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Post‐traumatic stress disorder (PTSD) has been associated with cardiovascular disease (CVD), but the mechanisms remain unclear. Autonomic dysfunction, associated with higher CVD risk, may be triggered by acute PTSD symptoms. We hypothesized that a laboratory‐based trauma reminder challenge, which induces acute PTSD symptoms, provokes autonomic dysfunction in a cohort of veteran twins. We investigated PTSD‐associated real‐time physiologic changes with a simulation of traumatic experiences in which the twins listened to audio recordings of a one‐minute neutral script followed by a one‐minute trauma script. We examined two heart rate variability metrics: deceleration capacity (DC) and logarithmic low frequency (log‐LF) power from beat‐to‐beat intervals extracted from ambulatory electrocardiograms. We assessed longitudinal PTSD status with a structured clinical interview and the severity with the PTSD Symptoms Scale. We used linear mixed‐effects models to examine twin dyads and account for cardiovascular and behavioral risk factors. We examined 238 male Veteran twins (age 68 ± 3 years old, 4% black). PTSD status and acute PTSD symptom severity were not associated with DC or log‐LF measured during the neutral session, but were significantly associated with lower DC and log‐LF during the traumatic script listening session. Long‐standing PTSD was associated with a 0.38 (95% confidence interval, −0.83,‐0.08) and 0.79 (−1.30,‐0.29) standardized unit lower DC and log‐LF, respectively, compared to no history of PTSD. Traumatic reminders in patients with PTSD lead to real‐time autonomic dysregulation and suggest a potential causal mechanism for increased CVD risk, based on the well‐known relationships between autonomic dysfunction and CVD mortality. Our study employed an innovative laboratory trauma recall challenge to examine the acute impact of PTSD symptoms on autonomic physiology in male veteran twins. We found evidence that PTSD leads to real‐time pathological effects on the autonomic nervous system such as vagal withdrawal. Our findings provide direct evidence to a causal mechanism linking PTSD to heart disease by comparing PTSD discordant twin brothers. [ABSTRACT FROM AUTHOR]

Introduction: Prior studies have shown inconsistent findings of an association between depression and epigenetic aging. DNA methylation (DNAm) age acceleration can measure biological aging. We adopted a robust co‐twin control study design to examine whether depression is associated with DNAm age acceleration after accounting for the potential confounding influences of genetics and family environment. Methods: We analyzed data on a sub‐cohort of the Vietnam Era Twin Registry. A total of 291 twins participated at baseline and 177 at follow‐up visit after a mean of 11.7 years, with 111 participants having DNA samples for both time points. Depression was measured using the Beck Depression Inventory II (BDI‐II). Six measures of DNAm age acceleration were computed at each time point, including Horvath's DNAm age acceleration (HorvathAA), intrinsic epigenetic age acceleration (IEAA), Hannum's DNAm age acceleration (HannumAA), extrinsic epigenetic age acceleration (EEAA), GrimAge acceleration (GrimAA), and PhenoAge acceleration (PhenoAA). Mixed‐effects modeling was used to assess the within‐pair association between depression and DNAm age acceleration. Results: At baseline, a 10‐unit higher BDI‐II total score was associated with HannumAA (0.73 years, 95% confidence interval [CI] 0.13–1.33, p =.019) and EEAA (0.94 years, 95% CI 0.22–1.66, p =.012). At follow‐up, 10‐unit higher BDI‐II score was associated with PhenoAA (1.32 years, 95% CI 0.18–2.47, p =.027). Conclusion: We identified that depression is associated with higher levels of DNAm age acceleration. Further investigation is warranted to better understand the underlying mechanisms for the potential causal relationship between depression and accelerated aging. [ABSTRACT FROM AUTHOR]

Background: Obstructive sleep apnea (OSA) has been associated with incidence of cardiovascular disease and with nocturnal angina, but evidence of a link with coronary atherosclerosis and myocardial ischemia is limited and previous studies may have been affected by selection bias or unmeasured confounding factors. Methods: We performed overnight polysomnography in 178 older male twins. The Apnea/Hypopnea Index (AHI) was calculated to assess OSA from the overnight sleep evaluation. AHI ≥15 was used as indicator of moderate/severe OSA. The following day, twins underwent myocardial perfusion imaging with [82Rb]-chloride positron emission tomography. Quantitative and semiquantitative measures of myocardial perfusion and absolute myocardial blood flow were obtained. Results: The mean age was 68 years and 40% of the sample had an AHI≥15, which indicates moderate to severe OSA. Abnormal myocardial perfusion, both with stress and at rest, was more common in twins with elevated AHI. After adjusting for clinical, lifestyle and behavioral factors, and previous history of cardiovascular disease, twins with AHI ≥15 had 3.6 higher odds (95% CI, 1.5–8.9) of an abnormal total severity score, defined as a score ≥100, and for each 5-point increment in AHI, the odds of abnormality increased by 20% (95% CI, 7%-34%). Twin pairs where both twins had OSA exhibited the greatest risk. There were no differences in measures of ischemia and absolute myocardial blood flow and flow reserve by AHI status. Conclusions: OSA is associated with myocardial perfusion abnormalities that suggest prior subclinical myocardial scarring or infarction. Early environmental factors that affect both twins equally may play a role and should be further explored. [ABSTRACT FROM AUTHOR]

Treating opioid use disorder (OUD) is a significant healthcare challenge in the United States. Remaining abstinent from opioids is challenging for individuals with OUD due to withdrawal symptoms that include restlessness. However, to our knowledge, studies of acute withdrawal have not quantified restlessness using involuntary movements. We hypothesized that wearable accelerometry placed mid-sternum could be used to detect withdrawal-related restlessness in patients with OUD. To study this, 23 patients with OUD undergoing active withdrawal participated in a protocol involving wearable accelerometry, opioid cues to elicit craving, and non-invasive Vagal Nerve Stimulation (nVNS) to dampen withdrawal symptoms. Using accelerometry signals, we analyzed how movements correlated with changes in acute withdrawal severity, measured by the Clinical Opioid Withdrawal Scale (COWS). Our results revealed that patients demonstrating sinusoidal–i.e., predominantly single-frequency oscillation patterns in their motion almost exclusively demonstrated an increase in the COWS, and a strong relationship between the maximum power spectral density and increased withdrawal over time, measured by the COWS (R = 0.92, p = 0.029). Accelerometry may be used in an ambulatory setting to indicate the increased intensity of a patient's withdrawal symptoms, providing an objective, readily-measurable marker that may be captured ubiquitously. [ABSTRACT FROM AUTHOR]

Background: Few studies have comprehensively evaluated the association of depression with sleep disturbance using a controlled twin study design.Purpose: To cross-sectionally evaluate the association of depression with both objective and subjective sleep disturbance.Methods: We studied 246 members of the Vietnam Era Twin Registry. We measured depressive symptoms using the Beck Depression Inventory-II (BDI) and assessed major depression using structured clinical interviews. Twins underwent one-night polysomnography and 7-day actigraphy to derive measures of objective sleep and completed the Pittsburgh Sleep Quality Index for subjective sleep. Multivariable mixed-effects models were used to examine the association.Results: Twins were all male, mostly white (97%), with a mean (SD) age of 68 (2). The mean (SD) BDI was 5.9 (6.3), and 49 (20%) met the criteria for major depression. For polysomnography, each 5-unit higher BDI, within-pair, was significantly associated with 19.7 min longer rapid eye movement (REM) sleep latency, and 1.1% shorter REM sleep after multivariable adjustment. BDI was not associated with sleep architecture or sleep-disordered breathing. For actigraphy, a higher BDI, within-pair, was significantly associated with lower sleep efficiency, more fragmentation and higher variability in sleep duration. BDI was associated with almost all dimensions of self-reported sleep disturbance. Results did not differ by zygosity, and remained consistent using major depression instead of BDI and were independent of the presence of comorbid posttraumatic stress disorder and antidepressant use.Conclusions: Depression is associated with REM sleep disruption in lab and sleep fragmentation and sleep variability at home, but not with sleep architecture or sleep-disordered breathing. [ABSTRACT FROM AUTHOR]

Background: Little is known about the role of DNA methylation (DNAm) epigenetic age acceleration in cognitive decline. Using a twin study design, we examined whether DNAm age acceleration is related to cognitive decline measured longitudinally in persons without a clinical diagnosis of dementia.Methods: We studied 266 paired male twins (133 pairs) with a mean age of 56 years at baseline. Of these, 114 paired twins returned for a follow-up after an average of 11.5 years. We obtained 6 indices of DNAm age acceleration based on epigenome-wide data from peripheral blood lymphocytes. At both baseline and follow-up, we administered a battery of cognitive measures and constructed 2 composite scores, one for executive function and one for memory function. We fitted multivariable mixed regression models to examine the association of DNAm age acceleration markers with cognitive function within pairs.Results: In cross-sectional analyses at baseline, there was no association between DNAm age acceleration and cognitive function scores. In longitudinal analyses, however, comparing twins within pairs, each additional year of age acceleration using the Horvath's method was associated with a 3% decline (95% CI, 1%-5%) in the composite executive function score and a 2.5% decline (95% CI, 0.01%-4.9%) in the memory function score. These results did not attenuate after adjusting for education and other risk factors.Conclusions: Middle-aged men who had older DNAm age relative to their brothers of the same demographic age showed a faster rate of cognitive decline in the subsequent 11.5 years. These results point to the role of epigenetic modifications in cognitive aging. [ABSTRACT FROM AUTHOR]

Importance: Depressive symptoms are associated with lower heart rate variability (HRV), an index of autonomic dysregulation, but the direction of the association remains unclear.Objective: To investigate the temporal association between depression and HRV.Design, Settings, and Participants: A longitudinal, cross-lagged twin difference study, with baseline assessments from March 2002 to March 2006 (visit 1) and a 7-year follow-up (visit 2) at an academic research center with participants recruited from a national twin registry. Twins (n = 166) from the Vietnam Era Twin Registry, who served in the US military during the Vietnam War, and were discordant for depression at baseline were recruited.Main Outcomes and Measures: At both visits, depressive symptoms were measured using the Beck Depression Inventory-II (BDI-II), and HRV was measured through 24-hour electrocardiogram monitoring. To assess the direction of the association, within-pair differences in multivariable mixed-effects regression models were examined, and standardized β coefficients for both pathways were calculated. The associations were evaluated separately in monozygotic and dizygotic twins.Results: In the final analytic sample (N = 146), all participants were men, 138 (95%) were white, and the mean (SD) age was 54 (3) years at baseline. Results showed consistent associations between visit 1 HRV and visit 2 BDI score across all HRV domains and models (β coefficients ranging from -0.14 to -0.29), which were not explained by antidepressants or other participant characteristics. The magnitude of the association was similar in the opposite pathway linking visit 1 BDI score to visit 2 HRV, with β coefficients ranging from 0.05 to -0.30, but it was largely explained by antidepressant use. In stratified analysis by zygosity, significant associations were observed in monozygotic and dizygotic twins for the path linking visit 1 HRV to visit 2 BDI score, although the associations were slightly stronger in dizygotic twins.Conclusions and Relevance: The association between depression and autonomic dysregulation, indexed by HRV, is bidirectional, with stronger evidence suggesting that autonomic function affects depression risk rather than vice versa. The opposite causal pathway from depression to lower HRV is mostly driven by antidepressant use. These findings highlight an important role of autonomic nervous system in the risk of depression and contribute new understanding of the mechanisms underlying the comorbidity of depression and cardiovascular disease. [ABSTRACT FROM AUTHOR]

Background: Posttraumatic Stress Disorder (PTSD) is a chronic psychiatric condition that develops after exposure to life‐threatening events. The negative impact of PTSD on a person's emotions and behavior can have long‐term deleterious effects on cognitive performance. The association between PTSD and cognition however can be confounded by unmeasured factors such as shared genetic and environmental factors. Twin studies allow us to explore this potential causal pathway by controlling for genetic and familial confounding. Methods: We examined 77 male monozygotic and 47 dizygotic twin pairs from the Vietnam Era Twin Registry in two examinations approximately 12 years apart. At both visits, we obtained information regarding demographic data, medical history, diagnosis of PTSD and cognitive tests. Memory and learning were measured by Trail making tests, Wechsler Memory Scale (Immediate and Delayed Memory tests and Visual Reproductive Test). Linear mixed‐effect regression models were used to examine the association between PTSD and cognitive tests accounting for twin pairing. Analysis was performed by treating twins as individuals and considering within twin pair differences (among twin pairs discordant for PTSD). Results: The mean age was 55 years (SD 3.0) at baseline, 96% were White, and 60% monozygotic twins. Lifetime history of PTSD was not associated with cognitive measures at baseline. At follow‐up, the mean age was 67.9 years (SD 2.5). In twins considered as individuals lifetime history of PTSD was associated with worse performance on Trails A (β = 4.9, 95% CI 8.6, 1.3, p‐value = 0.008) and Trails B (β = 14.6, 95% CI 26.8, 2.4, p‐value = 0.019). After adjusting for demographics, cardiovascular and behavioral risk factors, these associations persisted (Trails A, β = 5.4, 95% CI 9.4, 1.4, p‐value = 0.009; Trails B, β = 14.1, 95% CI 26.9, 1.2, p‐value = 0.032). The within‐pair estimates were similar to individual estimates. There was no association with Wechsler immediate or delayed story recall or Visual Reproductive Test. In stratified analyses, the results were similar by zygosity. Conclusions: Lifetime history of PTSD is associated with poor cognitive performance, primarily in the executive function domain, which manifests at older age. This association is not confounded by shared genetic and other familial factors. [ABSTRACT FROM AUTHOR]

Objectives: Depression is an adverse prognostic factor after an acute myocardial infarction (MI), and an increased propensity toward emotionally-driven myocardial ischemia may play a role. We aimed to examine the association between depressive symptoms and mental stress-induced myocardial ischemia in young survivors of an MI. Methods: We studied 98 patients (49 women and 49 men) age 38–60 years who were hospitalized for acute MI in the previous 6 months. Patients underwent myocardial perfusion imaging at rest, after mental stress (speech task), and after exercise or pharmacological stress. A summed difference score (SDS), obtained with observer-independent software, was used to quantify myocardial ischemia under both stress conditions. The Beck Depression Inventory-II (BDI-II) was used to measure depressive symptoms, which were analyzed as overall score, and as separate somatic and cognitive depressive symptom scores. Results: There was a significant positive association between depressive symptoms and SDS with mental stress, denoting more ischemia. After adjustment for demographic and lifestyle factors, disease severity and medications, each incremental depressive symptom was associated with 0.14 points higher SDS. When somatic and cognitive depressive symptoms were examined separately, both somatic [β = 0.17, 95% CI: (0.04, 0.30), p = 0.01] and cognitive symptoms [β = 0.31, 95% CI: (0.07, 0.56), p = 0.01] were significantly associated with mental stress-induced ischemia. Depressive symptoms were not associated with ischemia induced by exercise or pharmacological stress. Conclusion: Among young post-MI patients, higher levels of both cognitive and somatic depressive symptoms are associated with a higher propensity to develop myocardial ischemia with mental stress, but not with physical (exercise or pharmacological) stress. [ABSTRACT FROM AUTHOR]

Objective: Coronary heart disease is a leading cause of death and disability. Although psychological stress has been identified as an important potential contributor, mechanisms by which stress increases risk of heart disease and mortality are not fully understood. The purpose of this study was to assess mechanisms by which stress acts through the brain and heart to confer increased CHD risk., Methods: Coronary Heart Disease patients (N=10) underwent cardiac imaging with [Tc-99m] sestamibi single photon emission tomography at rest and during a public speaking mental stress task. Patients returned for a second day and underwent positron emission tomography imaging of the brain, heart, bone marrow, aorta (indicating inflammation) and subcutaneous adipose tissue, after injection of [ 18 F]2-fluoro-2-deoxyglucose for assessment of glucose uptake followed mental stress. Patients with (N=4) and without (N=6) mental stress-induced myocardial ischemia were compared for glucose uptake in brain, heart, adipose tissue and aorta with mental stress., Results: Patients with mental stress-induced ischemia showed a pattern of increased uptake in the heart, medial prefrontal cortex, and adipose tissue with stress. In the heart disease group as a whole, activity increase with stress in the medial prefrontal brain and amygdala correlated with stress-induced increases in spleen (r=0.69, p=0.038; and r=0.69, p=0.04 respectfully). Stress-induced frontal lobe increased uptake correlated with stress-induced aorta uptake (r=0.71, p=0.016). Activity in insula and medial prefrontal cortex was correlated with post-stress activity in bone marrow and adipose tissue. Activity in other brain areas not implicated in stress did not show similar correlations. Increases in medial prefrontal activity with stress correlated with increased cardiac glucose uptake with stress, suggestive of myocardial ischemia (r=0.85, p=0.004)., Conclusions: These findings suggest a link between brain response to stress in key areas mediating emotion and peripheral organs involved in inflammation and hematopoietic activity, as well as myocardial ischemia, in Coronary Heart Disease patients., Competing Interests: Conflict: The authors have no conflicts of interest to declare in reference to this research.

Pituitary adenylate cyclase-activating peptide (PACAP) is a neuropeptide that plays a key role in the neurobiology of the stress response, and prior studies suggest that its function is dysregulated in post-traumatic stress disorder (PTSD). Transcutaneous cervical vagus nerve stimulation (tcVNS) acts through PACAP and other neurobiological systems to modulate stress responses and/or symptoms of PTSD. In this pilot study, we examined the effects of tcVNS on PACAP in a three day chronic stress laboratory paradigm involving serial traumatic and mental stress exposures in healthy individuals with a history of exposure to psychological trauma (n ​= ​18) and patients with PTSD (n ​= ​12)., Methods: A total of 30 subjects with a history of exposure to psychological trauma experience were recruited (12 with PTSD diagnosis) for a three-day randomized double-blinded study of tcVNS or sham stimulation. Subjects underwent a protocol that included both personalized trauma recall and non-personalized mental stressors (public speaking, mental arithmetic) paired to tcVNS or sham stimulation over three days. Blood was collected at baseline and multiple time points after exposure to stressors. Linear mixed-effects models were used to assess changes in PACAP over time (in response to stressors) and its relation to active tcVNS or sham stimulation., Results: PACAP blood levels increased over the course of three days for both active tcVNS and sham groups. This increase was statistically-significant in the sham group at the end of the second (Cohen's d rm  ​= ​0.35, p ​= ​0.04), and third days (d rm  ​= ​0.41, p ​= ​0.04), but not in the active tcVNS group (d rm  ​= ​0.21, d rm  ​= ​0.18, and p ​> ​0.20)., Conclusion: These pilot findings suggest tcVNS may attenuate this neurobiological stress-response. Larger studies are needed to investigate gender and interaction effects., (© 2020 The Author(s).)

Transcutaneous vagus nerve stimulation (t-VNS) is a promising technology for modulating brain function and possibly treating disorders of the central nervous system. While handheld devices are available for t-VNS, stimulation efficacy can only be quantified using expensive imaging or blood biomarker analyses. Additionally, the parameters and "dosage" recommendations for t-VNS are typically fixed, as there are limited biomarkers that can assess downstream effects of the stimulation outside of clinical settings. In this proof-of-concept study, we evaluated non-invasive peripheral cardiovascular measurements as physiological biomarkers of t-VNS efficacy. Specifically, we hypothesized two physiological biomarkers: (1) the pre-ejection period (PEP) of the heart - a parameter closely linked to sympathetic tone - and (2) the amplitude of peripheral photoplethysmogram (PPG) waveforms - representing changes in vasomotor tone and thus parasympathetic / sympathetic activation. A total of six healthy human subjects participated in the multi-day study, half each undergoing active or sham t-VNS stimulus. The three subjects receiving t-VNS had no decrease in PEP and an increase in PPG amplitude following t-VNS, while the subjects receiving sham stimulus had a decrease in PEP and no change in PPG amplitude. When combined with mental stress (a traumatic script being read back to the subjects), the group with t-VNS had no decrease in PEP and only a slight decrease in PPG amplitude following stimulus, while the group receiving sham stimulus had a decrease in PEP and also a slight decrease in PPG amplitude. These studies suggest that PEP and PPG amplitude measures may provide non-invasive physiological biomarkers of t-VNS efficacy, including in the presence of mental stress.