
image. Bilateral activations in the inferior parietal lobule and
precuneus, cuneus, extrastriatal visual cortices, frontal cortices, and
mesial temporal structures (hippocampus and amygdala) were
observed in both studies. In contrast, bilateral activation in the
thalamus, anterior cingulate and hypothalamus, insula, and
secondary somatosensory cortex (SII) were found only in the
video stimulation study. In the video study, the regression analysis
with the penile turgidity showed an activation pattern very similar
to that observed with the contrast between erotic and sport visual
stimulation, indicating that the correlation of the time course of
fMRI response with the penile turgidity curve and the erotic
predictor is maximal roughly at the same voxels. This result shows
A. Ferretti et al. / NeuroImage 26 (2005) 10861096 1089
Fig. 3. Group results: cortical areas that are significantly more active (larger BOLDsignal) during erotic as compared to sport visual stimulation with still images.
The map is thresholded at P < 0.01 (Bonferroni corrected) and superimposed on the inflated cortex (light and dark grey indicate gyri and sulci, respectively).
Fig. 2. Group results: cortical areas that are significantly more active (larger BOLD signal) during erotic as compared to sport visual stimulation with video clips.
The map is thresholded at P < 0.01 (Bonferroni corrected) and superimposed on the inflated cortex (light and dark grey indicate gyri and sulci, respectively).
A. Ferretti et al. / NeuroImage 26 (2005) 10861096 1090
that there are no areas the time course of which correlates with only
the penile turgidity response or only with the erotic predictor. The
areas activated in the video study, as revealed by the contrast
between the erotic and the sport visual stimulation as well as by the
regression with penile turgidity, are listed in Table 1. The areas
activated in the still picture study, as revealed by the contrast
between the erotic and the sport pictures, are listed in Table 2. Note
that only a subset of the areas activated in the video study is also
activated in the still picture study.
The group results obtained for the video study with the
contrasts OE vs. NE and SE vs. NE are shown in Fig. 4 and
listed in Table 3. Recall that an activation revealed by these
contrasts indicates in fact an increase in activation across the
contrasted segments. Note that an increased activation in OE and
SE was observed for the insula, SII, anterior cingulate, and
amygdala, whereas an increase of activation in the hypothalamus
was observed in OE but not in SE.
fMRI dataresults from individual subject analysis
The activation patterns shown by the group analysis were
observed also in individual subject activation maps. Only 2
subjects out of 9 did not show insular activation. The BOLD
signal intensity variation during the three phases of the erotic
condition (NE, OE, SE) was evaluated with respect to the sport
condition for the brain areas that, in the group analysis, showed a
Table 1
Group results obtained with the voxel-wise whole-brain fixed-effects analysis: Talairach coordinates and Z scores of the peak activity in brain areas activated
during the video study as revealed by the contrast erotic vs. sport visual stimulation and by the regression analysis with the penile turgidity
Erotic vs. Sport visual stimulation (video clips) Regression analysis with penile turgidity
(video clips)
Area BA Talairach coordinates Z scores
Talairach coordinates Z scores
Right Precuneus 7 26, 54, 39 9.11 23, 56, 42 9.46
Left Precuneus 7 31, 53, 42 10.19 22, 58, 39 10.16
Right IPL/Ba40 40 53, 32, 31 15.51 50, 31, 33 15.43
Left IPL/Ba40 40 45, 32, 36 17.47 52, 27, 32 15.10
Right DLPFC 44, 4, 27 13.67 44, 0, 28 14.57
Left DLPFC 47, 4, 28 12.11 47, 2, 29 13.48
Right SII 49, 21, 19 8.67 50, 22, 20 14.71
Left SII 50, 22, 16 9.15 52, 20, 17 7.14
Right VLPFC 40, 26, 11 8.45 41, 25, 9 9.81
Left VLPFC 39, 26, 14 7.17 42, 27, 14 7.45
Right Insula 39, 2, 7 9.11 41, 1, 7 9.64
Left Insula 41, 2, 9 7.36 40, 4, 8 8.23
Right Thalamus 2, 14, 10 8.78 1, 15, 11 6.91
Left Thalamus 1, 11, 8 9.45 1, 13, 11 8.77
Right Cuneus 18 25, 86, 3 21.31 26, 89, 3 16.23
Left Cuneus 18 27, 89, 3 11.99 26, 88, 4 8.02
Right Anterior Cingulate 24 4, 25, 5 7.11 5, 24, 6 11.03
Left Anterior Cingulate 24 2, 22, 6 10.31 4, 24, 8 11.23
Right Inferior Temporal 44, 59, 7 21.53 43, 64, 9 19.67
Left Inferior Temporal 46, 63, 7 20.89 48, 65, 8 21.18
Right Hypothalamus 3, 2, 7 13.03 2, 1, 6 11.26
Left Hypothalamus 2, 0, 8 10.41 3, 0, 7 11.81
Right Hippocampus 28 17, 18, 9 7.08 18, 21, 9 7.45
Left Hippocampus 28 18, 17, 8 7.43 19, 20, 9 8.05
Right Fusiform 37 44, 51, 17 20.74 43, 59, 18 20.22
Left Fusiform 37 45, 50, 18 20.15 44, 55, 21 18.59
Right Amygdala 21, 2, 17 10.86 20, 3, 16 10.30
Left Amygdala 22, 1, 17 11.28 23, 4, and 15 9.62
BA, Brodmann area; DLPFC, dorsolateral prefrontal cortex; VLPFC, ventrolateral prefrontal cortex; IPL, inferior parietal lobule.
Table 2
Group results obtained with the voxel-wise whole-brain fixed-effects
analysis: Talairach coordinates and Z scores of the peak activity in brain
areas activated during the still images study as revealed by the contrast
between erotic and sport pictures
Area BA Talairach coordinates Z scores
Erotic vs. Sport visual stimulation (still images)
Right Precuneus 7 23, 57, 44 11.91
Left Precuneus 7 25, 59, 43 10.16
Right IPL/Ba40 40 54, 32, 29 5.73
Left IPL/Ba40 40 47, 32, 35 6.55
Right DLPFC 48, 3, 32 9.24
Left DLPFC 49, 1, 27 8.03
Right VLPFC 42, 29, 14 8.01
Left VLPFC
Right Cuneus 18 22, 86, 6 6.15
Left Cuneus 18 27, 89, 4 5.71
Right Inferior Temporal 43, 59, 7 12.49
Left Inferior Temporal 42, 62, 5 14.21
Right Hippocampus 28 19, 24, 7 5.53
Left Hippocampus 28 23, 30, 3 5.59
Right Fusiform 37 38, 51, 18 12.51
Left Fusiform 37 43, 51, 16 14.41
Right Amygdala 21, 6, 13 5.13
Left Amygdala 24, 9, 11 4.22
BA, Brodmann area; DLPFC, dorsolateral prefrontal cortex; VLPFC,
ventrolateral prefrontal cortex; IPL, inferior parietal lobule.
A. Ferretti et al. / NeuroImage 26 (2005) 10861096 1091
significant contrast between OE and NE, or between SE and NE:
hypothalamus, anterior cingulate, amygdala, insula, and SII. Mean
values across subjects are reported in Fig. 5. The statistical
comparison of activation was performed by means of ANOVA
designs in which the factor was the physiological condition (NE,
OE, SE) and the dependent variable was the relative variation of
the BOLD signal between each physiological condition and the
baseline condition (sport video clips). A statistical main effect was
observed for the factor physiological condition in the mentioned
brain regions: hypothalamus (F(2,16) = 5.96, P < 0.01), anterior
cingulate (F(2,16) = 4.27, P < 0.03), amygdala (right: F(2,16) =
9.97, P < 0.001; left: F(2,16) = 14.74, P < 0.0002), insula (right:
F(2,12) = 16.68, P < 0.0004; left: F(2,12) = 12.70, P < 0.001), SII
(right: F(2,16) = 12.95, P < 0.0004; left: F(2,16) = 11.69, P <
0.0007). Post hoc comparisons revealed that BOLD signal change
was not significantly different (P > 0.05, Duncan test) when
comparing SE with OE for the anterior cingulate and the left
amygdala, and when comparing SE with NE for the hypothalamus.
Discussion
General considerations
Several investigations have been devoted in recent years to
elucidate supraspinal mechanisms controlling masculine sexual
arousal and penile erection. These studies have focussed attention
on the medial preoptic hypothalamic area as well as the para-
ventricular hypothalamic nucleus, paragigantocellularis brainstem
nucleus, and the medial nucleus of amygdala (see Giuliano and
Rampin, 2004 for review). Disclosing dynamic behavior of the
neural network governing different phases of sexual arousal
through penile erection and detumescence has been attempted via
PET imaging, but limitations intrinsic to temporal discrimination of
such a technique did not allow to disentangle the transient
contributions of different centers (Holstege et al., 2003; Redoute
et al., 2000). In a recent study (Mouras et al., 2003), functional
MRI has been used to evaluate sexual desire or arousal, but the
presence and amount of penile reaction have not been recorded,
therefore preventing from extrapolating information on the timing
and dynamics of activation/deactivation patterns of CNS centers
during different phases of penile tumescence/detumescence.
From this bulk of studies, a neurobehavioral and multifaceted
model of neural mechanisms as further detailed belowfor sexual
arousal has been proposed (Redoute et al., 2000) which includes a
cognitive, an emotional, a motivational, and an autonomic
component. Cerebral areas which have been found to be linked
to the cognitive mechanism include the attentive network
relaying in orbitofrontal cortex and the superior parietal lobules,
motor imagery in inferior parietal lobules, while the motivational
component would be stored in the caudal part of the anterior
cingulate cortex, related to motor preparation processes; finally, the
autonomic mechanism would involve the hypothalamus, insula,
and the rostral part of the anterior cingulate cortex.
Our results integrate and expand evidences from previous
studies (Arnow et al., 2002; Beauregard et al., 2001; Bocher et al.,
2001; Hamann et al., 2004; Holstege et al., 2003; Karama et al.,
2002; Mouras et al., 2003; Park et al., 2001a,b; Redoute et al.,
2000, 2005; Stoleru et al., 1999), and clarify the neural circuit sub-
serving the processing of erotic visual stimuli. This circuit includes
Fig. 4. Group results: activation in the hypothalamus, anterior cingulate, insula, SII, and amygdala as revealed by the contrasts between phases of erotic video
stimulation with different conditions of penile reaction (NE, OE, SE). A, B, and C: OE vs. NE. D, E and F: SE vs. NE. Note that the hypothalamus shows a
significant increase in activation in condition OE but not in SE. The maps are thresholded at P < 0.01 (Bonferroni corrected).
A. Ferretti et al. / NeuroImage 26 (2005) 10861096 1092
limbic (hypothalamus, hippocampus and amygdala) and paralimbic
areas (anterior cingulate gyrus, frontal lobe, and insula), associative
cortices (inferior temporal and occipital cortices), and other
subcortical and cortical sensory relays (thalamus and SII). Along
the vein of a neurobehavioral interpretation, it can be hypothesized
that the autonomic and endocrine control of sexual behavior is
mediated by the hypothalamus, while the activation of the
amygdala is related to the appraisal process through which erotic
stimuli are evaluated as sexual incentives (Beauregard et al., 2001).
Indeed, the amygdaloid complex receives multimodal sensory
input, as well as input from the hippocampal formation, the
thalamus, and the association cortices, and relays processed
information to the ventral striatum, hypothalamus, autonomic
brainstem areas, and the prefrontal cortex. These findings support
the neurobehavioral model that the amygdala participates in the
evaluation of emotional content of the complex perceptual
information associated with the visual processing of the erotic
stimuli. In this study, a significant increase in activation in the
associative temporo-occipital areas in erotic video viewing as
compared to sport video viewing was also observed. As suggested
by previous PET data (Lane et al., 1999), the amygdala may
mediate a backward attentional modulation of the visual associa-
tion cortex activity during visual processing, induced by highly
arousing emotional stimuli. According to this view, the distributed
neuronal network that includes limbic structures and associative
cortices might be supportive of active processing of erotic visual
stimuli (Beauregard et al., 2001). Previous studies linked insular
activation to the somatosensory processing pathway (Arnow et al.,
2002); the activation in this area, together with thalamic and SII
activation, may therefore reflect the participant perception of his
own behavioral response. Finally, the anterior cingulate gyrus and
the prefrontal cortex play a role in the evaluation of the motiva-
tional/emotional information and in the initiation of goal-directed
behavior (Beauregard et al., 2001; Park et al., 2001a,b; Stoleru et
al., 1999), since these areas are specifically related to the
monitoring and the control of emotionally driven behaviors.
Comparison of the video and still picture studies
Compared to video clips, erotic still images that never induced
penile erectionactivated only a subset of this complex circuit. In
fact, activation was restricted to hippocampus, amygdala, and
associative areas (posterior temporal and parietal cortices). In
contrast, the hypothalamus, the anterior cingulate, frontal areas,
insular, and SII cortices were activated only by video clip viewing
and should therefore be related to a more complex and articulated
level of sexual response. We are aware that the different stimulus
type in the two paradigms (static vs. dynamic, short vs. long, etc.)
should in any case generate different patterns of activation.
However, the observation of a complete erection exclusively in
the paradigm where the activation of limbic and paralimbic
structures is clearly evident is a robust argument in favor of the
implication of the latter areas in the development of a relatively
complex and articulated sexual response.
Detailed analysis of the video study
We further analyzed the video clip paradigm data, looking for
time-resolved activity in specifically activated areas. If the
hierarchy of the distributed network was true, this type of analysis
would have further confirmed the correlation between the
activation in the limbic and paralimbic areas with a more complex
sexual response including penile erection. We therefore compared
the patterns of activation associated with the three phases (NE, OE,
SE) of behavioral response. The main results are summarized as
follows (Figs. 4 and 5): (1) when comparing OE with NE, a
statistically significant increase in activation in the most rostral
anterior cingulate region (BA 24, 25, 32), in the hypothalamus, in
the insula, and in SII was observed; (2) when comparing SE with
NE, a statistically significant increase in activation in the anterior
cingulate, in SII, and in the insula was observed, but not in the
hypothalamus; (3) finally, when comparing SE with OE, a
statistically significant increase in activation in SII and in the
insula, but not in the anterior cingulate, and a statistically
significant decrease in activation in the hypothalamus were
observed. An increase in activation was also observed, from NE
to SE in the amygdala. Compared with a previous study in which
fMRI data were analyzed using the erectile response as a reference
(Arnow et al., 2002), we were able to demonstrate that some of the
activated areas show a variable response within the erotic visual
stimulation epoch, and to resolve this variation in time according to
different phases of the erectile response. This analysis has provided
with a dynamic pattern of activation during the erectile response by
means of which these areas could be differentiated according to
their behavior in time, suggesting different roles in the control or
appraisal of the erection phenomenon. These patterns are clearly
visible in Fig. 5 that shows the BOLD signal response (as
compared with the sport epoch) in different phases of the erectile
response, as inferred from individual subject data. From this figure,
it can be appreciated that, during the SE phase, the activity in the
hypothalamus is decreased with respect to the OE phase while the
activation in the cingulate cortex remains approximately stable.
Table 3
Group results obtained with the voxel-wise whole-brain fixed-effects
analysis: Talairach coordinates and Z scores of the peak activity in brain
areas activated during the video study as revealed by the contrasts between
different phases of the erotic visual stimulation epoch (NE, no erection; OE,
onset of erection; SE, sustained erection; BA, Brodmann area)
Contrast Area BA Talairach
coordinates
Z
scores
OE vs. NE
(erotic video
clips)
Right SII 53, 22, 20 5.43
Left SII 50, 25, 19 5.26
Right Insula 38, 5, 8 5.32
Left Insula 39, 3, 12 5.48
Right Anterior
Cingulate
24 4, 24, 5 6.42
Left Anterior
Cingulate
24 3, 25, 6 6.64
Right Hypothalamus 3, 0, 8 5.33
Left Hypothalamus 4, 1, 8 5.96
Right Amygdala 19, 1, 18 5.59
Left Amygdala 19, 3, 18 5.26
SE vs. NE
(erotic video
clips)
Right SII 52, 23, 19 6.51
Left SII 51, 23, 16 6.21
Right Insula 38, 5, 8 6.59
Left Insula 40, 7, 10 6.25
Right Anterior
Cingulate
24 1, 24, 4 5.72
Left Anterior
Cingulate
24 4, 23, 4 5.11
Right Amygdala 20, 0, 17 6.73
Left Amygdala 21, 2, 17 5.81
A. Ferretti et al. / NeuroImage 26 (2005) 10861096 1093
Apparently, this might suggest that the hypothalamus plays a more
significant role during the OE than during the SE. Conversely, the
cingulate cortex activity might be correlated with both the OE and
the SE phase. These are interpretations of the data in terms of
dynamics of activation rather than in terms of causal relationships.
In this respect, further studies in selected patients with different
types of erectile abnormalities might be of great importance
(Redoute et al., 2005).
Altogether, it emerges that the hypothalamic and anterior
cingulate areas were maximally active during the initial part of
erection. From a neurobehavioral viewpoint, these regions are
known to be involved in modulating autonomic and endocrine
Fig. 5. Level of activation in the hypothalamus, anterior cingulate, amygdala, SII, and insula, (mean values across subjects) for different phases of penile
reaction (NE, OE, SE) in terms of the relative change of the BOLD signal with respect to sport clip viewing. Error bars are standard errors. Activation was
significantly different (P < 0.05) across conditions as assessed by means of the Duncan test, excepted the indicated cases (NS: not significant, P > 0.05).
A. Ferretti et al. / NeuroImage 26 (2005) 10861096 1094
functions including gonadal and adrenal secretion, and to be linked
to attentional processes by focusing reactivity to new environ-
mental stimuli. The hemodynamic peak of the hypothalamic
activation was found in the OE phase, suggesting that the
hypothalamus may serve the triggering of an overt sexual response.
The anterior cingulate cortex activation also peaks in the OE phase
and maintains the level of activation during the SE phase. The
anterior region of the cingulate is subdivided into affect and
cognition components, the former having extensive connections
with the amygdala and periacqueductal grey, assessing the
motivational content of the internal and external stimuli and
regulating context-dependent behaviors often engaged in responses
associated with affect (Devinsky et al., 1995). According to this
neurobehavioral view, the activation of the anterior cingulate
cortex may reflect the maintenance of the correspondence between
the sexual response and the affective value of the stimulus.
Bilateral activations in sub-insular/insular regions and secondary
somatosensory areas showed the highest correlation with the time
course of penile reaction, being increasingly recruited from NE to
SE. The insular brain region has been linked to motor, vestibular,
and language functions. It lies in the proximity of the secondary
somatosensory cortex and is bidirectionally connected to it; both
areas relay visceral and somatosensory perceptions related to the
processing of the cognitive content of the incoming sensory
stimuli. The activation in these regions may therefore support the
specific mechanisms responsible for the sustained behavioral
response to erotic visual stimulation. A similar trend was seen
for the amygdala, which may be related to the increasing intensity
of the emotional involvement during prolonged visual erotic
stimulation.
Summary
To summarize, our results confirm the involvement, in sexual
arousal, of a complex brain circuitry including cortical, limbic, and
paralimbic areas. Only a subpart of these areas (anterior cingulate,
insula, amygdala, hypothalamus, and secondary somatosensory
cortices) participate in the development of a complex and
articulated sexual response including full penile erection. Finally,
these areas show distinct dynamic behaviors during the develop-
ment of the sexual response. This suggests that the psychological
mechanisms of sexual arousal might findat least in part their
neural counterpart in the observed brain activation dynamics.
Although it is not possible, at this stage, to draw final conclusions
regarding these mechanisms, the observed time course of the
hemodynamic brain activations suggests that they might be related
to the hypothalamus/amygdala complex, to the anterior cingulate
and frontal cortices, and to the insula and the secondary
somatosensory cortex. Further experiments are needed to find
additional evidence to this hypothesis and to define more precisely
the role of these brain areas in human sexual behavior.
Conclusions
In conclusion, we believe that this study enriches knowledge of
the brain mechanisms involved in the behavioral response
following visual sexual stimuli by describing for the first time
the spatiotemporal dynamics of the activation of relevant brain
areas correlated with the time course of penile reaction. Such a
theoretical acquisition may have an important practical impact in
view of its potential clinical application in the evaluation of
pharmacological (Hagemann et al., 2003; Montorsi et al., 2003a,b)
and rehabilitative strategies of erectile dysfunction. Indeed, the
detailed knowledge of brain activation dynamics during sexual
arousal may allow to detect altered patterns correlated to
dysfunction, as well as modifications induced by pharmacological
treatment, which could also be monitored during a rehabilitation
therapy.
Acknowledgments
The authors thank Alberto Briganti, Luigi Di Donato, Gaetano
Di Michele, Bernardo Perfetti, Davide Rossi, and Andrea
Tangherlini for their skillful collaboration during the experimental
sessions. They are also grateful to Claudio Babiloni and to
Maurizio Corbetta for helpful discussion and suggestions and for
a critical revision of the manuscript.
This work was partially supported by a grant from the Italian
Ministry of Research to the Center of Excellence on Aging of the
University G. DAnnunzio.
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