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Non-invasive brain stimulation techniques such as repetitive transcranial magnetic stimulation (rTMS) offer a promising alternative to psychotherapeutic and pharmacological treatments for depression. This paper aims to present a practical guide for its clinical implementation based on evidence from the literature as well as on the experience of a group of leading German experts in the field.The current evidence base for the use of rTMS in depression was examined via review of the literature. From the evidence and from clinical experience, recommendations for the use of rTMS in clinical practice were derived. All members of the of the German Society for Brain Stimulation in Psychiatry and all members of the sections Clinical Brain Stimulation and Experimental Brain Stimulation of the German Society for Psychiatry, Psychotherapy, Psychosomatics and Mental Health were invited to participate in a poll on whether they consent with the recommendations.Among rTMS experts, a high consensus rate could be identified for clinical practice concerning the setting and the technical parameters of rTMS treatment in depression, indications and contra-indications, the relation of rTMS to other antidepressive treatment modalities and the frequency and management of side effects.

Brain communications 4(4), fcac190 (2022). doi:10.1093/braincomms/fcac190, Published by Oxford University Press, [Oxford]

Background Depressive disorders are linked to dysfunction in prefrontal cortical areas. Hence, non-invasive neurostimulation of the prefrontal cortex has demonstrated antidepressant efficacy. In the present study, we investigated the efficacy of high frequency transcranial random noise stimulation (hf-tRNS) as an add-on treatment for depression in a sham-controlled randomized trial. Methods Forty in-patients with depression were randomized and treated with real or sham hf-tRNS (100–650 Hz) with 0 mA offset. The electrodes were mounted over the left and right dorsolateral prefrontal cortex. The Hamilton Depression Rating Scale (primary outcome), the Major Depression Inventory, the Clinical Global Impression scale and the Global Assessment of Functioning scale were used for assessment at baseline, after 3 weeks of intervention (end of treatment), and 9 weeks after intervention. Safety parameters included cognitive functioning and reported side-effects. Results Comparison of real and sham treatment at the planned interim analysis showed an amelioration of symptoms in both groups for all outcomes with numeric but not statistically significant superiority of the sham arm for the primary outcome. Thus, the study was terminated prematurely after an interim analysis. There were no systematic differences with respect to safety parameters. Limitations The negative finding might be related to the specific stimulation parameters used in this study. Conclusions Our study suggests that prefrontal hf-tRNS is safe but not effective as an add-on treatment of depression. The challenge for future studies employing transcranial electric stimulation remains to identify effective stimulation parameters for the treatment of depression.

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.

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.

Combining antipsychotics is common in schizophrenia treatment, despite evidence-based guidelines generally not recommending such practice. Otherwise, evidence remains inconclusive, especially regarding specific combinations. The trial aimed to test whether a combination of amisulpride plus olanzapine is more effective than either intervention as a monotherapy.A multicentre, 16-week, randomised, double-blind, controlled trial was done at 16 psychiatric in-patient centres throughout Germany. Inclusion criteria were adults aged 18-65 years with non-first episode schizophrenia or schizoaffective disorder and with a Positive and Negative Syndrome Scale (PANSS) total score of at least 70 and at least two items of the positive symptoms subscale rated at least 4. Patients were randomly assigned to receive 16 weeks of treatment with either amisulpride plus olanzapine, amisulpride plus placebo, or olanzapine plus placebo (1:1:1), and block randomisation was stratified by study site. To keep patients and investigators masked throughout the duration of the trial, amisulpride, olanzapine, and placebo were administered as identical capsules. Flexibly dosed monotherapy of oral amisulpride (amisulpride plus placebo, 200-800 mg per day) or olanzapine (olanzapine plus placebo, 5-20 mg per day) was compared with a combination of amisulpride plus olanzapine. The primary outcome was symptom reduction measured by the PANSS total score after 8 weeks, in the modified intention-to-treat population (all patients randomly assigned to an intervention and receiving at least one study drug dose). As determined a priori, group differences were examined by t tests (Bonferroni-Holm-adjustment) followed by pre-planned Bayesian analyses as well as imputation methods based on mixed models to account for missing values and post-hoc ANCOVA adjusting for PANSS baseline scores. The study was registered on ClinicalTrials.gov, NCT01609153; the German Clinical Trials Register, DRKS00003603; and the European Union Drug Regulating Authorities Clinical Trials Database, EudraCT-No. 2011-002463-20.Between June 15, 2012, and Dec 15, 2018, 13 692 patients were assessed for eligibility. 13 364 patients were excluded (including for not meeting inclusion criteria, declining to participate, or inappropriate reasons for changing pharmacological treatment), and 328 were then randomly assigned to an intervention group. 112 patients were randomly assigned to receive amisulpride plus olanzapine, 109 were randomly assigned to receive amisulpride plus placebo, and 107 were randomly assigned to receive olanzapine plus placebo. 321 patients were analysed for the primary outcome in the modified intention-to-treat population after exclusion of screening failures and patients who did not receive the intervention (110 for amisulpride plus olanzapine, 109 for amisulpride plus placebo, and 102 for olanzapine plus placebo). Among the 321 patients who were randomly assigned to intervention groups and analysed for the primary outcome, 229 (71%) were male, 92 (29%) were female; the mean age was 40·2 years (SD 11·7); and 296 (92%) were White and 25 (8%) were classified as other ethnicity. PANSS total score improved significantly more at 8 weeks in the amisulpride plus olanzapine group (-29·6 [SD 14·5]) than in the olanzapine plus placebo group (-24·1 [13·4], p=0·049, Cohen's d=0·396). A significant difference was not observed in reduction of PANSS total score between the amisulpride and olanzapine group compared with the amisulpride and placebo group (-25·2 [SD 15·9], p=0·095, Cohen's d=0·29). After 8 weeks and 16 weeks, sexual dysfunction, weight, and waist circumference increase were significantly higher for patients receiving amisulpride plus olanzapine than for those receiving amisulpride plus placebo, with no differences in serious adverse events. Two patients died during study participation; one randomly assigned to the amisulpride plus olanzapine group, and one assigned to the olanzapine plus placebo group (both assessed with no relation to treatment).The advantages of amisulpride plus olanzapine have to be weighed against a higher propensity for side-effects. The use of this specific combination therapy could be an alternative to monotherapy in certain clinical situations, but side-effects should be considered.German Federal Ministry of Education and Research.

Transcranial random noise stimulation (tRNS) is a non-invasive brain stimulation technique which uses electrical alternating currents applied at random frequencies. Besides the ability to alter cortical excitability, past research demonstrated that high-frequency tRNS over the auditory cortex can modulate both spontaneous and auditory evoked oscillatory brain activity.The aim of the present study was to examine the effects of high- and low-frequency auditory tRNS on EEG power and evoked activity.Low-frequency (0.1-100Hz), high-frequency (100-640Hz) and sham tRNS were administered for a stimulation over the auditory cortex in 22 healthy subjects. Before and after tRNS stimulation auditory steady state responses (ASSR) of 20 and 40Hz stimuli as well as oscillatory brain activity were recorded with electroencephalography (EEG).Stimulation of both verum tRNS protocols revealed no significant changes either in ASSR or in resting state EEG activity. Unexpectedly, sham tRNS resulted in a significant decrease in 20Hz ASSR and an increase in the alpha frequency band (8-12.5Hz).We were not able to replicate previous findings of a modulation of resting state EEG activity and ASSR by tRNS.

The current study examines two different protocols of repetitive transcranial magnetic stimulation (rTMS) targeting three key hubs of cortical tinnitus networks. Patients chose whether they preferred to undergo rTMS treatment for 10 or 20 sessions and were randomized to the different rTMS protocols thereafter. Ninety patients were enrolled in the study with a total dropout rate of 10%. Both rTMS protocols were well tolerated by the patients without any serious adverse events. Overall treatment effects were small both for 2 weeks and 4 weeks of treatment. There was no significant interaction effect between measurement time point and treatment group for neither of the outcome measures nor any differences regarding the applied treatment regimens. The effects of this study contradict former observations suggesting multisite rTMS protocols as promising neuromodulatory strategies. This lack of effect could not be enhanced by increasing the number of treatment sessions in our study.

European archives of psychiatry and clinical neuroscience 271(7), 1245-1253 (2021). doi:10.1007/s00406-021-01287-3, Published by Springer, Berlin ; Heidelberg

Background: Transcranial random noise stimulation (tRNS) is a non-invasive brain stimulation technique which uses electrical alternating currents applied at random frequencies. Besides the ability to alter cortical excitability, past research demonstrated that high-frequency tRNS over the auditory cortex can modulate both spontaneous and auditory evoked oscillatory brain activity. Objectives: The aim of the present study was to examine the effects of high- and low-frequency auditory tRNS on EEG power and evoked activity. Methods: Low-frequency (0.1–100 Hz), high-frequency (100–640 Hz) and sham tRNS were administered for a stimulation over the auditory cortex in 22 healthy subjects. Before and after tRNS stimulation auditory steady state responses (ASSR) of 20 and 40 Hz stimuli as well as oscillatory brain activity were recorded with electroencephalography (EEG). Results: Stimulation of both verum tRNS protocols revealed no significant changes either in ASSR or in resting state EEG activity. Unexpectedly, sham tRNS resulted in a significant decrease in 20 Hz ASSR and an increase in the alpha frequency band (8–12.5 Hz). Conclusion: We were not able to replicate previous findings of a modulation of resting state EEG activity and ASSR by tRNS.

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., Behavioral Sciences & the Law, vol. 39, no. 6, p. 731

European archives of psychiatry and clinical neuroscience 271(1), 61-67 (2021). doi:10.1007/s00406-020-01160-9, Published by Steinkopff, Darmstadt

The current study examines two different protocols of repetitive transcranial magnetic stimulation (rTMS) targeting three key hubs of cortical tinnitus networks. Patients chose whether they preferred to undergo rTMS treatment for 10 or 20 sessions and were randomized to the different rTMS protocols thereafter. Ninety patients were enrolled in the study with a total dropout rate of 10%. Both rTMS protocols were well tolerated by the patients without any serious adverse events. Overall treatment effects were small both for 2 weeks and 4 weeks of treatment. There was no significant interaction effect between measurement time point and treatment group for neither of the outcome measures nor any differences regarding the applied treatment regimens. The effects of this study contradict former observations suggesting multisite rTMS protocols as promising neuromodulatory strategies. This lack of effect could not be enhanced by increasing the number of treatment sessions in our study.

Non-invasive brain stimulation can reduce the severity of tinnitus phantom sounds beyond the time of stimulation by inducing regional neuroplastic changes. However, there are no good clinical predictors for treatment outcome. We used machine learning to investigate whether brain anatomy can predict therapeutic outcome. Sixty-one chronic tinnitus patients received repetitive transcranial magnetic stimulation of left dorsolateral prefrontal and temporal cortex. Before repetitive transcranial magnetic stimulation, a structural magnetic resonance image was obtained from all patients. To predict individual treatment response in new subjects, we employed a support vector machine ensemble for individual out-of-sample prediction. In the cross-validation, the support vector machine ensemble based on stratified sub-sampling and feature selection yielded an area under the curve of 0.87 for prediction of therapy success in new, previously unseen subjects. This corresponded to a balanced accuracy of 83.5%, sensitivity of 77.2% and specificity of 87.2%. Investigating the most selected features showed the involvement of the auditory cortex but also revealed a network of non-auditory brain areas. These findings suggest that idiosyncratic brain patterns accurately predict individual responses to repetitive transcranial magnetic stimulation treatment for tinnitus. Our findings may hence pave the way for future investigations into the precision treatment of tinnitus, involving automatic identification of the appropriate treatment method for the individual patient., Graphical Abstract Graphical Abstract

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

This report presents the rationale and design of a multi-center clinical trial that examines the efficacy and safety of antipsychotic combination treatment in acutely ill schizophrenia patients compared to antipsychotic monotherapy. Antipsychotic combination treatment is common in clinical practice worldwide, despite clinical guidelines generally not recommending such practice due to lacking evidence for its efficacy and safety. Olanzapine has a related chemical structure and comparable receptor-binding profile as clozapine, which demonstrated superior efficacy in combination studies, but has a more unfavorable side-effect profile compared to olanzapine. Amisulpride and olanzapine have shown promising therapeutic efficacy in meta-analyses in monotherapy for people with schizophrenia. Combining amisulpride and olanzapine, complementary receptor-binding properties may enhance efficacy and possibly reduce (or at least not augment) side effects due to the different receptor profiles and metabolization pathways. Accordingly, we hypothesize that patients treated with amisulpride plus olanzapine show greater improvement on the Positive and Negative Syndrome Scale total score after 8 weeks versus either monotherapy. A randomized, double-blind controlled trial is performed at 16 German centers comparing flexibly dosed monotherapy of oral amisulpride (400-800 mg/day), and olanzapine (10-20 mg/day) and amisulpride-olanzapine co-treatment. Sample size was calculated to be n = 101 per treatment arm, assuming an effect size of 0.500 and a two-sided alpha = 0.025 and beta = 0.90. Recruitment for this trial started in June 2012. Until December 2018, 328 patients have been randomized. Trial conduct has been extended to reach the projected sample size. Publication of the study results is expected in 2019 informing an evidence-based recommendation regarding specific antipsychotic combination treatment.

Background: The red ear syndrome represents a rare symptom complex consisting of auricular erythema associated with painful and burning sensations. It has been described in combination with tinnitus rarely. It has been hypothesized to be etiologically related to altered trigeminal afferent input, temporomandibular disorders, and thalamic dysfunction. Objectives: The initial objective of applying transcranial random noise stimulation (tRNS) in a case of red ear syndrome in combination with tinnitus was the alleviation of the phantom sounds. Study Design: This is a case report on the successful treatment of red ear syndrome with tinnitus by means of transcranial random noise stimulation (tRNS) and a short review on the published cases of this condition. Setting: We present the case of a 50-year-old woman reporting a simultaneous onset of constant left-sided tinnitus and feelings of warmth accompanied by an intermittent stabbing and/or oppressive pain stretching from the ipsilateral ear to the head/neck/shoulder region, occasionally accompanied by nausea/vomiting and dizziness. After failure of pharmacological treatment attempts, either because of lacking clinical effects (gabapentin, zolmitriptan, and indomethacin) or because of adverse reactions (pregabaline), the patient was offered an experimental neuromodulatory treatment with bitemporal tRNS primarily targeting the tinnitus complaints of the patient. Methods: tRNS was conducted in 2 – 3 day sessions (stimulation site: bilateral temporal cortex/2.0 mA/10 s on-and-off-ramp/offset 0 mA/20 min/random frequencies 101 – 640Hz / NeuroConn Eldith DC-Stimulator plus). Results: In 3 consecutive pain attacks repeated sessions of tRNS resulted in substantial alleviation of pain intensity and a prolongation of the interval between attacks. This was an expected finding as the proposed tRNS treatment was initially offered to the patient aiming at an alleviation of the tinnitus complaints (which remained unaffected by tRNS). Limitations: The reported data derive from compassionate use treatment in one single patient. Application of a sham condition would have been desirable, but is not possible in the context of compassionate use treatment. Nevertheless, we would consider it rather unlikely that the reported effects are purely unspecific as the patient did exclusively report symptom alleviation of pain-related parameters without affecting the tinnitus. Conclusions: This case report demonstrates the feasibility and therapeutic potential of applying neuromodulatory treatment approaches in red ear syndrome, a rare form of trigemino-autonomal headache. Therefore, it deserves detailed observation in clinical routine applications as well as controlled trials further investigating its neurobiological effects. Key words: Red ear syndrome, pain, trigemino-autonomal headache, chronic tinnitus, transcranial electrical stimulation, random noise stimulation

Impaired neural plasticity may be a core pathophysiological process underlying the symptomatology of schizophrenia. Plasticity-enhancing interventions, including repetitive transcranial magnetic stimulation (rTMS), may improve difficult-to-treat symptoms; however, efficacy in large clinical trials appears limited. The high variability of rTMS-related treatment response may be related to a comparably large variation in the ability to generate plastic neural changes. The aim of the present study was to determine whether negative symptom improvement in schizophrenia patients receiving rTMS to the left dorsolateral prefrontal cortex (DLPFC) was related to rTMS-related brain volume changes. A total of 73 schizophrenia patients with predominant negative symptoms were randomized to an active (n=34) or sham (n=39) 10-Hz rTMS intervention applied 5 days per week for 3 weeks to the left DLPFC. Local brain volume changes measured by deformation-based morphometry were correlated with changes in negative symptom severity using a repeated-measures analysis of covariance design. Volume gains in the left hippocampal, parahippocampal and precuneal cortices predicted negative symptom improvement in the active rTMS group (all r⩽-0.441, all P⩽0.009), but not the sham rTMS group (all r⩽0.211, all P⩾0.198). Further analyses comparing negative symptom responders (⩾20% improvement) and non-responders supported the primary analysis, again only in the active rTMS group (F(9, 207)=2.72, P=0.005, partial η 2=0.106). Heterogeneity in clinical response of negative symptoms in schizophrenia to prefrontal high-frequency rTMS may be related to variability in capacity for structural plasticity, particularly in the left hippocampal region and the precuneus.

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.

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.

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 meta-data 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.

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.

We thank Robert Latzmann, Christopher Patrick, and Scott Lilienfeld for their interest in and thoughtful comment [1] on our paper [2]. The commentary provides the opportunity for clarification, to prevent possible misunderstanding regarding the potential of neuroimaging meta-analyses of (not only) psychopathy with this response.First, the authors of the comment briefly mention “a failure to distinguish among alternative measures of a target construct (i.e., psychopathy) and collapsing across non-interchangeable dependent measures (i.e., MRI-brain activations from different tasks)”, which they regard as limitations. We concur that our meta-analyses did not assess putative differences between measures that literally purport to capture the same entity (so-called psychopathy scales) or between various tasks performed by subjects with the same disorder (i.e., psychopathy). That is, our intention was not to isolate task-related differences in neural activity response in psychopathy nor to isolate neural differences between competing psychopathy concepts. Rather, the objective of our meta-analytic study was to identify brain regions showing aberrant activity associated with psychopathy across the whole neuroimaging literature. Indeed, it also seems interesting to investigate if above-mentioned differences can in fact be spotted. Unfortunately, there are simply not enough experiments available to disentangle such subtle effects in valid subanalyses presently (cf., work by Eickhoff et al. [3]). For instance, only 14 of the 24 experiments using an alternative measure of psychopathy (the Psychopathic Personality Inventory [4]) found any (i.e., either positive or negative) association of brain activity with the scale at all. From these 14 experiments, seven showed a positive and seven a negative relationship. Data underlying the experiments were collected in only four independent studies (i.e., samples). However, at least about 20 independent experiments would be needed for a valid activation likelihood estimation meta-analysis [3].The main criticism raised by Latzman and colleagues, however, is the “treatment of this condition as a unitary construct, largely neglecting its heterogeneity”. To illustrate the relevance to neuroimaging, they quote three individual studies in which diverging activity corresponding to psychopathy subdimensions was found within the same brain regions.In fact, there is a heated debate whether psychopathy is of a multidimensional or a unidimensional nature. Although there are arguments for its multidimensionality, there is also strong evidence against. The Psychopathy Checklist-Revised (PCL-R) as well as its derivative, the Psychopathy Checklist: Screening Version (PCL:SV), are arguably the most important psychometric instruments for assessing psychopathy. Most of the studies included in our meta-analyses relied on the PCL (113 out of 155 experiments). Both the PCL-R [5] and the PCL:SV [6] have been shown to be commensurate with a bifactor model of psychopathy that includes a general (g) factor [6]. One of the first applications of such a model to the PCL-R instruments was published by Patrick et al. [5]. According to these models [5, 6], the items of the PCL-R/SV instruments load onto a common factor, with specific portions of variance relegated to nuisance factors. Moreover, taxometric research [7] indicates that the disorder as such (i.e., psychopathy) is a dimensional trait, not a taxon. From this point of view, it may even be regarded as implausible to hypothesize that there should be subtraits of the disorder that do not add up to a common core and that have unique correlates in the brain. However, neuroimaging meta-analyses (of psychopathy subscales) could indeed serve as a useful tool to test if proposed subtraits are neurobiologically founded. Also for this purpose, there are unfortunately not enough experiments available from the literature.Irrespective of the dimensionality discussion, it has to be noted that the very same regions (where aforesaid studies located diverging activity) emerged in our meta-analyses. This militates against the concern that subdivisions of psychopathy scales would lead to divergent psychopathic subgroups or distinct traits which, in turn, could cancel each other out with respect to neural correlates. Apart from that, this issue does not apply to the analyses in our paper, which was looking for convergence in brain associations with psychopathy (scales). Interestingly, there was indeed strong concordance in several regions. Be it that the commentators’ argument of subscales neutralizing each other is valid, then why have these scales converging neural correlates?Moreover, our findings provide robust evidence for neural alterations associated with psychopathy and hence validate this psychological construct using rigorous neurobiological mapping. This result seems even more intriguing as similar attempts with respect to other disorders, such as depression, did not succeed [8]. In this context, we want to mention that—contrary to the presentation by Latzman and colleagues—we did not claim “that certain neural activation patterns are “pathognomonic” of psychopathy”. Rather, we used a general approach, which avoids a priori assumptions about (putative differences between) psychological constructs and their relationship among one another as well as to neurobiology, to meta-analyze brain activation changes associated with psychopathy. In a second step, we characterized the ensuing regions functionally using independent data from healthy subjects. These analyses indicated that brain regions showing aberrant activity in psychopaths fulfill mental functions in healthy subjects which, in turn, happen to be disturbed in psychopaths. We thus stated that these mental functions correspond with the deviant behavioral patterns that are characteristic and pathognomonic of psychopathy. This reverse approach hence validated that the neural aberrances were associated with (the overarching construct of) psychopathy (and not with epiphenomena).Although we provided robust evidence for a general neurobiological foundation of psychopathy, we agree that further investigations into particular aspects of this disorder are desirable. Therefore, we will wait together with Latzman and colleagues for “finer-grained meta-analyses”—for instance on psychopathy subdimensions. Many more individual studies on this topic, however, are necessary to constitute a solid basis for such endeavors. Until then, our consolidating results, establishing the robustness of a neural signature underlying common conceptualization of psychopathy, can provide guidance for future studies on the potential heterogeneity in psychopathic traits, once sufficiently large consortium datasets will be available in the future

Despite its 0.5-1% lifetime prevalence in men and its general societal relevance, neuroimag- ing 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 neuroi- maging 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 net- works 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. Hum Brain

Background Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral-prefrontal cortex (DLPFC) with conventional figure-of-8 (=butterfly) coils has been used as an antidepressant therapeutic tool for almost twenty years. Very recently, an innovative rTMS coil, the so-called double cone coil (DC), was introduced allowing the modulation of the anterior cingulate cortex (AC). We investigated safety and therapeutic effectiveness of this stimulation in a naturalistic clinical setting. Method Forty-five patients suffering a moderate to severe depressive episode were randomized to receive 15 sessions of either conventional rTMS of the left DLPFC (" butterfly -rTMS"; 10 Hz; 2000 stimuli/day, RMT 110%), mediofrontal double cone coil stimulation of the anterior cingulate cortex (" ACDC -rTMS" with equal parameters), or sham-stimulation. The primary outcome was the change in the 21-items Hamilton Rating Scale for Depression (HAMD) from baseline to the end of treatment. Secondary outcome measures were changes over the course of the trial regarding the HAMD, the Beck Depression Inventory (BDI), the Clinical Global Impression (CGI) and the Global Assessment of Functioning (GAF) scales. Results There was a significant group × time interaction effect regarding the primary outcome ( F = 3.269; df = 2,37; P = 0.049). Post-hoc t-testing revealed a significant effect for the comparison ACDC vs. butterfly at week 3/end of treatment ( T = 2.646; df = 26; P = 0.014). No severe adverse events occurred during the study. ACDC -stimulation was well tolerated by the majority of patients similar like butterfly -rTMS and sham-stimulation. Conclusion This pilot study demonstrated the feasibility of ACDC -rTMS-stimulation as an add-on-treatment for depression. Its clinical effects warrant further investigation in the future.

Rationale Measurement of motor cortex excitability with single and paired pulse transcranial magnetic stimulation has become an established method for in vivo characterization of the effects of central-acting drugs. The comparison of drug-free and medicated patients with schizophrenia suggests an association of neuroleptics intake and prolongation of the cortical silent period (CSP). However all available data come from cross-sectional non-randomized studies. Thus it is not clear whether the observed difference is an effect of medication or reflects differences in disease severity or both. Objectives We aimed to investigate whether the CSP or other parameters of cortical excitability change, when cortical excitability is measured in drug-free patients with acute psychosis before and after 3 week intake of the atypical neuroleptic quetiapine. Methods Different parameters of cortical excitability were studied in 24 drug-free patients with acute psychosis before and after 3 weeks of treatment with a mean dose of 352 ± 199 mg quetiapine. Results We observed a significant prolongation of the cortical silent period (CSP) after three week treatment with quetiapine. Other parameters of cortical excitability such as motor threshold (MT), short intracortical inhibition (SICI) and intracortical facilitation (ICF) remained unaffected. There was a significant improvement in clinical parameters (PANS, GAF) but no significant correlation between clinical improvement and changes in cortical excitability. Conclusions These longitudinal data are in line with previous reports from cross-sectional studies. The excitability changes induced by three-week intake of quetiapine in acute psychotic patients confirm the notion that neuroleptic treatment is associated with an increase in CSP.

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.

Studies applying structural neuroimaging to pedophiles are scarce and have shown conflicting results. Although first findings suggested reduced volume of the amygdala, pronounced gray matter decreases in frontal regions were observed in another group of pedophilic offenders. When compared to non-sexual offenders instead of community controls, pedophiles revealed deficiencies in white matter only. The present study sought to test the hypotheses of structurally compromised prefrontal and limbic networks and whether structural brain abnormalities are related to phenotypic characteristics in pedophiles. We compared gray matter volume of male pedophilic offenders and non-sexual offenders from high-security forensic hospitals using voxel-based morphometry in cross-sectional and correlational whole-brain analyses. The significance threshold was set to p < .05, corrected for multiple comparisons. Compared to controls, pedophiles exhibited a volume reduction of the right amygdala (small volume corrected). Within the pedophilic group, pedosexual interest and sexual recidivism were correlated with gray matter decrease in the left dorsolateral prefrontal cortex (r = −.64) and insular cortex (r = −.45). Lower age of victims was strongly associated with gray matter reductions in the orbitofrontal cortex (r = .98) and angular gyri bilaterally (r = .70 and r = .93). Our findings of specifically impaired neural networks being related to certain phenotypic characteristics might account for the heterogeneous results in previous neuroimaging studies of pedophilia. The neuroanatomical abnormalities in pedophilia seem to be of a dimensional rather than a categorical nature, supporting the notion of a multifaceted disorder.

The red ear syndrome represents a rare symptom complex consisting of auricular erythema associated with painful and burning sensations. It has been described in combination with tinnitus rarely. It has been hypothesized to be etiologically related to altered trigeminal afferent input, temporomandibular disorders, and thalamic dysfunction.The initial objective of applying transcranial random noise stimulation (tRNS) in a case of red ear syndrome in combination with tinnitus was the alleviation of the phantom sounds.This is a case report on the successful treatment of red ear syndrome with tinnitus by means of transcranial random noise stimulation (tRNS) and a short review on the published cases of this condition.We present the case of a 50-year-old woman reporting a simultaneous onset of constant left-sided tinnitus and feelings of warmth accompanied by an intermittent stabbing and/or oppressive pain stretching from the ipsilateral ear to the head/neck/shoulder region, occasionally accompanied by nausea/vomiting and dizziness. After failure of pharmacological treatment attempts, either because of lacking clinical effects (gabapentin, zolmitriptan, and indomethacin) or because of adverse reactions (pregabaline), the patient was offered an experimental neuromodulatory treatment with bitemporal tRNS primarily targeting the tinnitus complaints of the patient.tRNS was conducted in 2 - 3 day sessions (stimulation site: bilateral temporal cortex/2.0 mA/10 s on-and-off-ramp/offset 0 mA/20 min/random frequencies 101 - 640 Hz / NeuroConn Eldith DC-Stimulator plus).In 3 consecutive pain attacks repeated sessions of tRNS resulted in substantial alleviation of pain intensity and a prolongation of the interval between attacks. This was an expected finding as the proposed tRNS treatment was initially offered to the patient aiming at an alleviation of the tinnitus complaints (which remained unaffected by tRNS).The reported data derive from compassionate use treatment in one single patient. Application of a sham condition would have been desirable, but is not possible in the context of compassionate use treatment. Nevertheless, we would consider it rather unlikely that the reported effects are purely unspecific as the patient did exclusively report symptom alleviation of pain-related parameters without affecting the tinnitus.This case report demonstrates the feasibility and therapeutic potential of applying neuromodulatory treatment approaches in red ear syndrome, a rare form of trigemino-autonomal headache. Therefore, it deserves detailed observation in clinical routine applications as well as controlled trials further investigating its neurobiological effects. Key words: Red ear syndrome, pain, trigemino-autonomal headache, chronic tinnitus, transcranial electrical stimulation, random noise stimulation.

Neuroimaging studies of tinnitus suggest the involvement of wide-spread neural networks for perceptual, attentional, memory, and emotional processes encompassing auditory, frontal, parietal, and limbic areas. Despite sparse findings for tinnitus duration and laterality, tinnitus distress has been shown to be related to changes in non-auditory cortical areas. The aim of this study was to correlate tinnitus characteristics with grey matter volume in two large samples of tinnitus patients. High-resolution brain images were obtained using a 1.5 T magnetic resonance imaging scanner and analysed by means of voxel-based morphometry. In sample one (n = 257), tinnitus distress correlated negatively with grey matter volume in bilateral auditory areas including the Heschl's gyrus and insula, that is, the higher the tinnitus distress the lower the grey matter volume. The effects of this correlation were small, but stable after correction for potential confounders such as age, gender, and audiometric parameters. This negative correlation was replicated in a second independent sample (n = 78). Our results support the notion that the role of the auditory cortex in tinnitus is not restricted to perceptual aspects. The distress observed was dependent on grey matter alterations in the auditory cortex, which could reflect reverberations between perceptual and distress networks.

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.

Background Prefrontal and temporo-parietal repetitive transcranial magnetic stimulation (rTMS) in patients suffering from chronic tinnitus have shown significant but only moderate effectiveness with high interindividual variability in treatment response. This open-label pilot study was designed to examine the general feasibility of an individualized fronto-temporal rTMS protocol and to explore what criteria are needed for a more detailed evaluation in randomized clinical studies. Methods During the first session of a 2-week rTMS protocol, we applied different rTMS protocols to the left and right temporo-parietal and dorsolateral prefrontal cortex (DLPFC) in 25 tinnitus patients. Short trains of 1, 5, 10, and 20 Hz and continuous theta burst stimulation were applied, and patients were asked for immediate tinnitus reductions after each train. If a patient reported such improvements, rTMS treatment was applied over nine sessions with a combined protocol consisting of the most effective frontal and the most effective temporo-parietal stimulation protocol. Those patients who did not improve after the test session were treated with a standard prefrontal plus temporo-parietal protocol (20 Hz over left DLPFC + 1 Hz over temporo-parietal cortex). Results Almost half of the patients (12 of 25) reported immediate tinnitus reductions during the test session. In this group, the mean pre- to post-treatment amelioration in the tinnitus questionnaire was higher (medium to high effect sizes) in contrast to the patients who did not respond to the test session. Treatment outcome remained stable over a follow-up period of 10 weeks. Discussion Individualized rTMS was shown to be feasible and effective in chronic tinnitus. The results obtained from this study provide tentative evidence in support of an individualized rTMS treatment approach and might provide a basis for a “tailored” application of rTMS in tinnitus and other neuropsychiatric disorders.

Sexual preference determines mate choice for reproduction and hence guarantees conservation of species in mammals. Despite this fundamental role in human behavior, current knowledge on its target-specific neurofunctional substrate is based on lesion studies and therefore limited. We used meta-analytic remodeling of neuroimaging data from 364 human subjects with diverse sexual interests during sexual stimulation to quantify neural regions associated with sexual preference manipulations. We found that sexual preference is encoded by four phylogenetically old, subcortical brain structures. More specifically, sexual preference is controlled by the anterior and preoptic area of the hypothalamus, the anterior and mediodorsal thalamus, the septal area, and the perirhinal parahippocampus including the dentate gyrus. In contrast, sexual non-preference is regulated by the substantia innominata. We anticipate the identification of a core neural circuit for sexual preferences to be a starting point for further sophisticated investigations into the neural principles of sexual behavior and particularly of its aberrations.

Question Hyper-activity and hyper-synchronicity of auditory areas are involved in the pathology of chronic tinnitus. Transcranial random noise stimulation (tRNS) – a non-invasive electric brain stimulation method – was recently shown to be able to reduce tinnitus loudness and distress after single sessions in big samples and after daily sessions of tRNS in one small sample. For the first time, we investigate the tolerability and efficacy of daily sessions of tRNS in a bigger sample of chronic tinnitus. Methods In this one-arm study, thirty patients receive high-frequency tRNS of the left and right temporal cortex consisting of ten daily sessions. Study visits are baseline (treatment day 1), week 2 (treatment day 10), week 4 and 12 (two and ten weeks after treatment, respectively). Results Compatibility: Six patients perceived temporal increases in tinnitus loudness (two drop-outs) and two patients report headaches (one drop-out). One patient did not finish the treatment due to personal reasons. Typical side effects were mild to moderate tingling (87%), tiredness (67%), and itching (47%). There was no evidence for cognitive effects of the stimulation. Primary outcome: There were eight treatment responders for the rTMS and the tRNS trial with only two of them responding in the rTMS as well as in the tRNS treatment. Secondary outcomes: TQ, MDI, numeric ratings, and quality of life did not show significant effects of time or time by treatment except for the numeric rating unpleasantness (decrease from week baseline to week 2) and the quality of life domain physical well-being (increase from week 4 to week 12. Conclusions Treatment of chronic tinnitus with high-frequency tRNS is easy applicable, showed tolerable side effects and efficacy in the same range as rTMS (31% for this sample), but resulted in temporal increases in tinnitus loudness in 20% of the cases (including two drop-outs). Notably, treatment response to rTMS did not predict treatment response to tRNS favoring individualized treatment with brain stimulation which can be realized by using single test sessions as recommendation for daily treatment. Specific changes in unpleasantness after tRNS in contrast to rTMS might be explainable by the stimulation of more medial temporal areas such as posterior insula or hippocampus (summation of electric currents in border regions of different types of tissues).

Question Non-invasive brain stimulation can modify phantom sounds for longer periods by modulating neural activity and putatively inducing regional neuroplastic changes ( Elgoyhen, 2015 ). However, treatment response is limited and there are no good demographic or clinical predictors for treatment outcome ( Lehner, 2012 ). We used state-of-the-art voxel-based morphometry (VBM) to investigate whether transcranial magnetic stimulation-induced neuroplasticity determines therapeutic outcome. Methods 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 ( Langguth, 2014 ). Structural magnetic resonance imaging was performed before and after rTMS. In VBM whole-brain analyses (p Gerber, 2014 ). Results 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 non-responders (N = 38), as indicated by a group ×time interaction and post-hoc tests (Fig. 1 Download : Download high-res image (206KB) Download : Download full-size image ). These results were not 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 non-responders (Fig. 2 Download : Download high-res image (77KB) Download : Download full-size image ). Conclusions Our results reinforce the implication of non-auditory 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.

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. Hum Brain Mapp, 2013. © 2011 Wiley Periodicals, Inc.

Tinnitus is the perception of sound in the absence of an environmental sound source. Abnormal activity in central auditory pathways is considered as the neuronal correlate of tinnitus. However, there is increasing evidence from neuroimaging studies for an additional involvement of the frontal cortex in the pathophysiology of tinnitus, especially concerning its attentional and emotional aspects. Recently, in a subgroup of tinnitus patients, temporary reduction of tinnitus intensity and tinnitus-related distress has been reported after bifrontal tDCS with the anode over the right and the cathode over the left dorsolateral prefrontal cortex (DLPFC). The aim of this study was to investigate whether repeated application of bifrontal tDCS results in longer-lasting reduction of tinnitus and may represent a potential treatment approach. Thirty-two patients with chronic and treatment-resistant tinnitus received six sessions of bifrontal tDCS (1.5 mA, 30 min, two sessions per week) with the anode over the right and the cathode over the left DLPFC. Treatment outcome was assessed with several standardized tinnitus questionnaires, numeric rating scales, and a depression scale. In the entire group, beneficial effects of bifrontal tDCS on tinnitus were found for numeric rating scores of loudness, unpleasantness, and discomfort, but not in tinnitus or depression scales. Exploratory analysis revealed an effect of gender on treatment effects with female patients demonstrating a better response in several scores. Our open-label pilot study suggests some beneficial effect of bifrontal tDCS (anode right and cathode left) in the treatment of severe tinnitus, warranting further controlled studies.

Hintergrund Hypothermien unter Antipsychotikabehandlung sind seit Jahrzehnten bekannt, finden jedoch im klinischen Alltag nur geringe Beachtung.

Repetitive transcranial magnetic stimulation (rTMS) has been proposed as a tinnitus treatment option. Promising results have been obtained by consecutive stimulation of lateral frontal and auditory brain regions. We investigated a combined stimulation paradigm targeting the anterior cingulate cortex (ACC) with double cone coil rTMS, followed by stimulation of the temporo-parietal junction area with a figure-of-eight coil. The study was conducted as a randomized, double-blind pilot trial in 40 patients suffering from chronic tinnitus. We compared mediofrontal stimulation with double-cone-coil, (2000 stimuli, 10 Hz) followed by left temporo-parietal stimulation with figure-of-eight-coil (2000 stimuli, 1 Hz) to left dorsolateral-prefrontal-cortex stimulation with figure-of-eight-coil (2000 stimuli, 10 Hz) followed by temporo-parietal stimulation with figure-of-eight-coil (2000 stimuli, 1 Hz). The stimulation was feasible with comparable dropout rates in both study arms; no severe adverse events were registered. Responder rates did not differ in both study arms. There was a significant main effect of time for the change in the TQ score, but no significant time x group interaction. This pilot study demonstrated the feasibility of combined mediofrontal/temporoparietal-rTMS-stimulation with double cone coil in tinnitus patients but failed to show better outcome compared to an actively rTMS treated control group.

Sexual behavior involves motivational processes. Findings from both animal models and neuroimaging in humans suggest that the recruitment of neural motor networks is an integral part of the sexual response. However, no study so far has directly linked sexual motivation to physiologically measurable changes in cerebral motor systems in humans. Using transcranial magnetic stimulation in hetero- and homosexual men, we here show that sexual motivation modulates cortical excitability. More specifically, our results demonstrate that visual sexual stimuli corresponding with one’s sexual orientation, compared with non-corresponding visual sexual stimuli, increase the excitability of the motor cortex. The reflection of sexual motivation in motor cortex excitability provides evidence for motor preparation processes in sexual behavior in humans. Moreover, such interrelationship links theoretical models and previous neuroimaging findings of sexual behavior.