International Journal of Impotence Research (2003) 15, Suppl 5, S25–S32 & 2003 Nature Publishing Group All rights reserved 0955-9930/03 $25.00 www.nature.com/ijir Update on central function relevant to sex: remodeling the basis of drug treatments for sex and the brain

JPW Heaton1* and MA Adams1

1Queen’s University, Ontario, Canada

Sexual function draws on a complex network of peripheral and central neural pathways. The standard focus on erectile difficulties and peripheral therapies has been highly successful clinically but there are many unresolved issues in men and newly discussed issues in women that will likely benefit from improved understanding of the and sexual function. The spectrum of future therapies, based on evolving central neurophysiological understanding, will include the management of problems related to , , desire, motivation, anxiety, and pleasure. This new range of therapies will employ old and new neurochemicals and pathways singly or in combination. The capability of to modulate many of the sexual pathways will also contribute to the rise of multiagent therapy. The expanded understanding, in combination with enhanced imaging technologies, will renew the role of diagnosis and cause-specific treatment. International Journal of Impotence Research (2003) 15, Suppl 5, S25–S32. doi:10.1038/sj.ijir.3901069

Keywords: erection; brain; central nervous system; sex

Introduction Conceptual framework updated

Although, today, most neuroscientists say it is Sexual function is dominated by imagination. Just axiomatic that the phenomena of mind result from imagine an 18-y-old man, engaged in the erotic the operation of the brain, they could not tell you pursuit of a lovely young woman. His eyes are how.1 closed. He is immersed.y ‘Bang’, a car door slams, Is there need for another synthesis of the available the front door of the house opens. The young information on the pathophysiology of erectile woman’s mother is standing there. The 18-y-old’s function? Do we need another primer on penile erection is no longer. At an age when it takes just a anatomy? Can we appreciate the new details of the moment of daydreaming to create excitement and genomics of penile ? Is there a better erection, the balance of control is so fragile that in a way to show the wonders of and moment it can all come crashing down. That is the phosphodiesterase inhibitors? Is our knowledge of power of imagination. We all know it on some level, the central nervous system (CNS) ready for the kind but we are condemned to misunderstand it until it is of detailed review that has been repeatedly given to pointed out to us. (Those who cannot remember the the periphery? past are condemned to repeat it. George Santayana Clearly, our understanding of the CNS and sexual (1863–1952).) function is only ready for an impressionistic over- We all have a personal view and experience of sex view of the machine. In keeping with the modest and sexuality and through this the opportunity for understanding of CNS erectile physiology, this insight into sexual function and dysfunction. At the review will sketch some of the newer information same time as we learn about complex behavioral and on what is known of the CNS and sexual function physiological functions by looking at ourselves, we and how it fits together. are also constrained by a deep reluctance to face the objectivity of the camera turned inwards. That little exercise demonstrated one important input to the control of sexual function and some of its properties. We learn that imagination is an important and powerful stimulant; that the negative *Correspondence: Jeremy PW Heaton, 76 Stuart Street, side of the balance sheet carries more weight than Kingston, Ontario, Canada, K7L 2V7. the positive; that in a crowd, although we might Update on central function relevant to sex JPW Heaton and MA Adams S26 have intellectual awareness of excitement, it is not redundancyFwe even have two nervi erigentes, a proper to actually exhibit it. 100% redundancy, in anticipation of the advent of Recent developments in medical imaging have radical prostatectomy! been applied to mapping sexual function with the But while our understanding of the CNS remains result that we can begin to look at anatomic overwhelmed by the comparative complexity of the representations of sexual processing in the CNSF brain, the time may come when we can resolve even imagination. specific functions down to small clumps of neurons The simple scenario of the young lovers and the and unique receptor subtypes. At present we believe exercise in imagination that recaptures the scene these to be distributed in anatomical space and also demonstrate something else about our sexual multiple in terms of neurotransmitters and recep- wiring. We can imagine a stimulating and then tors. Or we may have the technology to unravel the stressful situation without actually embarrassing complexity of distributed processing served by brain ourselves in public. There is a filter for appropriate- regions, multiple neurons and multiple intercon- ness even though our limited scientific understand- nections. ing can only describe this as an abstract quality. The Think about complexity for a minute. It is no decision, ‘is now the right time for sex?’, may be wonder we have an excellent understanding of the vital. Sex in the path of a charging rhinoceros is not periphery. We can see the , we can see it conducive to the preservation of participating DNA respond to a sexual stimulus. Not seeing the and it is the medial amygdala that provides this has been a problemFand we are just learning to get service. around that one in our scientific inquiries. Not seeing The medial amygdala ‘organizes the appetitive the results of brain functionFexcept indirectly is a phase of recognition of an appropriate partner and huge problem. Not just because we have to be very ’.2 We know this from complex deductive as we learn about it but because it is of vast behavioral studies in rats combined with stereo- complexity. As an example, there are on average 19 tactic lesioning and direct brain injection studies. billion neocortical neurons in women and 23 billion We know that there are a number of phylogeneti- in men.4,5 And this is only 30% of the number that cally conserved peptide neurotransmitters, includ- form during gestation, and involute by birth.6 ing vasopressin and , which are closely Since interneurons account for approximately associated with these mechanisms. 15–30% of the total population of neurons, the The logic of CNS organization means it should be possibilities for interconnectivity are very large and no surprise that the proposed roles of nearby the mathematical description of the number of structures relate to reward and learned aspects of possible pathways is astronomical.7 Interneurons sexual behavior (imagination–permission–plea- provide the possibility of distributed function and sure). Nature, or the grand architect, put the means complex processing. Further to add to the complex- to find sexual reward next to the means to ity, interneurons are not only connected by chemical appreciate the sexual reward and used common synapses (unidirectional connections), but they may neurotransmitters. These links reinforced the func- also form electrical synapses through gap junctions tions and linked them to provide some positive (bidirectional). Interneurons are biochemically het- feedback. In fact, it has become evident that the erogeneous (mostly GABAergic but also expressing a overall schema of the brain contains many such number of different neurotransmitters or their beautiful economies of effort and space. synthesizing enzymes, neuropeptides and calcium- A barrier to our understanding has always come binding proteins). There may be two types of from the apparent conflict between the apparent electroneurochemical transmission: wiring trans- anatomic and physiological precision of the brain in mission (classical type of neural transmission based some regards and the functional fuzziness of it in on the physical substrate of neural chains) and other respects. We know that a small volume stroke volume transmission (consisting of chemical signals can produce language defects of astonishing diffusing in the extracellular fluid and reaching subtlety, suggesting that function is localizedFbut receptors on neuronal cells located far away from we have also discovered that recovery of adjacent the signal release site).8 tissue can recapture some of that functionFsuggest- Given the complexity of cortical circuits, it is ing that function may also be somewhat arbitrarily currently impossible to draw a diagram of cortical regionalized.3 So, in the representation of brain microcircuitry that is valid for anything except small areas vital to sexual function some specificity is to cortical areas. Some connectionists believe that it be expected and it may be possible to identify may not be possible to accurately the brain’s specific pathways and neurochemicals. But, recog- neural architecture.9 Others predict that eventually nizing the necessity for multiple and overlapping neurons may not be viewed as independent proces- systems, there will generally be areas involved sing units but as members of subsets of networks (nuclei, tracts, bodies) rather than individual neu- where their role is mapped in space–time coordi- rons. It is unlikely that something as vital to survival nates in relationship to the other neuronal mem- as sex would be trusted to single structures without bers.10

International Journal of Impotence Research Update on central function relevant to sex JPW Heaton and MA Adams S27 However, the CNS circuitry detail is arranged the understanding and treatment of CNS disease pro- inhibitory sides of the equations at almost any level gressed significantly over the same period but the are dominant.11 Conceptually, it seems almost complexity factor held back development of science universally accurate to portray control of sexual relevant to ED until the 1990s. Looking forward one function as a balance of erectogenic and erectolytic can imagine that with the current level of sophisti- influences. This balance is common in simpler cation in science, the understanding of CNS disease autonomic systems and permits subtle changes in will grow rapidly and with great diversity at the set point, equilibration at high or low levels of same time as cardiovascular understanding begins activation and time-dependent variations in bal- to decelerate as it reaches many significant goals. ance. There is a preponderance of inhibitory This understanding will have great implications for influence seen in the as well. Possibly, management and the interface man has the greatest presence of central inhibitory between sexual biology and behavior.15 As we controlFand this is one over-riding issue we have recognize the contributions of CNS dysfunctions to failed to address to this point in current therapies of sexual dysfunction CNS-based therapies will be- sexual dysfunction. The general schema for sexual come as logical as phosphodiesterase inhibitors are systems that link central and peripheral sites now in the treatment of vascular-based penile includes a vital level of hard wiring and organiza- smooth muscle dysfunction. tion in the spinal cord. Recent evidence has pointed to the probability that ejaculatory function as well as genital vascular response may undergo significant Pathways updated regulation in the cord itself. The scholarly descrip- tions of detailed organization of neural components of female12 and male13 sexual systems are best The importance to reproductive function of the covered in dedicated reviews. medial preoptic area (MPOA) of the midbrain has been shown in many studies. Neurons in the MPOA have been shown to regulate timing aspects of CNS or psychogenic? female rat copulatory behavior. This is probably achieved by regulation of vaginal and cervical stimulation. It is possible that both male and female Over the last century we relied on the latest medical sexual behaviors are regulated by similar neural advance to guide our perception of the medical basis substrates in the MPOA.16 of sexual dysfunction. When psychiatry and psy- The MPOA links through periaqueductal gray chology gained strength in the first half of the 20th (PAG) to the nucleus paragigantocellularis (nPGi) century, all impotence was explained on the basis of and has known importance in other vital regulatory psychogenic problems. In fact, we are still laboring functions such as pressure and respiratory under the distortions imposed by the persistence of control. It has recently been examined to confirm this label.14 Psychogenic meant ‘in your head’ and the presence of a linked neural pathway using implied the possibility of correction by psychother- typical tracing techniques and establish the poten- apy and nonorganicity. A sophisticated interpreta- tial for sex modulation.17 The presence of a tion of psychogenic today would include the high percentage of neurons with androgen or inevitability that the events of the CNS and mind estrogen receptors in a linked pathway with estab- are based on biochemical and cellular processes. So lished importance in copulatory function is highly it is not reasonable to continue to contrast psycho- suggestive that this is one of the important pathways genic and organic etiologies of sexual dysfunction linking higher centers with the spinal cord and on the basis that only organic implies treatability by peripheral genital tissue. Evidence also exists drugs or to confuse psychogenic with a lack of showing that neurons originating in the nPGi severity. Psychogenic has been misused to imply terminate in lumbosacral spinal cord neurons that either the imaginary nature of the problem or that go on to innervate pelvic viscera. It is well to drugs have little or no role. Since the distinction recognize that while finding sex steroid receptors in between organic and psychogenic is not clearly this pathway is suggestive more persuasive clarifi- defined, it is not testable and it seems perverse to cation would come from the demonstration of continue to use it. functional modulation of the pathway by these The contrast between organic and psychogenic steroids. Simply putFare these receptors hooked causes for ED is typical of the thinking of the 1970s up? and 1980s where vascular diseases and the vascular Some recent animal data update some well- basis of penile erection were under great scrutiny. established information on penile erections in rapid Vascular problems became understandable and even eye movement (REM) sleep.18 Both sleep generation treatable. Much of the driving force for this was and copulatory mechanisms are associated with the entirely outside the scope of ED, as heart disease preoptic areaFspecifically the lateral preoptic area was recognized as a great medical crisis. The (LPOA). These data also suggest divergence in

International Journal of Impotence Research Update on central function relevant to sex JPW Heaton and MA Adams S28 sexual and sleep erection pathways in that LPOA mon or parallel sets of neurons.23 5-HT and TRH lesions only ablated sleep erections. activity modulation may therefore be expected to have potential benefit for erectile function if suitable compounds and routes of delivery can be found. CNS neurotransmitters update Oxytocin, long associated with reproductive and erectile pathways, has been shown to be capable of inducing erection when introduced into the hippo- New studies have confirmed the role of dopamine campus (in the rat!). Intracavernous (systemic) (DA) in the MPOA in promoting erections. Increased oxytocin was not effective.24 The potential for levels of dopamine in the MPOA increased two oxytocinergic compounds that cross the blood–brain types of erections (reflexive and noncontact (NCE)) barrier and can be delivered readily has yet to be in rodents.19 The MPOA has been held as one of the fully explored. prime sites, along with the paraventricular nucleus Certain peptide analogs (EP peptides) of hexarelin, (PVN) and possibly some spinal centers, for action a growth hormone (GH) releasing peptide, have been of the dopamine agonist apomorphine in facilitating found to induce penile erection. EP peptides are erections. Human evidence of the effects of dopa- thought to act in the PVN and influence oxytociner- mine agonism in the erectile pathway derives from gic neurons in a similar pathway to dopaminergic clinical trial responses to sublingual apomor- and oxytocinergic agonists.25 This action of some EP phine.20 The complexity of the neural control of peptides in inducing penile erection is comparable erection is such that it is only when a compound is to that of apomorphine and oxytocin and has a applied clinically in man that it is possible to say different structure–activity relationship for proerec- that the theory works and has clinical utility. tile activity compared with the other biological Apomorphine has now been extensively studied actions (GH release and eating behavior) of these and prescribed and is an accepted safe and effective compounds. When other EP peptides prevent penile treatment for some men with ED. Although most of erection, it is associated with a reduction in the the evidence for site of action in humans is derived increase in nitric oxide (NO) production that occurs from the extensive body of animal research con- with proerectile stimulation.26 firmation of the functional importance of the PVN The expression of inducible NO synthase (iNOS) and MPOA in male and female human sexual increases with age in the PVN and MPOA and in response may be found in the recent imaging studies regions known to control the synthesis and release using functional magnetic resonance (fMRI) techni- of gonadotropin-releasing hormone (GnRH) and ques. Centrally and experimentally, dopamine has oxytocin. iNOS, and hence increased NO, may an impact on the perception of reward (more is impact serum , , and better) and the implications of this in the context of copulatory function in the aging male animal.27 sexual pleasure or reward in human males and Further evidence of the importance of NO in females are not yet fully investigated. As a first central signaling related to erectile function resulted glimpse, it is possible to say that apomorphine has from a series of experiments designed to alter CNS no impact on conventional measures of male sexual NO activity.28 Manipulation of NO or cGMP levels desire in men with normal desire. The data from altered MPOA triggered intracavernous pressure female subjects are scant, but there are indications response through CNS not peripheral mechanisms. that dopaminergic treatment (apomorphine) impacts The melanocortins have received further scrutiny positively on general measures of sexual function in and the MC4 receptor (MC4R) appears to be most certain women. responsible for the stimulation of penile erection Cells of the MPOA have high densities of alpha2- (and appetite control).29 Small molecule analogs noradrenergic receptors, as well as DA receptors. active at the MC4R have been assessed and one such Studies show that the effects of DA in the MPOA are is the second modern centrally active compound to most likely facilitated by the activation of alpha2 enter formal human studies.30 These are believed to (inhibition) and alpha1 (excitation) adrenoceptors work through the familiar hypothalamic pathways due to cross talk within CNS catecholamine sys- and have the rapidity of response that should tems.21 become familiar with CNS drugs for erection. Gamma aminobutyric acid (GABA)(A) receptor Efficacy has been shown at various dose levels and agonism in the PVN can reduce both pharmacologi- the results of phase III human clinical trials will be cally (apomorphine) and physiologically induced important. (NCE) erections. Increased GABAergic activity in the paraventricular nucleus provides a mechanism 22 to balance (inhibit) proerectile signaling. Imaging update Other candidates for inhibitory control are ser- otonin (5-HT) and thyrotropin-releasing hormone (TRH). Both 5-HT and TRH (intrathecal) exhibit Given the complexity of structural–functional rela- inhibitory effects on penile erection through com- tionships in the CNS, it is inevitable that imaging

International Journal of Impotence Research Update on central function relevant to sex JPW Heaton and MA Adams S29 functional activity in the living brain is a difficult Sexual arousal from VSS (compared with neutral objective. It is not easy to demonstrate single topic stimulus) has been observed using PET techniques function, like erectile function, because of the vast in normal young men. Activation was seen of overlay of contributing and background activity as bilateral (right4left) inferoposterior extrastriate cor- well as the present technical limitations including tices, of the right inferolateral prefrontal cortex and spatial resolution. of the midbrain.35 Sexual and generally pleasant imagery is primar- In other PET studies, VSS and documentation of ily associated with activation in the dominant or arousal were compared with evaluated signals. The L4R brain hemisphere. Conversely, unpleasant claustrum (unclear function) was significantly acti- imagery, phantogeusia, is generally associated with vated as were paralimbic areas (anterior cingulate the contralateral or R4L brain hemisphere. And as gyrus, orbito-frontal cortex), in the striatum (head of the imagery shifts from good to bad, so the caudate nucleus, putamen), and in the posterior preponderance of activation shifts.31 We know this hypothalamus. Decreased signal was patchy in from fMRI and derivative techniques. temporal areas.36 The functional neuroanatomy of the brain during Mapping human sexual response has some sig- sexual arousal has been assessed with blood nificant potential benefits aside from making ex- oxygenation level dependent (BOLD) fMRI.32 cellent material for learned communications. Visual (VSS) was compared Visualization of abnormal responses or functional with neutral stimulation and the occipital cortex anatomy will assist in the classification of the was more stimulated during VSS. Half of the elusive CNS states that contribute to sexual dysfunc- normal volunteers studied showed significant tion. Conversely, the impact of therapies on these activation in the inferior frontal lobe, cingulate CNS abnormalities may be imaged and possibly gyrus, insula gyrus, corpus callosum, thalamus, measured. caudate nucleus, globus pallidus, and inferior temporal lobe during VSS. VSS response in hypo- gonadal patients was decreased and trended to Orgasm update improve with testosterone supplementation. fMRI evaluation of VSS in men with ED showed a restoration of a pattern similar to potent men when Consistent with the PET-MRI studies reported the men with ED were treated with apomorphine. above, as many as 50% of previously orgasmic The methodology of these studies is different but women with SCI can continue to achieve evidence of activation associated with penile tumes- orgasm.37 cence has been documented in the right subinsular PET techniques (semiquantitative 99mTc-HMPAO) region including the claustrum, left caudate have been applied to the study of orgasm in healthy and putamen, right middle occipital and middle young men. Blood flow decreases during orgasm. temporal gyri, bilateral cingulate gyrus, right sensor- The exception is in the right prefrontal cortex, imotor and premotor regions and in the right where the cerebral blood flow increases.38 There is hypothalamus.33 no literature cited linking orgasm and new-onset Evidence from imaging in women with complete cerebrovascular accident (CVA), but it is conceivable (SCI) at the midthoracic level is that this could contribute to sudden death in particularly provocative. Using positron emission flagrante delicto! tomography (PET) and MRI techniques, various The literature on the neurophysiological basis for sexual and somatic sensory pathways were tested orgasm contains scant new material. Probably on a and compared in women with and without SCI. As cultural basis this is one of the least discussed expected, foot stimulation is blocked in SCI but aspects of male human sexual function but it is also normal women show activation of the somatosen- an issue of pivotal importance to the management of sory thalamus. Cervical self-stimulation increased many women with orgasmic problems as a primary activity in the region of the nucleus of the solitary complaint. In all probability, the physiological basis tract, which is the brainstem nucleus to which the of aspects of sexual function that have relevance to vagus nerves project even with SCI suggesting that pleasure, not merely procreation, will receive close vagus nerves can convey genital sensory input attention now that the study of female sexual directly to the brain in women.34 This concept is dysfunction (FSD) is receiving attention. A majority supported by animal studies and suggests the of men still have little understanding of the relative presence of at least four distinct pathways for the independence of erection and orgasm. The decline communication of genital signals in women: clitor- in parameters and experience of orgasm and ejacula- al, perineal and inner thigh via the pudendal nerves, tion with age is also well established but little cervix and proximal three-fifths of the uterus via the known to patients. hypogastric nerve, vagina, cervix, and perineal skin Plasma prolactin (PRL) concentrations (but not via the pelvic nerves, and now cervical and deep testosterone) increase for about an hour following pelvic via the vagus. orgasm ( and intercourse) in both men

International Journal of Impotence Research Update on central function relevant to sex JPW Heaton and MA Adams S30 and women. The equivalent stimulation but without Motivation update orgasm leaves PRL levels within the normal range.39 In other contexts (experimental and clinical) ele- vated levels of PRL are associated with reductions in In rodent experiments, it is possible to dissect sexual activity. This may suggest that the surge in components of sexual activity and they are given PRL post-orgasm may have a role in suppressing names that are broadly suggestive of recognizable sexual behavior through a feedback process that is human behaviors. Motivation in rats must be systemic but probably acts centrally. This may operating at a more basic level than that which represent a PRL-mediated neuroendocrine repro- drives man, but the appeal of a drug that would ductive reflex. A case study adds detail to this prolong the duration of copulation would seem to be concept in that a man who was able to experience immediately recognizable. The lucky experimental multiple (3) in quick succession was shown candidates were sexually sluggish male mice and not to have any elevation in PRL.40 they responded to the intracerbroventricular injec- Orgasm increases blood pressure, heart rate, tion of galanin. No other changes in sexual perfor- 46 plasma catecholamines and prolactin. After sexual mance were identified. Further investigation of , higher serum testosterone was seen but the galanin system has failed to reveal any important there was no impact on the other measured sex natural role. hormones.41 In general terms, DA is supportive of copulation In a more traditional deductive methodology, EEG and 5-HT is inhibitory. DA is also involved in the evaluations of men with orgasmic aurae suggest that reward from sexual activity. DA is released in the this is dominantly represented in the right hemi- MPOA at the time of ejaculation (5-HT is not) and sphere (87%).42 Neurologists may be able to infer changes in DA and 5-HT in different areas of the the most likely side for an epileptogenic focus if a brain may promote copulation and sexual satiety, 47 preictal aura is orgasmic, urologists and sex re- respectively. searchers may expect imaging studies to emphasize Testosterone enhances DA release in the MPOA at right-sided changes during orgasm. rest and with sexual challenge possibly by upregu- lating NOS, which increases NO thereby increasing DA release. The same pattern of copulatory activity promoting DA release in the MPOA and the Update on ejaculation enhanced effect of the presence of sex hormones is seen in female rats. Longer lasting changes may be seen through the postcopulatory effects of gene The most significant recent addition to the expression and this expression increases with understanding of the importance of spinal events increased sexual experienceFeffectively changing in sexual function comes from a study where a the phenotype of certain cells in sexually experi- population of lumbar spinothalamic cells have been enced animals. found to be essential to the generation of ejaculatory behavior.43 It is believed that these cells, which express neurokinin-1, relay ejaculation-related sig- Imagination update nals from reproductive organs to the brain. No other aspects of sexual behavior are altered if this population of cells is destroyed. Further work is The impact of imagination on human sexual needed to establish the human implications of this behavior has been measured. In healthy middle concept and how central and peripheral efferent and and older married couples imagination (about other sensory signals integrate with the experience of women), wife’s desire for sex and erectile compe- ejaculation. tence were universal determinants of sexual activ- Other studies have shown that certain central ity.48 Whereas, the health of the male subjects and structures (nucleus accumbens (NA)) are function- marital satisfaction appeared to be more culturally ally altered by the experience of even just one variable in their impact. ejaculation.44 This may have implications in sexual Imagination, here known as creative-dynamic motivation and reward. image synthesis (CDIS), has been compared with Horses are not noted for the subtlety of their the benefit of yohimbine and placebo in men with sexual responses although they do have ejaculatory of no evident organic cause.49 latencies similar to the average man at around 85 s Measures of potency were found to improve more (ejaculation latency B90 s). The evidence from with CDIS than with yohimbine or placebo. Based measurements of ejaculatory and erectile latency on this study claim ‘creative-dynamic image synth- suggests that the spinal networks subserving ejacu- esis is a potent initiator of erections in men with lation may be more fixed.45 In particular, ejaculation psychogenic erectile dysfunction, has no known latency does not vary between natural and assisted side effects and is very cost-effective’ Phase III breeding whereas erectile parameters do. studies and preparation of an NDA are the obvious

International Journal of Impotence Research Update on central function relevant to sex JPW Heaton and MA Adams S31 next steps. In certain men, enhancing the central experience of sexual response and how much proerectile signal by enhanced imagination or potential there is for errors of function and structure pharmacological means will reasonably be expected (from cells to whole organs and systems). No human to enhance the erection. More signal at the level of physiological system yet has been investigated that the periphery causes better erection as is seen in remains flawless across time and whole popula- postprostatectomy patients (where two nervi eri- tions. Therapy of problems in sexual life will be gentes are better than one or none), reversible nerve improved and expanded beyond the scope of lesioning experiments and with graded stimulation peripheral therapy and counseling by the applica- (imaginationoVSSovibratory stimulation). tion of knowledge of the working of central aspects The perspective of the imagination is also im- of sexual function. portant. Imagery or imagination is more effective in supporting penile erection if it is participant based 50 rather than spectator based. The same series of References studies documented the negative effects of habitua- tion to the sexual stimulusFa factor that is intuitive to humans with experience of monogamous sexual 1 Rowe PM. Neural networks: a bridge between neuroscience activity. When attention is measured, VSS is more and psychology. Mol Med Today 1995; 1: 168 – 173. 2 Smock T, Albeck D, Stark. 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