Accurate sex prediction of cisgender and transgender individuals without brain size bias.

The increasing use of machine learning approaches on neuroimaging data comes with the important concern of confounding variables which might lead to biased predictions and in turn spurious conclusions about the relationship between the features and the target. A prominent example is the brain size difference between women and men. This difference in total intracranial volume (TIV) can cause bias when employing machine learning approaches for the investigation of sex differences in brain morphology. A TIV-biased model will not capture qualitative sex differences in brain organization but rather learn to classify an individual's sex based on brain size differences, thus leading to spurious and misleading conclusions, for example when comparing brain morphology between cisgender- and transgender individuals. In this study, TIV bias in sex classification models applied to cis- and transgender individuals was systematically investigated by controlling for TIV either through featurewise confound removal or by matching the training samples for TIV. Our results provide strong evidence that models not biased by TIV can classify the sex of both cis- and transgender individuals with high accuracy, highlighting the importance of appropriate modeling to avoid bias in automated decision making.

Ensemble graph neural network model for classification of major depressive disorder using whole-brain functional connectivity.

Major depressive disorder (MDD) is characterized by impairments in mood and cognitive functioning, and it is a prominent source of global disability and stress. A functional magnetic resonance imaging (fMRI) can aid clinicians in their assessments of individuals for the identification of MDD. Herein, we employ a deep learning approach to the issue of MDD classification. Resting-state fMRI data from 821 individuals with MDD and 765 healthy controls (HCs) is employed for investigation. An ensemble model based on graph neural network (GNN) has been created with the goal of identifying patients with MDD among HCs as well as differentiation between first-episode and recurrent MDDs. The graph convolutional network (GCN), graph attention network (GAT), and GraphSAGE models serve as a base models for the ensemble model that was developed with individual whole-brain functional networks. The ensemble's performance is evaluated using upsampling and downsampling, along with 10-fold cross-validation. The ensemble model achieved an upsampling accuracy of 71.18% and a downsampling accuracy of 70.24% for MDD and HC classification. While comparing first-episode patients with recurrent patients, the upsampling accuracy is 77.78% and the downsampling accuracy is 71.96%. According to the findings of this study, the proposed GNN-based ensemble model achieves a higher level of accuracy and suggests that our model produces can assist healthcare professionals in identifying MDD.

Neural responses to monetary incentives in postpartum women affected by baby blues.

Up to 50% of new mothers experience baby blues (BB) within a week of delivery, with affective disturbances being the central symptoms. Because reward processing is known to be affected in depression, this study sought to investigate whether incentive processing during the experience of BB can be altered through the monetary incentive delay (MID) task. The MID task allows reward processing to be investigated based on responses to 'anticipation' and 'feedback of reward or loss'. 60 women participated in the fMRI-based MID task within 1-6 days of delivery, and 50% of them developed BB within the first few postpartum weeks. Over a 12-week observation period, a greater number of women in the BB group (52% vs. 13%) developed psychiatric conditions, with 24% of women with BB developing postpartum depression compared to only 3% of those without BB. During the feedback trials of the MID task, women with BB, compared to those without, showed increased activation in both the winning and losing trials (the temporal areas, the insula, the midbrain, and the inferior frontal gyrus). During the anticipation trials, however, subjects affected by BB showed reduced activation in the pregenual and the subgenual anterior cingulate cortices (pg/sg ACC). Our results demonstrate, for the first time, that the BB-related time window overlaps with alterations in the brain networks associated with incentive processing. Given the involvement of pg/sgACC in the development of depressive mood, the weaker involvement of these brain regions during anticipation in participants affected by BB is of particular interest.

Accurate machine learning prediction of sexual orientation based on brain morphology and intrinsic functional connectivity.

BACKGROUND: Sexual orientation in humans represents a multilevel construct that is grounded in both neurobiological and environmental factors. OBJECTIVE: Here, we bring to bear a machine learning approach to predict sexual orientation from gray matter volumes (GMVs) or resting-state functional connectivity (RSFC) in a cohort of 45 heterosexual and 41 homosexual participants. METHODS: In both brain assessments, we used penalized logistic regression models and nonparametric permutation. RESULTS: We found an average accuracy of 62% (±6.72) for predicting sexual orientation based on GMV and an average predictive accuracy of 92% (±9.89) using RSFC. Regions in the precentral gyrus, precuneus and the prefrontal cortex were significantly informative for distinguishing heterosexual from homosexual participants in both the GMV and RSFC settings. CONCLUSIONS: These results indicate that, aside from self-reports, RSFC offers neurobiological information valuable for highly accurate prediction of sexual orientation. We demonstrate for the first time that sexual orientation is reflected in specific patterns of RSFC, which enable personalized, brain-based predictions of this highly complex human trait. While these results are preliminary, our neurobiologically based prediction framework illustrates the great value and potential of RSFC for revealing biologically meaningful and generalizable predictive patterns in the human brain.

A Systematic Review on Common and Distinct Neural Correlates of Risk-taking in Substance-related and Non-substance Related Addictions.

Both substance-related as well as non-substance-related addictions may include recurrent engagement in risky actions despite adverse outcomes. We here apply a unified approach and review task-based neuroimaging studies on substance-related (SRAs) and non-substance related addictions (NSRAs) to examine commonalities and differences in neural correlates of risk-taking in these two addiction types. To this end, we conducted a systematic review adhering to the PRISMA guidelines. Two databases were searched with predefined search terms to identify neuroimaging studies on risk-taking tasks in individuals with addiction disorders. In total, 19 studies on SRAs (comprising a total of 648 individuals with SRAs) and 10 studies on NSRAs (comprising a total of 187 individuals with NSRAs) were included. Risk-related brain activation in SRAs and NSRAs was summarized individually and subsequently compared to each other. Results suggest convergent altered risk-related neural processes, including hyperactivity in the OFC and the striatum. As characteristic for both addiction types, these brain regions may represent an underlying mechanism of suboptimal decision-making. In contrast, decreased DLPFC activity may be specific to SRAs and decreased IFG activity could only be identified for NSRAs. The precuneus and posterior cingulate show elevated activity in SRAs, while findings regarding these areas were mixed in NSRAs. Additional scarce evidence suggests decreased ventral ACC activity and increased dorsal ACC activity in both addiction types. Associations between identified activation patterns with drug use severity underpin the clinical relevance of these findings. However, this exploratory evidence should be interpreted with caution and should be regarded as preliminary. Future research is needed to evaluate the findings gathered by this review.

Personal insult disrupts regulatory brain networks in violent offenders.

The failure to adequately regulate negative emotions represents a prominent characteristic of violent offenders. In this functional magnetic resonance imaging study, we used technical, nonsocial frustration to elicit anger in violent offenders (n = 19) and then increased the provocation by adding personal insults (social provocation). The aim was to investigate neural connectivity patterns involved in anger processing, to detect the effect of increasing provocation by personal insult, and to compare anger-related connectivity patterns between offenders and noncriminal controls (n = 12). During technical frustration, the offenders showed increased neural connectivity between the amygdala and prefrontal cortex compared to the controls. Conversely, personal insults, and thus increased levels of provocation, resulted in a significant reduction of neural connectivity between regions involved in cognitive control in the offenders but not controls. We conclude that, when (nonsocially) frustrated, offenders were able to employ regulatory brain networks by displaying stronger connectivity between regulatory prefrontal and limbic regions than noncriminal controls. In addition, offenders seemed particularly sensitive to personal insults, which led to increased implicit aggression (by means of motoric responses) and reduced connectivity in networks involved in cognitive control (including dorsomedial prefrontal cortex, precuneus, middle/superior temporal regions).

Dark triad personality traits are associated with decreased grey matter volumes in 'social brain' structures.

Introduction: Personality traits and the degree of their prominence determine various aspects of social interactions. Some of the most socially relevant traits constitute the Dark Triad - narcissism, psychopathy, and Machiavellianism - associated with antisocial behaviour, disregard for moral norms, and a tendency to manipulation. Sufficient data point at the existence of Dark Triad 'profiles' distinguished by trait prominence. Currently, neuroimaging studies have mainly concentrated on the neuroanatomy of individual dark traits, while the Dark Triad profile structure has been mostly overlooked. Methods: We performed a clustering analysis of the Dirty Dozen Dark Triad questionnaire scores of 129 healthy subjects using the k-means method. The variance ratio criterion (VRC) was used to determine the optimal number of clusters for the current data. The two-sample t-test within the framework of voxel-based morphometry (VBM) was performed to test the hypothesised differences in grey matter volume (GMV) for the obtained groups. Results: Clustering analysis revealed 2 groups of subjects, both with low-to-mid and mid-to-high levels of Dark Triad traits prominence. A further VBM analysis of these groups showed that a higher level of Dark Triad traits may manifest itself in decreased grey matter volumes in the areas related to emotional regulation (the dorsolateral prefrontal cortex, the cingulate cortex), as well as those included in the reward system (the ventral striatum, the orbitofrontal cortex). Discussion: The obtained results shed light on the neurobiological basis underlying social interactions associated with the Dark Triad and its profiles.

A Bayesian Modeling Approach to Examine the Role of Testosterone Administration on the Endowment Effect and Risk-Taking.

Financial risk-taking and loss aversion are multifaceted phenomena that are the focus of neuroscience, psychology, and economics research. A growing number of studies highlighted the role of hormones (particularly of testosterone) on socio-economic decision-making. However, the effects of testosterone on risk-taking under framing and consumer-based choices and preferences are inconclusive. We investigated the effects of 100 mg testosterone administration on aspects of decision-making within the Prospect Theory framework which is the most used descriptive model of decision-making under risk. We assessed risk-taking under framing and the endowment effect (effect of possession) using Bayesian modeling. Forty men participated in this double-blind placebo-controlled fully-randomized cross-over experiment and performed two tasks. One was a risk-taking task with binary choices under positive and negative framing associated with different probabilities. In the second task participants had to bid money for hedonic and utilitarian items. We observed a significant increase in serum testosterone concentrations after transdermal application. Compared to placebo, testosterone administration increased risk-taking under the positive framing (very large effect size) and decreased under the negative framing (moderate to small). The sensitivity to gain was positive in each framing. Our model showed that decision-making is jointly influenced by testosterone and the trade-off between gains and losses. However, while the endowment effect was more pronounced for hedonic than for utilitarian items, the effect was independent of testosterone. The findings provide novel information on the complex modulatory role of testosterone on risk-taking within the framework of prospect theory and shed light on mechanisms of behavioral economic biases. The proposed models of effects of individual differences in testosterone on risk-taking could be used as predictive models for reference-depended behavior under positive and negative framing with low and high probabilities.

Social Interaction With an Anonymous Opponent Requires Increased Involvement of the Theory of Mind Neural System: An fMRI Study.

An anonymous interaction might facilitate provoking behavior and modify the engagement of theory of mind (TOM) brain mechanisms. However, the effect of anonymity when processing unfair behavior of an opponent remains largely unknown. The current functional magnetic resonance imaging (fMRI) study applied the Taylor aggression paradigm, introducing an anonymous opponent to this task. Thirty-nine healthy right-handed subjects were included in the statistical analysis (13 males/26 females, mean age 24.5 ± 3.6 years). A player winning the reaction-time game could subtract money from the opponent during the task. Participants behaved similarly to both introduced and anonymous opponents. However, when an anonymous opponent (when compared to the introduced opponent) subtracted money, the right inferior frontal gyrus (IFG) demonstrated an increased BOLD signal and increased functional connectivity with the left IFG. Further, increased functional connectivity between the right IFG, the right temporal parietal junction and precuneus was observed during the perception of high provocation (subtracting a large amount of money) from the anonymous compared to the introduced opponent. We speculate that the neural changes may underlie different inferences about the opponents' mental states. The idea that this reorganization of the TOM network reflects the attempt to understand the opponent by "completing" socially relevant details requires further investigation.

Testosterone administration does not alter the brain activity supporting cognitive and affective empathy.

Although there is evidence that testosterone has deteriorating effects on cognitive and affective empathy, whether testosterone administration influences both routes to understanding others has not yet been simultaneously investigated. We conducted a functional magnetic resonance imaging (fMRI) pharmacological study using a within-subjects, randomized, placebo-controlled, double-blind crossover design to examine the effects of 100 mg transdermal testosterone administration on brain activation during a task that examines affective and cognitive empathy simultaneously in a sample of 23 healthy right-handed adult men. Relative to placebo, testosterone did not alter affective or cognitive empathy functional brain networks. Instead, the task yielded activation in the canonical networks associated with both types of empathy. Affective empathy yielded activation in the inferior and middle frontal gyri, inferior temporal gyri, and the cingulate cortex. Cognitive empathy was associated with activation of the temporoparietal junction, medial prefrontal cortex, middle and inferior temporal gyri, and temporal pole. Behaviourally, testosterone administration decreased error rates and increased participants' confidence in their responses regardless of response accuracy. Independent of testosterone administration, participants reported higher affective responses during emotionally negative scenarios. Even though our results provide further evidence that testosterone administration in healthy men does not alter brain activity underlying cognitive and affective empathy, testosterone administration does influence the empathic concern and hence socio-cognitive processes. The reproducibility and variability of the current and previous findings should nevertheless be addressed in upcoming studies.

Hormonal abnormalities in alexithymia.

Alexithymia is a personality trait characterized by difficulties in emotion recognition and regulation that is associated with deficits in social cognition. High alexithymia levels are considered a transdiagnostic risk factor for a range of psychiatric and medical conditions, including depression, anxiety, and autism. Hormones are known to affect social-emotional cognition and behavior in humans, including the neuropeptides oxytocin and vasopressin, the steroid hormones testosterone and estradiol, the stress hormone cortisol as well as thyroid hormones. However, few studies have investigated hormonal effects on alexithymia and on alexithymia-related impairments in emotion regulation and reactivity, stress response, and social cognition. Here, we provide a brief overview of the evidence linking alexithymia to abnormalities in hormone levels, particularly with regard to cortisol and oxytocin, for which most evidence exists, and to thyroid hormones. We address the current lack of research on the influence of sex hormones on alexithymia and alexithymia-related deficits, and lastly provide future directions for research on associations between hormonal abnormalities and deficits in emotion regulation and social cognition associated with alexithymia.

A Combined Administration of Testosterone and Arginine Vasopressin Affects Aggressive Behavior in Males.

Aggressive behavior is modulated by many factors, including personality and cognition, as well as endocrine and neural changes. To study the potential effects on the reaction to provocation, which was realized by an ostensible opponent subtracting money from the participant, we administered testosterone (T) and arginine vasopressin (AVP) or a respective placebo (PL). Forty males underwent a functional magnetic resonance imaging session while performing a provocation paradigm. We investigated differential hormone effects and the potential influence of Machiavellian traits on punishment choices (monetary subtractions by the participant) in the paradigm. Participants in the T/AVP group subtracted more money when they were not provoked but showed increased activation in the inferior frontal gyrus and inferior parietal lobule during feedback compared to PL. Higher Machiavellian traits significantly increased punishing behavior independent of provocation only in this group. The pilot study shows that T/AVP affects neural and behavioral responses during a provocation paradigm while personality characteristics, such as Machiavellian trait patterns, specifically interact with hormonal influences (T/AVP) and their effects on behavior.

The Interaction Between Caudate Nucleus and Regions Within the Theory of Mind Network as a Neural Basis for Social Intelligence.

The organization of socio-cognitive processes is a multifaceted problem for which many sophisticated concepts have been proposed. One of these concepts is social intelligence (SI), i.e., the set of abilities that allow successful interaction with other people. The theory of mind (ToM) human brain network is a good candidate for the neural substrate underlying SI since it is involved in inferring the mental states of others and ourselves and predicting or explaining others' actions. However, the relationship of ToM to SI remains poorly explored. Our recent research revealed an association between the gray matter volume of the caudate nucleus and the degree of SI as measured by the Guilford-Sullivan test. It led us to question whether this structural peculiarity is reflected in changes to the integration of the caudate with other areas of the brain associated with socio-cognitive processes, including the ToM system. We conducted seed-based functional connectivity (FC) analysis of resting-state fMRI data for 42 subjects with the caudate as a region of interest. We found that the scores of the Guilford-Sullivan test were positively correlated with the FC between seeds in the right caudate head and two clusters located within the right superior temporal gyrus and bilateral precuneus. Both regions are known to be nodes of the ToM network. Thus, the current study demonstrates that the SI level is associated with the degree of functional integration between the ToM network and the caudate nuclei.

A meta-analysis on shared and distinct neural correlates of the decision-making underlying altruistic and retaliatory punishment.

Individuals who violate social norms will most likely face social punishment sanctions. Those sanctions are based on different motivation aspects, depending on the context. Altruistic punishment occurs if punishment aims to re-establish the social norms even at cost for the punisher. Retaliatory punishment is driven by anger or spite and aims to harm the other. While neuroimaging research highlighted the neural networks supporting decision-making in both types of punishment in isolation, it remains unclear whether they rely on the same or distinct neural systems. We ran an activation likelihood estimation meta-analysis on functional magnetic resonance imaging data on 24 altruistic and 19 retaliatory punishment studies to investigate the neural correlates of decision-making underlying social punishment and whether altruistic and retaliatory punishments share similar brain networks. Social punishment reliably activated the bilateral insula, inferior frontal gyrus, midcingulate cortex (MCC), and superior and medial frontal gyri. This network largely overlapped with activation clusters found for altruistic punishment. However, retaliatory punishment revealed only one cluster in a posterior part of the MCC, which was not recruited in altruistic punishment. Our results support previous models on social punishment and highlight differential involvement of the MCC in altruistic and retaliatory punishments, reflecting the underlying different motivations.

Morphological profiles of fatigue in Sarcoidosis patients.

INTRODUCTION: Sarcoidosis is a chronic inflammatory disease often associated with chronic fatigue. Prevalence of fatigue can be measured via neuropsychological testing. Its pathophysiology is insufficiently understood. Structural analysis might help with the development of novel treatment methods. METHODS: We recruited 30 sarcoidosis patients whose fatigue severity and depressive symptom presence was measured through validated neuropsychological self-assessment. T1-weighted structural images were acquired and VBM preprocessing was conducted. Total scores of these tests and subscales were correlated through multiple regression analysis to the brain morphometry. RESULTS: Fatigue severity positively correlated with gray matter volumes in the striatum, the cingulate cortex and the cerebellum and negatively in the parietal and temporal lobe and posterior insula. Subscale analysis indicated a correlation between cognitive fatigue and striatum involvement as well as between physical and psychosocial fatigue and cerebellar alterations. DISCUSSION: Structural analysis delineated two structural patterns associated with the presence of fatigue. One such pattern mainly seemed to involve structures with a focus on decision-making processes while the other indicated alterations in regions vital for perception. Fatigue seems to be a heterogeneous disease, where varying dimensions of reported symptoms correlate with different patterns of structural changes.

The Neuroanatomy of Transgender Identity: Mega-Analytic Findings From the ENIGMA Transgender Persons Working Group.

BACKGROUND: In contrast to cisgender persons, transgender persons identify with a different gender than the one assigned at birth. Although research on the underlying neurobiology of transgender persons has been accumulating over the years, neuroimaging studies in this relatively rare population are often based on very small samples resulting in discrepant findings. AIM: To examine the neurobiology of transgender persons in a large sample. METHODS: Using a mega-analytic approach, structural MRI data of 803 non-hormonally treated transgender men (TM, n = 214, female assigned at birth with male gender identity), transgender women (TW, n = 172, male assigned at birth with female gender identity), cisgender men (CM, n = 221, male assigned at birth with male gender identity) and cisgender women (CW, n = 196, female assigned at birth with female gender identity) were analyzed. OUTCOMES: Structural brain measures, including grey matter volume, cortical surface area, and cortical thickness. RESULTS: Transgender persons differed significantly from cisgender persons with respect to (sub)cortical brain volumes and surface area, but not cortical thickness. Contrasting the 4 groups (TM, TW, CM, and CW), we observed a variety of patterns that not only depended on the direction of gender identity (towards male or towards female) but also on the brain measure as well as the brain region examined. CLINICAL TRANSLATION: The outcomes of this large-scale study may provide a normative framework that may become useful in clinical studies. STRENGTHS AND LIMITATIONS: While this is the largest study of MRI data in transgender persons to date, the analyses conducted were governed (and restricted) by the type of data collected across all participating sites. CONCLUSION: Rather than being merely shifted towards either end of the male-female spectrum, transgender persons seem to present with their own unique brain phenotype. Mueller SC, Guillamon A, Zubiaurre-Elorza L, et al. The Neuroanatomy of Transgender Identity: Mega-Analytic Findings From the ENIGMA Transgender Persons Working Group. J Sex Med 2021;18:1122-1129.

Replication of Previous Findings? Comparing Gray Matter Volumes in Transgender Individuals with Gender Incongruence and Cisgender Individuals.

The brain structural changes related to gender incongruence (GI) are still poorly understood. Previous studies comparing gray matter volumes (GMV) between cisgender and transgender individuals with GI revealed conflicting results. Leveraging a comprehensive sample of transmen (n = 33), transwomen (n = 33), cismen (n = 24), and ciswomen (n = 25), we employ a region-of-interest (ROI) approach to examine the most frequently reported brain regions showing GMV differences between trans- and cisgender individuals. The primary aim is to replicate previous findings and identify anatomical regions which differ between transgender individuals with GI and cisgender individuals. On the basis of a comprehensive literature search, we selected a set of ROIs (thalamus, putamen, cerebellum, angular gyrus, precentral gyrus) for which differences between cis- and transgender groups have been previously observed. The putamen was the only region showing significant GMV differences between cis- and transgender, across previous studies and the present study. We observed increased GMV in the putamen for transwomen compared to both transmen and ciswomen and for all transgender participants compared to all cisgender participants. Such a pattern of neuroanatomical differences corroborates the large majority of previous studies. This potential replication of previous findings and the known involvement of the putamen in cognitive processes related to body representations and the creation of the own body image indicate the relevance of this region for GI and its potential as a structural biomarker for GI.

Brain structure changes associated with sexual orientation.

Biological sex differences in brain function and structure are reliably associated with several cortico-subcortical brain regions. While sexual orientation (hetero- versus homosexuality) has been similarly linked to functional differences in several phylogenetically-old brain areas, the research on morphological brain phenotypes associated with sexual orientation is far from conclusive. We examined potential cerebral structural differences linked to sexual orientation in a group of 74 participants, including 37 men (21 homosexual) and 37 women (19 homosexual) using voxel-based morphometry (VBM). Gray matter volumes (GMV) were compared with respect to sexual orientation and biological sex across the entire sample using full factorial designs controlling for total intracranial volume, age, handedness, and education. We observed a significant effect of sexual orientation for the thalamus and precentral gyrus, with more GMV in heterosexual versus homosexual individuals, and for the putamen, with more GMV in homosexual + than heterosexual individuals. We found significant interactions between biological sex and sexual orientation, indicating that the significant effect for the putamen cluster was driven by homosexual women, whereas heterosexual women had increased precentral gyrus GMV. Heterosexual men exhibited more GMV in the thalamus than homosexual men. This study shows that sexual orientation is reflected in brain structure characteristics and that these differ between the sexes. The results emphasize the need to include or control for potential effects of participants' sexual orientation in neuroimaging studies. Furthermore, our findings provide important new insights into the brain morphology underlying sexual orientation and likely have important implications for understanding brain functions and behavior.

The early postpartum period - Differences between women with and without a history of depression.

Depression is a highly recurrent disorder. When in remission, it affords an important opportunity to understand the state-independent neurobiological alterations, as well as the socio-demographic characteristics, that likely contribute to the recurrence of major depressive disorder (MDD). The present study examined 110 euthymic women in their early postpartum period. A comparison was made between participants with (n = 20) and without (n = 90) a history of MDD by means of a multimodal approach including an fMRI experiment, assessment of hair cortisol concentration (HCC) and a clinical anamnestic interview. Women with a personal history of MDD were found to have decreased resting-state functional connectivity (RSFC) between the lateral parietal cortex (LPC) and the posterior cingulate cortex (PCC), and their Edinburgh Postnatal Depression Scale (EPDS) scores were significantly higher shortly after childbirth. More often than not, these women also had a family history of MDD. While women with no history of depression showed a negative association between hair cortisol concentration (HCC) and gray matter volume (GMV) in the medial orbitofrontal cortex (mOFC), the opposite trend was seen in women with a history of depression. This implies that women with remitted depression show distinctive neural phenotypes with subclinical residual symptoms, which likely predispose them to later depressive episodes.

Single-Dose of Testosterone and the MAOA VNTR Polymorphism Influence Emotional and Behavioral Responses in Men During a Non-social Frustration Task.

Previous studies suggest that testosterone and several neurotransmitters might interactively influence human aggression. The current study aimed to test potential interactions of a genetic variation linked to the catabolism of serotonin, dopamine, and norepinephrine and exogenous testosterone on the reaction towards non-social provocation. In total, 146 male participants were genotyped for a prominent polymorphism of the monoamine oxidase A (MAOA) gene resulting in a short and long variant. Participants completed a non-social frustration task after receiving either testosterone or a placebo gel in a double-blind set-up. Participants performed a non-social frustration task, where they had to direct a virtually moving ball into a barrel by pulling a joystick (neutral block). During a frustration block, the joystick repeatedly did not respond to participants' reactions thereby causing failed trials to which participants reacted with increased anger and stronger pulling of the joystick. We analyzed the effect of testosterone administration on emotion and behavior in individuals who either carried a low (L) or high (H) activity MAOA variant. Testosterone administration increased provocation-related self-reported anger and abolished the association between trait aggression and joystick deflection in the frustration block. In MAOA-H carriers endogenous testosterone levels at baseline were associated with increased joystick deflection in both blocks. There was, however, no interaction of testosterone administration and genotype. Although preliminary, the results rather indicate independent influences of exogenous testosterone administration and MAOA, but support an interaction of endogenous testosterone levels and MAOA genetics in a frustration task. The administration of testosterone seems to act on the subjective emotional experience in a provoking situation, while endogenous testosterone levels increased pulling impulses only in carriers of the MAOA-H variant.