Neuroelectric Correlates of Human Sexuality: A Review and Meta-Analysis.

Many reviews on sexual arousal in humans focus on different brain imaging methods and behavioral observations. Although neurotransmission in the brain is mainly performed through electrochemical signals, there are no systematic reviews of the electrophysiological correlates of sexual arousal. We performed a systematic search on this subject and reviewed 255 studies including various electrophysiological methods. Our results show how neuroelectric signals have been used to investigate genital somatotopy as well as basic genital physiology during sexual arousal and how cortical electric signals have been recorded during orgasm. Moreover, experiments on the interactions of cognition and sexual arousal in healthy subjects and in individuals with abnormal sexual preferences were analyzed as well as case studies on sexual disturbances associated with diseases of the nervous system. In addition, 25 studies focusing on brain potentials during the interaction of cognition and sexual arousal were eligible for meta-analysis. The results showed significant effect sizes for specific brain potentials during sexual stimulation (P3: Cohen's d = 1.82, N = 300, LPP: Cohen's d = 2.30, N = 510) with high heterogeneity between the combined studies. Taken together, our review shows how neuroelectric methods can consistently differentiate sexual arousal from other emotional states.

Exploring the neural correlates of (altered) moral cognition in psychopaths.

Research into the neurofunctional mechanisms of psychopathy has gathered momentum over the last years. Previous neuroimaging studies have identified general changes in brain activity of psychopaths. In an exploratory meta-analysis, we here investigated the neural correlates of impaired moral cognition in psychopaths. Our analyses replicated general effects in the dorsomedial prefrontal cortex, lateral prefrontal cortex, fronto-insular cortex, and amygdala, which have been reported recently. In addition, we found aberrant brain activity in the midbrain and inferior parietal cortex. Our preliminary findings suggest that alterations in both regions may represent more specific functional brain changes related to (altered) moral cognition in psychopaths. Furthermore, future studies including a more comprehensive corpus of neuroimaging studies on moral cognition in psychopaths should re-examine this notion.

A view behind the mask of sanity: meta-analysis of aberrant brain activity in psychopaths.

Psychopathy is a disorder of high public concern because it predicts violence and offense recidivism. Recent brain imaging studies suggest abnormal brain activity underlying psychopathic behavior. No reliable pattern of altered neural activity has been disclosed so far. This study sought to identify consistent changes of brain activity in psychopaths and to investigate whether these could explain known psychopathology. First, we used activation likelihood estimation (p < 0.05, corrected) to meta-analyze brain activation changes associated with psychopathy across 28 functional magnetic resonance imaging studies reporting 753 foci from 155 experiments. Second, we characterized the ensuing regions functionally by employing metadata of a large-scale neuroimaging database (p < 0.05, corrected). Psychopathy was consistently associated with decreased brain activity in the right laterobasal amygdala, the dorsomedial prefrontal cortex, and bilaterally in the lateral prefrontal cortex. A robust increase of activity was observed in the fronto-insular cortex on both hemispheres. Data-driven functional characterization revealed associations with semantic language processing (left lateral prefrontal and fronto-insular cortex), action execution and pain processing (right lateral prefrontal and left fronto-insular), social cognition (dorsomedial prefrontal cortex), and emotional as well as cognitive reward processing (right amygdala and fronto-insular cortex). Aberrant brain activity related to psychopathy is located in prefrontal, insular, and limbic regions. Physiological mental functions fulfilled by these brain regions correspond to disturbed behavioral patterns pathognomonic for psychopathy. Hence, aberrant brain activity may not just be an epiphenomenon of psychopathy but directly related to the psychopathology of this disorder.

Repetitive Transcranial Magnetic Stimulation as a Potential Tool to Reduce Sexual Arousal: A Proof of Concept Study.

BACKGROUND: Hypersexuality and hyposexuality occur frequently, often in a variety of psychiatric disorders, and are difficult to treat. While there is meta-analytic evidence for the significant effect of non-invasive brain stimulation on drug and food craving, no study has investigated the potential of this technique to modulate sexual behavior. AIM: Here, we tested the hypothesis that a single session of high-frequency repetitive transcranial magnetic stimulation (rTMS) over the dorsolateral prefrontal cortex (DLPFC) would reduce sexual arousal. METHODS: We employed a randomized, double-blind, sham-controlled crossover study design. 19 healthy male participants received high-frequency rTMS over the left DLPFC, high-frequency rTMS over the right DLPFC, and sham rTMS (each 10 Hz; 110% resting motor threshold; 60 trains with 50 pulses) in randomized and counterbalanced order with a 1-week interval between stimulation sessions to avoid carryover effects. Participants were exposed to neutral and sexual cues before and after each intervention and rated their sexual arousal after each block of cue presentation. MAIN OUTCOME MEASURE: Efficacy of the respective intervention was operationalized by the change of subjective sexual arousal according to a rating scale. RESULTS: rTMS of the right DLPFC significantly reduced subjective sexual arousal (t18 = 2.282, P = .035). In contrast, neither sham rTMS nor rTMS of the left DLPFC affected sexual arousal (P > .389). Greater rTMS-induced reduction of subjective sexual arousal was observed in participants with higher trait-based dyadic sexual desire within the last 12 months (r = -0.417, P = .038). CLINICAL IMPLICATION: Non-invasive brain stimulation might hold potential for influencing hypersexual behavior. STRENGTH & LIMITATION: This was a randomized, double-blind, sham-controlled crossover study with subjective but no physiological measures of sexual arousal. CONCLUSION: The results indicate that 1 session of high-frequency rTMS (10 Hz) of the right DLPFC could significantly reduce subjective sexual arousal induced by visual stimuli in healthy subjects. On this basis, future studies with larger sample sizes and more stimulation sessions are needed to explore the therapeutic potential of rTMS in hypersexual behavior. Schecklmann M, Sakreida K, Oblinger B, et al. Repetitive Transcranial Magnetic Stimulation as a Potential Tool to Reduce Sexual Arousal: A Roof of Concept Study. J Sex Med 2020;17:1553-1559.

Meta-analytic Evidence for Neural Dysactivity Underlying Sexual Dysfunction.

INTRODUCTION: About 30-40% of the population report sexual dysfunction. Although it is well known that the brain controls sexual behavior, little is known about the neural basis of sexual dysfunction. AIM: To assess convergence of altered brain activity associated with sexual dysfunction across available functional imaging studies. METHODS: We used activation likelihood estimation meta-analysis to quantify interstudy concordance across 14 functional imaging studies reporting 179 foci from 40 individual analyses involving 191 subjects with sexual dysfunction and 123 controls. MAIN OUTCOME MEASURE: Activation likelihood estimation scores were used to assess convergence of findings. RESULTS: Consistently decreased brain activity associated with sexual dysfunction was identified in the dorsal anterior cingulate cortex, ventral striatum, dorsal midbrain, anterior midcingulate cortex, and lateral orbitofrontal cortex. CLINICAL IMPLICATION: These findings can serve as a basis for further studies on the pathophysiology of this highly common disorder with the view to development of more-specific treatment strategies. STRENGTH & LIMITATIONS: Findings are based on an observer-independent meta-analysis that provides robust evidence for and anatomic localization of altered brain activity related to sexual dysfunction. Our analysis cannot distinguish between the putative sources of sexual dysfunction, but it provides a more ubiquitous and general pattern of related altered neural activity. CONCLUSION: The identified regions have previously been shown to be critically involved in mediating sexual arousal and to be part of the sympathetic division of the autonomic nervous system. This suggests that the disturbance of brain activity associated with sexual dysfunction primarily affects sexual arousal already at early stages that are controlled by the sympathetic nervous system. Poeppl TB, Langguth B, Laird AR, et al. Meta-analytic Evidence for Neural Dysactivity Underlying Sexual Dysfunction. J Sex Med 2019;16:614-617.

Brain stimulation-induced neuroplasticity underlying therapeutic response in phantom sounds.

Noninvasive brain stimulation can modify phantom sounds for longer periods by modulating neural activity and putatively inducing regional neuroplastic changes. However, treatment response is limited and there are no good demographic or clinical predictors for treatment outcome. We used state-of-the-art voxel-based morphometry (VBM) to investigate whether transcranial magnetic stimulation-induced neuroplasticity determines therapeutic outcome. Sixty subjects chronically experiencing phantom sounds (i.e., tinnitus) received repetitive transcranial magnetic stimulation (rTMS) of left dorsolateral prefrontal and temporal cortex according to a protocol that has been shown to yield a significantly higher number of treatment responders than sham stimulation and previous stimulation protocols. Structural magnetic resonance imaging was performed before and after rTMS. In VBM whole-brain analyses (P < 0.05, FWE corrected), we assessed longitudinal gray matter changes as well as structural connectivity between the ensuing regions. We observed longitudinal mesoscopic gray matter changes of left dorsolateral prefontal (DLPFC), left operculo-insular, and right inferior temporal cortex (ITC) in responders (N = 22) but not nonresponders (N = 38), as indicated by a group × time interaction and post-hoc tests. These results were neither influenced by age, sex, hearing loss nor by tinnitus laterality, duration, and severity at baseline. Furthermore, we found robust DLPFC-insula and insula-ITC connectivity in responders, while only relatively weak DLPFC-insula connectivity and no insula-ITC connectivity could be demonstrated in nonresponders. Our results reinforce the implication of nonauditory brain regions in phantom sounds and suggest the dependence of therapeutic response on their neuroplastic capabilities. The latter in turn may depend on (differences in) their individual structural connectivity. Hum Brain Mapp 39:554-562, 2018. © 2017 Wiley Periodicals, Inc.

The neural basis of sex differences in sexual behavior: A quantitative meta-analysis.

Sexuality as to its etymology presupposes the duality of sexes. Using quantitative neuroimaging meta-analyses, we demonstrate robust sex differences in the neural processing of sexual stimuli in thalamus, hypothalamus, and basal ganglia. In a narrative review, we show how these relate to the well-established sex differences on the behavioral level. More specifically, we describe the neural bases of known poor agreement between self-reported and genital measures of female sexual arousal, of previously proposed male proneness to affective sexual conditioning, as well as hints of unconscious activation of bonding mechanisms during sexual stimulation in women. In summary, our meta-analytic review demonstrates that neurofunctional sex differences during sexual stimulation can account for well-established sex differences in sexual behavior.

Imbalance in subregional connectivity of the right temporoparietal junction in major depression.

Major depressive disorder (MDD) involves impairment in cognitive and interpersonal functioning. The right temporoparietal junction (RTPJ) is a key brain region subserving cognitive-attentional and social processes. Yet, findings on the involvement of the RTPJ in the pathophysiology of MDD have so far been controversial. Recent connectivity-based parcellation data revealed a topofunctional dualism within the RTPJ, linking its anterior and posterior part (aRTPJ/pRTPJ) to antagonistic brain networks for attentional and social processing, respectively. Comparing functional resting-state connectivity of the aRTPJ and pRTPJ in 72 MDD patients and 76 well-matched healthy controls, we found a seed (aRTPJ/pRTPJ) × diagnosis (MDD/controls) interaction in functional connectivity for eight regions. Employing meta-data from a large-scale neuroimaging database, functional characterization of these regions exhibiting differentially altered connectivity with the aRTPJ/pRTPJ revealed associations with cognitive (dorsolateral prefrontal cortex, parahippocampus) and behavioral (posterior medial frontal cortex) control, visuospatial processing (dorsal visual cortex), reward (subgenual anterior cingulate cortex, medial orbitofrontal cortex, posterior cingulate cortex), as well as memory retrieval and social cognition (precuneus). These findings suggest that an imbalance in connectivity of subregions, rather than disturbed connectivity of the RTPJ as a whole, characterizes the connectional disruption of the RTPJ in MDD. This imbalance may account for key symptoms of MDD in cognitive, emotional, and social domains. Hum Brain Mapp 37:2931-2942, 2016. © 2016 Wiley Periodicals, Inc.

A proof-of-concept study on the combination of repetitive transcranial magnetic stimulation and relaxation techniques in chronic tinnitus.

Interference of ongoing neuronal activity and brain stimulation motivated this study to combine repetitive transcranial magnetic stimulation (rTMS) and relaxation techniques in tinnitus patients. Forty-two patients were enrolled in this one-arm proof-of-concept study to receive ten sessions of rTMS applied to the left dorsolateral prefrontal cortex and temporo-parietal cortex. During stimulation, patients listened to five different kinds of relaxation audios. Variables of interest were tinnitus questionnaires, tinnitus numeric rating scales, depressivity, and quality of life. Results were compared to results of historical control groups having received the same rTMS protocol (active control) and sham treatment (placebo) without relaxation techniques. Thirty-eight patients completed the treatment, drop-out rates and adverse events were low. Responder rates (reduction in tinnitus questionnaire (TQ) score ≥5 points 10 weeks after treatment) were 44.7 % in the study, 27.8 % in the active control group, and 21.7 % in the placebo group, differing between groups on a near significant level. For the tinnitus handicap inventory (THI), the main effect of group was not significant. However, linear mixed model analyses showed that the relaxation/rTMS group differed significantly from the active control group showing steeper negative THI trend for the relaxation/rTMS group indicating better amelioration over the course of the trial. Deepness of relaxation during rTMS and selection of active relaxation vs. passive listening to music predicted larger TQ. All remaining secondary outcomes turned out non-significant. This combined treatment proved to be a safe, feasible and promising approach to enhance rTMS treatment effects in chronic tinnitus.

Connectivity and functional profiling of abnormal brain structures in pedophilia.

Despite its 0.5-1% lifetime prevalence in men and its general societal relevance, neuroimaging investigations in pedophilia are scarce. Preliminary findings indicate abnormal brain structure and function. However, no study has yet linked structural alterations in pedophiles to both connectional and functional properties of the aberrant hotspots. The relationship between morphological alterations and brain function in pedophilia as well as their contribution to its psychopathology thus remain unclear. First, we assessed bimodal connectivity of structurally altered candidate regions using meta-analytic connectivity modeling (MACM) and resting-state correlations employing openly accessible data. We compared the ensuing connectivity maps to the activation likelihood estimation (ALE) maps of a recent quantitative meta-analysis of brain activity during processing of sexual stimuli. Second, we functionally characterized the structurally altered regions employing meta-data of a large-scale neuroimaging database. Candidate regions were functionally connected to key areas for processing of sexual stimuli. Moreover, we found that the functional role of structurally altered brain regions in pedophilia relates to nonsexual emotional as well as neurocognitive and executive functions, previously reported to be impaired in pedophiles. Our results suggest that structural brain alterations affect neural networks for sexual processing by way of disrupted functional connectivity, which may entail abnormal sexual arousal patterns. The findings moreover indicate that structural alterations account for common affective and neurocognitive impairments in pedophilia. The present multimodal integration of brain structure and function analyses links sexual and nonsexual psychopathology in pedophilia.

The functional neuroanatomy of male psychosexual and physiosexual arousal: a quantitative meta-analysis.

Reproductive behavior is mandatory for conservation of species and mediated by a state of sexual arousal (SA), involving both complex mental processes and bodily reactions. An early neurobehavioral model of SA proposes cognitive, emotional, motivational, and autonomic components. In a comprehensive quantitative meta-analysis on previous neuroimaging findings, we provide here evidence for distinct brain networks underlying psychosexual and physiosexual arousal. Psychosexual (i.e., mental sexual) arousal recruits brain areas crucial for cognitive evaluation, top-down modulation of attention and exteroceptive sensory processing, relevance detection and affective evaluation, as well as regions implicated in the representation of urges and in triggering autonomic processes. In contrast, physiosexual (i.e., physiological sexual) arousal is mediated by regions responsible for regulation and monitoring of initiated autonomic processes and emotions and for somatosensory processing. These circuits are interconnected by subcortical structures (putamen and claustrum) that provide exchange of sensorimotor information and crossmodal processing between and within the networks. Brain deactivations may imply attenuation of introspective processes and social cognition, but be necessary to release intrinsic inhibition of SA.

Amygdalohippocampal neuroplastic changes following neuroleptic treatment with quetiapine in first-episode schizophrenia.

Schizophrenia is a severe, debilitating, chronic disease that is accompanied by morphologic changes within the brain. However, it is unclear to what extent alterations of grey and white matter in schizophrenia are linked to the disease itself, or whether they are a consequence of neuroleptic treatment. Typical and atypical antipsychotics exert differential effects on brain structure. Moreover, atypical antipsychotics may have distinct profiles with respect to grey matter in schizophrenic patients. Findings on drug-induced grey matter changes are heterogeneous due to variation in stage of illness, duration of treatment and use of multiple antipsychotics. Using voxel-based morphometry applied to high-resolution magnetic resonance images, we show that monotherapy with the atypical agent quetiapine (mean daily dose = 445 mg ± 200 s.d.) may induce structural brain changes in first-episode schizophrenia patients (N = 20) within 21 d of treatment. Specifically, we demonstrate longitudinal macroscopic changes (i.e. grey matter increases) in the left amygdalohippocampal region that were predicted by drug plasma levels but not daily doses. These structural alterations were accompanied by a clinical improvement of schizophrenic symptoms. Comparison with healthy controls (n = 30) showed that grey matter amount in the respective amygdalar region was significantly reduced in unmedicated first-episode schizophrenia patients. These findings suggest that drug-induced neuroplastic changes in schizophrenia can occur quickly and are dependent on pharmacokinetics.

In vitro investigation of the efficacy of novel diamidines against Trypanosoma cruzi.

Chagas' disease is a neglected tropical disease caused by Trypanosoma cruzi and constitutes a serious public health problem for Latin America. Its unsatisfactory chemotherapy stimulates the search for novel antiparasitic compounds. Amidines and related compounds exhibit well-known activity towards different microbes including T. cruzi. In this vein, our present aim was to evaluate the biological effect of 10 novel structurally related amidines in vitro against bloodstream and intracellular forms of the parasite as well as their potential toxicity on cardiac cell cultures. Our results show that although active against the extracellular forms, with some of them like DB2247 being 6-fold more effective than benznidazole and displaying very low toxicity (>96 µm), none presented superior trypanocidal effect against intracellular forms as compared with the reference drug. These results may be due to differences in susceptibility profiles related to distinct uptake/extrusion mechanisms and cellular targets between bloodstream and amastigote forms. The present study adds to the knowledge base for the future design of novel amidines that may provide promising activity against T. cruzi.

Structural brain changes following left temporal low-frequency rTMS in patients with subjective tinnitus.

Repetitive transcranial magnetic stimulation (rTMS) of the temporal cortex has been used to treat patients with subjective tinnitus. While rTMS is known to induce morphological changes in healthy subjects, no study has investigated yet whether rTMS treatment induces grey matter (GM) changes in tinnitus patients as well, whether these changes are correlated with treatment success, and whether GM at baseline is a useful predictor for treatment outcome. Therefore, we examined magnetic resonance images of 77 tinnitus patients who were treated with rTMS of the left temporal cortex (10 days, 2000 stimuli/day, 1 Hz). At baseline and after the last treatment session high-resolution structural images of the brain were acquired and tinnitus severity was assessed. For a subgroup of 41 patients, additional brain scans were done after a follow-up period of 90 days. GM changes were analysed by means of voxel based morphometry. Transient GM decreases were detectable in several brain regions, especially in the insula and the inferior frontal cortex. These changes were not related to treatment outcome though. Baseline images correlated with change in tinnitus severity in the frontal cortex and the lingual gyrus, suggesting that GM at baseline might hold potential as a possible predictor for treatment outcome.

Reduced variability of auditory alpha activity in chronic tinnitus.

Subjective tinnitus is characterized by the conscious perception of a phantom sound which is usually more prominent under silence. Resting state recordings without any auditory stimulation demonstrated a decrease of cortical alpha activity in temporal areas of subjects with an ongoing tinnitus perception. This is often interpreted as an indicator for enhanced excitability of the auditory cortex in tinnitus. In this study we want to further investigate this effect by analysing the moment-to-moment variability of the alpha activity in temporal areas. Magnetoencephalographic resting state recordings of 21 tinnitus subjects and 21 healthy controls were analysed with respect to the mean and the variability of spectral power in the alpha frequency band over temporal areas. A significant decrease of auditory alpha activity was detected for the low alpha frequency band (8-10 Hz) but not for the upper alpha band (10-12 Hz). Furthermore, we found a significant decrease of alpha variability for the tinnitus group. This result was significant for the lower alpha frequency range and not significant for the upper alpha frequencies. Tinnitus subjects with a longer history of tinnitus showed less variability of their auditory alpha activity which might be an indicator for reduced adaptability of the auditory cortex in chronic tinnitus.

Neural correlates of tinnitus duration and distress: a positron emission tomography study.

Cerebral (18)F-deoxyglucose positron emission tomography (FDG-PET) has shown altered auditory pathway activity in tinnitus. However, the corresponding studies involved only small samples and analyses were restricted to the auditory cortex in most studies. Evidence is growing that also limbic, frontal, and parietal areas are involved in the pathophysiology of chronic tinnitus. These regions are considered to mediate perceptual, attentional, and emotional processes. Thus, the aim of the present study was the systematic evaluation of metabolic brain activity in a large sample of tinnitus patients. Ninety one patients with chronic tinnitus underwent FDG-PET. The effects of tinnitus severity (assessed by a tinnitus questionnaire score), duration and laterality were evaluated with statistical parametric mapping (SPM) in whole brain analyses. In addition, region of interest analyses were performed for primary auditory areas. Tinnitus duration correlated positively with brain metabolism in right inferior frontal, right ventro-medial prefrontal, and right posterior cingulate cortex. Tinnitus distress correlated positively with activation of left and right posterior inferior temporal gyrus as well as left and right posterior parahippocampal-hippocampal interface. Region of interest analysis demonstrated an overactivation of left in contrast to right Heschl's gyrus independently from tinnitus laterality and anatomical hemispheric differences. Tinnitus duration and distress were associated with areas involved in attentional and emotional processing. This is in line with recent findings indicating the relevance of higher order areas in the pathophysiology of tinnitus. Earlier results of asymmetric activation of the auditory cortices in tinnitus were confirmed, i.e., left-sided overactivation was found independently from tinnitus laterality.

Multisite rTMS for the treatment of chronic tinnitus: stimulation of the cortical tinnitus network--a pilot study.

Low-frequency repetitive transcranial magnetic stimulation (rTMS) of the auditory cortex has been shown to significantly reduce tinnitus severity in some patients. There is growing evidence that a neural network of both auditory and non-auditory cortical areas is involved in the pathophysiology of chronic subjective tinnitus. Targeting several core regions of this network by rTMS might constitute a promising strategy to enhance treatment effects. This study intends to test the effects of a multisite rTMS protocol on tinnitus severity. 45 patients with chronic tinnitus were treated with multisite stimulation (left dorsolateral prefrontal, 2,000 stimuli, 20 Hz; left temporoparietal, 1,000 stimuli, 1 Hz; right temporoparietal, 1,000 stimuli, 1 Hz). Results were compared with a historical control group consisting of 29 patients who received left temporal stimulation (2,000 stimuli, 1 Hz). Both groups were treated on ten consecutive working days. Tinnitus severity was assessed at three time points: at baseline, after the last treatment session (day 12) and after a follow-up period of 90 days. A change of tinnitus severity over time was tested using repeated measures ANOVA with the between-subjects factor treatment group. Both groups improved similarly from baseline to day 12. However, there was a difference on day 90: the multisite stimulation group showed an overall improvement whereas patients receiving temporal stimulation returned to their baseline level of tinnitus severity. These pilot data suggest that multisite rTMS is superior to temporal rTMS and represents a promising strategy for enhancing treatment effects of rTMS in tinnitus. Future studies should explore this new protocol with respect to clinical and neurobiological effects in more detail.