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.

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.

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.

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.

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.

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.

Relation between resting amygdalar activity and cardiovascular events: a longitudinal and cohort study.

BACKGROUND: Emotional stress is associated with increased risk of cardiovascular disease. We imaged the amygdala, a brain region involved in stress, to determine whether its resting metabolic activity predicts risk of subsequent cardiovascular events. METHODS: Individuals aged 30 years or older without known cardiovascular disease or active cancer disorders, who underwent 18F-fluorodexoyglucose PET/CT at Massachusetts General Hospital (Boston, MA, USA) between Jan 1, 2005, and Dec 31, 2008, were studied longitudinally. Amygdalar activity, bone-marrow activity, and arterial inflammation were assessed with validated methods. In a separate cross-sectional study we analysed the relation between perceived stress, amygdalar activity, arterial inflammation, and C-reactive protein. Image analyses and cardiovascular disease event adjudication were done by mutually blinded researchers. Relations between amygdalar activity and cardiovascular disease events were assessed with Cox models, log-rank tests, and mediation (path) analyses. FINDINGS: 293 patients (median age 55 years [IQR 45·0-65·5]) were included in the longitudinal study, 22 of whom had a cardiovascular disease event during median follow-up of 3·7 years (IQR 2·7-4·8). Amygdalar activity was associated with increased bone-marrow activity (r=0·47; p<0·0001), arterial inflammation (r=0·49; p<0·0001), and risk of cardiovascular disease events (standardised hazard ratio 1·59, 95% CI 1·27-1·98; p<0·0001), a finding that remained significant after multivariate adjustments. The association between amygdalar activity and cardiovascular disease events seemed to be mediated by increased bone-marrow activity and arterial inflammation in series. In the separate cross-sectional study of patients who underwent psychometric analysis (n=13), amygdalar activity was significantly associated with arterial inflammation (r=0·70; p=0·0083). Perceived stress was associated with amygdalar activity (r=0·56; p=0·0485), arterial inflammation (r=0·59; p=0·0345), and C-reactive protein (r=0·83; p=0·0210). INTERPRETATION: In this first study to link regional brain activity to subsequent cardiovascular disease, amygdalar activity independently and robustly predicted cardiovascular disease events. Amygdalar activity is involved partly via a path that includes increased bone-marrow activity and arterial inflammation. These findings provide novel insights into the mechanism through which emotional stressors can lead to cardiovascular disease in human beings. FUNDING: None.

Consolidation and reconsolidation are impaired by oral propranolol administered before but not after memory (re)activation in humans.

Propranolol administered immediately after learning or after recall has been found to impair memory consolidation or reconsolidation (respectively) in animals, but less reliably so in humans. Since reconsolidation impairment has been proposed as a treatment for mental disorders that have at their core an emotional memory, it is desirable to understand how to reliably reduce the strength of pathogenic memories in humans. We postulated that since humans (unlike experimental animals) typically receive propranolol orally, this introduces a delay before this drug can exert its memory impairment effects, which may render it less effective. As a means to test this, in two double-blind placebo-controlled experiments, we examined the capacity of propranolol to impair consolidation and reconsolidation as a function of timing of ingestion in healthy subjects. In Experiment 1, (n=36), propranolol administered immediately after learning or recall failed to impair the consolidation or reconsolidation of the memory of a standardized slideshow with an accompanying emotional story. In Experiment 2 (n=50), propranolol given 60-75min before learning or recall successfully impaired memory consolidation and reconsolidation. These results suggest that it is possible to achieve reliable memory impairment in humans if propranolol is given before learning or before recall, but not after.

Biological studies of post-traumatic stress disorder.

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.

Sleep Patterns and Neuropsychiatric Symptoms in Hospitalized Patients With Dementia.

The authors examined 28 dementia inpatients receiving treatment as usual. Beginning-to-end differences in neuropsychiatric symptoms and actigraphic sleep patterns were measured. Using a mixed-model, the authors regressed neuropsychiatric symptoms on average sleep minutes (between-subjects effect) and each night's deviation from average (within-subject effect). Sleep did not significantly differ from beginning to end of participation, whereas neuropsychiatric symptoms did. Average sleep minutes predicted average neuropsychiatric symptoms (p=0.002), but each night's deviation from the average did not predict next day's symptoms (p=0.90). These findings raise questions about the immediate benefits of treating sleep-wake disturbances on neuropsychiatric symptoms in hospitalized inpatients with dementias.

Positive Association Between Nightmares and Heart Rate Response to Loud Tones: Relationship to Parasympathetic Dysfunction in PTSD Nightmares.

Seventy-three women with posttraumatic stress disorder (PTSD) resulting from rape or physical assault participated in a loud-tone procedure, while skin conductance (SC), heart rate, and electromyogram responses were recorded. Pearson correlations were examined between each psychophysiological response and Clinician-Administered PTSD Scale (CAPS) symptom scores. Significant correlations were adjusted for each remaining individual PTSD symptom score. Heart rate response (HRR) significantly correlated with CAPS total score and with CAPS nightmares. The relationship between HRR and nightmares remained significant after controlling for each of the other 16 individual PTSD symptoms, for the remaining reexperiencing cluster, and for CAPS total score. The zero-order correlations between SC response and nightmares and between electromyography response and nightmares were both not significant. The association of nightmares with larger HRR in the absence of an association with larger SC response likely reflects reduced parasympathetic tone. Thus, our findings indirectly support a role for reduced parasympathetic tone in PTSD nightmares.

Mixed-Handedness in Identical Twins Discordant for Combat Exposure in Vietnam: Relationship to Posttraumatic Stress Disorder.

This study evaluated the degree of mixed-handedness in predominantly right-handed Vietnam combat veteran twins and their identical, combat-unexposed cotwins. The "high-risk" cotwins of combat veterans with combat-related posttraumatic stress disorder (PTSD) had more mixed-handedness (i.e., less right-handedness) than the "low-risk" cotwins of combat veterans without PTSD. Self-reported combat exposure in combat-exposed twins was a mediator of the association between handedness in their unexposed cotwins and PTSD in the twins themselves. We conclude that mixed-handedness is a familial risk factor for combat-related PTSD. This risk may be mediated in part by a proclivity for mixed-handed soldiers and Marines to experience heavier combat.

Learning and reconsolidation implicate different synaptic mechanisms.

Synaptic mechanisms underlying memory reconsolidation after retrieval are largely unknown. Here we report that synapses in projections to the lateral nucleus of the amygdala implicated in auditory fear conditioning, which are potentiated by learning, enter a labile state after memory reactivation, and must be restabilized through a postsynaptic mechanism implicating the mammalian target of rapamycin kinase-dependent signaling. Fear-conditioning-induced synaptic enhancements were primarily presynaptic in origin. Reconsolidation blockade with rapamycin, inhibiting mammalian target of rapamycin kinase activity, suppressed synaptic potentiation in slices from fear-conditioned rats. Surprisingly, this reduction of synaptic efficacy was mediated by post- but not presynaptic mechanisms. These findings suggest that different plasticity rules may apply to the processes underlying the acquisition of original fear memory and postreactivational stabilization of fear-conditioning-induced synaptic enhancements mediating fear memory reconsolidation.

Pilot Study of Neurological Soft Signs and Depressive and Postconcussive Symptoms During Recovery From Mild Traumatic Brain Injury (mTBI).

Neurological soft signs (NSSs) tap into a variety of perceptual, motor, and cognitive functions. The authors administered a battery of NSSs serially to a group of 14 pilot patients recruited from an emergency room after they experienced a mild traumatic brain injury. Patients were seen within 96 hours after injury, and again 30 and 90 days later. Measures of balance, mood, and postconcussive symptoms and impairment were also obtained. NSSs and balance improved across visits. Across visits, NSSs and balance were not significantly associated with any postconcussive outcome measures, although depressive symptoms were. Initial neurological impairment appeared to predict subsequent residual postconcussive symptoms and impairment, but this result requires replication.

Pilot study of the effect of lipophilic vs. hydrophilic beta-adrenergic blockers being taken at time of intracardiac defibrillator discharge on subsequent PTSD symptoms.

A pathophysiological model of posttraumatic stress disorder (PTSD) posits that an overly strong stress response at the time of the traumatic event leads to overconsolidation of the event's memory in part through a central ß-adrenergic mechanism. We hypothesized that the presence of a ß-blocker in the patient's brain at the time of the traumatic event would reduce the PTSD outcome by blocking this effect. The unpredictable, uncontrollable discharge of an implantable intracardiac defibrillator (ICD) is experienced by most patients as highly stressful, and it has previously been shown to be capable of causing PTSD symptoms. The present pilot study evaluated a convenience sample of 18 male cardiac patients who had been taking either a lipophilic ß-blocker (which penetrates the blood-brain barrier) or a hydrophilic ß-blocker (which does not) at the time of a discharge of their ICD. The self- report PTSD Checklist-Specific Version quantified 17 PTSD symptoms pertaining to the ICD discharge during the month preceding the evaluation. There was a statistical trend for patients who had been taking a lipophilic ß-blocker at the time of the ICD discharge to have (35%) less severe PTSD symptoms than patients who had been taking a hydrophilic ß-blocker (one-tailed p=0.07, g=0.64). Further, prospective, randomized, controlled studies are suggested.

Interactions of time of day and sleep with between-session habituation and extinction memory in young adult males.

Within-session habituation and extinction learning co-occur as do subsequent consolidation of habituation (i.e., between-session habituation) and extinction memory. We sought to determine whether, as we predicted: (1) between-session habituation is greater across a night of sleep versus a day awake; (2) time-of-day accounts for differences; (3) between-session habituation predicts consolidation of extinction memory; (4) sleep predicts between-session habituation and/or extinction memory. Participants (N = 28) completed 4-5 sessions alternating between mornings and evenings over 3 successive days (2 nights) with session 1 in either the morning (N = 13) or evening (N = 15). Twelve participants underwent laboratory polysomnography. During 4 sessions, participants completed a loud-tone habituation protocol, while skin conductance response (SCR), blink startle electromyography (EMG), heart-rate acceleration and heart-rate deceleration (HRD) were recorded. For sessions 1 and 2, between-session habituation of EMG, SCR and HRD was greater across sleep. SCR and HRD were generally lower in the morning. Between-session habituation of SCR for sessions 1 and 2 was positively related to intervening (first night) slow wave sleep. In the evening before night 2, participants also underwent fear conditioning and extinction learning phases of a second protocol. Extinction recall was tested the following morning. Extinction recall was predicted only by between-session habituation of SCR across the same night (second night) and by intervening REM. We conclude that: (1) sleep augments between-session habituation, as does morning testing; (2) extinction recall is predicted by concurrent between-session habituation; and (3) both phenomena may be influenced by sleep.

Stress, PTSD, and dementia.

The physiological consequences of acute and chronic stress on a range of organ systems have been well documented after the pioneering work of Hans Selye more than 70 years ago. More recently, an association between exposure to stressful life events and the development of later-life cognitive dysfunction has been proposed. Several plausible neurohormonal pathways and genetic mechanisms exist to support such an association. However, many logistical and methodological barriers must be overcome before a defined causal linkage can be firmly established. Here the authors review recent studies of the long-term cognitive consequences of exposures to cumulative ordinary life stressors as well as extraordinary traumatic events leading to posttraumatic stress disorder. Suggestive effects have been demonstrated for the role of life stress in general, and posttraumatic stress disorder in particular, on a range of negative cognitive outcomes, including worse than normal changes with aging, Alzheimer's disease, and vascular dementia. However, given the magnitude of the issue, well-controlled studies are relatively few in number, and the effects they have revealed are modest in size. Moreover, the effects have typically only been demonstrated on a selective subset of measures and outcomes. Potentially confounding factors abound and complicate causal relationships despite efforts to contain them. More well-controlled, carefully executed longitudinal studies are needed to confirm the apparent association between stress and dementia, clarify causal relationships, develop reliable antemortem markers, and delineate distinct patterns of risk in subsets of individuals.

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.