Impact of hormonal contraceptives on sex differences in fear conditioning and fear extinction in PTSD

Sex differences in the neurobiological mechanisms involved in fear conditioning and extinction have been suggested to contribute to differential vulnerability for the development of posttraumatic stress disorder (PTSD) in women compared with men. Reproductive hormones, such as estradiol, have been shown to facilitate fear conditioning and extinction learning and may explain some of these differences. However, the effect of commonly used hormonal contraceptives on the neurobiological mechanisms of fear conditioning and extinction is poorly understood. A laboratory study was conducted in trauma-exposed men and women with and without full or partial PTSD to examine effects of sex and use of hormonal birth control on fear conditioning, fear extinction learning, and extinction retention. Participants underwent fear conditioning with stimuli that were paired (CS+) or unpaired (CS−) with shock. Extinction learning occurred 72 h later, and extinction retention was tested 1 wk after extinction. Women on hormonal contraceptives (HCs) demonstrated enhanced acquisition of fear conditioning and enhanced extinction of fear as compared with women off hormonal birth control and men. While clinical implications have yet to be determined, these results suggest that hormonal contraceptives may facilitate learning during both fear acquisition and extinction. Understanding the impact of sex and hormones on fear conditioning and extinction processes may lead to new insights into the pathophysiology of PTSD and result in advancements in treatment that may vary by sex.

It is widely recognized that posttraumatic stress disorder (PTSD) is a common consequence of trauma exposure, and women are at particularly high risk, with some but not all studies finding that women develop PTSD at twice the rate of men, despite greater trauma exposure in men (Breslau et al. 1998; Tanielian et al. 2008). Although some have suggested that greater exposure to interpersonal violence may contribute to higher rates of PTSD in women, other evidence implicates sex differences in the neurobiological mechanisms that are involved in fear conditioning and extinction. Enhanced fear conditioning and diminished extinction of conditioned fear have been associated with higher levels of endogenous estrogen in women, as well as the development and maintenance of PTSD in both sexes (Orr et al. 2000; Milad et al. 2009b; Glover et al. 2012). Furthermore, as one of the most empirically supported treatments for PTSD is prolonged exposure therapy, which is largely based on fear extinction principles and the success of extinction learning (Rothbaum and Davis 2003), a clear understanding of the individual factors impacting fear conditioning and extinction is critical.Although some of the studies examining sex differences in fear conditioning are inconsistent (Guimaraes et al. 1991; Zorawski et al. 2005; Milad et al. 2006), an increasing body of evidence from rodent and human studies supports the existence of sex differences in fear extinction learning and recall (Maren et al. 1994; Pryce et al. 1999; Milad et al. 2009a; Merz et al. 2013). One possible explanation for the lack of consistent findings in the fear conditioning literature may be related to potential floor effects associated with subclinical impairment of nonclinical samples, as most laboratory studies examining sex differences were conducted in healthy humans. Another explanation that is gaining substantial support is the impact of hormones that differ between the sexes, among individuals, and even within individuals across time (Quirk and Mueller 2008; Lebron-Milad and Milad 2012; Arevalo et al. 2015; Hwang et al. 2015; Herrera et al. 2017; Maeng et al. 2017; Antov and Stockhorst 2018).The available literature indicates that estradiol, the primary estrogen in women during the childbearing years, is also present at overall lower concentrations in males and plays a large role in the fear conditioning and extinction differences observed between men and women (Gupta et al. 2001; Jasnow et al. 2006; Chang et al. 2009; Milad et al. 2009a, 2010; Zeidan et al. 2011; Maddox et al. 2018; Matsumoto et al. 2018; Carvalho et al. 2021). In both sexes, estradiol plays a variety of important functions in the brain, including the regulation of oxidative stress, inflammation, and gene expression, as well as in cognitive functions such as learning and memory (Hammoud et al. 2020). Estrogen receptors are found throughout brain regions that are important for fear conditioning and extinction processes (e.g., the amygdala, ventromedial prefrontal cortex, and hippocampus), likely via enhancements to learning and memory (Milad et al. 2008; Quirk and Mueller 2008; Lebron-Milad and Milad 2012). In women, as peripheral levels of estradiol vary over the course of the menstrual cycle, so do levels of estradiol in the brain (Arevalo et al. 2015). Estradiol has been shown to enhance memory consolidation across stages of fear conditioning, extinction, and retention (Lebron-Milad and Milad 2012). Most relevant to learning in PTSD, women with high levels of estradiol demonstrate enhanced memory formation in the presence of stress exposure (Herrera et al. 2017; Antov and Stockhorst 2018). In animal and human models, higher estradiol levels appear to facilitate acquisition of fear conditioning and extinction (Maeng et al. 2017). For example, women with high endogenous estradiol levels have enhanced responses in fear circuitry during fear conditioning, extinction, and recall as compared with men (Hwang et al. 2015). When phase of menstrual cycle has been taken into account, differences have been observed in conditioned fear responses and severity of PTSD symptoms. Specifically, when women are in the midluteal phase of the menstrual cycle (higher endogenous estradiol), they demonstrate a stronger positive relationship between SCR during fear conditioning and PTSD symptoms than women in the early follicular phase of menstruation (lower endogenous estradiol) (Carpenter et al. 2022). In the complimentary literature on the startle response, low-estradiol women demonstrated reduced discrimination between CS+ and CS− during fear conditioning and reduced inhibition of fear-potentiated startle during extinction and extinction recall, indicating less successful learning than their high-estradiol counterparts (Glover et al. 2012, 2013; Armbruster et al. 2018). This literature suggests that higher levels of estradiol relate to enhanced acquisition of associations between an unconditioned stimulus (UCS) and a conditioned stimulus (CS) during fear conditioning and enhanced extinction of this association during the extinction phase due to greater memory consolidation.A variety of factors can account for hormone differences in women, including menstrual phase, age, and use of hormonal birth control. Approximately 11%–20% of women aged 20–39 yr use oral contraceptives (OCs) (Daniels and Abma 2020). Commonly used OCs directly affect estradiol levels and hormonal fluctuation associated with the menstrual cycle. However, hormonal contraceptives (HCs) have received little attention in the fear conditioning literature. At the time of writing, we were unable to locate studies examining the impact of other HCs on fear conditioning circuitry, although these forms of birth control are increasingly popular among women, and evidence suggests that a variety of HCs has impacts on brain structure, function, and cognitive processes (Brønnick et al. 2020). Literature suggests that estradiol levels in women on HCs are typically low, similar to those of women in the early follicular phase of menstruation (Brynhildsen 2014). Although Hwang et al. (2015) did not demonstrate an effect of HCs on fear conditioning, many HCs contain ethinyl estradiol, which is synthetic estrogen that binds to estrogen receptors at high levels. Further research is needed to determine whether synthetic estrogen present in HCs impacts fear conditioning and fear extinction and contributes to associated sex differences, particularly in a highly sensitized population such as those with PTSD. In the current study, differences in fear conditioning, extinction, and retention were examined in women on hormonal birth control and in the early follicular phase of the menstrual cycle as compared with men to determine whether the synthetic hormones present in HCs confer any enhancement to these processes over and above women off of birth control with theoretically low levels of endogenous estradiol.Fear conditioning is measured by assessing the differential SCR to a conditioned stimulus (CS+) paired with an unconditioned stimulus (shock; UCS) and a stimulus unpaired with a shock (CS−). Greater acquisition of fear conditioning is evidenced by greater SCR response to the CS+ when compared with the CS−. Fear extinction refers to repeated exposure to the CS in the absence of the US, which results in diminishing reactivity to previously conditioned stimuli due to an inhibitory neural link that is formed (Myers and Davis 2007). Extinction is therefore operationalized by reduced discrimination of responding to the CS+ and CS− over time, and its retention is evidenced by a maintenance of low differential SCR in response to presentation of CS+ and CS− cues at follow-up.In previous work, our group examined sex differences in skin conductance responses to a fear conditioning paradigm in men and women with PTSD (Inslicht et al. 2013). In that sample, women were premenopausal and underwent conditioning during the follicular phase of the menstrual cycle. We found that women had greater differential fear acquisition compared with men. Other work has indicated that the effects of endogenous gonadal hormones on fear extinction are moderated by PTSD diagnosis, such that women with PTSD demonstrated impaired fear extinction during the midluteal phase of menstruation but not during the early follicular phase (Pineles et al. 2016b). The current study examines the effect of sex, HC use, and PTSD severity on fear conditioning, fear extinction, and extinction retention in medically healthy trauma-exposed premenopausal women on or off HCs and age-matched men across a range of PTSD symptom severity. We used a validated laboratory conditioning paradigm (Inslicht et al. 2021) that occurred over several days in which fear acquisition was separated from extinction by 72 h to avoid influencing consolidation of fear conditioning, and extinction retention was evaluated 1 wk after the fear extinction session to provide a test of durability of extinction over time.Given evidence for impaired fear extinction in PTSD, we hypothesized that participants high in PTSD (men and women combined) would have decreased fear extinction learning and extinction retention compared with those with low PTSD symptom scores. As estradiol appears to enhance learning during stress in women, we predicted that women on HCs would demonstrate higher differential SCR during acquisition and lower differential SCR during extinction and extinction retention than naturally cycling women in the early follicular phase of menstruation and men. Finally, we predicted a PTSD × sex interaction effect for extinction learning and retention; women on HCs with high levels of current PTSD would have enhanced acquisition but decreased extinction learning and retention compared with women with low levels of current PTSD and men.     

Wounds of Dislocation and the Yearning for Home: Re-Imagining Pastoral Theology

This article contributes to current conversations concerning the role pastoral care and theology can play in the renewal of public life.     

Higher Cost,Lower Validity and Higher Utility: Comparing the Utilities of Two Tests that Differ in Validity,Costs and Selectivity

Traditional approaches to comparing the utility of two tests have not systematically considered the effects of different levels of selectivity that are feasible and appropriate in various selection situations. For example, employers who hope to avoid adverse impact often find they can be more selective with some tests than with others. We conducted two studies to compare the utilities of two tests that differ in costs, validity, and feasible levels of selectivity which can be employed. First, an analytical solution was conducted starting with a standard formula for utility. This analysis showed that for both fixed and variable hiring costs, a higher-cost, lower-validity procedure can have higher utility than a lower-cost, higher-validity procedure when the selection ratios permissible using the two procedures are sufficiently (yet realistically) different. Second, using a computer simulation method, several combinations of the critical variables were varied systematically to detect the limits of this effect in a finite set of specific selection situations. The results showed that the existence of more severe levels of adverse impact greatly reduced the utility of a written test with relatively high validity and low cost in comparison with an assessment center with lower validity and higher cost. Both studies showed that the consideration of selectivity can yield surprising conclusions about the comparative utility of two tests. Even if one test has lower validity and higher cost than a second test, the first may yield higher utility if it allows the organization to exercise stricter levels of selectivity.     

Experience and grammatical agreement: Statistical learning shapes number agreement production

A robust result in research on the production of grammatical agreement is that speakers are more likely to produce an erroneous verb with phrases such as the key to the cabinets, with a singular noun followed by a plural one, than with phrases such as the keys to the cabinet, where a plural noun is followed by a singular. These asymmetries are thought to reflect core language production processes. Previous accounts have attributed error patterns to a syntactic number feature present on plurals but not singulars. An alternative approach is presented in which a process similar to structural priming contributes to the error asymmetry via speakers’ past experiences with related agreement constructions. A corpus analysis and two agreement production studies test this account. The results suggest that agreement production is shaped by statistical learning from past language experience. Implications for accounts of agreement are discussed.     

Support for Affirmative Action Initiatives Among Diverse Groups: The Role of Ethnic Identity

This study investigates the relationships among demographic factors (race/ethnicity, color, and gender), ethnic identity (i.e., the degree to which one identifies with and feels a part of one's racial or ethnic group), and support for affirmative action initiatives. Using a sample of 1,880 university employees, the results of this survey study reveal that women and minority group members express higher levels of ethnic identity and support for affirmative action initiatives, mirroring previous research. In addition, the findings indicate that ethnic identity and support for affirmative action initiatives are correlated and that ethnic identity serves as a mediator and moderator in the relationship between demographic variables and support for affirmative action for some subgroups.     

A long‐term fatty fish intervention improved executive function in inpatients with antisocial traits and a history of alcohol and drug abuse

The aim of the present study was to investigate the effects of fatty fish consumption on cognitive functioning in a group of inpatients characterized by antisocial behavior. Eighty‐three male forensic inpatients participated in this study. Participants were randomly assigned into a Fish or a Control group (e.g., meat, chicken, pork). One decision‐making task, the Iowa Gambling Task (IGT), and one planning task, the Tower of Hanoi (ToH), were administered before (pre‐test) and at the end of the intervention period (post‐test). For the IGT the Fish group showed improved performance from pre‐ to post‐ test. Moreover, the Fish group showed significantly better performance than the Control group on the IGT at post‐test. The Fish group also demonstrated improved performance from pre‐ to post‐test on the ToH; however, this was limited to participants with a history of substance abuse. Further, the improvement was only significant for tasks with high working memory load (5–7 move problems), and not for tasks with low working memory load (1–4 move problems). The Control group showed no improvement on any of the tasks regardless of alcohol or drug abuse history. The present study suggests that regular fatty fish consumption may improve executive functions in forensic inpatients with antisocial traits and a history of substance abuse. Thus, the current results may have important implications with regard to health care interventions.     

Training for pastoral care and its ecumenical dimension

Summary Responsible to a pluralistic society more directly than to a denominational constituency, ministers in training for pastoral care in public institutions engage simultaneously in ecumenical associations and in the construction of an ecumenically validated pastoral theology. The process was clearly under way in the pioneering work of Boisen, and it continues today with greater scope and a larger harvest. If present indications have predictive value, the history of ecumenicity in the last half of the Twentieth Century will make a modest but secure place for the discovery and use of clinical methods of training for pastoral care.     

Values Voters: The Conditional Effect of Income on the Relationship Between Core Values and Political Attitudes and Behavior

The postmaterialism thesis contends that newer cultural and social justice issues will supplant traditional, class‐based economic concerns as societies become increasingly wealthy. Although macrolevel evidence broadly supports this prediction, individual‐level evidence for the theory in the United States has been sparse. Moreover, alternative theories predict that postmaterialism will not travel well to the American context because religious cleavages that divide the major parties will be most salient. We test the postmaterialism thesis at the individual level using unique data that enable us to evaluate citizens' value‐preference structures across income levels, as well as the conditional effect of income on the relationship between individuals' ranked value preferences and political attitudes and behavior. Consistent with the theory, greater income strengthens the association between egalitarianism and ideology, partisanship, evaluations of President Obama, and presidential vote choice, and weakens the relationship between moral traditionalism and these same variables. However, income does not moderate the association between economic security and individuals' identities, evaluations, or behavior. Additionally, value‐preference hierarchies are quite similar across income groups after controlling for partisanship and ideology. The results lend insight into the nature of value‐ and income‐based cleavages in American politics.