Ovarian hormones shape brain structure, function, and chemistry: A neuropsychiatric framework for female brain health

There are robust sex differences in brain anatomy, function, as well as neuropsychiatric and neurodegenerative disease risk (1-6), with women approximately twice as likely to suffer from a depressive illness as well as Alzheimer’s Disease. Disruptions in ovarian hormones likely play a role in such disproportionate disease prevalence, given that ovarian hormones serve as key regulators of brain functional and structural plasticity and undergo major fluctuations across the female lifespan (7-9). From a clinical perspective, there is a wellreported increase in depression susceptibility and initial evidence for cognitive impairment or decline during hormonal transition states, such as the postpartum period and perimenopause (9-14). What remains unknown, however, is the underlying mechanism of how fluctuations in ovarian hormones interact with other biological factors to influence brain structure, function, and chemistry. While this line of research has translational relevance for over half the population, neuroscience is notably guilty of female participant exclusion in research studies, with the male brain implicitly treated as the default model and only a minority of basic and clinical neuroscience studies including a female sample (15-18). Female underrepresentation in neuroscience directly limits opportunities for basic scientific discovery; and without basic knowledge of the biological underpinnings of sex differences, we cannot address critical sexdriven differences in pathology. Thus, my doctoral thesis aims to deliberately investigate the influence of sex and ovarian hormones on brain states in health as well as in vulnerability to depression and cognitive impairment:Table of Contents List of Abbreviations ..................................................................................................................... i List of Figures .............................................................................................................................. ii Acknowledgements .....................................................................................................................iii 1 INTRODUCTION .....................................................................................................................1 1.1 Lifespan approach: Sex, hormones, and metabolic risk factors for cognitive health .......3 1.2 Reproductive years: Healthy models of ovarian hormones, serotonin, and the brain ......4 1.2.1 Ovarian hormones and brain structure across the menstrual cycle ........................4 1.2.2 Serotonergic modulation and brain function in oral contraceptive users .................6 1.3 Neuropsychiatric risk models: Reproductive subtypes of depression ...............................8 1.3.1 Hormonal transition states and brain chemistry measured by PET imaging ...........8 1.3.2 Serotonin transporter binding across the menstrual cycle in PMDD patients .......10 2 PUBLICATIONS ....................................................................................................................12 2.1 Publication 1: Association of estradiol and visceral fat with structural brain networks and memory performance in adults .................................................................................13 2.2 Publication 2: Longitudinal 7T MRI reveals volumetric changes in subregions of human medial temporal lobe to sex hormone fluctuations ..............................................28 2.3 Publication 3: One-week escitalopram intake alters the excitation-inhibition balance in the healthy female brain ...............................................................................................51 2.4 Publication 4: Using positron emission tomography to investigate hormone-mediated neurochemical changes across the female lifespan: implications for depression ..........65 2.5 Publication 5: Increase in serotonin transporter binding across the menstrual cycle in patients with premenstrual dysphoric disorder: a case-control longitudinal neuro- receptor ligand PET imaging study ..................................................................................82 3 SUMMARY ...........................................................................................................................100 References ..............................................................................................................................107 Supplementary Publications ...................................................................................................114 Author Contributions to Publication 1 .....................................................................................184 Author Contributions to Publication 2 .....................................................................................186 Author Contributions to Publication 3 .....................................................................................188 Author Contributions to Publication 4 .....................................................................................190 Author Contributions to Publication 5 .....................................................................................191 Declaration of Authenticity ......................................................................................................193 Curriculum Vitae ......................................................................................................................194 List of Publications ................................................................................................................195 List of Talks and Posters ......................................................................................................19

Specific factors and methodological decisions influencing brain responses to sexual stimuli in women

Most of the neuroimaging studies on sexual behavior have been conducted with male participants, leading to men-based models of sexual arousal. Here, possible factors and methodological decisions that might influence brain responses to sexual stimuli, specifically for the inclusion of women, will be reviewed. Based on this review, we suggest that future studies consider the following factors: menstrual phase, hormonal contraception use, history of sexual or psychiatric disorders or diseases, and medication use. Moreover, when researching sexual arousal, we suggest future studies assess sexual orientation and preferences, that women should select visual sexual stimuli, and a longer duration than commonly used. This review is thought to represent a useful guideline for future research in sexual arousal, which hopefully will lead to a higher inclusion of women and therefore more accurate neurobiological models of sexual arousal

Involuntary memories after stressor exposure: contribution of hormonal status and rumination in women.

Women experience fewer traumatic stressors over their lifespan than men, but demonstrate a higher prevalence of major depression and stressor-related disorders as a result of trauma exposure (Breslau & Anthony, 2007; Kessler et al., 2005). Differences in prevalence of stressor-related disorders may partially be due to sex-linked vulnerabilities related to emotional memory. Emotion assists in modulation of memory through neurological processes. This modulation enhances memory for emotional stimuli and can lead to a greater frequency of involuntary recall after stressor exposure. This involuntary memory is also a hallmark symptom of Posttraumatic Stress Disorder (PTSD). Sex-linked vulnerabilities, specifically hormonal status and frequency of brooding rumination may contribute to a higher prevalence of PTSD in women following stress exposure through their influence on emotional memory processes. The current study further examined these potential sex-linked vulnerabilities in 77 (43 hormonal contraceptive users and 34 naturally cycling) women. Participants were asked to report on their experience of involuntary memories each evening for seven days following exposure to a trauma analogue film. Contrary to hypotheses, neither hormonal contraceptive status nor brooding rumination were statistically significant predictors of involuntary memory frequency, related distress, or related activity interference during the seven day follow-up. Severity of depressive symptoms was the only statistically significant predictor in all tested models. Findings further highlight current depressive symptoms, as a robust vulnerability factor for developing intrusive memories following stressor exposure

Novel Research in Sexuality and Mental Health

Sexuality is considered as a great human value related to happiness and satisfaction, but unfortunately, when affecting mental disorders, they tend to be associated with second level human functions. Nevertheless, sexual dysfunction often accompanies psychiatric disorder, intensely influencing compliance, quality of life and human relationships. Sexuality could be influenced either by a mental disorder itself, difficulties to get and maintain couple relationships or by the use of psychotropic treatments. Treatment-related adverse events are unfortunately under-recognized by clinicians, scarcely spontaneously communicated by patients, and rarely investigated in clinical trials. The most frequent psychotropic compounds that could deteriorate sexuality and quality of life include antidepressants, antipsychotics and mood regulators. There are important differences between them related to some variations in mechanisms of action including serotonin, dopamine and prolactin levels. Little is known about the relevance of sexuality and its dysfunctions in chronic and frequent mental and neurological disorders, such as psychosis, mood disorders, anxiety, phobias, eating disorders, alcohol or drug dependencies, epilepsy and childhood pathology. Poor sexual life, low satisfaction and more frequent risky sex behavior than in the general population are associated with severe mental diseases. There is a need for increasing research in this field, including epidemiological, psychological, neurophysiological, neuroanatomical and genetic variables related to sexual life to get a better understanding of the implicated mechanisms. To increase the sensibility of clinicians, the identification and management of sexual disturbances after the onset of any mental disorder should be highlighted. This would avoid unnecessary suffering and deterioration of quality of life

Oral contraceptives and affective disorders: neurobiology and informed choice

Pregnancy prevention and female reproductive freedom have been some of the most contested political issues for decades. Abortion, a fundamental part of women’s healthcare, divides liberals and conservatives on an international scale. The consequences of unintended pregnancy without safe and reliable contraception are widespread, disproportionately impacting women of color, trans and non-binary folks, and poorer communities. The birth control pill is the most common form of oral contraception (OC) globally. Many people with ovaries begin the pill or other hormonal contraceptive (HC) methods as young as 11 years old. Exogenous progesterone and estrogen are known to impact mood, affect, physiology, and behavior. Ongoing research examining the relationship between OCs and affective disorders has yielded controversial results. Studies in various countries have different conclusions – a significant negative correlation with OC use and positive affect, some significant negative effect depending on age, or no significant relationship with mental health or quality of life between women taking or not taking OCs. Young women are more likely to develop an affective disorder like depression than men of the same age group. This vulnerability cannot be overlooked when considering the effects of HCs on mood. This review analyzes and contextualizes current data on the relationship between OCs and mental health disorders and provides future directions for research on this topic

The effects of estradiol on mood and behavior in human female adolescents: a systematic review

Mood disorders and health risk behaviors increase in adolescence. Puberty is considered to contribute to these events. However, the precise impact of pubertal hormone changes to the emergence of mood disorders and risk behaviors is relatively unclear. It is important that inappropriate attribution is not made. Our aim was to determine what is known about the effect of endogenous estradiol on human adolescent girls’ mood and behavior. The databases searched were MEDLINE, Embase, PsycINFO, Education Resources Information Center (ERIC), Pre-MEDLINE, Web of Science, and Scopus for all dates to October 2014. For inclusion, contemporaneous hormone and mood or behavioral assessment was required. Data were extracted following a template created by the authors. Fourteen studies met our inclusion criteria. There was some consistency in findings for mood and estradiol levels, with associations between estradiol and depression and emotional tone and risk taking. Results were less consistent for studies assessing other mood and behavioural outcomes. Most studies were cross-sectional in design; assay methodologies used in older studies may lack the precision to detect early pubertal hormone levels. Conclusion: Three longitudinal and several cross-sectional studies indicate potential associations between estradiol and certain mood or affective states, especially depression and mood variability though there are insufficient data to confirm that the rise in estradiol during puberty is causative. We believe that it is important for health professionals to take care when attributing adolescent psychopathology to puberty hormones, as the current data supporting these assertions are limited.Australian National Health and Medical Research Council (NHMRC

Ovarian hormones: a long overlooked but critical contributor to cognitive brain structures and function

Cognitive neuroscience research has traditionally overlooked half of the population. Arguing that variability in ovarian hormones confounds empirical findings, girls and women have been excluded from research for decades. But times are changing. This review summarizes historical trends that have led to a knowledge gap in the role of ovarian hormones in neuroscience, synthesizes recent findings on ovarian hormone contributions to cognitive brain structures and function, and highlights areas ripe for future work. This is accomplished by reviewing research that has leveraged natural experiments in humans across the life span that focus on puberty, the menstrual cycle, hormonal contraceptive use, menopause, and menopausal hormone therapy. Although findings must be considered in light of study designs (e.g., sample characteristics and group comparisons versus randomized crossover trials), across natural experiments there is consistent evidence for associations of estradiol with cortical thickness, especially in frontal regions, and hippocampal volumes, as well as with frontal regions during cognitive processing. There are also emerging investigations of resting state connectivity and progesterone along with exciting opportunities for future work, particularly concerning biopsychosocial moderators of and individual differences in effects in novel natural experiments. Thus, delineating complex ovarian hormone contributions to cognitive brain structures and function will advance neuroscience.This review summarizes historical trends that have led to a knowledge gap in the role of ovarian hormones in neuroscience, synthesizes recent findings on ovarian hormone contributions to cognitive brain structures and function, and highlights areas ripe for future work.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154624/1/nyas14255_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154624/2/nyas14255.pd

Estradiol and Daily Affective Experiences in Trauma-Exposed Women

People who experience trauma can develop enduring trauma-related symptoms. In daily life, post-trauma symptoms (e.g., elevated physiological arousal) can be triggered by affectively salient cues in the environment, especially by cues that act as trauma reminders. Trauma exposure is associated with enduring changes in two biological stress systems: the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenal (HPA) axis. In women, activity in both systems is additionally modulated by fluctuations in levels of sex hormones (e.g., estradiol), which could influence physiological responses to trauma reminders. Additionally, previous work has linked the sex hormone estradiol with affect, suggesting that menstrual cycle might influence trauma-related symptoms or daily affect more broadly within the context of trauma exposure. However, we do not yet have a clear understanding of how estradiol influences affective experiences post-trauma. We used a multi-method approach to examine the influence of estradiol on daily affective experiences in a non-clinical, trauma-exposed sample of 40 naturally cycling premenopausal women. The first specific goal of this study was to test the hypothesis that low estradiol would be related to trauma symptoms, including an asymmetrical profile of SNS and HPA axis stress reactivity to a naturalistic trauma reminder. Lower estradiol was related to greater number and severity of PTSD symptoms, and participants in low versus high estradiol menstrual cycle phases showed higher SNS and reduced HPA axis reactivity to a trauma reminder. These results suggest that lower estradiol is associated with a less adaptive profile of stress system reactivity and increased PTSD symptom expression. The second specific goal of this study was to test the influence of menstrual cycle phase on daily affect in a subset of 30 participants. We assessed affective experience over the course of a 10-day ecological momentary assessment (EMA) period, which included the early follicular (low estradiol) and late follicular (high estradiol) phases. We selected these menstrual cycle phases to capture a portion of the cycle where estradiol increased, whereas progesterone remained low, allowing us to test the effects of estradiol without the confound of progesterone. Participants reported more frequent aversive affective experiences, defined as negatively valenced, high arousal states, including PTSD symptoms, during the early versus late follicular phase. During the early versus late follicular phase, participants also reported greater negative and positive affect and showed greater variability in affective ratings. These results suggest that lower estradiol menstrual cycle phases are characterized by more frequent aversive affective experiences, greater affective lability and increased PTSD symptom severity. Together, these results have potential implications for clinical assessment, as menstrual cycle phase at the time of assessment could influence diagnosis of PTSD or symptom severity. Additionally, clinicians working with women with PTSD might anticipate greater affective lability and increased symptom severity during low estradiol phases of the menstrual cycle

Spectral dynamic causal modelling in healthy women reveals brain connectivity changes along the menstrual cycle

Longitudinal menstrual cycle studies allow to investigate the effects of ovarian hormones on brain organization. Here, we use spectral dynamic causal modelling (spDCM) in a triple network model to assess effective connectivity changes along the menstrual cycle within and between the default mode, salience and executive control networks (DMN, SN, and ECN). Sixty healthy young women were scanned three times along their menstrual cycle, during early follicular, pre-ovulatory and mid-luteal phase. Related to estradiol, right before ovulation the left insula recruits the ECN, while the right middle frontal gyrus decreases its connectivity to the precuneus and the DMN decouples into anterior/posterior parts. Related to progesterone during the mid-luteal phase, the insulae (SN) engage to each other, while decreasing their connectivity to parietal ECN, which in turn engages the posterior DMN. When including the most confident connections in a leave-one out cross-validation, we find an above-chance prediction of the left-out subjects’ cycle phase. These findings corroborate the plasticity of the female brain in response to acute hormone fluctuations and may help to further understand the neuroendocrine interactions underlying cognitive changes along the menstrual cycle