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OBJECTIVE: Variations in respiration patterns are a characteristic response to distress due to underlying neurorespiratory couplings. Yet, no work to date has quantified respiration pattern variability (RPV) in the context of traumatic stress and studied its functional neural correlates – this analysis aims to address this gap. METHODS: Fifty human subjects with prior traumatic experiences (24 with posttraumatic stress disorder (PTSD)) completed a ~3-hr protocol involving personalized traumatic scripts and active/sham (double-blind) transcutaneous cervical vagus nerve stimulation (tcVNS). High-resolution positron emission tomography functional neuroimages, electrocardiogram (ECG), and respiratory effort (RSP) data were collected during the protocol. Supplementing the RSP signal with ECG-derived respiration for quality assessment and timing extraction, RPV metrics were quantified and analyzed. Specifically, correlation analyses were performed using neuroactivity in selected limbic regions, and responses to active and sham tcVNS were compared. RESULTS: The single-lag unscaled autocorrelation of respiration rate correlated negatively with left amygdala activity and positively with right rostromedial prefrontal cortex (rmPFC) activity for non-PTSD; it also correlated negatively with left and right insulae activity and positively with right rmPFC activity for PTSD. The single-lag unscaled autocorrelation of expiration time was greater following active stimulation for non-PTSD. CONCLUSION: Quantifying RPV is of demonstrable importance to assessing trauma-induced changes in neural function and tcVNS effects on respiratory physiology. SIGNIFICANCE: This is the first demonstration of RPV’s pertinence to traumatic stress- and tcVNS-induced neurorespiratory responses. The open-source processing pipeline elucidated herein uniquely includes both RSP and ECG-derived respiration signals for quality assessment, timing estimation, and RPV extraction.

OBJECTIVE Posttraumatic stress disorder (PTSD) is a disabling condition affecting a large segment of the population; however, current treatment options have limitations. New interventions that target the neurobiological alterations underlying symptoms of PTSD could be highly beneficial. Transcutaneous cervical (neck) vagal nerve stimulation (tcVNS) has the potential to represent such an intervention. The goal of this study was to determine the effects of tcVNS on neural responses to reminders of traumatic stress in PTSD. METHODS Twenty-two participants were randomized to receive either sham (n = 11) or active (n = 11) tcVNS stimulation in conjunction with exposure to neutral and personalized traumatic stress scripts with high-resolution positron emission tomography scanning with radiolabeled water for brain blood flow measurements. RESULTS Compared with sham, tcVNS increased brain activations during trauma scripts (p < .005) within the bilateral frontal and temporal lobes, left hippocampus, posterior cingulate, and anterior cingulate (dorsal and pregenual), and right postcentral gyrus. Greater deactivations (p < .005) with tcVNS were observed within the bilateral frontal and parietal lobes and left thalamus. Compared with tcVNS, sham elicited greater activations (p < .005) in the bilateral frontal lobe, left precentral gyrus, precuneus, and thalamus, and right temporal and parietal lobes, hippocampus, insula, and posterior cingulate. Greater (p < .005) deactivations were observed with sham in the right temporal lobe, posterior cingulate, hippocampus, left anterior cingulate, and bilateral cerebellum. CONCLUSIONS tcVNS increased anterior cingulate and hippocampus activation during trauma scripts, potentially indicating a reversal of neurobiological changes with PTSD consistent with improved autonomic control.Trial Registration: No. NCT02992899.

Background: Individuals with coronary artery disease (CAD) have worse executive function compared to the general population but the mechanisms are unknown. Objective: To investigate the role of acute mental stress (MS) on the executive function of patients with CAD. Methods: Participants with stable CAD underwent acute MS testing with simultaneous peripheral vascular function measurements and brain imaging using high resolution-positron emission tomography. Digital pulse wave amplitude was continuously measured using peripheral artery tonometry (PAT, Itamar Inc). Stress/rest PAT ratio (sPAT) of pulse wave amplitude during MS/baseline was calculated as a measure of microvascular constriction during MS. Plasma levels of catecholamine and interleukin-6 were assessed at baseline and after MS. Executive function was assessed both at baseline and at 2 years follow-up using the Trail Making Test parts A and B. Results: We studied 389 individuals with brain data available for 148 participants. Of this population follow-up cognitive assessments were performed in 226 individuals (121 with brain imaging). After multivariable adjustment for baseline demographics, risk factors, and medication use, a lower sPAT, indicating greater vasoconstriction, a higher inferior frontal lobe activation with MS, and increases in norepinephrine and IL-6 levels with MS were all independently associated with greater time to complete Trail B test.-38.4pt Conclusion: In response to acute MS, greater peripheral vasoconstriction, higher inferior frontal lobe brain activation, and increases in the levels of norepinephrine and IL-6 are associated with worse executive function.

Background Traumatic stress can have lasting effects on neurobiology and result in psychiatric conditions such as posttraumatic stress disorder (PTSD). We hypothesize that non-invasive cervical vagal nerve stimulation (nVNS) may alleviate trauma symptoms by reducing stress sympathetic reactivity. This study examined how nVNS alters neural responses to personalized traumatic scripts. Methods Nineteen participants who had experienced trauma but did not have the diagnosis of PTSD completed this double-blind sham-controlled study. In three sequential time blocks, personalized traumatic scripts were presented to participants immediately followed by either sham stimulation (n = 8; 0–14 V, 0.2 Hz, pulse width = 5s) or active nVNS (n = 11; 0–30 V, 25 Hz, pulse width = 40 ms). Brain activity during traumatic scripts was assessed using High Resolution Positron Emission Tomography (HR-PET) with radiolabeled water to measure brain blood flow. Results Traumatic scripts resulted in significant activations within the bilateral medial and orbital prefrontal cortex, premotor cortex, anterior cingulate, thalamus, insula, hippocampus, right amygdala, and right putamen. Greater activation was observed during sham stimulation compared to nVNS within the bilateral prefrontal and orbitofrontal cortex, premotor cortex, temporal lobe, parahippocampal gyrus, insula, and left anterior cingulate. During the first exposure to the trauma scripts, greater activations were found in the motor cortices and ventral visual stream whereas prefrontal cortex and anterior cingulate activations were more predominant with later script presentations for those subjects receiving sham stimulation. Conclusion nVNS decreases neural reactivity to an emotional stressor in limbic and other brain areas involved in stress, with changes over repeated exposures suggesting a shift from scene appraisal to cognitively processing the emotional event.

Background:Psychological stress is a risk factor for major adverse cardiovascular events (MACE) in individuals with coronary artery disease. Certain brain regions that control both emotional states and cardiac physiology may be involved in this relationship. The rostromedial prefrontal cortex (rmPFC) is an important brain region that processes stress and regulates immune and autonomic functions. Changes in rmPFC activity with emotional stress (reactivity) may be informative of future risk for MACE.Methods:Participants with stable coronary artery disease underwent acute mental stress testing using a series of standardized speech/arithmetic stressors and simultaneous brain imaging with high-resolution positron emission tomography brain imaging. We defined high rmPFC activation as a difference between stress and control scans greater than the median value for the entire cohort. Interleukin-6 levels 90 minutes after stress, and high-frequency heart rate variability during stress were also assessed. We defined MACE as a composite of cardiovascular death, myocardial infarction, unstable angina with revascularization, and heart failure hospitalization.Results:We studied 148 subjects (69% male) with mean±SD age of 62±8 years. After adjustment for baseline demographics, risk factors, and baseline levels of interleukin-6 and high-frequency heart rate variability, higher rmPFC stress reactivity was independently associated with higher interleukin-6 and lower high-frequency heart rate variability with stress. During a median follow-up of 3 years, 34 subjects (21.3%) experienced a MACE. Each increase of 1 SD in rmPFC activation with mental stress was associated with a 21% increase risk of MACE (hazard ratio, 1.21 [95% CI, 1.08–1.37]). Stress-induced interleukin-6 and high-frequency heart rate variability explained 15.5% and 32.5% of the relationship between rmPFC reactivity and MACE, respectively. Addition of rmPFC reactivity to conventional risk factors improved risk reclassification for MACE prediction, and C-statistic improved from 0.71 to 0.76 (P=0.03).Conclusions:Greater rmPFC stress reactivity is associated with incident MACE. Immune and autonomic responses to mental stress may play a contributory role.

BACKGROUND: Accelerated biological aging, as indicated by telomere shortening, is associated with CAD pathogenesis. In a cross-sectional study, we investigated neural correlates of acute psychological stress and short telomeres in patients with CAD. METHODS: Individuals with CAD (N = 168) underwent a validated mental stress protocol including public speaking and mental arithmetic. Imaging of the brain with [O-15] water and high-resolution positron emission tomography (HR-PET) was performed during mental stress and control conditions. Blood flow during stressful tasks (average of speech and arithmetic) and control tasks were assessed. Telomere length in peripheral leucocytes was measured by quantitative polymerase chain reaction and expressed as Telomere/Single Copy Gene (T/S) ratio. Voxel-wise regression models were constructed to assess the association between brain areas and activity during rest and mental stress after adjustments for demographic factors and clinical characteristics. RESULTS: The mean (SD) age of the sample was 62 (8) years, and 69% were men. Increased activation with mental stress in the lingual gyrus, cerebellum and superior and inferior frontal gyri were associated with reduced telomere length; 1.6 higher voxel activation of these areas was associated with 0.1 T/S-units reduction in telomere length (P < 0.005). Additionally, during neutral counting and speaking tasks, brain activity in the precentral, middle and superior frontal and middle temporal gyri was inversely associated with telomere length. Results remained consistent after adjustment for demographic and clinical risk factors. CONCLUSION: Increased stress-induced activity in brain areas mediating the stress response was associated with shortened telomere length in CAD patients.

Transcutaneous electrical stimulation of the vagus nerve is believed to deliver afferent signaling to the brain that, in turn, yields downstream changes in peripheral physiology, including cardiovascular and respiratory parameters. While the effects of transcutaneous cervical vagus nerve stimulation (tcVNS) on these parameters have been studied broadly, little is known regarding the specific effects of tcVNS on exhalation time and the spontaneous respiration cycle. By understanding such effects, tcVNS could be used to counterbalance sympathetic hyperactivity following distress by enhancing vagal tone through parasympathetically favored modulation of inspiration and expiration – specifically, lengthened expiration relative to inspiration. We thus investigated the effects of tcVNS on respiration timings by decomposing the respiration cycle into inspiration and expiration times and incorporating state-of-the-art respiration quality assessment algorithms for respiratory effort belt and electrocardiogram derived respiration signals. This enabled robust estimation of respiration timings from quality measurements alone. We thereby found that tcVNS increases expiration time minutes after stimulation, compared to a sham control (N = 26). This suggests that tcVNS could counteract sympathovagal imbalance, given the relationship between expiration and heightened vagal tone.

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

BACKGROUND: Early childhood trauma is known to independently increase adverse outcome risk in coronary artery disease (CAD) patients, although the neurological correlates are not well understood. The purpose of this study was to examine whether early childhood trauma alters neural responses to acute mental stress in CAD patients. METHODS: Participants (n = 152) with CAD underwent brain imaging with High Resolution Positron Emission Tomography and radiolabeled water during control (verbal counting, neutral speaking) and mental stress (mental arithmetic, public speaking). Traumatic events in childhood were assessed with the Early Trauma Inventory (ETI-SR-SF) and participants were separated by presence (ETI+) or absence (ETI−) of early childhood trauma. Brain activity during mental stress was compared between ETI+ and ETI−. RESULTS: Compared to ETI−, ETI+ experienced greater (p < 0.005) activations during mental stress within the left anterior cingulate, left occipital lobe, bilateral frontal lobe and deactivations (p < 0.005) within the left insula, left parahippocampal gyrus, right dorsal anterior cingulate, bilateral cerebellum, bilateral fusiform gyrus, left inferior temporal gyrus, right occipital lobe, and right parietal lobe. Significant (p < 0.005) positive correlations between brain activation and ETI-SR-SF scores were observed within the left hippocampus, bilateral frontal lobe, left occipital cuneus, right parietal precuneus, and bilateral temporal lobe. LIMITATIONS: Results in non-CAD samples may differ and ETI may be subject to recall bias. CONCLUSION: Early childhood trauma exacerbated activations in stress-responsive limbic and cognitive brain areas with direct and indirect connections to the heart, potentially contributing to adverse outcomes in CAD patients.

Coronary heart disease and psychological stress factors such as depression are prevalent and associated with high morbidity/mortality; they are also challenging to manage, especially when treated in isolation of each other. Recent advances support an integrated approach to their management that is built on a foundation of an extensive, multi-component network of neurological structures. In this review, we describe this extensive cardioneural network that encompasses the heart, brain, spinal cord, and ganglia throughout the body, and then discuss ambulatory and laboratory-based non-invasive measures of this network that both measure psychological stress and heart disease severity. Lastly, we discuss their potential transformative clinical and public health applications, and also possible cardioneural interventions such as exercise and biofeedback.

Importance Compared with older patients, young adults with a history of myocardial infarction (MI) tend to have a higher burden of psychosocial adversity. Exposure to early-life stressors may contribute to the risk of adverse outcomes in this patient population, potentially through inflammatory pathways. Objective To investigate the association of early-life trauma with adverse events and examine whether inflammation plays a role. Design, Setting, and Participants This cohort study included patients aged 18 to 60 years with a verified history of MI in the past 8 months from a university-affiliated hospital network. Baseline data were collected from June 2011 to March 2016, and follow-up data were obtained through July 2019. Analysis began September 2019. Exposures Early-life trauma was assessed using the Early Trauma Inventory–Self Report short form (ETI-SR-SF), both as a continuous and as a binary variable at the threshold of a score of 7 or higher. Inflammatory biomarkers, interleukin 6, and C-reactive protein were obtained at baseline. Main Outcomes and Measures A composite end point of recurrent MI, stroke, heart failure hospitalization, and cardiovascular death over a median 3-year follow-up. Results Of 300 patients, the mean (SD) age was 51 (7) years, 198 (66%) were African American, and 150 (50%) were women. Compared with participants with MI with an ETI-SR-SF score less than 7, those with a score of 7 or higher had higher levels of interleukin 6 and C-reactive protein at baseline. Compared with participants with an ETI-SR-SF score less than 7, those with a score of 7 or higher were at a greater risk for adverse outcomes, with a hazards ratio of 2.3 (95% CI, 1.3-3.9). Results remained consistent in multivariable analysis. Further adjustment for C-reactive protein rendered the results no longer statistically significant. Early-life trauma displayed a dose-dependent response when analyzed as a continuous variable and by quartiles. Conclusions and Relevance Early-life trauma is an independent risk factor for adverse outcomes in young and middle-aged individuals with a history of MI. Neurobiological mechanisms leading to lifetime activation of systemic inflammatory cascades may be implicated.

Objective Exacerbated autonomic responses to acute stress are prevalent in posttraumatic stress disorder (PTSD). The purpose of this study was to assess the effects of transcutaneous cervical VNS (tcVNS) on autonomic responses to acute stress in patients with PTSD. The authors hypothesized tcVNS would reduce the sympathetic response to stress compared to a sham device. Methods Using a randomized double-blind approach, we studied the effects of tcVNS on physiological responses to stress in patients with PTSD (n = 25) using noninvasive sensing modalities. Participants received either sham (n = 12) or active tcVNS (n = 13) after exposure to acute personalized traumatic script stress and mental stress (public speech, mental arithmetic) over a three-day protocol. Physiological parameters related to sympathetic responses to stress were investigated. Results Relative to sham, tcVNS paired to traumatic script stress decreased sympathetic function as measured by: decreased heart rate (adjusted β = −5.7%; 95% CI: ±3.6%, effect size d = 0.43, p, Highlights • We studied the effects of tcVNS on physiological responses to stress in patients with posttraumatic stress disorder (PTSD). • TcVNS modulates physiologic reactivity to acute traumatic and mental stress. • Peripheral autonomic measures could serve as real-time measures to evaluate the therapy response in longitudinal settings.

Background: Vagal Nerve Stimulation (VNS) has been shown to be efficacious for the treatment of depression, but to date, VNS devices have required surgical implantation, which has limited widespread implementation. Methods: New noninvasive VNS (nVNS) devices have been developed which allow external stimulation of the vagus nerve, and their effects on physiology in patients with stress-related psychiatric disorders can be measured with brain imaging, blood biomarkers, and wearable sensing devices. Advantages in terms of cost and convenience may lead to more widespread implementation in psychiatry, as well as facilitate research of the physiology of the vagus nerve in humans. nVNS has effects on autonomic tone, cardiovascular function, inflammatory responses, and central brain areas involved in modulation of emotion, all of which make it particularly applicable to patients with stress-related psychiatric disorders, including posttraumatic stress disorder (PTSD) and depression, since dysregulation of these circuits and systems underlies the symptomatology of these disorders. Results: This paper reviewed the physiology of the vagus nerve and its relevance to modulating the stress response in the context of application of nVNS to stress-related psychiatric disorders. Conclusions: nVNS has a favorable effect on stress physiology that is measurable using brain imaging, blood biomarkers of inflammation, and wearable sensing devices, and shows promise in the prevention and treatment of stress-related psychiatric disorders.

Background: The inferior frontal lobe is an important area of the brain involved in the stress response, and higher activation with acute mental stress may indicate a more severe stress reaction. However, it is unclear if activation of this region with stress correlates with angina in individuals with coronary artery disease. Methods: Individuals with stable coronary artery disease underwent acute mental stress testing using a series of standardized speech/arithmetic stressors in conjunction with high resolution positron emission tomography imaging of the brain. Blood flow to the inferior frontal lobe was evaluated as a ratio compared with whole brain flow for each scan. Angina was assessed with the Seattle Angina Questionnaire’s angina frequency subscale at baseline and 2 years follow-up. Results: We analyzed 148 individuals with coronary artery disease (mean age [SD] 62 [8] years; 69% male, and 35.8% Black). For every doubling in the inferior frontal lobe activation, angina frequency was increased by 13.7 units at baseline ( , 13.7 [95% CI, 6.3–21.7]; P =0.008) and 11.6 units during follow-up ( , 11.6 [95% CI, 4.1–19.2]; P =0.01) in a model adjusted for baseline demographics. Mental stress-induced ischemia and activation of other brain pain processing regions (thalamus, insula, and amygdala) accounted for 40.0% and 13.1% of the total effect of inferior frontal lobe activation on angina severity, respectively. Conclusions: Inferior frontal lobe activation with mental stress is independently associated with angina at baseline and during follow-up. Mental stress-induced ischemia and other pain processing brain regions may play a contributory role.

Introduction: There has long been an interest in the effects of diet on mental health, and the interaction of the two with stress; however, the nature of these relationships is not well understood. Although associations between diet, obesity and the related metabolic syndrome (MetS), stress, and mental disorders exist, causal pathways have not been established. Methods: We reviewed the literature on the relationship between diet, stress, obesity and psychiatric disorders related to stress. Results: Diet and obesity can affect mood through direct effects, or stress-related mental disorders could lead to changes in diet habits that affect weight. Alternatively, common factors such as stress or predisposition could lead to both obesity and stress-related mental disorders, such as depression and posttraumatic stress disorder (PTSD). Specific aspects of diet can lead to acute changes in mood as well as stimulate inflammation, which has led to efforts to assess polyunsaturated fats (PUFA) as a treatment for depression. Bidirectional relationships between these different factors are also likely. Finally, there has been increased attention recently on the relationship between the gut and the brain, with the realization that the gut microbiome has an influence on brain function and probably also mood and behavior, introducing another way diet can influence mental health and disorders. Brain areas and neurotransmitters and neuropeptides that are involved in both mood and appetite likely play a role in mediating this relationship. Conclusions: Understanding the relationship between diet, stress and mood and behavior could have important implications for the treatment of both stress-related mental disorders and obesity.

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 drm ​= ​0.35, p ​= ​0.04), and third days (drm ​= ​0.41, p ​= ​0.04), but not in the active tcVNS group (drm ​= ​0.21, drm ​= ​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.

BACKGROUND Transcutaneous cervical vagus nerve stimulation (tcVNS) is a promising alternative to implantable stimulation of the vagus nerve. With demonstrated potential in myriad applications, ranging from systemic inflammation reduction to traumatic stress attenuation, closed-loop tcVNS during periods of risk could improve treatment efficacy and reduce ineffective delivery. However, achieving this requires a deeper understanding of biomarker changes over time. OBJECTIVE The aim of the present study was to reveal the dynamics of relevant cardiovascular biomarkers, extracted from wearable sensing modalities, in response to tcVNS. METHODS Twenty-four human subjects were recruited for a randomized double-blind clinical trial, for whom electrocardiography and photoplethysmography were used to measure heart rate and photoplethysmogram amplitude responses to tcVNS, respectively. Modeling these responses in state-space, we (1) compared the biomarkers in terms of their predictability and active vs sham differentiation, (2) studied the latency between stimulation onset and measurable effects, and (3) visualized the true and model-simulated biomarker responses to tcVNS. RESULTS The models accurately predicted future heart rate and photoplethysmogram amplitude values with root mean square errors of approximately one-fifth the standard deviations of the data. Moreover, (1) the photoplethysmogram amplitude showed superior predictability (P=.03) and active vs sham separation compared to heart rate; (2) a consistent delay of greater than 5 seconds was found between tcVNS onset and cardiovascular effects; and (3) dynamic characteristics differentiated responses to tcVNS from the sham stimulation. CONCLUSIONS This work furthers the state of the art by modeling pertinent biomarker responses to tcVNS. Through subsequent analysis, we discovered three key findings with implications related to (1) wearable sensing devices for bioelectronic medicine, (2) the dominant mechanism of action for tcVNS-induced effects on cardiovascular physiology, and (3) the existence of dynamic biomarker signatures that can be leveraged when titrating therapy in closed loop. CLINICALTRIAL ClinicalTrials.gov NCT02992899; https://clinicaltrials.gov/ct2/show/NCT02992899 INTERNATIONAL REGISTERED REPORT RR2-10.1016/j.brs.2019.08.002

OBJECTIVE Psychological trauma is an important public health problem, but previous measurement tools have primarily focused on childhood traumatic events while trauma exposure in adulthood (>18 years of age) has received less attention. The purpose of this study was to examine the psychometric properties of an instrument for assessment of psychological trauma in adulthood, the Adulthood Trauma Inventory (ATI). METHOD Participants (n = 893) completed the ATI, a 33-item questionnaire modeled after the Early Trauma Inventory-Self Report (ETI-SR), assessing traumatic events occurring after 18 years of age. Participants also completed instruments to assess depression, posttraumatic stress disorder (PTSD), and early trauma (ETI-SR). Internal consistency and item response theory metrics were examined. RESULTS ATI total score (number of items endorsed) yielded the greatest internal consistency (Cronbach's α = .77) and was significantly (p < .0001) correlated with indices of PTSD (ρ = 0.40), depression (ρ = 0.31), and early trauma (ρ = 0.56). Area under the curve and accuracy values ranged from 0.65 and 70% (depression) to 0.75 and 95% (current PTSD). CONCLUSIONS The ATI is a valid measure of adult psychological trauma that may be useful for both clinical assessment and research involving the long-term effects on the individual and psychobiology. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Objective This study aimed to investigate the relationship between waist circumference as a measure of abdominal obesity and brain responses to stress among patients with coronary artery disease (CAD). Methods Patients with CAD (N = 151) underwent acute mental stress tasks in conjunction with high-resolution positron emission tomography and radiolabeled water imaging of the brain. Brain responses to mental stress were correlated with waist circumference. Results Waist circumference was positively correlated with increased activation in the right and left frontal lobes (β values ranging from 2.81 to 3.75 in the paracentral, medial, and superior gyri), left temporal lobe, left hippocampal, left amygdala, left uncus, and left anterior and posterior cingulate gyri (β values ranging from 2.93 to 3.55). Waist circumference was also negatively associated with the left and right parietal lobes, right superior temporal gyrus, and right insula and precuneus (β values ranging from 2.82 to 5.20). Conclusion Increased brain activation in the brain regions involved in the stress response and autonomic regulation of the cardiovascular system during psychological stress may underlie stress-induced overeating and abdominal obesity in patients with CAD.

Da Costa originally described Soldier's Heart in the 19th Century as a syndrome that occurred on the battlefield in soldiers of the American Civil War. Soldier's Heart involved symptoms similar to modern day posttraumatic stress disorder (PTSD) as well as exaggerated cardiovascular reactivity felt to be related to an abnormality of the heart. Interventions were appropriately focused on the cardiovascular system. With the advent of modern psychoanalysis, psychiatric symptoms became divorced from the body and were relegated to the unconscious. Later, the physiology of PTSD and other psychiatric disorders was conceived as solely residing in the brain. More recently, advances in psychosomatic medicine led to the recognition of mind-body relationships and the involvement of multiple physiological systems in the etiology of disorders, including stress, depression PTSD, and cardiovascular disease, has moved to the fore, and has renewed interest in the validity of the original model of the Soldier's Heart syndrome.

ObjectiveExacerbated autonomic responses to acute stress are prevalent in posttraumatic stress disorder (PTSD). The purpose of this study was to assess the effects of transcutaneous cervical VNS (tcVNS) on autonomic responses to acute stress in patients with PTSD. The authors hypothesized tcVNS would reduce the sympathetic response to stress compared to a sham device.MethodsUsing a randomized double-blind approach, we studied the effects of tcVNS on physiological responses to stress in patients with PTSD (n=25) using noninvasive sensing modalities. Participants received either sham or active tcVNS after exposure to acute personalized traumatic script stress and mental stress (public speech, mental arithmetic) over a three-day protocol. Physiological parameters related to sympathetic responses to stress were investigated.ResultsRelative to sham, tcVNS paired to traumatic script stress decreased sympathetic function as measured by: decreased heart rate (adjusted ß=-5.7%; 95% CI: ±3.6%, effect size d=0.43, pConclusiontcVNS attenuates sympathetic arousal associated with stress related to traumatic memories as well as mental stress in patients with PTSD, with effects persisting throughout multiple traumatic stress and stimulation testing days. These findings show that tcVNS has beneficial effects on the underlying neurophysiology of PTSD. Such autonomic metrics may also be evaluated in daily life settings in tandem with tcVNS therapy to provide closed-loop delivery and measure efficacy.ClinicalTrials.gov Registration # NCT02992899HighlightsWe studied the effects of tcVNS on physiological responses to stress in patients posttraumatic stress disorder (PTSD).tcVNS modulates physiologic reactivity to traumatic and mental stress in PTSD, and modulates autonomic tone when applied without acute stress.Repeated tcVNS enhances resilience in the face of repeated stress in PTSD as quantified by peripheral autonomic measures which potentially could serve as real-time measures to evaluate the therapy response in longitudinal settings.

Transcutaneous cervical vagal nerve stimulation (tcVNS) devices are attractive alternatives to surgical implants, and can be applied for a number of conditions in ambulatory settings, including stress-related neuropsychiatric disorders. Transferring tcVNS technologies to at-home settings brings challenges associated with the assessment of therapy response. The ability to accurately detect whether tcVNS has been effectively delivered in a remote setting such as the home has never been investigated. We designed and conducted a study in which 12 human subjects received active tcVNS and 14 received sham stimulation in tandem with traumatic stress, and measured continuous cardiopulmonary signals including the electrocardiogram (ECG), photoplethysmogram (PPG), seismocardiogram (SCG), and respiratory effort (RSP). We extracted physiological parameters related to autonomic nervous system activity, and created a feature set from these parameters to: 1) detect active (vs. sham) tcVNS stimulation presence with machine learning methods, and 2) determine which sensing modalities and features provide the most salient markers of tcVNS-based changes in physiological signals. Heart rate (ECG), vasomotor activity (PPG), and pulse arrival time (ECG+PPG) provided sufficient information to determine target engagement (compared to sham) in addition to other combinations of sensors. resulting in 96% accuracy, precision, and recall with a receiver operator characteristics area of 0.96. Two commonly utilized sensing modalities (ECG and PPG) that are suitable for home use can provide useful information on therapy response for tcVNS. The methods presented herein could be deployed in wearable devices to quantify adherence for at-home use of tcVNS technologies.

This chapter reviews the relationship between stress and brain function in patients with neuropsychiatric disorders, with an emphasis on disorders that have most clearly been linked to traumatic stress exposure. These disorders, which have been described as trauma spectrum disorders, include posttraumatic stress disorder (PTSD), a subgroup of major depression, borderline personality disorder (BPD) and dissociative disorders; they share in common a neurobiological footprint, including smaller hippocampal volume, and are distinguished from other disorders that may share symptom similarities, like some of the anxiety disorders, but are not as clearly linked to stress. The relationship between environmental events such as stressors, especially in early childhood, and their effects on brain and neurobiology is important to understand in approaching these disorders as well as the development of therapeutic interventions. Addressing patients with stress-related disorders from multiple developmental (age at onset of trauma) as well as levels of analysis (cognitive, cultural, neurobiological) approaches will provide the most complete picture and result in the most successful treatment outcomes.

BACKGROUND: Circulating progenitor cells (CPC) have been associated with memory function and cognitive impairment in healthy adults. However, it is unclear whether such associations also exist in patients with coronary artery disease (CAD). OBJECTIVE: To assess the association between CPCs and memory performance among individuals with CAD. METHODS: We assessed cognitive function in 509 patients with CAD using the verbal and visual Memory subtests of the Wechsler memory scale-IV and the Trail Making Test parts A and B. CPCs were enumerated with flow cytometry as CD45(med)/CD34+ blood mononuclear cells, those co-expressing other epitopes representing populations enriched for hematopoietic and endothelial progenitors. RESULTS: After adjusting for demographic and cardiovascular risk factors, lower number of endothelial progenitor cell counts were independently associated with lower visual and verbal memory scores (p for all < 0.05). There was a significant interaction in the magnitude of this association with race (p < 0.01), such that the association of verbal memory scores with endothelial progenitor subsets was present in Black but not in non-Black participants. No associations were present with the hematopoietic progenitor-enriched cells or with the Trail Making Tests. CONCLUSION: Lower numbers of circulating endothelial progenitor cells are associated with cognitive impairment in patients with CAD, suggesting a protective effect of repair/regeneration processes in the maintenance of cognitive status. Impairment of verbal memory function was more strongly associated with lower CPC counts in Black compared to non-Black participants with CAD. Whether strategies designed to improve regenerative capacity will improve cognition needs further study.

Dehydration (DEH) is believed to impair cognitive performance but which domains are affected and at what magnitude of body mass loss (BML) remains unclear.To conduct systematic literature review and meta-analysis to determine the effect size (ES) of DEH on cognitive performance and influence of experimental design factors (e.g., DEH2% BML).Thirty-three studies were identified, providing 280 ES estimates from 413 subjects with DEH ranging from 1% to 6% BML. Outcome variables (accuracy, reaction time), cognitive domains, and methods to induce DEH varied. Effect sizes were calculated using standardized mean differences and multivariate meta-analysis.Impairment of cognitive performance (all domains/outcomes) with DEH was small but significant (ES = -0.21; 95% confidence interval [CI]: -0.31 to -0.11; P0.0001) with significant heterogeneity (Q(279) = 696.0, P0.0001; I = 37.6%). Tasks of executive function (ES = -0.24; 95% CI: -0.37 to -0.12), attention (ES = -0.52; 95% CI: -0.66 to -0.37), and motor coordination (ES = -0.40 to 95% CI: -0.63 to -0.17) were significantly impaired (P ≤ 0.01) after DEH, and attention/motor coordination was different (P0.001) from reaction time specific tasks (ES = -0.10; 95% CI: -0.23 to 0.02). Body mass loss was associated with the ES for cognitive impairment (P = 0.04); consequently, impairment was greater (P = 0.04) for studies reporting2% BML (ES = -0.28; 95% CI: -0.41 to -0.16) compared with ≤2%; (ES = -0.14; 95% CI: -0.27 to 0.00).Despite variability among studies, DEH impairs cognitive performance, particularly for tasks involving attention, executive function, and motor coordination when water deficits exceed 2% BML.

Men outperform women in sports requiring muscular strength and/or endurance, but the relative influence of "nurture" versus "nature" remains difficult to quantify. Performance gaps between elite men and women are well documented using world records in second, centimeter, or kilogram sports. However, this approach is biased by global disparity in reward structures and opportunities for women. Despite policies enhancing female participation (Title IX legislation), US women only closed performance gaps by 2% and 5% in Olympic Trial swimming and running, respectively, from 1972 to 1980 (with no change thereafter through 2016). Performance gaps of 13% in elite middistance running and 8% in swimming (∼4-min duration) remain, the 5% differential between sports indicative of load carriage disadvantages of higher female body fatness in running. Conversely, sprint swimming exhibits a greater sex difference than sprint running, suggesting anthropometric/power advantages unique to swim-block starts. The ∼40-y plateau in the performance gap suggests a persistent dominance of biological influences (eg, longer limb levers, greater muscle mass, greater aerobic capacity, and lower fat mass) on performance. Current evidence suggests that women will not swim or run as fast as men in Olympic events, which speaks against eliminating sex segregation in these individual sports. Whether hormone reassignment sufficiently levels the playing field in Olympic sports for transgender females (born and socialized male) remains an issue to be tackled by sport-governing bodies.

Background: Stress is associated with activation of the sympathetic nervous system, and can lead to lasting alterations in autonomic function and in extreme cases symptoms of posttraumatic stress disorder (PTSD). Vagal nerve stimulation (VNS) is a potentially useful tool as a modulator of autonomic nervous system function, however currently available implantable devices are limited by cost and inconvenience. Objective: The purpose of this study was to assess the effects of transcutaneous cervical VNS (tcVNS) on autonomic responses to stress. Methods: Using a double-blind approach, we investigated the effects of active or sham tcVNS on peripheral cardiovascular and autonomic responses to stress using wearable sensing devices in 24 healthy human participants with a history of exposure to psychological trauma. Participants were exposed to acute stressors over a three-day period, including personalized scripts of traumatic events, public speech, and mental arithmetic tasks. Results: tcVNS relative to sham applied immediately after traumatic stress resulted in a decrease in sympathetic function and modulated parasympathetic/sympathetic autonomic tone as measured by increased pre-ejection period (PEP) of the heart (a marker of cardiac sympathetic function) of 4.2 ms (95% CI 1.6–6.8 ms, p

BackgroundTranscutaneous cervical vagus nerve stimulation (tcVNS) is a promising alternative to implantable stimulation of the vagus nerve. With demonstrated potential in myriad applications, ranging from systemic inflammation reduction to traumatic stress attenuation, closed-loop tcVNS during periods of risk could improve treatment efficacy and reduce ineffective delivery. However, achieving this requires a deeper understanding of biomarker changes over time.ObjectiveThe aim of the present study was to reveal the dynamics of relevant cardiovascular biomarkers, extracted from wearable sensing modalities, in response to tcVNS.MethodsTwenty-four human subjects were recruited for a randomized double-blind clinical trial, for whom electrocardiography and photoplethysmography were used to measure heart rate and photoplethysmogram amplitude responses to tcVNS, respectively. Modeling these responses in state-space, we (1) compared the biomarkers in terms of their predictability and active vs sham differentiation, (2) studied the latency between stimulation onset and measurable effects, and (3) visualized the true and model-simulated biomarker responses to tcVNS.ResultsThe models accurately predicted future heart rate and photoplethysmogram amplitude values with root mean square errors of approximately one-fifth the standard deviations of the data. Moreover, (1) the photoplethysmogram amplitude showed superior predictability (P=.03) and active vs sham separation compared to heart rate; (2) a consistent delay of greater than 5 seconds was found between tcVNS onset and cardiovascular effects; and (3) dynamic characteristics differentiated responses to tcVNS from the sham stimulation.ConclusionsThis work furthers the state of the art by modeling pertinent biomarker responses to tcVNS. Through subsequent analysis, we discovered three key findings with implications related to (1) wearable sensing devices for bioelectronic medicine, (2) the dominant mechanism of action for tcVNS-induced effects on cardiovascular physiology, and (3) the existence of dynamic biomarker signatures that can be leveraged when titrating therapy in closed loop.Trial RegistrationClinicalTrials.gov NCT02992899; https://clinicaltrials.gov/ct2/show/NCT02992899International Registered Report Identifier (IRRID)RR2-10.1016/j.brs.2019.08.002

Angina pectoris is associated with increased risk of adverse cardiovascular events in coronary artery disease (CAD) patients, an effect not entirely attributable to the severity of CAD. OBJECTIVE: Examine brain correlates of mental stress in patients with CAD with and without a history of angina. METHODS: Participants (n = 170) with stable CAD completed the Seattle Angina Questionnaire along with other psychometric assessments. In this cross-sectional study, participants underwent laboratory-based mental stress testing using mental arithmetic and public speaking tasks along with control conditions in conjunction with positron emission tomography brain imaging using radiolabeled water. Brain activity during mental stress was compared between participants who did or did not report chest pain/angina in the previous month. A factor analysis was coupled with dominance analysis to identify brain regions associated with angina. RESULTS: Participants reporting angina in the past month experienced greater (p < .005) activations within the left: frontal lobe (z = 4.01), temporal gyrus (z = 3.32), parahippocampal gyrus (z = 3.16), precentral gyrus (z = 3.14), right fusiform gyrus (z = 3.07), and bilateral cerebellum (z = 3.50) and deactivations within the right frontal gyrus (z = 3.67), left precuneus (z = 3.19), and left superior temporal gyrus (z = 3.11) during mental stress. A factor containing the left motor areas, inferior frontal lobe, and operculum (average McFadden’s number addition = 0.057) in addition to depression severity (0.10) and adulthood trauma exposure (0.064) correlated with angina history. CONCLUSIONS: Self-reported angina in patients with stable CAD is associated with increased neural responses to stress in a network including the inferior frontal lobe, motor areas, and operculum, potentially indicating an upregulated pain perception response.

The influence of acute psychological stress on cardiovascular disease is an emerging public health concern. Identification of brain mechanisms underlying this may aid in the discovery of possible treatments. Acute psychological stress may induce arteriolar vasoconstriction and reduce blood flow to vital organs. We hypothesized that functional changes in brain regions involved with memory and autonomic/emotional regulation are implicated in the vasoconstrictive stress response, including the medial prefrontal cortex (anterior cingulate), insula, and dorsolateral prefrontal cortex. Subjects with a history of coronary artery disease (CAD) (N = 59) underwent measurement of microvascular vasomotor tone with the EndoPAT device and O-15 positron emission tomography (PET) imaging of the brain during exposure to mental stress and control conditions. The peripheral arterial tonometry (PAT) ratio was calculated as the mean peripheral vasomotor tone during stress divided by the mean tone during rest. Whole brain contrasts were performed between groups above and below the median PAT ratio, and significant contrasts were defined with cutoff p < 0.005. Stress-induced peripheral vasoconstriction (below median PAT ratio) was associated with increased stress activation in insula and parietal cortex, and decreased activation in the medial prefrontal cortex with stress tasks compared to control tasks. These findings demonstrate that stress-induced vasoreactivity is associated with changes in brain responses to stress in areas involved in emotion, and autonomic regulation. These findings have important implications on possible treatments for mental stress-induced vascular toxicity.

Purpose:The impact of mild hypohydration on physiological responses and cognitive performance following exercise-heat stress (EHS) were examined compared with conditions when fluids were ingested ad libitum (AL) or replaced to match sweat losses (FR).Methods:Twelve unacclimatized, recreationally-active men (22.2 ± 2.4 y) completed 50 min cycling (60%VO2peak) in the heat (32°C; 65% RH) under three conditions: no fluid (NF), AL, and FR. Before and after EHS, a cognitive battery was completed: Trail making, perceptual vigilance, pattern comparison, match-to-sample, and letter-digit recognition tests.Results:Hypohydration during NF was greater compared with AL and FR (NF: -1.5 ± 0.6; AL: -0.3 ± 0.8; FR: -0.1 ± 0.3% body mass loss) resulting in higher core temperature (by 0.4, 0.5 °C), heart rate (by 13 and 15 b·min-1), and physiological strain (by 1.3, 1.5) at the end of EHS compared with AL and FR, respectively. Cognitive performance (response time and accuracy) was not altered by fluid condition; however, mean response time improved (p < .05) for letter-digit recognition (by 56.7 ± 85.8 ms or 3.8%; p < .05) and pattern comparison (by 80.6 ± 57.4 ms or 7.1%; p < .001), but mean accuracy decreased in trail making (by 1.2 ± 1.4%; p = .01) after EHS (across all conditions).Conclusions:For recreational athletes, fluid intake effectively mitigated physiological strain induced by mild hypohydration; however, mild hypohydration resulting from EHS elicited no adverse changes in cognitive performance.

This study investigated the effects that a form fitted, moisture-wicking fabric shirt, promoted to have improved evaporative and ventilation properties, has on the physiological and perceptual responses during exercise in the heat. Ten healthy male participants completed two heat stress tests consisting of 45 min of exercise (50% VO2peak) in a hot environment (33 °C, 60% RH). One heat stress test was conducted with the participant wearing a 100% cotton short sleeved t-shirt and the other heat stress test was conducted with the participant wearing a short sleeved synthetic shirt (81% polyester and 19% elastane). Rectal temperature was significantly lower (P

Effects of exercise‐heat stress with and without water replacement on brain structure and visuomotor performance were examined. Thirteen healthy adults (23.6 ± 4.2 years) completed counterbalanced 150 min trials of exercise‐heat stress (45°C, 15% RH) with water replacement (EHS) or without (~3% body mass loss; EHS‐DEH) compared to seated rest (CON). Anatomical scans and fMRI Blood‐Oxygen‐Level‐Dependent responses during a visuomotor pacing task were evaluated. Accuracy decreased (P 0.50) between structural changes and visuomotor accuracy. EHS‐DEH increased neural activation (P

Plasma osmolality (POsm) is a gold standard to assess hydration status but requires venipuncture. POsm obtained by lancing a digit, a source of capillary puncture blood (CAP), has not been validated. This study compared POsm from CAP versus venous blood (VEN) and validated its sensitivity to detect dehydration.Healthy young adults (Study A: n=20 men, 22 women; Study B: n=23 men, 23 women) participated. In Study A, CAP and VEN were compared under controlled euhydration meeting dietary reference intakes for water (3.7 L men, 2.7 L women). In Study B, CAP was assessed for sensitivity to detect dehydration with receiver operating characteristic analysis over two 24 h periods: euhydration for 24 h followed by water restriction over 24 h. POsm was measured using freezing point depression.For all subjects, CAP POsm (283.0±3.9 mOsm/kg) was not significantly different (p=0.07) from VEN (284.2±3.5) during euhydration and met analytical goals for individuality and heterogeneity. When outliers (n=3) were eliminated, mean difference was –1.6 (±3.2) lower (pPOsm via CAP exhibited similar coefficients of variation and analytical goals compared to VEN combined with excellent accuracy and sensitivity to detect dehydration. Although CAP values were approximately 2 mOsm/kg lower than VEN, CAP appears an adequate substitute for tracking changes in non-clinical settings.