Search Results (1,157)

The relationship between metabolic dysfunction and mental health disorders is complex and has received increasing attention. This review integrates current research to explore how stress-related growth differentiation factor 15 (GDF15) signaling, ceramides derived from gut microbiota, and mitochondrial dysfunction in the brain interact to influence both metabolic and psychiatric conditions. Evidence suggests that these pathways converge to regulate brain energy homeostasis through feedback mechanisms involving the autonomic nervous system and the hypothalamic–pituitary–adrenal axis. GDF15 emerges as a key stress-responsive biomarker that links peripheral metabolism with brainstem GDNF family receptor alpha-like (GFRAL)-mediated anxiety circuits. Meanwhile, ceramides impair hippocampal mitochondrial function via membrane incorporation and disruption of the respiratory chain. These disruptions may contribute to sustained pathological states such as depression, anxiety, and cognitive dysfunction. Although direct mechanistic data are limited, integrating these pathways provides a conceptual framework for understanding metabolic–psychiatric comorbidities. Furthermore, differences in age, sex, and genetics may influence these systems, highlighting the need for personalized interventions. Targeting mitochondrial function, GDF15-GFRAL signaling, and gut microbiota composition may offer new therapeutic strategies. This integrative perspective helps conceptualize how metabolic and psychiatric mechanisms interact for understanding the pathophysiology of metabolic and psychiatric comorbidities and highlights therapeutic targets for precision medicine. Full article

The focal “hot spot” neuropathologies in COVID-19 infection are revealing footprints of a hidden underlying collapse of a novel ultrafast ultradian Piezo2 signaling system within the nervous system. Paradoxically, the same initiating pathophysiology may underpin the systemic findings in COVID-19 infection, namely the multiorgan SARS-CoV-2 infection-induced vascular pathologies and brain–body-wide systemic pro-inflammatory signaling, depending on the concentration and exposure to infecting SARS-CoV-2 viruses. This common initiating microdamage is suggested to be the primary damage or the acquired channelopathy of the Piezo2 ion channel, leading to a principal gateway to pathophysiology. This Piezo2 channelopathy-induced neural switch could not only explain the initiation of disrupted cell–cell interactions, metabolic failure, microglial dysfunction, mitochondrial injury, glutamatergic synapse loss, inflammation and neurological states with the central involvement of the hippocampus and the medulla, but also the initiating pathophysiology without SARS-CoV-2 viral intracellular entry into neurons as well. Therefore, the impairment of the proposed Piezo2-induced quantum mechanical free-energy-stimulated ultrafast proton-coupled tunneling seems to be the principal and critical underlying COVID-19 infection-induced primary damage along the brain axes, depending on the loci of SARS-CoV-2 viral infection and intracellular entry. Moreover, this initiating Piezo2 channelopathy may also explain resultant autonomic dysregulation involving the medulla, hippocampus and heart rate regulation, not to mention sleep disturbance with altered rapid eye movement sleep and cognitive deficit in the short term, and even as a consequence of long COVID. The current opinion piece aims to promote future angles of science and research in order to further elucidate the not entirely known initiating pathophysiology of SARS-CoV-2 infection. Full article

Spinal cord injury (SCI) is a major disability that, to this day, does not have a permanent cure. The spinal cord extends caudally through the body structure of the vertebral column and is part of the central nervous system (CNS). The spinal cord enables neural communication and motor coordination, so injuries can disrupt sensation, movement, and autonomic functions. Mechanical and traumatic damage to the spinal cord causes lesions to the nerves, resulting in the disruption of relayed messages to the extremities. Various forms of treatment for the spinal cord include functional electrical stimulation (FES), epidural electrical stimulation (EES), ‘SMART’ devices, exoskeleton and robotic systems, transcranial magnetic stimulation, and neuroprostheses using AI for the brain–computer interface. This research is going to analyse and review these current treatment methods for spinal cord injury and identify the current gaps and limitations in these, such as long-term biocompatibility, wireless adaptability, cost, regulatory barriers, and risk of surgery. Future advancements should work on implementing wireless data logging with AI algorithms to increase SCI device adaptability, as well as maintaining regulatory and health system integration. Full article

Stress is a major factor that threatens the body’s homeostasis or well-being. Excessive stress causes psychological anxiety and tension, which disrupts the balance of the autonomic nervous system that maintains the body’s balance, resulting in hormonal imbalance and brain changes. In this study, we investigated the effects of Withania somnifera (Ashwagandha) extract on depression, neurobehavior, and hippocampal changes in model mice exposed to stress. Using an excessive restraint stress-induced depression model, we measured the behavioral changes and the levels of brain-derived neurotrophic factor (BDNF) and antioxidant genes in five groups: control, stress, low-dose W. somniferous extract (20 mg/kg/day), high-dose W. somniferous extract (40 mg/kg/day), and L-theanine (50 mg/kg/day, positive control). Stressed mice showed poorer performance in the open field and elevated plus maze tests compared with the control group. The impaired performance was restored following W. somniferous extract administration. In addition, W. somniferous extract restored the decreased expression of BDNF in the hippocampus caused by restraint stress, improved the balance of stress hormones (i.e., cortisol, dopamine, and norepinephrine), and also regulated BDNF, inflammatory genes, and antioxidant genes in brain tissue. Therefore, W. somniferous extract can induce antidepressant and anti-stress effects by maintaining brain BDNF expression and preventing hippocampal tissue alterations caused by restraint stress. Full article

Central nervous system (CNS) insulin signaling is involved in a broad array of cardiometabolic physiology, including glucose and lipid metabolism, feeding, energy expenditure, and blood pressure regulation. A key role for hypothalamic neuroendocrine and autonomic centers in regulating insulin-associated cardiovascular and metabolic physiology has been highlighted. However, it is still unclear which CNS site(s) initiate insulin-dependent neural cascades. While some investigations have suggested that circulating insulin can access hypothalamic regions by crossing the blood-brain barrier, other studies point to a necessity of other brain areas upstream of the hypothalamus to initiate central insulin actions. In this context, accumulating evidence points to a possible involvement of the sensory circumventricular organs (CVOs), unique areas located outside of the blood-brain barrier, in insulin-dependent cardiometabolic homeostasis. Here, the multifaceted roles for the sensory CVOs in cardiovascular and metabolic regulation, with a special emphasis on insulin receptor pathways, are discussed. Full article

The heart is innervated by the autonomic nervous system (ANS), which plays a role in regulating the heart rate. Cross-country mountain biking (MTBXC) is a sport with high physiological demands, where the autonomic nervous system plays a significant role. The main objective of this study was to analyze the asymmetry of heart rate in Colombian National Team mountain bikers, sub-23 category, during a 20 min cardiovascular autonomic profile test. Method: The cardiovascular autonomic profile was measured through heart rate variability during a 20 min test, divided into eight phases (supine, controlled ventilation at 10 cycles/min, controlled ventilation at 12 cycles/min, postural change, orthostasis, Ruffier test, 1 min recovery, and final recovery) in a group of n = 10 MTB cyclists from the National Sub-23 Team, including 5 males and 5 females. Results: The results for the male athletes were as follows: age: 19 ± 1 years; VO2max: 67.5 mL/kg/min; max power: 355 W; HRmax: 204 bpm. The results for the female athletes were as follows: age: 19 ± 1 years; VOmax: 58.5 mL/kg/min; max power: 265 W; HRmax: 194 bpm. Both genders showed the expected autonomic behavior in each phase. Asymmetrical propagation of heart rate was observed, with a greater deceleration pattern after postural changes and effort and a symmetrical acceleration pattern in these two phases. Discussion: Athletes exhibit increased vagal response compared to non-athletes. Mountain bikers show rapid heart rate reduction after exertion. Conclusion: This study demonstrates how mountain bikers exhibit increased heart rate deceleration following sympathetic stimuli. Full article

Sudden Unexpected Death in Epilepsy (SUDEP) is a leading cause of mortality among individuals with epilepsy, particularly those with drug-resistant forms. This review explores the complex multisystem mechanisms underpinning SUDEP, integrating recent findings on brain, cardiac, and pulmonary dysfunctions. Background/Objectives: The main objective of this review is to elucidate how seizures disrupt critical physiological systems, especially the brainstem, heart, and lungs, contributing to SUDEP, with emphasis on respiratory control failure and autonomic instability. Methods: The literature from experimental models, clinical observations, neuroimaging studies, and genetic analyses was systematically examined. Results: SUDEP is frequently preceded by generalized tonic–clonic seizures, which trigger central and obstructive apnea, hypoventilation, and cardiac arrhythmias. Brainstem dysfunction, particularly in areas such as the pre-Bötzinger complex and nucleus tractus solitarius, plays a central role. Genetic mutations affecting ion channels (e.g., SCN1A, KCNQ1) and neurotransmitter imbalances (notably serotonin and GABA) exacerbate autonomic dysregulation. Risk is compounded by a prone sleeping position, reduced arousal capacity, and impaired ventilatory responses. Conclusions: SUDEP arises from a cascade of interrelated failures in respiratory and cardiac regulation initiated by seizure activity. The recognition of modifiable risk factors, implementation of monitoring technologies, and targeted therapies such as serotonergic agents may reduce mortality. Multidisciplinary approaches integrating neurology, cardiology, and respiratory medicine are essential for effective prevention strategies. Full article

Microglia, as the immune guardians of the central nervous system (CNS), have the ability to maintain neural homeostasis, respond to environmental changes, and remodel the synaptic landscape. However, persistent microglial activation can lead to chronic neuroinflammation, which can alter neuronal signaling pathways, resulting in accelerated cognitive decline. Phosphoinositol 3-kinase (PI3K) has emerged as a critical driver, connecting inflammation to neurodegeneration, serving as the nexus of numerous intracellular processes that govern microglial activation. This review focuses on the relationship between PI3K signaling and microglial activation, which might lead to cognitive impairment, inflammation, or even neurodegeneration. The review delves into the components of the PI3K signaling cascade, isoforms, and receptors of PI3K, as well as the downstream effects of PI3K signaling, including its effectors such as protein kinase B (Akt) and mammalian target of rapamycin (mTOR) and the negative regulator phosphatase and tensin homolog (PTEN). Experiments have shown that the overproduction of certain cytokines, coupled with abnormal oxidative stress, is a consequence of poor PI3K regulation, resulting in excessive synapse pruning and, consequently, impacting learning and memory functions. The review also highlights the implications of autonomously activated microglia exhibiting M1/M2 polarization driven by PI3K on hippocampal, cortical, and subcortical circuits. Conclusions from behavioral studies, electrophysiology, and neuroimaging linking cognitive performance and PI3K activity were evaluated, along with new approaches to therapy using selective inhibitors or gene editing. The review concludes by highlighting important knowledge gaps, including the specific effects of different isoforms, the risks associated with long-term pathway modulation, and the limitations of translational potential, underscoring the crucial role of PI3K in mitigating cognitive impairment driven by neuroinflammation. Full article

Heart rate (HR) is strongly affected by the autonomic nervous system (ANS), while its spontaneous fluctuations, called heart rate variability (HRV), report about the dynamics of the complex, vegetative regulation of the heart rhythm. Hence, HRV is widely considered an important marker of the ANS effects on the cardiac system, and as such, a crucial diagnostic tool in cardiology. In order to obtain nontrivial results from HRV analysis, it would be desirable to establish exact, universal interrelations between the typical HRV parameters and HR itself. That, however, has not yet been fully accomplished. Hence, our aim was to perform a comparative statistical analysis of ECG recordings from a public database, with a focus on the HR dependence of typical HRV parameters. We revealed their fundamental connections, which were substantiated by basic mathematical considerations, and were experimentally demonstrated via the analysis of 24 h of ECG recordings of more than 200 healthy individuals. The large database allowed us to perform unique age-cohort analyses. We confirmed the HR dependence of typical time-domain parameters, such as RMSSD and SDNN, frequency-domain parameters such as the VLF, LF, and HF components, and nonlinear indices such as sample entropy and DFA exponents. In addition to shedding light on their relationship, we are the first, to our knowledge, to identify a new, diffuse structure in the VHF regime as an important indicator of SNS activity. In addition, the demonstrated age dependence of the HRV parameters gives important new insight into the long-term changes in the ANS regulation of the cardiac system. As a possible molecular physiological mechanism underlying our new findings, we suggest that they are associated with Piezo2 channel function and its age-related degradation. We expect our results to be utilized in HRV analysis related to both medical research and practice. Full article

Neuronal ceroid lipofuscinoses (NCLs) are paediatric neurodegenerative disorders that primarily affect the central nervous system (CNS). The high prevalence of gastrointestinal (GI) symptoms has prompted researchers and clinicians to move beyond an exclusively “brain-centric” perspective. At the molecular level, mutations in CLN genes lead to lysosomal dysfunction and impaired autophagy, resulting in intracellular accumulation of storage material that disrupts both central and enteric neuronal homeostasis. To systematically examine current clinical and preclinical knowledge on gut involvement in NCLs, with a focus on recent findings related to the enteric nervous system and gut microbiota. We conducted a systematic review following the PRISMA guidelines using PubMed as the sole database. Both clinical (human) and preclinical (animal) studies were included. A total of 18 studies met the inclusion criteria, focusing on gastrointestinal dysfunction, nervous system involvement, and gut microbiota. We found that the nature of GI symptoms was multifactorial in NCLs, involving not only the CNS but also the autonomic and enteric nervous systems, which were affected early by lysosomal deposits and enteric neuron degeneration. Of note, preclinical studies showed that gene therapy could improve not only CNS manifestations but also GI ones, which may have beneficial implications for patient care. While the role of the ENS seems to be clearer, that of gut microbiota needs to be further clarified. Current evidence from preclinical models highlighted alterations in the composition of the microbiota and suggested a possible influence on the progression and modulation of neurological symptoms. However, these results need to be confirmed by further studies demonstrating the causality of this relationship. GI involvement is a key feature of NCLs, with early impact on the enteric nervous system and possible links to gut microbiota. Although preclinical findings—particularly on gene therapy—are encouraging due to their dual impact on both CNS and GI manifestations, the causal role of the gut microbiota remains to be fully elucidated. In this context, the development of sensitive and specific outcome measures to assess GI symptoms in clinical trials is crucial for evaluating the efficacy of future therapeutic interventions. Full article

Continuous blood pressure (BP) monitoring provides valuable insight into the body’s dynamic cardiovascular regulation across various physiological states such as physical activity, emotional stress, postural changes, and sleep. Continuous BP monitoring captures different variations in systolic and diastolic pressures, reflecting autonomic nervous system activity, vascular compliance, and circadian rhythms. This enables early identification of abnormal BP trends and allows for timely diagnosis and interventions to reduce the risk of cardiovascular diseases (CVDs) such as hypertension, stroke, heart failure, and chronic kidney disease as well as chronic stress or anxiety disorders. To facilitate continuous BP monitoring, we propose an AI-powered estimation framework. The proposed framework first uses an expert-driven feature engineering approach that systematically extracts physiological features from photoplethysmogram (PPG)-based arterial pulse waveforms (APWs). Extracted features include pulse rate, ascending/descending times, pulse width, slopes, intensity variations, and waveform areas. These features are fused with demographic data (age, gender, height, weight, BMI) to enhance model robustness and accuracy across diverse populations. The framework utilizes a Tab-Transformer to learn rich feature embeddings, which are then processed through an ensemble machine learning framework consisting of CatBoost, XGBoost, and LightGBM. Evaluated on a dataset of 1000 subjects, the model achieves Mean Absolute Errors (MAE) of 3.87 mmHg (SBP) and 2.50 mmHg (DBP), meeting British Hypertension Society (BHS) Grade A and Association for the Advancement of Medical Instrumentation (AAMI) standards. The proposed architecture advances non-invasive, AI-driven solutions for dynamic cardiovascular health monitoring. Full article

Background/Objectives: Heart rate variability (HRV) is a marker of autonomic nervous system function, based on fluctuations in heartbeat intervals. Although several studies have investigated the association between frequency-domain HRV parameters and glaucoma, evidence based on large sample sizes remains limited. Therefore, the present study aimed to examine the relationship between frequency-domain HRV parameters and glaucoma subtypes, including primary open-angle glaucoma (PG) and exfoliation glaucoma (EG), using a larger sample size. Methods: Participants with primary open-angle glaucoma (PG), exfoliation glaucoma (EG), or no ocular disease other than cataract (controls) were recruited at Shimane University between June 2023 and July 2024. Frequency-domain HRV parameters (total power [TP], very-low-frequency [VLF], low-frequency [LF], high-frequency [HF], and LF/HF) were measured using a sphygmograph (TAS9 Pulse Analyzer Plus View). Group comparisons were conducted using unpaired t-tests, Fisher’s exact tests, and Tukey’s HSD test. Multivariate analyses were performed to identify factors associated with each HRV parameter. Results: A total of 809 participants were analyzed, including 522 with PG, 191 with EG, and 96 controls. The EG group showed significantly lower values across all frequency-domain HRV parameters compared to the PG group, and significantly lower LnLF values than the control group (p = 0.012). Multivariate analyses revealed that no significant associations were found between HRV measures and the presence of glaucoma or pseudoexfoliation material (PEM) deposition. Older age was significantly associated with lower values across all HRV parameters. Conclusions: In elderly glaucoma patients, age-related alterations in frequency-domain HRV parameters have been observed. Full article

Non-pharmacological interventions, such as physical activity and exercise, are essential in managing type 1 diabetes mellitus by improving glycemic control, cardiovascular health and autonomic function. Given the chronic nature and long-term complications associated with type 1 diabetes, strategies beyond pharmacotherapy are essential. This review examines the effects of exercise on heart rate variability, a key indicator of autonomic nervous system activity. A systematic search was conducted in March 2024 across PubMed, Embase, Cochrane and CINAHL databases. Studies evaluating the retrospective or prospective impact of exercise or physical activity on heart rate variability parameters were included. Utilizing best evidence synthesis, the methodological quality of the included studies was evaluated. Seven studies met the inclusion criteria, all of which were rated as methodologically weak. Moderate evidence suggests that exercise may enhance heart rate variability, particularly by increasing parasympathetic activity and improving sympathovagal balance. However, evidence remains limited regarding the optimal type, frequency and intensity of exercise. Exercise appears to support autonomic function in individuals with type 1 diabetes mellitus. Nonetheless, further high-quality research is needed to determine the most effective exercise modalities and to inform evidence-based clinical guidelines. Full article

In recent years, a long list of relevant studies has highlighted the engagement of the nervous system in the fine-tuning of tumor development and progression. Several authors have shown that different types of nerve fibres (sympathetic, parasympathetic/vagal or somatosensory fibres) may contribute to tumor innervation affecting cancer initiation, progression and metastasis. A large presence of nerve fibres is frequently observed in tumors with respect to the corresponding healthy tissues. In this regard, it is worth noting that in some cases a reduced innervation may associate with slow tumor growth in a tissue-specific manner. Current studies have begun to shed light over the role played in this specific process by Schwann cells (SCs), the most abundant glial cells of the peripheral nervous system. SCs observed in cancer tissues share strong similarities with repair SCs that appear after nerve injury. A large body of research indicates that SCs may have a role in shaping the microenvironment of tumors by regulating the immune response and influencing their invasiveness. In this review, we summarize data relevant to the role of peripheral innervation in general, and of SCs in particular, in defining the progression of different tumors: melanoma that originate in the skin with mainly sensory innervation; pancreatic and liver-derived tumors (e.g., pancreatic adenocarcinoma and cholangiocarcinoma) with mainly autonomous innervation. We conclude by summarizing data regarding hepatocarcinoma (with anatomical predominance of small autonomic nerve fibres) in which the potential relationship between innervation and tumor progression has been little explored, and largely remains to be defined. Full article

This review explores current and emerging neuromodulation techniques targeting the cardiac autonomic nervous system for the treatment and prevention of atrial and ventricular arrhythmias. Arrhythmias remain a significant cause of morbidity and mortality, with the autonomic nervous system playing a crucial role in arrhythmogenesis. Interventions span surgical, pharmacological, and bioelectronic methods. We discuss the range of neuromodulation methods targeting the stellate ganglion, the spinal region, the parasympathetic system, and other promising methods. These include stellate ganglion block, stellate ganglion ablation, cardiac sympathetic denervation, subcutaneous electrical stimulation, thoracic epidural anesthesia, spinal cord stimulation, dorsal root ganglion stimulation, vagus nerve stimulation, baroreflex activation therapy, carotid body ablation, renal denervation, ganglionated plexi ablation, acupuncture, and transcutaneous magnetic stimulation. Both preclinical and clinical studies are presented as evidence for arrhythmia management. Full article