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Background Gender minority individuals, on average, experience higher rates of mental health problems. Mounting work suggests that gender minority stress (GMS) contributes to mental health outcomes in transgender/gender-nonconforming individuals. Aim We assessed whether GMS decreased in transgender people after initiating gender-affirming hormone therapy (GAHT), and we identified social predictors and hormonal associations for GMS at 2 time points. Methods GMS was surveyed through self-report questionnaires tapping into proximal and distal stressors and coping constructs following the minority stress framework. Eighty-five transgender persons wishing to undertake hormonal interventions were assessed prospectively at start of GAHT and after 7.7 ± 3.5 months (mean ± SD). Sixty-five cisgender persons served as a control group. Outcomes (1) Proximal stressors were surveyed by the Beck Depression Inventory II, State-Trait Anxiety Inventory, Scale for Suicide Ideation, Suicidal Thoughts/Attempts, Stigma Consciousness Questionnaire, and Perceived Stress Scale; (2) distal stressors by the Everyday Discrimination Scale; and (3) coping constructs by the Resilience Scale, social network, social standing, and Marlowe Crowne Social Desirability Scale. Results Transgender people experienced higher rates of proximal stressors (Beck Depression Inventory II, State-Trait Anxiety Inventory, Scale for Suicide Ideation, Suicidal Thoughts/Attempts, Perceived Stress Scale) and had lower protective factors (social standing) prior to and during GAHT than cisgender people. Social network and resilience were lower in transgender people relative to cisgender peers only at baseline. Prospectively, decreasing trait anxiety was observed in transgender people. Social factors were adequate predictors of multiple GMS constructs. Specifically, a major role for social network emerged. As for hormonal associations, only serum estradiol levels in transgender women with GAHT were negatively associated with trait anxiety and suicidal thoughts/attempts but positively with resilience and social desirability. Clinical Implications Stimulating a social environment supportive of diverse identities, particularly by investing in social networks as a resource for resilience, is likely to alleviate GMS. Strengths and Limitations Longer duration of interventions with sex steroid treatment, with continued resilience-enhancing strategies, is needed to observe further alleviation of GMS in transgender persons. Also, objective and subjective GMS identification with heteronormative attitudes and beliefs should be surveyed for good measure when assessing GMS. Conclusion Transgender people experienced more GMS throughout study visits than cisgender people did. With a relatively short period of GAHT, some significant changes in and predictors for experienced GMS emerged.

Social anxiety (SA) and depression have been associated with negative interpretation biases of social stimuli. Studies often assess these biases with ambiguous faces, as people with SA and depression tend to interpret such faces negatively. However, the test–retest reliability of this type of task is unknown. Our objectives were to develop a new interpretation bias task with ambiguous faces and analyse its properties in terms of test–retest reliability and in relation to SA, depression, and looming maladaptive style (LMS). Eight hundred sixty-four participants completed a task in which they had to interpret morphed faces as negative or positive on a continuum between happy and angry facial expressions. In addition, they filled out scales on SA, depressive symptoms, and LMS. Eighty-four participants completed the task again after 1–2 months. The test–retest reliability was moderate (r = .57–.69). The data revealed a significant tendency to interpret faces as negative for people with higher SA and depressive symptoms and with higher LMS. Longer response times to interpret the happy faces were positively associated with a higher level of depressive symptoms. The reliability of the present task was moderate. The results highlight associations between the bias interpretation task and SA, depression, and LMS.

BackgroundCurrent clinical assessments of Posttraumatic stress disorder (PTSD) rely solely on subjective symptoms and experiences reported by the patient, rather than objective biomarkers of the illness. Recent advances in data-driven computational approaches have been helpful in devising tools to objectively diagnose psychiatric disorders. Here we aimed to classify individuals with PTSD versus controls using heterogeneous brain datasets from the ENIGMA-PGC PTSD Working group.MethodsWe analyzed brain MRI data from 3,527 structural-MRI; 2,502 resting state-fMRI; and 1,953 diffusion-MRI. First, we identified the brain features that best distinguish individuals with PTSD from controls (TEHC and HC) using traditional machine learning methods. Second, we assessed the utility of the denoising variational autoencoder (DVAE) and evaluated its classification performance. Third, we assessed the generalizability and reproducibility of both models using leave-one-site-out cross-validation procedure for each modality.ResultsWe found lower performance in classifying PTSD vs. controls with data from over 20 sites (60% test AUC for s-MRI, 59% for rs-fMRI and 56% for d-MRI), as compared to other studies run on single-site data. The performance increased when classifying PTSD from HC without trauma history across all three modalities (75% AUC). The classification performance remained intact when applying the DVAE framework, which reduced the number of features. Finally, we found that the DVAE framework achieved better generalization to unseen datasets compared with the traditional machine learning frameworks, albeit performance was slightly above chance.ConclusionOur findings highlight the promise offered by machine learning methods for the diagnosis of patients with PTSD. The utility of brain biomarkers across three MRI modalities and the contribution of DVAE models for improving generalizability offers new insights into neural mechanisms involved in PTSD.Significance⍰Classifying PTSD from trauma-unexposed healthy controls (HC) using three imaging modalities performed well (∼75% AUC), but performance suffered markedly when classifying PTSD from trauma-exposed healthy controls (TEHC) using three imaging modalities (∼60% AUC).⍰Using deep learning for feature reduction (denoising variational auto-encoder; DVAE) dramatically reduced the number of features with no concomitant performance degradation.⍰Utilizing denoising variational autoencoder (DVAE) models improves generalizability across heterogeneous multi-site data compared with the traditional machine learning frameworks

BackgroundThe cerebellum critically contributes to higher-order cognitive and emotional functions such fear learning and memory. Prior research on cerebellar volume in PTSD is scant and has neglected neuroanatomical subdivisions of the cerebellum that differentially map on to motor, cognitive, and affective functions.MethodsWe quantified cerebellar lobule volumes using structural magnetic resonance imaging in 4,215 adults (PTSD n= 1640; Control n=2575) across 40 sites from the from the ENIGMA-PGC PTSD working group. Using a new state-of-the-art deep-learning based approach for automatic cerebellar parcellation, we obtained volumetric estimates for the total cerebellum and 28 subregions. Linear mixed effects models controlling for age, gender, intracranial volume, and site were used to compare cerebellum total and subregional volume in PTSD compared to healthy controls. The Benjamini-Hochberg procedure was used to control the false discovery rate (p-FDR< .05).ResultsPTSD was associated with significant grey and white matter reductions of the cerebellum. Compared to controls, people with PTSD demonstrated smaller total cerebellum volume. In addition, people with PTSD showed reduced volume in subregions primarily within the posterior lobe (lobule VIIB, crus II), but also the vermis (VI, VIII), flocculonodular lobe (lobule X), and cerebellar white matter (allp-FDR< 0.05). Effects of PTSD on volume were consistent, and generally more robust, when examining symptom severity rather than diagnostic status.ConclusionsThese findings implicate regionally specific cerebellar volumetric differences in the pathophysiology of PTSD. The cerebellum appears to play an important role in high-order cognitive and emotional processes, far beyond its historical association with vestibulomotor function. Further examination of the cerebellum in trauma-related psychopathology will help to clarify how cerebellar structure and function may disrupt cognitive and affective processes at the center of translational models for PTSD.

Background: Posttraumatic stress disorder (PTSD) is accompanied by disrupted cortical neuroanatomy. We investigated alteration in covariance of structural networks associated with PTSD in regions that demonstrate the case-control differences in cortical thickness (CT) and surface area (SA). Methods: Neuroimaging and clinical data were aggregated from 29 research sites in >1300 PTSD cases and >2000 trauma-exposed control subjects (ages 6.2–85.2 years) by the ENIGMA-PGC (Enhancing Neuro Imaging Genetics through Meta Analysis–Psychiatric Genomics Consortium) PTSD working group. Cortical regions in the network were rank ordered by the effect size of PTSD-related cortical differences in CT and SA. The top-n (n = 2–148) regions with the largest effect size for PTSD > non-PTSD formed hypertrophic networks, the largest effect size for PTSD < non-PTSD formed atrophic networks, and the smallest effect size of between-group differences formed stable networks. The mean structural covariance (SC) of a given n-region network was the average of all positive pairwise correlations and was compared with the mean SC of 5000 randomly generated n-region networks. Results: Patients with PTSD, relative to non-PTSD control subjects, exhibited lower mean SC in CT-based and SA-based atrophic networks. Comorbid depression, sex, and age modulated covariance differences of PTSD-related structural networks. Conclusions: Covariance of structural networks based on CT and cortical SA are affected by PTSD and further modulated by comorbid depression, sex, and age. The SC networks that are perturbed in PTSD comport with converging evidence from resting-state functional connectivity networks and networks affected by inflammatory processes and stress hormones in PTSD.

We present here a unifying framework for affective phenomena: the Human Affectome. By synthesizing a large body of literature, we have converged on definitions that disambiguate the commonly used terms—affect, feeling, emotion, and mood. Based on this definitional foundation, and under the premise that affective states reflect allostatic concerns, we take a goal-directed, enactive perspective. The human affectome is comprised of allostatic features (valence, motivation, and arousal) and allostatic concerns, which differ in the amount of action required to alleviate allostatic load. Allostatic concerns often fall into three ranges: physiological (the most immediate), operational (intermediate to distal), and global. Global concerns involve summations of overall trajectory, general wellbeing, and self-identity. Within this organizational scheme, the human affectome allows vastly different scientific interests to reside within the same theoretical framework and relate to each other. We hope this framework serves as a common focal point for affective research.

Studies of posttraumatic stress disorder (PTSD) report volume abnormalities in multiple regions of the cerebral cortex. However, findings for many regions, particularly regions outside commonly studied emotion-related prefrontal, insular, and limbic regions, are inconsistent and tentative. Also, few studies address the possibility that PTSD abnormalities may be confounded by comorbid depression. A mega-analysis investigating all cortical regions in a large sample of PTSD and control subjects can potentially provide new insight into these issues. Given this perspective, our group aggregated regional volumes data of 68 cortical regions across both hemispheres from 1379 PTSD patients to 2192 controls without PTSD after data were processed by 32 international laboratories using ENIGMA standardized procedures. We examined whether regional cortical volumes were different in PTSD vs. controls, were associated with posttraumatic stress symptom (PTSS) severity, or were affected by comorbid depression. Volumes of left and right lateral orbitofrontal gyri (LOFG), left superior temporal gyrus, and right insular, lingual and superior parietal gyri were significantly smaller, on average, in PTSD patients than controls (standardized coefficients = −0.111 to −0.068, FDR corrected P values < 0.039) and were significantly negatively correlated with PTSS severity. After adjusting for depression symptoms, the PTSD findings in left and right LOFG remained significant. These findings indicate that cortical volumes in PTSD patients are smaller in prefrontal regulatory regions, as well as in broader emotion and sensory processing cortical regions.

Background Whereas mounting work has begun to document the neural correlates underlying sexual arousal (SA) in humans, the associations between gender identity and the brain correlates of SA as well as their hormonal contributions remain unknown. Aim This study investigated neural activation to sexual arousal in transgender and cisgender persons. Methods 20 transgender men and 19 transgender women (TW) already living in their identified gender were compared to 21 cisgender men (CM) and 19 cisgender women. Participants viewed erotic and neutral video clips while undergoing 3 Tesla magnetic resonance imaging. Outcomes Group-specific brain activation, brain functional connectivity, and brain-hormone associations within the neurophenomenological model of sexual arousal (Stoleru et al, 2012). Results Consistent with the model, participants activated most of its components. However, between-group differences were mostly showing larger activation for CM relative to any of the other 3 groups. Moreover, functional connectivity analyses (psychophysiological interactions) indicated unique patterns for CM, cisgender women, and TW in how different components of SA communicated with one another. Finally, androgens in transgender men and estrogens in TW correlated negatively with parietal cortex and primary (sensori-) motor regions, respectively, while CM showed positive correlations of androgens with parietal cortex, somatosensory regions, and the insula. Clinical Implications Data provide information on neurobiological changes in sexual arousal during treatment with gender-affirming hormone therapy. Strengths & Limitations Although a limitation is the lack of pretreatment data, the present study provides comprehensive information including brain activation, functional connectivity, and hormonal associations in a large sample. Conclusions The results highlight a complex picture of the neural correlates of SA in gender identity and sex assigned at birth.

The number of adolescent refugees around the world has been continuously increasing over the past few years trying to escape war and terror, among other things. Such experience not only increases the risk for mental health problems including anxiety, depression, and post-traumatic stress disorder (PTSD), but also may have implications for socio-cognitive development. This study tested cognitive-affective processing in refugee adolescents who had escaped armed conflict in Syria and now resided in Istanbul, Turkey. Adolescents were split into a high trauma (n = 31, 12 girls, mean age = 11.70 years, SD = 1.15 years) and low trauma (n = 27, 14 girls, mean age = 11.07 years, SD = 1.39 years) symptom group using median split, and performed a working memory task with emotional distraction to assess cognitive control and a surprise faces task to assess emotional interpretation bias. The results indicated that high (vs. low) trauma symptom youth were ~ 20% worse correctly remembering the spatial location of a cue, although both groups performed at very low levels. However, this finding was not modulated by emotion. In addition, although all youths also had a ~ 20% bias toward interpreting ambiguous (surprise) faces as more negative, the high (vs. low) symptom youth were faster when allocating such a face to the positive (vs. negative) emotion category. The findings suggest the impact of war-related trauma on cognitive-affective processes essential to healthy development.

Although the neuroanatomy of transgender persons is slowly being charted, findings are presently discrepant. Moreover, the major body of work has focused on Western populations. One important factor is the issue of power and low signal-to-noise (SNR) ratio in neuroimaging studies of rare study populations including endocrine or neurological patient groups. The present study focused on the structural neuroanatomy of a Non-Western (Iranian) sample of 40 transgender men (TM), 40 transgender women (TW), 30 cisgender men (CM), and 30 cisgender women (CW), while assessing whether the reliability of findings across structural anatomical measures including gray matter volume (GMV), cortical surface area (CSA), and cortical thickness (CTh) could be increased by using two back-to-back within-session structural MRI scans. Overall, findings in transgender persons were more consistent with sex assigned at birth in GMV and CSA, while no group differences emerged for CTh. Repeated measures analysis also indicated that having a second scan increased SNR in all regions of interest, most notably bilateral frontal poles, pre- and postcentral gyri and putamina. The results suggest that a simple time and cost-effective measure to improve SNR in rare clinical populations with low prevalence rates is a second anatomical scan when structural MRI is of interest.

Background:Depressive symptoms are associated with impaired social functioning, arguably because of reduced mentalizing abilities. However, findings in persons with depressive symptoms and/or major depressive disorder (MDD) are presently mixed, finding evidence both for and against the hypothesis of reduced mentalizing abilities.Aims:This study investigated spontaneous cognitive mentalizing in 36 age-, sex- and education-matched students with depressive symptoms and 45 comparisons with minimal depressive symptoms.Method:To assess spontaneous mentalizing, we used the implicit theory of mind (ToM) task, which looks specifically at spontaneous computation of false belief.Results:Bayesian analysis did not support the hypothesis of impaired mentalizing; in fact, it suggested that the results were 3.90 times more likely to have occurred under the null hypothesis. Results remained stable when comparing depressed and non-depressed individuals without maltreatment exposure but were inconclusive in the maltreatment-exposed groups.Conclusion:The findings suggest no effect of spontaneous mentalizing in a high-functioning depressed sample. Moreover, the findings also emphasize the need to control for childhood maltreatment experiences in future ToM and social functioning research, as these may constitute subgroups within depressed samples. Tailored therapy for maltreated depression individuals may be beneficial.

Experience of childhood abuse impairs complex social functioning in children; however, much less is known about its effects on basic socio-cognitive processes and even fewer studies have investigated these in adult survivors. Using two behavioral tasks, this study investigated spontaneous theory of mind (ToM) and imitative behavior in 41 women with childhood abuse (CA) and 26 unaffected comparison women (UC). In the spontaneous ToM task, UCs showed a larger ToM index than CAs, indicating more facilitation by knowledge of another’s false belief. In the imitation-inhibition task, CAs experienced less interference than UCs when observing another’s incongruent movements. After controlling for depression, differences in ToM became marginally significant, yet remained highly significant for inhibiting imitative behavior. The findings suggest childhood abuse survivors have altered perspective-taking, and are less influenced by others’ perspectives, potentially due to changes in self-other distinction. Clinical implications regarding therapeutic practice with survivors of childhood abuse are discussed.

This randomized controlled trial (NCT04786496) examined the effects of a preventive intervention based on Incremental Theory of the Personality (ITP) on psychophysiological responses to social stress and evaluated whether levels of depression moderate the intervention effects. The participants, 107 first-year university students, were randomly assigned to one of three conditions: ITP intervention, ITP + a self-affirmation intervention (SA), and a control condition (CC). Indicators of the Hypothalamic–Pituitary–Adrenal axis, autonomic nervous system, and subjective mood were assessed with the Trier Social Stress Task. Participants in the ITP condition displayed a lower decline in respiratory sinus arrythmia (RSA) compared to those in the CC during the first phases of the task [Slopes: -0.08 (0.09) vs -0.21 (0.09), z = 2.86, p = .004] and a higher decrease in cortisol at recovery [β = -0.18 (0.08), z = -2.37, p = .018]. Depressive symptoms moderated the effect of ITP [β = -0.10 (0.05), z = -2.15, p =.032] and ITP+SA [β = -0.09 (0.04), z = -2.06, p =.039] in the decline during stress and recovery in RSA. In participants with low/medium levels of depressive symptoms, both interventions predicted a lower decline during stress [Slopes: -0.06 (0.09) for ITP, -0.17 (.09) for ITP+SA, and -0.26 (0.09) for CC] and higher recovery in RSA [Slopes: 0.18 (0.01) for ITP, 0.24 (0.01) for ITP+SA, and 0.30 (0.01) for CC]. The findings suggest that the ITP intervention has the potential to be an effective preventive intervention to reduce the stress response.

Some transgender people desire a transition through gender-affirming hormone treatment (GAHT). To date, it is unknown how GAHT changes emotion perception in transgender people.Thirty transgender men (TM), 30 cisgender men (CM), and 35 cisgender women (CW) underwent 3 Tesla functional magnetic resonance imaging (fMRI) while passively viewing emotional faces (happy, angry, surprised faces) at two timepoints (T0 and T1). At T0 all participants were hormone-naïve, while TM immediately commenced testosterone supplementation at T0. The second scanning session (T1) occurred after 6-10 months of GAHT in TM. All 3 groups completed both T0 and T1 RESULTS: GAHT in TM shifted the neural profile whilst processing emotions from a sex-assigned at birth pattern at T0 (similar to CW) to a consistent with gender identity pattern at T1 (similar to CM). Overall, the brain patterns stayed the same for the cis people at T0 and T1.These findings document the impact of hormone treatment, and testosterone supplementation specifically, on emotion perception in TM.

Results of neuroimaging datasets aggregated from multiple sites may be biased by site- specific profiles in participants’ demographic and clinical characteristics, as well as MRI acquisition protocols and scanning platforms. We compared the impact of four different harmonization methods on results obtained from analyses of cortical thickness data: (1) linear mixed-effects model (LME) that models site-specific random intercepts (LMEINT), (2) LME that models both site-specific random intercepts and age-related random slopes (LMEINT+SLP), (3) ComBat, and (4) ComBat with a generalized additive model (ComBat-GAM). Our test case for comparing harmonization methods was cortical thickness data aggregated from 29 sites, which included 1,343 cases with posttraumatic stress disorder (PTSD) (6.2-81.8 years old) and 2,067 trauma-exposed controls without PTSD (6.3-85.2 years old). We found that, compared to the other data harmonization methods, data processed with ComBat-GAM were more sensitive to the detection of significant case-control differences in regional cortical thickness (X2(3) = 34.339, p < 0.001), and case-control differences in age-related cortical thinning (X2(3) = 15.128, p = 0.002). Specifically, ComBat-GAM led to larger effect size estimates of cortical thickness reductions (corrected p-values < 0.001), smaller age-appropriate declines (corrected p-values < 0.001), and lower female to male contrast (corrected p-values < 0.001) in cases compared to controls relative to other harmonization methods. Harmonization with ComBat-GAM also led to greater estimates of age-related declines in cortical thickness (corrected p-values < 0.001) in both cases and controls compared to other harmonization methods. Our results support the use of ComBat-GAM for harmonizing cortical thickness data aggregated from multiple sites and scanners to minimize confounds and increase statistical power.

Background Minority stress via discrimination, stigmatization, and exposure to violence can lead to development of mood and anxiety disorders and underlying neurobiochemical changes. To date, the neural and neurochemical correlates of emotion processing in transgender people (and their interaction) are unknown. Methods This study combined functional magnetic resonance imaging and magnetic resonance spectroscopy to uncover the effects of anxiety and perceived stress on the neural and neurochemical substrates, specifically choline, on emotion processing in transgender men. Thirty transgender men (TM), 30 cisgender men, and 35 cisgender women passively viewed angry, neutral, happy, and surprised faces in the functional magnetic resonance imaging scanner, underwent a magnetic resonance spectroscopy scan, and filled out mood- and anxiety-related questionnaires. Results As predicted, choline levels modulated the relationship between anxiety and stress symptoms and the neural response to angry and surprised (but not happy faces) in the amygdala. This was the case only for TM but not cisgender comparisons. More generally, neural responses in the left amygdala, left middle frontal gyrus, and medial frontal gyrus to emotional faces in TM resembled that of cisgender women. Conclusions These results provide first evidence, to our knowledge, of a critical interaction between levels of analysis and that choline may influence neural processing of emotion in individuals prone to minority stress.

IntroductionThe main objective was to carry out a global DNA methylation analysis in a population with gender incongruence before gender-affirming hormone treatment (GAHT), in comparison to a cisgender population.MethodsA global CpG (cytosine-phosphate-guanine) methylation analysis was performed on blood from 16 transgender people before GAHT vs. 16 cisgender people using the Illumina© Infinium Human Methylation 850k BeadChip, after bisulfite conversion. Changes in the DNA methylome in cisgender vs. transgender populations were analyzed with the Partek® Genomics Suite program by a 2-way ANOVA test comparing populations by group and their sex assigned at birth.ResultsThe principal components analysis (PCA) showed that both populations (cis and trans) differ in the degree of global CpG methylation prior to GAHT. The 2-way ANOVA test showed 71,515 CpGs that passed the criterion FDR p < 0.05. Subsequently, in male assigned at birth population we found 87 CpGs that passed both criteria (FDR p < 0.05; fold change ≥ ± 2) of which 22 were located in islands. The most significant CpGs were related to genes: WDR45B, SLC6A20, NHLH1, PLEKHA5, UBALD1, SLC37A1, ARL6IP1, GRASP, and NCOA6. Regarding the female assigned at birth populations, we found 2 CpGs that passed both criteria (FDR p < 0.05; fold change ≥ ± 2), but none were located in islands. One of these CpGs, related to the MPPED2 gene, is shared by both, trans men and trans women. The enrichment analysis showed that these genes are involved in functions such as negative regulation of gene expression (GO:0010629), central nervous system development (GO:0007417), brain development (GO:0007420), ribonucleotide binding (GO:0032553), and RNA binding (GO:0003723), among others.Strengths and LimitationsIt is the first time that a global CpG methylation analysis has been carried out in a population with gender incongruence before GAHT. A prospective study before/during GAHT would provide a better understanding of the influence of epigenetics in this process.ConclusionThe main finding of this study is that the cis and trans populations have different global CpG methylation profiles prior to GAHT. Therefore, our results suggest that epigenetics may be involved in the etiology of gender incongruence.

Experience of interpersonal trauma and violence alters self-other distinction and mentalising abilities (also known as theory of mind, or ToM), yet little is known about their neural correlates. This fMRI study assessed temporoparietal junction (TPJ) activation, an area strongly implicated in interpersonal processing, during spontaneous mentalising in 35 adult women with histories of childhood physical, sexual, and/or emotional abuse (childhood abuse; CA) and 31 women without such experiences (unaffected comparisons; UC). Participants watched movies during which an agent formed true or false beliefs about the location of a ball, while participants always knew the true location of the ball. As hypothesised, right TPJ activation was greater for UCs compared to CAs for false vs true belief conditions. In addition, CAs showed increased functional connectivity relative to UCs between the rTPJ and dorsomedial prefrontal cortex. Finally, the agent’s belief about the presence of the ball influenced participants’ responses (ToM index), but without group differences. These findings highlight that experiencing early interpersonal trauma can alter brain areas involved in the neural processing of ToM and perspective-taking during adulthood.

Much research has been conducted on sexual differences of the human brain to determine whether and to what extent a brain gender exists. Consequently, a variety of studies using different neuroimaging techniques attempted to identify the existence of a brain phenotype in people with gender dysphoria (GD). However, to date, brain sexual differences at the metabolite level using magnetic resonance spectroscopy (1H-MRS) have not been explored in transgender people. In this study, 28 cisgender men (CM) and 34 cisgender women (CW) and 29 transgender men with GD (TMGD) underwent 1H-MRS at 3 Tesla MRI to characterize common brain metabolites. Specifically, levels of N–acetyl aspartate (NAA), choline (Cho), creatine (Cr), glutamate and glutamine (Glx), and myo-inositol + glycine (mI + Gly) were assessed in two brain regions, the amygdala-anterior hippocampus and the lateral parietal cortex. The results indicated a sex-assigned at birth pattern for Cho/Cr in the amygdala of TMGD. In the parietal cortex, a sex-assigned at birth and an intermediate pattern were found. Though assessed post-hoc, exploration of the age of onset of GD in TMGD demonstrated within-group differences in absolute NAA and relative Cho/Cr levels, suggestive for a possible developmental trend. While brain metabolite levels in TMGD resembled those of CW, some interesting findings, such as modulation of metabolite concentrations by age of onset of GD, warrant future inquiry.

Background and objectives Childhood abuse and neglect increase the risk for psychiatric disorders (e.g., depression and anxiety) during adulthood and have been associated with deficits in cognitive control. The specific mechanisms underlying these cognitive control deficits are still unknown. Methods This study examined the expectation for reward to improve inhibitory control in young women (ages 18–35 years) with a history of childhood sexual and/or physical abuse (AG, N = 28), childhood emotional and/or physical neglect (NG, N = 30), or unaffected comparison women (HC, N = 40). They completed a previously validated rewarded (color-word) Stroop task and filled out questionnaires on depression, anxiety, and resilience. Results Surprisingly, a significant group by reward interaction revealed larger performance benefits under reward prospect (relative to no-reward) for the AG group relative to both the NG and HC groups. Limitations A small sample size limiting generalizability. Conclusions These results demonstrate sensitivity of abused subjects to reward in modulating cognitive control and might aid in discussing whether using reward schedules during therapeutic interventions could be effective.

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.

IntroductionCortical thickness (CT) and surface area (SA) are established biomarkers of brain pathology in posttraumatic stress disorder (PTSD). Structural covariance networks (SCN) constructed from CT and SA may represent developmental associations, or unique interactions between brain regions, possibly influenced by a common causal antecedent. The ENIGMA-PGC PTSD Working Group aggregated PTSD and control subjects’ data from 29 cohorts in five countries (n=3439).MethodsUsing Destrieux Atlas, we built SCNs and compared centrality measures between PTSD subjects and controls. Centrality is a graph theory measure derived using SCN.ResultsNotable nodes with higher CT-based centrality in PTSD compared to controls were left fusiform gyrus, left superior temporal gyrus, and right inferior temporal gyrus. We found sex-based centrality differences in bilateral frontal lobe regions, left anterior cingulate, left superior occipital cortex and right ventromedial prefrontal cortex (vmPFC). Comorbid PTSD and MDD showed higher CT-based centrality in the right anterior cingulate gyrus, right parahippocampal gyrus and lower SA-based centrality in left insular gyrus.ConclusionUnlike previous studies with smaller sample sizes (≤318), our study found differences in centrality measures using a sample size of 3439 subjects. This is the first cross-sectional study to examine SCN interactions with age, sex, and comorbid MDD. Although limited to group level inferences, centrality measures offer insights into a node’s relationship to the entire functional connectome unlike approaches like seed-based connectivity or independent component analysis. Nodes having higher centrality have greater structural or functional connections, lending them invaluable for translational treatments like neuromodulation.

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of “big data” (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA’s activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material.

Background: Empathy is essential for interpersonal relationships, yet remains difficult to measure. Some evidence suggests that early traumatic experiences leads to alterations in empathic responding. Objective: This study sought to differentiate connections between subtypes of childhood maltreatment, a pictorial test of affective empathy (PET), and self-reported empathy (Interpersonal Reactivity Index; IRI) by using network analysis approach to investigate the structure of relationships between childhood maltreatment and later empathic responding. Method: 301 participants completed the PET, the Early Trauma Inventory Self Report-Short Form (ETISR-SF), the IRI, and questionnaires assessing current mood and perceived stress levels. Results: The PET showed a strong positive association with the IRI subscale empathic concern (EC), after conditioning on all other nodes in the network. EC proved to be a highly central node and was positively related to severity of childhood sexual abuse (CSA), yet not to childhood physical abuse or emotional maltreatment. Pathways between emotional maltreatment and physical abuse and the PET were indirect, passing through self-reported EC and CSA. Conclusions: Our study suggests that CSA more so than other childhood maltreatment experiences is associated with increased self-reported affective empathy, but is not captured directly through a pictorial test of affective empathy.

The number of adolescent refugees around the world has been continuously increasing over the past few years trying to escape war and terror, among other things. Such experience not only increases the risk for mental health problems including anxiety, depression, and post-traumatic stress disorder (PTSD), but also may have implications for socio-cognitive development. This study tested cognitive-affective processing in refugee adolescents who had escaped armed conflict in Syria and now resided in Istanbul, Turkey. Adolescents were split into a high trauma (n = 31, 12 girls, mean age = 11.70 years, SD = 1.15 years) and low trauma (n = 27, 14 girls, mean age = 11.07 years, SD = 1.39 years) symptom group using median split, and performed a working memory task with emotional distraction to assess cognitive control and a surprise faces task to assess emotional interpretation bias. The results indicated that high (vs. low) trauma symptom youth were ~ 20% worse correctly remembering the spatial location of a cue, although both groups performed at very low levels. However, this finding was not modulated by emotion. In addition, although all youths also had a ~ 20% bias toward interpreting ambiguous (surprise) faces as more negative, the high (vs. low) symptom youth were faster when allocating such a face to the positive (vs. negative) emotion category. The findings suggest the impact of war-related trauma on cognitive-affective processes essential to healthy development.

We provide T2 *-weighted and T1-weighted images acquired on a 3T MRI scanner obtained from 17 transwomen and 29 transmen with gender incongruence; and 22 ciswomen and 19 cismen that identified themselves to the sex assigned at birth. Data from three different techniques that describe global and regional connectivity differences within functional resting-state networks in transwomen and trans men with early-in-life onset gender incongruence are provided: (1) we obtained spatial maps from data-driven independent component analysis using the melodic tool from FSL software; (2) we provide the functional networks interactions of two functional atlases' seeds from a seed to-seed approach; (3) and global graph-theoretical metrics such as the smallworld organization, and the segregation and integration properties of the networks. Interpretations of the present dataset can be found in the original article, doi:10.1016/j.neuroimage.2020.116613 [1] . The original and pro cessed nifti images are available in Mendeley datasets. In addition, correlation matrices for the seed-to-seed and graph theory analyses as well as the graph-theoretical measures were made available in Matlab files. Finally, we present supplementary information for the original article. (C) 2020 The Author(s). Published by Elsevier Inc.

Recent cognitive models suggest that the ability to control emotional information in working memory (WM) may be implicated in the etiology and maintenance of depression. However, few studies have examined the effects of processing relevant and irrelevant emotional stimuli on WM performance in depressed adolescents. In the current study, depressed adolescents (n = 27) and healthy adolescents (n = 49) completed two versions of an emotional n-back task: a low WM load (0-back) task and a high WM load (2-back) task. In the emotion-relevant condition participants were asked to attend to the emotional expression of an angry, happy, or neutral face, whereas in the emotion-irrelevant condition participants were asked to attend to the gender of the face. The results showed a WM improvement for happy faces in the emotion-relevant condition and a WM impairment for happy faces in the emotion-irrelevant condition for healthy adolescents but not for depressed adolescents. No biases toward angry faces were found. These results demonstrate that depressed adolescents do not show a preferential processing of angry faces but rather fail to show a positivity bias as seen in healthy adolescents. This supports the theoretical notion that a depressive disorder is characterized by a blunted reactivity toward positive information and may provide new insights into the underlying mechanisms of youth depression.

Background: Much research has been conducted on sexual dimorphisms of the human brain to determine whether and to what extent a brain gender exists. Consequently, a variety of studies using different neuroimaging techniques attempted to identify the existence of a brain phenotype in people with gender dysphoria (GD). However, to date, brain sexual dimorphisms at the metabolite level in transgender people have not been explored using magnetic resonance spectroscopy (1H-MRS). Methods: In this study, 29 transgender men, 30 cisgender men and 35 cisgender women underwent 1H-MRS at 3 Tesla MRI to characterize common brain metabolites. Specifically, absolute levels of N –acetyl aspartate (NAA), choline (Cho), creatine (Cr), glutamate (Glu), myo-inositol (mI) and their respective ratios were assessed in two brain regions, i.e. the amygdala-anterior hippocampus and the lateral parietal cortex. Influences of nicotine consumption, physical activity, education and psychopathology were considered. Results: The results indicated a sex-assigned at birth pattern for choline and glutamate ratios in the amygdala-anterior hippocampus of trans men. In the lateral parietal cortex cis men and cis women differed in the majority of metabolites (i.e. mI; Cr; NAA/Cr; Cho/Cr; mI/Cr; NAA/mI). Moreover, except for mI, trans men did not differ from either cisgender group, showing a pattern subtly moving towards the experienced gender identity. Post-hoc, careful exploration of the age of onset of GD in transgender men demonstrated the possibility of a developmental trend in absolute NAA levels, as a measure of neuronal function. Conclusion: We found sex-typical 1H-MRS spectra and they appear to be brain region specific. While the brain metabolite levels in trans men mostly resembled that of cis women, interesting findings such as modulation by age of onset warrant future enquiry to address potential neurobiological underpinnings of GD.