Effect of Stress-Related Neural Pathways on the Cardiovascular Benefit of Physical Activity.

BACKGROUND: The mechanisms underlying the psychological and cardiovascular disease (CVD) benefits of physical activity (PA) are not fully understood. OBJECTIVES: This study tested whether PA: 1) attenuates stress-related neural activity, which is known to potentiate CVD and for its role in anxiety/depression; 2) decreases CVD in part through this neural effect; and 3) has a greater impact on CVD risk among individuals with depression. METHODS: Participants from the Mass General Brigham Biobank who completed a PA survey were studied. A subset underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomographic imaging. Stress-related neural activity was measured as the ratio of resting amygdalar-to-cortical activity (AmygAC). CVD events were ascertained from electronic health records. RESULTS: A total of 50,359 adults were included (median age 60 years [Q1-Q3: 45-70 years]; 40.1% male). Greater PA was associated with both lower AmygAC (standardized ß: -0.245; 95% CI: -0.444 to -0.046; P = 0.016) and CVD events (HR: 0.802; 95% CI: 0.719-0.896; P < 0.001) in multivariable models. AmygAC reductions partially mediated PA's CVD benefit (OR: 0.96; 95% CI: 0.92-0.99; P < 0.05). Moreover, PA's benefit on incident CVD events was greater among those with (vs without) preexisting depression (HR: 0.860; 95% CI: 0.810-0.915; vs HR: 0.929; 95% CI: 0.910-0.949; P interaction = 0.011). Additionally, PA above guideline recommendations further reduced CVD events, but only among those with preexisting depression (P interaction = 0.023). CONCLUSIONS: PA appears to reduce CVD risk in part by acting through the brain's stress-related activity; this may explain the novel observation that PA reduces CVD risk to a greater extent among individuals with depression.

The impact of PTSD on associations between sex hormones and cardiovascular disease symptoms.

Background: Women have twice the lifetime prevalence of posttraumatic stress disorder (PTSD) relative to men, and PTSD is a known risk factor for cardiovascular disease (CVD). Two sex hormones - estradiol and progesterone - have been found to impact both PTSD and CVD symptomatology, but the way in which sex hormones influence cardiovascular physiology among individuals with PTSD is not well understood.Objective: This study sought to clarify the association between sex hormones, PTSD, and CVD among trauma-exposed women.Method: Sixty-six trauma-exposed women (M age = 31.45, SD = 8.92) completed a clinical interview for PTSD and self-reported CVD symptoms; estradiol and progesterone were assayed from blood samples. The association between each sex hormone and CVD symptoms was analyzed, controlling for age, systolic blood pressure (BP), and diastolic BP.Results: Neither estradiol nor the PTSD-by-estradiol interaction was significantly associated with CVD symptoms. Higher progesterone and, relatedly, progesterone-to-estradiol ratio (PE ratio) were each significantly associated with greater CVD symptom severity, but only for individuals with lower relative PTSD severity.Conclusions: The findings indicate that PTSD moderates the relationship between progesterone and CVD symptoms, and further research is warranted to reconcile findings in existing literature regarding the direction of and mechanisms behind this relationship.

Posttraumatic stress disorder (PTSD) is a risk factor for cardiovascular disease (CVD) and sex hormones have been implicated in their link.The current study examined associations between sex hormones, PTSD, and CVD symptoms among 66 trauma-exposed women.Estradiol was not significantly associated with CVD symptoms, but higher progesterone was significantly associated with greater CVD symptom severity, but only for individuals with lower relative PTSD severity.

PTSD increases risk for major adverse cardiovascular events through neural and cardio-inflammatory pathways.

While posttraumatic stress disorder (PTSD) is known to associate with an elevated risk for major adverse cardiovascular events (MACE), few studies have examined mechanisms underlying this link. Recent studies have demonstrated that neuro-immune mechanisms, (manifested by heightened stress-associated neural activity (SNA), autonomic nervous system activity, and inflammation), link common stress syndromes to MACE. However, it is unknown if neuro-immune mechanisms similarly link PTSD to MACE. The current study aimed to test the hypothesis that upregulated neuro-immune mechanisms increase MACE risk among individuals with PTSD. This study included N = 118,827 participants from a large hospital-based biobank. Demographic, diagnostic, and medical history data collected from the biobank. SNA (n = 1,520), heart rate variability (HRV; [n = 11,463]), and high sensitivity C-reactive protein (hs-CRP; [n = 15,164]) were obtained for a subset of participants. PTSD predicted MACE after adjusting for traditional MACE risk factors (hazard ratio (HR) [95 % confidence interval (CI)] = 1.317 [1.098, 1.580], ß = 0.276, p = 0.003). The PTSD-to-MACE association was mediated by SNA (CI = 0.005, 0.133, p < 0.05), HRV (CI = 0.024, 0.056, p < 0.05), and hs-CRP (CI = 0.010, 0.040, p < 0.05). This study provides evidence that neuro-immune pathways may play important roles in the mechanisms linking PTSD to MACE. Future studies are needed to determine if these markers are relevant targets for PTSD treatment and if improvements in SNA, HRV, and hs-CRP associate with reduced MACE risk in this patient population.

PTSD and depression severity are associated with cardiovascular disease symptoms in trauma-exposed women.

Background: Posttraumatic stress disorder (PTSD) and depression are associated with increased risk for cardiovascular disease (CVD), which is the leading cause of death and disability worldwide. Epidemiological studies have revealed these illnesses to be highly comorbid, particularly among women. In the current study, we explored associations between indices of cardiovascular health, PTSD, and depression among a sample of trauma-exposed individuals assigned female at birth.Methods: Participants were N = 49 individuals without CVD who reported lifetime Criterion A trauma exposure. Blood pressure (BP), heart rate (HR), and high-frequency heart rate variability (HF-HRV) were collected during a 5-minute resting period. Symptoms of CVD (e.g. extremity pain and swelling, shortness of breath), PTSD, and depression were assessed, along with an exploratory measure of anhedonia.Results: Trauma exposure was positively correlated with systolic BP (r = .32, p = .029) and diastolic BP (r = .30, p = .040). The number of reported CVD symptoms was positively correlated with symptoms of PTSD (r = .41, p = .004), depression (r = .40, p = .005) and anhedonia (r = .38, p = .007). CVD symptoms were also significantly associated with PTSD (ß = .41, t = 2.43, p = .023), depression (ß = .40, t = 2.76, p = .009), and anhedonia (ß = .38, t = 2.51, p = .017) after controlling for age and trauma exposure. These associations were not moderated by HF-HRV in our sample.Conclusions: Our results support the association between PTSD and depressive symptoms and worse cardiovascular functioning among an often-overlooked population that is particularly vulnerable to these illnesses. Future studies should investigate residual impacts of PTSD and depression treatment on CVD risk among trauma-exposed individuals, particularly women.

Trauma exposure and PTSD are associated with depression and cardiovascular disease (CVD) risk.We explored cardiovascular health, PTSD, and depression among 49 trauma-exposed individuals assigned female at birth.Trauma exposure positively correlated with blood pressure.CVD symptoms were positively correlated with PTSD, depression, and anhedonia.Associations were not moderated by heart rate variability.

Structural inequities contribute to racial/ethnic differences in neurophysiological tone, but not threat reactivity, after trauma exposure.

Considerable racial/ethnic disparities persist in exposure to life stressors and socioeconomic resources that can directly affect threat neurocircuitry, particularly the amygdala, that partially mediates susceptibility to adverse posttraumatic outcomes. Limited work to date, however, has investigated potential racial/ethnic variability in amygdala reactivity or connectivity that may in turn be related to outcomes such as post-traumatic stress disorder (PTSD). Participants from the AURORA study (n = 283), a multisite longitudinal study of trauma outcomes, completed functional magnetic resonance imaging and psychophysiology within approximately two-weeks of trauma exposure. Seed-based amygdala connectivity and amygdala reactivity during passive viewing of fearful and neutral faces were assessed during fMRI. Physiological activity was assessed during Pavlovian threat conditioning. Participants also reported the severity of posttraumatic symptoms 3 and 6 months after trauma. Black individuals showed lower baseline skin conductance levels and startle compared to White individuals, but no differences were observed in physiological reactions to threat. Further, Hispanic and Black participants showed greater amygdala connectivity to regions including the dorsolateral prefrontal cortex (PFC), dorsal anterior cingulate cortex, insula, and cerebellum compared to White participants. No differences were observed in amygdala reactivity to threat. Amygdala connectivity was associated with 3-month PTSD symptoms, but the associations differed by racial/ethnic group and were partly driven by group differences in structural inequities. The present findings suggest variability in tonic neurophysiological arousal in the early aftermath of trauma between racial/ethnic groups, driven by structural inequality, impacts neural processes that mediate susceptibility to later PTSD symptoms.

Vagal control moderates the association between endothelial function and PTSD symptoms in women with T2DM.

Background: Individuals with posttraumatic stress disorder (PTSD) are more likely to present with metabolic diseases such as type-2 diabetes mellitus (T2DM), and cardiovascular dysfunction has been implicated in this link. These diseases disproportionately affect women and individuals exposed to chronic environmental stressors (e.g., community violence, poverty). We examined associations among PTSD, cardiovascular indices, and metabolic function in highly trauma-exposed Black women with T2DM. Methods: Participants (N = 80) were recruited for a follow-up study of stress and T2DM as part of the Grady Trauma Project. PTSD symptoms were assessed with the Clinician Administered PTSD Scale (CAPS-IV). Cardiovascular indices included heart rate (HR), blood pressure (BP), respiratory sinus arrhythmia (RSA), and endothelial function (assessed via flow-mediated dilation; FMD). An oral glucose tolerance test was used as an indicator of metabolic function. Results: Of the cardiovascular indices, only FMD was significantly associated with PTSD symptoms (CAPS Avoidance symptoms; ß = -0.37, p = .042), and glucose tolerance (ß = -0.44, p = .019), controlling for age and body mass index. The association between FMD and PTSD Avoidance was moderated by RSA such that the effect of FMD was only significant at low levels of RSA (simple slopes ß = -0.87, p = .004). Conclusions: Our results indicate that endothelial function is significantly related to PTSD and glucose tolerance, over and above other cardiovascular measures (HR, BP, RSA). Further, our results suggest that low RSA may be a risk factor for the link between poor endothelial function and PTSD in women with T2DM.

Leveraging Large-Scale Genetics of PTSD and Cardiovascular Disease to Demonstrate Robust Shared Risk and Improve Risk Prediction Accuracy.

OBJECTIVE: Individuals with posttraumatic stress disorder (PTSD) are significantly more likely to be diagnosed with cardiovascular disease (CVD) (e.g., myocardial infarction, stroke). The evidence for this link is so compelling that the National Institutes of Health convened a working group to determine gaps in the literature, including the need for large-scale genomic studies to identify shared genetic risk. The aim of the present study was to address some of these gaps by utilizing PTSD and CVD genome-wide association study (GWAS) summary statistics in a large biobank sample to determine the shared genetic risk of PTSD and CVD. METHODS: A large health care biobank data set was used (N=36,412), combined with GWAS summary statistics from publicly available large-scale PTSD and CVD studies. Disease phenotypes (e.g., PTSD) were collected from electronic health records. De-identified genetic data from the biobank were genotyped using Illumina SNP array. Summary statistics data sets were processed with the following quality-control criteria: 1) SNP heritability h2 >0.05, 2) compute z-statistics (z=beta/SE or z=log(OR)/SE), 3) filter nonvariable SNPs (0

Hippocampal Threat Reactivity Interacts with Physiological Arousal to Predict PTSD Symptoms.

Hippocampal impairments are reliably associated with post-traumatic stress disorder (PTSD); however, little research has characterized how increased threat-sensitivity may interact with arousal responses to alter hippocampal reactivity, and further how these interactions relate to the sequelae of trauma-related symptoms. In a sample of individuals recently exposed to trauma (N=116, 76 Female), we found that PTSD symptoms at 2-weeks were associated with decreased hippocampal responses to threat as assessed with functional magnetic resonance imaging (fMRI). Further, the relationship between hippocampal threat sensitivity and PTSD symptomology only emerged in individuals who showed transient, high threat-related arousal, as assayed by an independently collected measure of Fear Potentiated Startle. Collectively, our finding suggests that development of PTSD is associated with threat-related decreases in hippocampal function, due to increases in fear-potentiated arousal.Significance StatementAlterations in hippocampal function linked to threat-related arousal are reliably associated with post-traumatic stress disorder (PTSD); however, how these alterations relate to the sequelae of trauma-related symptoms is unknown. Prior models based on non-trauma samples suggest that arousal may impact hippocampal neurophysiology leading to maladaptive behavior. Here we show that decreased hippocampal threat sensitivity interacts with fear-potentiated startle to predict PTSD symptoms. Specifically, individuals with high fear-potentiated startle and low, transient hippocampal threat sensitivity showed the greatest PTSD symptomology. These findings bridge literatures of threat-related arousal and hippocampal function to better understand PTSD risk.

Heart Rate Variability Features as Predictors of Intermittent Theta-Burst Stimulation Response in Posttraumatic Stress Disorder.

BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with autonomic dysfunction as indicated by deficits in the sympathetic and parasympathetic nervous systems. These abnormalities are expressed as elevated heart rate and reduced heart rate variability (HRV), respectively. Intermittent theta-burst stimulation (iTBS), a form of transcranial magnetic stimulation, has demonstrated effectiveness in PTSD. Nevertheless, it remains unclear whether HRV may be an iTBS biomarker for PTSD and whether iTBS impacts autonomic activity. MATERIALS AND METHODS: Fifty veterans with PTSD participated in a randomized controlled trial, receiving ten daily sessions of sham-controlled iTBS (right dorsolateral prefrontal cortex, 1800 pulses/day, 80% active motor threshold, 9.5 min). With a usable dataset (N = 47), HRV parameters were assessed as predictors of clinical response immediately after stimulation. iTBS effects on autonomic response (mean RR interval, root mean square of successive differences [RMSSD], total power [TP], and low-frequency/high-frequency [LF/HF] ratio) were evaluated using an ultra-short approach. RESULTS: TP and RMSSD were significant predictors of acute clinical response to iTBS. Individuals with higher TP had better response to iTBS with improved symptoms on the Clinician-Administered PTSD Scale (rs = -0.58, p = 0.004), and higher functionality on the Social and Occupational Function Scale (rs = 0.43, p = 0.04). Similarly, higher RMSSD was associated with superior outcomes (rs = -0.44, p = 0.04). No other significant changes in HRV metrics were observed (p ≥ 0.05). CONCLUSIONS: Our findings indicate that autonomic activity is a potential low-cost and technically simple predictive biomarker of iTBS response in PTSD. Less autonomic dysfunction was associated with superior clinical improvements with iTBS. Future studies might consider HRV acquisition during iTBS, as well as prospective testing of these findings in patients with elevated hyperarousal.

Involvement of the brain-heart axis in the link between PTSD and cardiovascular disease.

Posttraumatic stress disorder (PTSD) has long been associated with a heightened risk of cardiovascular disease (CVD). A number of mechanisms have been implicated to underlie this brain-heart axis relationship, such as altered functioning of the autonomic nervous system and increased systemic inflammation. While neural alterations have repeatedly been observed in PTSD, they are rarely considered in the PTSD-CVD link. The brain-heart axis is a pathway connecting frontal and limbic brain regions to the brainstem and periphery via the autonomic nervous system and it may be a promising model for understanding CVD risk in PTSD given its overlap with PTSD neural deficits. We first provide a summary of the primary mechanisms implicated in the association between PTSD and CVD. We then review the brain-heart axis and its relevance to PTSD, as well as findings from PTSD trials demonstrating that a number of PTSD treatments have effects on areas of the brain-heart axis. Finally, we discuss sex considerations in the PTSD-CVD link. A critical next step in this study is to determine if PTSD treatments that affect the brain-heart axis (e.g., brain stimulation that improves autonomic function) also reduce the risk of CVD.

Heart rate variability and HbA1c predict plasma interleukin-6 response to psychosocial stress challenge in trauma-exposed women with type 2 diabetes.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a major public health problem in the United States. Although cardiovascular autonomic functioning, blood glucose control, and inflammation are known to play a role in T2DM, the interaction between these variables remains largely unexplored, particularly in the context of stress. To address this gap, we examined the relationship between these variables in a sample that is uniquely vulnerable to the health consequences of T2DM. METHODS: Participants were 37 trauma-exposed Black women with a diagnosis of T2DM. High frequency heart rate variability (HF-HRV), blood glucose control (HbA1c), and a stressor-evoked biomarker of inflammation (interleukin 6; IL-6) were obtained as part of a larger study of the genetic risk factors for and consequences of trauma exposure. RESULTS: The interaction of HbA1c and HF-HRV was significantly associated with IL-6 response calculated as area under the curve with respect to ground. Post-hoc simple slopes analyses revealed HbA1c, rather than HF-HRV, as the moderator in this association such that higher HF-HRV conferred higher circulating levels of IL-6 only in the presence of lower HbA1c, (ߠ​= â€‹0.60, t â€‹= â€‹3.51, p â€‹= â€‹.001). CONCLUSIONS: Cardiovascular autonomic functioning and blood glucose control were significantly associated with stressor-evoked IL-6 responses when controlling for BMI and age. Moreover, the association between cardiovascular autonomic functioning and inflammation varied at different levels of HbA1c. This highlights the possibility that individuals with trauma exposure and T2DM may benefit from stratification by HbA1c levels for research analysis and treatment decision making.

A prospective examination of sex differences in posttraumatic autonomic functioning.

BACKGROUND: Cross-sectional studies have found that individuals with posttraumatic stress disorder (PTSD) exhibit deficits in autonomic functioning. While PTSD rates are twice as high in women compared to men, sex differences in autonomic functioning are relatively unknown among trauma-exposed populations. The current study used a prospective design to examine sex differences in posttraumatic autonomic functioning. METHODS: 192 participants were recruited from emergency departments following trauma exposure (Mean age = 35.88, 68.2% female). Skin conductance was measured in the emergency department; fear conditioning was completed two weeks later and included measures of blood pressure (BP), heart rate (HR), and high frequency heart rate variability (HF-HRV). PTSD symptoms were assessed 8 weeks after trauma. RESULTS: 2-week systolic BP was significantly higher in men, while 2-week HR was significantly higher in women, and a sex by PTSD interaction suggested that women who developed PTSD demonstrated the highest HR levels. Two-week HF-HRV was significantly lower in women, and a sex by PTSD interaction suggested that women with PTSD demonstrated the lowest HF-HRV levels. Skin conductance response in the emergency department was associated with 2-week HR and HF-HRV only among women who developed PTSD. CONCLUSIONS: Our results indicate that there are notable sex differences in autonomic functioning among trauma-exposed individuals. Differences in sympathetic biomarkers (BP and HR) may have implications for cardiovascular disease risk given that sympathetic arousal is a mechanism implicated in this risk among PTSD populations. Future research examining differential pathways between PTSD and cardiovascular risk among men versus women is warranted.

Randomized, Placebo-Controlled Trial of the Angiotensin Receptor Antagonist Losartan for Posttraumatic Stress Disorder.

BACKGROUND: Evidence-based pharmacological treatments for posttraumatic stress disorder (PTSD) are few and of limited efficacy. Previous work suggests that angiotensin type 1 receptor inhibition facilitates fear inhibition and extinction, important for recovery from PTSD. This study tests the efficacy of the angiotensin type 1 receptor antagonist losartan, an antihypertensive drug, repurposed for the treatment of PTSD. METHODS: A randomized controlled trial was conducted for 10 weeks in 149 men and women meeting DSM-5 PTSD criteria. Losartan (vs. placebo) was flexibly titrated from 25 to 100 mg/day by week 6 and held at highest tolerated dose until week 10. Primary outcome was the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) change score at 10 weeks from baseline. A key secondary outcome was change in CAPS-5 associated with a single nucleotide polymorphism of the ACE gene. Additional secondary outcomes included changes in the PTSD Checklist for DSM-5 and the Patient Health Questionnaire-9, and proportion of responders with a Clinical Global Impressions-Improvement scale of "much improved" or "very much improved." RESULTS: Both groups had robust improvement in PTSD symptoms, but there was no significant difference on the primary end point, CAPS-5 measured as week 10 change from baseline, between losartan and placebo (mean change difference, 0.9, 95% confidence interval, -3.2 to 5.0). There was no significant difference in the proportion of Clinical Global Impressions-Improvement scale responders for losartan (58.6%) versus placebo (57.9%), no significant differences in changes in PTSD Checklist for DSM-5 or Patient Health Questionnaire-9, and no association between ACE genotype and CAPS-5 improvement on losartan. CONCLUSIONS: At these doses and durations, there was no significant benefit of losartan compared with placebo for the treatment of PTSD. We discuss implications for failure to determine the benefit of a repurposed drug with strong a priori expectations of success based on preclinical and epidemiological data.

Thalamic volume and fear extinction interact to predict acute posttraumatic stress severity.

Posttraumatic stress disorder (PTSD) is associated with lower gray matter volume (GMV) in brain regions critical for extinction of learned threat. However, relationships among volume, extinction learning, and PTSD symptom development remain unclear. We investigated subcortical brain volumes in regions supporting extinction learning and fear-potentiated startle (FPS) to understand brain-behavior interactions that may impact PTSD symptom development in recently traumatized individuals. Participants (N = 99) completed magnetic resonance imaging and threat conditioning two weeks following trauma exposure as part of a multisite observational study to understand the neuropsychiatric effects of trauma (AURORA Study). Participants completed self-assessments of PTSD (PTSD Checklist for DSM-5; PCL-5), dissociation, and depression symptoms two- and eight-weeks post-trauma. We completed multiple regressions to investigate relationships between FPS during late extinction, GMV, and PTSD symptom development. The interaction between thalamic GMV and FPS during late extinction at two weeks post-trauma predicted PCL-5 scores eight weeks (t (75) = 2.49, ß = 0.28, p = 0.015) post-trauma. Higher FPS predicted higher PCL-5 scores in the setting of increased thalamic GMV. Meanwhile, lower FPS also predicted higher PCL-5 scores in the setting of decreased thalamic GMV. Thalamic GMV and FPS interactions also predicted posttraumatic dissociative and depressive symptoms. Amygdala and hippocampus GMV by FPS interactions were not associated with posttraumatic symptom development. Taken together, thalamic GMV and FPS during late extinction interact to contribute to adverse posttraumatic neuropsychiatric outcomes. Multimodal assessments soon after trauma have the potential to distinguish key phenotypes vulnerable to posttraumatic neuropsychiatric outcomes.

Epigenetic prediction of 17ß-estradiol and relationship to trauma-related outcomes in women.

17ß-estradiol (E2) levels in women correlate with multiple neuropsychiatric symptoms, including those that are stress-related. Furthermore, prior work from our group has demonstrated that E2 status influences DNA methylation (DNAm) across the genome. We developed and validated a DNAm-based predictor of E2 (one of four naturally occurring estrogens) using a training set of 183 females and a test set of 79 females from the same traumatized cohort. We showed that predicted E2 levels were highly correlated with measured E2 concentrations in our testing set (r â€‹= â€‹0.75, p â€‹= â€‹1.8e-15). We further demonstrated that predicted E2 concentrations, in combination with measured values, negatively correlated with current post-traumatic stress disorder (PTSD) (ߠ​= â€‹-0.38, p â€‹= â€‹0.01) and major depressive disorder (MDD) diagnoses (ߠ​= â€‹-0.45, p â€‹= â€‹0.02), as well as a continuous measure of PTSD symptom severity (ߠ​= â€‹-2.3, p â€‹= â€‹0.007) in females. Finally, we tested our predictor in an independent data set (n â€‹= â€‹85) also comprised of recently traumatized female subjects to determine if the predictor would generalize to a different population than the one on which it was developed. We found that the correlation between predicted and actual E2 concentrations in the external validation data set was also high (r â€‹= â€‹0.48, p â€‹= â€‹3.0e-6). While further validation is warranted, a DNAm predictor of E2 concentrations will advance our understanding of hormone-epigenetic interactions. Furthermore, such a DNAm predictor may serve as an epigenetic proxy for E2 concentrations and thus provide an important biomarker to better evaluate the contribution of E2 to current and potentially future psychiatric symptoms in samples for which E2 is not measured.

Neurophysiological responses to safety signals and the role of cardiac vagal control.

BACKGROUND: Deficits in safety signal learning are well-established in fear-related disorders (e.g., PTSD, phobias). The current study used a fear conditioning paradigm to test associations among eye blink startle and event-related brain potential (ERP) latency measures of safety signal learning, as well as the role of cardiac vagal control (a measure of top-down inhibition necessary for safety learning). METHODS: Participants were 49 trauma-exposed women ages 17 to 28 years. Eyeblink startle response and ERP amplitudes/latencies were derived for conditioned stimuli associated (CS+) and not associated (CS-) with an aversive unconditioned stimulus. ERPs included the P100 and late positive potential (LPP), which index early visual processing and sustained emotional encoding, respectively. Cardiac vagal control was assessed with resting heart rate variability (HRV). RESULTS: P100 and LPP latencies for the CS- (safety signal stimulus) were significantly negatively associated with startle to the CS-, but not the CS + . LPP CS- latencies were significantly negatively associated with PTSD Intrusion scores, and this relationship was moderated by vagal control, such that the effect was only present among those with low HRV. CONCLUSIONS: ERP-based markers of safety signal learning were associated with startle response to the CS- (but not CS+) and PTSD symptoms, indicating that these markers may have relevance for fear-related disorders. Cardiac vagal control indexed by HRV is a moderating factor in these associations and may be relevant to safety signal learning.

The Influence of Sexual Assault Resistance on Reporting Tendencies and Law Enforcement Response: Findings From the National Crime Victimization Survey.

Despite its prevalence, sexual assault remains a vastly underreported crime. Previous research suggests that engagement in certain types of resistance during an assault affects the way in which both victims and others perceive the attack; such perceptions influence victims' likelihood of reporting the assault to law enforcement as well as the criminal justice system response to reported allegations. Using a fight/flight/freeze theoretical framework, the current study sought to examine how forceful, nonforceful, and freeze responding influenced victim reporting and the extent to which reported assaults were pursued and investigated by law enforcement. Using data from the National Crime Victimization Survey between 2010 and 2016, logistic regression analysis indicated that victims are significantly less likely to report to law enforcement if they froze during the attack. Interestingly, although engagement in forceful resistance increases victims' likelihood of reporting to law enforcement, it has no bearing on law enforcement response beyond the effect of physical injury. Rather, physical injury (e.g., bruises, cuts, broken bones) is the only predictor of law enforcement response to sexual assault allegations. Findings suggest that whereas fight and freeze responses to sexual victimization influence victims' willingness to report to law enforcement, resistance is not uniquely predictive of law enforcement response once physical injury is considered.

The renin-angiotensin system in PTSD: a replication and extension.

Prior observational studies have suggested that medications targeting the renin-angiotensin system, such as angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs), may be associated with decreased PTSD symptoms. Given known sex differences in PTSD prevalence and cardiovascular disease, here we tested whether the effects of ACE-I/ARB status on PTSD differ by sex. We also expanded these observations with replication analyses in a large biorepository database. Participants in the initial sample included 840 trauma-exposed individuals recruited as part of the Grady Trauma Project. The Modified PTSD Symptom Scale (M-PSS) was administered and ACE-I/ARB status was determined by self-report. Replication analyses were conducted using a large biorepository database (Partners Healthcare Biobank, N = 116,389) with diagnoses and medication status based on available electronic health records. Among individuals treated with ACE-Is/ARBs in the initial sample, women had significantly higher M-PSS total and Re-experiencing severity compared to men (p's < 0.05). Analyses with the large biorepository sample robustly replicated the overall effects of ACE-I/ARB medication associated with lower rate of PTSD diagnosis (p < 0.001). We also demonstrated that this effect may be specific to the renin-angiotensin system as it did not replicate for beta-blockers, calcium channel blockers, or diuretics. When we examined more specific drug classes, results indicated that the ACE-I/ARB effect on PTSD may be driven more by ARBs (e.g., Losartan) than by ACE-Is. Post-hoc analyses indicated that racial differences may exist in these effects. Overall, our results replicate and extend prior observations that the renin-angiotensin system is associated with PTSD. Medications targeting this system may be worthy of further investigation for PTSD treatment. Our findings suggest that sex and race effects should be considered in future treatment research.

Translational studies of estradiol and progesterone in fear and PTSD.

Translational models of fear have greatly informed our understanding of PTSD and its underlying fear circuitry. One of the most replicated findings in the field is the two-fold higher PTSD incidence in females compared to males. While sociocultural factors play a role, the most robust biological influencers to date are gonadal hormones, such as estradiol and progesterone, which fluctuate across the menstrual cycle. Among studies that account for these hormones, most do so in isolation or collect both and only report one. Variation in study findings suggests that the ratio between these two hormones (the P/E ratio) may be an important and missing variable to further understand gonadal hormone influences on fear. Here we review cross-species examinations of fear and PTSD, within the contexts of estradiol and progesterone as well as P/E ratios that were calculated based on extant literature. We then provide recommendations for best practices in assay methods and reporting to improve research on the P/E ratio in fear and PTSD. Ultimately, greater understanding of this important variable will advance efforts to characterize gonadal hormone influences on fear learning processes in humans and animals.

Los modelos traslacionales del miedo han enriquecido nuestro conocimiento sobre el TEPT y el circuito del miedo subyacente. Uno de los hallazgos más replicados en el campo es la incidencia dos veces mayor de TEPT en mujeres en comparación a los hombres. Aunque los factores socioculturales juegan un rol, las influencias biológicas más robustas a la fecha son las hormonas gonadales, tales como el estradiol y la progesterona, que fluctúan durante el ciclo menstrual. Entre los estudios que dan cuenta de estas hormonas, la mayoría las estudian de forma aislada u obtienen ambas y solo reportan una. La variación en los hallazgos de los estudios sugiere que la razón entre estas dos hormonas (la razón P/E) puede ser una variable poco estudiada e importante para mejorar la comprensión de la influencia de las hormonas gonadales en el miedo. En este trabajo hacemos una revisión de hallazgos trans-especie sobre el miedo y el TEPT, dentro del contexto del estradiol y la progresterona así como de la razón P/E que fue calculada basándose en la literatura existente Posteriormente proveemos recomendaciones para mejorar las prácticas en los métodos de ensayo y reportes para mejorar la investigación sobre la razón P/E en miedo y TEPT. En última instancia, mayor comprensión de esta importante variable hará que progresen los esfuerzos para caracterizar la influencia de las hormonas gonadales en procesos de aprendizaje del miedo en humanos y animales.