Rhinorrhea and watery eyes in infancy and risk of attention-deficit hyperactivity disorder in school-age children.

Increased parasympathetic nervous system (PNS) activity is associated with attention-deficit/hyperactivity disorder (ADHD) inattentive symptoms, but not hyperactive-impulsive symptoms, and may contribute to inattentive subtype etiology. Guided by prior work linking infant rhinorrhea and watery eyes without a cold (RWWC) to PNS dysregulation, we examined associations between infant RWWC and childhood ADHD symptoms in a longitudinal cohort of Black and Latinx children living in the context of economic disadvantage (N = 301 youth: 158 females, 143 males). Infant RWWC predicted higher inattentive (relative risk [RR] 2.16, p < .001) but not hyperactive-impulsive (RR 1.53, p = .065) ADHD symptoms (DuPaul scale), administered to caregivers at child age 8-14 years. Stratified analyses revealed that these associations were present in females but not males, who were three times more likely to have higher ADHD current total symptoms if they had infant RWWC than if they did not. Additionally, associations between RWWC and inattention symptoms were observed only in females. RWWC may thus serve as a novel risk marker of ADHD inattentive-type symptoms, especially for females.

Efficacy and safety of trigeminal parasympathetic pathway stimulation for dry eye: A systematic review and meta-analysis.

This study aimed to investigate the efficacy and safety of trigeminal parasympathetic pathway (TPP) stimulation in the treatment of dry eye. A comprehensive search for randomized clinical trials was performed in seven databases (MEDLINE, Embase, CENTRAL, etc.) up to 28 February 2023. After screening the suitable studies, the data were extracted and transformed as necessary. Data synthesis and analysis were performed using Review Manager 5.4, and the risk of bias and quality of evidence were evaluated with the recommended tools. Fourteen studies enrolling 1714 patients with two methods (electrical and chemical) of TPP stimulation were included. Overall findings indicate that TPP stimulation was effective in reducing subjective symptom score (standardized mean difference [SMD], -0.45; 95% confidence interval [CI], -0.63 to -0.28), corneal fluorescence staining (mean difference [MD], -0.78; 95% CI, -1.39 to -0.18), goblet cell area (MD, -32.10; 95% CI, -54.58 to -9.62) and perimeter (MD, -5.90; 95% CI, -10.27 to -1.53), and increasing Schirmer's test score (SMD, 0.98; 95% CI, 0.65 to 1.31) and tear film break-up time (SMD, 0.57; 95% CI, 0.19 to 0.95). Compared to inactive or low-activity stimulation controls, it has a higher incidence of adverse events. Therefore, TPP stimulation may be an effective treatment for dry eye, whether electrical or chemical. Adverse events are relatively mild and tolerable. Due to the high heterogeneity and low level of evidence, the current conclusions require to be further verified.

ALM Fluid Therapy Shifts Sympathetic Hyperactivity to Parasympathetic Dominance in the Rat Model of Non-Compressible Hemorrhagic Shock.

ABSTRACT: Excessive sympathetic outflow following trauma can lead to cardiac dysfunction, inflammation, coagulopathy, and poor outcomes. We previously reported that buprenorphine analgesia decreased survival after hemorrhagic trauma. Our aim is to examine the underlying mechanisms of mortality in a non-compressible hemorrhage rat model resuscitated with saline or adenosine, lidocaine, magnesium (ALM). Anesthetized adult male Sprague-Dawley rats were randomly assigned to Saline control group or ALM therapy group (both n = 10). Hemorrhage was induced by 50% liver resection. After 15 min, 0.7 mL/kg 3% NaCl ±â€ŠALM intravenous bolus was administered, and after 60 min, 0.9% NaCl ±â€ŠALM was infused for 4 h (0.5 mL/kg/h) with 72 h monitoring. Animals received 6-12-hourly buprenorphine for analgesia. Hemodynamics, heart rate variability, echocardiography, and adiponectin were measured. Cardiac tissue was analyzed for adrenergic/cholinergic receptor expression, inflammation, and histopathology. Four ALM animals and one Saline control survived to 72 h. Mortality was associated with up to 97% decreases in adrenergic (ß-1, α-1A) and cholinergic (M2) receptor expression, cardiac inflammation, myocyte Ca2+ loading, and histopathology, indicating heart ischemia/failure. ALM survivors had higher cardiac output and stroke volume, a 30-fold increase in parasympathetic/sympathetic receptor expression ratio, and higher circulating adiponectin compared to Saline controls. Paradoxically, Saline cardiac adiponectin hormone levels were higher than ALM, with no change in receptor expression, indicating intra-cardiac synthesis. Mortality appears to be a "systems failure" associated with CNS dysregulation of cardiac function. Survival involves an increased parasympathetic dominance to support cardiac pump function with reduced myocardial inflammation. Increased cardiac α-1A adrenergic receptor in ALM survivors may be significant, as this receptor is highly protective during heart dysfunction/failure.

Cardiac Changes in Parkinson's Disease: Lessons from Clinical and Experimental Evidence.

Dysautonomia is a common non-motor symptom in Parkinson's disease (PD). Most dysautonomic symptoms appear due to alterations in the peripheral nerves of the autonomic nervous system, including both the sympathetic and parasympathetic nervous systems. The degeneration of sympathetic nerve fibers and neurons leads to cardiovascular dysfunction, which is highly prevalent in PD patients. Cardiac alterations such as orthostatic hypotension, heart rate variability, modifications in cardiogram parameters and baroreflex dysfunction can appear in both the early and late stages of PD, worsening as the disease progresses. In PD patients it is generally found that parasympathetic activity is decreased, while sympathetic activity is increased. This situation gives rise to an imbalance of both tonicities which might, in turn, promote a higher risk of cardiac damage through tachycardia and vasoconstriction. Cardiovascular abnormalities can also appear as a side effect of PD treatment: L-DOPA can decrease blood pressure and aggravate orthostatic hypotension as a result of a negative inotropic effect on the heart. This unwanted side effect limits the therapeutic use of L-DOPA in geriatric patients with PD and can contribute to the number of hospital admissions. Therefore, it is essential to define the cardiac features related to PD for the monitorization of the heart condition in parkinsonian individuals. This information can allow the application of intervention strategies to improve the course of the disease and the proposition of new alternatives for its treatment to eliminate or reverse the motor and non-motor symptoms, especially in geriatric patients.

Effects of Hypoxia on Selected Psychophysiological Stress Responses of Military Aircrew.

There is a lack of information on the psychophysiological response of pilots under hypoxic conditions. The study of the physiological, psychological, cardiorespiratory, neurological, behavioural, sensory, and cognitive symptoms that may appear during training in hypobaric chambers is essential to optimize the training processes of aircrew members. Thus, the present study is aimed at analyzing the psychophysiological responses of aircrew members in an incremental hypoxia training protocol. Psychophysiological responses of 44 aircrew members (34 males and 10 females) in an incremental hypoxia training protocol (3 minutes at 0 meters, 8 minutes at 5,000 meters, and maximum time at 7500 meters) were measured. Results suggested that the incremental hypoxia training protocol did not affect cortical arousal and handgrip strength; however, it increased the sympathetic tone, perceived stress, perceived effort, and heart rate and decreased forced expiratory volume and blood oxygen saturation. Thus, we concluded that acute hypoxic hypobaric exposure leads to decreased parasympathetic tone, blood oxygen saturation, and maximal spirometry values, without negatively affecting handgrip strength and cortical arousal. This information will lead to find specific training systems that meet the real needs of aircrew.

Angiotensin II and the Cardiac Parasympathetic Nervous System in Hypertension.

The renin-angiotensin-aldosterone system (RAAS) impacts cardiovascular homeostasis via direct actions on peripheral blood vessels and via modulation of the autonomic nervous system. To date, research has primarily focused on the actions of the RAAS on the sympathetic nervous system. Here, we review the critical role of the RAAS on parasympathetic nerve function during normal physiology and its role in cardiovascular disease, focusing on hypertension. Angiotensin (Ang) II receptors are present throughout the parasympathetic nerves and can modulate vagal activity via actions at the level of the nerve endings as well as via the circumventricular organs and as a neuromodulator acting within brain regions. There is tonic inhibition of cardiac vagal tone by endogenous Ang II. We review the actions of Ang II via peripheral nerve endings as well as via central actions on brain regions. We review the evidence that Ang II modulates arterial baroreflex function and examine the pathways via which Ang II can modulate baroreflex control of cardiac vagal drive. Although there is evidence that Ang II can modulate parasympathetic activity and has the potential to contribute to impaired baseline levels and impaired baroreflex control during hypertension, the exact central regions where Ang II acts need further investigation. The beneficial actions of angiotensin receptor blockers in hypertension may be mediated in part via actions on the parasympathetic nervous system. We highlight important unknown questions about the interaction between the RAAS and the parasympathetic nervous system and conclude that this remains an important area where future research is needed.

Autonomic Imbalance Increases the Risk for Non-alcoholic Fatty Liver Disease.

Background: Although autonomic imbalance is associated with an increased risk for metabolic disease, its effects on nonalcoholic fatty liver disease (NAFLD) remains unclear. We aimed to evaluate whether autonomic dysfunction predicts the risk for nonalcoholic fatty liver disease (NAFLD). Methods: A total of 33,899 participants without NAFLD who underwent health screening programs between 2011 and 2018 were enrolled. NAFLD was identified by ultrasonography. Autonomic activity was estimated using heart rate variability (HRV). Time domain [standard deviation of the normal-to-normal interval (SDNN) and root mean square difference (RMSSD)]; frequency domain [total power (TP), low frequency (LF), and high frequency (HF), and LF/HF ratio were analyzed. Findings: A total 6,466 participants developed NAFLD within a median of 5.7 years. Subjects with incident NAFLD showed decreased overall autonomic modulation and vagal activity with lowered SDNN, RMSSD, HF, normalized HF, compared to those without NAFLD. As the SDNN, RMSSD, TP, LF, and HF tertiles increased, the risk of NAFLD decreased with tertile 1 being the reference group [the hazard ratios (95% confidence intervals) of tertile 3 were 0.90 (0.85-0.96), 0.83 (0.78-0.88), 0.91 (0.86-0.97), 0.93 (0.87-0.99) and 0.89 (0.83-0.94), respectively] after adjusting for potential confounders. The risk for NAFLD was significantly higher in subjects in whom sustained elevated heart rate, normalized LF, and LF/HF ratio values than in those with sustained decrease in these parameters during follow-up. Conclusions: Overall autonomic imbalance, decreased parasympathetic activity, and recently increased sympathetic activity might increase the risk of NAFLD.

Sensory Behaviours and Resting Parasympathetic Functions among Children with and without ADHD.

Previous studies suggest that parasympathetic functions support sensory behaviours. However, the relationship between sensory behaviours and parasympathetic functions remain inconclusive and inconsistent among children with and without attention-deficit hyperactivity disorder (ADHD). This research aims to examine the sensory behaviours and resting parasympathetic functions among children with and without ADHD. We compared sensory behaviours and baseline parasympathetic functions of 64 participants, with 42 typically developing and 24 ADHD male children aged 7-12 years. Sensory behaviours were evaluated using the sensory profile. Baseline parasympathetic functions were indexed using the normalized unit of heart rate variability high-frequency bands (HF n.u.). Children underwent an experimental protocol consisting of watching a silent cartoon movie while HF n.u. is continuously monitored, within a controlled environment. The results of this research showed significantly lower HF n.u. (t(64) = 7.84, p < 0.01) and sensory processing total score (t(64) = 14.13 = p < 0.01) among children with ADHD compared to their typically developing peers. Likewise, a significant moderate positive correlation (r = 0.36, p < 0.05) was found between the HF n.u. and sensory profile total scores among children with ADHD. Children with ADHD have significantly lower resting state parasympathetic functions compared to their typically developing peers.

The involvement of the central cholinergic system in the hyperventilation effect of centrally injected nesfatin-1 in rats.

We recently demonstrated that peripheral and central administration of nesfatin-1 in fasting and satiety states generate hyperventilation activity by increasing tidal volume (TV), respiratory rate (RR), and respiratory minute ventilation (RVM). The present study aimed to investigate the mediation of central cholinergic receptors effective in respiratory control in the hyperventilation activity of nesfatin-1. Besides this, we intended to determine possible changes in blood gases due to hyperventilation activity caused by nesfatin-1 and investigate the mediation of central cholinergic receptors in these changes. Intracerebroventricular (ICV) administration of nesfatin-1 revealed a hyperventilation response with an increase in TV, RR, RMV, and pO2 and a decrease in pCO2 in saturated Sprague Dawley rats. ICV pretreatment with the muscarinic receptor antagonist atropine partially blocked the RR, RMV, pO2, and pCO2 responses produced by nesfatin-1 while completely blocking the TV response. However, central pretreatment with nicotinic receptor antagonist mecamylamine blocked the respiratory and blood gas responses induced by nesfatin-1. The study's conclusion demonstrated that nesfatin-1 had active hyperventilation effects resulting in an increase in pO2 and a decrease in pCO2. The critical finding of the study was that activation of central cholinergic receptors was involved in nesfatin-1-evoked hyperventilation and blood gas responses.

CalDAG-GEFI mediates striatal cholinergic modulation of dendritic excitability, synaptic plasticity and psychomotor behaviors.

CalDAG-GEFI (CDGI) is a protein highly enriched in the striatum, particularly in the principal spiny projection neurons (SPNs). CDGI is strongly down-regulated in two hyperkinetic conditions related to striatal dysfunction: Huntington's disease and levodopa-induced dyskinesia in Parkinson's disease. We demonstrate that genetic deletion of CDGI in mice disrupts dendritic, but not somatic, M1 muscarinic receptors (M1Rs) signaling in indirect pathway SPNs. Loss of CDGI reduced temporal integration of excitatory postsynaptic potentials at dendritic glutamatergic synapses and impaired the induction of activity-dependent long-term potentiation. CDGI deletion selectively increased psychostimulant-induced repetitive behaviors, disrupted sequence learning, and eliminated M1R blockade of cocaine self-administration. These findings place CDGI as a major, but previously unrecognized, mediator of cholinergic signaling in the striatum. The effects of CDGI deletion on the self-administration of drugs of abuse and its marked alterations in hyperkinetic extrapyramidal disorders highlight CDGI's therapeutic potential.

Quantitative assessment of the relationship between behavioral and autonomic dynamics during propofol-induced unconsciousness.

During general anesthesia, both behavioral and autonomic changes are caused by the administration of anesthetics such as propofol. Propofol produces unconsciousness by creating highly structured oscillations in brain circuits. The anesthetic also has autonomic effects due to its actions as a vasodilator and myocardial depressant. Understanding how autonomic dynamics change in relation to propofol-induced unconsciousness is an important scientific and clinical question since anesthesiologists often infer changes in level of unconsciousness from changes in autonomic dynamics. Therefore, we present a framework combining physiology-based statistical models that have been developed specifically for heart rate variability and electrodermal activity with a robust statistical tool to compare behavioral and multimodal autonomic changes before, during, and after propofol-induced unconsciousness. We tested this framework on physiological data recorded from nine healthy volunteers during computer-controlled administration of propofol. We studied how autonomic dynamics related to behavioral markers of unconsciousness: 1) overall, 2) during the transitions of loss and recovery of consciousness, and 3) before and after anesthesia as a whole. Our results show a strong relationship between behavioral state of consciousness and autonomic dynamics. All of our prediction models showed areas under the curve greater than 0.75 despite the presence of non-monotonic relationships among the variables during the transition periods. Our analysis highlighted the specific roles played by fast versus slow changes, parasympathetic vs sympathetic activity, heart rate variability vs electrodermal activity, and even pulse rate vs pulse amplitude information within electrodermal activity. Further advancement upon this work can quantify the complex and subject-specific relationship between behavioral changes and autonomic dynamics before, during, and after anesthesia. However, this work demonstrates the potential of a multimodal, physiologically-informed, statistical approach to characterize autonomic dynamics.

Brain-heart autonomic axis across different clinical status and severity of chronic obstructive pulmonary disease.

PURPOSE: Impairment of cardiac autonomic integrity is common in chronic obstructive pulmonary disease (COPD) patients. The influence of the interaction between clinical and severity status on brain-heart autonomic axis (BHAA) is not well known. We aimed to investigate the BHAA function across different clinical status and severity of COPD. METHODS: Cross-sectional study involving 77 COPD patients allocated into four groups according to clinical status [acute exacerbation (GAE) or stable (GST)] and severity [less (-) or more (+)]: 1) GAE-, n = 13; 2) GAE+, n = 20; 3) GST-, n = 23; and 4) GST+, n = 21. Heart rate variability (HRV) at rest and heart rate recovery (HRR) after 6-min walk test were markers of BHAA. Mean R-R, STDRR, RMSSD, RRtri, HF, LF, SD1, SD2, ApEn and SampEn were the HRV indexes and, HRR was obtained as: HR at 1st min of recovery minus peak HR. RESULTS: A main effect of clinical status (p < 0.001) was found to vagal modulation in GAE-vs. GST- (RMSSD: 25.0 ± 14.8 vs. 12.6 ± 5.5 ms; SD1: 18.0 ± 10.6 vs. 8.9 ± 3.9 ms) and to GAE + vs. GST+ (RMSSD: 26.4 ± 15.2 vs. 15.4 ± 6.3 ms; SD1: 18.3 ± 11.2 vs. 10.9 ± 4.5 ms). An effect of clinical status (p = 0.032) and severity (p = 0.030) were found to HF (vagal) in GAE + compared to GAE- and GST+ (264.7 ± 239.0 vs. 134.7 ± 169.7 and 135.8 ± 139.7 ms2). Lower HRR was found in GAE-compared to GST- (8.0 ± 2.4 vs. 19.6 ± 2.4 bpm), p = 0.002. CONCLUSION: In COPD patients, clinical status (AECOPD or stable) was more dominant than the severity on BHAA function. A more pronounced parasympathetic modulation was found in AECOPD patients with a lower HRR to exercise.

Within-mother variability in vagal functioning and concurrent socioemotional dysregulation.

During dyadic interactions, well-regulated autonomic responses may support and be supported by socioemotional regulation, whereas autonomic responses that are inappropriate for the social context may be linked with socioemotional dysregulation. We evaluated women's parasympathetic and socioemotional responses during playful interaction with their 24-week-old infants, hypothesizing that insufficient or excessive variability in second-by-second vagal functioning would be associated with concurrent socioemotional dysregulation. Among a sample of 322 low-income, Mexican origin mothers (Mage  = 27.8; SD = 6.5 years), variability in second-by-second vagal functioning was indexed by within-mother standard deviation (SD) in respiratory sinus arrhythmia (RSA) during a 5-min unstructured play task. A latent construct of socioemotional dysregulation was identified using factor analyses. Structural equation modeling was used to evaluate linear and quadratic relations between within-mother SD of RSA and concurrent socioemotional dysregulation. Analyses revealed a positively accelerated relationship between within-mother SD of RSA and concurrent maternal socioemotional dysregulation during play with her infant. Within-mother SD of RSA during a non-interactive baseline task was not related to maternal dysregulation. The results illustrate mothers' dynamic autonomic and socioemotional responses are intertwined during real-time interactions with her infant and lend support for the discriminant validity of within-mother SD of RSA during free play.

Role of Choline in Ocular Diseases.

Choline is essential for maintaining the structure and function of cells in humans. Choline plays an important role in eye health and disease. It is a precursor of acetylcholine, a neurotransmitter of the parasympathetic nervous system, and it is involved in the production and secretion of tears by the lacrimal glands. It also contributes to the stability of the cells and tears on the ocular surface and is involved in retinal development and differentiation. Choline deficiency is associated with retinal hemorrhage, glaucoma, and dry eye syndrome. Choline supplementation may be effective for treating these diseases.

Loss of nigral excitation of cholinergic interneurons contributes to parkinsonian motor impairments.

Progressive loss of dopamine inputs in Parkinson's disease leads to imbalances in coordinated signaling of dopamine and acetylcholine (ACh) in the striatum, which is thought to contribute to parkinsonian motor symptoms. As reciprocal interactions between dopamine inputs and cholinergic interneurons (ChIs) control striatal dopamine and ACh transmission, we examined how partial dopamine depletion in an early-stage mouse model for Parkinson's disease alters nigral regulation of cholinergic activity. We found region-specific alterations in how remaining dopamine inputs regulate cholinergic excitability that differ between the dorsomedial (DMS) and dorsolateral (DLS) striatum. Specifically, we found that dopamine depletion downregulates metabotropic glutamate receptors (mGluR1) on DLS ChIs at synapses where dopamine inputs co-release glutamate, abolishing the ability of dopamine inputs to drive burst firing. This loss underlies parkinsonian motor impairments, as viral rescue of mGluR1 signaling in DLS ChIs was sufficient to restore circuit function and attenuate motor deficits in early-stage parkinsonian mice.

Parasympathetic modulation withdrawal improves functional capacity in pulmonary arterial hypertension.

In 15 pulmonary arterial hypertension patients, the relation of functional capacity to their peripheral endothelial function and sympathaovagal modulation was studied by carrying out brachial artery ultrasound and electrocardiogram spectral analysis, respectively. The functional capacity was assessed by cardiopulmonary exercise testing and six-minute walking test. The sympathovagal modulation was correlated with the predicted peak oxygen consumption (peak VO2 %; r = 0.692, P < 0.05), peak O2 pulse (mL/beat; r = 0.661, P < 0.05), VE, minute ventilation, VCO2 carbon dioxide production (VE/VCO2 slope; r=-0.806, P < 0.01) and distance walked predicted (%6MWT; r = 0.694, P < 0.05). Moreover, there were negative correlations between parasympathetic modulation with peak VO2 (r = 0.755, P < 0.01), peak VO2% (r=-0.727, P < 0.01) and peak O2 pulse (r = 0.615, P < 0.05), %6MWT (r=-0.834, P < 0.01). Collectively these correlations indicate that parasympathetic withdrawal is crucial for improving functional capacity. This conclusion is supported by both positive and negative correlations of parasympathetic modulation with the functional capacity parameters. The sympathetic modulation predominance, although increases the cardiovascular risk, is probably crucial to facilitate the bronchodilation and the oxygen uptake.

Brain control of blood glucose levels: implications for the pathogenesis of type 2 diabetes.

Despite a rapidly growing literature, the role played by the brain in both normal glucose homeostasis and in type 2 diabetes pathogenesis remains poorly understood. In this review, we introduce a framework for understanding the brain's essential role in these processes based on evidence that the brain, like the pancreas, is equipped to sense and respond to changes in the circulating glucose level. Further, we review evidence that glucose sensing by the brain plays a fundamental role in establishing the defended level of blood glucose, and that defects in this control system contribute to type 2 diabetes pathogenesis. We also consider the possibility that the close association between obesity and type 2 diabetes arises from a shared defect in the highly integrated neurocircuitry governing energy homeostasis and glucose homeostasis. Thus, whereas obesity is characterised by an increase in the defended level of the body's fuel stores (e.g. adipose mass), type 2 diabetes is characterised by an increase in the defended level of the body's available fuel (e.g. circulating glucose), with the underlying pathogenesis in each case involving impaired sensing of (or responsiveness to) relevant humoral negative feedback signals. This perspective is strengthened by growing preclinical evidence that in type 2 diabetes the defended level of blood glucose can be restored to normal by therapies that restore the brain's ability to properly sense the circulating glucose level. Graphical abstract.

Features of autonomic cardiovascular control during cognition in major depressive disorder.

Previous research has suggested reduced parasympathetic cardiac regulation during cognitive activity in major depressive disorder (MDD). However, little is known about possible abnormalities in sympathetic control and cardiovascular reactivity. This study aimed to provide a comprehensive analysis of autonomic cardiovascular control in the context of executive functions in MDD. Thirty six MDD patients and 39 healthy controls participated. Parameters of sympathetic (pre-ejection period, PEP) and parasympathetic control (high and low frequency heart rate variability, HF HRV, LF HRV; and baroreflex sensitivity, BRS) as well as RR interval were obtained at rest and during performance of executive function tasks (number-letter task, n-back task, continuous performance test, and Stroop task). Patients, as compared to controls, exhibited lower HF HRV and LF HRV during task execution and smaller shortenings in PEP and RR interval between baseline and tasks. They displayed longer reaction times during all conditions of the tasks and more omission errors and false alarms on the continuous performance test. In the total sample, on-task HF HRV, LF HRV and BRS, and reactivity in HF HRV, LF HRV, and PEP, were positively associated with task performance. As performance reduction arose independent of executive function load of the tasks, the behavioral results reflect impairments in attention and processing speed rather than executive dysfunctions in MDD. Abnormalities in cardiovascular control during cognition in MDD appear to involve both divisions of the autonomic nervous system. Low tonic parasympathetic control and blunted sympathetic reactivity imply reduced physiological adjustment resources and, by extension, provide suboptimal conditions for cognitive performance.

Effects of Chronic and State Loneliness on Heart Rate Variability in Women.

BACKGROUND: Loneliness, the subjective experience of social isolation, represents one of the largest risk factors for physical illness and early death in humans. However, the mechanisms by which loneliness leads to adverse health outcomes are not well understood. PURPOSE: In this study, we examined altered parasympathetic nervous system function as a potential pathway by which chronic loneliness and state loneliness may "get under the skin" to impact cardiovascular physiology. METHODS: In a controlled laboratory setting, vagally mediated resting heart rate variability (HRV), HRV reactivity to an induction of state loneliness, and HRV reactivity to a cognitive challenge task were assessed in a sample of 316 healthy women (18-28 years). RESULTS: Greater chronic loneliness in women predicted lower resting HRV, an independent risk factor for cardiovascular disease and all-cause mortality, after controlling for demographic, psychosocial, and health behavior covariates. Furthermore, women higher in chronic loneliness experienced significantly larger increases in HRV to state loneliness and reported significantly higher levels of negative affect immediately following state loneliness, compared with their less chronically lonely counterparts. Chronic loneliness also predicted blunted HRV reactivity-a maladaptive physiological response-to cognitive challenge. CONCLUSIONS: The current findings provide evidence that chronic loneliness is associated with altered parasympathetic function (both resting HRV and HRV reactivity) in women, and that the immediate experience of state loneliness is linked to a proximate increase in HRV among chronically lonely women. Results are discussed in terms of implications for cardiovascular health and the evolutionary functions of loneliness.