Transcutaneous vagal nerve stimulation modulates stress-induced plasma ghrelin levels: A double-blind, randomized, sham-controlled trial.

BACKGROUND: Transcutaneous cervical vagus nerve stimulation (tcVNS) has emerged as a potential treatment strategy for patients with stress-related psychiatric disorders. Ghrelin is a hormone that has been postulated to be a biomarker of stress. While the mechanisms of action of tcVNS are unclear, we hypothesized that tcVNS reduces the levels of ghrelin in response to stress. METHODS: Using a randomized double-blind approach, we studied the effects of tcVNS on ghrelin levels in individuals with a history of exposure to traumatic stress. Participants received either sham (n = 29) or active tcVNS (n = 26) after exposure to acute personalized traumatic script stress and mental stress challenges (public speech, mental arithmetic) over a three day period. RESULTS: There were no significant differences in the levels of ghrelin between the tcVNS and sham stimulation groups at either baseline or in the absence of trauma scripts. However, tcVNS in conjunction with personalized traumatic scripts resulted in lower ghrelin levels compared to the sham stimulation group (265.2 ± 143.6 pg/ml vs 478.7 ± 349.2 pg/ml, P = 0.01). Additionally, after completing the public speaking and mental arithmetic tests, ghrelin levels were found to be lower in the group receiving tcVNS compared to the sham group (293.3 ± 102.4 pg/ml vs 540.3 ± 203.9 pg/ml, P = 0.009). LIMITATIONS: Timing of ghrelin measurements, and stimulation of only left vagus nerve. CONCLUSION: tcVNS decreases ghrelin levels in response to various stressful stimuli. These findings are consistent with a growing literature that tcVNS modulates hormonal and autonomic responses to stress.

The temporal relationships between sleep disturbance and autonomic dysregulation: A co-twin control study.

INTRODUCTION: Sleep disturbance is associated with autonomic dysregulation, but the temporal directionality of this relationship remains uncertain. The objective of this study was to evaluate the temporal relationships between objectively measured sleep disturbance and daytime or nighttime autonomic dysregulation in a co-twin control study. METHODS: A total of 68 members (34 pairs) of the Vietnam Era Twin Registry were studied. Twins underwent 7-day in-home actigraphy to derive objective measures of sleep disturbance. Autonomic function indexed by heart rate variability (HRV) was obtained using 7-day ECG monitoring with a wearable patch. Multivariable vector autoregressive models with Granger causality tests were used to examine the temporal directionality of the association between daytime and nighttime HRV and sleep metrics, within twin pairs, using 7-day collected ECG data. RESULTS: Twins were all male, mostly white (96%), with mean (SD) age of 69 (2) years. Higher daytime HRV across multiple domains was bidirectionally associated with longer total sleep time and lower wake after sleep onset; these temporal dynamics were extended to a window of 48 h. In contrast, there was no association between nighttime HRV and sleep measures in subsequent nights, or between sleep measures from previous nights and subsequent nighttime HRV. CONCLUSIONS: Daytime, but not nighttime, autonomic function indexed by HRV has bidirectional associations with several sleep dimensions. Dysfunctions in autonomic regulation during wakefulness can lead to subsequent shorter sleep duration and worse sleep continuity, and vice versa, and their influence on each other may extend beyond 24 h.

Early life stress and autonomic response to acute mental stress in individuals with coronary heart disease.

Early life stress (ELS) has been associated with an increased risk of cardiovascular disease. We examined whether ELS was associated with autonomic function and stress reactivity among individuals with coronary heart disease (CHD). We included patients with stable CHD from two parallel studies, the Mental Stress Ischemia Prognosis Study (MIPS) and the Myocardial Infarction and Mental Stress Study 2 (MIMS2), and assessed ELS using the Early Trauma Inventory-Self-Report-Short Form. Participants underwent a laboratory-based mental stress task while undergoing ambulatory electrocardiographic monitoring. We used multivariate linear regression models to estimate the associations between ELS and heart rate variability (HRV; low frequency [LF], high frequency [HF], and LF and HF [LH] ratio). The analytic sample included 405 MIPS and 284 MIMS2 participants. Most participants endorsed at least one experience of ELS (92.2%). Although we did not observe associations between ELS and HRV outcomes in the overall sample, ELS was associated with lower LH ratio HRV during recovery in the posttraumatic stress disorder (PTSD) subgroup, ELS x PTSD interaction, p = .041. In the MIMS2 subgroup, ELS was associated with lower resting period LF HRV, B ̂ $ \widehat{B} $  = -0.16 ln ms2 ; 95% CI [-0.31, -0.02]. Exposure to physical trauma was associated with decreased HF HRV overall reactivity only among participants with high to moderate depressive symptoms, B ̂ $ \widehat{B} $  = -0.52 ln ms2 vs. B ̂ $ \widehat{B} $  = 0.01 ln ms2 , p = .013. Overall, heterogeneous associations between ELS and HRV emerged, suggesting the need for additional research regarding longer-term ambulatory HRV.

Association Between Posttraumatic Stress Disorder and Epigenetic Age Acceleration in a Sample of Twins.

OBJECTIVE: Posttraumatic stress disorder (PTSD) has been related to accelerated biological aging processes, but objective evidence for this association is limited. DNA methylation (DNAm) age acceleration is a novel measure of biological aging that may help clarify if PTSD is related to biological aging processes. We aim to examine whether PTSD is associated with biological aging using a comprehensive set of DNAm age acceleration markers and to what extent the unshared environment contributes to the association. METHODS: Using a cross-sectional co-twin control study design, we investigated the association of the clinical diagnosis and symptom severity of PTSD with six measurements of DNAm age acceleration based on epigenome-wide data derived from peripheral blood lymphocytes of 296 male twins from the Vietnam Era Twin Registry. RESULTS: Twins with current PTSD had significantly advanced DNAm age acceleration compared with twins without PTSD for five of six measures of DNAm age acceleration. Across almost all measures of DNAm age acceleration, twins with current PTSD were "epigenetically older" than their twin brothers without PTSD: estimated differences ranged between 1.6 (95% confidence interval = 0.0-3.1) and 2.7 (95% confidence interval = 0.5-4.8) biological age year-equivalents. A higher Clinician-Administered PTSD Scale score was also associated with a higher within-pair DNAm age acceleration. Results remained consistent after adjustment for behavioral and cardiovascular risk factors. CONCLUSIONS: PTSD is associated with epigenetic age acceleration, primarily through unshared environmental mechanisms as opposed to genetic or familial factors. These results suggest that PTSD is related to systemic processes relevant to biological aging.

Association of Depressive Symptoms with Sleep Disturbance: A Co-twin Control Study.

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.

Posttraumatic Stress Disorder, Myocardial Perfusion, and Myocardial Blood Flow: A Longitudinal Twin Study.

BACKGROUND: The link between posttraumatic stress disorder (PTSD) and ischemic heart disease remains elusive owing to a shortage of longitudinal studies with a clinical diagnosis of PTSD and objective measures of cardiac compromise. METHODS: We performed positron emission tomography in 275 twins who participated in two examinations approximately 12 years apart. At both visits, we obtained a clinical diagnosis of PTSD, which was classified as long-standing (both visit 1 and visit 2), late onset (only visit 2), and no PTSD (no PTSD at both visits). With positron emission tomography, we assessed myocardial flow reserve (MFR), which, in absence of significant coronary stenoses, indexes coronary microvascular function. We compared positron emission tomography data at visit 2 across the three categories of longitudinally assessed PTSD and examined changes between the two visits. RESULTS: Overall, 80% of the twins had no or minimal obstructive coronary disease. Yet, MFR was depressed in twins with PTSD and was progressively lower across groups with no PTSD (2.13), late-onset PTSD (1.97), and long-standing PTSD (1.93) (p = .01). A low MFR (a ratio <2.0) was present in 40% of the twins without PTSD, in 56% of those with late-onset PTSD, and in 72% of those with long-standing PTSD (p < .001). Associations persisted in multivariable analysis, when examining changes in MFR between visit 1 and visit 2, and within twin pairs. Results were similar by zygosity. CONCLUSIONS: Longitudinally, PTSD is associated with reduced coronary microcirculatory function and greater deterioration over time. The association is especially noted among twins with chronic, long-standing PTSD and is not confounded by shared environmental or genetic factors.

Transcutaneous Cervical Vagal Nerve Stimulation in Patients with Posttraumatic Stress Disorder (PTSD): A Pilot Study of Effects on PTSD Symptoms and Interleukin-6 Response to Stress.

BACKGROUND: Posttraumatic stress disorder (PTSD) is a highly disabling condition associated with alterations in multiple neurobiological systems, including increases in inflammatory and sympathetic function, responsible for maintenance of symptoms. Treatment options including medications and psychotherapies have limitations. We previously showed that transcutaneous Vagus Nerve Stimulation (tcVNS) blocks inflammatory (interleukin (IL)-6) responses to stress in PTSD. The purpose of this study was to assess the effects of tcVNS on PTSD symptoms and inflammatory responses to stress. METHODS: Twenty patients with PTSD were randomized to double blind active tcVNS (N=9) or sham (N=11) stimulation in conjunction with exposure to personalized traumatic scripts immediately followed by active or sham tcVNS and measurement of IL-6 and other biomarkers of inflammation. Patients then self administered active or sham tcVNS twice daily for three months. PTSD symptoms were measured with the PTSD Checklist (PCL) and the Clinician Administered PTSD Scale (CAPS), clinical improvement with the Clinical Global Index (CGI) and anxiety with the Hamilton Anxiety Scale (Ham-A) at baseline and one-month intervals followed by a repeat of measurement of biomarkers with traumatic scripts. After three months patients self treated with twice daily open label active tcVNS for another three months followed by assessment with the CGI. RESULTS: Traumatic scripts increased IL-6 in PTSD patients, an effect that was blocked by tcVNS (p<.05). Active tcVNS treatment for three months resulted in a 31% greater reduction in PTSD symptoms compared to sham treatment as measured by the PCL (p=0.013) as well as hyperarousal symptoms and somatic anxiety measured with the Ham-A p<0.05). IL-6 increased from baseline in sham but not tcVNS. Open label tcVNS resulted in improvements measured with the CGI compared to the sham treatment period p<0.05). CONCLUSIONS: These preliminary results suggest that tcVNS reduces inflammatory responses to stress, which may in part underlie beneficial effects on PTSD symptoms.

Epigenetic Age Acceleration and Cognitive Decline: A Twin Study.

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.

Transcutaneous vagal nerve stimulation blocks stress-induced activation of Interleukin-6 and interferon-γ in posttraumatic stress disorder: A double-blind, randomized, sham-controlled trial.

Posttraumatic stress disorder (PTSD) is a highly disabling condition associated with alterations in multiple neurobiological systems, including increases in inflammatory function. Vagus nerve stimulation (VNS) decreases inflammation, however few studies have examined the effects of non-invasive VNS on physiology in human subjects, and no studies in patients with PTSD. The purpose of this study was to assess the effects of transcutaneous cervical VNS (tcVNS) on inflammatory responses to stress. Thirty subjects with a history of exposure to traumatic stress with (N â€‹= â€‹10) and without (N â€‹= â€‹20) PTSD underwent exposure to stressful tasks immediately followed by active or sham tcVNS and measurement of multiple biomarkers of inflammation (interleukin-(IL)-6, IL-2, IL-1ß, Tumor Necrosis Factor alpha (TNFα) and Interferon gamma (IFNγ) over multiple time points. Stressful tasks included exposure to personalized scripts of traumatic events on day 1, and public speech and mental arithmetic (Mental Stress) tasks on days 2 and 3. Traumatic scripts were associated with a pattern of subjective anger measured with Visual Analogue Scales and increased IL-6 and IFNγ in PTSD patients that was blocked by tcVNS (p â€‹< â€‹.05). Traumatic stress had minimal effects on these biomarkers in non-PTSD subjects and there was no difference between tcVNS or sham. No significant differences were seen between groups in IL-2, IL-1ß, or TNFα. These results demonstrate that tcVNS blocks behavioral and inflammatory responses to stress reminders in PTSD.

Longitudinal association of inflammation with depressive symptoms: A 7-year cross-lagged twin difference study.

BACKGROUND: The direction of the association between inflammation and depressive symptoms remains inconsistent. The objective of this study was to evaluate the temporal relationship between inflammation and depressive symptoms, and to assess the role of genetic factors on this association. METHODS: In this longitudinal cross-lagged twin difference study, we examined 166 (83 pairs) middle-aged male twins recruited from the Vietnam Era Twin Registry, who were assessed at baseline and after 7 years of follow-up. We assayed plasma levels of two inflammatory biomarkers, interleukin-6 (IL-6) and high sensitivity C-reactive protein (CRP) and measured depressive symptoms using the Beck Depression Inventory-II (BDI). To evaluate the direction of the association, we constructed multivariable mixed-effects regression models and calculated standardized beta-coefficients to compare the strength of the within-pair association for both pathways. We then conducted a stratified analysis by zygosity and assessed the associations in monozygotic and dizygotic twin pairs separately. RESULTS: The 166 twins were 95% white and had a mean (SD) age of 54 (3) years at baseline. The cross-lagged analysis showed significant and positive associations from visit 1 IL-6 to visit 2 BDI across all models (beta-coefficients ranging from 0.18 to 0.22). However, the opposite pathway (visit 1 BDI to visit 2 IL-6) was not significant after adjusting for confounding factors. In contrast, visit 1 BDI was significantly associated with visit 2 CRP in all models (beta-coefficients ranging from 0.23 to 0.33), while the opposite pathway (visit 1 CRP to visit 2 BDI) showed no significant association. When stratifying by zygosity, significant associations from IL-6 to depression were only seen in monozygotic twins, but associations from depression to CRP were more robust in dizygotic twins, which implies that genetic factors may play a role in this association. CONCLUSIONS: The association between inflammation and depression may be bidirectional. Elevated IL-6 levels are more likely to be a risk factor of depression rather than a consequence, while the opposite may be true for elevated CRP. The biological underpinnings of these bidirectional pathways need further evaluation.

Association of Depressive Symptoms and Heart Rate Variability in Vietnam War-Era Twins: A Longitudinal Twin Difference Study.

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 ß 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 (ß 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 ß 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.