Cognition and Ventral Attention Network Connectivity: Associations With Treatment Response in Posttraumatic Stress Disorder.

OBJECTIVE: Posttraumatic stress disorder (PTSD) is a highly heterogeneous disorder, which makes it difficult to link clinical phenotypes with biomarkers to improve treatment outcomes. Findings from previous studies suggest that cognitive measures such as verbal memory or attention paired with within-ventral attention network (VAN) or salience network resting-state functional connectivity may predict treatment response among individuals with PTSD. METHODS: In a sample comprising 20 individuals with PTSD and 10 healthy control group individuals, the investigators subtyped individuals by using both discriminant function analysis and standardized norms for a single measure of memory and neuropsychological batteries of memory, attention, and executive functioning; attempted to replicate previous findings of lower within-VAN connectivity among individuals with cognitive impairment; and explored whether within-VAN connectivity paired with cognitive impairment predicted treatment outcomes. RESULTS: PTSD patients with cognitive impairment (defined by using a discriminant function analysis with verbal memory performance) had greater within-VAN resting-state functional connectivity compared with control group individuals and cognitively intact PTSD patients at a level that fell short of statistical significance (F=3.41; df=2, 21; ηp2=0.237). The interaction between verbal memory performance and within-VAN connectivity also predicted treatment-related change in PTSD symptoms at a level that also fell short of statistical significance (ß=-0.442). CONCLUSIONS: These findings somewhat support the clinical utility of identifying cognitive phenotypes within PTSD (by using discriminant function analysis and verbal memory performance) to predict treatment outcomes.

Anxiety and Depression Associated With Increased Cardiovascular Disease Risk Through Accelerated Development of Risk Factors.

Background: Prior studies have incompletely assessed whether the development of cardiometabolic risk factors (CVDRF) (hypertension, hyperlipidemia, and diabetes mellitus) mediates the association between anxiety and depression (anxiety/depression) and cardiovascular disease (CVD). Objectives: The authors aimed to evaluate the following: 1) the association between anxiety/depression and incident CVDRFs and whether this association mediates the increased CVD risk; and 2) whether neuro-immune mechanisms and age and sex effects may be involved. Methods: Using a retrospective cohort design, Mass General Brigham Biobank subjects were followed for 10 years. Presence and timing of anxiety/depression, CVDRFs, and CVD were determined using ICD codes. Stress-related neural activity, chronic inflammation, and autonomic function were measured by the assessment of amygdalar-to-cortical activity ratio, high-sensitivity CRP, and heart rate variability. Multivariable regression and mediation analyses were employed. Results: Among 71,214 subjects (median age 49.6 years; 55.3% female), 27,048 (38.0%) developed CVDRFs during follow-up. Pre-existing anxiety/depression associated with increased risk of incident CVDRF (OR: 1.71 [95% CI: 1.59-1.83], P < 0.001) and with a shorter time to their development (ß = -0.486 [95% CI: -0.62 to -0.35], P < 0.001). The development of CVDRFs mediated the association between anxiety/depression and CVD events (log-odds: 0.044 [95% CI: 0.034-0.055], P < 0.05). Neuro-immune pathways contributed to the development of CVDRFs (P < 0.05 each) and significant age and sex effects were noted: younger women experienced the greatest acceleration in the development of CVDRFs after anxiety/depression. Conclusions: Anxiety/depression accelerate the development of CVDRFs. This association appears to be most notable among younger women and may be mediated by stress-related neuro-immune pathways. Evaluations of tailored preventive measures for individuals with anxiety/depression are needed to reduce CVD risk.

Anxiety and depression are associated with heightened risk of incident deep vein thrombosis: Mediation through stress-related neural mechanisms.

Controversy exists as to whether anxiety and depression increase deep vein thrombosis (DVT) risk, and the mechanisms mediating potential links remain unknown. We aimed to evaluate the association between anxiety and depression and DVT risk and determine whether upregulated stress-related neural activity (SNA), which promotes chronic inflammation, contributes to this link. Our retrospective study included adults (N = 118 871) enrolled in Mass General Brigham Biobank. A subset (N = 1520) underwent clinical 18F-FDG-PET/CT imaging. SNA was measured as the ratio of amygdalar to cortical activity (AmygAC). High-sensitivity C-reactive protein (hs-CRP) and heart rate variability (HRV) were also obtained. Median age was 58 [interquartile range (IQR) 42-70] years with 57% female participants. DVT occurred in 1781 participants (1.5%) over median follow-up of 3.6 years [IQR 2.1-5.2]. Both anxiety and depression independently predicted incident DVT risk after robust adjustment (HR [95% CI]: 1.53 [1.38-1.71], p < .001; and 1.48 [1.33-1.65], p < .001, respectively). Additionally, both anxiety and depression associated with increased AmygAC (standardized beta [95% CI]: 0.16 [0.04-0.27], p = .007, and 0.17 [0.05-0.29], p = .006, respectively). Furthermore, AmygAC associated with incident DVT (HR [95% CI]: 1.30 [1.07-1.59], p = .009). Mediation analysis demonstrated that the link between anxiety/depression and DVT was mediated by: (1) higher AmygAC, (2) higher hs-CRP, and (3) lower HRV ( < .05 for each). Anxiety and depression confer an attributable risk of DVT similar to other traditional DVT risk factors. Mechanisms appear to involve increased SNA, autonomic system activity, and inflammation. Future studies are needed to determine whether treatment of anxiety and depression can reduce DVT risk.

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.

A late-life neurogenetic signature of exposure to combat stress - A monozygotic discordant twin study.

Animal models suggest that experiencing high-stress levels induces changes in amygdalar circuitry and gene expression. In humans, combat exposure has been shown to alter amygdalar responsivity and connectivity, but abnormalities have been indicated to normalize at least partially upon the termination of stress exposure. In contrast, other evidence suggests that combat exposure continues to exert influence on exposed individuals well beyond deployment and homecoming, as indicated by longitudinal psychosocial evidence from veterans, and observation of greater health decline in veterans late in life. Accordingly, the experience of combat stress early in life may affect amygdalar responsivity late in life, a possibility requiring careful consideration of the confounding effects of aging, genetic factors, and symptoms of post-traumatic stress disorder. Here, we investigated amygdalar responsivity in a unique sample of 16 male monozygotic (MZ) twin pairs in their sixties, where one but not the other sibling had been exposed to combat stress in early adulthood. Forty years after combat experience, a generally blunted amygdalar response was observed in combat-exposed veterans compared to their non-exposed twin siblings. Spatial associations between these phenotypical changes and patterns of gene expression in the brain were found for genes involved in the synaptic organization and chromatin structure. Protein-protein interactions among the set of identified genes pointed to histone modification mechanisms. We conclude that exposure to combat stress early in life continues to impact brain function beyond the termination of acute stress and appears to exert prolonged effects on amygdalar function later in life via neurogenetic mechanisms.

Amygdalar activity measured using FDG-PET/CT at head and neck cancer staging independently predicts survival.

IMPORTANCE: The mechanisms underlying the association between chronic stress and higher mortality among individuals with cancer remain incompletely understood. OBJECTIVE: To test the hypotheses that among individuals with active head and neck cancer, that higher stress-associated neural activity (ie. metabolic amygdalar activity [AmygA]) at cancer staging associates with survival. DESIGN: Retrospective cohort study. SETTING: Academic Medical Center (Massachusetts General Hospital, Boston). PARTICIPANTS: 240 patients with head and neck cancer (HNCA) who underwent 18F-FDG-PET/CT imaging as part of initial cancer staging. MEASUREMENTS: 18F-FDG uptake in the amygdala was determined by placing circular regions of interest in the right and left amygdalae and measuring the mean tracer accumulation (i.e., standardized uptake value [SUV]) in each region of interest. Amygdalar uptake was corrected for background cerebral activity (mean temporal lobe SUV). RESULTS: Among individuals with HNCA (age 59±13 years; 30% female), 67 died over a median follow-up period of 3 years (IQR: 1.7-5.1). AmygA associated with heightened bone marrow activity, leukocytosis, and C-reactive protein (P<0.05 each). In adjusted and unadjusted analyses, AmygA associated with subsequent mortality (HR [95% CI]: 1.35, [1.07-1.70], P = 0.009); the association persisted in stratified subset analyses restricted to patients with advanced cancer stage (P<0.001). Individuals within the highest tertile of AmygA experienced a 2-fold higher mortality rate compared to others (P = 0.01). The median progression-free survival was 25 months in patients with higher AmygA (upper tertile) as compared with 36.5 months in other individuals (HR for progression or death [95%CI], 1.83 [1.24-2.68], P = 0.001). CONCLUSIONS AND RELEVANCE: AmygA, quantified on routine 18F-FDG-PET/CT images obtained at cancer staging, independently and robustly predicts mortality and cancer progression among patients with HNCA. Future studies should test whether strategies that attenuate AmygA (or its downstream biological consequences) may improve cancer survival.

Exaggerated amygdala activation to ambiguous facial expressions is a familial vulnerability factor for posttraumatic stress disorder.

OBJECTIVE: Previous research has reported hyperresponsivity in the amygdala and hyporesponsivity in ventral portions of the medial prefrontal cortex to threat-related stimuli in posttraumatic stress disorder (PTSD). Whether such findings generalize to more ambiguous stimuli and whether such brain activation abnormalities reflect familial vulnerabilities, trauma-exposure, or acquired characteristics of PTSD remain unclear. In this study, we measured brain responses to emotionally ambiguous stimuli (i.e., surprised facial expressions) in identical twin pairs discordant for trauma exposure to elucidate the origin of brain activation abnormalities. METHODS: Participants with PTSD (n = 12) and their trauma-unexposed identical cotwins (n = 12), as well as trauma-exposed participants without PTSD (n = 15) and their trauma-unexposed identical cotwins (n = 15), passively viewed surprised and neutral facial expressions during functional magnetic resonance imaging (fMRI). Afterward, participants labeled and rated each facial expression on valence and arousal. RESULTS: Amygdala activation to Surprised and Neutral facial expressions (versus Fixation) was greater in the participants with PTSD and their trauma-unexposed identical cotwins without PTSD, compared to the control twin pairs. In contrast, medial frontal gyrus (MFG) activation to Surprised facial expressions (versus Fixation) was diminished in the PTSD group relative to the other three groups. CONCLUSIONS: Amygdala hyperresponsivity to emotionally ambiguous facial expressions may be a familial vulnerability factor that increases the likelihood of developing PTSD after experiencing a traumatic event. In contrast, MFG hyporesponsivity may be an acquired characteristic of the disorder.

Impairing memory reconsolidation with propranolol in healthy and clinical samples: a meta-analysis.

BACKGROUND: Reconsolidation impairment using propranolol is a novel intervention for mental disorders with an emotional memory at their core. In this systematic review and meta-analysis, we examined the evidence for this intervention in healthy and clinical adult samples. METHODS: We searched 8 databases for randomized, double-blind studies that involved at least 1 propranolol group and 1 placebo group. We conducted a meta-analysis of 14 studies (n = 478) in healthy adults and 12 studies in clinical samples (n = 446). RESULTS: Compared to placebo, reconsolidation impairment under propranolol resulted in reduced recall of aversive material and cue-elicited conditioned emotional responses in healthy adults, as evidenced by an effect size (Hedges g) of -0.51 (p = 0.002, 2-tailed). Moreover, compared to placebo, reconsolidation impairment under propranolol alleviated psychiatric symptoms and reduced cue-elicited reactivity in clinical samples with posttraumatic stress disorder, addiction or phobia (g = -0.42, p = 0.010). LIMITATIONS: Methodological differences between studies posed an obstacle for identifying sources of heterogeneity. CONCLUSION: Reconsolidation impairment is a robust, well-replicated phenomenon in humans. Its clinical use is promising and deserves further controlled investigation.

A neurobiological link between transportation noise exposure and metabolic disease in humans.

BACKGROUND: Chronic transportation noise exposure associates with cardiovascular events through a link involving heightened stress-associated neurobiological activity (as amygdalar metabolic activity, AmygA) on 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT). Increased AmygA also associates with greater visceral adipose tissue (VAT) and type 2 diabetes mellitus (DM). While relationships between noise exposure and VAT and DM have been reported, the underlying mechanisms remain incompletely understood. We tested whether: (1) transportation noise exposure associates with greater (a) baseline and gains in VAT and (b) DM risk, and (2) heightened AmygA partially mediates the link between noise exposure and these metabolic diseases. METHODS: VAT was measured in a retrospective cohort (N = 403) who underwent clinical 18F-FDG-PET/CT. AmygA was measured in those with brain imaging (N = 238). Follow-up VAT was remeasured on available imaging (N = 67). Among individuals (N = 224) without baseline DM, incident DM was adjudicated over 2 years from clinical records. Noise (24-h average) was modeled at each individual's home address. Linear regression, survival, and mediation analyses were employed. RESULTS: Higher noise exposure (upper tertile vs. others) associated with greater: baseline VAT (standardized ß [95% confidence interval (CI)]= 0.230 [0.021, 0.438], p = 0.031), gains in VAT (0.686 [0.185, 1.187], p = 0.008 adjusted for baseline VAT), and DM (hazard ratio [95% CI]=2.429 [1.031, 5.719], p = 0.042). The paths of: ↑noise exposure→↑AmygA→↑baseline VAT and ↑noise exposure→↑AmygA→↑subsequent DM were significant (p < 0.05). CONCLUSIONS: Increased transportation noise exposure associates with greater VAT and DM. This relationship is partially mediated by stress-associated neurobiological activity. These findings suggest altered neurobiology contributes to noise exposure's link to metabolic diseases.

Stress-associated neurobiological activity associates with the risk for and timing of subsequent Takotsubo syndrome.

AIMS: Activity in the amygdala, a brain centre involved in the perception of and response to stressors, associates with: (i) heightened sympathetic nervous system and inflammatory output and (ii) risk of cardiovascular disease. We hypothesized that the amygdalar activity (AmygA) ratio is heightened among individuals who develop Takotsubo syndrome (TTS), a heart failure syndrome often triggered by acute stress. We tested the hypotheses that (i) heightened AmygA precedes development of TTS and (ii) those with the highest AmygA develop the syndrome earliest. METHODS AND RESULTS: Individuals (N=104, median age 67.5 years, 72% female, 86% with malignancy) who underwent clinical 18 F-FDG-PET/CT imaging were retrospectively identified: 41 who subsequently developed TTS and 63 matched controls (median follow-up 2.5 years after imaging). AmygA was measured using validated methods. Individuals with (vs. without) subsequent TTS had higher baseline AmygA (P=0.038) after adjusting for TTS risk factors. Further, AmygA associated with the risk for subsequent TTS after adjustment for risk factors [standardized hazard ratio (95% confidence interval): 1.643 (1.189, 2.270), P=0.003]. Among the subset of individuals who developed TTS, those with the highest AmygA (>mean + 1 SD) developed TTS ∼2 years earlier after imaging vs. those with lower AmygA (P=0.028). CONCLUSION: Higher AmygA associates with an increased risk for TTS among a retrospective population with a high rate of malignancy. This heightened neurobiological activity is present years before the onset of TTS and may impact the timing of the syndrome. Accordingly, heightened stress-associated neural activity may represent a therapeutic target to reduce stress-related diseases, including TTS.

Traumatic memories of childbirth relate to maternal postpartum posttraumatic stress disorder.

The trauma memory is a crucial feature of PTSD etiology and maintenance. Nonetheless, the nature of memories associated with childbirth-related posttraumatic stress disorder (CB-PTSD) requires explication. The present study, as part of a larger project on psychological outcomes of childbirth, utilized a multi-method approach to characterize childbirth memories in relation to CB-PTSD symptoms. We here assessed 413 women who completed self-report measures pertaining to CB-PTSD, postpartum depression, and childbirth memories. Additionally, a subset of 209 women provided written childbirth narratives, analyzed using Linguistic Inquiry and Word Count software. Women endorsing CB-PTSD symptoms on the PTSD-Checklist (PCL)-5 reported more incoherent childbirth memories with more emotional and sensory details, and more frequent involuntary recall and reliving of the memory. They also indicated the childbirth experience was more central to their identity. Written narratives in those with probable CB-PTSD were characterized by less (positive) affective processes, and more cognitive processes. We infer that childbirth memories in women who endorse symptoms of CB-PTSD in the early postpartum period resemble those described in the general PTSD literature. This suggests that childbirth may be experienced as traumatic and evoke a traumatic memory, implicated in symptom endorsement. Opportunities for therapeutic interventions modifying traumatic memories of childbirth in women at risk for CB-PTSD need to be investigated. Future research examining characteristics of traumatic childbirth memories is needed to advance our understanding of this overlooked postpartum condition.

Disentangling the Links Between Psychosocial Stress and Cardiovascular Disease.

Stress is a pervasive component of the human experience. While often considered an adversity to be ignored, chronic stress has important pathological consequences, including cardiovascular disease (CVD). Stress also increases the prevalence and severity of several CVD risk factors, including hypertension, diabetes mellitus, and obesity. Yet even after adjustment, stress' attributable CVD risk is similar to those risk factors, suggesting it is a particularly potent contributor. Nevertheless, there has been insufficient study of mechanisms linking stress to CVD or of methods to attenuate stress' pathological impact. This review covers the current concepts of how stress impacts CVD and emerging approaches to mitigate stress-attributable CVD risk.

Greater Neurobiological Resilience to Chronic Socioeconomic or Environmental Stressors Associates With Lower Risk for Cardiovascular Disease Events.

BACKGROUND: Chronic exposure to socioeconomic or environmental stressors associates with greater stress-related neurobiological activity (ie, higher amygdalar activity [AmygA]) and higher risk of major adverse cardiovascular events (MACE). However, among individuals exposed to such stressors, it is unknown whether neurobiological resilience (NBResilience, defined as lower AmygA despite stress exposure) lowers MACE risk. We tested the hypotheses that NBResilience protects against MACE, and that it does so through decreased bone marrow activity and arterial inflammation. METHODS: Individuals underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomography; AmygA, bone marrow activity, and arterial inflammation were quantified. Chronic socioeconomic and environmental stressors known to associate with AmygA and MACE (ie, transportation noise exposure, neighborhood median household income, and crime rate) were quantified. Heightened stress exposure was defined as exposure to at least one chronic stressor (ie, the highest tertile of noise exposure or crime or lowest tertile of income). MACE within 5 years of imaging was adjudicated. Relationships were evaluated using linear and Cox regression, Kaplan-Meier survival, and mediation analyses. RESULTS: Of 254 individuals studied (median age [interquartile range]: 57 years [46-67], 36.7% male), 166 were exposed to at least one chronic stressor. Among stress-exposed individuals, 12 experienced MACE over a median follow-up of 3.75 years. Among this group, higher AmygA (ie, lower resilience) associated with higher bone marrow activity (standardized ß [95% CI]: 0.192 [0.030-0.353], P=0.020), arterial inflammation (0.203 [0.055-0.351], P=0.007), and MACE risk (standardized hazard ratio [95% CI]: 1.927 [1.370-2.711], P=0.001). The effect of NBResilience on MACE risk was significantly mediated by lower arterial inflammation (P<0.05). CONCLUSIONS: Among individuals who are chronically exposed to socioeconomic or environmental stressors, NBResilience (AmygA <1 SD above the mean) associates with a >50% reduction in MACE risk, potentially via reduced arterial inflammation. These data raise the possibility that enhancing NBResilience may decrease the burden of cardiovascular disease.

Baseline Cognitive Performance and Treatment Outcomes From Cognitive-Behavioral Therapies for Posttraumatic Stress Disorder: A Naturalistic Study.

OBJECTIVE: Approximately 5%-20% of U.S. troops returning from Iraq and Afghanistan have posttraumatic stress disorder (PTSD), and another 11%-23% have traumatic brain injury (TBI). Cognitive-behavioral therapies (CBTs) are empirically validated treatment strategies for PTSD. However, cognitive limitations may interfere with an individual's ability to adhere to as well as benefit from such therapies. Comorbid TBI has not been systematically taken into consideration in PTSD outcome research or in treatment planning guidance. The authors hypothesized that poorer pretreatment cognitive abilities would be associated with poorer treatment outcomes from CBTs for PTSD. METHODS: This study was designed as a naturalistic examination of treatment as usual in an outpatient clinic that provides manualized CBTs for PTSD to military service members and veterans. Participants were 23 veterans, aged 18-50 years, with combat-related PTSD and a symptom duration of more than 1 year. Of these, 16 participants had mild TBI (mTBI). Predictor variables were well-normed objective tests of cognitive ability measured at baseline. Outcome variables were individual slopes of change of the PTSD Checklist for DSM-5 (PCL-5) and the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) over weeks of treatment, and of pretreatment-to-posttreatment change in PCL-5 and CAPS-5 (ΔPCL-5 and ΔCAPS-5, respectively). RESULTS: Contrary to prediction, neither pretreatment cognitive performance nor the presence of comorbid mTBI predicted poorer response to CBTs for PTSD. CONCLUSIONS: These results discourage any notion of excluding patients with PTSD and poorer cognitive ability from CBTs.

Chronic Stress-Related Neural Activity Associates With Subclinical Cardiovascular Disease in Psoriasis: A Prospective Cohort Study.

OBJECTIVES: This study hypothesized that there is an association between chronic stress (as indexed by resting amygdalar activity [AmygA]), hematopoietic system activity (HMPA), and subclinical cardiovascular indexes (aortic vascular inflammation [VI] and noncalcified coronary plaque burden [NCB]) in psoriasis (PSO). The study also hypothesized that treatment of PSO would improve these parameters. BACKGROUND: PSO is a stress-related chronic inflammatory condition that is associated with increased prevalence of subclinical cardiovascular disease (CVD). In individuals without PSO, stress has been linked to CVD through a serial biological pathway that involves the amygdala, hematopoietic tissues, and atherosclerotic plaques. METHODS: A total of 164 consecutive patients with PSO and 47 healthy volunteers underwent 18-fluorodeoxyglucose positron emission tomography/computed tomography scans for assessment of AmygA, HMPA, and VI, as well as coronary computed tomography angiography scans for quantifying NCB. Furthermore, a consecutive subset of 30 patients with severe PSO (Psoriasis Area Severity Index Score >10) were followed at 1 year to assess the relationship between skin disease improvement and AmygA, HMPA, VI, and NCB. RESULTS: The PSO cohort was middle-aged (mean age: 50 years), had low cardiovascular risk (Framingham risk score: median: 3) and had mild to moderate PSO activity (median Psoriasis Area Severity Index Score: 5.6). AmygA was higher in patients with PSO compared to volunteer participants. AmygA was associated with HMPA (bone marrow activity: ß = 0.20, p = 0.01) and subclinical CVD (VI: ß = 0.31, p < 0.001; NCB: ß = 0.27, p < 0.001) The AmygA-CVD association was in part mediated by HMPA (VI: 20.9%, NCB: 36.7%). Following 1 year of PSO treatment in those with severe disease, improvement in skin disease was accompanied by a reduction in AmygA, bone marrow activity, and VI, with no progression of NCB. CONCLUSIONS: In PSO, a chronic inflammatory disease state, AmygA, which is a manifestation of chronic stress, substantially contributes to the risk of subclinical CVD. Additional studies that use psychometric measures of stress are required to explore therapeutic impact.

A neurobiological mechanism linking transportation noise to cardiovascular disease in humans.

AIMS: Chronic noise exposure associates with increased cardiovascular disease (CVD) risk; however, the role of confounders and the underlying mechanism remain incompletely defined. The amygdala, a limbic centre involved in stress perception, participates in the response to noise. Higher amygdalar metabolic activity (AmygA) associates with increased CVD risk through a mechanism involving heightened arterial inflammation (ArtI). Accordingly, in this retrospective study, we tested whether greater noise exposure associates with higher: (i) AmygA, (ii) ArtI, and (iii) risk for major adverse cardiovascular disease events (MACE). METHODS AND RESULTS: Adults (N = 498) without CVD or active cancer underwent clinical 18F-fluorodeoxyglucose positron emission tomography/computed tomography imaging. Amygdalar metabolic activity and ArtI were measured, and MACE within 5 years was adjudicated. Average 24-h transportation noise and potential confounders were estimated at each individual's home address. Over a median 4.06 years, 40 individuals experienced MACE. Higher noise exposure (per 5 dBA increase) predicted MACE [hazard ratio (95% confidence interval, CI) 1.341 (1.147-1.567), P < 0.001] and remained robust to multivariable adjustments. Higher noise exposure associated with increased AmygA [standardized ß (95% CI) 0.112 (0.051-0.174), P < 0.001] and ArtI [0.045 (0.001-0.090), P = 0.047]. Mediation analysis suggested that higher noise exposure associates with MACE via a serial mechanism involving heightened AmygA and ArtI that accounts for 12-26% of this relationship. CONCLUSION: Our findings suggest that noise exposure associates with MACE via a mechanism that begins with increased stress-associated limbic (amygdalar) activity and includes heightened arterial inflammation. This potential neurobiological mechanism linking noise to CVD merits further evaluation in a prospective population.

Stress-Associated Neurobiological Pathway Linking Socioeconomic Disparities to Cardiovascular Disease.

BACKGROUND: Lower socioeconomic status (SES) associates with a higher risk of major adverse cardiac events (MACE) via mechanisms that are not well understood. OBJECTIVES: Because psychosocial stress is more prevalent among those with low SES, this study tested the hypothesis that stress-associated neurobiological pathways involving up-regulated inflammation in part mediate the link between lower SES and MACE. METHODS: A total of 509 individuals, median age 55 years (interquartile range: 45 to 66 years), underwent clinically indicated whole-body 18F-fluorodeoxyglucose positron emission tomography/computed tomography imaging and met pre-defined inclusion criteria, including absence of known cardiovascular disease or active cancer. Baseline hematopoietic tissue activity, arterial inflammation, and in a subset of 289, resting amygdalar metabolism (a measure of stress-associated neural activity) were quantified using validated 18F-fluorodeoxyglucose positron emission tomography/computed tomography methods. SES was captured by neighborhood SES factors (e.g., median household income and crime). MACE within 5 years of imaging was adjudicated. RESULTS: Over a median 4.0 years, 40 individuals experienced MACE. Baseline income inversely associated with amygdalar activity (standardized ß: -0.157 [95% confidence interval (CI): -0.266 to -0.041]; p = 0.007) and arterial inflammation (ß: -0.10 [95% CI: -0.18 to -0.14]; p = 0.022). Further, income associated with subsequent MACE (standardized hazard ratio: 0.67 [95% CI: 0.47 to 0.96]; p = 0.029) after multivariable adjustments. Mediation analysis demonstrated that the path of: ↓ neighborhood income to ↑ amygdalar activity to ↑ bone marrow activity to ↑ arterial inflammation to ↑ MACE was significant (ß: -0.01 [95% CI: -0.06 to -0.001]; p < 0.05). CONCLUSIONS: Lower SES: 1) associates with higher amygdalar activity; and 2) independently predicts MACE via a serial pathway that includes higher amygdalar activity, bone marrow activity, and arterial inflammation. These findings illuminate a stress-associated neurobiological mechanism by which SES disparities may potentiate adverse health outcomes.

Delivery mode is associated with maternal mental health following childbirth.

Childbirth is a life-transforming event often followed by a time of heightened psychological vulnerability in the mother. There is a growing recognition of the importance of obstetrics aspects in maternal well-being with the way of labor potentially influencing psychological adjustment following parturition or failure thereof. Empirical scrutiny on the association between mode of delivery and postpartum well-being remains limited. We studied 685 women who were on average 3 months following childbirth and collected information concerning mode of delivery and pre- and postpartum mental health. Analysis of variance revealed that women who had cesarean section or vaginal instrumental delivery had higher somatization, obsessive compulsive, depression, and anxiety symptom levels than those who had natural or vaginal delivery as well as overall general distress, controlling for premorbid mental health, maternal age, education, primiparity, and medical complication in newborn. Women who underwent unplanned cesarean also had higher levels of childbirth-related PTSD symptoms excluding those with vaginal instrumental. The risk for endorsing psychiatric symptoms reflecting clinically relevant cases increased by twofold following unplanned cesarean and was threefold for probable childbirth-related PTSD. Maternal well-being following childbirth is associated with the experienced mode of delivery. Increasing awareness in routine care of the implications of operative delivery and obstetric interventions in delivery on a woman's mental health is needed. Screening at-risk women could improve the quality of care and prevent enduring symptoms. Research is warranted on the psychological and biological factors implicated in the mode of delivery and their role in postpartum adjustment.

Psychosocial Stress and Cardiovascular Disease.

PURPOSE OF REVIEW: This manuscript reviews the epidemiological data linking psychosocial stress to cardiovascular disease (CVD), describes recent advances in understanding the biological pathway between them, discusses potential therapies against stress-related CVD, and identifies future research directions. RECENT FINDINGS: Metabolic activity of the amygdala (a neural center that is critically involved in the response to stress) can be measured on 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) yielding a neurobiological signal that independently predicts subsequent CVD events. Furthermore, a serial pathway from ↑amygdalar activity → ↑hematopoietic tissue activity → ↑arterial inflammation → ↑CVD events has been elucidated, providing new insights into the mechanism linking stress to CVD. Psychosocial stress and stress conditions are independently associated with CVD in a manner that depends on the degree and duration of stress as well as the individual response to a stressor. Nevertheless, the fundamental biology remains incompletely defined, and stress is often confounded by adverse health behaviors. Thus, most clinical guidelines do not yet recognize psychosocial stress as an independent CVD risk factor or advocate for its treatment in CVD prevention. Clarification of this neurobiological pathway provides a better understanding of the underlying pathophysiology and suggests opportunities to develop novel preventive strategies and therapies.