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Neural activity during traumatic film viewing is linked to endogenous estradiol and hormonal contraception
Abstract
Women are at higher risk for Posttraumatic Stress Disorder (PTSD) and recent research has highlighted a modulating role of female sex hormones for cognitive and emotional processes potentially underlying PTSD symptoms. However, studies combining fMRI recordings of brain activity during trauma film viewing with assessment of female sex hormones are missing. The trauma film paradigm − a widely used experimental analogue for trauma exposure − confronts healthy participants with traumatic film clips and thus allows studying peritraumatic processing under laboratory conditions. Following this paradigm, the current fMRI study examined the role of endogenous estradiol and synthetic sex hormones for the neural processing of traumatic (i.e., depicting interpersonal violence) vs. neutral films in 53 healthy women (mean age 22.3 years; 23 using hormonal contraception, HC). As predicted, traumatic films strongly activated areas of the fear processing network, such as amygdala, insula, and dorsal anterior cingulate cortex. Estradiol levels in women not using HC were positively correlated with ventromedial prefrontal activity. Furthermore, women using HC as compared to women without HC demonstrated heightened insula and dorsal anterior cingulate cortex activity during traumatic film viewing. These experimental results highlight the effects of both gonadal hormone status and HC intake on peritraumatic processing in neural regions relevant for emotion generation and regulation that have been found to be abnormal in PTSD.
... Estradiol and progesterone have been proposed as key factors influencing intrusive emotional memories in humans (Cover et al., 2014;Li and Graham, 2017;Miedl et al., 2018;Ney et al., 2019;Seligowski et al., 2020a). High levels of estradiol have been associated with an increased consolidation of fear extinction memory, while low estradiol levels have been correlated with more and stronger intrusive memories at encoding and consolidation (Cover et al., 2014;Soni et al., 2013;Wegerer et al., 2014). ...
... Our study is not without limitations. First, participants reported a relatively low number of intrusions among a total of 48 participants for the primary outcome and 40 participants for the secondary outcome, although this finding approximates those of other studies that have employed the trauma film paradigm (Chou et al., 2014;Ferree et al., 2011;Miedl et al., 2018). This limitation could relate to the fact that our participants opted into the research while aware of the stressful nature of the film. ...
Background
Trauma- and stress-related disorders, such as post-traumatic stress disorder (PTSD), are more common in females than in males. Sex hormones affect learning and emotional memory formation and may be associated with the development of PTSD. Most previous studies have indexed these hormones in isolation. Objectives: To investigate associations of sex hormones and cortisol during memory consolidation on the development of intrusive memories. Methods: We employed an experimental trauma film paradigm in 61 healthy women and indexed salivary testosterone, progesterone, estradiol, and cortisol on day one and day two post experimental trauma exposure and their effects on intrusion frequency, distress, and vividness. Intrusive trauma memories were indexed by means of a diary in which participants documented intrusion frequency, distress, and vividness. Results and conclusion: Participants reported an average of 5.3 intrusions over the course of seven days (SD = 4.6, range 0-26). Progesterone, and estradiol indexed on day one predicted intrusion frequency, with higher progesterone and lower estradiol predicting more intrusive memories (p-values AUC progesterone 0.01 and estradiol 0.02). There was no evidence for associations between hormone concentration indices on day two and intrusion outcomes. Further research on the roles of gonadal and adrenal hormones in trauma memory formation is needed to advance our efforts to understand their influence on PTSD development.
HIGHLIGHTS
• We examined effects of sex hormones and cortisol post-experimental trauma on intrusive memories.
• Progesterone and estradiol indexed on day one were associated with intrusion frequency.
• No significant association between hormones on day two and intrusive memory outcomes emerged
... OC users show increased blood-oxygen-level-dependent (BOLD) response in frontal brain regions (inferior, superior, and middle frontal gyri), as well as in the insula, fusiform gyrus, lingual gyrus, and supplementary motor area when exposed to an emotionally arousing picture n-back task (Sharma et al., 2020). While this heightened BOLD response is consistent with other OC-related functional tasks such as following traumatic film exposure (Miedl et al., 2018), OC users show less BOLD signal in frontal brain regions and in the insula compared to NC women during an emotional face matching task (Gingnell et al., 2013). Thus, OC use alters task-dependent brain activity in areas involved in memory and emotion regulation. ...
... The higher connectivity in the ACC and the superior medial frontal gyrus of both these networks could provide a mechanism for the heightened emotional reactivity observed in OC users. For example, OC users show a higher BOLD signal in the ACC following presentation to fear-evoking stimuli and traumatic video clips compared to NC women (Merz et al., 2012;Miedl et al., 2018). Similarly, in our previous study, we found that OC users demonstrate an increased BOLD signal in the inferior, middle, and superior frontal gyri as well as in the insula, lingual gyrus, and supplementary motor area during working memory processing for negatively arousing images compared to NC women (Sharma et al., 2020). ...
... OC users show increased blood-oxygen-level-dependent (BOLD) response in frontal brain regions (inferior, superior, and middle frontal gyri), as well as in the insula, fusiform gyrus, lingual gyrus, and supplementary motor area when exposed to an emotionally arousing picture n-back task (Sharma et al., 2020). While this heightened BOLD response is consistent with other OC-related functional tasks such as following traumatic film exposure (Miedl et al., 2018), OC users show less BOLD signal in frontal brain regions and in the insula compared to NC women during an emotional face matching task (Gingnell et al., 2013). Thus, OC use alters task-dependent brain activity in areas involved in memory and emotion regulation. ...
... The higher connectivity in the ACC and the superior medial frontal gyrus of both these networks could provide a mechanism for the heightened emotional reactivity observed in OC users. For example, OC users show a higher BOLD signal in the ACC following presentation to fear-evoking stimuli and traumatic video clips compared to NC women (Merz et al., 2012;Miedl et al., 2018). Similarly, in our previous study, we found that OC users demonstrate an increased BOLD signal in the inferior, middle, and superior frontal gyri as well as in the insula, lingual gyrus, and supplementary motor area during working memory processing for negatively arousing images compared to NC women (Sharma et al., 2020). ...
Millions of women worldwide use oral contraceptives (OCs), often starting during puberty/adolescence. It is, however, unknown how OC use during this critical period of development affects the brain. The objective of the current study was to examine resting state functional connectivity (FC) in the default mode network (DMN), central executive network (CEN), salience network (SN), reward network (RN), and subcortical limbic network of the brain using independent component analysis (ICA) between pubertal- and adult-onset OC users (n = 27) and naturally cycling women (n = 48). It was hypothesized that OC use would result in network-specific increases and decreases in FC and that pubertal-onset OC use would result in differences to the aforementioned networks compared to adult-onset OC use. Pubertal-onset OC use is related to heightened FC in the SN compared to adult-onset OC users. In general, OC use also increases connectivity in the SN, CEN, RN, and subcortical limbic network compared to NC women. No significant differences in connectivity were observed in the DMN between OC users and NC women. These findings provide a mechanistic insight for the altered executive functioning and emotion/reward processing previously seen in OC users, which may then increase their vulnerability to mental health conditions.
... OC users show increased blood-oxygen-level-dependent (BOLD) response in frontal brain regions (inferior, superior, and middle frontal gyri), as well as in the insula, fusiform gyrus, lingual gyrus, and supplementary motor area when exposed to an emotionally arousing picture n-back task (Sharma et al., 2020). While this heightened BOLD response is consistent with other OC-related functional tasks such as following traumatic film exposure (Miedl et al., 2018), OC users show less BOLD signal in frontal brain regions and in the insula compared to NC women during an emotional face matching task (Gingnell et al., 2013). Thus, OC use alters task-dependent brain activity in areas involved in memory and emotion regulation. ...
... The higher connectivity in the ACC and the superior medial frontal gyrus of both these networks could provide a mechanism for the heightened emotional reactivity observed in OC users. For example, OC users show a higher BOLD signal in the ACC following presentation to fear-evoking stimuli and traumatic video clips compared to NC women (Merz et al., 2012;Miedl et al., 2018). Similarly, in our previous study, we found that OC users demonstrate an increased BOLD signal in the inferior, middle, and superior frontal gyri as well as in the insula, lingual gyrus, and supplementary motor area during working memory processing for negatively arousing images compared to NC women (Sharma et al., 2020). ...
Millions of women worldwide use oral contraceptives (i.e., birth control pill; OCs), often starting during puberty/adolescence; however, it is unknown how OC use during this critical period of development affects the brain, especially with regard to emotional working memory. Here, we examined stress reactivity, and brain structure and function in OC users using the Trier Social Stress Test and structural and functional magnetic resonance imaging (MRI). Our results show that OC use during puberty/adolescence gives rise to a blunted stress response and alters brain activation during working memory processing. OC use, in general, is also linked to increased prefrontal brain activation during working memory processing for negatively arousing stimuli. OC use is also related to significant structural changes in brain regions implicated in memory and emotional processing. Together, these findings highlight that OC use induces changes to brain structure and function and alters stress reactivity. These findings may provide a mechanistic insight for the increased vulnerability to mood-related mental illness in women after OC use.
... One study reported differences in the specific areas of the brain activated during viewing of traumatic content based on contraceptive use [35]. These results likely indicate elevated fear responses in women using hormone-based contraceptives, a finding that is central to cognitive behavioural models of PTSD development. ...
... These results likely indicate elevated fear responses in women using hormone-based contraceptives, a finding that is central to cognitive behavioural models of PTSD development. A positive correlation was also found between oestradiol levels and activity in brain areas associated with PTSD in naturally cycling women [35]. Women with PTSD have further been found to experience reduced extension of extinction of fear response during the mid-luteal phase when levels of oestradiol and progesterone are at their highest compared to the early follicular phase, when concentrations of the same two hormones are low [36]. ...
Purpose of review:
Sex differences in PTSD are well-established with a 2:1 sex ratio favouring women. Less well-established is the basis of such differences. The purpose of this review is to explore recent research examining potential gender- and sex-based contributors to sex differences in PTSD.
Recent findings:
We identified 19 studies published since 2015. Masculinity is inconclusively associated with PTSD, but masculine ideals and masculine gender role stress are positively associated with PTSD. Among the sex-related factors, testosterone, oestradiol, progesterone, and ALLO/5α-progesterone ratio are believed to be involved in the development of PTSD. These factors likely affect PTSD risk directly and through epigenetic mechanisms. Findings suggest that gender and sex have multiple ways of affecting PTSD, including gender roles, genetic predisposition, and hormonal influences. These factors work together to put women at a particular risk of developing PTSD. By conducting more research, we may improve prediction, prevention, and treatment of PTSD.
... For example, in healthy women, lower salivary estradiol levels have been associated with greater intrusive memories following exposure to aversive affective content [42]. In addition, lower estradiol was associated with activity in limbic (i.e., amygdala, insula) and cingulate areas (e.g., dorsal anterior cingulate cortex), which amplify fear and stress-related responses [43], whereas higher estradiol was associated with increased activity in the ventromedial prefrontal cortex, which is implicated in effective emotion regulation, during aversive information processing [43]. Thus, changes in neural activity across the menstrual cycle are associated with changes in estradiol, and the combination might render women more susceptible to psychological distress, especially following normatively stressful or more serious adverse events. ...
... For example, in healthy women, lower salivary estradiol levels have been associated with greater intrusive memories following exposure to aversive affective content [42]. In addition, lower estradiol was associated with activity in limbic (i.e., amygdala, insula) and cingulate areas (e.g., dorsal anterior cingulate cortex), which amplify fear and stress-related responses [43], whereas higher estradiol was associated with increased activity in the ventromedial prefrontal cortex, which is implicated in effective emotion regulation, during aversive information processing [43]. Thus, changes in neural activity across the menstrual cycle are associated with changes in estradiol, and the combination might render women more susceptible to psychological distress, especially following normatively stressful or more serious adverse events. ...
The sex hormone estradiol, as measured through saliva, represents a non-invasive and cost-effective approach to understanding the influence of hormonal factors on physical and psychological well-being among women. Estradiol levels dramatically change at hormonal transitions, such as puberty, menopause, and postpartum. It is at these transitions where women are at increased risk for psychological and somatic distress. Salivary estradiol also has implications for decision-making and has been broadly associated with engagement in health-compromising behaviors which can influence women’s ability to cope with and manage chronic health conditions. This review summarizes the evidence for salivary estradiol as a marker of physical and psychological health, and discusses practical information regarding saliva collection and assay. The overall intent is to expand and clarify knowledge of the relation between changes in salivary estradiol and women’s health as well as to provide a means of integrating salivary estradiol into future behavioral medicine research.
... Both encoding and involuntary recall of intrusive memories were associated with inferior frontal cortex activity . Miedl et al. (2018) revealed enhanced neural threat processing (comprising dACC, amygdala, and AI) during viewing of aversive film clips relative to a neutral control condition, which was modulated by estradiol levels and hormonal contraception. Exploratory analyses showed that heightened rostral ACC, middle, and inferior frontal cortex activity during aversive film-viewing was associated with lower intrusion frequency three months after the experiment, suggesting regulatory frontal activity to attenuate long-term intrusion formation. ...
Background: Posttraumatic stress disorder and medically unexplained pain frequently co-occur. While pain is common during traumatic events, the processing of pain during trauma and its relation to audiovisual and pain intrusions is poorly understood.
Objective: Here we investigate neural activations during painful analogue trauma, focusing on areas that have been related to threat and pain processing, and how they predict intrusion formation. We also examine the moderating role of cumulative lifetime adversity.
Methods: Sixty-five healthy women were assessed using functional magnetic resonance imaging. An analogue trauma was induced by an adaptation of the trauma-film paradigm extended by painful electrical stimulation in a 2 (film: aversive, neutral) x 2 (pain: pain, no-pain) design, followed by 7-day audiovisual and pain intrusion assessment using event-based ecological momentary assessment. Intrusions were fitted with Bayesian multilevel regression and a hurdle lognormal distribution.
Results: Conjunction analysis confirmed a wide network including anterior insula (AI) and dorsal anterior cingulate cortex (dACC) being active both, during aversive films and pain. Pain resulted in activation in areas amongst posterior insula and deactivation in a network around ventromedial prefrontal cortex (VMPFC). Higher AI and dACC activity during aversive>neutral film predicted greater audiovisual intrusion probability over time and predicted greater audiovisual intrusion frequency particularly for participants with high lifetime adversity. Lower AI, dACC, hippocampus, and VMPFC activity during pain>no-pain predicted greater pain intrusion probability particularly for participants with high lifetime adversity. Weak regulatory VMPFC activation was associated with both increased audiovisual and pain intrusion frequency.
Conclusions: Enhanced AI and dACC processing during aversive films, poor pain vs. no-pain discrimination in AI and dACC, as well as weak regulatory VMPFC processing may be driving factors for intrusion formation, particularly in combination with high lifetime adversity. Results shed light on a potential path for the etiology of PTSD and medically unexplained pain.
... Both the anterior cingulate cortex (ACC) and the amygdala, at the core of this network, express steroid receptors (1,3), and have shown differential functionality depending on the hormonal status of the participant (20-22). ACC not only shows differences in activation across the menstrual cycle, but also has been reported to be thinner (23) and to increase its activation to emotional stimuli (24) in HC users compared to naturally cycling women. Likewise, amygdala structure (25) and response to emotional stimuli differs between naturally cycling women and HC users (26), and across the menstrual cycle (27,28). ...
Introduction
Hormonal contraceptives (HCs), nowadays one of the most used contraceptive methods, downregulate endogenous ovarian hormones, which have multiple plastic effects in the adult brain. HCs usually contain a synthetic estrogen, ethinyl-estradiol, and a synthetic progestin, which can be classified as androgenic or anti-androgenic, depending on their interaction with androgen receptors. Both the anterior cingulate cortex (ACC) and the amygdala express steroid receptors and have shown differential functionality depending on the hormonal status of the participant and the use of HC. In this work, we investigated for the first time the relationship between ACC and amygdala resting state functional connectivity (rs-FC) and HC use duration, while controlling for progestin androgenicity.
Methods
A total of 231 healthy young women participated in five different magnetic resonance imaging studies and were included in the final analysis. The relation between HC use duration and (i) gray matter volume, (ii) fractional amplitude of low-frequency fluctuations, and (iii) seed-based connectivity during resting state in the amygdalae and ACC was investigated in this large sample of women.
Results
In general, rs-FC of the amygdalae with frontal areas, and between the ACC and temporoparietal areas, decreased the longer the HC exposure and independently of the progestin’s androgenicity. The type of HC’s progestin did show a differential effect in the gray matter volume of left ACC and the connectivity between bilateral ACC and the right inferior frontal gyrus.
... El uso de ACH se asocia también con una actividad cerebral elevada en la corteza cingulada anterior dorsal y la ínsula, es decir, las regiones que típicamente se encuentran hiperactivas en el trastorno de estrés post traumático (Miedl, 2018). ...
Since the beginning of the commercialization, in 1960, of combined estrogen-progestin hormonal contraceptives (CHCs), their use has become widespread for other non-contraceptive indications: dysmenorrhea, irregular cycle length, hypermenorrhea and acne, among others (Lete, 2009; Barranco, 2016). In all cases, these are mild pathologies or minor symptoms for which there are effective therapeutic alternatives. Millions of women in the world receive this treatment, which acts by inhibiting the hypothalamic-pituitary-ovarian hormonal axis (HHO Axis), the central axis and regulator of the entire sexual and reproductive physiology of women. Despite the existence of an enormous number of women subjected to this inhibition (ACHs are currently used by some 214 million women around the world, with an annual market of close to 18 billion dollars), very little research has been done on the consequences of suppressing the HHO axis. Only in recent years, and in parallel to the demonstration of the existence of functional receptors for gonadotropins at different levels in the central and peripheral nervous systems, have publications on the neuropsychological effects of HCAs begun to appear. It is also striking that, despite being the most widely used drugs and for the longest time for the treatment of functional gynecological disorders, their use is outside the technical data sheet (i.e., they are used for purposes other than those listed in the official indication approved in their technical data sheet and which appear in the package insert). Although the use of these hormonal products causes a wide variety of side effects, which have been widely studied in the medical literature, the present study proposes, after an exposition of the different aspects of the use of HCAs, a detailed review of the available literature on the neuropsychological effects due to the annulment of the HHO axis. This in order to, after a biological analysis, subsequently establish whether there is an ethical appropriateness in the use that concerns us.
... This is a region of the brain known to play a role in emotion regulation, suggesting that these differences may play a role in some of the mood-related changes that can occur among women taking HCs. Indeed, research finds emotional processing differences between HC users non-users, with HC users exhibiting decreased memory of negative emotional stimuli (Person & Oinonenm, 2020), decreased amygdala activation in response to viewing negative emotional stimuli (Peteresen & Cahill, 2015), heightened insula and dorsal anterior cingulate cortex activity while viewing a traumatic film (Miedl et al., 2018), andin women with previous negative experiences with HCs lower reactivity in the left insula, left middle frontal gyrus, and bilateral inferior frontal gyri in response to emotional stimuli, when compared to NC women or those given an HC placebo (Gingnell et al., 2013). ...
Women’s psychological and behavioral responses to hormonal contraceptive (HC) treatment can be highly variable. One of the great challenges to researchers seeking to improve the experiences of women who use HCs is to identify the sources of this variability to minimize unpleasant psychobehavioral side-effects. In the following, we provide recommendations for programs of research aimed at identifying sources of heterogeneity in women’s experiences with HC. First, we review research demonstrating person- and prescription- based heterogeneity in women’s psychobehavioral responses to HCs. Next, we identify several promising person- and prescription- based sources of this heterogeneity that warrant future research. We close with a discussion of research approaches that are particularly well-suited to address the research questions raised in article. Together, this review provides researchers with several promising research pathways to help support the development of a precision medicine approach to HC treatment.
... all detected clusters remain significant, see in Supplementary Fig. S1 for comparison) and motion parameters were entered as regressors (see Statistical Analysis Section), all participants were kept in the analyses. The sample size was based on past, conceptually related behavioral and fMRI studies (Derntl et al. 2013;Hwang et al. 2015;Petersen and Cahill 2015;Radke and Derntl 2016;Merz et al. 2018;Miedl et al. 2018;Sharma et al. 2021). We aimed for a minimum group size of 30 to have sufficient statistical power to detect small-to-medium effect sizes. ...
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.
... All three of these retrospective studies showed significant and usage durationdependent effects of previous COC use: (i) the duration of previous COC treatment was positively related to gray matter volume in the hippocampus and the basal ganglia, while the time since discontinuation was negatively related to gray matter volume in the hippocampus but not in the basal ganglia ; (ii) ever users of COCs performed significantly better than never users in the domains of visuospatial ability and speed and flexibility, with duration-dependent increases in performance, especially in ever users with ≥ 15 years of use (Egan and Gleason, 2012); (iii) women with short-term use (≤5 years) of COCs had 26 % lower odds of having cognitive impairment compared with those who had never used COCs, whereas the association was not statistically significant (although it was 13 % lower) for those who used for more than 5 years (Song et al., 2020). Unfortunately, there is no information about the progestins used by all (Egan and Gleason, 2012;Song et al., 2020) or the majority of participants in these retrospective studies, as in many other studies that evaluated the effects of COCs on the brain structure,function and cognitive function of women (e.g., Beck et al., 2008;Chen et al., 2021;De Bondt et al., 2013, 2015Hamstra et al., 2014;Holloway et al., 2011;Kuhlmann and Wolf, 2005;McFadden, 2000;Miedl et al., 2018;Mihalik et al., 2009;Nielsen et al., 2011;Petersen et al., 2015b;Pletzer et al., 2010;Rosenberg and Park, 2002;Rumberg et al., 2010;Wen et al., 2021). Some studies provided information about the type of progestins but did not take this factor into consideration in data analyses (Gogos, 2013;Gravelsins et al., 2021;Hamstra et al., 2015;Høgsted et al., 2021;Kerschbaum et al., 2017;Kimmig et al., 2022;Lisofsky et al., 2016;Merz, 2017;Mordecai et al., 2008;Plamberger et al., 2021;Pletzer, 2019;Pletzer et al., 2014a;Sharma et al., 2020), and other studies combined data from participants using different types of HCs (COCs, minipills, IUDs, implants, vaginal rings, etc.) (e.g., Bernal et al., 2020;Nobile et al., 2021;Petersen et al., 2015a). ...
Progestins are an important component of hormonal contraceptives (HCs) and hormone replacement therapies (HRTs). Despite an increasing number of studies elucidating the effects of HCs and HRTs, little is known about the effects of different types of progestins included in these medications on the brain. Animal studies suggest that various progestins interact differently with sex steroid, mineralocorticoid and glucocorticoid receptors and have specific modulatory effects on neurotransmitter systems and on the expression of neuropeptides, suggesting differential impacts on cognition and behavior. This review focuses on the currently available knowledge from human behavioral and neuroimaging studies pooled with evidence from animal research regarding the effects of progestins on the brain. The reviewed information is highly relevant for improving women’s mental health and making informed choices regarding specific types of contraception or treatment.
... Also available treatment options such as exposure therapy might work differently under HC intake as already shown in women with anxiety disorders (Graham et al., 2018;Raeder et al., 2019). In light of first experimental studies on the influence of HCs on trauma processing (Miedl et al., 2018), an exploration of HC usage in the context of therapeutic interventions in posttraumatic stress disorder also seems highly needed. More generally, large-scaled and longitudinal clinical studies should be realized including HC intake, early childhood adversity with its known longlasting impact on mental health (Hakamata et al., 2022;Rudd et al., 2021) as well as comprehensive measures of different psychopathologies. ...
Men and women partially differ in how they respond to stress and how stress in return affects their cognition and emotion. The influence of hormonal contraceptives (HCs) on this interaction has received little attention, which is surprising given the prevalence of HC usage. This selective review illustrates how HC usage modulates the effects of stress hormones on cognition and emotion. As three examples, we discuss stress hormone effects on episodic memory, fear conditioning and cognitive emotion regulation. The identified studies revealed that stress effects on cognitive-emotional processes in women using HCs were at times reduced or even absent when compared to men or naturally cycling women. Especially striking were the few examples of reversed effects in HC women. As underlying neuroendocrine mechanisms, we discuss influences of HCs on the neuroendocrine stress response and effects of HCs on central glucocorticoid sensitivity. The summarized findings emphasize the need for additional translational research.
... Besides supporting contextualized memories by providing a spatial and temporal framework for relating experiences, the hippocampus has been involved in promoting danger from safety discrimination through pattern separation processes (Besnard and Sahay, 2016) and conditioned inhibition of threat responding (Meyer et al., 2019). Additionally, some studies have suggested that higher E2 inhibited negative emotional responding to threatening stimuli (Goldstein et al., 2010;Miedl et al., 2018). This potential stress-inhibiting effect of E2 is particularly important when considering evidence suggesting that fear spreads to a wider array of harmless stimuli when the threat (US) is more intense (Dunsmoor et al., 2017). ...
Intrusions, a key symptom of posttraumatic stress disorder (PTSD), can occur in the form of images but also as pain sensations. Similar to audiovisual intrusions, the frequency and persistence of pain intrusions varies greatly between individuals. In the current study, we examined whether peritraumatic circulating 17β-estradiol (E2) levels are a biologic factor associated with subsequent audiovisual (i.e., film) and pain intrusion development, and whether peritraumatic stress levels modulate this relationship.
Forty-one free-cycling women participated in an ecologically informed trauma-pain-conditioning (TPC) paradigm, using trauma-films and pain as unconditioned stimuli. Independent variables were salivary peritraumatic E2 levels and stress indexed by salivary cortisol and self-reported state-anxiety during TPC. Outcomes were film- and pain-intrusions occurring during daily-life in the week following TPC and a Memory-Triggering-Task in response to conditioned stimuli 24 h after TPC.
In the week after analogue-trauma, higher peritraumatic E2 levels were associated with a greater probability of experiencing film-intrusions in the beginning of the week, which switched to a lower probability toward the end of the week. This time-dependent relationship between E2 and film-intrusions only held for higher state-anxious women. In contrast, results indicated a consistent inverse relationship between peritraumatic E2 levels and pain-intrusions during daily-life and Memory-Triggering-Task. Together, these data suggest that higher peritraumatic E2 levels could be associated with lower long-term visual trauma intrusions, as well as lower pain-intrusions, and thereby possibly constitute a protective biologic factor for PTSD and potentially also for chronic pain.
... Resembling self-reported-pain CRs, NPS-pos and whole-brain differences to CS pain vs. CS nopain during acquisition only emerged within the neutral-film condition. A likely explanation for this is that the wide-spread neural activation associated with the highlyaversive film [64] masked the effects of the painful stimulation. In contrast, during MTT, participants showed greater NPS-pos responses to CS pain vs. CS nopain only within the aversivefilm condition 3 . ...
Psychological trauma is typically accompanied by physical pain, and posttraumatic stress disorder (PTSD) often co-occurs with chronic pain. Clinical reports suggest that pain after trauma may be part of a re-experiencing symptomatology. Classical conditioning can underlie visual re-experiencing since intrusions can occur as conditioned responses (CRs) to trauma-related cues. If individuals also experience pain to cues previously paired with, but not anymore inflicting nociceptive stimulation (CSs), conditioning could also explain re-experiencing of pain. Sixty-five participants underwent classical conditioning, where painful electrocutaneous stimulation and aversive film-clips served as unconditioned stimuli (USs) in a 2(pain/no pain)×2(aversive/neutral film) design. CSs were neutral pictures depicting contextual details from the films. One day later, participants were re-exposed to CSs during a memory-triggering-task (MTT). We assessed pain-CRs by self-report and an fMRI-based marker of nociceptive pain, the neurologic pain signature (NPS); and recorded spontaneous daily-life pain-intrusions with an e-diary. During conditioning, pain-signaling CSs elicited more self-reported-pain and NPS-responses than no-pain-signaling CSs. Possibly because the aversive-film masked differences in participants' responses to pain-signaling vs. no-pain-signaling CSs, pain-CRs during acquisition only emerged within the neutral-film condition. When participants were re-exposed to CSs during MTT, self-reported-pain-CRs during the neutral-film condition and, though more uncertain, NPS-CRs during the aversive-film condition persisted. Importantly, participants with stronger pain-CRs showed a greater probability and severity of experiencing spontaneous pain intrusions during daily-life. Our data support that pain can emerge as a CR with emotional and sensory components. Classical conditioning presents a possible mechanism explaining pain-intrusions, and more broadly, pain experienced without nociceptive input.
... Based on these results and our prior studies, we speculate that the differential impact of exogenous estrogen administration on the two subgroups (OC and NC) observed here is likely due to the chronic use of OC and its impact on the brain. This speculative interpretation is consistent with studies showing that the use of OC changes brain structures and FC underlying affective and cognitive processing [80,81], both during rest [68,82] and during tasks [79,83]. There is also evidence that the use of OC is associated with mental health outcomes [81,84,85], though these findings have not been consistently reported [86]. ...
Fluctuations of endogenous estrogen modulates fear extinction, but the influence of exogenous estradiol is less studied. Moreover, little focus has been placed on the impact of estradiol on broad network connectivity beyond the fear extinction circuit. Here, we examined the effect of acute exogenous estradiol administration on fear extinction-induced brain activation, whole-brain functional connectivity (FC) during the fear extinction task and post-extinction resting-state. Ninety healthy women (57 using oral contraceptives [OC], 33 naturally cycling [NC]) were fear conditioned on day 1. They ingested an estradiol or placebo pill prior to extinction learning on day 2 (double-blind design). Extinction memory was assessed on day 3. Task-based functional MRI data were ascertained on days 2 and 3 and resting-state data were collected post-extinction on day 2 and pre-recall on day 3. Estradiol administration significantly modulated the neural signature associated with fear extinction learning and memory, consistent with prior studies. Importantly, estradiol administration induced significant changes in FC within multiple networks, including the default mode and somatomotor networks during extinction learning, post-extinction, and during extinction memory recall. Exploratory analyses revealed that estradiol impacted ventromedial prefrontal cortex (vmPFC) activation and FC differently in the NC and OC women. The data implicate a more diffused and significant effect of acute estradiol administration on multiple networks. Such an effect might be beneficial to modulating attention and conscious processes in addition to engaging neural processes associated with emotional learning and memory consolidation.
... Thus, higher E2 might enhance the consolidation of precise memories through its actions on hippocampal functioning. Additionally, some studies have suggested that higher E2 inhibited negative emotional responding to threatening stimuli (Goldstein et al., 2005Miedl et al., 2018). This potential stress-inhibiting effect of E2 is particularly important when considering evidence suggesting that fear spreads to a wider array of harmless stimuli when the threat (US) is more intense (Dunsmoor, Kroes, et al., 2017). ...
Intrusions, a key symptom of posttraumatic stress disorder (PTSD), can occur as classically conditioned responses to trauma-related cues, both in the form of images and pain sensations. Women are more vulnerable to experiencing intrusions, and gonadal hormones may underlie this sex difference. Yet so far, particularly estradiol's influence on intrusions is unclear, as PTSD-symptom studies suggesting a vulnerable window for intrusions during the high estradiol-progesterone phase diverge from fear-conditioning studies suggesting a protective role of estradiol. Here, we aim to address this discrepancy and examine the effects of estradiol on intrusions while also considering stress as potential moderator. Forty free-cycling women participated in an ecologically informed trauma-pain-conditioning (TPC) paradigm, using trauma-films and pain as unconditioned stimuli. Predictors were salivary estradiol and stress indexed by salivary cortisol and self-reported state-anxiety during TPC. Outcomes were film-and pain-intrusions occurring during daily-life in the week following TPC and a memory-triggering-task in response to conditioned stimuli 24h after TPC. Estradiol yielded time-and stress-dependent effects on film-intrusions during daily-life: women with higher estradiol showed initially greater probability of experiencing film-intrusions, switching to lower probability toward the end of the week. This late protective effect of estradiol on film-intrusions only held for higher state-anxious women. In contrast, estradiol showed consistent protective effects on pain-intrusions during daily-life and memory-triggering-task. Together, these data suggest that high estradiol during trauma may shield women from long-term audiovisual trauma intrusions, as well as from pain-intrusions, and thereby possibly constitute a protective factor for PTSD and potentially also for chronic pain. ESTRADIOL, STRESS, AND INTRUSIVE MEMORIES 3
... Included in the functional studies was a randomized controlled trial (Merz et al., 2012) which found that women on oral contraceptives had enhanced fear learning when exposed to cortisol and electrical stimulation, perhaps resulting in increased anxiety in women taking hormonal contraceptives. Cognitive and emotional processes potentially underlying PTSD (post-traumatic stress disorder) symptoms were found to be heightened by hormonal contraception in the insula and dorsal anterior cingulate cortex (both involved in the fear processing network of the brain) during traumatic film viewing (Miedl et al., 2018). Hormonal contraception has also been found to interfere with oxytocin, a peptide and key modulator of pair-bonding in men and women. ...
In the past decade, two large prospective cohort studies of British and American women have been conducted which found a statistically significant increase in the risk of violent death in ever-users of hormonal contraceptives. Research on the effects of hormonal contraceptives upon the behaviors of intimate partners and on the physiology of women using hormonal contraceptives has provided insight into the possible basis for the resulting increase in violent death. This review examines the changes that are potential contributors to the reported increase.
... Nonetheless, there is evidence that estrogen receptors are expressed strongly in brain regions involved in social cognition broadly and social rejection specifically, including the amygdala, hippocampus, ACC, and vmPFC [55][56][57][58]. Several studies have also found that women with comparably higher levels of estradiol (endogenous or synthetic) show greater amygdala-based restingstate functional connectivity and activation in ACC and vmPFC, which are key regions involved in processing salient information [59][60][61]. Similarly, longitudinal studies with naturally cycling women have documented larger hippocampal gray matter volumes during periods of relatively high estradiol (late follicular/preovulatory phases) than of relatively low estradiol early follicular/premenstrual phases [62,63]. ...
Suicide is the second leading cause of death among adolescents. While clinicians and researchers have begun to recognize the importance of considering multidimensional factors in understanding risk for suicidal thoughts and behaviors (STBs) during this developmental period, the role of puberty has been largely ignored. In this review, we contend that the hormonal events that occur during puberty have significant effects on the organization and development of brain systems implicated in the regulation of social stressors, including amygdala, hippocampus, striatum, medial prefrontal cortex, orbitofrontal cortex, and anterior cingulate cortex. Guided by previous experimental work in adults, we also propose that the influence of pubertal hormones and social stressors on neural systems related to risk for STBs is especially critical to consider in adolescents with a neurobiological sensitivity to hormonal changes. Furthermore, facets of the pubertal transition, such as pubertal timing, warrant deeper investigation and may help us gain a more comprehensive understanding of sex differences in the neurobiological and psychosocial mechanisms underlying adolescent STBs. Ultimately, advancing our understanding of the pubertal processes that contribute to suicide risk will improve early detection and facilitate the development of more effective, sex-specific, psychiatric interventions for adolescents.
... Resembling self-reported-pain CRs, NPS-pos and whole-brain differences to CS pain vs. CS nopain during acquisition only emerged within the neutral-film condition. A likely explanation for this is that the wide-spread neural activation associated with the highlyaversive film [64] masked the effects of the painful stimulation. In contrast, during MTT, participants showed greater NPS-pos responses to CS pain vs. CS nopain only within the aversivefilm condition 3 . ...
Psychological trauma is typically accompanied by physical pain, and posttraumatic stress disorder (PTSD) often co-occurs with chronic pain. Clinical reports suggest that pain in the aftermath of trauma may be part of a re-experiencing symptomatology. Previously, we demonstrated that classical conditioning can underlie visual re-experiencing since intrusions appear to occur as conditioned responses (CRs) to trauma-related cues. Possibly, classical conditioning also plays a role in re-experiencing of pain. However, this hypothesis has so far remained untested. Sixty-five participants underwent classical conditioning, where painful electrical stimulation and highly aversive film-clips served as unconditioned stimuli (USs) in a 2 (pain/no pain) x 2 (aversive/neutral film) design. Conditioned stimuli (CSs) were neutral pictures depicting contextual details from the films. One day later, participants were re-exposed to CSs during a memory-triggering-task (MTT). Pain-CRs were assessed by self-report and an fMRI-based marker of nociceptive pain, the neurologic pain signature (NPS).During conditioning, pain-signaling CSs elicited more self-reported pain and NPS responses than no-pain-signaling CSs. Self-reported pain-CRs but not NPS CRs recurred 24h later when participants were re-exposed to CSs during MTT. Both during acquisition and MTT, the aversive affective film-context blurred the difference in participants´ pain-reports to pain-signaling and no-pain-signaling CSs.Our data support the hypothesis that pain can emerge as a classically conditioned response. Pain as a CR to pain-signaling cues could represent an instance of pain re-experiencing in PTSD. Possibly, this mechanism may perpetuate pain beyond tissue healing and thereby explain the comorbidity between chronic pain and PTSD.
... An fMRI "traumatic" film viewing paradigm was utilized by Miedl et al. (2018) to assess the effects of endogenous estradiol and synthetic sex hormones on the neural processing of trauma exposure using films depicting severe interpersonal violence vs. neutral films in NC and HC-using women. The HC group showed increased insula and dorsal ACC activity relative to NC women upon viewing traumatic films. ...
Background: Hormonal contraceptive drugs are being used by adult and adolescent women all over the world. Convergent evidence from animal research indicates that contraceptive substances can alter both structure and function of the brain, yet such effects are not part of the public discourse or clinical decision-making concerning these drugs. We thus conducted a systematic review of the neuroimaging literature to assess the current evidence of hormonal contraceptive influence on the human brain.
Methods: The review was registered in PROSPERO and conducted in accordance with the PRISMA criteria for systematic reviews. Structural and functional neuroimaging studies concerning the use of hormonal contraceptives, indexed in Embase, PubMed and/or PsycINFO until February 2020 were included, following a comprehensive and systematic search based on predetermined selection criteria.
Results: A total of 33 articles met the inclusion criteria. Ten of these were structural studies, while 23 were functional investigations. Only one study investigated effects on an adolescent sample. The quality of the articles varied as many had methodological challenges as well as partially unfounded theoretical claims. However, most of the included neuroimaging studies found functional and/or structural brain changes associated with the use of hormonal contraceptives.
Conclusion: The included studies identified structural and functional changes in areas involved in affective and cognitive processing, such as the amygdala, hippocampus, prefrontal cortex and cingulate gyrus. However, only one study reported primary research on a purely adolescent sample. Thus, there is a need for further investigation of the implications of these findings, especially with regard to adolescent girls.
... In contrast, a recent meta-analysis (29) showed no consistent amygdala involvement and hippocampus deactivations during fear acquisition, which could be related to differences in the designs relative to our conditioning study. While fMRI trauma-film studies consistently demonstrated amygdala and hippocampus activity (25)(26)(27)42), the present design combined trauma-films as US with classical fear conditioning, where participants probably transferred emotional responding to the complex trauma-films to the CS+, which might be less pronounced and/or qualitatively different in designs using e.g. electric shock as US. ...
Background:
Deficient extinction learning has been suggested as an important mechanism involved in the etiology of posttraumatic stress disorder (PTSD). A key feature of PTSD, re-experiencing the trauma in form of intrusions, may be linked to deficient extinction learning. This link is investigated in a novel, fMRI-compatible fear conditioning procedure that uses trauma-films. Based on previous results, we expected deficient fear extinction indexed by exaggerated responding in anterior insula and dorsal anterior cingulate cortex (dACC) to predict subsequent intrusions.
Methods:
Fifty-eight healthy participants underwent acquisition and extinction learning with faces as conditioned stimuli (CS) and highly aversive 16-sec films depicting interpersonal violence as unconditioned stimuli (US). During three subsequent days, participants reported intrusive memories on their smartphone.
Results:
Successful fear acquisition was evidenced by differential (CS+>CS-) activity of a widespread network including anterior insula and dACC whereas extinction was characterized exclusively by differential anterior insula activity. Differential conditioned responding during late extinction in anterior insula and dACC was positively related to intrusive memory frequency independently of US responding. Exploratory analysis additionally revealed intrusion sensitivity of hippocampus, rostral anterior cingulate cortex and ventromedial prefrontal cortex amongst others.
Conclusions:
Results support the role of extinction learning in intrusive memory formation: a failure to uncouple conditioned emotional responding from external threat cues was associated with subsequent intrusive memories, representing a potential risk marker for developing PTSD-symptomatology after trauma.
... Several investigations indicate that oral contraceptive use is related to altered brain activity and connectivity in many brain areas, known to regulate emotional behavior (Engman et al., 2018;Gingnell et al., 2013;Lisofsky et al., 2016;Miedl et al., 2018;Petersen and Cahill, 2015;Petersen et al., 2014;Pletzer et al., 2016Pletzer et al., , 2015. However, whereas there is quite consistent evidence that hormonal contraceptive use can alter brain reactivity, activity, and connectivity, results concerning COC effects on emotion recognition and emotional memory are limited and mixed. ...
Combined oral contraceptive (COC) use is associated with small, albeit significant, increases in mental symptom scores, predominantly irritability, depressed mood, and anxiety. Yet, randomized prospective trials are needed to better characterize the women at risk for COC-induced negative mood change. Thus, the primary aim of this sub-study to a placebo-controlled randomized trial was to determine whether COC use influences emotional interference by negative and positive stimuli. Secondly, we wanted to evaluate what factors would predict depressive symptoms at the end of the trial, taking personality factors, history of mental disorders and other demographic factors into account. Sixty-nine women were included, randomized to three cycles of treatment with a COC (1.5 mg estradiol and 2.5 mg nomegestrolacetate) or placebo. An emotional verbal Stroop task was used to measure interference of emotional stimuli, in which participants were asked to only name the color of a presented word, while ignoring the meaning of the word. Four different word categories were used; neutral, positive, depression, and anxiety. For the second aim of the study, rating on the Montgomery-Åsberg Depression Rating Scale during the final days of the trial was used as outcome. We found no interaction between emotional verbal Stroop word category and treatment, indicating that COC treatment did not evoke any differences in emotional interference to the three word categories. Significant predictors for depressive symptoms at the end of the trial were trait anxiety at baseline and prior adverse mood effects by hormonal contraceptive use. Treatment (i.e. whether women had been treated with the COC or placebo) did not play a role in predicting depression scores at the end of the trial. In conclusion, we found no evidence that combined oral contraceptive use is associated with impaired cognitive-emotional processing. Instead, the main predictors of self-rated depression at the end of the trial were baseline trait anxiety and previous mental symptoms during hormonal contraceptive use.
... As a control condition (CC) the CS− was followed by neutral film clips (matched to the traumatic film clips for the number of people interacting with each other and film quality). All film clips were generated from different commercial feature films (supplementary Information) and some have been employed in previous studies 26,33 . ...
Cortisol is a stress hormone and potent modulator of learning and memory processes. If administered after learning, cortisol can enhance memory consolidation. Yet it is unknown whether cortisol administration after fear extinction learning strengthens extinction memory. Extinction is a crucial mechanism underlying psychotherapy of posttraumatic stress disorder (PTSD). The present study examined whether extinction can be enhanced by administering cortisol after extinction training. In a registered, randomized, double-blind and placebo controlled trial, 50 healthy participants were exposed to a differential fear-conditioning paradigm with neutral faces as conditioned stimuli (CS) and traumatic film clips as unconditioned stimuli (US). They received either cortisol (n = 25) or placebo (n = 25) immediately after extinction. The cortisol group showed less fear during a return of fear manipulation (reinstatement) evidenced by attenuated fear potentiated startle responses and US-expectancy ratings than the placebo group. Results indicate that cortisol administration after fear extinction strengthens extinction memory and suggest that it might be advantageous to administer cortisol subsequent to successful exposure treatment sessions.
... On the other hand, levels of progesterone, a precursor of most neurosteroids did not correlate with fear response, in contrast to estradiol, which was negatively correlated to PTSD-predispositions and fear response [135]. Interestingly, in healthy women, using contraception compared to those who did not, levels of estradiol was positively correlated to ventromedial prefrontal activity and they were more predisposed to overreact to traumatic film paradigm [136]. ...
Recent progress in the field of neurobiology supported by clinical evidence gradually reveals the mystery of human brain functioning. So far, many psychiatric disorders have been described in great detail, although there are still plenty of cases that are misunderstood. These include posttraumatic stress disorder (PTSD), which is a unique disease that combines a wide range of neurobiological changes, which involve disturbances of the hypothalamic–pituitary–adrenal gland axis, hyperactivation of the amygdala complex, and attenuation of some hippocampal and cortical functions. Such multiplicity results in differential symptomatology, including elevated anxiety, nightmares, fear retrieval episodes that may trigger delusions and hallucinations, sleep disturbances, and many others that strongly interfere with the quality of the patient's life. Because of widespread neurological changes and the disease manifestation, the pharmacotherapy of PTSD remains unclear and requires a multidimensional approach and involvement of polypharmacotherapy. Hopefully, more and more neuroscientists and clinicians will study PTSD, which will provide us with new information that would possibly accelerate establishment of well-tolerated and effective pharmacotherapy. In this review, we have focused on neurobiological changes regarding PTSD, addressing the most disturbed brain structures and neurotransmissions, as well as discussing in detail the recently taken and novel therapeutic paths.
... When considering the present findings, some limitations should be considered. First, Miedl, Wegerer, Kerschbaum, Blechert, and Wilhelm (2018) showed that in women low levels M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT SEX DIFFERENCES IN REACTION TO ANALOG TRAUMA 28 of estradiol as well as oral contraceptive use are associated with elevated neural fear network responding to trauma films, with initial evidence also pointing to a relationship with long-term intrusions (see also Merz, Kinner, & Wolf, 2018). Thus, as the present study did not control for menstrual cycle phase or oral contraceptive use, we cannot be sure if the here demonstrated peritraumatic risk factors will generalize to all gonadal hormone status subgroups of women (different cycle phases, oral contraceptive use). ...
Higher prevalence of posttraumatic stress disorder (PTSD) in women than men may be explained by sex differences in fear learning processes. Initial evidence points to elevated unconditioned and conditioned fear responding as well as to elevated state anxiety in women as potential peritraumatic mechanisms. Using the “conditioned-intrusion-paradigm” which combines differential fear conditioning with the trauma-film paradigm, neutral sounds were presented as predictors of the occurrence (CS+) or non-occurrence (CS-) of highly aversive films. Intrusions were elicited by these sounds in the laboratory after conditioning and naturalistic intrusions were assessed in daily-life on subsequent days. Compared to men (n = 62), women (n = 60) reported more intrusions and associated distress following analogue trauma. Sex differences in intrusive symptoms were mediated by a) higher unconditioned trauma responding, b) slowed extinction of differential CS valence ratings, and c) elevated state anxiety increase across conditioning in women. Secondary analyses revealed that state anxiety was the strongest mediator, followed by slowed extinction learning. Mediation models were unrelated to sex differences in trait anxiety or depressive symptoms. Thus, associative (extinction learning) and non-associative (state anxiety, trauma responding) mechanisms contribute to sex differences in intrusive symptoms after analogue trauma and might add to the heightened vulnerability to PTSD in women.
... Hippocampal hyperactivity plays a critical role in perceptual processing/ encoding of arousing autobiographical memories (69), as well as their consolidation (58). As increased arousal and unpleasantness of aversive films have recently been linked to higher hippocampal activity (70), hippocampal hyperactivity may have induced increased memory formation or consolidation of trauma films, increasing subsequent recollections especially in participants with high lifetime adversity. In addition, increased hippocampal activity has also been linked to increased mental integration as well as autobiographical memory retrieval (69), with both processes playing a role in intrusive memory formation. ...
Background:
Pathological peritraumatic encoding is proposed as a proximal risk factor for the development of posttraumatic stress disorder (PTSD), with trauma-analog studies linking increased neural processing of trauma films to intrusive trauma recollections, a core symptom of PTSD. Cumulative lifetime adversity is proposed as a more distal risk factor, with research indicating a tipping point at about five events with regard to PTSD development following re-exposure to trauma. Thus, within a diathesis × stress framework, increased peritraumatic neural processing may constitute a specific risk factor for PTSD, particularly in individuals with several lifetime adversities.
Methods:
Fifty-three healthy women watched highly aversive films depicting severe interpersonal violence versus neutral films during functional magnetic resonance imaging, and they reported involuntary recollections during subsequent days. Moderation analyses tested the interactive relationship between peritraumatic neural processing and lifetime adversity in predicting intrusion load, i.e., the total number of intrusions weighted for their average distress.
Results:
Increased processing of aversive versus neutral films in the amygdala, anterior insula, dorsal and rostral anterior cingulate cortices, and hippocampus predicted increased intrusion load only in participants reporting above five lifetime adversities; for participants reporting few to none, no such relationship was found. This interactive relationship explained ≤59% of variance. Conditioned stimuli preceding film viewing mirrored this pattern.
Conclusions:
Peritraumatic neural processing in multiple salience network regions and cumulative lifetime adversity interactively predicted PTSD-like symptomatology, representing a diathesis × stress framework that might guide identification of at-risk individuals and potential targets for symptom prevention after traumatic incidents.
... Second, women at risk for postpartum depression were randomly assigned to receive either depot medroxyprogesterone acetate (DMPA) or an intrauterine device; those who received DMPA showed greater postnatal depression (6). Neuroimaging studies have shown alterations in brain structure and function associated with hormonal contraceptive use, with thinning in the lateral orbital frontal cortex and posterior cingulate (7), heightened insula and dorsal anterior cingulate cortex activation during the viewing of a traumatic film (8), and alterations in restingstate connectivity (9). However, in one elegant randomized study, women who had previously experienced affective symptoms while on hormonal contraceptives were studied in the follicular phase and then randomly assigned to receive either placebo or 30 mg of ethinyl estradiol/0.15 ...
... For analyses of a-priori hypothesized brain regions, the threshold was set to p < .05 corrected for multiple comparisons (based on the familywise error rate) using reduced search volumes (small volume correction (svc) option within SPM; similar to previous work, Miedl, Büchel, & Peters, 2014;Miedl, Wegerer, Kerschbaum, Blechert, & Wilhelm, 2018). We performed correction for multiple comparisons using spherical search volumes centered at bilateralized peak voxels for the ventral striatum (±12, 10, −8) derived from 671 imaging studies on "reward", as well as bilateralized peak voxels for the dlPFC (±32, 32, 10) derived from 707 imaging studies on "suppression or regulation or craving" as determined by a meta-analysis conducted on the neurosynth.org ...
Hormonal contraceptives have given women historic freedoms and control over their fertility. At the same time, the potential side effects and unintended consequences of hormonal contraceptive use remain unclear due to a severe lack of funding and research. In this review, we summarize what is currently known about the impact of hormonal contraceptive use on mood symptoms, depression, and premenstrual disorders, and propose using the Social Signal Transduction Theory of Depression as a framework to generate predictions about the mechanistic pathways through which contraceptive use is associated with depression risk. The highest-quality evidence suggests that some types of contraceptives increase depression risk for some women. However, some contraceptives also appear to decrease depression risk in some instances. Key risk factors that predict depression following hormonal contraceptive use include age/age at onset of contraceptive use and mental health history/susceptibility. Hormonal contraceptives differ in ways that influence mood-related outcomes and can be used to treat depression in some women, especially those whose depression symptoms fluctuate across the cycle, indicating the potential presence of a premenstrual disorder. Looking forward, research, and funding for this research, is needed to elucidate the mechanistic pathways through which the use of different contraceptives impacts mood in different women to allow for a precision medicine approach to contraceptive treatment. In the meantime, health care providers should adopt patient-centered, “mindful prescribing” approaches to contraceptive counseling.
Despite the well-known influence of ovarian hormones on the brain and widespread use of hormonal contraception (HC) since the 1960s, our knowledge of HC's cognitive effects remains limited. To date, the cognitive findings have been inconsistent. In order to establish what might make HC studies more consistent, we surveyed the literature on HCs and cognition to determine whether studies considered HC formulation, phase, pharmacokinetics, duration, and gene interactions, and assessed whether oversight of these factors might contribute to variable findings. We found that synthetic HC hormones exert dose-dependent effects, the day of oral contraceptive (Pill) ingestion is critical for understanding cognitive changes, and gene-cognition relationships differ in women taking the Pill likely due to suppressed endogenous hormones. When these factors were overlooked, results were not consistent. We close with recommendations for research more likely to yield consistent findings and be therefore, translatable.
In this review we systematically summarize the effects of progesterone and synthetic progestins on neurogenesis, synaptogenesis, myelination and six neurotransmitter systems. Several parallels between progesterone and older generation progestin actions emerged, suggesting actions via progesterone receptors. However, existing results suggest a general lack of knowledge regarding the effects of currently used progestins in hormonal contraception regarding these cellular and molecular brain parameters. Human neuroimaging studies were reviewed with a focus on randomized placebo-controlled trials and cross-sectional studies controlling for progestin type. The prefrontal cortex, amygdala, salience network and hippocampus were identified as regions of interest for future preclinical studies. This review proposes a series of experiments to elucidate the cellular and molecular actions of contraceptive progestins in these areas and link these actions to behavioral markers of emotional and cognitive functioning. Emotional effects of contraceptive progestins appear to be related to 1) alterations in the serotonergic system, 2) direct/indirect modulations of inhibitory GABA-ergic signalling via effects on the allopregnanolone content of the brain, which differ between androgenic and anti-androgenic progestins. Cognitive effects of combined oral contraceptives appear to depend on the ethinylestradiol dose.
Hormonal contraception has been widely prescribed for decades. Although safety and efficacy are well-established, much uncertainty remains regarding brain effects of hormonal contraception. We systematically review human and animal studies on the brain effects of hormonal contraception which employed neuroimaging techniques such as MRI, PET and EEG, as well as animal studies which reported on neurotransmitter and other brain biochemical effects. We screened 1001 articles and ultimately extracted data from 70, comprising 51 human and 19 animal studies. Of note, there were no animal studies which employed structural or functional MRI, MRS or PET. In summary, our review shows hormonal contraceptive associations with changes in the brain have been documented. Many questions remain and more studies are needed to describe the effects of hormonal contraception on the brain.
Exposure therapy is a central component of the first-line treatment for anxiety disorders, a common mental health condition that is twice as prevalent in women relative to men. A key underlying mechanism of exposure therapy is fear extinction, which is an active learning process supported by a neural circuitry that is highly regulated by ovarian hormones. This review synthesises research examining the impact of hormonal contraceptives on laboratory fear extinction tasks in female rats and women, and on exposure therapy in women with anxiety disorders. The evidence indicates that hormonal contraceptives have a detrimental impact on fear extinction and exposure therapy that is consistent across species, and from laboratory to clinical settings. Candidate pathways by which hormonal contraceptives impede fear extinction and exposure therapy include suppression of endogenous ovarian hormones and glucocorticoids, and downregulation of signalling pathways that support extinction learning. Key areas of focus for future research are discussed.
Emotion processing is known to interact with memory. Ovarian steroid hormones, such as progesterone and estradiol, modulate emotion processing and memory. However, it is unclear how these hormones influence brain activity when emotion processing is integrated with working memory (WM). Therefore, the objective of this study was to examine the relationship between endogenous hormonal concentration and brain activity during emotion processing in the context of a WM n-back task in 74 young women using functional magnetic resonance imaging (fMRI). Results show that positive emotion processing activates reward-related areas, such as the caudate and putamen, whereas negative emotion processing activates a corticolimbic network, including the amygdala and hippocampus. Furthermore, our findings provide evidence that progesterone modulates more bottom-up brain activation during both positive and negative emotion processing, whereas estradiol activates lateralized, top-down regulation. These findings provide insight on the neural correlates of emotion processing during an n-back task in young women and highlight how important it is to consider women’s endogenous hormonal concentration in neurobiological and cognition research.
This study found that OC use is related to brain activity differences following an emotional picture n-back task. OC users show more frontal and insular activity during working memory processing for negative pictures compared to non-OC users. Women who began using OCs during puberty show more regional brain activation during working memory processing for neutral images compared to women who began using OCs after the age of 18.
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.
Summary
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.
Women are twice as likely than men to suffer from posttraumatic stress disorder (PTSD). While women have increased exposure to traumatic events of many types and have greater prevalence of comorbid psychiatric disorders compared to men, these differences do not account for the overall sex difference in the prevalence of PTSD. The current review summarizes significant findings that implicate the role of estradiol, progesterone, and allopregnanolone in female risk for PTSD symptoms and dysregulation of fear psychophysiology that is cardinal to PTSD. We also discuss how these steroid hormones influence the stress axis and neural substrates critical for the regulation of fear responses. Understanding the role of ovarian steroid hormones in risk and resilience for trauma-related adverse mental health outcomes across the lifespan in women has important translational, clinical, and intergenerational implications for mitigating the consequences of trauma exposure.
Background
The combined oral contraceptive pill (OC), containing synthetic estrogens and progestins, is used by millions of women worldwide, yet little is known about its effects on cognition or on psychiatric disorders. The progestin component of OCs determines their androgenicity, i.e. whether the OC has androgen binding components with masculinising effects or antiandrogenic components with feminising effects.
Objective
The present review discusses the literature surrounding OC use and cognition in healthy women. Given the important role that sex hormones play in psychiatric disorders, we also consider the influence of OCs on symptoms of schizophrenia, post-traumatic stress disorder, depression, bipolar disorder, anxiety disorders and indirectly, sleep quality.
Results
Research has shown that while there are no differences between OC users and non-users, androgenic OCs enhance visuospatial ability and anti-androgenic OCs enhance verbal fluency. Little is known about OCs effects on other cognitive domains, such as memory and executive function. There is little research examining OC use in schizophrenia, post-traumatic stress disorder, bipolar disorder and anxiety disorders. There is some evidence that OC use is associated with depression, however the exact causality of this association remains to be verified.
Conclusion
We maintain that future studies need to address several methodological limitations, such as separating OCs based on androgenicity to avoid the masking effects that occur when various OCs are considered as one group. As this review highlights several significant effects of OC use on the brain, the implications of OC use needs to be considered in future research.
Background
Neurobiological models of posttraumatic stress disorder (PTSD) implicate fear processing impairments in the maintenance of the disorder. Specific deficits in extinction recall, the retention of learned extinction, have been demonstrated. While deficient extinction recall, and the associated activation pattern of prefrontal and hippocampal regions, distinguishes individuals with PTSD from controls, research has not yet examined changes following treatment. We examined the behavioral and neural correlates of extinction recall before and after cognitive behavioral treatment of PTSD.
Methods
Fifty-eight participants (30 with PTSD, 28 trauma-exposed matched controls) underwent a 2-day behavioral fear conditioning, extinction, and recall paradigm during functional magnetic resonance imaging (fMRI). The same procedures were repeated 10 weeks later, after PTSD patients had completed prolonged exposure treatment. We analyzed fMRI data from 32 subjects (16 PTSD; 16 controls) and skin conductance response (SCR) data from 33 subjects (16 PTSD; 17 controls). Neural activity during extinction recall, SCR, and PTSD symptoms were compared across groups and over time.
Results
PTSD patients exhibited pre- to post-treatment reduction in rostral anterior cingulate cortex (rACC) activation during extinction recall, and increase in functional coherence between the rACC and the ventromedial prefrontal cortex (vmPFC) and subgenual anterior cingulate cortex (sgACC). Reduced PTSD symptom severity from pre- to post-treatment was significantly associated with reduced subgenual ACC and parahippocampal activation during this task. SCR during the extinction recall phase did not significantly change with treatment in the PTSD group, but change in SCR was associated with reduction in PTSD symptom severity.
Conclusions
Prolonged exposure treatment appears to alter neural activation in PTSD patients during recall of fear extinction, and change in extinction recall (measured by SCR) is associated with symptom reduction. We discuss results in the context of neural systems involved in response to affective stimuli.
Although intrusive memories are characteristic of many psychological disorders, the neurobiological underpinning of these involuntary recollections are largely unknown. In this study we used functional magentic resonance imaging (fMRI) to identify the neural networks associated with encoding of negative stimuli that are subsequently experienced as intrusive memories. Healthy partipants (N = 42) viewed negative and neutral images during a visual/verbal processing task in an fMRI context. Two days later they were assessed on the Impact of Event Scale for occurrence of intrusive memories of the encoded images. A sub-group of participants who reported significant intrusions (n = 13) demonstrated stronger activation in the amygdala, bilateral ACC and parahippocampal gyrus during verbal encoding relative to a group who reported no intrusions (n = 13). Within-group analyses also revealed that the high intrusion group showed greater activity in the dorsomedial (dmPFC) and dorsolateral prefrontal cortex (dlPFC), inferior frontal gyrus and occipital regions during negative verbal processing compared to neutral verbal processing. These results do not accord with models of intrusions that emphasise visual processing of information at encoding but are consistent with models that highlight the role of inhibitory and suppression processes in the formation of subsequent intrusive memories.
Background:
Although numerous studies have investigated the neurobiology and neuroendocrinology of posttraumatic stress disorder (PTSD) after single finished trauma, studies on PTSD under ongoing threat are scarce and it is still unclear whether these individuals present similar abnormalities.
Objective:
The purpose of this review is to present the neurobiological and neuroendocrine findings on PTSD under ongoing threat. Ongoing threat considerably affects PTSD severity and treatment response and thus disentangling its neurobiological and neuroendocrine differences from PTSD after finished trauma could provide useful information for treatment.
Method:
Eighteen studies that examined brain functioning and cortisol levels in relation to PTSD in individuals exposed to intimate partner violence, police officers, and fire fighters were included.
Results:
Hippocampal volume was decreased in PTSD under ongoing threat, although not consistently associated with symptom severity. The neuroimaging studies revealed that PTSD under ongoing threat was not characterized by reduced volume of amygdala or parahippocampal gyrus. The neurocircuitry model of PTSD after finished trauma with hyperactivation of amygdala and hypoactivation of prefrontal cortex and hippocampus was also confirmed in PTSD under ongoing threat. The neuroendocrine findings were inconsistent, revealing increased, decreased, or no association between cortisol levels and PTSD under ongoing threat.
Conclusions:
Although PTSD under ongoing threat is characterized by abnormal neurocircuitry patterns similar to those previously found in PTSD after finished trauma, this is less so for other neurobiological and in particular neuroendocrine findings. Direct comparisons between samples with ongoing versus finished trauma are needed in future research to draw more solid conclusions before administering cortisol to patients with PTSD under ongoing threat who may already exhibit increased endogenous cortisol levels.
A better understanding of psychological trauma is fundamental to clinical psychology. Following traumatic event(s), a clinically significant number of people develop symptoms, including those of Acute Stress Disorder and/or Post Traumatic Stress Disorder. The trauma film paradigm offers an experimental psychopathology model to study both exposure and reactions to psychological trauma, including the hallmark symptom of intrusive memories. We reviewed 74 articles that have used this paradigm since the earliest review (Holmes & Bourne, 2008) until July 2014. Highlighting the different stages of trauma processing, i.e. pre, peri and post trauma, the studies are divided according to manipulations before, during and after film viewing, for experimental as well as correlational designs. While the majority of studies focussed on the frequency of intrusive memories, other reactions to trauma were also modelled. We discuss the strengths and weaknesses of the trauma film paradigm as an experimental psychopathology model of trauma, consider ethical issues, and suggest future directions. By understanding the basic mechanisms underlying trauma symptom development, we can begin to translate findings from the laboratory to the clinic, test innovative science-driven interventions, and in the future reduce the debilitating effects of psychopathology following stressful and/or traumatic events.
Posttraumatic stress disorder (PTSD) is a common reaction to traumatic events. Many people recover in the ensuing months, but in a significant subgroup the symptoms persist, often for years. A cognitive model of persistence of PTSD is proposed. It is suggested that PTSD becomes persistent when individuals process the trauma in a way that leads to a sense of serious, current threat. The sense of threat arises as a consequence of: (1) excessively negative appraisals of the trauma and/or ist sequelae and (2) a disturbance of autobiographical memory characterised by poor elaboration and contextualisation, strong associative memory and strong perceptual priming. Change in the negative appraisals and the trauma memory are prevented by a series of problematic behavioural and cognitive strategies. The model is consistent with the main clinical features of PTSD, helps explain several apparently puzzling phenomena and provides a framework for treatment by identifying three key targets for change. Recent studies provided preliminary support for several aspects of the model.
Fear acquisition and extinction are valid models for the etiology and treatment of anxiety, trauma- and stressor-related disorders. These disorders are assumed to involve aversive learning under acute and/or chronic stress. Importantly, fear conditioning and stress share common neuronal circuits. The stress response involves multiple changes interacting in a time-dependent manner: (a) the fast first-wave stress response (with central actions of noradrenaline, dopamine, serotonin, corticotropin-releasing hormone, plus increased sympathetic tone and peripheral catecholamine release) and (b) the second-wave stress response (with peripheral release of glucocorticoids after activation of the hypothalamus-pituitary-adrenocortical axis). Control of fear during extinction is also sensitive to these stress-response mediators. In the present review, we will thus examine current animal and human data, addressing the role of stress and single stress-response mediators for successful acquisition, consolidation and recall of fear extinction. We report studies using pharmacological manipulations targeting a number of stress-related neurotransmitters and neuromodulators (monoamines, opioids, endocannabinoids, neuropeptide Y, oxytocin, glucocorticoids) and behavioral stress induction. As anxiety, trauma- and stressor-related disorders are more common in women, recent research focuses on female sex hormones and identifies a potential role for estradiol in fear extinction. We will thus summarize animal and human data on the role of estradiol and explore possible interactions with stress or stress-response mediators in extinction. This also aims at identifying time-windows of enhanced (or reduced) sensitivity for fear extinction, and thus also for successful exposure therapy.
Background:
A hallmark symptom after psychological trauma is the presence of intrusive memories. It is unclear why only some moments of trauma become intrusive, and how these memories involuntarily return to mind. Understanding the neural mechanisms involved in the encoding and involuntary recall of intrusive memories may elucidate these questions.
Method:
Participants (n = 35) underwent functional magnetic resonance imaging (fMRI) while being exposed to traumatic film footage. After film viewing, participants indicated within the scanner, while undergoing fMRI, if they experienced an intrusive memory of the film. Further intrusive memories in daily life were recorded for 7 days. After 7 days, participants completed a recognition memory test. Intrusive memory encoding was captured by comparing activity at the time of viewing 'Intrusive scenes' (scenes recalled involuntarily), 'Control scenes' (scenes never recalled involuntarily) and 'Potential scenes' (scenes recalled involuntarily by others but not that individual). Signal change associated with intrusive memory involuntary recall was modelled using finite impulse response basis functions.
Results:
We found a widespread pattern of increased activation for Intrusive v. both Potential and Control scenes at encoding. The left inferior frontal gyrus and middle temporal gyrus showed increased activity in Intrusive scenes compared with Potential scenes, but not in Intrusive scenes compared with Control scenes. This pattern of activation persisted when taking recognition memory performance into account. Intrusive memory involuntary recall was characterized by activity in frontal regions, notably the left inferior frontal gyrus.
Conclusions:
The left inferior frontal gyrus may be implicated in both the encoding and involuntary recall of intrusive memories.
A review of 2,647 studies of posttraumatic stress disorder (PTSD) yielded 476 potential candidates for a meta-analysis of predictors of PTSD or of its symptoms. From these, 68 studies met criteria for inclusion in a meta-analysis of 7 predictors: (a) prior trauma, (b) prior psychological adjustment, (c) family history of psychopathology, (d) perceived life threat during the trauma, (e) posttrauma social support, (f) peritraumatic emotional responses, and (g) peritraumatic dissociation. All yielded significant effect sizes, with family history, prior trauma, and prior adjustment the smallest (weighted r = .17) and peritraumatic dissociation the largest (weighted r = .35). The results suggest that peritraumatic psychological processes, not prior characteristics, are the strongest predictors of PTSD.
Background:
Findings about sex differences in the field of fear conditioning and fear extinction have been mixed. At the psychophysiological level, sex differences emerge only when taking estradiol levels of women into consideration. This suggests that this hormone may also influence sex differences with regards to activations of brain regions involved in fear conditioning and its extinction. Importantly, the neurobiological correlates associated with the use of hormonal oral contraceptives in women have not been fully contrasted against men and against naturally cycling women with different levels of estradiol. In this study, we begin to fill these scientific gaps.
Methods:
We recruited 37 healthy men and 48 healthy women. Of these women, 16 were using oral contraceptives (OC) and 32 were naturally cycling. For these naturally cycling women, a median split was performed on their serum estradiol levels to create a high estradiol (HE) group (n = 16) and a low estradiol (LE) group (n = 16). All participants underwent a 2-day fear conditioning and extinction paradigm in a 3 T MR scanner. Using the 4 groups (men, HE women, LE women, and OC users) and controlling for age and coil type, one-way ANCOVAs were performed to look at significant activations within the nodes of the fear circuit. Using post-hoc analyses, beta-weights were extracted in brain regions showing significant effects in order to unveil the differences based on hormonal status (men, HE, LE, OC).
Results:
Significant main effect of hormonal status group was found across the different phases of the experiment and in different sub-regions of the insular and cingulate cortices, amygdala, hippocampus, and hypothalamus. During conditioning, extinction and recall, most of the observed differences suggested higher activations among HE women relative to men. During the unconditioned response, however, a different pattern was observed with men showing significantly higher brain activations.
Conclusions:
Our data further support the important contribution of estradiol levels in the activation of brain regions underlying fear learning and extinction. The results highlight the need to document gonadal hormonal levels, menstrual cycle phase as well as oral contraceptive use in women in order to avoid overlooking sex differences when investigating the neurobiology of emotional regulation.
This hypothesis and theory paper presents a pragmatic framework to help bridge the clinical presentation and neuroscience of intrusive memories following psychological trauma. Intrusive memories are a hallmark symptom of post-traumatic stress disorder (PTSD). However, key questions, including those involving etiology, remain. In particular, we know little about the brain mechanisms involved in why only some moments of the trauma return as intrusive memories while others do not. We first present an overview of the patient experience of intrusive memories and the neuroimaging studies that have investigated intrusive memories in PTSD patients. Next, one mechanism of how to model intrusive memories in the laboratory, the trauma film paradigm, is examined. In particular, we focus on studies combining the trauma film paradigm with neuroimaging. Stemming from the clinical presentation and our current understanding of the processes involved in intrusive memories, we propose a framework in which an intrusive memory comprises five component parts; autobiographical (trauma) memory, involuntary recall, negative emotions, attention hijacking, and mental imagery. Each component part is considered in turn, both behaviorally and from a brain imaging perspective. A mapping of these five components onto our understanding of the brain is described. Unanswered questions that exist in our understanding of intrusive memories are considered using the proposed framework. Overall, we suggest that mental imagery is key to bridging the experience, memory, and intrusive recollection of the traumatic event. Further, we suggest that by considering the brain mechanisms involved in the component parts of an intrusive memory, in particular mental imagery, we may be able to aid the development of a firmer bridge between patients’ experiences of intrusive memories and the clinical neuroscience behind them.
This article is part of a Special Issue "SBN 2014". Women are more vulnerable to stress- and fear-based disorders, such as anxiety and post-traumatic stress disorder. Despite the growing literature on this topic, the neural basis of these sex differences remains unclear, and the findings appear inconsistent. The neurobiological mechanisms of fear and stress in learning and memory processes have been extensively studied, and the crosstalk between these systems is beginning to explain the disproportionate incidence and differences in symptomatology and remission within these psychopathologies. In this review, we discuss the intersect between stress and fear mechanisms and their modulation by gonadal hormones and discuss the relevance of this information to sex differences in anxiety and fear-based disorders. Understanding these converging influences is imperative to the development of more effective, individualized treatments that take sex and hormones into account.
Copyright © 2015. Published by Elsevier Inc.
The amygdala is a highly interconnected region of the brain that is critically important to emotional processing and affective networks. Previous studies have shown that the response of the amygdala to emotionally-arousing stimuli can be modulated by sex hormones. Because oral contraceptive pills dramatically lower circulating sex hormone levels with potent analogs of those hormones, we performed a functional magnetic resonance imaging experiment to measure amygdala reactivity in response to emotional stimuli in women using oral contraceptives, and compared their amygdala reactivity to that of naturally-cycling women. Here, we show that women who use oral contraceptive pills have significantly decreased bilateral amygdala reactivity in response to negatively-valenced, emotionally arousing stimuli compared to naturally-cycling women. We suggest that by modulating amygdala reactivity, oral contraceptive pills may influence behaviors that have previously been shown to be amygdala-dependent - in particular, emotional memory.
© The Author (2015). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.
The menstrual cycle has been implicated as a sex-specific biological process influencing psychological symptoms across a variety of disorders. Limited research exists regarding the role of the menstrual cycle in psychological symptoms among women with posttraumatic stress disorder (PTSD). The current study examined the severity of a broad range of psychological symptoms in both the early follicular (Days 2–6) and midluteal (6–10 days postlutenizing hormone surge) phases of the menstrual cycle in a sample of trauma-exposed women with and without PTSD (N = 49). In the sample overall, total psychological symptoms (d = 0.63), as well as depression (d = 0.81) and phobic anxiety (d = 0.81) symptoms, specifically, were increased in the early follicular compared to midluteal phase. The impact of menstrual cycle phase on phobic anxiety was modified by a significant PTSD × Menstrual Phase interaction (d = 0.63). Women with PTSD reported more severe phobic anxiety during the early follicular versus midluteal phase, whereas phobic anxiety did not differ across the menstrual cycle in women without PTSD. Thus, the menstrual cycle appears to impact fear-related symptoms in women with PTSD. The clinical implications of the findings and future research directions are discussed.
Posttraumatic stress disorder (PTSD) can be conceptualized as a disorder of emotional memory showing strong (conditioned) responses to trauma reminders and intrusive memories among other symptoms. Women are at greater risk of developing PTSD than men. Recent studies have demonstrated an influence of ovarian steroid hormones in both fear conditioning and intrusive memory paradigms. However, although intrusive memories are considered non-extinguished emotional reactions to trauma reminders, none of the previous studies has investigated effects of ovarian hormones on fear conditioning mechanisms and intrusive memories in conjunction. This may have contributed to an overall inconsistent picture of the role of these hormones in emotional learning and memory. To remedy this, we exposed 37 healthy women with a natural menstrual cycle (during early follicular or luteal cycle phase) to a novel conditioned-intrusion paradigm designed to model real-life traumatic experiences. The paradigm included a differential fear conditioning procedure with short violent film clips as unconditioned stimuli. Intrusive memories about the film clips were assessed ambulatorily on subsequent days. Women with lower levels of estradiol displayed elevated differential conditioned skin conductance responding during fear extinction and showed stronger intrusive memories. The inverse relationship between estradiol and intrusive memories was at least partially accounted for by the conditioned responding observed during fear extinction. Progesterone levels were not associated with either fear acquisition/extinction or with intrusive memories. This suggests that lower levels of estradiol might promote stronger symptoms of PTSD through associative processes.
Hormonal contraceptives are on the market for more than 50 years and used by 100 million women worldwide. However, while endogenous steroids have been convincingly associated with change in brain structure, function and cognitive performance, the effects of synthetic steroids contained in hormonal contraceptives on brain and cognition have barely been investigated. In this article we summarize the sparse findings, describing brain structural, functional and behavioral findings from the literature and suggest that synthetic steroids may contribute to masculinizing as well as feminizing effects on brain and behavior. We try to identify methodological challenges, explain, how results on endogenous steroids may transfer into research on hormonal contraceptives and point out factors that need to be controlled in the study of hormonal contraceptive dependent effects. We conclude that there is a strong need for more systematic studies, especially on brain structural, functional and cognitive changes due to hormonal contraceptive use. The hormonal contraceptive pill is the major tool for population control. Hence, such behavioral changes could cause a shift in society dynamics and should not stay unattended.
Narcissism is a complex phenomenon, involving a level of defensive self-enhancement. Narcissists have avoidant attachment
styles, maintain distance in relationships and claim not to need others. However, they are especially sensitive to others’
evaluations, needing positive reflected appraisals to maintain their inflated self-views, and showing extreme responses (e.g.
aggression) when rejected. The current study tested the hypothesis that narcissists also show hypersensitivity in brain systems
associated with distress during exclusion. We measured individual differences in narcissism (Narcissistic Personality Inventory)
and monitored neural responses to social exclusion (Cyberball). Narcissism was significantly associated with activity in an
a priori anatomically defined social pain network (anterior insula, dorsal anterior cingulate cortex and subgenual anterior
cingulate cortex) during social exclusion. Results suggest hypersensitivity to exclusion in narcissists may be a function
of hypersensitivity in brain systems associated with distress, and suggests a potential pathway that connects narcissism to
negative consequences for longer-term physical and mental health—findings not apparent with self-report alone.
Impulsive behavior such as steep temporal discounting is a hallmark of addiction and is associated with relapse. In pathological gamblers, discounting may be further increased by the presence of gambling-related cues in the environment, but the extent to which the gambling relatedness of task settings affects reward responses in gambling addiction is debated. In the present study, human problem gamblers made choices between immediate rewards and individually tailored larger-but-later rewards while visual gambling-related scenes were presented in the background. N = 17 participants were scanned using fMRI, whereas N = 5 additional participants completed a behavioral version of the task. Postscan craving ratings were acquired for each image, and behavioral and neuroimaging data were analyzed separately for high- and low-craving trials (median split analysis). Discounting was steeper for high versus low craving trials. Neuroimaging revealed a positive correlation with model-based subjective value in midbrain and striatum in low-craving trials that was reversed in high-craving trials. These findings reveal a modulation of striatal reward responses in gamblers by addiction-related cues, and highlight a potentially important mechanism that may contribute to relapse. Cue-induced changes in striatal delayed reward signals may lead to increased discounting of future rewards, which might in turn affect the likelihood of relapse.
Intrusive memories - a hallmark symptom of posttraumatic stress disorder (PTSD) - are often triggered by stimuli possessing similarity with cues that predicted or accompanied the traumatic event. According to learning theories, intrusive memories can be seen as a conditioned response to trauma reminders. However, direct laboratory evidence for the link between fear conditionability and intrusive memories is missing. Furthermore, fear conditioning studies have predominantly relied on standardized aversive stimuli (e.g. electric stimulation) that bear little resemblance to typical traumatic events. To investigate the general relationship between fear conditionability and aversive memories, we tested 66 mentally healthy females in a novel conditioned-intrusion paradigm designed to model real-life traumatic experiences. The paradigm included a differential fear conditioning procedure with neutral sounds as conditioned stimuli and short violent film clips as unconditioned stimuli. Subsequent aversive memories were assessed through a memory triggering task (within 30 minutes, in the laboratory) and ambulatory assessment (involuntary aversive memories in the 2 days following the experiment). Skin conductance responses and subjective ratings demonstrated successful differential conditioning indicating that naturalistic aversive film stimuli can be used in a fear conditioning experiment. Furthermore, aversive memories were elicited in response to the conditioned stimuli during the memory triggering task and also occurred in the 2 days following the experiment. Importantly, participants who displayed higher conditionability showed more aversive memories during the memory triggering task and during ambulatory assessment. This suggests that fear conditioning constitutes an important source of persistent aversive memories. Implications for PTSD and its treatment are discussed.
Background
Psychological traumatic events, such as war or road traffic accidents, are widespread. A small but significant proportion of survivors develop post-traumatic stress disorder (PTSD). Distressing, sensory-based involuntary memories of trauma (henceforth ‘flashbacks’) are the hallmark symptom of PTSD. Understanding the development of flashbacks may aid their prevention. This work is the first to combine the trauma film paradigm (as an experimental analogue for flashback development) with neuroimaging to investigate the neural basis of flashback aetiology. We investigated the hypothesis that involuntary recall of trauma (flashback) is determined during the original event encoding.
Method
A total of 22 healthy volunteers viewed a traumatic film whilst undergoing functional magnetic resonance imaging (fMRI). They kept a 1-week diary to record flashbacks to specific film scenes. Using a novel prospective fMRI design, we compared brain activation for those film scenes that subsequently induced flashbacks with both non-traumatic control scenes and scenes with traumatic content that did not elicit flashbacks (‘potentials’).
Results
Encoding of scenes that later caused flashbacks was associated with widespread increases in activation, including in the amygdala, striatum, rostral anterior cingulate cortex, thalamus and ventral occipital cortex. The left inferior frontal gyrus and bilateral middle temporal gyrus also exhibited increased activation but only relative to ‘potentials’. Thus, these latter regions appeared to distinguish between traumatic content that subsequently flashed back and comparable content that did not.
Conclusions
Results provide the first prospective evidence that the brain behaves differently whilst experiencing emotional events that will subsequently become involuntary memories – flashbacks. Understanding the neural basis of analogue flashback memory formation may aid the development of treatment interventions for this PTSD feature.
The ventromedial prefrontal cortex (vmPFC) comprises a set of interconnected regions that integrate information from affective sensory and social cues, long-term memory, and representations of the 'self'. Alhough the vmPFC is implicated in a variety of seemingly disparate processes, these processes are organized around a common theme. The vmPFC is not necessary for affective responses per se, but is critical when affective responses are shaped by conceptual information about specific outcomes. The vmPFC thus functions as a hub that links concepts with brainstem systems capable of coordinating organism-wide emotional behavior, a process we describe in terms of the generation of affective meaning, and which could explain the common role played by the vmPFC in a range of experimental paradigms.
In emotional learning tasks, sex differences, stress effects and an interaction of these two moderators have often been observed.
The sex hormones estradiol (E2) and progesterone (P4) vary over the menstrual cycle. We tested groups with different sex hormone
status: 39 men, 30 women in the luteal phase (LU, high E2+P4) and 29 women taking oral contraceptives (OC, low E2+P4). They
received either 30 mg cortisol or placebo prior to instructed differential fear conditioning consisting of neutral conditioned
stimuli (CS) and an electrical stimulation (unconditioned stimulus; UCS). One figure (CS+) was paired with the UCS, the other
figure (CS−) never. During extinction, no electrical stimulation was administered. Regarding fear acquisition, results showed
higher skin conductance and higher brain responses to the CS+ compared to the CS− in several structures that were not modulated
by cortisol or sex hormones. However, OC women exhibited higher CS+/CS− differentiations than men and LU women in the amygdala,
thalamus, anterior cingulate and ventromedial prefrontal cortex during extinction. The suppression of endogenous sex hormones
by OC seems to alter neuronal correlates of extinction. The observation that extinction is influenced by the current sex hormone
availability is relevant for future studies and might also be clinically important.
Men and women differ in their ability to extinguish fear. Fear extinction requires the activation of brain regions, including the ventromedial prefrontal cortex (vmPFC) and amygdala. Could estradiol modulate the activity of these brain regions during fear extinction?
All rat experiments were conducted in naturally cycling females. Rats underwent fear conditioning on Day 1. On Day 2, they underwent extinction training during the metestrus phase of the cycle (low estrogen and progesterone). Extinction recall was assessed on Day 3. Systemic injections of estrogen receptor-beta and -alpha agonists and of estradiol were administered at different time points to assess their influence on extinction consolidation and c-Fos expression in the vmPFC and amygdala. In parallel, healthy naturally cycling women underwent an analogous fear conditioning extinction training in a 3T functional magnetic resonance scanner. Measurement of their estradiol levels and skin conductance responses were obtained throughout the experiment.
In female rats, administration of the estrogen-receptor beta (but not alpha) agonist facilitated extinction recall. Immediate (but not delayed) postextinction training administration of estradiol facilitated extinction memory consolidation and increased c-Fos expression in the vmPFC while reducing it in the amygdala. In parallel, natural variance in estradiol in premenopausal cycling women modulated vmPFC and amygdala reactivity and facilitated extinction recall.
We provide translational evidence that demonstrates the influence of endogenous and exogenous estradiol on the fear extinction network. Our data suggest that women's endogenous hormonal status should be considered in future neurobiological research related to anxiety and mood disorders.
During decision making, valuation of different types of rewards may involve partially distinct neural systems, but efficient choice behavior requires a common neural coding of stimulus value. We addressed this issue by measuring neural activity with functional magnetic resonance imaging while volunteers processed delayed and probabilistic decision options. Behaviorally, participants discounted both types of rewards in a hyperbolic manner, and discount rates, reflecting individual preferences, varied considerably between participants. Ventral striatum and orbitofrontal cortex showed a domain-general coding of subjective value regardless of whether rewards were delayed or probabilistic, strongly implicating these regions in the implementation of a common neural currency of value. In contrast, fronto-polar and lateral parietal cortex, as well as a region in the posterior cingulate cortex only correlated with the value of delayed rewards, whereas superior parietal cortex and middle occipital areas only represented the value of probabilistic rewards. These results suggest a mechanism for the neural coding of subjective value in the human brain that is based on the combination of domain-general and domain-specific valuation networks.
Emotion theories commonly postulate that emotions impose coherence across multiple response systems. However, empirical support for this coherence postulate is surprisingly limited. In the present study, the authors (a) examined the within-individual associations among experiential, facial behavioral, and peripheral physiological responses during emotional responding and (b) assessed whether emotion intensity moderates these associations. Experiential, behavioral, and physiological responses were measured second-by-second during a film that induced amusement and sadness. Results indicate that experience and behavior were highly associated but that physiological responses were only modestly associated with experience and behavior. Intensity of amusement experience was associated with greater coherence between behavior and physiological responding; intensity of sadness experience was not. These findings provide new evidence about response system coherence in emotions.
Sex-specific behaviors are in part based on hormonal regulation of brain physiology. This functional magnetic resonance imaging (fMRI) study demonstrated significant differences in activation of hypothalamic-pituitary-adrenal (HPA) circuitry in adult women with attenuation during ovulation and increased activation during early follicular phase. Twelve normal premenopausal women were scanned twice during the early follicular menstrual cycle phase compared with late follicular/midcycle, using negative valence/high arousal versus neutral visual stimuli, validated by concomitant electrodermal activity (EDA). Significantly greater magnitude of blood oxygenation level-dependent signal changes were found during early follicular compared with midcycle timing in central amygdala, paraventricular and ventromedial hypothalamic nuclei, hippocampus, orbitofrontal cortex (OFC), anterior cingulate gyrus (aCING), and peripeduncular nucleus of the brainstem, a network of regions implicated in the stress response. Arousal (EDA) correlated positively with brain activity in amygdala, OFC, and aCING during midcycle but not in early follicular, suggesting less cortical control of amygdala during early follicular, when arousal was increased. This is the first evidence suggesting that estrogen may likely attenuate arousal in women via cortical-subcortical control within HPA circuitry. Findings have important implications for normal sex-specific physiological functioning and may contribute to understanding higher rates of mood and anxiety disorders in women and differential sensitivity to trauma than men.
Supported by recent human neuroimaging studies, the insula is re-emerging as an important brain area not only in the physiological understanding of the brain, but also in pathological contexts in clinical research. In this opinion article, we briefly introduce the anatomical and histological features of the human insula. We then summarize the physiological functions of the insula and underscore its pathological roles in psychiatric and neurological disorders that have long been underestimated. We finally propose possible strategies through which the role of the insula may be further understood for both basic and clinical neuroscience.
Anxiety disorders are more prevalent in women than men. One contributing factor may be the sex hormone estradiol, which is known to impact the long term recall of conditioned fear extinction, a laboratory procedure that forms the basis of exposure therapy for anxiety disorders. To date, the literature examining estradiol and fear extinction in humans has focused primarily on physiological measures of fear, such as skin conductance response (SCR) and fear potentiated startle. This is surprising, given that models of anxiety identify at least three important components: physiological symptoms, cognitive beliefs, and avoidance behavior. To help address this gap, we exposed women with naturally high (n = 20) or low estradiol (n = 19), women using hormonal contraceptives (n = 16), and a male control group (n = 18) to a fear extinction task, and measured SCR, US expectancy and CS valence ratings. During extinction recall, low estradiol was associated with greater recovery of SCR, but was not related to US expectancy or CS evaluation. Importantly, women using hormonal contraceptives showed a dissociation between SCR and cognitive beliefs: they exhibited a greater recovery of SCR during extinction recall, yet reported similar US expectancy and CS valence ratings to the other female groups. This divergence underscores the importance of assessing multiple measures of fear when examining the role of estradiol in human fear extinction, especially when considering the potential of estradiol as an enhancement for psychological treatments for anxiety disorders.
Previous neuroimaging research has demonstrated that female gonadal hormones can alter the structure and function of adult women's brains. So far, we do not know how hormonal contraceptives affect female brain structure, in part because within-person longitudinal observations are lacking. Here, we compared 28 young women before and after three months of regular contraceptive intake with 28 naturally cycling women of comparable age. The goal was to explore within-person neural change in women using contraceptives. Neuroimaging, hormonal, cognitive, and affect data were collected at two time points for each participant. A voxel-wise whole-brain comparison of both groups revealed decreased gray matter volume in the left amygdala/anterior parahippocampal gyrus in women using contraceptives as compared to the control group. Resting-state functional connectivity of this region with the dorsolateral prefrontal cortex changed from positive to negative connectivity following contraceptive intake whereas the opposite held for the control group. An exploratory analysis revealed that gray matter volume in the left amygdala/anterior parahippocampal gyrus was associated with positive affect at the second time point. There were no systematic differences in cognitive performance change between the groups. These findings provide initial insights into effects of hormonal contraceptives on the human brain and expand previous findings on hormone-related amygdala/hippocampal complex plasticity. The affected brain regions may be related to psychological wellbeing, underlining the importance of future studies on contraceptive-induced brain changes.
The amygdala is a hub in emotional processing, including that of negative affect. Healthy men and women have distinct differences in amygdala responses, potentially setting the stage for the observed sex differences in the prevalence of fear, anxiety, and pain disorders. Here, we examined how amygdala subnuclei resting-state functional connectivity is affected by sex, as well as explored how the functional connectivity is related to estrogen levels. Resting-state functional connectivity was measured using functional magnetic resonance imaging (fMRI) with seeds placed in the left and right laterobasal (LB) and centromedial (CM) amygdala. Sex differences were studied in 48 healthy men and 48 healthy women, matched for age, while the association with estrogen was analyzed in a subsample of 24 women, for whom hormone levels had been assessed. For the hormone analyses, the subsample was further divided into a lower and higher estrogen levels group based on a median split. We found distinct sex differences in the LB and CM amygdala resting-state functional connectivity, as well as preliminary evidence for an association between estrogen levels and connectivity patterns. These results are potentially valuable in explaining why women are more afflicted by conditions of negative affect than are men, and could imply a mechanistic role for estrogen in modulating emotion.
Oral contraceptives (OCs), often referred to as "the pill", are the most commonly employed form of reversible contraception. OCs are comprised of combined synthetic estrogen and progestin, which work to suppress ovulation and subsequently protect against pregnancy. To date, almost 200 million women have taken various formulations of OC, making it one of the most widely consumed classes of medication in the world. While a substantial body of literature has been dedicated to understanding the physical effects of OCs, much less is known about the long term consequences of OC use on brain anatomy and the associated cognitive effects. Accumulating evidence suggests that sex hormones may significantly affect human cognition. This phenomenon has been commonly studied in older populations, such as in post-menopausal women, while research in healthy, pre-menopausal women remains limited. The current review focused on the effects of OCs on human cognition, with the majority of studies comparing pre-menopausal OC users to naturally cycling women. Human neuroimaging data and animal studies are also described herein. Taken together, the published findings on OC use and human cognition are varied. Of those that do report positive results, OC users appear to have improved verbal memory, associative learning and spatial attention. We recommend future research to employ blinding procedures and randomised designs. Further, more detailed information pertaining to the specific generation and phasic type of OCs, as well as menstrual cycle phase of the OC non-users should be considered to help unmask the potential impact of OC use on human cognition.
Background
Almost half of children with an inhibited temperament will develop social anxiety disorder by late adolescence. Importantly, this means that half of children with an inhibited temperament will not develop social anxiety disorder. Studying adults with an inhibited temperament provides a unique opportunity to identify neural signatures of both risk and resilience to social anxiety disorder.Methods
Functional magnetic resonance imaging (fMRI) was used to measure brain activation during the anticipation of viewing fear faces in 34 young adults (17 inhibited, 17 uninhibited). To identify neural signatures of risk, we tested for group differences in functional activation and connectivity in regions implicated in social anxiety disorder, including the prefrontal cortex, amygdala, and insula. To identify neural signatures of resilience, we tested for correlations between brain activation and both emotion regulation and social anxiety scores.ResultsInhibited subjects had greater activation of a prefrontal network when anticipating viewing fear faces, relative to uninhibited subjects. No group differences were identified in the amygdala. Inhibited subjects had more negative connectivity between the rostral anterior cingulate cortex (ACC) and the bilateral amygdala. Within the inhibited group, those with fewer social anxiety symptoms and better emotion regulation skills had greater ACC activation and greater functional connectivity between the ACC and amygdala.Conclusions
These findings suggest that engaging regulatory prefrontal regions during anticipation may be a protective factor, or putative neural marker of resilience, in high-risk individuals. Cognitive training targeting prefrontal cortex function may provide protection against anxiety, especially in high-risk individuals, such as those with inhibited temperament.
At rest, brain activity can be characterized not by an absence of organized activity but instead by spatially and temporally correlated patterns of activity. In this experiment, we investigated whether and to what extent resting state functional connectivity is modulated by sex hormones in women, both across the menstrual cycle and when altered by oral contraceptive pills. Sex hormones have been shown to have important effects on task-related activity, but few studies have investigated the extent to which they can influence the behavior of functional networks at rest. These hormones are dramatically altered by the use of hormonal contraception, which is used by approximately 100 million women worldwide. However, potential cognitive side effects of hormonal contraception have been given little attention. Here, we collected resting state data for naturally-cycling women (n=45) and women using combined oral contraceptive pills (n=46) and evaluated the differences in resting state activity between these two groups using Independent Components Analysis. We found that in the default mode network and in a network associated with executive control, resting state dynamics were altered both by the menstrual cycle and by oral contraceptive use. Specifically, the connectivity of the left angular gyrus, the left middle frontal gyrus, and the anterior cingulate cortex were different between groups. Because the anterior cingulate cortex and left middle frontal gyrus are important for higher-order cognitive and emotional processing, including conflict monitoring, changes in the relationship of these structures to the functional networks with which they interact may have important consequences for attention, affect, and/or emotion regulation.
Background:
Fear extinction is a laboratory model of fear inhibition and is the basis of exposure therapy for anxiety disorders. Emerging evidence from naturally cycling female rodents and women indicates that estrogens are necessary to the consolidation of fear extinction. Hormonal contraceptives (HCs) inhibit estrogen production; yet, their effects on fear extinction are unknown.
Methods:
We used a cross-species translational approach to investigate the impact of HCs and estradiol supplementation on fear extinction in healthy women (n=76) and female rats (n = 140).
Results:
Women using HCs exhibited significantly poorer extinction recall compared with naturally cycling women. The extinction impairment was also apparent in HC-treated female rats and was associated with reduced serum estradiol levels. The impairment could be rescued in HC-treated rats either by terminating HC treatment after fear learning or by systemic injection of estrogen-receptor agonists before fear extinction, all of which restored serum estradiol levels. Finally, a single administration of estradiol to naturally cycling women significantly enhanced their ability to recall extinction memories.
Conclusions:
Together, these findings suggest that HCs may impact women's ability to inhibit fear but that this impairment is not permanent and could potentially be alleviated with estrogen treatment.
Post-traumatic stress disorder (PTSD) is the only major mental disorder for which a cause is considered to be known: that is, an event that involves threat to the physical integrity of oneself or others and induces a response of intense fear, helplessness or horror. Although PTSD is still largely regarded as a psychological phenomenon, over the past three decades the growth of the biological PTSD literature has been explosive, and thousands of references now exist. Ultimately, the impact of an environmental event, such as a psychological trauma, must be understood at organic, cellular and molecular levels. This Review attempts to present the current state of this understanding on the basis of psychophysiological, structural and functional neuroimaging, and endocrinological, genetic and molecular biological studies in humans and in animal models.
Conservative estimates indicate that 18-25% of women in the United States will be exposed to some form of sexual assault in their lifetime. A great number of these women will develop post-traumatic stress disorder (PTSD). The current study explores the relationship between emergency contraception (EC) administration and subsequent post-traumatic stress symptoms in female sexual assault (SA) survivors. In a study population of 111 participants, post-traumatic stress symptoms were assessed approximately six months after the SA. Women who were already taking hormonal contraception (HC) at the time of the SA and those who declined EC were compared to women who took either Ogestrel or Plan B following the SA. While the administration of traditional HC and both types of EC were associated with fewer intrusive symptoms, women who took Ogestrel reported significantly lower post-traumatic stress total symptom levels than did those who took Plan B or those who declined EC. The results suggest that the manipulation of sex hormone levels with HC and EC in the immediate aftermath of trauma may influence subsequent post-traumatic stress symptoms. The current results may be useful in guiding the choice of EC.
Women are twice as likely to develop posttraumatic stress disorder (PTSD) than men. As shown in our previous work, the inability to suppress fear responses in safe conditions may be a biomarker for PTSD. Low estrogen in naturally cycling women is associated with deficits in fear extinction. On the basis of these findings, we have now examined the influence of estrogen levels on fear extinction in women with and without PTSD.
We measured fear-potentiated startle during fear conditioning and extinction in women. The study sample (N = 81) was recruited from an urban, highly traumatized civilian population at Grady Memorial Hospital in Atlanta, Georgia. We assayed serum estrogen levels and used a median split to divide the sample into high and low estradiol (E(2)) groups. Seventeen of 41 women (41.5%) in the low E(2) group and 15 of 40 women (37.5%) met criteria for PTSD in the high E(2) group.
The results showed that all groups had equivalent levels of fear conditioning. However, we found significant interaction effects between high versus low E(2) groups and PTSD diagnosis [F(1,71) = 4.55, p < .05] on extinction. Among women with low estrogen levels, fear-potentiated startle was higher during extinction in the PTSD group compared with traumatized control women [F(1,38) = 5.04, p < .05]. This effect was absent in the High E(2) group.
This study suggests that low estrogen may be a vulnerability factor for development of PTSD in women with trauma histories. Research on the role of estrogen in fear regulation may provide insight into novel treatment strategies for PTSD.
In a series of studies, we evaluated the susceptibility of immunoassays for saliva biomarkers to interference effects caused by cotton materials used to absorb saliva during sample collection. Salivary assay results for testosterone, DHEA, progesterone, and estradiol are artificially high, and for sIgA artificially low, when samples are collected using cotton absorbent materials. In contrast, results for salivary cortisol, DHEA–S, and cotinine are not affected by the use of cotton collection methods. The order of individual results from samples collected using cotton versus no-cotton methods for certain markers is not conserved, suggesting that for some biomarkers this collection method can be a significant source of unsystematic error. It was shown, using DHEA as an example, that the cotton interference effect is of sufficient magnitude to attenuate the association between serum and saliva levels. Awareness of this issue is critical to ensure measurement validity in future studies and analyses of archived samples collected using cotton materials.
Posttraumatic stress disorder (PTSD) may develop from impaired extinction of conditioned fear responses. Exposure-based treatment of PTSD is thought to facilitate extinction learning (Charney, 2004). Fear extinction is mediated by inhibitory control of the ventromedial prefrontal cortex (vmPFC) over amygdala-based fear processes (Phelps, Delgado, Nearing, & LeDoux, 2004; Quirk, Russo, Barron, & LeBron, 2000). Most neuroimaging studies of PTSD reveal reduced vmPFC activity (particularly in rostral anterior cingulate cortex, or rACC; Lanius et al., 2001; Shin et al., 2005), and some find increased amygdala activity during threat processing (Shin et al., 2005). In addition, increased amygdala activity during fear conditioning and reduced vmPFC activity during extinction have been reported in PTSD (Bremner et al., 2005).
Although PTSD patients show increased orbitofrontal and medial prefrontal activity following treatment with serotonin reuptake inhibitors (SSRIs; Fernandez et al., 2001; Seedat et al., 2004), no studies have investigated neural networks before and after exposure-based treatment of PTSD. We report the first such study. We hypothesized that symptom reduction would be associated with increased rACC activity and reduced amygdala activity during fear processing.
Negative emotional stimuli activate a broad network of brain regions, including the medial prefrontal (mPFC) and anterior cingulate (ACC) cortices. An early influential view dichotomized these regions into dorsal-caudal cognitive and ventral-rostral affective subdivisions. In this review, we examine a wealth of recent research on negative emotions in animals and humans, using the example of fear or anxiety, and conclude that, contrary to the traditional dichotomy, both subdivisions make key contributions to emotional processing. Specifically, dorsal-caudal regions of the ACC and mPFC are involved in appraisal and expression of negative emotion, whereas ventral-rostral portions of the ACC and mPFC have a regulatory role with respect to limbic regions involved in generating emotional responses. Moreover, this new framework is broadly consistent with emerging data on other negative and positive emotions.
Women in the mid-luteal phase of the menstrual cycle have been shown to have stronger emotional memories than other women. We investigated the extent to which experiencing a traumatic event during the luteal phase of the menstrual cycle is associated with stronger traumatic flashback memories.
Consecutive female patients admitted to hospital after traumatic injury (n=138) were assessed for days since last menstruation, as well as assessment of flashbacks. Twenty three (17%) women were in the mid-luteal phase (18-24) days at the time of trauma exposure and 29 (21%) were in the mid-luteal phase at the time of assessment.
Women were more likely to experience flashback memories if they were in the luteal phase during the trauma (22% vs. 9%), adjusted OR: 3.64 [95%CI: 0.99-13.29] after controlling for injury severity, age, trauma type, and mild traumatic brain injury. Women in the luteal phase at assessment were 4.89 times more likely to have flashbacks. Adjusted OR: 4.89 [95%CI: 1.39-17.86].
Increased glucocorticoid release associated with the luteal phase of the menstrual cycle may facilitate consolidation of trauma memories.
Sex differences in human brain structure have repeatedly been described, but results are inconsistent. However, these studies hardly controlled for cycle phase of women or the use of hormonal contraceptives. Our study shows that these factors are not negligible, but have a considerable influence on human brain structure. We acquired high-resolution structural images from the brains of 14 men, 14 women, who did not use, and 14 women, who did use hormonal contraceptives. Women, who did not use hormonal contraceptives, were scanned twice, once during their early follicular and once during their mid-luteal cycle-phase. Regional gray matter volumes were compared by voxel-based morphometry. Men had larger hippocampi, parahippocampal and fusiform gyri, amygdalae and basal ganglia than women. Women showed larger gray matter volumes in the prefrontal cortex, pre- and postcentral gyri. These sex-dependent effects were modulated by menstrual cycle phases and hormonal contraceptives. We found larger volumes in the right fusiform/parahippocampal gyrus during early follicular compared to mid-luteal cycle phase. Women using hormonal contraceptives showed significantly larger prefrontal cortices, pre- and postcentral gyri, parahippocampal and fusiform gyri and temporal regions, compared to women not using contraceptives.
Threat-related stimuli are strong competitors for attention, particularly in anxious individuals. We used functional magnetic resonance imaging (fMRI) with healthy human volunteers to study how the processing of threat-related distractors is controlled and whether this alters as anxiety levels increase. Our work builds upon prior analyses of the cognitive control functions of lateral prefrontal cortex (lateral PFC) and anterior cingulate cortex (ACC). We found that rostral ACC was strongly activated by infrequent threat-related distractors, consistent with a role for this area in responding to unexpected processing conflict caused by salient emotional stimuli. Participants with higher anxiety levels showed both less rostral ACC activity overall and reduced recruitment of lateral PFC as expectancy of threat-related distractors was established. This supports the proposal that anxiety is associated with reduced top-down control over threat-related distractors. Our results suggest distinct roles for rostral ACC and lateral PFC in governing the processing of task-irrelevant, threat-related stimuli, and indicate reduced recruitment of this circuitry in anxiety.
Epidemiologic surveys in the general population documented a higher rate of posttraumatic stress disorder (PTSD) in women than in men. To date, the finding has received little scientific attention. This study examines the extent to which sex differences in PTSD might be explained by previously identified risk factors and whether the sex difference in PTSD varied by age at exposure to traumatic events.
The NIMH-DIS (NIMH Diagnostic Interview Schedule, Version III Revised) was used to measure DSM-IIIR disorders in a random sample of 1007 young adults. Cox proportional hazards models were used to estimate changes in the hazards ratio for PTSD associated with sex when potential risk factors were included.
Lifetime prevalence of exposure to traumatic events and number of traumatic events did not vary by sex. The prevalence of PTSD was higher for women than for men exposed to traumatic events (hazards ratio, 2.3; 95% confidence interval, 1.5-3.6). Preexisting anxiety disorders or major depressive disorders played a part in the observed sex difference in PTSD. Family history of anxiety disorder and early separation from parents, although significant risk factors for PTSD in subjects of both sexes, were unrelated to the sex difference in PTSD. The sex difference in PTSD was markedly greater if exposure occurred in childhood than later on.
Posttraumatic stress disorder is more likely to develop in females than in males after exposure to a traumatic event. Susceptibility to PTSD in females might be greater in childhood than after age 15 years. Explanations of the sex difference might involve characteristics of individuals and of the traumatic experiences.
Probabilistic maps of neocortical areas and subcortical fiber tracts, warped to a common reference brain, have been published using microscopic architectonic parcellations in ten human postmortem brains. The maps have been successfully applied as topographical references for the anatomical localization of activations observed in functional imaging studies. Here, for the first time, we present stereotaxic, probabilistic maps of the hippocampus, the amygdala and the entorhinal cortex and some of their subdivisions. Cytoarchitectonic mapping was performed in serial, cell-body stained histological sections. The positions and the extent of cytoarchitectonically defined structures were traced in digitized histological sections, 3-D reconstructed and warped to the reference space of the MNI single subject brain using both linear and non-linear elastic tools of alignment. The probability maps and volumes of all structures were calculated. The precise localization of the borders of the mapped regions cannot be predicted consistently by macroanatomical landmarks. Many borders, e.g. between the subiculum and entorhinal cortex, subiculum and Cornu ammonis, and amygdala and hippocampus, do not match sulcal landmarks such as the bottom of a sulcus. Only microscopic observation enables the precise localization of the borders of these brain regions. The superposition of the cytoarchitectonic maps in the common spatial reference system shows a considerably lower degree of intersubject variability in size and position of the allocortical structures and nuclei than the previously delineated neocortical areas. For the first time, the present observations provide cytoarchitectonically verified maps of the human amygdala, hippocampus and entorhinal cortex, which take into account the stereotaxic position of the brain structures as well as intersubject variability. We believe that these maps are efficient tools for the precise microstructural localization of fMRI, PET and anatomical MR data, both in healthy and pathologically altered brains.
The prevailing neurocircuitry models of anxiety disorders have been amygdalocentric in form. The bases for such models have progressed from theoretical considerations, extrapolated from research in animals, to in vivo human imaging data. For example, one current model of posttraumatic stress disorder (PTSD) has been highly influenced by knowledge from rodent fear conditioning research. Given the phenomenological parallels between fear conditioning and the pathogenesis of PTSD, we have proposed that PTSD is characterized by exaggerated amygdala responses (subserving exaggerated acquisition of fear associations and expression of fear responses) and deficient frontal cortical function (mediating deficits in extinction and the capacity to suppress attention/response to trauma-related stimuli), as well as deficient hippocampal function (mediating deficits in appreciation of safe contexts and explicit learning/memory). Neuroimaging studies have yielded convergent findings in support of this model. However, to date, neuroimaging investigations of PTSD have not principally employed conditioning and extinction paradigms per se. The recent development of such imaging probes now sets the stage for directly testing hypotheses regarding the neural substrates of fear conditioning and extinction abnormalities in PTSD.
Analysis and interpretation of functional MRI (fMRI) data have traditionally been based on identifying areas of significance on a thresholded statistical map of the entire imaged brain volume. This form of analysis can be likened to a "fishing expedition." As we become more knowledgeable about the structure-function relationships of different brain regions, tools for a priori hypothesis testing are needed. These tools must be able to generate region of interest masks for a priori hypothesis testing consistently and with minimal effort. Current tools that generate region of interest masks required for a priori hypothesis testing can be time-consuming and are often laboratory specific. In this paper we demonstrate a method of hypothesis-driven data analysis using an automated atlas-based masking technique. We provide a powerful method of probing fMRI data using automatically generated masks based on lobar anatomy, cortical and subcortical anatomy, and Brodmann areas. Hemisphere, lobar, anatomic label, tissue type, and Brodmann area atlases were generated in MNI space based on the Talairach Daemon. Additionally, we interfaced these multivolume atlases to a widely used fMRI software package, SPM99, and demonstrate the use of the atlas tool with representative fMRI data. This tool represents a necessary evolution in fMRI data analysis for testing of more spatially complex hypotheses.