Search Results (53)

Conventional and electronic cigarette (e-cig) users face an increased risk of cardiorespiratory diseases, driven by well-characterized pathways involving inflammation and oxidative stress (OS). Conventional cigarettes contain numerous harmful chemicals, such as nicotine and non-nicotine compounds, which produce reactive oxygen species. Although initially considered a safer alternative, the e-cig still generates toxic aldehydes that are capable of triggering oxidative responses. Heart rate variability (HRV) is an important tool for assessing autonomic function and predicting prognosis. Cardiac autonomic dysfunction, indicated by reduced HRV, has emerged as a critical cardiovascular risk factor associated with several diseases. Clinical and experimental studies show that increased OS is directly associated with heightened sympathetic activity and inversely with parasympathetic modulation. This review demonstrates that exposure to conventional cigarettes smoking and e-cigs adversely affects cardiac autonomic function, detectable by a global reduction in HRV that reflects a shift toward sympathetic dominance and a consequent increase in cardiovascular risk. These changes are associated with increased OS due to nicotine and non-nicotine compounds maintaining sympathovagal imbalance in smokers. Thus, we suggest that autonomic dysfunction, detected by HRV, correlates with oxidative responses and may be used as a modifiable risk factor in longitudinal studies involving both smoking modalities. Full article

The liver is intricately innervated by sympathetic, parasympathetic, and sensory fibres, forming a dynamic neurovascular and neuroimmune network that regulates hepatic function and contributes to disease pathogenesis. While traditionally underexplored, hepatic innervation is now recognised as a key modulator of metabolic homeostasis, immune surveillance, and vascular tone. Historically, the liver was not considered a major target of neural regulation, but recent advances in neurology and imaging have revealed complex and dynamic interactions between neural circuits and hepatic functions. This review provides a comprehensive overview of liver innervation, detailing its anatomical organisation and functional roles in both physiological and pathological contexts. We investigate the role of liver innervation in shaping immune responses, particularly in the context of metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, and autoimmune liver diseases, including autoimmune hepatitis and primary biliary cholangitis. Special attention is given to the neuroimmune crosstalk that governs inflammation, fibrosis, malignancy, and tissue remodelling. Furthermore, we examine how neural inputs influence hepatic blood flow, sinusoidal endothelial function, and portal hypertension, highlighting the interplay between neural and vascular systems. We highlight neuromodulatory approaches, including vagus nerve stimulation and other agents to modulate liver inflammation, vascular dysfunction, and immune dysregulation. Finally, we discuss emerging research models, including liver organoids, Artificial Intelligence-based digital twins and biomaterials as innovative platforms designed to study neural-liver interactions and test new therapeutic strategies. By integrating neuromorphology, immunology, and hepatology, this review aims to advance our understanding of liver innervation as a central player in hepatic health and disease and to identify novel targets for therapeutic intervention. Full article

Background/Objectives: Heart rate variability (HRV) reflects autonomic nervous system modulation and may be altered in both unexplained syncope and obstructive sleep apnea (OSA). However, the nocturnal autonomic patterns underlying these conditions and their coexistence remain poorly understood. This study aimed to characterize nocturnal autonomic modulation in patients with unexplained syncope, OSA, or both, compared with individuals without these conditions. Methods: In this multicenter, cross-sectional, comparative study, 304 adults were assigned to four groups: controls (no syncope or OSA), OSA without syncope, syncope without OSA, and syncope with OSA. Time- and frequency-domain HRV parameters were derived from overnight respiratory polygraphy and compared across groups. Results: OSA was associated with increased root mean square of successive differences (RMSSD) and reduced low-frequency (LF) power, indicating enhanced vagal activity and lower nocturnal sympathetic tone. Syncope was characterized by further reductions in sympathetic indices (LF and very low frequency, VLF) with increased RMSSD, suggesting blunted sympathetic reserve. Patients with both conditions exhibited a mixed autonomic profile—elevated overall HRV with concurrent reductions in both sympathetic and parasympathetic components—indicating more profound dysautonomia despite milder OSA severity. Conclusions: OSA and syncope show distinct nocturnal autonomic patterns, and their coexistence leads to deeper autonomic imbalance. Incorporating nocturnal HRV analysis into routine polygraphy may improve pathophysiological stratification of unexplained syncope and identify clinically significant OSA. Full article

Bone immunity represents a dynamic interface where skeletal homeostasis intersects with systemic immune regulation. We synthesize emerging paradigms by contrasting two functionally distinct microenvironments: the marrow cavity, a hematopoietic and immune cell reservoir, and cancellous bone, a metabolically active hub orchestrating osteoimmune interactions. The marrow cavity not only generates innate and adaptive immune cells but also preserves long-term immune memory through stromal-derived chemokines and survival factors, while cancellous bone regulates bone remodeling via macrophage-osteoclast crosstalk and cytokine gradients. Breakthroughs in lymphatic vasculature identification challenge traditional views, revealing cortical and lymphatic networks in cancellous bone that mediate immune surveillance and pathological processes such as cancer metastasis. Central to bone immunity is the neuro–immune–endocrine axis, where sympathetic and parasympathetic signaling bidirectionally modulate osteoclastogenesis and macrophage polarization. Gut microbiota-derived metabolites, including short-chain fatty acids and polyamines, reshape bone immunity through epigenetic and receptor-mediated pathways, bridging systemic metabolism with local immune responses. In disease contexts, dysregulated immune dynamics drive osteoporosis via RANKL/IL-17 hyperactivity and promote leukemic evasion through microenvironmental immunosuppression. We further propose the “brain–gut–bone axis” as a systemic regulatory framework, wherein vagus nerve-mediated gut signaling enhances osteogenic pathways, while leptin and adipokine circuits link marrow adiposity to inflammatory bone loss. These insights redefine bone as a multidimensional immunometabolic organ, integrating neural, endocrine, and microbial inputs to maintain homeostasis. By elucidating the mechanisms of immune-driven bone pathologies, this work highlights therapeutic opportunities through biomaterial-mediated immunomodulation and microbiota-targeted interventions, paving the way for next-generation treatments in osteoimmune disorders. Full article

Cardiomyopathies affect over 3 million individuals globally, with conventional treatments exhibiting up to 60% resistance and 25% 30-day readmission rates. This review synthesizes the current evidence on the role of neuro-immune interactions in the pathogenesis of cardiomyopathy and evaluates emerging therapies targeting this axis. We systematically examined clinical trials and mechanistic and multi-omics data across cardiomyopathy phenotypes, focusing on autonomic-immune dysregulation. Sympathetic overactivation, present in approximately 85% of patients, correlates with elevated pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) and contributes significantly to therapeutic non-response. Concurrent parasympathetic withdrawal impairs cholinergic anti-inflammatory pathways, as reflected by reduced heart rate variability and baroreflex sensitivity. At the molecular level, shared mechanisms include inflammasome activation, neuroimmune synaptic signaling, and neurogenic inflammation. Emerging therapies targeting this axis are promising. Vagus nerve stimulation, as demonstrated in the INOVATE-HF trial, improves functional outcomes, whereas IL-1β antagonists reduce cardiovascular events by 15–20% in the context of inflammatory diseases. Bioelectronic interventions, such as transcutaneous vagal nerve stimulation and baroreflex activation therapy, offer noninvasive dual-modulatory strategies that address both neural and immune pathways, positioning the neuroimmune axis as a central driver of cardiomyopathy, regardless of etiology. The integration of genetic and metabolomic profiling may enable precision therapies targeting neuroimmune circuits, thereby overcoming the limitations of hemodynamic-focused care. This mechanistic framework shifts the therapeutic paradigm from symptomatic relief to targeted modulation of pathogenic pathways, with implications for millions of patients with cardiomyopathy and broader inflammatory cardiovascular disorders. Full article

Background: As we age, our autonomic function declines, resulting in altered autonomic balance during postural transitions. These changes can affect the dynamic interplay between sympathetic and parasympathetic modulation, compromising short-term compensatory responses to active standing. Objectives: This study aimed to compare heart rate variability (HRV) at baseline, cardiac parasympathetic modulation (CPM), and cardiac baroreflex gain (CRG) between younger adults (YA) and older adults (OA) following active standing orthostatic stress. A secondary objective was to analyze the incidence of orthostatic intolerance (OI) symptoms. Methods: Participants (n = 76) completed sit-to-stand and lie-to-stand maneuvers with continuous beat-to-beat blood pressure and heart rate (HR, electrocardiogram). HRV at baseline was analyzed in both time and frequency domains. CPM was measured by the HR 30:15 ratio on standing. CBG was determined as the ratio of HR and SBP changes (ΔHR/ΔSBP) at specific phase time points (30 s, 60 s, 180 s, and 420 s). Results: At baseline, OA showed reduced Standard Deviation of RR intervals (SDRR), Root Mean Square of Successive Differences (RMSSD), low-frequency (LF), and high-frequency (HF) power, and elevated LF/HF ratio (all p < 0.05), indicating a shift toward sympathetic dominance. During active standing orthostatic stress, OA demonstrated a lower HR30:15 ratio and CBG in later phases (phases 2–4) (all p < 0.05). Also, OA reported more symptoms (14%) of OI than YA (0%) (p = 0.041). Conclusions: These findings indicate that older adults have impaired autonomic function characterized by reduced HRV, CPM and CBG responses. These impairments lead to diminished autonomic regulation under active-standing orthostatic stress and a higher incidence of OI symptoms. Full article

This study investigates the effects of transcutaneous electroacupuncture stimulation (TEAS) on eyeblink rate, EEG, and heart rate variability (HRV), emphasising whether eyeblink data—often dismissed as artefacts—can serve as useful physiological markers. Sixty-six participants underwent four TEAS sessions with different stimulation frequencies (2.5, 10, 80, and 160 pps, with 160 pps as a low-amplitude sham). EEG, ECG, PPG, and respiration data were recorded before, during, and after stimulation. Using non-parametric statistical analyses, including Friedman’s test, Wilcoxon, Conover–Iman, and bootstrapping, the study found significant changes across eyeblink, EEG, and HRV measures. Eyeblink laterality, particularly at 2.5 and 10 pps, showed strong frequency-specific effects. EEG power asymmetry and spectral centroids were associated with HRV indices, and 2.5 pps stimulation produced the strongest parasympathetic HRV response. Blink rate correlated with increased sympathetic and decreased parasympathetic activity. Baseline HRV measures, such as lower heart rate, predicted participant dropout. Eyeblinks were analysed using BLINKER software (v. 1.1.0), and additional complexity and entropy (‘CEPS-BLINKER’) metrics were derived. These measures were more predictive of adverse reactions than EEG-derived indices. Overall, TEAS modulates multiple physiological markers in a frequency-specific manner. Eyeblink characteristics, especially laterality, may offer valuable insights into autonomic function and TEAS efficacy in neuromodulation research. Full article

Background: Chronic pain is closely associated with dysregulation of the autonomic nervous system, often reflected by reduced heart rate variability (HRV). While observational studies have demonstrated this association, the extent to which pain interventions modulate HRV and the impact of individual factors on HRV changes remain unclear. Objective: To evaluate the impact of pain interventions on HRV parameters through meta-analysis of randomized controlled trials (RCTs), and to examine whether intervention type and individual factors such as body mass index (BMI) moderate HRV responses. Methods: We conducted a systematic review of 23 RCTs and a meta-analysis of 21 RCTs (1262 subjects) involving patients with acute and chronic pain. HRV outcomes were extracted pre- and post-intervention. Both between-group (active vs. sham/control) and one-group (pre-post within active group) analyses were performed for time-domain indices—standard deviation of normal-to-normal intervals (SDNN), root mean square of successive differences (RMSSD), and percentage of successive normal-to-normal intervals > 50 ms (pNN50)—and frequency-domain indices—high-frequency (HF) and low-frequency (LF) components. Meta-regressions tested moderators including BMI, age, and pain phenotype. The protocol was registered in PROSPERO (CRD42023448264). Results: Twenty-three RCTs involving 1262 participants with a wide range of pain conditions were included. Meta-analysis of time-domain HRV parameters showed a trend toward improvement: SDNN (g = 0.435, p = 0.059) approached significance, while RMSSD (g = 0.361, p = 0.099) and pNN50 (g = 0.222, p = 0.548) showed smaller, non-significant effects. Frequency-domain analysis revealed a significant moderate reduction in the LF/HF ratio (g = −0.378, p = 0.003), suggesting a shift toward parasympathetic dominance. HF and LF showed small, non-significant changes. One-group meta-analysis confirmed significant improvements in vagally mediated HRV, with large effects for RMSSD (g = 1.084, p < 0.001) and HF (g = 0.622, p < 0.001), and a moderate effect for SDNN (g = 0.455, p = 0.004). Meta-regression identified BMI as a significant moderator: higher BMI was associated with attenuated improvements in HF and RMSSD and a slight shift toward sympathetic predominance. Conclusions: Pain interventions can significantly modulate autonomic function, as reflected in HRV improvements, particularly in vagally mediated indices. These effects are influenced by patient characteristics such as BMI. HRV may serve as a valuable biomarker for both treatment efficacy and autonomic recovery in pain management. In this context, HRV highlights its role as a biomarker for pain dysregulation and compensatory failure, reflecting shared top-down modulation between nociception and autonomic regulation. Full article

Understanding the mechanisms of immune activation and deactivation is paramount. A host must initiate effective immunity against pathogenic infections while avoiding triggering immunity against self-antigens, which can lead to detrimental autoimmune disorders. Host immunological pathways can be categorized as Immunoglobulin (Ig)G-dominant eradicable immune reactions and IgA-dominant tolerable immune reactions. Eradicable immune reactions include Th1, Th2, Th22, and Thαβ immune responses against four different types of pathogens. Tolerable immune reactions include Th1-like, Th9, Th17, and Th3 immune responses against four different types of pathogens. Here, we try to determine the mechanisms of activation and deactivation of host immune reactions. The spleen and liver play contrasting roles in mediating immune responses: the spleen is primarily involved in immune activation, whereas the liver is responsible for immune deactivation. Similarly, the sympathetic and parasympathetic nervous systems have opposing functions in immune modulation, with the sympathetic system promoting pro-inflammatory responses and the parasympathetic system facilitating anti-inflammatory processes. Furthermore, adrenocorticotropic hormone (ACTH) and glucocorticosteroids exhibit contrasting effects on immune regulation: ACTH is involved in activating adaptive immunity while inhibiting innate immunity, whereas glucocorticosteroids activate natural IgM antibody associated with innate immunity while inhibiting adaptive immunity. Heat shock proteins, particularly molecular chaperones induced by fever, play pivotal roles in immune activation. Conversely, IgD B cells and gamma/delta T cells contribute to immune deactivation through mechanisms such as clonal anergy. Understanding these mechanisms provides insights into immunological pathways, aiding in the better management of infectious diseases and autoimmune disorders. Full article

The intricate brain–heart interaction, essential for physiological balance, is largely governed by the autonomic nervous system (ANS). This bidirectional communication, involving both the sympathetic and parasympathetic branches of the ANS, is critical for maintaining cardiac homeostasis. Dysregulation of the ANS is a significant factor in cardiovascular diseases. Beyond the ANS, higher brain functions, particularly through interoceptive prediction, contribute to this dynamic interplay. The Cav1.3 L-type calcium channel, expressed in both the central nervous system (CNS) and the heart, is crucial for this interaction. Cav1.3, a key regulator of cellular excitability, exhibits genetic variations that are linked to both neurological and cardiac disorders, highlighting its pivotal role in the brain–heart axis. This review aims to delve into the under-explored role of Cav1.3 in brain–heart interaction, specifically examining how it modulates ANS activity and, consequently, the cardiac function. This will illuminate its significant role in the broader context of brain–heart interactions. Full article

Background: Spinal manual therapy (SMT) is widely used in the management of musculoskeletal pain. In addition to mechanical effects, SMT may induce neurophysiological changes at both central and autonomic levels. However, the extent and consistency of these short-term effects remain unclear. Objective: To systematically review the short-term effects of SMT on pain perception, central nervous system (CNS) activity, and autonomic nervous system (ANS) responses in adults with musculoskeletal pain or in healthy controls. Methods: A systematic review was conducted. Three databases (PubMed, ScienceDirect, Embase) were searched up to October 2023, with a final update in March 2025. Randomized controlled trials involving SMT and assessing outcomes related to pain, CNS, or ANS function were included. The methodological quality was assessed using the PEDro scale. The results were synthesized narratively and categorized by outcome domain. Four summary tables were created to present the study characteristics, main findings, methodological quality, and risk of bias. Results: Eleven trials were included. SMT produced variable effects on pain perception, with more consistent results observed when the treatment was applied frequently and followed standardized protocols. The CNS-related outcomes (e.g., fMRI connectivity, motor-evoked potentials) suggested short-term modulation of brain and spinal excitability in some studies. The ANS responses were heterogeneous, ranging from parasympathetic activation to sympathetic stimulation, depending on the intervention and population. The methodological quality was moderate to high in most studies, although the small sample sizes and limited blinding increased the risk of bias. The effect sizes were not consistently reported. Conclusions: SMT may induce short-term neuromodulatory effects on pain, CNS, and ANS activity. These effects appear to be context-dependent and require precise, repeated, and purposeful application. Full article

Stress responses can impact bladder cancer (BC) outcomes via immune–inflammatory pathway modulation. This study explores heart rate variability (HRV) associations with serum immune–inflammatory biomarkers, blood count inflammatory markers, and psychosocial self-report measures in patients versus healthy controls. The TREM-1 and TREM-2 expressions on peripheral blood monocytes were analysed via flow cytometry; serum inflammatory biomarkers by ELISA; HRV (5-min ECG) pre-tumour resection; blood counts by haematology analyser; and psychosocial factors by validated questionnaires. Patients exhibited altered immune–inflammatory profiles with increased TREM-1/TREM-2, sTREM-1, sTREM-1/sTREM-2 ratio, BDNF, MCP-1, and NLR, and reduced IFN-γ, IL-10, LMR, and PMR. HRV analysis indicated sympathetic dominance (SNS, Stress indices, ACmod) and reduced parasympathetic modulation (PNS index, SDNN, RMSSD, 2UV%, DCmod, SD1). Sympathetic HRV indices correlated positively with sTREM-1, sTREM-1/sTREM-2 ratio, fractalkine, and inflammatory markers (SII, NLR, PLR) and negatively with parasympathetic HRV indices—correlations absent in controls. Only in patients, reduced physical function and social support, and higher anxiety, depression, and fatigue, associated positively with sympathetic HRV indices and inflammatory markers. This study links immune–inflammatory markers, HRV parameters, and psychosocial factors in BC, suggesting that immune and autonomic variations may relate to unfavourable outcomes. Incorporating these assessments could help tailor more personalised treatment strategies for BC patients. Full article

Background: The modulation of the autonomic nervous system’s activity, particularly increasing its parasympathetic tone, is of significant interest in clinical physiotherapy due to its potential benefits for stress-related conditions and recovery processes. This study evaluated the effectiveness of the addition of neurodynamics in enhancing parasympathetic activation in subjects with chronic stress. Methods: A clinical trial randomly assigned participants to a group with neurodynamics (6 bpm breathing protocol + manual therapy + neurodynamic technique) or a group without neurodynamics (6 bpm breathing protocol + manual therapy only). Metrics of heart rate variability (HRV), including the Mean Heart Rate (Mean HR), standard deviation of intervals between consecutive heartbeats (SDNN), Heart Rate Difference (Diff. HR), Root Mean Square of Successive Differences (RMSSD), number of intervals differing by more than 50 ms (NN50), percentage of consecutive NN intervals that differed by more than 50 ms (pNN50), and the high-frequency component measured in standardized units (HF), were assessed before, during, and after the intervention. Results: During the intervention, the group with neurodynamics showed significant changes in all variables except in the pNN50 and HF while the group without neurodynamics only showed improvements in the Mean HR, SDNN, and RMSSD. In the post-intervention phase, the group with neurodynamics maintained an increase in HRV while the group without neurodynamics experienced a decrease, suggesting an increase in sympathetic activity. Conclusions: Vagal nerve neurodynamics appear to represent an effective method for enhancing parasympathetic activation in patients with chronic stress. The results highlight the importance of a more comprehensive analysis of HRV variables in order to obtain a correct picture of the impact of interventions on the complex and multifaceted functioning of the autonomic nervous system. Full article

Background and Objectives: Exercise enhances cardiovascular health through various mechanisms, including the modulation of autonomic nervous system activity. This study aimed to systematically examine the impact of exercise on heart rate variability (HRV) in adults during and within one hour after exercise (WHAE). Materials and Methods: A comprehensive literature review was conducted using the MEDLINE, Embase, Cochrane Library, Scopus, and PubMed databases to identify published studies that reported the impact of exercise on autonomic nervous system activity in adults. The studies measured the absolute power of the low-frequency band (0.04–0.15 Hz) to the absolute power of the high-frequency band (0.015–0.4 Hz) (LF/HF ratio) to assess sympathetic activity and the root mean square of successive differences between normal heartbeats (RMSSD) to assess parasympathetic activity. Results: A total of 3329 studies were screened for relevance, and finally, 10 articles that utilized methods for measuring autonomic nervous system activity, such as the LF/HF ratio and RMSSD, covering 292 adult patients, were included for meta-analysis. In the current meta-analysis, we observed a significant decrease in parasympathetic activity during and after exercise, as indicated by RMSSD, compared to pre-exercise levels (mean difference [MD] = −4.96, 95% confidence interval [CI]: −8.00 to −1.91, p = 0.003). However, sympathetic activity after exercise, represented by the LF/HF ratio, showed a borderline significant increase compared to pre-exercise levels (MD = 1.06, 95% CI: −0.01 to 2.12, p = 0.052). The meta-regression model found that factors associated with RMSSD included mean age, male gender, and duration post-exercise. Additionally, the factor associated with the LF/HF ratio was the healthy condition of participants. The trial sequential analysis provided robust evidence of a decrease in RMSSD and an increase in the LF/HF ratio during and WHAE. Conclusions: Given the limitations of the current study, the findings suggest that a significant decrease in parasympathetic activity and a borderline significant increase in sympathetic activity in adults during and WHAE, as confirmed by trial sequential analysis. Meta-regression analysis indicated that parasympathetic activity was negatively associated with participant age and male gender, but positively associated with duration post-exercise. Additionally, increased sympathetic activity was linked to the healthy conditions of participants. This study suggests that exercise might differentially affect autonomic balance in individuals with chronic conditions compared to healthy individuals. This highlights the potential need for tailored exercise interventions to improve autonomic function across different populations. Full article

Patients with major depressive disorder (MDD) have an increased risk for cardiac events. This is partly attributed to a disbalance of the autonomic nervous system (ANS) indicated by a reduced vagal tone and a (relative) sympathetic hyperactivity. However, in most studies, heart rate variability (HRV) was only examined while resting. So far, it remains unclear whether the dysbalance of the ANS in patients with MDD is restricted to resting or whether it is also evident during sympathetic and parasympathetic activation. The aim of this study was to compare the responses of the ANS to challenges that stimulated the sympathetic and, respectively, the parasympathetic nervous systems in patients with MDD. Forty-six patients with MDD (female 27 (58.7%), mean age 44 ± 17 years) and 46 healthy controls (female 26 (56.5%), mean age 44 ± 20 years) underwent measurement of time- and frequency-dependent domains of HRV at rest, while standing (sympathetic challenge), and during slow-paced breathing (SPB, vagal, i.e., parasympathetic challenge). Patients with MDD showed a higher heart rate, a reduced HRV, and a diminished vagal tone during resting, standing, and SPB compared to controls. Patients with MDD and controls responded similarly to sympathetic and vagal activation. However, the extent of modulation of the ANS was impaired in patients with MDD, who showed a reduced decrease in the vagal tone but also a reduced increase in sympathetic activity when switching from resting to standing. Assessing changes in the ANS during sympathetic and vagal activation via respective challenges might serve as a future biomarker and help to allocate patients with MDD to therapies like HRV biofeedback and psychotherapy that were recently found to modulate the vagal tone. Full article