Functional Magnetic Resonance Imaging Studies in Sexual Medicine: A Primer.

BACKGROUND: Over the past 30 years, functional magnetic resonance imaging (fMRI) has emerged as a powerful tool to non-invasively study the activity and function of the human brain. But along with the potential of fMRI to shed light on neurological, psychiatric, and psychological processes, there are methodological challenges and criticisms. AIM: We herein provide an fMRI primer designed for a diverse audience, from the neuroimaging novice to the experienced user. METHODS: This primer is structured as follows: Part 1: Overview: "What is fMRI and what can it tell us?." Part 2: Basic fMRI principles: MR physics, the BOLD signal, and components of a typical scan session. Part 3: Basic fMRI experimental design: why timing is critical, and common sources of noise in the signal. Part 4: Basic fMRI analysis methods: software, the 3 stages of data analysis (preprocessing, individual, and group level), and a survey of advanced topics and methods including connectivity, machine learning, and assessing statistical significance. Part 5: Criticism, crises, and opportunities related to power of studies, computing requirements, logistical, and interpretational challenges, and methodological debate (assessing causality, circular correlations, and open science best practices). OUTCOMES N/A CLINICAL TRANSLATION: fMRI has primarily been used in clinical research to elucidate the brain correlates of sexual behavior. The translational potential of the method into clinical practice has not yet been realizedfMRI has primarily been used in clinical research to elucidate the brain correlates of sexual behavior. The translational potential of the method into clinical practice has not yet been realized STRENGTHS AND LIMITATIONS: fMRI is a useful and powerful tool for understanding the brain basis of human sexuality. However, it is also expensive, requires extensive methods expertise, and lacks the precision needed to be immediately translatable to clinical practice. The recency of the method, need for basic research, technical limitations, as well as inherent variability in individuals brain activity also impact the pace at which fMRI for sexual medicine can move from the scanner to the clinic. CONCLUSION: This primer provides the novice an understanding of the appropriate uses and limitations of fMRI, and for the experienced user, a concise update on current issues and methodological advances. Mills-Finnerty C, Frangos E, Allen K, et al. Functional Magnetic Resonance Imaging Studies in Sexual Medicine: A Primer. J Sex Med 2022;19:1073-1089.

The role of the inferior parietal lobule in writer's cramp.

Humans have a distinguishing ability for fine motor control that is subserved by a highly evolved cortico-motor neuronal network. The acquisition of a particular motor skill involves a long series of practice movements, trial and error, adjustment and refinement. At the cortical level, this acquisition begins in the parieto-temporal sensory regions and is subsequently consolidated and stratified in the premotor-motor cortex. Task-specific dystonia can be viewed as a corruption or loss of motor control confined to a single motor skill. Using a multimodal experimental approach combining neuroimaging and non-invasive brain stimulation, we explored interactions between the principal nodes of the fine motor control network in patients with writer's cramp and healthy matched controls. Patients and healthy volunteers underwent clinical assessment, diffusion-weighted MRI for tractography, and functional MRI during a finger tapping task. Activation maps from the task-functional MRI scans were used for target selection and neuro-navigation of the transcranial magnetic stimulation. Single- and double-pulse TMS evaluation included measurement of the input-output recruitment curve, cortical silent period, and amplitude of the motor evoked potentials conditioned by cortico-cortical interactions between premotor ventral (PMv)-motor cortex (M1), anterior inferior parietal lobule (aIPL)-M1, and dorsal inferior parietal lobule (dIPL)-M1 before and after inducing a long term depression-like plastic change to dIPL node with continuous theta-burst transcranial magnetic stimulation in a randomized, sham-controlled design. Baseline dIPL-M1 and aIPL-M1 cortico-cortical interactions were facilitatory and inhibitory, respectively, in healthy volunteers, whereas the interactions were converse and significantly different in writer's cramp. Baseline PMv-M1 interactions were inhibitory and similar between the groups. The dIPL-PMv resting state functional connectivity was increased in patients compared to controls, but no differences in structural connectivity between the nodes were observed. Cortical silent period was significantly prolonged in writer's cramp. Making a long term depression-like plastic change to dIPL node transformed the aIPL-M1 interaction to inhibitory (similar to healthy volunteers) and cancelled the PMv-M1 inhibition only in the writer's cramp group. These findings suggest that the parietal multimodal sensory association region could have an aberrant downstream influence on the fine motor control network in writer's cramp, which could be artificially restored to its normal function.

Default mode network changes in fibromyalgia patients are largely dependent on current clinical pain.

Differences in fMRI resting-state connectivity of the default mode network (DMN) seen in chronic pain patients are often interpreted as brain reorganization due to the chronic pain condition. Nevertheless, patients' pain at the time of fMRI might influence the DMN because pain, like cognitive stimuli, engages attentional mechanisms and cognitive engagement is known to alter DMN activity. Here, we aimed to dissociate the influence of chronic pain condition (trait) from the influence of current pain experience (state) on DMN connectivity in patients with fibromyalgia (FM). We performed resting-state fMRI scans to test DMN connectivity in FM patients and matched healthy controls in two separate cohorts: (1) in a cohort not experiencing pain during scanning (27 FM patients and 27 controls), (2) in a cohort with current clinical pain during scanning (16 FM patients and 16 controls). In FM patients without pain during scanning, the connectivity of the DMN did not differ significantly from controls. By contrast, FM patients with current clinical pain during the scan had significantly increased DMN connectivity to bilateral anterior insula (INS) similar to previous studies. Regression analysis showed a positive relationship between DMN-midINS connectivity and current pain. We therefore suggest that transient DMN disruptions due to current clinical pain during scanning (current pain state) may be a substantial contributor to DMN connectivity disruptions observed in chronic pain patients.

Male Urogenital System Mapped Onto the Sensory Cortex: Functional Magnetic Resonance Imaging Evidence.

INTRODUCTION: The projection of the human male urogenital system onto the paracentral lobule has not previously been mapped comprehensively. AIM: To map specific urogenital structures onto the primary somatosensory cortex toward a better understanding of sexual response in men. METHODS: Using functional magnetic resonance imaging, we mapped primary somatosensory cortical responses to self-stimulation of the penis shaft, glans, testicles, scrotum, rectum, urethra, prostate, perineum, and nipple. We further compared neural response with erotic and prosaic touch of the penile shaft. MAIN OUTCOME MEASURE: We identified the primary mapping site of urogenital structures on the paracentral lobule and identified networks involved in perceiving touch as erotic. RESULTS: We mapped sites on the primary somatosensory cortex to which components of the urogenital structures project in men. Evidence is provided that penile cutaneous projection is different from deep penile projection. Similar to a prior report in women, we show that the nipple projects to the same somatosensory cortical region as the genitals. Evidence of differential representation of erotic and nonerotic genital self-stimulation is also provided, the former activating sensory networks other than the primary sensory cortex, indicating a role of "top-down" activity in erotic response. CLINICAL IMPLICATIONS: We map primary sites of projection of urogenital structures to the primary somatosensory cortex and differentiate cortical sites of erotic from nonerotic genital self-stimulation. STRENGTH & LIMITATIONS: To our knowledge, this is the first comprehensive mapping onto the primary somatosensory cortex of the projection of the components of the urogenital system in men and the difference in cortical activation in response to erotic vs nonerotic self-stimulation. The nipple was found to project to the same cortical region as the genitals. Evidence is provided that superficial and deep penile stimulation project differentially to the cortex, suggesting that sensory innervation of the penis is provided by more than the (pudendal) dorsal nerve. CONCLUSION: This study reconciles prior apparently conflicting findings and offers a comprehensive mapping of male genital components to the paracentral lobule. We provide evidence of differential projection of light touch vs pressure applied to the penile shaft, suggesting differential innervation of its superficial, vs deep structure. Similar to the response in women, we found nipple projection to genital areas of the paracentral lobule. We also provide evidence of differential representation of erotic and nonerotic genital self-stimulation, the former activating sensory networks other than the primary sensory cortex, indicating a role of top-down activity in erotic response. Allen K, Wise N, Frangos E, et al. Male Urogenital System Mapped Onto the Sensory Cortex: Functional Magnetic Resonance Imaging Evidence. J Sex Med 2020;17:603-613.

Attitudes and Perceptions Toward Authorized Deception: A Pilot Comparison of Healthy Controls and Fibromyalgia Patients.

OBJECTIVE: Little is known about the perceptions and attitudes of participants who volunteer in studies involving authorized deception. Thus, this cross-sectional pilot study measured, for the first time, the perceptions about participation in an authorized-deception placebo analgesia study in chronic pain patients with fibromyalgia and assessed whether their perceptions differed from healthy controls. METHODS: An anonymous survey with questions about trust in research and willingness to participate in future research involving deception was mailed to participants in both groups after completion of the parent study. Statistical analyses were performed using the Mann-Whitney U and chi-square tests (31 controls and 16 fibromyalgia patients were included in the analyses). RESULTS: The majority of participants expressed little or no concern about the deception, still trusted the scientific process, and found the debriefing procedure helpful and worthwhile. Group differences were found in willingness to 1) participate in the parent study had the deceptive element been disclosed in advance (controls = definitely, fibromyalgia patients = probably, U = 341.5, P = 0.01) and 2) participate in future studies (controls = definitely, fibromyalgia patients = probably, U = 373, P < 0.001). CONCLUSIONS: Despite slightly less favorable responses of fibromyalgia patients and the relatively small size of the study, these findings suggest that attitudes and perceptions about participating in an authorized placebo study remain positive in both healthy and chronic pain populations.

Brain Activity Unique to Orgasm in Women: An fMRI Analysis.

BACKGROUND: Although the literature on imaging of regional brain activity during sexual arousal in women and men is extensive and largely consistent, that on orgasm is relatively limited and variable, owing in part to the methodologic challenges posed by variability in latency to orgasm in participants and head movement. AIM: To compare brain activity at orgasm (self- and partner-induced) with that at the onset of genital stimulation, immediately before the onset of orgasm, and immediately after the cessation of orgasm and to upgrade the methodology for obtaining and analyzing functional magnetic resonance imaging (fMRI) findings. METHODS: Using fMRI, we sampled equivalent time points across female participants' variable durations of stimulation and orgasm in response to self- and partner-induced clitoral stimulation. The first 20-second epoch of orgasm was contrasted with the 20-second epochs at the beginning of stimulation and immediately before and after orgasm. Separate analyses were conducted for whole-brain and brainstem regions of interest. For a finer-grained analysis of the peri-orgasm phase, we conducted a time-course analysis on regions of interest. Head movement was minimized to a mean less than 1.3 mm using a custom-fitted thermoplastic whole-head and neck brace stabilizer. OUTCOMES: Ten women experienced orgasm elicited by self- and partner-induced genital stimulation in a Siemens 3-T Trio fMRI scanner. RESULTS: Brain activity gradually increased leading up to orgasm, peaked at orgasm, and then decreased. We found no evidence of deactivation of brain regions leading up to or during orgasm. The activated brain regions included sensory, motor, reward, frontal cortical, and brainstem regions (eg, nucleus accumbens, insula, anterior cingulate cortex, orbitofrontal cortex, operculum, right angular gyrus, paracentral lobule, cerebellum, hippocampus, amygdala, hypothalamus, ventral tegmental area, and dorsal raphe). CLINICAL TRANSLATION: Insight gained from the present findings could provide guidance toward a rational basis for treatment of orgasmic disorders, including anorgasmia. STRENGTHS AND LIMITATIONS: This is evidently the first fMRI study of orgasm elicited by self- and partner-induced genital stimulation in women. Methodologic solutions to the technical issues posed by excessive head movement and variable latencies to orgasm were successfully applied in the present study, enabling identification of brain regions involved in orgasm. Limitations include the small sample (N = 10), which combined self- and partner-induced stimulation datasets for analysis and which qualify the generalization of our conclusions. CONCLUSION: Extensive cortical, subcortical, and brainstem regions reach peak levels of activity at orgasm. Wise NJ, Frangos E, Komisaruk BR. Brain Activity Unique to Orgasm in Women: An fMRI Analysis. J Sex Med 2017;14:1380-1391.

PIEZO2 and perineal mechanosensation are essential for sexual function.

Despite the potential importance of genital mechanosensation for sexual reproduction, little is known about how perineal touch influences mating. We explored how mechanosensation affords exquisite awareness of the genitals and controls reproduction in mice and humans. Using genetic strategies and in vivo functional imaging, we demonstrated that the mechanosensitive ion channel PIEZO2 (piezo-type mechanosensitive ion channel component 2) is necessary for behavioral sensitivity to perineal touch. PIEZO2 function is needed for triggering a touch-evoked erection reflex and successful mating in both male and female mice. Humans with complete loss of PIEZO2 function have genital hyposensitivity and experience no direct pleasure from gentle touch or vibration. Together, our results help explain how perineal mechanoreceptors detect the gentlest of stimuli and trigger physiologically important sexual responses, thus providing a platform for exploring the sensory basis of sexual pleasure and its relationship to affective touch.

PIEZO2-dependent rapid pain system in humans and mice.

The PIEZO2 ion channel is critical for transducing light touch into neural signals but is not considered necessary for transducing acute pain in humans. Here, we discovered an exception - a form of mechanical pain evoked by hair pulling. Based on observations in a rare group of individuals with PIEZO2 deficiency syndrome, we demonstrated that hair-pull pain is dependent on PIEZO2 transduction. Studies in control participants showed that hair-pull pain triggered a distinct nocifensive response, including a nociceptive reflex. Observations in rare Aß deafferented individuals and nerve conduction block studies in control participants revealed that hair-pull pain perception is dependent on Aß input. Single-unit axonal recordings revealed that a class of cooling-responsive myelinated nociceptors in human skin is selectively tuned to painful hair-pull stimuli. Further, we pharmacologically mapped these nociceptors to a specific transcriptomic class. Finally, using functional imaging in mice, we demonstrated that in a homologous nociceptor, Piezo2 is necessary for high-sensitivity, robust activation by hair-pull stimuli. Together, we have demonstrated that hair-pulling evokes a distinct type of pain with conserved behavioral, neural, and molecular features across humans and mice.

Vagus nerve afferent stimulation: Projection into the brain, reflexive physiological, perceptual, and behavioral responses, and clinical relevance.

The afferent vagus nerves project to diverse neural networks within the brainstem and forebrain, based on neuroanatomical, neurophysiological, and functional (fMRI) brain imaging evidence. In response to afferent vagal stimulation, multiple homeostatic visceral reflexes are elicited. Physiological stimuli and both invasive and non-invasive electrical stimulation that activate the afferent vagus elicit perceptual and behavioral responses that are of physiological and clinical significance. In the present review, we address these multiple roles of the afferent vagus under normal and pathological conditions, based on both animal and human evidence.

Women's clitoris, vagina, and cervix mapped on the sensory cortex: fMRI evidence.

INTRODUCTION: The projection of vagina, uterine cervix, and nipple to the sensory cortex in humans has not been reported. AIMS: The aim of this study was to map the sensory cortical fields of the clitoris, vagina, cervix, and nipple, toward an elucidation of the neural systems underlying sexual response. METHODS: Using functional magnetic resonance imaging (fMRI), we mapped sensory cortical responses to clitoral, vaginal, cervical, and nipple self-stimulation. For points of reference on the homunculus, we also mapped responses to the thumb and great toe (hallux) stimulation. MAIN OUTCOME MEASURES: The main outcome measures used for this study were the fMRI of brain regions activated by the various sensory stimuli. RESULTS: Clitoral, vaginal, and cervical self-stimulation activated differentiable sensory cortical regions, all clustered in the medial cortex (medial paracentral lobule). Nipple self-stimulation activated the genital sensory cortex (as well as the thoracic) region of the homuncular map. CONCLUSION: The genital sensory cortex, identified in the classical Penfield homunculus based on electrical stimulation of the brain only in men, was confirmed for the first time in the literature by the present study in women applying clitoral, vaginal, and cervical self-stimulation, and observing their regional brain responses using fMRI. Vaginal, clitoral, and cervical regions of activation were differentiable, consistent with innervation by different afferent nerves and different behavioral correlates. Activation of the genital sensory cortex by nipple self-stimulation was unexpected, but suggests a neurological basis for women's reports of its erotogenic quality.

Hysterectomy improves sexual response? Addressing a crucial omission in the literature.

The prevailing view in the literature is that hysterectomy improves the quality of life. This is based on claims that hysterectomy alleviates pain (dyspareunia and abnormal bleeding) and improves sexual response. Because hysterectomy requires cutting the sensory nerves that supply the cervix and uterus, it is surprising that the reports of deleterious effects on sexual response are so limited. However, almost all articles that we encountered report that some of the women in the studies claim that hysterectomy is detrimental to their sexual response. It is likely that the degree to which a woman's sexual response and pleasure are affected by hysterectomy depends not only on which nerves were severed by the surgery, but also the genital regions whose stimulation the woman enjoys for eliciting sexual response. Because clitoral sensation (via pudendal and genitofemoral nerves) should not be affected by hysterectomy, this surgery would not diminish sexual response in women who prefer clitoral stimulation. However, women whose preferred source of stimulation is vaginal or cervical would be more likely to experience a decrement in sensation and consequently sexual response after hysterectomy because the nerves that innervate those organs, that is, the pelvic, hypogastric, and vagus nerves, are more likely to be damaged or severed in the course of hysterectomy. However, all published reports of the effects of hysterectomy on sexual response that we encountered fail to specify the women's preferred sources of genital stimulation. As discussed in the present review, we believe that the critical lack of information as to women's preferred sources of genital stimulation is key to accounting for the discrepancies in the literature as to whether hysterectomy improves or attenuates sexual pleasure.

Neural effects of placebo analgesia in fibromyalgia patients and healthy individuals.

ABSTRACT: Placebo analgesia is hypothesized to involve top-down engagement of prefrontal regions that access endogenous pain inhibiting opioid pathways. Fibromyalgia (FM) patients have neuroanatomical and neurochemical alterations in pathways relevant to placebo analgesia. Thus, it remains unclear whether placebo analgesic mechanisms would differ in FM patients compared to healthy controls (HCs). Here, using placebo-analgesia-inducing paradigms that included verbal suggestions and conditioning manipulations, we examined whether behavioral and neural placebo analgesic responses differed between 32 FM patients and 46 age- and sex-matched HCs. Participants underwent a manipulation scan, where noxious high and low heat were paired with the control and placebo cream, respectively, and a placebo experimental scan with equal noxious heat temperatures. Before the experimental scan, each participant received saline or naloxone, an opioid receptor antagonist. Across all participants, the placebo condition decreased pain intensity and unpleasantness ratings, decreased activity within the right insula and bilateral secondary somatosensory cortex, and modulated the neurologic pain signature. There were no differences between HCs and FM patients in pain intensity ratings or neural responses during the placebo condition. Despite the perceptual and neural effects of the placebo manipulation, prefrontal circuitry was not activated during the expectation period and the placebo analgesia was unaltered by naloxone, suggesting placebo effects were driven more by conditioning than expectation. Together, these findings suggest that placebo analgesia can occur in both HCs and chronic pain FM patients, without the involvement of opioidergic prefrontal modulatory networks.

Innocuous pressure sensation requires A-type afferents but not functional ΡΙΕΖΟ2 channels in humans.

The sensation of pressure allows us to feel sustained compression and body strain. While our understanding of cutaneous touch has grown significantly in recent years, how deep tissue sensations are detected remains less clear. Here, we use quantitative sensory evaluations of patients with rare sensory disorders, as well as nerve blocks in typical individuals, to probe the neural and genetic mechanisms for detecting non-painful pressure. We show that the ability to perceive innocuous pressures is lost when myelinated fiber function is experimentally blocked in healthy volunteers and that two patients lacking Aß fibers are strikingly unable to feel innocuous pressures at all. We find that seven individuals with inherited mutations in the mechanoreceptor PIEZO2 gene, who have major deficits in touch and proprioception, are nearly as good at sensing pressure as healthy control subjects. Together, these data support a role for Aß afferents in pressure sensation and suggest the existence of an unknown molecular pathway for its detection.

tVNS Increases Liking of Orally Sampled Low-Fat Foods: A Pilot Study.

Recently a role for the vagus nerve in conditioning food preferences was established in rodents. In a prospective controlled clinical trial in humans, invasive vagus nerve stimulation shifted food choice toward lower fat content. Here we explored whether hedonic aspects of an orally sampled food stimulus can be modulated by non-invasive transcutaneous vagus nerve stimulation (tVNS) in humans. In healthy participants (n = 10, five women, 20-32 years old, no obesity) we tested liking and wanting ratings of food samples with varying fat or sugar content with or without tVNS in a sham-controlled within-participants design. To determine effects of tVNS on food intake, we also measured voluntary consumption of milkshake. Spontaneous eye blink rate was measured as a proxy for dopamine tone. Liking of low-fat, but not high-fat puddings, was higher for tVNS relative to sham stimulation. Other outcomes showed no differences. These findings support a role for the vagus nerve promoting post-ingestive reward signals. Our results suggest that tVNS may be used to increase liking of low-calorie foods, which may support healthier food choices.

International Consensus Based Review and Recommendations for Minimum Reporting Standards in Research on Transcutaneous Vagus Nerve Stimulation (Version 2020).

Given its non-invasive nature, there is increasing interest in the use of transcutaneous vagus nerve stimulation (tVNS) across basic, translational and clinical research. Contemporaneously, tVNS can be achieved by stimulating either the auricular branch or the cervical bundle of the vagus nerve, referred to as transcutaneous auricular vagus nerve stimulation(VNS) and transcutaneous cervical VNS, respectively. In order to advance the field in a systematic manner, studies using these technologies need to adequately report sufficient methodological detail to enable comparison of results between studies, replication of studies, as well as enhancing study participant safety. We systematically reviewed the existing tVNS literature to evaluate current reporting practices. Based on this review, and consensus among participating authors, we propose a set of minimal reporting items to guide future tVNS studies. The suggested items address specific technical aspects of the device and stimulation parameters. We also cover general recommendations including inclusion and exclusion criteria for participants, outcome parameters and the detailed reporting of side effects. Furthermore, we review strategies used to identify the optimal stimulation parameters for a given research setting and summarize ongoing developments in animal research with potential implications for the application of tVNS in humans. Finally, we discuss the potential of tVNS in future research as well as the associated challenges across several disciplines in research and clinical practice.

Access to Vagal Projections via Cutaneous Electrical Stimulation of the Neck: fMRI Evidence in Healthy Humans.

BACKGROUND: Stimulation of the vagus nerve via implanted electrodes is currently used to treat refractory epilepsy and depression. Recently, a non-invasive approach to vagal stimulation has demonstrated similar beneficial effects, but it remains unclear whether these effects are mediated via activation of afferent vagal fibers. OBJECTIVE: The present study was designed to ascertain whether afferent vagal projections can be accessed non-invasively by transcutaneous electrical stimulation of the antero-lateral surface of the neck, which overlies the course of the vagus nerve. METHODS: Thirteen healthy subjects underwent 2 fMRI scans in one session. Transcutaneous electrical stimulation was applied for 2 min to the right postero-lateral surface of the neck during scan #1 (control condition, sternocleidomastoid stimulation: "SCM") and to the right antero-lateral surface of the neck during scan #2 (experimental condition, non-invasive vagus nerve stimulation: "nVNS"). Two analyses were conducted using FSL (whole-brain and brainstem; corrected, p < 0.01) to determine whether nVNS activated vagal projections in the brainstem and forebrain, compared to baseline and SCM stimulation. RESULTS: Compared to baseline and control (SCM) stimulation, nVNS significantly activated primary vagal projections including: nucleus of the solitary tract (primary central relay of vagal afferents), parabrachial area, primary sensory cortex, and insula. Regions of the basal ganglia and frontal cortex were also significantly activated. Deactivations were found in the hippocampus, visual cortex, and spinal trigeminal nucleus. CONCLUSION: The present findings provide evidence in humans that cervical vagal afferents can be accessed non-invasively via transcutaneous electrical stimulation of the antero-lateral surface of the neck, which overlies the course of the nerve, suggesting an alternative and feasible method of stimulating vagal afferents.

Do the psychological effects of vagus nerve stimulation partially mediate vagal pain modulation?

There is preclinical and clinical evidence that vagus nerve stimulation modulates both pain and mood state. Mechanistic studies show brainstem circuitry involved in pain modulation by vagus nerve stimulation, but little is known about possible indirect descending effects of altered mood state on pain perception. This possibility is important, since previous studies have shown that mood state affects pain, particularly the affective dimension (pain unpleasantness). To date, human studies investigating the effects of vagus nerve stimulation on pain perception have not reliably measured psychological factors to determine their role in altered pain perception elicited by vagus nerve stimulation. Thus, it remains unclear how much of a role psychological factors play in vagal pain modulation. Here, we present a rationale for including psychological measures in future vagus nerve stimulation studies on pain.

Activation of sensory cortex by imagined genital stimulation: an fMRI analysis.

BACKGROUND: During the course of a previous study, our laboratory made a serendipitous finding that just thinking about genital stimulation resulted in brain activations that overlapped with, and differed from, those generated by physical genital stimulation. OBJECTIVE: This study extends our previous findings by further characterizing how the brain differentially processes physical 'touch' stimulation and 'imagined' stimulation. DESIGN: Eleven healthy women (age range 29-74) participated in an fMRI study of the brain response to imagined or actual tactile stimulation of the nipple and clitoris. Two additional conditions - imagined dildo self-stimulation and imagined speculum stimulation - were included to characterize the effects of erotic versus non-erotic imagery. RESULTS: Imagined and tactile self-stimulation of the nipple and clitoris each activated the paracentral lobule (the genital region of the primary sensory cortex) and the secondary somatosensory cortex. Imagined self-stimulation of the clitoris and nipple resulted in greater activation of the frontal pole and orbital frontal cortex compared to tactile self-stimulation of these two bodily regions. Tactile self-stimulation of the clitoris and nipple activated the cerebellum, primary somatosensory cortex (hand region), and premotor cortex more than the imagined stimulation of these body regions. Imagining dildo stimulation generated extensive brain activation in the genital sensory cortex, secondary somatosensory cortex, hippocampus, amygdala, insula, nucleus accumbens, and medial prefrontal cortex, whereas imagining speculum stimulation generated only minimal activation. CONCLUSION: The present findings provide evidence of the potency of imagined stimulation of the genitals and that the following brain regions may participate in erogenous experience: primary and secondary sensory cortices, sensory-motor integration areas, limbic structures, and components of the 'reward system'. In addition, these results suggest a mechanism by which some individuals may be able to generate orgasm by imagery in the absence of physical stimulation.

Non-invasive Access to the Vagus Nerve Central Projections via Electrical Stimulation of the External Ear: fMRI Evidence in Humans.

BACKGROUND: Tract-tracing studies in cats and rats demonstrated that the auricular branch of the vagus nerve (ABVN) projects to the nucleus tractus solitarii (NTS); it has remained unclear as to whether or not the ABVN projects to the NTS in humans. OBJECTIVE: To ascertain whether non-invasive electrical stimulation of the cymba conchae, a region of the external ear exclusively innervated by the ABVN, activates the NTS and the "classical" central vagal projections in humans. METHODS: Twelve healthy adults underwent two fMRI scans in the same session. Electrical stimulation (continuous 0.25ms pulses, 25Hz) was applied to the earlobe (control, scan #1) and left cymba conchae (scan #2). Statistical analyses were performed with FSL. Two region-of-interest analyses were performed to test the effects of cymba conchae stimulation (compared to baseline and control, earlobe, stimulation) on the central vagal projections (corrected; brainstem P < 0.01, forebrain P < 0.05), followed by a whole-brain analysis (corrected, P < 0.05). RESULTS: Cymba conchae stimulation, compared to earlobe (control) stimulation, produced significant activation of the "classical" central vagal projections, e.g., widespread activity in the ipsilateral NTS, bilateral spinal trigeminal nucleus, dorsal raphe, locus coeruleus, and contralateral parabrachial area, amygdala, and nucleus accumbens. Bilateral activation of the paracentral lobule was also observed. Deactivations were observed bilaterally in the hippocampus and hypothalamus. CONCLUSION: These findings provide evidence in humans that the central projections of the ABVN are consistent with the "classical" central vagal projections and can be accessed non-invasively via the external ear.