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In humans, sex disparities exist in the prevalence of social stress-related disorders, yet our understanding of the predisposing factors and underlying mechanisms is still elusive. Also at the preclinical level, the investigation of sex differences in social stress responses is limited. In this study, adult male and female wild-type Groningen rats were repeatedly exposed to witness social defeat stress (WS) to assess sex-specific behavioral, neuroendocrine, and cardiac responses to the same social stress paradigm. Male and female rats bore witness to an aggressive social defeat episode between two males for nine consecutive days or were exposed to a control (CTR) procedure. Stress-related parameters were assessed in correspondence to the first and last WS/CTR exposure and also during subsequent exposure to the stress context alone in the absence of social defeat. During WS, rats of both sexes displayed larger amounts of burying behavior and smaller amounts of rearing and grooming behaviors, but with a greater extent in female witnesses. Cardiac autonomic responses to WS were similar between the sexes, yet only females displayed higher plasma corticosterone levels after the first WS exposure compared to CTRs, and had a larger corticosterone increase than male witnesses upon repeated WS. Exposure to the stress context alone (i.e., without the presence of the aggressive resident rat) elicited greater amount of burying behavior and more pronounced and persistent tachycardic responses in females than males with a history of WS. Our findings suggest sex-disparities in the response of adult rats to WS at multiple behavioral, cardiac, and neuroendocrine levels, highlighting the utility of this social stress paradigm for investigating predisposing factors and pathophysiological mechanisms underlying sex-specific vulnerabilities to stress-related pathologies., Competing Interests: Declaration of competing interest The authors state no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The identification of reliable biomarkers of transcutaneous auricular vagus nerve stimulation (taVNS) responsiveness is a key challenge both at the clinical and preclinical level. Vagally-mediated heart rate variability (vmHRV), a surrogate measure of cardiac vagal efferent activity, is an ideal candidate. Yet, the effects of taVNS on vmHRV remain inconclusive, likely due to the high degree of heterogeneity in stimulation protocols (e.g., taVNS parameters and side of the ear target), and little consideration of contributing factors such as sex differences. This study investigates sex differences in heart rate and vmHRV responses to different protocols of taVNS in adult rats. Male and female wild-type Groningen rats received sham or active stimulation (6 Hz or 20 Hz, 1 ms, 6 V) on the left or right auricular concha region. ECG signals were recorded before (10 min), during (20 min) and after (10 min) each session in a between-subject design. We found differential side-, frequency- and sex-specific chronotropic responses to taVNS, whereby heart rate decreased and vmHRV indexes increased at 6 Hz in males and at 20 Hz in females. Also, increases in vmHRV were only observed for right-side taVNS. The current findings suggest that biological sex should be considered for fine-tuning regulation of taVNS-induced cardiac responses and provide information regarding the side-specific effects of taVNS on vmHRV. These results will likely guide future rodent research to the choice of the most appropriate stimulation protocol in both sexes for generating information that can be translated into taVNS-related strategies in humans., Competing Interests: Declaration of competing interest Nothing to declare., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Driver Monitoring Systems (DMSs) play a key role in preventing hazardous events (e.g., road accidents) by providing prompt assistance when anomalies are detected while driving. Different factors, such as traffic and road conditions, might alter the psycho-physiological status of a driver by increasing stress and workload levels. This motivates the development of advanced monitoring architectures taking into account psycho-physiological aspects. In this work, we propose a novel in-vehicle Internet of Things (IoT)-oriented monitoring system to assess the stress status of the driver. In detail, the system leverages heterogeneous components and techniques to collect driver (and, possibly, vehicle) data, aiming at estimating the driver's arousal level, i.e., their psycho-physiological response to driving tasks. In particular, a wearable sensorized bodice and a thermal camera are employed to extract physiological parameters of interest (namely, the heart rate and skin temperature of the subject), which are processed and analyzed with innovative algorithms. Finally, experimental results are obtained both in simulated and real driving scenarios, demonstrating the adaptability and efficacy of the proposed system.

Understanding the association between autonomic nervous system [ANS] function and brain morphology across the lifespan provides important insights into neurovisceral mechanisms underlying health and disease. Resting-state ANS activity, indexed by measures of heart rate [HR] and its variability [HRV] has been associated with brain morphology, particularly cortical thickness [CT]. While findings have been mixed regarding the anatomical distribution and direction of the associations, these inconsistencies may be due to sex and age differences in HR/HRV and CT. Previous studies have been limited by small sample sizes, which impede the assessment of sex differences and aging effects on the association between ANS function and CT. To overcome these limitations, 20 groups worldwide contributed data collected under similar protocols of CT assessment and HR/HRV recording to be pooled in a mega-analysis (N = 1,218 (50.5% female), mean age 36.7 years (range: 12-87)). Findings suggest a decline in HRV as well as CT with increasing age. CT, particularly in the orbitofrontal cortex, explained additional variance in HRV, beyond the effects of aging. This pattern of results may suggest that the decline in HRV with increasing age is related to a decline in orbitofrontal CT. These effects were independent of sex and specific to HRV; with no significant association between CT and HR. Greater CT across the adult lifespan may be vital for the maintenance of healthy cardiac regulation via the ANS-or greater cardiac vagal activity as indirectly reflected in HRV may slow brain atrophy. Findings reveal an important association between CT and cardiac parasympathetic activity with implications for healthy aging and longevity that should be studied further in longitudinal research., (© 2020 The Authors. Psychophysiology published by Wiley Periodicals LLC on behalf of Society for Psychophysiological Research.)

Background: African Americans have the highest rates of hypertension-related disease of any ethnic group in the USA. Importantly, racism and discrimination have been linked to these higher rates of morbidity and mortality. Discrimination is deleterious not only to those that are the recipients of this unfair treatment but also to the partners and family members of those affected as well to those that perpetrate this bias., Purpose: In this paper, we identify a unique pattern of physiological response to unfair treatment, we have called the "cardiovascular conundrum." This pattern is characterized by greater heart rate variability and greater total peripheral resistance in African Americans compared to their European American counterparts., Methods and Results: We review the evidence supporting the existence of this pattern and propose several physiological and psychological factors that might underpin it. We also propose a number of factors that might help to mitigate the deleterious effects associated with it., Conclusions: Whereas the context of the current review is on Black/White disparities the framework we propose may be relevant to others exposed to unfair treatment. Ultimately, the systemic factors that perpetuate these inequalities will require that we first acknowledge and then face the challenges they present if we are to address the wealth and health disparities in our country., (© Society of Behavioral Medicine 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Stress related to parenting a child with autism spectrum disorder can differently affect caregiver's physiological reactivity to acute stress. Here, parental stress levels, psychological characteristics, and coping strategies were assessed alongside measures of heart rate, heart rate variability, and cortisol during a psychosocial stress test in mothers of children with ASD (M-ASD, n = 15) and mothers of typically developing children (n = 15). M-ASD reported significantly higher levels of parental stress, anxiety, negative affectivity, social inhibition, and a larger preference for avoidance strategies. M-ASD showed larger heart rate and cortisol responses to the psychosocial stress test. A positive relationship was found between parental stress levels and the magnitude of the cortisol stress response in both groups. The present findings indicate exaggerated physiological reactivity to acute psychosocial stress in M-ASD and prompt further research to explore the role of individual differences in mediating the effects of parental stress on physiological stress responses., (©2019 John Wiley & Sons, Ltd.)

The inflammatory reflex is known as the body's primary defense against infection and has been implicated in a number of diseases. The magnitude of the inflammatory response is important, as an extreme or insufficient response can be differentially harmful to the individual. Converging evidence suggests that the autonomic nervous system (ANS) regulates the inflammatory reflex. Heart rate variability (HRV) can be separated into components that primarily reflect parasympathetic (PNS) or vagal activity (i.e., indices of vagally mediated HRV) and a combination of both sympathetic (SNS) and PNS influences. Given the physiological relation between the vagus and inflammatory processes, one would expect to find higher HRV, especially indices of vagally-mediated HRV, to be associated with decreased levels of inflammation via the cholinergic anti-inflammatory pathway. However, existing findings here are mixed, such that studies have also shown a positive association between indices of HRV and markers of inflammation. Therefore, the present meta-analysis aimed to synthesize existing studies, estimating the general direction and strength of the relationship between different indices of HRV and inflammatory markers. A systematic search of the literature yielded 2283 studies that were screened for inclusion eligibility (159 studies eligible for inclusion); in sum, 51 studies reported/provided adequate information for inclusion in meta-analyses. Results generally showed negative associations between indices of HRV and markers of inflammation. In this regard, the standard deviation of R-R intervals (SDNN) and power in the high frequency band of HRV (HF-HRV) showed the strongest and most robust associations with inflammatory markers compared to other time- and frequency-domain measures of HRV. Overall, we propose that indices of HRV can be used to index activity of the neurophysiological pathway responsible for adaptively regulating inflammatory processes in humans., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Seizures are frequently observed in neurological conditions affecting newborns. Since autonomic alterations are commonly associated with neonatal seizures (NS), we investigated the utility of heart rate variability (HRV) indexes of cardiac autonomic regulation for NS detection., Methods: HRV analysis was conducted on ECG tracings recorded during video-EEG monitoring in newborns with NS and matched-controls. The effects of gestational age on HRV were also evaluated., Results: Newborns with NS showed lower resting state HRV compared to controls. Moreover, seizure episodes were characterized by a short-lasting increase in vagal indexes of HRV. Pre-term newborns with NS had a lower HRV than full-term at rest. In pre-term newborns, no changes in HRV were observed before and during NS. On the contrary, full-term newborns showed significantly higher HRV before and during NS compared to the respective baseline values., Conclusion: Our data point to resting autonomic impairment in newborns with NS. In addition, an increment in HRV has been observed during NS only in full term newborns., Significance: Although these findings do not allow validation of HRV measures for NS prediction and detection, they suggest that a putative protective vagal mechanism might be adopted when an advanced maturation of autonomic nervous system is achieved., (Copyright © 2018 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Ruminative thinking about negative feelings has been prospectively associated with increases in depressive symptoms and heightened risk for new onsets of major depression. One putative pathophysiological mechanism underlying this link might be represented by autonomic nervous system dysfunction. The objective of this longitudinal study was to evaluate the interplay between rumination, autonomic function (as revealed by heart rate variability (HRV) analysis), and depressive symptoms in healthy young subjects, over a three-year period. Rumination and depressive symptoms were evaluated in twenty-two women and twenty men at three assessment points (Time 0, 1 and 2) by the score on the Ruminative Response Scale, and the Center for Epidemiological Studies Depression Scale, respectively. Vagally-mediated HRV was assessed in a laboratory session (Time 0) and in two ambulatory sessions at Time 1 and Time 2 (~13 and 34months after Time 0, respectively). Ruminative thinking was found to be (i) a stable trait characteristic, (ii) more prevalent in women than men, and (iii) positively correlated with depressive symptoms. Moreover, resting HRV was negatively correlated with both rumination and depressive symptoms. Finally, HRV at Time 1 mediated the relationship between rumination at Time 0 and depressive symptoms at Time 2. We conclude that autonomic dysfunction, specifically low vagal tone, may be prospectively implicated in the generation of depressive symptoms in a non-clinical setting., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Central neuropeptide Y (NPY) signaling participates in the regulation of cardiac autonomic outflow, particularly via activation of NPY-Y1 receptors (Y1Rs). However, the specific brain areas and neural pathways involved have not been completely identified yet. Here, we evaluate the role of hippocampal Y1Rs in the modulation of the autonomic control of cardiac function using a conditional knockout mouse model. Radiotelemetric transmitters were implanted in 4-month-old male mice exhibiting reduced forebrain expression (rfb) of the Y1R (Npy1r rfb , n=10) and their corresponding controls (Npy1r 2lox , n=8). ECG signals were recorded (i) during resting conditions, (ii) under selective pharmacological manipulation of cardiac vagal activity, and (iii) during acute and chronic psychosocial stress challenges, and analyzed via time- and frequency-domain analysis of heart rate variability. Npy1r rfb mice showed a lower Npy1r mRNA density in the dentate gyrus and in the CA1 region of the hippocampus. Under resting undisturbed conditions, Npy1r rfb mice exhibited (i) a higher heart rate, (ii) a reduced overall heart rate variability, and (iii) lower values of the indices of vagal modulation compared to Npy1r 2lox counterparts. Following pharmacological vagal inhibition, heart rate was higher in control but not in Npy1r rfb mice compared to their respective baseline values, suggesting that tonic vagal influences on heart rate were reduced in Npy1r rfb mice. The magnitude of the heart rate response to acute stressors was smaller in Npy1r rfb mice compared to Npy1r 2lox counterparts, likely due to a concurrent lower vagal withdrawal. These findings suggest that reduced Y1R expression leads to a decrease in resting vagal modulation and heart rate variability, which, in turn, may determine a reduced cardiac autonomic responsiveness to acute stress challenges., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Depression occurs in people of all ages across all world regions; it is the second leading cause of disability and its global burden increased by 37.5% between 1990 and 2010. Autonomic changes are often found in altered mood states and appear to be a central biological substrate linking depression to a number of physical dysfunctions. Alterations of autonomic nervous system functioning that promotes vagal withdrawal are reflected in reductions of heart rate variability (HRV) indexes. Reduced HRV characterizes emotional dysregulation, decreased psychological flexibility and defective social engagement, which in turn are linked to prefrontal cortex hypoactivity. Altogether, these pieces of evidence support the idea that HRV might represent a useful endophenotype for psychological/physical comorbidities, and its routine application should be advised to assess the efficacy of prevention/intervention therapies in a number of psychosomatic and psychiatric dysfunctions. Further research, also making use of appropriate animal models, could provide a significant support to this point of view and possibly help to identify appropriate antidepressant therapies that do not interefere with physical health.

Advanced age alone appears to be a risk factor for increased susceptibility to cardiac arrhythmias. We previously observed in the aged rat heart that sinus rhythm ventricular activation is delayed and characterized by abnormal epicardial patterns although conduction velocity is normal. While these findings relate to an advanced stage of aging, it is not yet known when and how ventricular electrical impairment originates and which is the underlying substrate. To address these points, we performed continuous telemetry ECG recordings in freely moving rats over a six-month period to monitor ECG waveform changes, heart rate variability and the incidence of cardiac arrhythmias. At the end of the study, we performed in-vivo multiple lead epicardial recordings and histopathology of cardiac tissue. We found that the duration of ECG waves and intervals gradually increased and heart rate variability gradually decreased with age. Moreover, the incidence of cardiac arrhythmias gradually increased, with atrial arrhythmias exceeding ventricular arrhythmias. Epicardial multiple lead recordings confirmed abnormalities in ventricular activation patterns, likely attributable to distal conducting system dysfunctions. Microscopic analysis of aged heart specimens revealed multifocal connective tissue deposition and perinuclear myocytolysis in the atria. Our results demonstrate that aging gradually modifies the terminal part of the specialized cardiac conducting system, creating a substrate for increased arrhythmogenesis. These findings may open new therapeutic options in the management of cardiac arrhythmias in the elderly population.

In humans, variants of the fat mass and obesity associated (FTO) gene have recently been associated with obesity. However, the physiological function of FTO is not well defined. Previous investigations in mice have linked FTO deficiency to growth retardation, loss of white adipose tissue, increased energy metabolism and enhanced systemic sympathetic activation. In this study we investigated for the first time the effects of global knockout of the mouse FTO gene on cardiac function and its autonomic neural regulation. ECG recordings were acquired via radiotelemetry in homozygous knockout (n = 12) and wild-type (n = 8) mice during resting and stress conditions, and analyzed by means of time- and frequency-domain indexes of heart rate variability. In the same animals, cardiac electrophysiological properties (assessed by epicardial mapping) and structural characteristics were investigated. Our data indicate that FTO knockout mice were characterized by (i) higher heart rate values during resting and stress conditions, (ii) heart rate variability changes (increased LF to HF ratio), (iii) larger vulnerability to stress-induced tachyarrhythmias, (iv) altered ventricular repolarization, and (v) cardiac hypertrophy compared to wild-type counterparts. We conclude that FTO deficiency in mice leads to an imbalance of the autonomic neural modulation of cardiac function in the sympathetic direction and to a potentially proarrhythmic remodeling of electrical and structural properties of the heart.

In humans, there is a documented association between anxiety disorders and cardiovascular disease. Putative underlying mechanisms may include an impairment of the autonomic nervous system control of cardiac function. The primary objective of the present study was to characterize cardiac autonomic modulation and susceptibility to arrhythmias in genetic lines of rats that differ largely in their anxiety level. To reach this goal, electrocardiographic recordings were performed in high-anxiety behavior (HAB, n=10) and low-anxiety behavior (LAB, n=10) rats at rest, during stressful stimuli and under autonomic pharmacological manipulations, and analyzed by means of time- and frequency-domain indexes of heart rate variability. During resting conditions, HAB rats displayed a reduced heart rate variability, mostly in terms of lower parasympathetic (vagal) modulation compared to LAB rats. In HAB rats, this relatively low cardiac vagal control was associated with smaller heart rate responsiveness to acute stressors compared to LAB counterparts. In addition, beta-adrenergic pharmacological stimulation induced a larger incidence of ventricular tachyarrhythmias in HABs compared to LABs. At sacrifice, a moderate increase in heart-body weight ratio was observed in HAB rats. We conclude that high levels of anxiety-related behavior in rats are associated with signs of i) impaired autonomic modulation of heart rate (low vagally-mediated heart rate variability), ii) poor adaptive heart rate responsiveness to stressful stimuli, iii) increased arrhythmia susceptibility, and iv) cardiac hypertrophy. These results highlight the utility of the HAB/LAB model for investigating the mechanistic basis of the comorbidity between anxiety disorders and cardiovascular disease., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Personality characteristics, e.g. aggressiveness, have long been associated with an increased risk of cardiac disease. However, the underlying mechanisms remain unclear. In this study we used a rodent model for characterizing cardiac autonomic modulation in rats that differ widely in their level of aggressive behavior. To reach this goal, high-aggressive (HA, n = 10) and non-aggressive (NA, n = 10) rats were selected from a population (n = 121) of adult male Wild-type Groningen rats on the basis of their latency time to attack (ALT, s) a male intruder in a resident-intruder test lasting 600 s. In order to obtain information on their cardiac autonomic modulation, ECG recordings were subsequently obtained via radiotelemetry at rest, during stressful stimuli and under autonomic pharmacological manipulations, and analyzed by means of time- and frequency-domain indexes of heart rate variability. During resting conditions, HA rats (ALT<90 s) displayed reduced heart rate variability, mostly in terms of lower vagal modulation compared to NA rats (ALT>600 s). Exposure to stressful stimuli (i.e. restraint and psychosocial stress) provoked similar tachycardic responses between the two groups. However, under stress conditions HA rats displayed a reduced vagal antagonism and an increased incidence of tachyarrhythmias compared to NA rats. In addition, beta-adrenergic pharmacological stimulation induced a much larger incidence of ventricular tachyarrhythmias in HA rats compared to NA counterparts. These findings are consistent with the view that high levels of aggressive behavior in rats are associated to signs of cardiac autonomic impairment and increased arrhythmogenic susceptibility that may predict vulnerability to cardiac morbidity and mortality.

Adverse social environments play a relevant role in the onset and progression of mood disorders. On the other hand, depression is an independent risk factor for cardiovascular morbidity. This study was aimed at (i) corroborating the validity of a rat model of depression based on a negative social episode followed by social isolation and (ii) verifying its impact on cardiac function and structure. Pair housed, wild-type Groningen rats (Rattus norvegicus) were implanted with radiotransmitters for ECG, temperature and activity recordings. They were either exposed to a social defeat episode followed by 4-week isolation or left undisturbed with their female partners. The social challenge induced a series of biological changes that are commonly taken as markers of depression in rats, including decreased body weight gain and reduced preference for sucrose consumption, functional and structural changes of the hypothalamic-pituitary-adrenocortical axis, increased anxiety in the elevated plus maze test. The cardiovascular alterations consisted in (i) transitory heart rate circadian rhythm alterations, (ii) lack of habituation of cardiac autonomic responsivity (tachycardia and vagal withdrawal) to an acute stressor, and (iii) moderate hypertrophy affecting the right ventricle of the heart. These results indicate that a depression-like state induced via this model of social challenge was associated with a few modest cardiovascular changes. Further studies are required to confirm the validity of this rat model of depression as a valid preclinical approach to the comprehension of the biological substrates underlying depression-cardiovascular comorbidity., (Copyright © 2012 Elsevier Inc. All rights reserved.)

In humans, chronic stressors have long been recognized as potential causes for cardiac dysregulation. Despite this, the underlying mechanistic links responsible for this association are still poorly understood. The purpose of this study was to determine whether exposure to a paradigm of subchronic stress can provoke enduring changes on the heart rate of experimental rats and, if so, to reveal the autonomic and neural mechanisms that mediate these effects. The study was conducted on adult male Sprague-Dawley rats instrumented for telemetric recording of heart rate and locomotor activity. Animals were submitted to a subchronic stress protocol, consisting of a 1-h foot shock session on five consecutive days. Heart rate and locomotor activity were recorded continuously for 3 days before and for 6 days after the subchronic stress period. Subchronic foot shock produced significant and enduring reduction in heart rate both during the dark/active [Δ= -23 ± 3 beats per minute (bpm)] and light/inactive (Δ= -20 ± 3 bpm) phases of the circadian cycle, and a reduction in locomotor activity during the dark/active phase [Δ= -54 ± 6 counts per hour (cph)]. The bradycardic effect of subchronic stress was not related to a reduced locomotion. Selective sympathetic (atenolol) and vagal (methyl-scopolamine) blockades were performed to reveal which autonomic component was responsible for this effect. We found that the fall in heart rate persisted after subchronic stress in animals treated with atenolol (active phase Δ= -16 ± 3 bpm, inactive phase Δ= -19 ± 2 bpm), whereas vagal blockade with scopolamine transiently prevented this effect, suggesting that the bradycardia following subchronic stress was predominantly vagally mediated. Fluoxetine (selective serotonin reuptake inhibitor) and metyrapone (inhibitor of corticosterone synthesis) treatments did not affect heart rate changes but prevented the reduction in locomotion. We conclude that subchronic stress exposure in rats reduces heart rate via a rebound in vagal activation and that this effect is serotonin- and corticosterone-independent.