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Susceptibility and resilience to stress depend on 1) the timing of the exposure with respect to development, 2) the time across the life span at which effects are measured, and 3) the behavioral or biological phenotype under consideration. This translational review examines preclinical stress models that provide clues to causal mechanisms and their relationship to the more complex phenomenon of stress-related psychiatric and cognitive disorders in humans. We examine how genetic sex and epigenetic regulation of hormones contribute to the proximal and distal effects of stress at different epochs of life. Stress during the prenatal period and early postnatal life puts male offspring at risk of developing diseases involving socialization, such as autism spectrum disorder, and attention and cognition, such as attention-deficit/hyperactivity disorder. While female offspring show resilience to some of the proximal effects of prenatal and early postnatal stress, there is evidence that risk associated with developmental insults is unmasked in female offspring following periods of hormonal activation and flux, including puberty, pregnancy, and perimenopause. Likewise, stress exposures during puberty have stronger proximal effects on girls, including an increased risk of developing mood-related and stress-related illnesses, such as depression, anxiety, and posttraumatic stress disorder. Hormonal changes during menopause and andropause impact the processes of memory and emotion in women and men, though women are preferentially at risk for dementia, and childhood adversity further impacts estradiol effects on neural function. We propose that studies to determine mechanisms for stress risk and resilience across the life span must consider the nature and timing of stress exposures as well as the sex of the organism under investigation. [ABSTRACT FROM AUTHOR]

Abstract Background Major depressive disorder (MDD) affects 10% of pregnancies. Because transcranial magnetic stimulation (TMS) is a nonmedication option, psychiatric patients who do not tolerate or prefer to avoid antidepressants are good candidates for TMS. Method In a randomized controlled trial of twenty-two women with MDD in the second or third trimester of pregnancy, subjects were randomized to active TMS (n=11) or sham TMS (n=11). This study took place at a single academic center. Subjects received 20 sessions of TMS to the right dorsolateral prefrontal cortex at 1 Hz as a single train of 900 pulses per session at 100% motor threshold. Estradiol and progesterone and were measured before session 1 and after session 20. Results Results demonstrated significantly decreased Hamilton Depression Rating Scale (HDRS-17) scores for the active compared to the sham group (p=0.003). Response rates were 81.82% for the active and 45.45% for the sham coil (p=0.088). Remission rates were 27.27% for the active 18.18% for the sham coil (p=0.613). Late preterm birth (PTB) occurred in three women receiving active TMS. All other maternal and delivery outcomes were normal. Conclusions Right-sided, low frequency TMS was effective in reducing depressive symptoms in this sample of pregnant women. There may be a possibility that TMS is associated with late PTB although a larger sample size would be needed for adequate power to detect a true difference between groups. This study demonstrated that TMS is low risk during pregnancy although larger trials would provide more information about the efficacy and safety of TMS in this population. This trial shows that an RCT of a biologic intervention in pregnant women with psychiatric illness can be conducted. Highlights • MDD during pregnancy is common but women experience challenges regarding treatment. • Transcranial magnetic stimulation is a non-pharmacologic treatment option for pregnant women with depression. • In an RCT of LF-TMS over the right DLPFC, women in the active TMS group showed a larger decrease in depressive symptoms than the sham group. • There were 3 late pre-term births in the active group which was statistically non-significant. • There was no change difference in hormone levels between the active and sham groups. [ABSTRACT FROM AUTHOR]

Background Adverse childhood experiences (ACEs) are one of the greatest predictors of affective disorders for women. Periods of dynamic hormonal flux, including pregnancy, exacerbate the risk for affective disturbance and promote hypothalamic-pituitary-adrenal (HPA) axis dysregulation, a key feature of affective disorders. Little is understood as to how stress experienced in late childhood, defined as preadolescence, alters the programming unique to this period of brain maturation and its interaction with the hormonal changes of pregnancy and postpartum. Methods Preadolescent female mice were exposed to chronic stress and examined for changes in their HPA axis during pregnancy and postpartum, including assessment of maternal-specific stress responsiveness and transcriptomics of the paraventricular nucleus of the hypothalamus. Translationally, pregnant women with low or high ACEs were examined for their maternal stress responsiveness. Results As predicted, preadolescent stress in mice resulted in a significant blunting of the corticosterone response during pregnancy. Transcriptomic analysis of the paraventricular nucleus revealed widespread changes in expression of immediate early genes and their targets, supporting the likely involvement of an upstream epigenetic mechanism. Critically, in our human studies, the high ACE women showed a significant blunting of the HPA response. Conclusions This unique mouse model recapitulates a clinical outcome of a hyporesponsive HPA stress axis, an important feature of affective disorders, during a dynamic hormonal period, and suggests involvement of transcriptional regulation in the hypothalamus. These studies identify a novel mouse model of female ACEs that can be used to examine how additional life adversity may provoke disease risk or resilience. [ABSTRACT FROM AUTHOR]

The article reports on research which investigated whether there is an association between hospitalization and cognitive decline in older people and attempted to find whether the nature of the association could be determined. Researchers conducted a literature review. They found that there is evidence to support an association between hospitalization and development of cognitive decline in older adults and that several factors, including delirium, medications and stress, could mediate the association.

Abstract: This meta-analysis assessed the efficacy of a wide range of preventive interventions designed to reduce the severity of postpartum depressive symptoms or decrease the prevalence of postpartum depressive episodes. A systematic review identified 37 randomized or quasi-randomized controlled trials in which an intervention was compared to a control condition. Differences between treatment and control conditions in the level of depressive symptoms and prevalence of depressive episodes by 6months postpartum were assessed in separate analyses. Depressive symptoms were significantly lower at post-treatment in intervention conditions, with an overall effect size in the small range after exclusion of outliers (Hedges' g =0.18). There was a 27% reduction in the prevalence of depressive episodes in intervention conditions by 6months postpartum after removal of outliers and correction for publication bias. Later timing of the postpartum assessment was associated with smaller differences between intervention and control conditions in both analyses. Among studies that assessed depressive symptoms using the EPDS, higher levels of depressive symptoms at pre-treatment were associated with smaller differences in depressive symptoms by 6months postpartum. These findings suggest that interventions designed to prevent postpartum depression effectively reduce levels of postpartum depressive symptoms and decrease risk for postpartum depressive episodes. [Copyright &y& Elsevier]

Summary: While cognitive changes and mood instability are frequent symptoms reported by menopausal women, the degree to which the decline in estrogen production is responsible is not yet clear. Several lines of evidence suggest that estrogen may produce its effects on cognition and mood through modulation of serotonergic function. To test this hypothesis, we used the tryptophan depletion (TD) paradigm to lower central serotonin levels and pharmacologically manipulated estrogen levels in healthy menopausal women. We examined the individual and combined effects of estradiol and serotonin on working memory, emotion processing and task-related brain activation. Eight healthy predominantly early postmenopausal women underwent TD or sham depletion followed by functional magnetic resonance imaging (fMRI) both before and after short-term transdermal estradiol 75–150μg/d administration. There was an estradiol treatment by TD interaction for brain activation during performance on both the N-back Task (working memory) and Emotion Identification Task (affective processing). During the 2-back condition, TD attenuated activation prior to, but not after, estradiol treatment in the right and left dorsal lateral prefrontal and middle frontal/cingulate gyrus. During emotion identification, TD heightened activation in the orbital frontal cortex and bilateral amygdala, and this effect was attenuated by estradiol treatment. These results provide preliminary evidence that serotonergic effects directly mediate the impact of estrogen on brain activation during working memory and affective processing. [ABSTRACT FROM AUTHOR]

Abstract: This meta-analysis assessed efficacy of pharmacologic and psychological interventions for treatment of perinatal depression. A systematic review identified 27 studies, including open trials (n =9), quasi-randomized trials (n =2), and randomized controlled trials (n =16) assessing change from pretreatment to posttreatment or comparing these interventions to a control group. Uncontrolled and controlled effect sizes were assessed in separate meta-analyses. There was significant improvement in depressive symptoms from pretreatment to posttreatment, with an uncontrolled overall effect size (Hedges'' g) of 1.61 after removal of outliers and correction for publication bias. Symptom levels at posttreatment were below cutoff levels indicative of clinically significant symptoms. At posttreatment, intervention groups demonstrated significantly greater reductions in depressive symptoms compared to control groups, with an overall controlled effect size (Hedges'' g) of 0.65 after removal of outliers. Individual psychotherapy was superior to group psychotherapy with regard to changes in symptoms from pretreatment to posttreatment. Interventions including an interpersonal therapy component were found to have greater effect sizes, compared to control conditions, than interventions including a cognitive–behavioral component. Implications of the findings for clinical practice and future research are discussed. [Copyright &y& Elsevier]

Abstract: In a series of exploratory analyses, we examined the roles of gender, reproductive status and negative affect on smoking abstinence in subjects participating in a large (n =385) 6-week randomized clinical trial (RCT) of nicotine patch therapy, with varying doses of oral naltrexone (0mg, 25mg, 50mg, 100mg) treatment. Negative affect was assessed daily during the first post-quit week via telephone interactive voice response (IVR). Weight and adverse events were recorded weekly. In the intent to treat sample, the effects of dose on continuous abstinence were non-significant in the overall model for men and women. In the 295 study completers, there was a significant effect of dose on continuous abstinence in women only (F =8.53, p =0.04). In the 100mg group, 71% of women were continuously abstinent compared to 41% in the placebo group (p <0.05). Women in the active naltrexone groups gained less weight (F =2.91, df=3, p =0.04). Women in the 100mg vs. placebo group were less adherent with medication (F =3.19, p <0.05). These effects were not significant in men. Naltrexone treatment condition (100mg vs. placebo, p =0.02, odds ratio (OR)=0.28), gender (OR=0.55 p =0.09), and IVR ratings of negative affect (OR 1.02, p =0.04) predicted abstinence at Week 1 in study completers. Menstrual cycle status on quit day had a modest affect on abstinence. These data suggest that naltrexone dose, gender, and negative affect play a role in smoking abstinence, particularly in the early stages of treatment. When used in conjunction with nicotine replacement therapy, naltrexone dose may be important in women. [Copyright &y& Elsevier]

Background: Given that nicotine modulates amino acid neurotransmission, we sought to examine the impact of nicotine on cortical γ-aminobutyric acid (GABA) levels in male and female smokers. Methods: Healthy nicotine-dependent men (n = 10) and women (n = 6) underwent proton magnetic resonance spectroscopy (1H-MRS) to measure occipital cortex GABA concentrations. A subset of the smoking men (n = 5) underwent 1H-MRS scans before and after 48 hours of smoking abstinence, whereas each of the women were scheduled to undergo pre- and postabstinence scans during the follicular and luteal phases of one menstrual cycle. Healthy nonsmoking men (n = 7) and women (n = 13) underwent 1H-MRS for comparison. Results: Short-term abstinence had no significant effect on cortical GABA concentrations in either men or women. There was, however, a significant effect of sex, diagnosis (smoker/nonsmoker), and menstrual cycle phase on cortical GABA levels, such that female smokers experienced a significant reduction in cortical GABA levels during the follicular phase and no cyclicity in GABA levels across the menstrual cycle, whereas cortical GABA levels were similar in smoking and nonsmoking men. Conclusions: Taken together with previous 1H-MRS data showing abnormalities in occipital cortex GABA concentrations in several affective disorders, our preliminary finding that nicotine modulation of GABA levels varies by sex provides a further rationale for investigating the impact of nicotine on central GABAergic function as a potential risk factor for women to experience depressive symptoms during smoking cessation. [Copyright &y& Elsevier]

Adverse childhood experiences (ACEs) increase risk for mental illness in women and their children, and dysregulation of the hypothalamic-pituitary-adrenal axis may play a role. The impact of ACEs on the hypothalamic-pituitary-adrenal axis may be strongest when ACEs occur prepubertally and in people who are exposed to abuse ACEs. To test this, we measured salivary cortisol in 96 mother-infant dyads while mothers were separated from their infants, who were experiencing a laboratory stressor. Mothers completed the Adverse Childhood Experiences Questionnaire; ACEs that occurred prepubertally (pACEs) were measured, and mother-infant dyads were grouped based on maternal pACE history as follows: no pACEs, ≥1 pACEs with abuse, or ≥1 pACEs but no abuse. Mothers with ≥1 pACEs exhibited decreases in cortisol (relative to preinfant stressor), which differed significantly from the cortisol increase experienced by mothers with no pACEs, regardless of abuse presence (p =.001) or absence (p =.002). These pACE groups did not differ from one another (p =.929). Significant sex differences in infant cortisol were observed in infants of mothers with ≥1 pACEs (regardless of abuse) but not in infants of mothers with no pACEs. When mothers had experienced ≥1 pACEs, males showed decreases in cortisol in response to a stressor whereas females demonstrated increases, and males and females differed significantly when their mothers had ≥1 pACEs with (p =.025) and without (p =.032) abuse. Regardless of maternal exposure to childhood abuse, in response to a stressor, pACEs were associated with lower cortisol response in mothers and sex differences in 6-month-old infants, with males showing a lower cortisol response than females. [ABSTRACT FROM AUTHOR]

This study investigated the intersectionality of adverse childhood experiences (ACEs) among subgroups of sex, race/ethnicity, and sexual orientation. Using data from the Behavioral Risk Factor Surveillance Survey across 34 states (N=116,712) from 2009 to 2018, authors stratified subgroups of sex (male/female), race/ethnicity (White/Hispanic/Black/multiracial/other), and sexual orientation (heterosexual/bisexual/gay) to investigate the number of ACEs across groups. Analyses were conducted in 2022. Stratification resulted in 30 distinct subgroups (e.g., bisexual Black females, straight multiracial males) with significant post hoc differences per group. Generally, those identifying as sexual minority individuals had the highest number of ACEs (the top 14 of 30 subgroups), whereas seven of the top ten subgroups were female. Surprisingly, no clear patterns emerged by race/ethnicity, although the two largest groups (straight White females and straight White males) were 27th and 28th of 30, respectively. Although studies have examined ACEs by individual demographic variables, less is known about the extent to which ACEs are present in stratified subgroups. Sexual minority subgroups (particularly female bisexual subgroups) trend toward a higher number of ACEs, whereas heterosexual subgroups (regardless of sex) comprised the lowest 6 groups with respect to ACEs. Implications include further examination of bisexual and female subgroups (including specific ACE domain investigations) to identify the vulnerable population. [ABSTRACT FROM AUTHOR]

• Compared with premenopausal women, perimenopausal and surgical postmenopausal women experience more perceived executive dysfunction. • Problems with perceived executive dysfunction were significantly higher in natural postmenopausal than in premenopausal women without controlling for difficulty sleeping, anxiety, and depression, but not when adjusting for these variables. • Menopause type (natural vs. surgical) and psychological symptoms (sleep, anxiety, and depression) are important confounders of the relationship between menopause and perceived executive function. The menopause transition is associated with difficulties in executive function. However, it is unclear whether these difficulties persist past perimenopause. This study investigated whether potential confounders, including natural vs. surgical postmenopause and menopause-related psychological symptoms, influence whether executive dysfunction persists into postmenopause. A cross-sectional sample of women aged 35–65 years (N = 1971) in one of four groups, premenopause, perimenopause, natural postmenopause, and surgical postmenopause, were surveyed. Participants self-reported executive functioning with the Brown Attention Deficit Disorder Scale (BADDS), anxiety symptom severity with the Generalized Anxiety Disorder Questionnaire (GAD-7), and depression symptom severity with the Center for Epidemiologic Studies Depression Scale (CES D). We analyzed the association between group and BADDS scores using linear regression models – first, by controlling for age, education, and self-reported attention deficit hyperactivity disorder (ADHD) diagnosis (Model #1) and, second, by further controlling for current difficulty sleeping, anxiety, and depression (Model #2). In both models, BADDS scores were significantly elevated (indicating more difficulties in executive function) among women in the perimenopausal and surgical postmenopausal groups compared with those in the premenopausal group. Likewise, the perimenopausal and surgical postmenopausal groups had the highest proportions of participants who reported difficulty sleeping and clinical levels of anxiety and depression. BADDS scores were significantly higher in natural postmenopausal vs. premenopausal women without controlling for difficulty sleeping, anxiety, and depression (Model #1), but not when adjusting for these variables (Model #2). The type of menopause and psychological symptoms are important confounders of the relationship between the menopause transition and executive dysfunction, and help explain whether executive dysfunction persists or recovers in postmenopause. [ABSTRACT FROM AUTHOR]

Objectives Diagnostic imaging may be a major source of cancer-related distress, a condition known as “scanxiety”. Scant scholarly work has been performed to evaluate scan-associated distress in cancer. We sought to characterize risk factors for scan-associated distress among patients with Non-Small Cell Lung Cancer (NSCLC), and to evaluate the impact of scan-associated distress on quality of life. Materials and methods We conducted a cross-sectional survey study of patients with recurrent/metastatic NSCLC treated at an academic medical center. Clinical and demographic variables were obtained through chart abstraction and patient self-report. We used a modified version of the Impact of Event Scale 6 (IES-6) to specifically assess distress associated with scans, and quality of life was measured using the Functional Assessment of Cancer Therapy − Lung (FACT-L). Results Among 103 participants (survey response rate 76.3%), median age was 67, 61.2% were women, and 82.5% were white. At the study visit, 72.8% of subjects discussed a recent scan, and 83% reported some scan-associated distress. Scan-associated distress was not associated with whether the patient had a recent scan, progressive disease or time from diagnosis. Scan-associated distress was associated with impaired quality of life (p = 0.004); each unit increase in IES-6 corresponded to an approximately one-unit decrease in FACT-L score. Conclusion Scan-associated distress is a common problem among patients with NSCLC, and is associated with impaired quality of life. Scan-associated distress severity was not associated with time since diagnosis or whether a recent scan was discussed at the study visit, which implies scan-associated distress may be a persistent problem. [ABSTRACT FROM AUTHOR]

Premenstrual dysphoric disorder (PMDD) is characterized by severe affective symptoms during the luteal phase of the menstrual cycle. There is some evidence of altered interactions between the hypothalamic pituitary gonadal (HPG) and hypothalamic pituitary adrenal (HPA) axes in PMDD. There is also evidence that similar affective disorders such as major depression and perinatal depression are associated with dysregulation in immune factors, but this has not been characterized in PMDD. The goals of this exploratory study were to identify 1) whether HPA-HPG axis interactions and immune markers differ between PMDD patients and controls across the menstrual cycle; 2) how luteal phase sertraline treatment impacts stress and inflammatory markers. Participants were females age 18–50 with regular menstrual cycles, not using psychotropic or hormonal medications, and were assigned to a control group or PMDD group based on prospective daily symptom ratings and clinical interview. Blood was drawn in the follicular and luteal phases, during laboratory sessions involving a mildly stressful task. In a second luteal phase, PMDD participants received open-label sertraline (50 mg/d) from ovulation to menses. Serum cortisol and ACTH were measured via ELISA and operationalized as area under the curve with respect to ground (AUCg), and peak level following laboratory task. Serum TNF-α, IL-6, CXCL-8, and IL-1β were measured using multiplex kits. Serum allopregnanolone (ALLO) was measured by gas chromatography/mass spectroscopy. To characterize HPA-HPG axis interactions across the menstrual cycle in PMDD participants and controls, multilevel linear models predicted cortisol and ACTH from the interaction of cycle phase (controlling for sertraline treatment), ALLO, and group. To determine the effects of sertraline treatment on inflammatory markers and how groups might differ in cyclical change on each marker, multilevel linear models predicted inflammatory markers from cycle phase (controlling for sertraline treatment) and group. A final set of exploratory models tested whether inflammatory markers predict premenstrual symptom score severity. The sample included n=77 participants (41 controls, 36 PMDD); 28 participants with PMDD completed sertraline treatment. Group x phase x ALLO interactions showed that higher ALLO levels predicted lower cortisol peak in the treated luteal phase (interaction between phase and ALLO, p=0.042), and there was a higher cortisol peak in the treated luteal phase than the untreated luteal phase (p=0.038). CXCL-8 was significantly associated with premenstrual symptom severity after controlling for group and cycle phase (p=0.011). There were no main effects of group, phase, or ALLO on cortisol AUCg, ACTH AUCg, IL-6, CXCL-8, IL-1β, nor TNF-α (p's>0.05). Serum markers of HPA axis and immune function did not vary by menstrual cycle phase nor PMDD status. However, sertraline treatment in the luteal phase was associated with higher ALLO levels predicting lower cortisol peak in response to mild laboratory stress, suggesting that sertraline treatment may normalize HPG-HPA axis interactions among individuals with PMDD. Greater premenstrual symptomatology was associated with higher levels of the inflammatory marker CXCL-8, but further research is needed into the potential role of inflammation in PMDD. • We assessed markers of HPA axis and inflammation in individuals with PMDD. • Samples were collected in the follicular and luteal phases of the menstrual cycle. • Premenstrual symptoms positively correlated with the inflammatory marker CXCL-8. • Luteal phase sertraline associated with higher allopregnanolone levels predicting lower cortisol peak. [ABSTRACT FROM AUTHOR]

Premenstrual dysphoric disorder (PMDD) affects approximately 5% of menstruating individuals, with significant negative mood symptoms in the luteal phase of the menstrual cycle. PMDD's pathophysiology and treatment mechanisms are poorly characterized, but may involve altered neuroactive steroid function in the brain. Selective serotonin reuptake inhibitors (SSRIs), a first-line PMDD treatment, reportedly alter gamma-aminobutyric acid (GABA)ergic neuroactive steroid levels in PMDD. The aims of this study were to determine whether the SSRI sertraline increased serum levels of neuroactive steroids that modulate the effect of GABA at GABA-A receptors (GABAAR) and if so, whether an increase was associated with improvement in PMDD symptoms. Participants included controls and individuals with PMDD. Serum levels of 9 neuroactive steroids were measured (3α,5α-THP; 3α5β-THP; pregnenolone; 3α,5α-androsterone; 3α,5β-androsterone; 3α,5α-A-diol; 3α5β-A-diol; 3α,5α-THDOC; 3α5β-THDOC) in the follicular and luteal phases. In the subsequent luteal phase, neuroactive steroids were measured during sertraline treatment (50 mg sertraline from approximate ovulation to menses onset) in the PMDD group. Mixed models assessed associations among diagnostic group, menstrual cycle phase, and sertraline treatment. Participants included 38 controls and 32 women with PMDD. There were no significant differences in neuroactive steroid levels between controls and participants with PMDD in the luteal phase (p > 0.05). Within the PMDD group, sertraline treatment significantly increased serum pregnanolone levels and the pregnanolone:progesterone ratio, and decreased 3α,5α-androsterone. This was the first study to assess the impact of SSRI treatment on peripheral levels of GABAergic neuroactive steroids in PMDD. Within the PMDD group, sertraline treatment was associated with a significant increase in luteal phase serum pregnanolone levels and a significantly increased pregnanolone:progesterone ratio, a novel finding. Future research should examine alterations in the metabolic pathways among GABAergic neuroactive steroids in individuals with PMDD, in a placebo-controlled design. • SSRIs may affect GABAergic neuroactive steroids. • We assessed SSRI (50 mg sertraline) effect on serum neuroactive steroids in PMDD. • Luteal phase sertraline increased pregnanolone, pregnanolone:progesterone ratio. • Luteal phase sertraline decreased 3α,5α-androsterone levels. • Sertraline did not affect other neuroactive steroids, including allopregnanolone. [ABSTRACT FROM AUTHOR]

Abstract During pregnancy, programming of the fetal central nervous system establishes vulnerabilities for emergence of neuropsychiatric phenotypes later in life. Psychosocial influences during pregnancy, such as stressful life events and chronic stress, correlate with offspring neuropsychiatric disorders and inflammation, respectively. Stress promotes inflammation, but the role of inflammation as a mediator between maternal psychosocial stress and offspring neuropsychiatric outcomes has not been extensively studied in humans. This review summarizes clinical evidence linking specific types of stress to maternal inflammatory load during pregnancy. We propose that inflammation is a mediator in the relationship between psychosocial stress and offspring neuropsychiatric outcomes, potentially influenced by poor maternal glucocorticoid–immune coordination. We present relevant experimental animal research supporting this hypothesis. We conclude that clinical and preclinical research supports the premise that stress-induced maternal immune activation contributes in part to prenatal programming of risk. Programming of risk is likely due to a combination of vulnerabilities, including multiple or repeated inflammatory events; timing of such events; poor maternal regulation of inflammation; genetic vulnerability; and lifestyle contributors. [ABSTRACT FROM AUTHOR]

During the menopause transition, women are at increased risk of subjective symptoms of executive dysfunction. Evidence from animal and human participant studies suggests adverse childhood experiences (ACE) may be a risk factor for executive complaints during this hormonal transition. Preclinical literature indicates early life adversity effects on serotonin function may play a role in this increased susceptibility. However, the mechanisms underlying this increase in vulnerability in human participants remain relatively unknown. Here we examined the impact of ACE and tryptophan depletion (TD), a paradigm used to lower central serotonin levels, on functional network connectivity in discovery and replication datasets. We hypothesized that ACE would be associated with decreased within-network connectivity. We predicted that TD would further lower connectivity in women with high levels of early adversity, but have no effect in women with low levels of early adversity. Forty women underwent two functional imaging sequences at two time points (141 total scans) in a double-blind, placebo controlled, crossover study. The effects of ACE and TD were evaluated using generalized estimating equations (GEE). As predicted, ACE was associated with lower within-network connectivity. While TD had no effect on connectivity in the low ACE group, TD increased connectivity in the high ACE group. The robust effect of ACE remained significant in the replication dataset, though the ACE × TD interaction did not. Together, these results suggest that early life adversity has lasting impacts on large-scale functional networks underlying executive function. Alterations in functional network connectivity may be one mechanism by which early life adversity increases the risk of cognitive disorders during menopause. [ABSTRACT FROM AUTHOR]

Women with a history of adverse childhood experiences (ACEs) enter pregnancy and the postpartum with a physiologic system programmed by early life stress, potentially reflected in psychophysiologic reactivity. We enrolled pregnant, psychiatrically healthy women ≥18 years old. Using the ACE Questionnaire, women were categorized as high (≥2 ACEs; n = 77) or low ACE (<2 ACEs; n = 72). Participants completed an affective modulation of acoustic startle response (ASR) task during pregnancy and postpartum, in which ASR magnitude was measured while participants viewed pleasant, unpleasant, and neutral pictures. Two types of control trials were included (habituation trials presented at baseline and intertrial interval trials presented when no picture was present). Among high ACE women, ASR was significantly higher postpartum compared with pregnancy in the unpleasant (p = 0.002, β = 0.46, 95% CI [0.18, 0.74], χ 2 = 10.12, z = 3.18) and intertrial interval trials (p = 0.002, β = 0.44, 95% CI [0.16, 0.73], χ 2 = 9.25, z = 3.04), accounting for multiple comparisons using a Bonferroni correction at p < 0.005. Among low ACE women, ASR was similar in pregnancy and postpartum. Physiological reactivity increased in high ACE women from pregnancy to postpartum, but no change was observed in low ACE women. [ABSTRACT FROM AUTHOR]

Abstract: A growing literature suggests that hormonal fluctuations occurring across the menstrual cycle, during and after pregnancy, and during the menopausal transition are associated with onset of affective disorders or exacerbation of existing disorders. This influence of the neuroendocrine system on psychiatric disorders is thought to be mediated by an abnormality in central nervous system response to neuroactive steroids such as estradiol, progesterone, and the progesterone derivative allopregnanolone (ALLO). This interplay is considerably complex as neuroactive steroids modulate the function of multiple neurotransmitter systems throughout various stages of development. While one could choose to study any number of steroid–neurotransmitter interactions, our group in addition to others has focused our investigative efforts on unraveling the contribution of neuroactive steroids to psychiatric syndromes and disorders via their modulation of gamma aminobutyric acid (GABA), the brain''s major inhibitory neurotransmitter. The goal of this article is two-fold: to synthesize the clinical and preclinical research focusing on the interplay between neuroactive steroids and GABA as they relate to neuropsychiatric and substance use disorders in women and to integrate data from our laboratory using proton magnetic resonance spectroscopy into this context. [Copyright &y& Elsevier]

Background: Gamma-aminobutyric acid (GABA)ergic adaptations contribute to the neurobiology of ethanol dependence and withdrawal. Clinical data suggest that tobacco smoking attenuates alcohol withdrawal symptoms. This study’s objective was to measure time-dependent cortical GABA levels with sobriety in ethanol-dependent patients with mild to moderate withdrawal severity, controlling for alcoholism-related neurotoxicity and smoking. Methods: Proton magnetic resonance spectroscopy (MRS) was used to measure occipital cortical N-acetylaspartate (NAA), glutamate plus glutamine, and GABA in 12 ethanol-dependent men at approximately 1 week and 1 month of medication-free sobriety on an inpatient unit. Eight healthy men were studied once. The tissue composition of the MRS volume was determined. Results: Adjusting for less white matter in patients, GABA differed insignificantly between ethanol-dependent patients (smokers plus nonsmokers) and healthy subjects. In early sobriety, nonsmoking patients had more GABA than did smoking patients, but by 1 month, GABA decreased in nonsmokers without changing in smokers. Smoking was associated with increased glutamate plus glutamine in patients and healthy subjects, adjusting for NAA levels. Conclusions: These data do not show that deficits in cortical GABA contribute directly to acute ethanol withdrawal. If smoking prevents withdrawal-related changes in cortical GABA systems, it may contribute to comorbidity of alcoholism and tobacco smoking. [Copyright &y& Elsevier]

Recent studies have suggested that neuroimmune abnormalities may play an important role in the pathogenesis of obsessive–compulsive disorder (OCD) and related disorders. This study was undertaken to determine whether cerebrospinal fluid (CSF) concentrations of the proinflammatory cytokine interleukin (IL)-6 differ between OCD and trichotillomania patients and healthy control subjects. Lumbar puncture with a standardized procedure was performed on 26 patients with OCD and 9 with trichotillomania. All patients were drug-free and met DSM-IV criteria. Twenty-six age- and sex-matched healthy volunteers underwent the same procedure. CSF was assayed for IL-6 using a quantitative ‘sandwich’ enzyme immunoassay technique. Mean±S.D. CSF IL-6 levels did not differ between OCD patients (n=26) (2.4±1.1 pg/ml) and controls (n=26) (2.4±1.9 pg/ml) or between trichotillomania patients (n=9) (2.3±0.8 pg/ml) and their matched controls (n=14) (1.9±0.5 pg/ml). These findings fail to support speculation that ongoing immune activation may be causally involved in the pathogenesis of OCD or trichotillomania. [Copyright &y& Elsevier]

Women with premenstrual dysphoric disorder (PMDD) experience mood symptoms related to the increase in progesterone and the neuroactive steroid allopregnanolone. Our hypothesis is that allopregnanolone is the symptom provoking factor. The rationale for the present study was to treat PMDD patients with the GABA A receptor modulating steroid antagonist, sepranolone (isoallopregnanolone). Patients (n = 206) with PMDD from 12 European centers were randomized in a parallel double-blind study and treated with placebo, sepranolone 10 mg and 16 mg. Patients administered sepranolone subcutaneously every 48 h during the 14 premenstrual days of three consecutive menstrual cycles. After obtaining informed consent, the PMDD diagnosis was confirmed according to DSM-5 and verified with two menstrual cycles of daily symptom ratings using the Daily Record of Severity of Problems (DRSP) scale in an eDiary. Inclusion and exclusion criteria stipulated that the women should be essentially healthy, not pregnant, have no ongoing psychiatric disorder or take interfering medications, and have regular menstrual cycles. The study's primary endpoint was the Total symptom score (Sum21, the score for all 21 symptom questions in the DRSP). In the prespecified statistical analysis the average score of the 5 worst premenstrual days in treatment cycles 2 and 3 were subtracted from the corresponding average score in the two diagnostic cycles. The treatment effects were tested using analysis of variance in a hierarchal order starting with the combined active sepranolone treatments vs. placebo. The prespecified analysis of Sum21 showed a large treatment effect of all three treatments but no statistically significant difference to placebo. However, the ratings of distress showed a significant treatment effect of sepranolone compared to placebo (p = 0.037) and the ratings of impairment showed a trend to greater treatment effect of sepranolone compared to placebo. Many women with PMDD had symptoms during a longer period than the late luteal phase. It has previously been shown that 9 premenstrual days may be more representative for comparison of PMDD symptom periods than the 5 worst premenstrual days. A post hoc analysis was undertaken in the per protocol population investigating the treatment effect during 9 premenstrual days in the third treatment cycle. The Sum21 results of this analysis showed that the sepranolone 10 mg was significantly better than placebo (p = 0.008). Similar significant treatment effects were found for the impairment and distress scores. A significantly larger number of individuals experienced no or minimal symptoms (Sum21 <42 points) with the 10 mg sepranolone treatment compared to placebo (p = 0.020). The results indicate that there is an attenuating effect by sepranolone on symptoms, impairment, and distress in women with PMDD especially by the 10 mg dosage. Sepranolone was well tolerated, and no safety concerns were identified. • A randomized, double-blind study using a GABA A receptor modulating steroid antagonist, sepranolone (isoallopregnanolone). • Sepranolone attenuates symptoms, impairment, and distress in women with PMDD especially by the 10 mg dosage. • Sepranolone was well tolerated, and no safety concerns were identified. [ABSTRACT FROM AUTHOR]

• Functional brain networks reconfigure during executive tasks. • Optimal network dynamics are necessary for efficient executive function. • Too much network reconfiguration may indicate poorer executive function. • adversity is associated with greater network reconfiguration during menopause. • Decreasing a precursor of serotonin increases functional network reconfiguration. Many women with no history of cognitive difficulties experience executive dysfunction during menopause. Significant adversity during childhood negatively impacts executive function into adulthood and may be an indicator of women at risk of a mid-life cognitive decline. Previous studies have indicated that alterations in functional network connectivity underlie these negative effects of childhood adversity. There is growing evidence that functional brain networks are not static during executive tasks; instead, such networks reconfigure over time. Optimal dynamics are necessary for efficient executive function; while too little reconfiguration is insufficient for peak performance, too much reconfiguration (supra-optimal reconfiguration) is also maladaptive and associated with poorer performance. Here we examined the impact of adverse childhood experiences (ACEs) on network flexibility, a measure of dynamic reconfiguration, during a letter n-back task within three networks that support executive function: frontoparietal, salience, and default mode networks. Several animal and human subject studies have suggested that childhood adversity exerts lasting effects on executive function via serotonergic mechanisms. Tryptophan depletion (TD) was used to examine whether serotonin function drives ACE effects on network flexibility. We hypothesized that ACE would be associated with higher flexibility (supra-optimal flexibility) and that TD would further increase this measure. Forty women underwent functional imaging at two time points in this double-blind, placebo controlled, crossover study. Participants also completed the Penn Conditional Exclusion Test, a task assessing abstraction and mental flexibility. The effects of ACE and TD were evaluated using generalized estimating equations. ACE was associated with higher flexibility across networks (frontoparietal β = 0.00748, D = 2.79, p = 0.005; salience β = 0.00679, D = 3.02, p = 0.003; and default mode β = 0.00910, D = 3.53, p = 0.0004). While there was no interaction between ACE and TD, active TD increased network flexibility in both ACE groups in comparison to sham depletion (frontoparietal β = 0.00489, D = 2.15, p = 0.03; salience β = 0.00393, D = 1.91, p = 0.06; default mode β = 0.00334, D = 1.73, p = 0.08). These results suggest that childhood adversity has lasting impacts on dynamic reconfiguration of functional brain networks supporting executive function and that decreasing serotonin levels may exacerbate these effects. [ABSTRACT FROM AUTHOR]

• Higher estradiol levels in adolescent girls predicted greater DLPFC activity during cognitive reappraisal of negative emotion. • No association between progesterone and DLPFC activity during cognitive reappraisal of negative emotion during adolescence. • The association effect of estradiol on DLPFC was differentiated from maturational changes associated with age. Non-human primate models have been useful in clarifying estradiol's role in cognitive processing. These animal studies indicate estradiol impacts cognitive processes supported by regions within dorsolateral prefrontal cortex (DLPFC). Although human functional neuroimaging studies have begun to find similar relationships between estradiol in women for some forms of 'cold' cognitive control, to date no studies have examined the relationship between estradiol and DLPFC function in the context of active attempts to regulate one's emotions. Here, we asked whether peripheral 17-beta estradiol levels in adolescent girls in different pubertal developmental stages (age = 14.9 years ± 1.74) were related to engagement of DLPFC regions during the use of a cognitive strategy for regulating emotion known as reappraisal using functional Magnetic Resonance Imaging. Findings indicated that higher estradiol levels predicted greater DLPFC activity during the down-regulation of negative emotion using reappraisal. This is the first report of an association between estradiol level and DLPFC activity during cognitive reappraisal of negative emotion. The study suggests a possibility that estradiol might positively contribute to regulatory function of a cortical system important for emotional experiences. [ABSTRACT FROM AUTHOR]

Objective: To compare the effects of cognitive-behavioral therapy (CBT) and lifestyle modification (LS) versus LS alone on weight, depressive and anxiety symptoms, and stress response in women with polycystic ovary syndrome (PCOS), overweight/obesity, and depressive symptoms.Design: A 16-week pilot randomized clinical trial.Setting: Tertiary-care PCOS center.Patient(s): Overweight/obese women with PCOS and depressive symptoms.Intervention(s): Weekly CBT (n = 7) or contact only/no therapy (n = 8) for 8 weeks. Both groups received weekly LS for 16 weeks.Main Outcome Measure(s): Changes in weight, depression (Center for Epidemiologic Studies Depression Scale [CES-D]), anxiety (State-Trait Anxiety Inventory [STAI]), quality of life (Polycystic Ovary Syndrome Health-Related Quality of Life Questionnaire [PCOSQ]), laboratory tests, and response to a Trier Social Stress Test (TSST).Result(s): The CBT+LS group lost more weekly weight (-0.35 kg/wk vs. -0.16 kg/wk) compared with the LS group. Overall, the CBT+LS group lost 3.2 kg versus 1.8 kg for the LS group. The CBT+LS group had greater improvement in PCOSQ at 8 weeks (+3.7 vs. +1.2 points). In the overall cohort, STAI and CES-D decreased by -0.27 points per week and -0.31 points/wk, respectfully, and total and free T decreased at week 8. Heart rate response to TSST was lower at 15 minutes after stressor in the CBT+LS group.Conclusion(s): Weekly CBT+LS for 8 weeks compared with LS alone resulted in significant weight loss and improved quality of life in overweight/obese women with PCOS and depressive symptoms. These interventions were associated with a decreased autonomic response to a laboratory stressor, suggesting a potential link between CBT, weight loss, and modulation of the stress response.Clinical Trial Registration Number: NCT01899001. [ABSTRACT FROM AUTHOR]