Sex differences in cortisol levels in depression: A systematic review and meta-analysis.

Higher prevalence of depression in females might be associated with sex-specific cortisol levels. Evidence exists that cortisol levels differ between healthy females and males, however a sex-specific association in depression has not been systematically assessed. Thus, the current study quantifies the existing literature on different cortisol parameters, i.e., basal cortisol, hair cortisol, cortisol awakening response (CAR), and cortisol stress reactivity comparing depressed females and males as well as sex-specific comparisons with healthy controls. Following an extensive literature research, fifty original articles were included. Depressed females had significantly higher hair cortisol, higher CAR, and lower cortisol stress reactivity compared to depressed males. In comparison with sex-matched controls, female patients had significantly higher evening basal cortisol, higher CAR and lower cortisol stress reactivity, and male patients had significantly higher general, morning and evening basal cortisol. Overall, sex as a fundamental driver of cortisol levels in depression needs to be taken into account.

Symptoms of mental disorders and oral contraception use: A systematic review and meta-analysis.

Worldwide, over 150 million adolescent and adult women use oral contraceptives (OC). An association between OC-use and the emergence of symptoms of mental disorders has been suggested. This systematic review and meta-analysis provide an overview of published research regarding symptoms of mental disorders in association with OC-use, factoring the influence of OC types, age of first-use, duration of OC-intake, and previous diagnoses of mental disorders. A systematic literature search was conducted between June-July 2022. 22 studies were included. While most found no significant OC-use effects on mental symptoms, some hinted at OCs as a potential risk. The existing evidence regarding the potential link between progestin-only OC-use and an elevated risk of mental symptoms in comparison to combined OC-use remains inconclusive. However, due to emerging indications suggesting that the formulation of OC might play a role in mental health outcomes, this topic warrants further investigation. Moreover, indications of an increased risk for depressive symptoms in adolescent OC-users should be noted. Hence, while general population effects seem unlikely, they cannot be completely disregarded. The decision on OC-use should depend on the patient's medical history and should be re-evaluated regularly.

Sex-dependent multimodal response profiles to psychosocial stress.

INTRODUCTION: Sex differences in stress reactions are often reported in the literature. However, the sex-dependent interplay of different facets of stress is still not fully understood. Particularly in neuroimaging research, studies on large samples combining different indicators of stress remain scarce. MATERIALS AND METHODS: In a functional magnetic resonance imaging study, a sample of 140 healthy participants (67 females using oral contraceptives) underwent a standardized stress induction protocol, the ScanSTRESS. During the experiment, salivary cortisol and subjective ratings were obtained at multiple time points and heart rate was recorded. RESULTS: Sex differences emerged in different facets of the stress response:Women reacted with enhanced subjective feelings of stress and increases in heart rate, while men showed more pronounced neural activation in stress-related brain regions such as the inferior frontal gyrus and insula. Subjective feelings of stress and (para) hippocampal activity were negatively related in women,whereas a slightly positive association was observed in men. DISCUSSION: These results provide further insight in the sex-specific stress response patterns. Moreover, they emphasize the role of the hippocampus in the regulation of the stress response. This paves the way for the identification of sex-dependent vulnerability factors that can, in the future, be implemented in the prevention and treatment of stress-related disorders.

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.

Lower affective empathy in oral contraceptive users: a cross-sectional fMRI study.

Evidence accumulates that oral contraceptive (OC) use modulates various socio-affective behaviors, including empathic abilities. Endogenous and synthetic sex hormones, such as estrogens and progestogens, bind to receptor sites in brain regions (i.e. frontal, limbic, and cerebellar) involved in socio-affective processing. Therefore, the aim of this study was to investigate the role of OC use in empathy. In a cross-sectional functional magnetic resonance imaging study, women in different hormonal states, including OC use (n = 46) or being naturally cycling in the early follicular (fNC: n = 37) or peri-ovulatory phase (oNC: n = 28), performed a visual, sentence-based empathy task. Behaviorally, OC users had lower empathy ratings than oNC women. Congruently, whole-brain analysis revealed significantly larger task-related activation of several brain regions, including the left dorsomedial prefrontal gyrus (dmPFG), left precentral gyrus, and left temporoparietal junction in oNC compared to OC women. In OC users, the activity of the left dmPFG and precentral gyrus was negatively associated with behavioral and self-reported affective empathy. Furthermore, empathy-related region-of-interest analysis indicated negative associations of brain activation with synthetic hormone levels in OC women. Overall, this multimodal, cross-sectional investigation of empathy suggests a role of OC intake in especially affective empathy and highlights the importance of including synthetic hormone levels in OC-related analyses.

Imaging the human brain on oral contraceptives: A review of structural imaging methods and implications for future research goals.

Worldwide over 150 million women use oral contraceptives (OCs), which are the most prescribed form of contraception in both the United States and in European countries. Sex hormones, such as estradiol and progesterone, are important endogenous hormones known for shaping the brain across the life span. Synthetic hormones, which are present in OCs, interfere with the natural hormonal balance by reducing the endogenous hormone levels. Little is known how this affects the brain, especially during the most vulnerable times of brain maturation. Here, we review studies that investigate differences in brain gray and white matter in women using OCs in comparison to naturally cycling women. We focus on two neuroimaging methods used to quantify structural gray and white matter changes, namely structural MRI and diffusion MRI. Finally, we discuss the potential of these imaging techniques to advance knowledge about the effects of OCs on the brain and wellbeing in women.

Influence of ovarian hormones on value-based decision-making systems: Contribution to sexual dimorphisms in mental disorders.

Women and men exhibit differences in behavior when making value-based decisions. Various hypotheses have been proposed to explain these findings, stressing differences in functional lateralization of the brain, functional activation, neurotransmitter involvement and more recently, sex hormones. While a significant interaction of neurotransmitter systems and sex hormones has been shown for both sexes, decision-making in women might be particularly affected by variations of ovarian hormones. In this review we have gathered information from animal and human studies on how ovarian hormones affect decision-making processes in females by interacting with neurotransmitter systems at functionally relevant brain locations and thus modify the computation of decision aspects. We also review previous findings on impaired decision-making in animals and clinical populations with substance use disorder and depression, emphasizing how little we know about the role of ovarian hormones in aberrant decision-making.

Association of levonorgestrel intrauterine devices with stress reactivity, mental health, quality of life and sexual functioning: A systematic review.

Levonorgestrel-intrauterine-devices (LNG-IUD) are one of the most used contraceptive methods worldwide. While several reviews exist on how LNG-IUDs impact physiology and gynaecological functions, this systematic review focuses on stress, mental health, quality of life, sexual functioning, and effects on brain architecture. While data on stress is scarce, results on mental health are ambiguous. More consistently, LNG-IUD use seems to improve quality of life and sexual functioning. No studies highlighting the consequences of LNG-IUD use on the brain were found. The reviewed studies are characterized by a substantial variation in approaches, participant groups, and study quality. More high-quality research assessing the effects of LNG-IUD on mental health, including response to stressors and brain function and structure, is needed to identify women vulnerable to adverse effects of LNG-IUD, also in comparison to oral contraceptives, and to empower women to make more informed choices concerning hormonal contraception.

Neuroimaging the menstrual cycle: A multimodal systematic review.

Increasing evidence indicates that ovarian hormones affect brain structure, chemistry and function of women in their reproductive age, potentially shaping their behavior and mental health. Throughout the reproductive years, estrogens and progesterone levels fluctuate across the menstrual cycle and can modulate neural circuits involved in affective and cognitive processes. Here, we review seventy-seven neuroimaging studies and provide a comprehensive and data-driven evaluation of the accumulating evidence on brain plasticity associated with endogenous ovarian hormone fluctuations in naturally cycling women (n = 1304). The results particularly suggest modulatory effects of ovarian hormones fluctuations on the reactivity and structure of cortico-limbic brain regions. These findings highlight the importance of performing multimodal neuroimaging studies on neural correlates of systematic ovarian hormone fluctuations in naturally cycling women based on careful menstrual cycle staging.

The peripartum human brain: Current understanding and future perspectives.

The peripartum period offers a unique opportunity to improve our understanding of how dramatic fluctuations in endogenous ovarian hormones affect the human brain and behavior. This notwithstanding, peripartum depression remains an underdiagnosed and undertreated disorder. Here, we review recent neuroimaging findings with respect to the neuroplastic changes in the maternal brain during pregnancy and the postpartum period. We seek to provide an overview of multimodal neuroimaging designs of current peripartum depression models of hormone withdrawal, changes in monoaminergic signaling, and maladaptive neuroplasticity, which likely lead to the development of a condition that puts the lives of mother and infant at risk. We discuss the need to effectively integrate the available information on psychosocial and neurobiological risk factors contributing to individual vulnerability. Finally, we propose a systematic approach to neuroimaging the peripartum brain that acknowledges important co-morbidities and variation in disease onset.

The association of the 5-HTTLPR polymorphism and the response to different stressors in healthy males.

The experience of stress is related to individual wellbeing and vulnerability to psychopathology. Therefore, understanding the determinants of individual differences in stress reactivity is of great concern from a clinical perspective. The functional promotor polymorphism of the serotonin transporter gene (5-HTTLPR/rs25531) is such a factor, which has been linked to the acute stress response as well as the adverse effect of life stressors. In the present study, we compared the impact of two different stress induction protocols (Maastricht Acute Stress Test and ScanSTRESS) and the respective control conditions on affective ratings, salivary cortisol levels and cognitive performance. To this end, 156 healthy young males were tested and genotyped for the 5-HTTLPR/rs25531 polymorphism. While combined physiological and psychological stress in the MAST led to a greater cortisol increase compared to control conditions as well as the psychosocial ScanSTRESS, subjective stress ratings were highest in the ScanSTRESS condition. Stress induction in general affected working memory capacity but not response inhibition. Subjective stress was also influenced by 5-HTTLPR/rs25531 genotype with the high expression group showing lower stress ratings than lower expression groups. In line with previous research, we identified the low expression variant of the serotonin transporter gene as a risk factor for increased stress reactivity. While some dimensions of the human stress response may be stressor specific, cognitive outcomes such as working memory performance are influenced by stress in general. Different pathways of stress processing and possible underlying mechanisms are discussed.

Shaping of the Female Human Brain by Sex Hormones: A Review.

Traditionally sex hormones have been associated with reproductive and developmental processes only. Since the 1950s we know that hormones can have organizational effects on the developing brain and initiate hormonal transition periods such as puberty. However, recent evidence shows that sex hormones additionally structure the brain during important hormonal transition periods across a woman's life including short-term fluctuations during the menstrual cycle. However, a comprehensive review focusing on structural changes during all hormonal transition phases of women is still missing. Therefore, in this review structural changes across hormonal transition periods (i.e., puberty, menstrual cycle, oral contraceptive intake, pregnancy and menopause) were investigated in a structured way and correlations with sex hormones evaluated. Results show an overall reduction in grey matter and region-specific decreases in prefrontal, parietal and middle temporal areas during puberty. Across the menstrual cycle grey matter plasticity in the hippocampus, the amygdala as well as temporal and parietal regions were most consistently reported. Studies reporting on pre- and post-pregnancy measurements revealed volume reductions in midline structures as well as prefrontal and temporal cortices. During perimenopause, the decline in sex hormones was paralleled with a reduction in hippocampal and parietal cortex volume. Brain volume changes were significantly correlated with estradiol, testosterone and progesterone levels in some studies, but directionality remains inconclusive between studies. These results indicate that sex hormones play an important role in shaping women's brain structure during different transition periods and are not restricted to specific developmental periods.

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.

Do Social Cognition Deficits Recover with Abstinence in Alcohol-Dependent Patients?

BACKGROUND: Despite growing evidence of the presence and clinical relevance of deficits in social cognition in individuals with alcohol use disorder (AUD), less is known about the potential of "natural" recovery with abstinence in this neurocognitive domain. This study investigated the abstinence-based recovery of neurocognitive social abilities in alcohol-dependent patients (ADP) using a prospective longitudinal design with follow-up assessment under controlled conditions of abstinence during alcohol dependence inpatient treatment. METHODS: Seventy-seven participants (42 ADP and 35 healthy controls [HC]) performed social cognition testing, including facial emotion recognition, perspective taking, and affective responsiveness twice (baseline/T1 and follow-up/T2) during comparable follow-up periods. Assessment of social cognition in abstinent ADP was conducted at the beginning (T1; within the first 2 weeks) and at the end (T2; within the last 2 weeks) of long-term (2 months) abstinence-oriented alcohol dependence inpatient treatment. Only patients abstinent for >14 days (last heavy drinking day >21 days) at baseline (T1) and who remained abstinent at follow-up (T2) were included. RESULTS: ADP, who on average were nearly 2 months abstinent at T1, showed poorer social cognition in all 3 areas (emotion recognition, perspective taking, and affective responsiveness) than HC. There was no difference between groups on the change in performance over time, and group differences (ADP vs. HC) remained significant at T2, indicating persistent social cognition deficits in ADP following controlled abstinence during inpatient treatment. CONCLUSIONS: Our findings indicate no natural recovery of social cognition impairments in ADP during an intermediate to long-term period of abstinence (2+ months), the usual active treatment phase. Research aimed at developing interventions that focus on the improvement of social cognition deficits (e.g., social cognition training) and determining whether they benefit short- and long-term clinical outcomes in AUD seems warranted.

Predictive Pattern Classification Can Distinguish Gender Identity Subtypes from Behavior and Brain Imaging.

The exact neurobiological underpinnings of gender identity (i.e., the subjective perception of oneself belonging to a certain gender) still remain unknown. Combining both resting-state functional connectivity and behavioral data, we examined gender identity in cisgender and transgender persons using a data-driven machine learning strategy. Intrinsic functional connectivity and questionnaire data were obtained from cisgender (men/women) and transgender (trans men/trans women) individuals. Machine learning algorithms reliably detected gender identity with high prediction accuracy in each of the four groups based on connectivity signatures alone. The four normative gender groups were classified with accuracies ranging from 48% to 62% (exceeding chance level at 25%). These connectivity-based classification accuracies exceeded those obtained from a widely established behavioral instrument for gender identity. Using canonical correlation analyses, functional brain measurements and questionnaire data were then integrated to delineate nine canonical vectors (i.e., brain-gender axes), providing a multilevel window into the conventional sex dichotomy. Our dimensional gender perspective captures four distinguishable brain phenotypes for gender identity, advocating a biologically grounded reconceptualization of gender dimorphism. We hope to pave the way towards objective, data-driven diagnostic markers for gender identity and transgender, taking into account neurobiological and behavioral differences in an integrative modeling approach.

The relationship between emotional intelligence and quality of life in schizophrenia and bipolar I disorder.

PURPOSE: Social cognitive skills, both psychosocial functioning and well-being of patients with schizophrenia (SZ) or bipolar disorder (BD), have consistently been shown to be interrelated. While previous research mainly focused on emotion perception, the present study investigates the impact of the other subdomains of emotion processing on a subjective Quality of Life (QoL) estimate and objective QoL indicators. We hypothesized that patients with better performance in the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT) report better QoL; and assumed that SZ and BD patients report comparable subjective QoL, whereas BD patients show higher levels of objective QoL. METHODS: Patients diagnosed with either SZ (n = 63) or BD (n = 60), as well as 80 healthy controls, were included into a cross-sectional study. Emotional Intelligence (EI) and QoL were assessed using the MSCEIT and the German version of the Lancashire Quality of Life Profile. RESULTS: The two patient groups were comparable with regard to overall EI, as well as subjective and objective QoL, but indicated significantly lower levels of EI and QoL than healthy controls. Whereas EI was not associated with both patient groups' subjective QoL, a significant correlation of EI with objective QoL was only observed in SZ. However, overall effect sizes were small. CONCLUSION: Our findings point to a difference in the interrelation between EI and QoL in patients suffering from SZ and BD, and suggest that they may have different needs to achieve recovery. It will be critical to develop training programs targeting EI in SZ, and to examine their impact on objective QoL in these patients.

Acute relaxation during pregnancy leads to a reduction in maternal electrodermal activity and self-reported stress levels.

BACKGROUND: Prenatal maternal stress can have adverse effects on birth outcomes and fetal development. Relaxation techniques have been examined as potential countermeasures. This study investigates different relaxation techniques and their effect on self-reported stress levels and physiological stress levels in pregnant women. METHODS: In this cross-sectional study, 38 pregnant women in their 30th to 40th gestational week were assigned to one of three, 20-min lasting relaxation groups: listening to music (N = 12), following a guided imagery (N = 12) or resting (N = 12). The intervention, i.e., acute relaxation (music, guided imagery or resting) took place once for each study participant. Study inclusion criteria were age over 18 years, German speaking, singleton and uncomplicated pregnancy during the 30th and 40th week of gestation. The stress levels were determined during the study. Current stress level during the study was assessed by a visual analogue scale. Chronic stress levels were assessed by the Trier Inventory of Chronic Stress and the Pregnancy Distress questionnaire. Multivariate analyses of covariance were performed and dependent measures included stress levels as well as physiological measures, i.e., cardiovascular activity (electrocardiogram) and skin conductance levels. RESULTS: All three forms of relaxation led to reduced maternal stress which manifested itself in significantly decreased skin conductance, F(3,94) = 18.011, p = .001, ηp2 = .365, and subjective stress levels after the interventions with no significant group difference. Post-intervention stress ratings were further affected by gestational age, with less subjective relaxation in women later in gestation, F (1, 34)=4.971, p = .032, ηp2 = .128. CONCLUSION: Independent of relaxation technique, single, 20-min relaxation intervention (music, guided imagery or resting) can significantly reduce maternal stress. Notably, women at an earlier stage in their pregnancy reported higher relaxation after the intervention than women later in gestation. Hence, gestational age may influence perceived stress levels and should be considered when evaluating relaxation or stress management interventions during pregnancy. TRIAL REGISTRATION: Not applicable.

Brain-based ranking of cognitive domains to predict schizophrenia.

Schizophrenia is a devastating brain disorder that disturbs sensory perception, motor action, and abstract thought. Its clinical phenotype implies dysfunction of various mental domains, which has motivated a series of theories regarding the underlying pathophysiology. Aiming at a predictive benchmark of a catalog of cognitive functions, we developed a data-driven machine-learning strategy and provide a proof of principle in a multisite clinical dataset (n = 324). Existing neuroscientific knowledge on diverse cognitive domains was first condensed into neurotopographical maps. We then examined how the ensuing meta-analytic cognitive priors can distinguish patients and controls using brain morphology and intrinsic functional connectivity. Some affected cognitive domains supported well-studied directions of research on auditory evaluation and social cognition. However, rarely suspected cognitive domains also emerged as disease relevant, including self-oriented processing of bodily sensations in gustation and pain. Such algorithmic charting of the cognitive landscape can be used to make targeted recommendations for future mental health research.

Imaging stress: an overview of stress induction methods in the MR scanner.

Processing of acute stress has potential implications for mental and physical health. At the same time, individuals differ largely in how strongly they react to stress. Neuroimaging paradigms have been developed to characterize the neural underpinnings of the stress response in general and to understand the mechanisms that differentiate high and low susceptible individuals. The goal of the present review was to summarize the current literature on psychosocial stress in the brain imaging environment. That is, we focused on the most common neuroimaging paradigms that have been used to induce acute stress and map out the questions that have been addressed with respect to the determinants, the consequences, and the processing of stress. We identified four major paradigms that have been used with different scientific aims. The Montreal Imaging Stress Test and the ScanSTRESS involve cognitive challenge and social-evaluative threat and yielded a stress-related network including most significantly the perigenual ACC, the hippocampus, and the amygdala. The social-evaluative threat paradigm was used to predict the autonomic stress response on the basis of multivariate pattern analysis. The aversive video paradigm, on the other hand, was mainly used to investigate the consequences of stress on emotional and cognitive processes and their neural correlates. We conclude our review with a critical evaluation of methodological and conceptual issues in the study of the neural correlates of acute stress.

Effects of Hormonal Contraceptives on Mood: A Focus on Emotion Recognition and Reactivity, Reward Processing, and Stress Response.

PURPOSE OF REVIEW: We review recent research investigating the relationship of hormonal contraceptives and mood with a focus on relevant underlying mechanisms, such as emotion recognition and reactivity, reward processing, and stress response. RECENT FINDINGS: Adverse effects of hormonal contraceptives (HCs) on mood seem most consistent in women with a history of depressive symptoms and/or previous negative experience with HC-intake. Current evidence supports a negativity bias in emotion recognition and reactivity in HC-users, although inconsistent to some extent. Some data, however, do indicate a trend towards a blunted reward response and a potential dysregulation of the stress response in some HC-users. HC-effects on psychological and neurophysiological mechanisms underlying mood are likely context-dependent. We provide suggestions on how to address some of the contributing factors to this variability in future studies, such as HC-dose, timing, administration-mode, and individual risk. A better understanding of how and when HCs affect mood is critical to provide adequate contraceptive choices to women worldwide.