Lipopolysaccharide-induced sepsis impairs M2R-GIRK signaling in the mouse sinoatrial node.

Sepsis has emerged as a global health burden associated with multiple organ dysfunction and 20% mortality rate in patients. Numerous clinical studies over the past two decades have correlated the disease severity and mortality in septic patients with impaired heart rate variability (HRV), as a consequence of impaired chronotropic response of sinoatrial node (SAN) pacemaker activity to vagal/parasympathetic stimulation. However, the molecular mechanism(s) downstream to parasympathetic inputs have not been investigated yet in sepsis, particularly in the SAN. Based on electrocardiography, fluorescence Ca2+ imaging, electrophysiology, and protein assays from organ to subcellular level, we report that impaired muscarinic receptor subtype 2-G protein-activated inwardly-rectifying potassium channel (M2R-GIRK) signaling in a lipopolysaccharide-induced proxy septic mouse model plays a critical role in SAN pacemaking and HRV. The parasympathetic responses to a muscarinic agonist, namely IKACh activation in SAN cells, reduction in Ca2+ mobilization of SAN tissues, lowering of heart rate and increase in HRV, were profoundly attenuated upon lipopolysaccharide-induced sepsis. These functional alterations manifested as a direct consequence of reduced expression of key ion-channel components (GIRK1, GIRK4, and M2R) in the mouse SAN tissues and cells, which was further evident in the human right atrial appendages of septic patients and likely not mediated by the common proinflammatory cytokines elevated in sepsis.

Low-Intensity Focused Ultrasound to the Human Dorsal Anterior Cingulate Attenuates Acute Pain Perception and Autonomic Responses.

The dorsal anterior cingulate cortex (dACC) is a critical brain area for pain and autonomic processing, making it a promising noninvasive therapeutic target. We leverage the high spatial resolution and deep focal lengths of low-intensity focused ultrasound (LIFU) to noninvasively modulate the dACC for effects on behavioral and cardiac autonomic responses using transient heat pain stimuli. A N = 16 healthy human volunteers (6 M/10 F) received transient contact heat pain during either LIFU to the dACC or Sham stimulation. Continuous electroencephalogram (EEG), electrocardiogram (ECG), and electrodermal response (EDR) were recorded. Outcome measures included pain ratings, heart rate variability, EDR response, blood pressure, and the amplitude of the contact heat-evoked potential (CHEP).LIFU reduced pain ratings by 1.09 ± 0.20 points relative to Sham. LIFU increased heart rate variability indexed by the standard deviation of normal sinus beats (SDNN), low-frequency (LF) power, and the low-frequency/high-frequency (LF/HF) ratio. There were no effects on the blood pressure or EDR. LIFU resulted in a 38.1% reduction in the P2 CHEP amplitude. Results demonstrate LIFU to the dACC reduces pain and alters autonomic responses to acute heat pain stimuli. This has implications for the causal understanding of human pain and autonomic processing in the dACC and potential future therapeutic options for pain relief and modulation of homeostatic signals.

Mapping Early Brain-Body Interactions: Associations of Fetal Heart Rate Variation with Newborn Brainstem, Hypothalamic, and Dorsal Anterior Cingulate Cortex Functional Connectivity.

The autonomic nervous system (ANS) regulates the body's physiology, including cardiovascular function. As the ANS develops during the second to third trimester, fetal heart rate variability (HRV) increases while fetal heart rate (HR) decreases. In this way, fetal HR and HRV provide an index of fetal ANS development and future neurobehavioral regulation. Fetal HR and HRV have been associated with child language ability and psychomotor development behavior in toddlerhood. However, their associations with postbirth autonomic brain systems, such as the brainstem, hypothalamus, and dorsal anterior cingulate cortex (dACC), have yet to be investigated even though brain pathways involved in autonomic regulation are well established in older individuals. We assessed whether fetal HR and HRV were associated with the brainstem, hypothalamic, and dACC functional connectivity in newborns. Data were obtained from 60 pregnant individuals (ages 14-42) at 24-27 and 34-37 weeks of gestation using a fetal actocardiograph to generate fetal HR and HRV. During natural sleep, their infants (38 males and 22 females) underwent a fMRI scan between 40 and 46 weeks of postmenstrual age. Our findings relate fetal heart indices to brainstem, hypothalamic, and dACC connectivity and reveal connections with widespread brain regions that may support behavioral and emotional regulation. We demonstrated the basic physiologic association between fetal HR indices and lower- and higher-order brain regions involved in regulatory processes. This work provides the foundation for future behavioral or physiological regulation research in fetuses and infants.

Resting heart rate causally affects the brain cortical structure: Mendelian randomization study.

Resting heart rate (RHR) has been linked to impaired cortical structure in observational studies. However, the extent to which this association is potentially causal has not been determined. Using genetic data, this study aimed to reveal the causal effect of RHR on brain cortical structure. A Two-Sample Mendelian randomization (MR) analysis was conducted. Sensitivity analyses, weighted median, MR Pleiotropy residual sum and outlier, and MR-Egger regression were conducted to evaluate heterogeneity and pleiotropy. A causal relationship between RHR and cortical structures was identified by MR analysis. On the global scale, elevated RHR was found to decrease global surface area (SA; P < 0.0125). On a regional scale, the elevated RHR significantly decreased the SA of pars triangularis without global weighted (P = 1.58 × 10-4) and the thickness (TH) of the paracentral with global weighted (P = 3.56 × 10-5), whereas it increased the TH of banks of the superior temporal sulcus in the presence of global weighted (P = 1.04 × 10-4). MR study provided evidence that RHR might be causally linked to brain cortical structure, which offers a different way to understand the heart-brain axis theory.

Cardiac sympathetic-vagal activity initiates a functional brain-body response to emotional arousal.

A century-long debate on bodily states and emotions persists. While the involvement of bodily activity in emotion physiology is widely recognized, the specificity and causal role of such activity related to brain dynamics has not yet been demonstrated. We hypothesize that the peripheral neural control on cardiovascular activity prompts and sustains brain dynamics during an emotional experience, so these afferent inputs are processed by the brain by triggering a concurrent efferent information transfer to the body. To this end, we investigated the functional brain­heart interplay under emotion elicitation in publicly available data from 62 healthy subjects using a computational model based on synthetic data generation of electroencephalography and electrocardiography signals. Our findings show that sympathovagal activity plays a leading and causal role in initiating the emotional response, in which ascending modulations from vagal activity precede neural dynamics and correlate to the reported level of arousal. The subsequent dynamic interplay observed between the central and autonomic nervous systems sustains the processing of emotional arousal. These findings should be particularly revealing for the psychophysiology and neuroscience of emotions.

Transcutaneous vagal nerve stimulation for treating gastrointestinal symptoms in individuals with diabetes: a randomised, double-blind, sham-controlled, multicentre trial.

AIMS/HYPOTHESIS: Diabetic gastroenteropathy frequently causes debilitating gastrointestinal symptoms. Previous uncontrolled studies have shown that transcutaneous vagal nerve stimulation (tVNS) may improve gastrointestinal symptoms. To investigate the effect of cervical tVNS in individuals with diabetes suffering from autonomic neuropathy and gastrointestinal symptoms, we conducted a randomised, sham-controlled, double-blind (participants and investigators were blinded to the allocated treatment) study. METHODS: This study included adults (aged 20-86) with type 1 or 2 diabetes, gastrointestinal symptoms and autonomic neuropathy recruited from three Steno Diabetes Centres in Denmark. Participants were randomly allocated 1:1 to receive active or sham stimulation. Active cervical tVNS or sham stimulation was self-administered over two successive study periods: 1 week of four daily stimulations and 8 weeks of two daily stimulations. The primary outcome measures were gastrointestinal symptom changes as measured using the gastroparesis cardinal symptom index (GCSI) and the gastrointestinal symptom rating scale (GSRS). Secondary outcomes included gastrointestinal transit times and cardiovascular autonomic function. RESULTS: Sixty-eight participants were randomised to the active group, while 77 were randomised to the sham group. Sixty-three in the active and 68 in the sham group remained for analysis in study period 1, while 62 in each group were analysed in study period 2. In study period 1, active and sham tVNS resulted in similar symptom reductions (GCSI: -0.26 ± 0.64 vs -0.17 ± 0.62, p=0.44; GSRS: -0.35 ± 0.62 vs -0.32 ± 0.59, p=0.77; mean ± SD). In study period 2, active stimulation also caused a mean symptom decrease that was comparable to that observed after sham stimulation (GCSI: -0.47 ± 0.78 vs -0.33 ± 0.75, p=0.34; GSRS: -0.46 ± 0.90 vs -0.35 ± 0.79, p=0.50). Gastric emptying time was increased in the active group compared with sham (23 min vs -19 min, p=0.04). Segmental intestinal transit times and cardiovascular autonomic measurements did not differ between treatment groups (all p>0.05). The tVNS was well-tolerated. CONCLUSIONS/INTERPRETATION: Cervical tVNS, compared with sham stimulation, does not improve gastrointestinal symptoms among individuals with diabetes and autonomic neuropathy. TRIAL REGISTRATION: ClinicalTrials.gov NCT04143269 FUNDING: The study was funded by the Novo Nordisk Foundation (grant number NNF180C0052045).

Dynamics of cardio-muscular networks in exercise and fatigue.

A fundamental question in cardiovascular and muscle physiology is how the heart operates in synchrony with distinct muscles to regulate homeostasis, enable movement and adapt to exercise demands and fatigue. Here we investigate how autonomic regulation of cardiac function synchronizes and integrates as a network with the activity of distinct muscles during exercise. Further, we establish how the network of cardio-muscular interactions reorganizes with fatigue. Thirty healthy young adults performed two body weight squat tests until exhaustion. Simultaneous recordings were taken of a 3-lead electrocardiogram (EKG) along with electromyography (EMG) signals from the left and right vastus lateralis, and left and right erector spinae. We first obtained instantaneous heart rate (HR) derived from the EKG signal and decomposed the EMG recordings in 10 frequency bands (F1-F10). We next quantified pair-wise coupling (cross-correlation) between the time series for HR and all EMG spectral power frequency bands in each leg and back muscle. We uncovered the first profiles of cardio-muscular network interactions, which depend on the role muscles play during exercise and muscle fibre histochemical characteristics. Additionally, we observed a significant decline in the degree of cardio-muscular coupling with fatigue, characterized by complex transitions from synchronous to asynchronous behaviour across a range of timescales. The network approach we utilized introduces new avenues for the development of novel network-based markers, with the potential to characterize multilevel cardio-muscular interactions to assess global health, levels of fatigue, fitness status or the effectiveness of cardiovascular and muscle injury rehabilitation programmes. KEY POINTS: The heart operates in synchrony with muscles to regulate homeostasis, enable movement, and adapt to exercise demands and fatigue. However, the precise mechanisms regulating cardio-muscular coupling remain unknown. This study introduces a pioneering approach to assess cardio-muscular network interactions by examining the synchronization of cardiac function with muscle activity during exercise and fatigue. We uncover the first profiles of cardio-muscular interactions characterized by specific hierarchical organization of link strength. We observe a significant decline in the degree of cardio-muscular coupling with fatigue, marked by complex transitions from synchronous to asynchronous behaviour. This network approach offers new network-based markers to characterize multilevel cardio-muscular interactions to assess global health, levels of fatigue, fitness status or the effectiveness of cardiovascular and muscle injury rehabilitation programmes.

Impact of stress on cardiac phenotypes in mice harboring an ankyrin-B disease variant.

Encoded by ANK2, ankyrin-B (AnkB) is a multifunctional adapter protein critical for the expression and targeting of key cardiac ion channels, transporters, cytoskeletal-associated proteins, and signaling molecules. Mice deficient for AnkB expression are neonatal lethal, and mice heterozygous for AnkB expression display cardiac structural and electrical phenotypes. Human ANK2 loss-of-function variants are associated with diverse cardiac manifestations; however, human clinical 'AnkB syndrome' displays incomplete penetrance. To date, animal models for human arrhythmias have generally been knock-out or transgenic overexpression models and thus the direct impact of ANK2 variants on cardiac structure and function in vivo is not clearly defined. Here, we directly tested the relationship of a single human ANK2 disease-associated variant with cardiac phenotypes utilizing a novel in vivo animal model. At baseline, young AnkBp.E1458G+/+ mice lacked significant structural or electrical abnormalities. However, aged AnkBp.E1458G+/+ mice displayed both electrical and structural phenotypes at baseline including bradycardia and aberrant heart rate variability, structural remodeling, and fibrosis. Young and old AnkBp.E1458G+/+ mice displayed ventricular arrhythmias following acute (adrenergic) stress. In addition, young AnkBp.E1458G+/+ mice displayed structural remodeling following chronic (transverse aortic constriction) stress. Finally, AnkBp.E1458G+/+ myocytes harbored alterations in expression and/or localization of key AnkB-associated partners, consistent with the underlying disease mechanism. In summary, our findings illustrate the critical role of AnkB in in vivo cardiac function as well as the impact of single AnkB loss-of-function variants in vivo. However, our findings illustrate the contribution and in fact necessity of secondary factors (aging, adrenergic challenge, pressure-overload) to phenotype penetrance and severity.

Relationship between central autonomic effective connectivity and heart rate variability: A Resting-state fMRI dynamic causal modeling study.

The central autonomic network (CAN) serves as a regulatory hub with top-down regulatory control and integration of bottom-up physiological feedback via the autonomic nervous system. Heart rate variability (HRV)-the time variance of the heart's beat-to-beat intervals-is an index of the CAN's affective and behavioral regulatory capacity. Although neural functional connectivities that are associated with HRV and CAN have been well studied, no published report to date has studied effective (directional) connectivities (EC) that are associated with HRV and CAN. Better understanding of neural EC in the brain has the potential to improve our understanding of how the CAN sub-regions regulate HRV. To begin to address this knowledge gap, we employed resting-state functional magnetic resonance imaging and dynamic causal modeling (DCM) with parametric empirical Bayes analyses in 34 healthy adults (19 females; mean age= 32.68 years [SD= 14.09], age range 18-68 years) to examine the bottom-up and top-down neural circuits associated with HRV. Throughout the whole brain, we identified 12 regions associated with HRV. DCM analyses revealed that the ECs from the right amygdala to the anterior cingulate cortex and to the ventrolateral prefrontal cortex had a negative linear relationship with HRV and a positive linear relationship with heart rate. These findings suggest that ECs from the amygdala to the prefrontal cortex may represent a neural circuit associated with regulation of cardiodynamics.

The recovery of decreased executive attention in Tibetan migrants at high-altitude.

Attention is one of the basic cognitive functions sensitive to high altitude, and most studies have focussed on exposure times of approximately 3 years; however, it is unclear how attention changes in migrants who have lived and worked at high altitude for nearly 20 years. We explored the dynamics of attentional networks and neurophysiological mechanisms in migrants over 3-20 years using the Attentional Network Test combined with Electrocardiograph and Electroencephalography and found a consistent quadratic correlation between exposure and executive control efficiency, P3 amplitude and heart rate variability (HRV), with a decrease followed by an increase/relative stability, with approximately 10 years being the breakpoint. However, neither linear nor quadratic trajectories were observed for the alerting and orienting network. Mediation analysis revealed that the P3 amplitude mediated the decrease and increase in executive control efficiency with exposure time depends on the breakpoint. Correlations between HRV and executive control efficiency and P3 amplitude suggest that U-shaped changes in executive control in migrants may be related to body homeostasis maintained by the autonomic nervous system, and that P3 amplitude may serve as a neurophysiological marker of migrants' adaptation/recovery from high-altitude exposure.

Effects of transcutaneous auricular vagus nerve stimulation at left cymba concha on experimental pain as assessed with the nociceptive withdrawal reflex, and correlation with parasympathetic activity.

The aim of this study was to clarify the effects of transcutaneous auricular vagus nerve stimulation (taVNS) to the left cymba concha on the pain perception using nociceptive withdrawal reflex (NWR), which is known to be associated with chronic pain, and to investigate whether there is a relationship between taVNS-induced suppression of the NWR and parasympathetic activation. We applied either 3.0 mA, 100 Hz taVNS for 120 s on the left cymba concha (taVNS condition) or the left earlobe (Sham condition) for 20 healthy adults. NWR threshold was measured before (Baseline), immediately after (Post 0), 10 min (Post 10) and 30 min after (Post 30) stimulation. The NWR threshold was obtained from biceps femoris muscle by applying electrical stimulation to the sural nerve. During taVNS, electrocardiogram was recorded, and changes in autonomic nervous activity measured by heart rate variability (HRV) were analyzed. We found that the NWR thresholds at Post 10 and Post 30 increased compared with baseline in the taVNS group (10 min after: p = .008, 30 min after: p = .008). In addition, increased parasympathetic activity by taVNS correlated with a greater increase in NWR threshold at Post 10 and Post 30 (Post 10: p = .003; Post 30: p = .001). The present results of this single-blinded study demonstrate the pain-suppressing effect of taVNS on NWR threshold and suggest that the degree of parasympathetic activation during taVNS may predict the pain-suppressing effect of taVNS after its application.

Preeclampsia-exposed children's heart rate variability 8-12 yr after index pregnancy: FINNCARE study.

Preeclampsia is related with elevated systolic blood pressure (SBP) in children. We studied if preeclampsia-exposed (PE) children develop alterations in heart rate variability (HRV) and if this is reflected in their blood pressure (BP), as well as overall associations with body size and composition, gestational and perinatal factors. We examined 182 PE (46 early-onset PE) and 85 unexposed (non-PE) children 8-12 yr after preeclampsia exposure. HRV monitoring was performed 5 min in supine followed by 5 min in standing position and compared with office, 24-h ambulatory, and central BPs in relation to body anthropometrics and composition, gestational, and perinatal data. There were no major differences in HRV between PE and non-PE children. HRV in supine position was strongly associated with office and ambulatory heart rates (HRs), and HR was independently associated with office BPs. However, HRV was not related with office or 24-h SBP and PP, nor with elevated SBP in PE compared with non-PE children [adjusted mean differences for office and 24-h SBP 4.8 (P < 0.001) and 2.5 mmHg (P = 0.049), respectively]. In supine position, high-frequency (HF) power [ß, -0.04 (95% CI -0.06 to -0.01)], root mean square of successive differences in R-R intervals (rMSSD) [-0.015 (-0.028 to -0.002)], and the ratio of low-frequency (LF) to HF power [0.03 (0.01-0.04)] were independently associated with child fat mass. LF and HF power and rMSSD displayed independent inverse associations with child age. There were no significant associations between child HRV and gestational and perinatal factors. During prepuberty, the HRV in children with PE is similar to that in non-PE children. Elevated SBP following preeclampsia exposure is not related with HRV. Child adiposity could be related to decreased cardiac vagal tone.NEW & NOTEWORTHY Heart rate variability in preadolescent children exposed to preeclampsia in utero is no different from age-matched controls. Preeclampsia-exposed children's elevated SBP is not related to alterations in heart rate variability, which is a noninvasive measure of the modulation of heart rate by autonomic tone. However, childhood adiposity might be coupled with diminished cardiac vagal tone.

Sex differences in the age-related decrease of spontaneous baroreflex function in healthy individuals.

The baroreflex is a powerful physiological mechanism for rapidly adjusting heart rate in response to changes in blood pressure. Spontaneous baroreflex sensitivity (BRS) has been shown to decrease with age. However, studies of sex differences in these age-related changes are rare. Here we investigated several markers of spontaneous baroreflex function in a large sample of healthy individuals. Cardiovascular signals were recorded in the supine position under carefully controlled resting conditions. After quality control, n = 980 subjects were divided into five age groups [age < 30 yr (n = 612), 30-39 yr (n = 140), 40-49 yr (n = 95), 50-59 yr (n = 61), and >60 yr (n = 72)]. Spontaneous baroreflex function was assessed in the time domain (bradycardic and tachycardic slope) and in the frequency domain in the low- and high-frequency band (LF-α, HF-α) applying the transfer function. General linear models showed a significant effect of factor age (P < 0.001) and an age × sex interaction effect (P < 0.05) on each indicator of the baroreflex function. Simple main effects showed a significantly higher BRS as indicated by tachycardic slope, LF-α and HF-α in middle-aged women compared with men (30-39 yr) and higher LF-α, bradycardic and tachycardic slope in men compared with women of the oldest age group (>60 yr). Changes in BRS over the lifespan suggest that baroreflex function declines more slowly but earlier in life in men than in women. Our findings could be linked to age-related changes in major sex hormone levels, suggesting significant implications for diverse cardiovascular outcomes and the implementation of targeted preventive strategies.NEW & NOTEWORTHY In this study, we demonstrate that the age-related decrease of spontaneous baroreflex sensitivity is different in men and women by analyzing resting state cardiovascular data of a large sample of healthy individuals.

Cardiac autonomic function is preserved in young adults with major depressive disorder.

The prevalence of major depressive disorder (MDD) is highest in young adults and contributes to an increased risk of developing future cardiovascular disease (CVD). However, the underlying mechanisms remain unclear. The studies examining cardiac autonomic function that have included young unmedicated adults with MDD report equivocal findings, and few have considered the potential influence of disease severity or duration. We hypothesized that heart rate variability (HRV) and cardiac baroreflex sensitivity (BRS) would be reduced in young unmedicated adults with MDD (18-30 yr old) compared with healthy nondepressed young adults (HA). We further hypothesized that greater symptom severity would be related to poorer cardiac autonomic function in young adults with MDD. Heart rate and beat-to-beat blood pressure were continuously recorded during 10 min of supine rest to assess HRV and cardiac BRS in 28 HA (17 female, 22 ± 3 yr old) and 37 adults with MDD experiencing current symptoms of mild-to-moderate severity (unmedicated; 28 female, 20 ± 3 yr old). Neither HRV [root mean square of successive differences between normal heartbeats (RMSSD): 63 ± 34 HA vs. 79 ± 36 ms MDD; P = 0.14] nor cardiac BRS (overall gain, 21 ± 10 HA vs. 23 ± 7 ms/mmHg MDD; P = 0.59) were different between groups. In young adults with MDD, there was no association between current depressive symptom severity and either HRV (RMSSD, R2 = 0.004, P = 0.73) or cardiac BRS (overall gain, R2 = 0.02, P = 0.85). Taken together, these data suggest that cardiac autonomic dysfunction may not contribute to elevated cardiovascular risk factor profiles in young unmedicated adults with MDD of mild-to-moderate severity.NEW & NOTEWORTHY This study investigated cardiac autonomic function in young unmedicated adults with major depressive disorder (MDD). The results demonstrated that both heart rate variability and cardiac baroreflex sensitivity were preserved in young unmedicated adults with MDD compared with healthy nondepressed young adults. Furthermore, in young adults with MDD, current depressive symptom severity was not associated with any indices of cardiac autonomic function.

Increased heart rate fragmentation in those with Williams-Beuren syndrome suggests nonautonomic mechanistic contributors to sudden death risk.

Williams-Beuren syndrome (WBS) is a rare genetic condition caused by a chromosomal microdeletion at 7q11.23. It is a multisystem disorder characterized by distinct facies, intellectual disability, and supravalvar aortic stenosis (SVAS). Those with WBS are at increased risk of sudden death, but mechanisms underlying this remain poorly understood. We recently demonstrated autonomic abnormalities in those with WBS that are associated with increased susceptibility to arrhythmia and sudden cardiac death (SCD). A recently introduced method for heart rate variability (HRV) analysis called "heart rate fragmentation" (HRF) correlates with adverse cardiovascular events (CVEs) and death in studies where heart rate variability (HRV) failed to identify high-risk subjects. Some argue that HRF quantifies nonautonomic cardiovascular modulators. We, therefore, sought to apply HRF analysis to a WBS cohort to determine 1) if those with WBS show differences in HRF compared with healthy controls and 2) if HRF helps characterize HRV abnormalities in those with WBS. Similar to studies of those with coronary artery disease (CAD) and atherosclerosis, we found significantly higher HRF (4 out of 7 metrics) in those with WBS compared with healthy controls. Multivariable analyses showed a weak-to-moderate association between HRF and HRV, suggesting that HRF may reflect HRV characteristics not fully captured by traditional HRV metrics (autonomic markers). We also introduce a new metric inspired by HRF methodology, significant acute rate drop (SARD), which may detect vagal activity more directly. HRF and SARD may improve on traditional HRV measures to identify those at greatest risk for SCD both in those with WBS and in other populations.NEW & NOTEWORTHY This work is the first to apply heart rate fragmentation analyses to individuals with Williams syndrome and posits that the heart rate fragmentation parameter W3 may enable detection and investigation of phenomena underlying the proarrhythmic short-long-short RR interval sequences paradigm known to precede ventricular fibrillation and ventricular tachycardia. It also forwards a novel method for quantifying sinus arrhythmia and sinus pauses that likely correlate with parasympathetic activity.

Intracortical brain-heart interplay: An EEG model source study of sympathovagal changes.

The interplay between cerebral and cardiovascular activity, known as the functional brain-heart interplay (BHI), and its temporal dynamics, have been linked to a plethora of physiological and pathological processes. Various computational models of the brain-heart axis have been proposed to estimate BHI non-invasively by taking advantage of the time resolution offered by electroencephalograph (EEG) signals. However, investigations into the specific intracortical sources responsible for this interplay have been limited, which significantly hampers existing BHI studies. This study proposes an analytical modeling framework for estimating the BHI at the source-brain level. This analysis relies on the low-resolution electromagnetic tomography sources localization from scalp electrophysiological recordings. BHI is then quantified as the functional correlation between the intracortical sources and cardiovascular dynamics. Using this approach, we aimed to evaluate the reliability of BHI estimates derived from source-localized EEG signals as compared with prior findings from neuroimaging methods. The proposed approach is validated using an experimental dataset gathered from 32 healthy individuals who underwent standard sympathovagal elicitation using a cold pressor test. Additional resting state data from 34 healthy individuals has been analysed to assess robustness and reproducibility of the methodology. Experimental results not only confirmed previous findings on activation of brain structures affecting cardiac dynamics (e.g., insula, amygdala, hippocampus, and anterior and mid-cingulate cortices) but also provided insights into the anatomical bases of brain-heart axis. In particular, we show that the bidirectional activity of electrophysiological pathways of functional brain-heart communication increases during cold pressure with respect to resting state, mainly targeting neural oscillations in the δ $$ \delta $$ , ß $$ \beta $$ , and γ $$ \gamma $$ bands. The proposed approach offers new perspectives for the investigation of functional BHI that could also shed light on various pathophysiological conditions.

The effectiveness of a standardized tobacco cessation program on psychophysiological parameters in patients with addiction undergoing long-term rehabilitation: a quasi-experimental pilot study.

BACKGROUND: Although there is a very high comorbidity between tobacco dependence and other addictive disorders, there are only few studies examining the implementation and outcomes of a tobacco cessation program in patients with addictive diseases. Therefore, the aim of this study is to investigate to what extent a standardized tobacco cessation program leads to improvements regarding psychological/physical parameters in patients with addiction undergoing therapy and whether there is a reduction in tobacco consumption. METHODS: The study took place in a therapeutic community specialized in addiction therapy. A total sample of 56 participants were non-randomly assigned to an intervention group (IG; n = 31) and a treatment as usual group (TAUG; n = 25). The IG participated in a 6-week tobacco cessation program, while the TAUG received no additional treatment. Both groups were assessed for changes in primary outcomes (tobacco dependence, smoked cigarettes per day (CPD), and general substance-related craving) and secondary outcomes (heart rate variability (HRV): root mean square of successive differences, self-efficacy, and comorbid psychiatric symptoms) at two measurement time points (pre- and post-treatment/6 weeks). RESULTS: We observed significant improvements in self-efficacy (F(1,53) = 5.86; p < .05; ηp2 = .11) and decreased CPD in the IG (ß = 1.16, ρ < .05), while no significant changes were observed in the TAUG. No significant interaction effects were observed in psychiatric symptoms, general substance-related craving, and HRV. CONCLUSIONS: The results highlight the potential benefit of an additional tobacco cessation program as part of a general addiction treatment. Although no improvements in the physiological domain were observed, there were significant improvements regarding self-efficacy and CPD in the IG compared to the TAUG. Randomized controlled trials on larger samples would be an important next step. TRIAL REGISTRATION: ISRCTN15684371.

Osteoarthritis patients exhibit an autonomic dysfunction with indirect sympathetic dominance.

BACKGROUND: Osteoarthritis (OA) is a chronic degenerative joint disease causing limited mobility and pain, with no curative treatment available. Recent in vivo studies suggested autonomic alterations during OA progression in patients, yet clinical evidence is scarce. Therefore, autonomic tone was analyzed in OA patients via heart rate variability (HRV) measurements. METHODS: Time-domain (SDRR, RMSSD, pRR50) and frequency-domain (LF, HF, LF/HF) HRV indices were determined to quantify sympathetic and parasympathetic activities. In addition, perceived stress, WOMAC pain as well as serum catecholamines, cortisol and dehydroepiandrosterone-sulphate (DHEA-S) were analyzed. The impact of the grade of disease (GoD) was evaluated by linear regression analysis and correlations with clinical data were performed. RESULTS: GoD significantly impacted the autonomic tone in OA patients. All time-domain parameters reflected slightly decreased HRV in early OA patients and significantly reduced HRV in late OA patients. Moreover, frequency-domain analysis revealed decreased HF and LF power in all OA patients, reflecting diminished parasympathetic and sympathetic activities. However, LF/HF ratio was significantly higher in early OA patients compared to late OA patients and implied a clear sympathetic dominance. Furthermore, OA patients perceived significantly higher chronic stress and WOMAC pain levels compared to healthy controls. Serum cortisol and cortisol/DHEA-S ratio significantly increased with GoD and positively correlated with WOMAC pain. In contrast, serum catecholamines only trended to increase with GoD and pain level. CONCLUSIONS: This prospective study provides compelling evidence of an autonomic dysfunction with indirect sympathetic dominance in early and late knee OA patients for the first time based on HRV analyses and further confirmed by serum stress hormone measurements. Increased sympathetic activity and chronic low-grade inflammation in OA as well as in its major comorbidities reinforce each other and might therefore create a vicious cycle. The observed autonomic alterations coupled with increased stress and pain levels highlight the potential of HRV as a prognostic marker. In addition, modulation of autonomic activity represents an attractive future therapeutic option.

Acute Autonomic Nervous System Response to Direct Sacral Nerve Root Stimulation in Lower Urinary Tract Dysfunction: A New Approach to Understand the Mechanism of Action of Sacral Nerve Modulation.

PURPOSE: Our goal was to assess acute autonomic nervous system (ANS) response to direct sacral nerve root (SNR) stimulation in the context of lower urinary tract dysfunction. MATERIALS AND METHODS: In this retrospective monocentric study, patients undergoing 2-stage sacral nerve modulation for overactive bladder, nonobstructive urinary retention, or chronic bladder pain syndrome between March 2022 and June 2023 were analyzed. A standardized stimulation protocol was applied during the lead implantation, each of the 4 contact points being sequentially stimulated at the amplitude required to elicit anal motor response. Stimulations were labeled as StimA, StimB, StimC, and StimD, ordered by ascending order of minimum amplitude required for anal motor response. Heart rate variability parameters were collected using PhysioDoloris Monitor, and computed through the time-domain (standard deviation of normal-to-normal intervals [SDNN], root mean square of successive differences), the frequency-domain (low frequency, high frequency) and the graphical (Analgesia Nociception Index [ANI]) methods. RESULTS: Fifty patients were analyzed, including 35 females. Twelve patients had an underlying neurological disease. Efficacy was deemed achieved in 54% of patients. SDNN variability significantly increased during StimA to StimC, while maximum SDNN significantly increased only during StimA. ANI variability significantly increased during all 4 stimulations, while maximum ANI significantly increased only during StimA. CONCLUSIONS: Direct stimulation of SNR is responsible for a significant increase in ANS and relative parasympathetic nervous system activity, with a greater effect observed when the stimulation was delivered closer to the SNR. These results shed light on potential mechanisms underlying sacral nerve modulation, particularly regarding the treatment of ANS dysregulation in lower urinary tract dysfunction.

Actigraphy Study Endpoints to Reduce Sample Size and Facilitate Drug Development for Pediatric Pulmonary Arterial Hypertension.

OBJECTIVES: To investigate the feasibility of using actigraphy to measure physical activity (pA) and heart rate variability (HRV) as study endpoints in pediatric pulmonary arterial hypertension (PAH) and to compare their performance to six-minute-walk distance (6MWD), a common primary endpoint used in PAH clinical trials in adults and children who can walk and understand the test process. STUDY DESIGN: We conducted a prospective, multicenter, non-interventional study in pediatric PAH patients and healthy children. Actiheart™ and Fitbit Charge 2™ recorded pA and heart rate (HR) data. HRV was defined as standard deviation of daily HR. Actigraphy pA and HRV and 6MWD from the same subjects were analyzed to compare children with PAH with controls, and Panama functional classification (FC) III versus II. Power/sample size simulations were conducted to detect hypothetical treatment effect equivalent to differences seen between FC III and FC II. RESULTS: We enrolled 116 children; 90 and 98 adhered with Actiheart and Fitbit, respectively. Actigraphy daily pA was ∼36% lower (P<0.05) and daily HRV was ∼18% lower (P<0.05) in children with PAH (n=62) than healthy controls (n=54). Daily pA and daily HRV trended ∼17% lower in FC III than FC II, whereas 6MWD showed little difference. Simulation at 80% power showed that pA required 175 subjects per group and HRV required 40 per group to detect the difference/effect, whereas 6MWD required over our maximum sample size of 200. CONCLUSIONS: Actigraphy is a feasible measure in pediatric PAH. Compared with 6MWD, pA and HRV may be more sensitive in differentiating Panama FC III from II. HRV may improve actigraphy's utility in pediatric PAH.