Functional MRI of the Brain During Orgasm in Women

Barry R. Komisaruk Beverly Whipple

Rutgers, The State University of New Jersey
Women diagnosed with complete spinal eord injury (SCI) at TIO or higher report sensations generated hy vaginal-eervical mechanical self-stimulation (CSS). In this paper we review brain responses to sexual arousal and orgasm in such women, and further hypothesize that the afferent pathway for this unexpected perception is provided by the Vagus nerves, which bypass the spinal cord. Using functional magnetic resonance imaging (fMRIl, we ascertained that the region of the medulla ohiongata to which the Vagus nerves project (the Nucleus of the Solitary Tract or NTSl is activated hy CSS. We also used an objective measure, CSS-induced analge.sia response to experimentally induced finger pain, to ascertain the functionality of this pathway. During CSS, several women experienced orgasms. Brain regions activated during orgasm included the hypothalamic paraventricular nucleus, amygdala, accumbens-bed nucleus of the stria terminalis-preoptic area, hippocampus, basal ganglia (especially putamen), cerebellum, and anterior cingulate, insular, parietal and frontal cortices, and lower hrainstem (central gray, mesencephalic reticular formation, and NTS). We conclude that the Vagus nerves provide a spinal cord-hypass pathway for vaginal-cervical sensibility and that activation of this pathway ean produce analgesia and orgasm. Key Words: hrain imaging, fMRI, orgasm, spinal cord, vagina, Vagus nerves.

As a phenomenon worthy of neurobiological research, orgasm has received less attention than its impact on human perceptual experience would predict, likely, at least in part, because of its inherently sensitive (inter)personal properties and historically limited research funding. We investigate orgasm for two reasons: first, to explore further its intriguing neurobiological reality; second, to validate the experiences of certain groups of women who report that they feel orgasms la) despite their health professionals' denying the possibility due to the women's neurological condition, for example, complete spinal cord injury; (b) in
Barr>' R. Komisaruk, PhD, is a Professor II in the Department of Psychology, and Beverly Whipple, PhD, RN, FAAN, is Professor Emerita of the College of Nursing, Rutgers, The State University of New Jer.sey, Newark, NJ- The authors gratefully acknowledge the following funding support: The Christopher Reeve Paralysis Foundation (BRK and BWi, NIH-R25GM60826 (BRK), and the Charles and Johanna Busch Foundation, Rutgers, The State University of New Jersey (BRK and BW). Figures 1, 2, 4, and 6-9 are reprinted from Komisaruk et al. 12004) with permission from Elsevier, Coirespondence concerning this article should be addressed to Barry R. Komisaruk, Department of Psychology, Rutgers, The State University of New Jersey, Newark, NJ 07102. (brk@psychology.rutgers.edu) 62

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response to vaginal ("G spot") stimulation; (c) in response to cervical stimulation; and/or (d) by thought alone, without physical stimulation. Orgasms-Genital and Nongenital Although orgasm is characteristically a response to genital stimulation, there are many reports that other types of sensory stimulation also generate orgasms, some perceived as feeling "genital" but others as "nongenital." For example, we have documented cases of women who claim that they can experience orgasms just hy thinking, without any physical stimulation; their bodily reactionsdoubling of heart rate, blood pressure, pupil dilation, and pain thresholdhear out their claim (Whipple, Ogden, & Komisaruk, 1992). Men and women who have spinal cord injury have described to us that the skin near their injury feels hypersensitive to touch. Painful and intensely aversive if accidentally brushed, when stimulated in the right way and/or by the right person, touch can produce orgasmic feelings that may or may not be perceived as emanating from the genitalia. One woman with complete spinal cord injury at the upper thoracic level experienced an area of hypersensitivity at the neck and shoulder and claimed to have orgasms from stimulation of the skin of her neck. In the laboratory, her heart rate and blood pressure increased markedly during self-application of a vibrator to her neck-shoulder junction, and she described experiencing an orgasm accompanied by a "tingling" sensation in her vagina (Sipski, Komisaruk, Whipple, & Alexander, 1993). Kinsey, Pomeroy, and Martin (1948), Masters and Johnson {1966), and Paget (2001) each reported women who stated that they experience orgasms from breast or nipple stimulation; in addition, Paget {2001) described orgasms produced by stimulation of mouth or anus in women and men. The heroine in the novel Kinflicks, realizing that she had had an orgasm when her lover held her hand, says that she can experience orgasms from stimulation anywhere on her body (Alther, 1975). Consideration of the sensory pathways likely activated in some of the above examples can suggest the bases for these experiences of orgasm. The pelvic nerve provides afferent innervation of the vagina, cervix, and rectum (Berkley, Hotta, Robbins, & Sato, 1990; Komisaruk, Adler, & Hutchison, 1972; Peters, Kristal, & Komisaruk, 1987). Because activation of this nerve through vaginal stimulation can generate orgasm, it is not surprising that when activated nongenitally (i.e., rectally) it can also generate orgasm. Indeed, women have described feeling the need to defecate during uterine contractions at parturition, indicating a second context in which "cross-talk" exists between at least two organs innervated by the same (pelvic) nerve, leading to a form of referred sensation.

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In men, afferent activity from the prostate (via the hypogastric nerve) during ejaculation contributes to the pleasurable sensation of orgasm, on the basis that prostatectomy is reported to diminish this feeling (Koeman, Van Driel, Schultz, & Mensink, 1996). The orgasmcontributory role of this afferent activity could help account for the experience of orgasm in men receiving mechanostimulation of the prostate during anal intercourse, which would add to the afferent activity generated via the pelvic nerve anal afferents. The hypogastric nerve also conveys afferent activity from the uterus and cervix (Berkley et al., 1990; Bonica, 1967; Peters et al., 1987). The orgasmic role of afferent activity via this nerve in men may help to account for the parallel drawn between the feelings generated through uterine and vaginal stimulation during childhirth and during orgasm (Newton, 1955). The orgasm-inducing effect of breast or nipple stimulation may be related to the functional convergence in the central nervous system of their afferent (spinal nerve) pathways with vaginal and cervical afferents (for a review see Komisaruk & Whipple, 2000). The evidence of such convergence is that, in women, oxytocin is secreted from the posterior pituitary into the systemic circulation in response to either of these two sources of stimulation, in the "milk-ejection" reflex and the Ferguson Reflex, respectively. The oxytocin released hy suckling stimulates the contraction of myoepithelial cells that envelop the milk-secreting glands in the breast, forcibly expelling milk. The released oxytocin can concurrently stimulate the uterine smooth muscle to contract. Conversely, intrauterine pressure and the consequent mechanical stimulus against the cervix exerted hy the fetus at parturition stimulates pelvic nerve afferents that lead to release of oxytocin in a positive feedback mechanism, the Ferguson Reflex (Ferguson, 1941). The oxytocin thus released can also produce expulsion of milk from the hreast in women who are lactating at term. Because the final common pathway for oxytocin secretion is primarily the paraventricular nucleus of the hypothalamus (and secondarily the supraoptic nucleus of the hypothalamus; Cross & Wakerly, 1977), breast, nipple, cervical, and vaginal afferent activity each evidently converge on these nuclei. Oxytocin is released into the systemic circulation during orgasm in women and men (Blaicher et al., 1999, Carmichael et al., 1987; Carmichael, Warburton, Dixen, & Davidson, 1994). We have reported that the paraventricular nucleus of the hypothalamus is activated during orgasm in women (Komisaruk et al., 2004, and this article). The perception of orgasm is most likely not produced by oxytocin, for injection of oxytocin neither induced nor intensified orgasm (Gooren, 1991). (However, there is a report based on a single case of a woman who described

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heightened subjective pleasure related to intensified uterine and vaginal contractions upon self-treatment with intranasal oxytocin [AndersonHunt & Dennerstein, 19941). Although a direct action of oxytocin on the brain to modulate orgasm cannot be ruled out, it seems more likely that oxytocin has an augmenting action via the uterine and vaginal afferent activity it generates by oxytocin, stimulating the contraction of smooth muscle of the vagina, cervix, and/or uterus. A sexually activating effect of oxytocin, via its stimulating contraction of genital muscular organs that in turn generate sensory input, is supported by findings in the laboratory rat. Although the female rat shows no evidence of orgasm, oxytocin injected subcutaneously increased the rats' sexual receptivity; cutting the sensory nerves from the vagina, cervix, and uterus abolished that effect (Moody, Steinman, Komisaruk, & Adler, 1994). We speculate that another factor is more significant for orgasm than the action of oxytocin alone. The two sources of sensation (breast-nipple and cervix-vagina) that converge on the paraventricular nucleus may interact with each other there (e.g., breast stimulation altering the sensory quality of concurrent vaginal stimulation) and activate the paraventricular nucleus, which in turn projects to, and activates, a neural system that generates the perceptual experience of orgasm. We do not rule out, however, that oxytocin could influence this system via a direct effect on the brain. Evidence of a Spinal Cord-Bypass Pathway: The Vagus Nerves Although we had already convinced ourselves of the need to extend the concept of orgasm beyond the genitalia, we were further intrigued by anecdotal reports in the literature that women with complete spinal cord injury experience orgasms (Whipple, 1990). We were even more encouraged to try to understand this phenomenon when women with complete spinal cord injury in our own research studies reported to us that they were responding to vaginal and/or cervical self-stimulation {CSS). Some could perceive it, and some experienced orgasms in response to it. In earlier reports, women diagnosed with "complete" spinal cord injury had claimed they could perceive genital sensations, including orgasm {Cole, 1975; Kettl et al., 1991; Whipple, 1990), which we {Komisaruk, Gerdes, & Whipple, 1997; Komisaruk & Whipple, 1994; Whipple, Gerdes, & Komisaruk, 1996; Whipple & Komisaruk, 1997) and others {Sipski & Alexander, 1995; Sipski, Alexander, & Rosen, 1995) confirmed. In addition, Berard (1989) reported that pregnant women with spinal cord injury below T12 could feel uterine contractions and movement of their fetus in utero.

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We hypothesized that some genital sensation could occur if the complete spinal cord injury extended as high as spinal cord level Thoracic 11. This choice was based on evidence of the peripheral distribution and level of entry into the spinal cord of the genital sensory nerves in women (Bonica, 1967), as well as our and others' mapping of the sensory fields and zones of entry into the spinal cord of the genital sensory nerves in the female rat (Berkley et al., 1990; Cunningham, Steinman, Whipple, Mayer. & Komisaruk, 1991; Komisaruk et al., 1972; Kow & Pfaff, 19731974; Peters et al., 1987). We formulated this hypothesis on the basis that the hypogastric nerves aseend in the sympathetic chain and enter the spinal cord at thoracic levels 10-12 (Bonica, 1967; Netter, 1986). Consistent with this nerve distribution, we found that a group of 10 women ("lower-injury" group), whose complete spinal cord injury was below TIO (thus presumably allowing some genitospinal input to enter the brain at TIO). could indeed feel the CSS. They also could feel the application of the stimulator by one of the investigators, and they showed significant analgesia (an objective measure of response) at the fingertips during CSS (Whipple & Komisaruk, 1985, 1988). Furthermore, two of the women experienced orgasms to the self-stimulation (Komisaruk, Gerdes, et al., 1997; Komisaruk & Whipple, 1994; Whipple et al., 1996; Whipple & Komisaruk, 1997). Of greater interest, a group of six women with complete spinal cord injury at or above TIO (as high as T7, the"upper-injury" group) had perceptual responses comparable to the other, lower-injury group. Specifically, four of the six had perceptual responses to the cervical stimulation by the investigator and could feel the CSS; all experienced analgesia measured at the fingertips (a significant group effect); and one of the women experienced orgasms in the laboratory. In addition, in both groups of women, all but one (in the lower-injury group) reported that they commonly experience menstrual discomfort. Based on these unexpected and surprising findings, we proposed that the women with the higher level of complete spinal cord injury (i.e., the upper-injury group) experience the vaginocervical stimulation via the Vagus nerves (i.e.. Cranial Nerve 10), which bypasses the spinal cord in its course to the brain (Komisaruk, Gerdes, et al., 1997; Komisaruk & Whipple, 1994; Komisaruk, Whipple, Gerdes, Harkness, & Keyes, 1997; Whipple et al., 1996; Whipple & Komisaruk, 1997). To provide some perspective on our conjecture, the traditional view of the pathway by which genital stimulation reaches the brain is via the spinothalamic tract. In cases of traumatic spinal cord injury, if this tract is interrupted, genital stimulation-induced orgasm is blocked in women and men (Beric & Light, 1993). Curiously, this pathway also

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contains axons that convey pain impulses to the brain. In such cases as the intractable pain of cancer, the spinothalamic tract may be therapeutically transected by surgery. For one noninjured male patient, this procedure has been reported to block genitally stimulated orgasm along with blocking the pain. His pain blockage persisted for several months; when the pain reappeared, so did his genital orgasmic response (Elliott, 1969). Our hypothesis that the Vagus nerves provide an additional genital sensory pathway in women is plausible as follows. Evidence for a vaginocervical sensory role for the Vagus nerves was first presented by Guevara-Guzman and colleagues, based on their studies in the laboratory rat (Ortega-Villalobos et al., 1990). They reported that the neural tracer, horseradish peroxidase, when injected into the cervix, produced labeling of neurons in the nodose ganglion, which is the dorsal root (i.e., sensory) ganglion of the Vagus nerves. More recently, the innervation of the uterus and cervix by the Vagus nerves in the rat was confirmed by Papka and colleagues (Collins, Lin, Berthoud, & Papka, 1999). Support for a vaginocervical sensory role for the Vagus nerves in the rat was also provided by functional studies. Vagal electrical stimulation has been shown to produce analgesia in rats (Maixner & Randich, 1984; Ness, Randich, Fillingim, Faught, & Backensto, 2001; Randich & Gebhart, 1992) and in humans (Kirchner, Birklein, Stefan, tSt Handwerker, 2000), and we reported that vaginocervical probing in rats produces analgesia even after combined bilateral transection of the known genitospinal nerves (pudendal, pelvic, and hypogastric; Cueva-Rolon et al., 1996). In the same individual rats (Cueva-Rolon et al., 1994), the analgesia was abolished after subsequent bilateral transection of the Vagus nerves. Furthermore, in a separate study in rats, we found that significant pupil dilatation in response to vaginocervical stimulation persisted, although at a diminished magnitude, after total surgical ablation of the spinal cord at the midthoracic level (T7); subsequent bilateral transection of the Vagus nerves at the subdiaphragmatic level abolished that pupil dilatation response (Komisaruk, Bianca, et al., 1996). Furthermore, electrical stimulation of the central end of the transected Vagus nerves produced marked and immediate pupil dilatation (Bianca et al., 1994; Komisaruk et al., 1995). In addition, Hubscher and Berkley (1994, 1995) reported that neurons of the Nucleus of the Sohtary Tract (NTS) in the medulla oblongata in rats responded to mechanical stimulation of the vagina, cervix, uterus, or rectum, and that vagotomy altered these responses. Thus, various lines of evidence, both anatomical and functional, support a genital sensory role for the Vagus nerves, at least in the laboratory rat.

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Evidence That the Vagus Nerves Are Genital-Sensory in Women To ascertain whether the Vagus nerves function comparably in women, we used functional magnetic resonance imaging (fMRI) to observe whether vaginocervical self-stimulation (CSS) produces activation of the region of the brain to which the sensory vagus projects {i.e., the NTS). For this study, we identified women whose complete spinal cord injury above TIO was due to mechanical interruption (gunshot wound) rather than to compressive injury, in order to reduce the possibility of undetected residual spinal cord pathways. The region of the NTS was identified in a prior fMRI study in which the participants tasted a sweet-salty-sour-bitter liquid mixture (Komisaruk, Mosier, et al., 2002) in order to activate the superior region of the NTS, which conveys gustatory afference (Travers & Norgren, 1995). We determined whether this re^on was activated in our participants by squirting a 1 ml sample of our tasting mixture into the mouth of the women and recording the fMRI activation pattern. The women then performed CSS. In humans, the NTS is a long tubular nucleus that is situated vertically in the medulla oblongata of the brainstem, which itself is situated vertically as an extension of the spinal cord. In the rat, the NTS has been shown to have a viscerotopic organization which, if extrapolated to humans, would place oral input at the uppermost region, followed sequentially hy input from esophageal, gastric, and intestinal stimulation, respectively, in descending order toward the lowermost region of the NTS (Altschuler, Rinaman, & Miselis, 1992). Because of this, we hypothesized that responses to CSS would occur at the lowermost region of the NTS (i.e., at the NTS pole opposite and below that activated by the tasting mixture). The fMRI of woman #1 shows the anatomical location of the NTS based on histological atlases; it also shows, in sagittal (top) and coronal (bottom) views, the regions activated by taste and by CSS, respectively (Figure 1). The results support our hypothesis. This woman reported that she experienced orgasms during the CSS. Figure 2 is a composite of five different women with spinal cord injury, in coronal view, showing the individual location of activation of the NTS during CSS. Note the similarity of location of the responses. Each of these women could feel the stimulator in the vagina or against the cervix. When it was inserted against the cervix, one woman, AN, described a feeling of changing pressure as the stimulator was moved, and another woman, VA, described a feeling of a "chill inside," which increased if increasing pressure was exerted against the cervix. The perceptual responses to CSS reported by these two women were

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Figure 1. Brain regions activated by cervical setf-stimulation and by a strong taste in a woman with complete spinal cord injury that would block genital sensory pathways through the spinal cord. Activation regions correspond to the lower and upper limits of tbe Nucleus of the Solitary Tract (NTS), wbich is the sensory nucleus of the Vagus nerves in the brainstem medulla oblongata.

consistent with our earlier tindings in other women with comparable completeness and dermatomal levels of spinal cord injury (Komisaruk, Gerdes, et al., 1997). Participant AP described a feeling of "touch inside" when the stimulator was inserted against the cervix. She showed a 93.5% increase in pain detection threshold during the CSS. Participant ED had normal sensibility at TIO hut none below that level. She stated that she could feel stimulation of the anterior vaginal wall, and she showed the greatest magnitude of elevation of pain detection threshold. Each of the above four women fulfilled the American Spinal Injury Association (ASIA; 1992) criterion of "complete" spinal cord injury in that they reported no sensory awareness of digital anal stimulation. Participant EL had no cutaneous sensibility below T9; however, she did have awareness of digital anal stimulation and was consequently diagnosed as having an "incomplete" spinal cord injury. The spinal cord MRI of EL showed spinal cord injury in the form of a syrinx (i.e., a pathologic tubular cavity in the spinal cord) at T7-T8, although it is not clear whether the spinal cord was completely interrupted (Figure 2, EL). She

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Figure 2. Activation of the NTS by cervical self-stimulation in five women with spinal eord injury. (In this and the following figures, for clarity, the regions of interest have heen highlighted with outlining and/or arrows, i The level and completeness of the spinal cord injury are specified below each image. The ASIA criteria signify the lowest dermatomal level at which normal bilateral cutaneous (pinprick and/or cotton wisp) sensihility exists. "A" signifies "complete" spinal cord injury li,e,, no sensation or voluntary movement heiow that level, and no awareness of digital anal stimulation); "B" signifies "incomplete" injury; in this case, there was no sensation or voluntary movement below the level of injury, but there was awareness of digital anal stimulation. The label Neur is the more stringent categorization of the injury that we used in our earlier study of women with spinal cord injury (Komisaruk, Gerdes, et al., 19971 that is, the lowest level at which there was any sensation at all, rather than the ASIA criterion of the lowest level of "normal" sensation. In addition, the numhers "1" and "2" represent impaired and normal sensibility, respectively. Thus, "1@T7" in the case of woman AN signifies that there was impaired sensibility at T7, but no sensibility below T7, and "2@T7" in the case of participant VA signifies that there was normal sensibility at T7, but no sensibility below T7. Both these women experienced an increase in pain detection threshold measured at the fingers in response to CSS by 21,4':^ and 45.3'7(, respectively, over resting control levels. Concurrently, tactile thresholds, measured at the hand using von Frey fibers, remained unchanged, stated that she had a sensation of "touch inside" and of vaginal muscle contraction when the stimulator was inserted. EL showed an increase in pain detection threshold of 39.6%. As indicated in Figure 2, some of these women also experienced orgasms during CSS while we were recording their fMRI activity. This enabled us to observe regional brain activity during CSS prior to, during, and after the occurrence of orgasm. Figure 3 provides an overall view of the brain at the beginning of CSS compared with the activity at orgasm. Note the much greater and widespread activation in the lower brainstem, forebrain, and cerebellum during orgasm. This pattern of widespread activation of the brain during orgasm was a common observation in the women. Figure 4 shows, at two different threshold imaging criteria (p < 0.05 and p < 0.01), that brain regions activated during orgasm included

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e (minutes) Figure .'J. Activity at sequential levels of the brain ("sections" in the frontal plane) during cervical self-stimulation before, compared to during, orgasm.

hypothalamus, amygdala, cingulate cortex, and insular cortex. The images at the left of this figure show the MRI anatomical image of the same brain on which the activity is superimposed.

start CSS

" Orgasm

Cingulate Cortex Insula

Amygdala

Hypothalamus

Figure 4. Some regions of the forebrain activated during orgasm.

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The involvement of the amygdala in orgasm per se, more than its "simply" showing a sensory response to CSS, is evidenced in Figure 5. In this case, CSS was applied continuously, generating multiple orgasms that occurred during only the first 3 of the 5 min shown. The CSS was maintained during the entire 5 min. In this case, activation of the amygdala occurred only during the 3 min when orgasms were occurring. During the last 2 min, although CSS continued, both the activation of the amygdala and the orgasms ceased. We concluded that the amygdala does not simply respond sensorially to CSS, but instead its activation is concomitant with vaginocervical-induced orgasm per se. It is not possible to discern from this finding whether activation of amygdala is a cause or an effect of orgasm, but it is possible to conclude that the amygdala is not simply a sensory target region for genital afferent activity. Figure 6 shows fMRI images at two different brain regions in a woman with complete spinal cord injury during CSS. In this figure and Figures 2, 4, 7, 8, and 10, the areas of activation that are mentioned have heen highlighted for clarity. The upper images show the fMRI activity at orgasm; the lower images show the same activity superimposed on the corresponding hrain anatomy. Note the activation in the region of the paraventricular nucleus of the hypothalamus, amygdala, cingulate cortex, insular cortex, and region of the nucleus accumhens. Figure 7 shows fMRI activity in the region of the paraventricular nucleus of the hypothalamus during orgasm. The schematic view on the right shows an artist's diagram (Netter, 1986) of this region, locating the paraventricular nucleus to the left and slightly helow the anterior commissure. The anatomical MRI image shows the comparable region.

Continuous Cervical Selt-Stimulation ORGASMS OCCUR

HHHpH^^

^IBI^^DBB''

^^H^^^^H

Successive Minutes
Figure 5. Repeated "snapshots" of amygdala activity in a woman with spinal cord injury. Note that the amygdala was activated only while orgasm was occurring, despite continuous cervical self-stimulation.

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Cingulate cortex Septum 'n. Accumberis

Paraventricular t). Hypothalatmis Amygdala p = .005 Figure 6. Additional regions of the forebrain activated during orgasm.

Figure 7. Activation of the paraventricular nucleus of the hypothalamus, which produces oxytocin, during, but not before, orgasm. Cervical self-stimulation was applied before and during orgasm.

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the crosshairs identifying the anterior commissure. The image to the right shows the fMRI activity at orgasm superimposed on this anatomical image. The two lower images show the fMRI at the beginning of CSS (left) and at orgasm (right). Note the activation in the region of the paraventricular nucleus only at orgasm. Figure 8 shows a greater activation of the hippocampus at orgasm than at the onset of CSS. Figure 9 shows a sequence of activation of forebrain components as orgasm developed in one of the women (EL) during continuous CSS over an 8-min period. Initially, none of the seven brain regions was activated. But, over the course of the 8-min period leading up to orgasm, the medial amygdala, basal ganglia, and insula showed the earliest activation; then the cingulate cortex entered into activation, and, at orgasm, the nucleus accumhens, paraventricular nucleus of the hypothalamus, and hippocampus became activated. In addition, the activation of insula and basal ganglia became more extensive. The brain activity observed during CSS necessarily includes that which generates the arm and hand movement producing the CSS, as well as that indicating the sensory response to that stimulation. Rather than trying to discount such motor and sensory representation from the orgasm records, and in order to clarify which brain activity relates directly to orgasm, we studied (or selected) women who can experience

Cortex: frontal parietal

Orgasm

Hippocampus

CSS
Anatomical only fMRI saperimposed on anatotvjcal fMRI only
Figure 8. Activation of the hippocampus during orgasm

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Figure 9. Sequential "snapshots," in a selected hrain "seetion." of activation of different brain regions as orgasm developed in response to continuous cervieal self-stimulation.

orgasm by thought alone, without any physical self- or other-stimulation. We previously reported autonomic responses during orgasm in 10 women who claimed that they could generate orgasms by thought alone (Whipple et al., 1992). Initially skeptical of their claims, we compared the autonomic responses under two conditions in each woman: one during genital self-stimulation-induced orgasm and the other during thought-induced orgasm. We found to our surprise that each of the parameters measured in a counterbalanced design (i.e., heart rate, blood pressure, pupil dilatation, and pain threshold) approximately doubled during orgasm compared to initial resting baseline under both the conditions. The women described the imagery they experienced during the thought-induced orgasms variously: in some cases, erotic; others, pastoral; and still others, abstract (e.g., as "energy flow" repeatedly ascending and descending the body axis). Preliminary findings from our fMRI study of other women who can generate thought orgasms indicate that, similar to the case of CSSinduced orgasms, regions of the nucleus accumbens, paraventricular nucleus of the hypothalamus, hippocampus, and anterior cingulate cortex are activated during thought-induced orgasm (Figure 10). This suggests that activation of these brain regions is rather specifically related to orgasm, in the sense that they are not related to the brain control of the efferent and the consequent "re-afferent" activity that generates orgasm via hand movement in response to genital self-stimulation. We noted that the amygdala was not activated during the thought orgasms, leading us to speculate that the amygdala may have a genital sensory role in orgasm, whereas the other regions activated may have a more cognitive role.

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Figure 10. Brain regions aetivated during orgasm generated by thought alone, without physieal stimtilation.

Discussion Brain Regions Activated During Genital Self-Stimulation and Orgasm The brain regions that we found to be activated during CSS-induced orgasms include hypothalamus, limbic system (including amygdala, hippocampus, cingulate cortex and insular cortex, and the region of the accumbens-bed nucleus of the stria terminalis-preoptic area), neocortex (including parietal and frontal cortices), hasal ganglia (especially putamen). and cerehellum, in addition to lower hrainstem (central gray, mesencephalic reticular formation, and NTS). Differences between regional activation during, versus before or after, orgasm suggest that areas more directly related to orgasm include the paraventricular area of the hypothalamus, anterior cingulate region of the limhic cortex, and region of the nucleus accumbens. Although there is no evidence of orgasm in female rats, a number of researchers have reported that some of the same-named brain regions become activated during mating or vaginocervical stimulation. Thus, using the c-fos immunocytochemical method in rats, activation was reported in amygdala (Erskine & Hanrahan, 1997; Pfaus & Heeh, 1997; Rowe & Erskine, 1993; Tetel, Getzinger, & Blaustein, 1993; Veening & Coolen, 1998; Wersinger, Baum, & Erskine, 1993); paraventricular nucleus of the hypothalamus (Pfaus & Heeb, 1997; Rowe & Erskine, 1993); medial preoptic area {Erskine & Hanrahan, 1997; Reyna-Neyra, Camacho-Arroyo, Cerbon, & Gonzalez-Mariscal, 2000: Tetel et al., 1993; Wersinger et al., 1993); midbrain central gray (Pfaus & Heeb, 1997;

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Tetel et al., 1993); and, based on local release of dopamine, the nucleus accumhens (Pfaus, Damsma, Wenkstern, & Fibiger, 1995). To our knowledge, we are the tirst to report activation of hypothalamus during orgasm in men or women. An earlier study of orgasm in men, based on positron emission tomography (PET), reported activation in prefrontal cortex, but not subcortical structures {Tiihonen et al., 1994). Also in men, using PET, Holstege and colleagues (Georgiadis et aL, 2002; Holstege et al., 2003) reported that the mesodiencephalic area, cerebellum, pontine reticular formation, basal ganglia (putamen and claustrum), and several cortical regions, including the lateral prefrontal cortex but not the hypothalamus, were activated during orgasm. In men during sexual arousal (hut not orgasm) elicited hy their viewing photographs, Wallen and colleagues (Hamann, Herman, Nolan, & Wallen, 2002) reported that fMRI activity was increased relative to the activity in women in the amygdala, hippocampus, and hypothalamus. Striatal regions (caudate and nucleus accumbens) were activated in both men and women. In a separate study (Karama et al., 2002), when the fMRI of men and women were compared while they watched erotic film segments, the men showed greater activity than the women in the hypothalamus and thalamus. The level of hypothalamic activity correlated with the subjective level of sexual arousal reported by the men. Brain regions activated in hoth the men and women were the amygdala, ventral striatum, and the following cortices; anterior cingulate, insular, orhitofrontal, medial prefrontal, and occi pi totem poral. In an fMRI study of women observing erotic visual stimuli (Park et al., 2001), activation was found in the thalamus, striatum (caudate and glohus pallidus), and the following cortical regions: cingulate, insular, inferior temporal, inferior frontal, occipital, and corpus callosum. The occipital cortex {visual cortex) was much more highly activated hy the erotic than the nonerotic films. There does not seem to be a simple means of accounting for the differences in hrain area activation reported among the various studies summarized ahove. Although one could generate some "just-so" cognitive neuroscience stories (e.g., different brain areas independently found in other studies to be related to "emotional," "expectancy,'" "initiative," etc. responses), it seems more prudent to postpone such speculation pending information generated by "differential diagnostic" types of studies. We, however, not heeding this caveat, throw caution to the winds and make the following speculations. Suggested Role of Some Brain Regions in Orgasm Activation in the region of the paraventricular nucleus (PVN) of the hypothalamus is consistent with reports of oxytocin release during

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orgasm. The PVN neurons secrete oxytocin, which is stored in the posterior pituitary gland (Cross & Wakerley, 1977). Vaginal or cervical stimulation releases the oxytocin from the posterior gland into the bloodstream, in the Ferguson Reflex (Ferguson, 1941). And orgasm releases the oxytocin into the bloodstream (Blaieher et al., 1999; Carmichael et al., 1987, 1994). Thus, it is probable that the release of oxytocin at orgasm is due to the activation of the PVN that we observed at orgasm. During orgasm, the insular cortex and anterior eingulate cortices are active, as they have been reported to be during response to pain (Bornhovd et al., 2002; Casey, Morrow, Lorenz, & Minoshima, 2001; Ploner, Gross, Timmermann, & Schnitzler, 2002). These reports suggest an interesting local interaction between regions of the brain. Further research is needed to compare, within the same individual, brain regions activated during pleasure with those activated during pain (i.e., a "differential diagnosis" study). The region of the nucleus accumbens also showed activation during orgasm in the present study, suggesting it has a role in mediating orgasmic pleasure in women. This brain region has also been reported to show fMRI activation during the "rush" induced by an intravenous injection of nicotine (Stein et al., 1998). Reliably, the cerebellum was activated during orgasm. The cerebellum modulates muscle tension via the gamma efferent system, and it receives proprioceptive information (Netter, 1986). Muscle tension can reach peak levels during orgasm (Masters & Johnson, 1966) and contribute to the sensory pleasure of orgasm (Komisaruk & Whipple, 1998, 2000). It is likely that the cerebellum thereby plays a significant motoric role in orgasm; our present research makes it tempting to speculate that it has a significant perceptual/cognitive-hedonic role in orgasm. Previous Studies of Brain Regions Involved in Orgasm: Epilepsy Much of what is known about how the brain produces orgasms is based on studies of epileptic seizures. In numerous reports, men and women describe orgasmic feelings just prior to the onset of an epileptic seizure, a condition called an "orgasmic aura" (Calleja, Carpizo, & Berciano, 1988; Janszky et al., 2002, 2004; Reading & Will, 1997). Electroencephalographs show that the most common brain region from which these orgasmic auras originate is the right temporal lobe, which contains the hippocampus and the amygdala. The aura may have a spontaneous onset or may be triggered by some specific stimulus, for example in one woman, brushing her teeth (Chuang, Lin. Lui, Chen, & Chang, 2004). Although seizure-related orgasms may be described as "unwelcome" (e.g., Reading

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& Will, 1997), in other cases they have been described as pleasurable. One woman was reported to have refused anti-epileptic medication or brain surgery because she enjoyed her orgasmic auras and did not want them eliminated (Janszky et al, 2004). An interesting and instructive observation in the case of these orgasmic auras is that they are not necessarily experienced as involving genital sensation. In contrast, other reports document epileptic seizures originating in the sensory cortex, the region to which the genitalia project. In the latter cases, the individuals reported an experience of genital sensation developing into an orgasm that feels as if it were indeed generated by genital stimulation (e.g., Calleja et al., 1988). Some Methodological Considerations It is evident from the above discussion that different methodologies provide different types of insights into the neural basis of orgasm and that each methodology has its unique advantages and limitations. In the context of the present findings it is most germane to address fMRI and PET methodologies. Both of these methods work in awake humans to provide a three-dimensional map of brain regions active during the condition of interest (e.g., CSS orgasm) relative to control conditions (e.g., unstimulated resting, or CSS prior or subsequent to orgasm). These two methods have an advantage over the EEG (electroencephalogram) in that the latter does not provide information on localized activation that occurs deep in the brain. They also have an advantage over implanted electrode recording of multineuronal activity in that neither fMRI nor PET is invasive, in contrast with methods that utilize acutely or chronically inserted electrodes. The major limitation of the fMRI and PET methods is that, rather than providing a measure of neural activity per se, they both make use of a hemodynamic response that indirectly measures neural activity. That is, typically in PET methodology, water is first synthesized in a biochemistry laboratory close to the participant and radioactively labeled with Oxygen^^, which has a half-life of only 2 min; then, after its intravenous injection, the distribution of the radioactivity in the brain is mapped in three dimensions. Blood fiow normally increases locally in regions of increased neuronal activity, creating a relative increase in the amount of radioactivity per unit time in those regions. This relative change provides the data in PET. Because of the 2-min half-life, subsequent injections of the labeled water are typically administered at 15-min intervals (i.e., alternating control and experimental stimulus conditions). The hmitations of the PET method include its invasive intravenous injections of radioactivity, as well as its complexity and temporal constraints: coordinating the on-site produc-

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tion of radioactive oxygen using a cyclotron, immediate utilization of the oxygen in the synthesis of water, immediate injection of the water intravenously, time lag waiting for the water to he distributed to the brain, and difficulty of timing the pulse of radioactivity to concur with the orgasm-a rather heroic effort (e.g., Komisaruk, Whipple, et al., 2002; Whipple & Komisaruk, 2002). Furthermore, because the region of increased radioactivity is relatively diffuse, the method is hetter suited to experimental paradigms in which a relatively large hrain region (neocortex or basal ganglia) is expected to be involved, rather than relatively small regions such as specific brain stem nuclei. The fMRI method is also hased on the increased blood flow to activated neurons. When the neurons become more active, they use more oxygen. Two processes result: First, oxygen is removed from the hemoglobin of the blood originally supplying the neurons; second, to compensate, more oxygenated hlood flows to the re^on. Because the magnetic property of the iron in the hemoglobin of the blood is affected by whether it is combined with oxygen or depleted of oxygen, these two processes create a perturbation in the local magnetic environment that is mapped in three dimensions, providing the data for the fMRI method (Ogawa, Lee, Kay, & Tank, 1990). The resolution of the fMRI method is sharper than that of the PET method, to the extent that it can map the brainstem location of different specific motor and sensory clusters of neurons (i.e., specific cranial nerve nuclei) activated hy specific motor or sensory tasks (Komisaruk, Mosier, et al., 20021. Researchers use various strategies for analyzing fMRI or PET data, comparing the observed activity, for example, either to other regions concurrently in the same hrain "slice" and/or to activity in the absence of sensory stimulation. Another consideration is whether to use an inductive strategy, with no prior hypothesis, that analyzes where regional activity differs significantly from other regional activity, or whether to make an a priori selection for analysis of specific "regions of interest," comparing their activity in stimulation and no-stimulation conditions. Still another consideration is how to establish the threshold at which activation will be considered significantly greater than at selected controls; if the threshold is too stringent, areas of activation will be missed; if it is too low, activity in the "background" will obscure activity in specific regions (e.g., Poline, Holmes, Worsley. & Friston, 1997). In genera! in our studies, the highest thresholds that showed activation of specific brain regions at orgasm were selected and maintained constant when compared with the same brain regions prior to orgasm. In that way, we observed changes related specifically to orgasm. This strategy could, theoretically, lead to the conclusion that some brain

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regions were not active until orgasm, but, practically, it enables us to ascertain those brain regions tbat are differentially activated during orgasm. We have been careful to interpret our findings as indicating relative, rather than absolute, changes in brain activity related to orgasm. With the exception of the brain images shown in Figures 5 and 10, the images have been published previously. Tbe specific selection criteria are presented in that publication (Komisaruk et al., 2004). Which Brain Regions Generate the Feeling of Orgasm? It is tempting to speculate that activity of one or more of the abovecited regions activated during orgasm produces the voluptuous sensation of orgasm. This consideration raises one of the ultimate questions in neuroscience (indeed, the reason many of us entered the field): Which brain regions generate conscious awareness and by what mechanism? Are we aware of the activity of the nucleus accumbens? Does it generate feelings of craving and/or pleasure? The cingulate cortex? Insula? Paraventricular nucleus of the hypothalamus? Does activation of any of these brain regions give rise to awareness? What makes some activated neurons produce feelings of pleasure and others, feelings of pain? How does one bridge the gap between locating the brain correlates of orgasm and understanding how that hrain activity generates the pleasurable feeling of orgasm? In a new study, Dunn, Cherkas, and Spector (2005) suggested another dimension to take into account. In a large survey of the relative frequency of orgasm during intercourse or during masturbation they found a higher correlation among identical twins (31% and 391, respectively) than among fraternal twins (109r and 179^, respectively). These findings indicate a possible genetic component to mecbanisms underlying orgasm. Thus, the study adds another element to the perennially intriguing question: What factors mediate orgasm? These are fundamental questions, unanswered but perhaps not unanswerable. If orgasm is a phenomenon of the brain that is somehow more than the sum of the reafferent sensory activity generated from the smooth and striated muscles, we are again led to ask the linked questions: Which neurons generate our experience of pleasure and how do they do so? The answer must lie in developing a concept of orgasm that includes but transcends the understandings available through PET and fMRI. References
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