Reconceptualizing autonomic function testing in migraine: a systematic review and meta-analysis.

BACKGROUND: Autonomic nervous system (ANS) testing has aided in our ability to evaluate autonomic dysfunction in migraine patients. We reviewed the literature in multiple databases which investigate ANS function in migraine patients and healthy subjects. METHODS: This systematic review and meta-analysis examined the respective deep breathing, Valsalva manoeuvre, orthostatic and isometric challenge results, using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Meta-analyses of Observational Studies in Epidemiology (MOOSE) statements. RESULTS: Seven articles met all inclusion criteria. Fixed-effects meta-analysis showed migraine patients (n = 424), collectively, had lower interictal autonomic test results compared with healthy controls (n = 268). In detail, this was true for the standardized mean difference (g) of deep breathing (g= -0.32; 95% confidence interval (CI) -0.48, -0.16), orthostatic challenge (g= -0.28; 95% CI -0.44, -0.13) and isometric challenge (g= -0.55; 95% CI -0.71, -0.39) and for the difference of means (MD) of the Valsalva ratio (MD = -0.17; 95% CI -0.23, -0.10). CONCLUSIONS: Interictal ANS dysfunction can be identified in migraine patients when compared to healthy controls. These findings indicate the importance to evaluate ANS function in migraine patients - especially, as migraine-specific prophylactic therapies (such as anti-calcitonin gene-related peptide (CGRP) antibodies) may affect the function of the ANS.

The challenge of ecological validity in temporomandibular disorders research.

OBJECTIVE: To review the ecological validity of outcomes from current research involving temporomandibular disorders (TMDs), with an emphasis on chronic myofascial pain and the precocious development of degenerative disease of the temporomandibular joint (TMJ). MATERIALS AND METHODS: Current approaches used to study TMDs in terms of neuromechanics, masticatory muscle behaviours, and the dynamics of the autonomic nervous system (ANS) were assessed for ecological validity in this review. In particular, the available literature was scrutinized regarding the effects of sampling, environmental and psychophysiological constraints and averaging data across biological rhythms. RESULTS: Validated computer-assisted numerical modelling of the neuromechanics used biological objective functions to accurately predict muscle activation patterns for jaw-loading tasks that were individual-specific. With respect to masticatory muscle behaviour, current findings refute the premise that sustained bruxing and clenching at high jaw-loading magnitudes were associated with painful TMDs such as myofascial pain. Concerning the role of the ANS in TMDs, there remains the need for personalized assessments based on biorhythms, and where the detection of dysregulated physiologic oscillators may inform interventions to relieve pain and restore normal function. CONCLUSIONS: Future human research which focuses on TMD myofascial pain or the precocious development and progression of TMJ degenerative joint disease requires experimental designs with ecological validity that capture objectively measured data which meaningfully reflect circadian and ultradian states.

Neuronal glucose sensing mechanisms and circuits in the control of insulin and glucagon secretion.

Glucose homeostasis is mainly under the control of the pancreatic islet hormones insulin and glucagon, which, respectively, stimulate glucose uptake and utilization by liver, fat, and muscle or glucose production by the liver. The balance between the secretion of these hormones is under the control of blood glucose concentrations. Indeed, pancreatic islet b-cells and a-cells can sense variations in glycemia and respond by an appropriate secretory response to restore euglycemia. However, the secretory activity of these cells is also under multiple additional metabolic, hormonal, and neuronal signals that combine to ensure the perfect control of glycemia over a lifetime. The central nervous system (CNS), which has an almost absolute requirement for glucose as a source of metabolic energy and, thus, a vital interest in ensuring that glycemic levels never fall below ~5mM, is equipped with populations of neurons responsive to changes in glucose concentrations. These neurons control pancreatic islet cells secretion activity in multiple ways: through both branches of the autonomic nervous system, through the hypothalamic-pituitary-adrenal axis, and by secreting vasopressin (AVP) in the blood at the level of the posterior pituitary. Here, we will present the autonomic innervation of the pancreatic islets; the mechanisms of neurons activation by a rise or a fall in glucose concentration; how current viral tracing, chemogenetic, and optogenetic techniques allow to integrate specific glucose sensing neurons in defined neuronal circuits that control endocrine pancreas function. Finally, how genetic screens in mice can untangle the diversity of the hypothalamic mechanisms controlling the response to hypoglycemia.

The effects of cold exposure (cold water immersion, whole- and partial- body cryostimulation) on cardiovascular and cardiac autonomic control responses in healthy individuals: A systematic review, meta-analysis and meta-regression.

BACKGROUND: Cryostimulation and cold-water immersion (CWI) have recently gained widespread attention due to their association with changes in cardiovascular and cardiac autonomic control responses. Therefore, the aim of the present systematic review and meta-analysis was to identify the global impact of such cold exposures on cardiovascular and cardiac autonomic activity. METHODS: Three databases (PubMed, Embase, Web-of-Science) were used. Studies were eligible for inclusion if they were conducted on healthy participants using cryostimulation and/or CWI. The outcomes included measurements of blood pressure (BP), heart rate (HR), and heart rate variability (HRV) indices: RR interval (RR), Root mean square of successive RR interval differences (RMSSD), low frequency band (LF), high frequency band (HF), and LF/HF ratio. RESULTS: Among the 27 articles included in our systematic literature review, only 24 were incorporated into the meta-analysis. Our results reveal a significant increase in HRV indices: RMSSD (Standardized mean difference (SMD) = 0.61, p < 0.001), RR (SMD = 0.77, p < 0.001), and HF (SMD = 0.46, p < 0.001), as well as significantly reduced LF (SMD = -0.41, p < 0.001) and LF/HF ratio (SMD = -0.25, p < 0.01), which persisted up to 15 min following cold exposure. Significantly decreased heart rate (SMD = -0.16, p < 0.05), accompanied by slightly increased mean BP (SMD = 0.28, p < 0.001), was also observed. These results seem to depend on individual characteristics and the cooling techniques. CONCLUSION: Our meta-analysis suggests that cryostimulation and/or CWI exposure enhance parasympathetic nervous activity. There is scarce scientific literature regarding the effect of individual characteristics on cold-induced physiological responses.

A case report of cardiac neuromodulation in a young patient with a third-degree atrioventricular block.

Background: There are some functional bradyarrhythmias that are caused by a dysregulation of the autonomic nervous system, for which a therapeutic strategy of cardioneuroablation (CNA) is conceivable. Case summary: In this study, we report the case of a 19-year-old woman with a non-congenital third-degree atrioventricular block (AVB), symptomatic for lipothymia and dyspnea caused by mild exertion. She had a structurally normal heart and no other comorbidities. The atropine test and the exercise stress test documented a sinus tachycardia at 190 bpm with a 2:1 AVB, a narrow QRS, and an atrioventricular conduction of 1:1 until reaching a sinus rhythm rate of 90 bpm. She underwent the CNA procedure, which targeted the inferior paraseptal ganglion plexus, with a gradual change in the ECG levels recorded during the radiofrequency delivery from a third-degree AVB to a first-degree AVB. After the procedure, we observed a complete regression of the third-degree AVB, with evidence of only a first-degree AVB and a complete regression of symptoms until the 6-month follow-up. Conclusions: Although not yet included in current guidelines, the CNA procedure could be used to treat AV node dysfunction in young subjects, as it could represent an alternative to pacemaker implantation. However, more randomized studies are needed to assess the long-term efficacy of this promising technique.

Vagotomy accelerates the onset of symptoms during early disease progression and worsens joint-level pathogenesis in a male rat model of chronic knee osteoarthritis.

Objective: Low vagal tone is common in osteoarthritis (OA) comorbidities and results in greater peripheral inflammation. Characterizing vagal tone's role in OA pathogenesis may offer insights into OA's influences beyond the articular joint. We hypothesized that low vagal tone would accelerate onset of OA-related gait changes and worsen joint damage in a rat knee OA model. Methods: Knee OA was induced in male Sprague Dawley rats by transecting the medial collateral ligament and medial meniscus. Then, left cervical vagus nerve transection (VGX, n â€‹= â€‹9) or sham VGX (non-VGX, n â€‹= â€‹6) was performed. Gait and tactile sensitivity were assessed at baseline and across 12 weeks, with histology and systemic inflammation evaluated at endpoint. Results: At week 4, VGX animals showed limping gait characteristics through shifted stance times from their OA to non-OA limb (p â€‹= â€‹0.055; stance time imbalance â€‹= â€‹1.6 â€‹± â€‹1.6%) and shifted foot strike locations (p â€‹< â€‹0.001; spatial symmetry â€‹= â€‹48.4 â€‹± â€‹0.835%), while non-VGX animals walked with a balanced and symmetric gait. Also at week 4, while VGX animals had a mechanical sensitivity (50% withdrawal threshold) of 13.97 â€‹± â€‹7.70 compared to the non-VGX animal sensitivity of 29.74 â€‹± â€‹9.43, this difference was not statistically significant. Histologically, VGX animals showed thinner tibial cartilage and greater subchondral bone area than non-VGX animals (p â€‹= â€‹0.076; VGX: 0.80 â€‹± â€‹0.036 â€‹mm2; non-VGX: 0.736 â€‹± â€‹0.066 â€‹mm2). No group differences in systemic inflammation were observed at endpoint. Conclusions: VGX resulted in quicker onset of OA-related symptoms but remained unchanged at later timepoints. VGX also had thinner cartilage and abnormal bone remodeling than non-VGX. Overall, low vagal tone had mild effects on OA symptoms and joint remodeling, and not at the level seen in common OA comorbidities.

Your blush gives you away: detecting hidden mental states with remote photoplethysmography and thermal imaging.

Multimodal emotion recognition techniques are increasingly essential for assessing mental states. Image-based methods, however, tend to focus predominantly on overt visual cues and often overlook subtler mental state changes. Psychophysiological research has demonstrated that heart rate (HR) and skin temperature are effective in detecting autonomic nervous system (ANS) activities, thereby revealing these subtle changes. However, traditional HR tools are generally more costly and less portable, while skin temperature analysis usually necessitates extensive manual processing. Advances in remote photoplethysmography (r-PPG) and automatic thermal region of interest (ROI) detection algorithms have been developed to address these issues, yet their accuracy in practical applications remains limited. This study aims to bridge this gap by integrating r-PPG with thermal imaging to enhance prediction performance. Ninety participants completed a 20-min questionnaire to induce cognitive stress, followed by watching a film aimed at eliciting moral elevation. The results demonstrate that the combination of r-PPG and thermal imaging effectively detects emotional shifts. Using r-PPG alone, the prediction accuracy was 77% for cognitive stress and 61% for moral elevation, as determined by a support vector machine (SVM). Thermal imaging alone achieved 79% accuracy for cognitive stress and 78% for moral elevation, utilizing a random forest (RF) algorithm. An early fusion strategy of these modalities significantly improved accuracies, achieving 87% for cognitive stress and 83% for moral elevation using RF. Further analysis, which utilized statistical metrics and explainable machine learning methods including SHapley Additive exPlanations (SHAP), highlighted key features and clarified the relationship between cardiac responses and facial temperature variations. Notably, it was observed that cardiovascular features derived from r-PPG models had a more pronounced influence in data fusion, despite thermal imaging's higher predictive accuracy in unimodal analysis.

Effect of manual osteopathic techniques on the autonomic nervous system, respiratory system function and head-cervical-shoulder complex-a systematic review.

Background: Osteopathic manual techniques are now widely used in medicine worldwide. At present, there are no clear conclusions regarding the possibility of affecting the function of the autonomic nervous system (ANS), respiratory system and head-cervical-shoulder complex by manual osteopathic techniques. Objectives: The aim of the study was to review the current literature regarding the possible impact of osteopathic manual techniques on the state of the autonomic nervous system, spirometric parameters of the respiratory system and the state of the head-collar-shoulder complex. Methods: Publications have been searched in the following databases: PubMed, Virtual Health Library and Cochrane Central Register of Controlled Trials. The search strategy included keywords related to manual osteopathic treatment, autonomic nervous system, spirometry, respiratory function and head, neck and shoulder pain. The methodological quality of the included studies was assessed. The PRISMA guidelines were used for the systematic review. Studies from 2010 to 2023 were selected. Results: Using the proposed descriptions and manual searches from the literature of other works, 40 studies were found, out of which 22 were rejected because they did not meet the inclusion criteria. The analysis included: 15 randomized controlled trials, 3 pilot studies. Conclusion: Studies clearly show the effect of OMT on both spirometric parameters and the condition of the head-collar-shoulder complex. Most often this translates into improved ANS performance, but there are exceptions. Systematic review registration: https://www.crd.york.ac.uk/prospero/, CRD42023476963.

From Psychostasis to the Discovery of Cardiac Nerves: The Origins of the Modern Cardiac Neuromodulation Concept.

This review explores the historical development of cardiology knowledge, from ancient Egyptian psychostasis to the modern comprehension of cardiac neuromodulation. In ancient Egyptian religion, psychostasis was the ceremony in which the deceased was judged before gaining access to the afterlife. This ritual was also known as the "weighing of the heart" or "weighing of the soul". The Egyptians believed that the heart, not the brain, was the seat of human wisdom, emotions, and memory. They were the first to recognize the cardiocentric nature of the body, identifying the heart as the center of the circulatory system. Aristotle (fourth century BC) considered the importance of the heart in human physiology in his philosophical analyses. For Galen (third century AD), the heart muscle was the site of the vital spirit, which regulated body temperature. Cardiology knowledge advanced significantly in the 15th century, coinciding with Leonardo da Vinci and Vesalius's pioneering anatomical and physiological studies. It was William Harvey, in the 17th century, who introduced the concept of cardiac circulation. Servet's research and Marcello Malpighi's discovery of arterioles and capillaries provided a more detailed understanding of circulation. Richard Lower emerged as the foremost pioneer of experimental cardiology in the late 17th century. He demonstrated the heart's neural control by tying off the vagus nerve. In 1753, Albrecht von Haller, a professor at Göttingen, was the first to discover the heart's automaticity and the excitation of muscle fibers. Towards the end of the 18th century, Antonio Scarpa challenged the theories of Albrecht von Haller and Johann Bernhard Jacob Behrends, who maintained that the myocardium possessed its own "irritability", on which the heartbeat depended, and was independent of neuronal sensitivity. Instead, Scarpa argued that the heart required innervation to maintain life, refuting Galenic notions. In contemporary times, the study of cardiac innervation has regained prominence, particularly in understanding the post-acute sequelae of SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) infection (PASC), which frequently involves cardiorespiratory symptoms and dysregulation of the intrinsic cardiac innervation. Recently, it has been recognized that post-acute sequelae of acute respiratory infections (ARIs) due to other pathogens can also be a cause of long-term vegetative and somatic symptoms. Understanding cardiac innervation and modulation can help to recognize and treat long COVID and long non-COVID-19 (coronavirus disease 2019) ARIs. This analysis explores the historical foundations of cardiac neuromodulation and its contemporary relevance. By focusing on this concept, we aim to bridge the gap between historical understanding and modern applications. This will illuminate the complex interplay between cardiac function, neural modulation, cardiovascular health, and disease management in the context of long-term cardiorespiratory symptoms and dysregulation of intrinsic cardiac innervations.

Disrupted autonomic pathways in spinal cord injury: Implications for the immune regulation.

Spinal Cord Injury (SCI) disrupts critical autonomic pathways responsible for the regulation of the immune function. Consequently, individuals with SCI often exhibit a spectrum of immune dysfunctions ranging from the development of damaging pro-inflammatory responses to severe immunosuppression. Thus, it is imperative to gain a more comprehensive understanding of the extent and mechanisms through which SCI-induced autonomic dysfunction influences the immune response. In this review, we provide an overview of the anatomical organization and physiology of the autonomic nervous system (ANS), elucidating how SCI impacts its function, with a particular focus on lymphoid organs and immune activity. We highlight recent advances in understanding how intraspinal plasticity that follows SCI may contribute to aberrant autonomic activity in lymphoid organs. Additionally, we discuss how sympathetic mediators released by these neuron terminals affect immune cell function. Finally, we discuss emerging innovative technologies and potential clinical interventions targeting the ANS as a strategy to restore the normal regulation of the immune response in individuals with SCI.

Identifying New Subtypes of Multiple System Atrophy Using Cluster Analysis.

Background: Multiple system atrophy (MSA) is a disease with diverse symptoms and the commonly used classifications, MSA-P and MSA-C, do not cover all the different symptoms seen in MSA patients. Additionally, these classifications do not provide information about how the disease progresses over time or the expected outcome for patients. Objective: To explore clinical subtypes of MSA with a natural disease course through a data-driven approach to assist in the diagnosis and treatment of MSA. Methods: We followed 122 cases of MSA collected from 3 hospitals for 3 years. Demographic characteristics, age of onset, clinical signs, scale assessment scores, and auxiliary examination were collected. Age at onset; time from onset to assisted ambulation; and UMSARS I, II, and IV, COMPASS-31, ICARS, and UPDRS III scores were selected as clustering elements. K-means, partitioning around medoids, and self-organizing maps were used to analyze the clusters. Results: The results of all three clustering methods supported the classification of three MSA subtypes: The aggressive progression subtype (MSA-AP), characterized by mid-to-late onset, rapid progression and severe clinical symptoms; the typical subtype (MSA-T), characterized by mid-to-late onset, moderate progression and moderate severity of clinical symptoms; and the early-onset slow progression subtype (MSA-ESP), characterized by early-to-mid onset, slow progression and mild clinical symptoms. Conclusions: We divided MSA into three subtypes and summarized the characteristics of each subtype. According to the clustering results, MSA patients were divided into three completely different types according to the severity of symptoms, the speed of disease progression, and the age of onset.

Neural cell-types and circuits linking thermoregulation and social behavior.

Understanding how social and affective behavioral states are controlled by neural circuits is a fundamental challenge in neurobiology. Despite increasing understanding of central circuits governing prosocial and agonistic interactions, how bodily autonomic processes regulate these behaviors is less resolved. Thermoregulation is vital for maintaining homeostasis, but also associated with cognitive, physical, affective, and behavioral states. Here, we posit that adjusting body temperature may be integral to the appropriate expression of social behavior and argue that understanding neural links between behavior and thermoregulation is timely. First, changes in behavioral states-including social interaction-often accompany changes in body temperature. Second, recent work has uncovered neural populations controlling both thermoregulatory and social behavioral pathways. We identify additional neural populations that, in separate studies, control social behavior and thermoregulation, and highlight their relevance to human and animal studies. Third, dysregulation of body temperature is linked to human neuropsychiatric disorders. Although body temperature is a "hidden state" in many neurobiological studies, it likely plays an underappreciated role in regulating social and affective states.

Effect of "needle sensation" and the real-time changes in autonomic nervous system activity during acupuncture analgesia.

Introduction: Acupuncture analgesia (AA) is widely used in clinical practice. The autonomic nervous system (ANS) may be an important pathway for acupuncture signal transduction. However, real-time changes in autonomic function during AA and the effect of "needle sensation" remain unclear. Methods: We established a human pain model in healthy adults and randomly assigned 128 participants to the model, sham acupuncture, and acupuncture groups in a 1:1:2 ratio. Heart rate variability (HRV), including total power (TP), low-frequency power (LF), high-frequency power (HF), ratio of LF to HF (LF/HF), standard deviation of the normal-normal intervals (SDNN), and root mean square of successive interval differences (RMSSD), were used to assess autonomic function. The visual analog scale (VAS) and efficiency were used to assess the analgesic effect of acupuncture. The Massachusetts General Hospital acupuncture sensation scale (MASS) was used to indicate the intensity of the needle sensation. Anxiety levels were also measured. Finally, the correlation of MASS with HRV, VAS, and anxiety levels was analyzed. Results: VAS decreased after 10 min of needling and 5 min after needle withdrawal in the acupuncture group compared with those in the model group (p = 0.038, p = 0.020). The efficacy rates were 82.0, 50.0, and 61.3% in the acupuncture, model, and sham groups, respectively. These represent significant differences between the acupuncture group and the model and sham acupuncture groups (p < 0.001 in each case). No differences were observed between the model and sham acupuncture groups. HF, TP, SDNN, and RMSSD were all increased in the acupuncture group compared with those in the model group (p = 0.045, p = 0.041, p = 0.002, p = 0.006, respectively). No differences were observed in the sham acupuncture group compared to the model group (p = 0.632, p = 0.542, p = 0.093, p = 0.222, respectively). The LF and LF/HF did not differ among all three groups. A positive correlation was observed between MASS and RMSSD2, LF2, RMSSD4, TP4, VAS5, and anxiety levels. Conclusion: AA was associated with enhanced vagal activity. The intensity of needle sensation was positively correlated with vagal and sympathetic nerve activities. Acupuncture is an effective means of regulating autonomic function, and needle sensation may be an important modulator.

The effect of anabolic androgenic steroids on heart rate recovery index and electrocardiographic parameters in male bodybuilders.

BACKGROUND: The control of the cardiovascular system depends on the autonomic nerve system. Chronic anabolic andorogenic steroids (AAS) use causes sympathovagal imbalance and increases sympathetic nerve activity. OBJECTIVE: The reduction in heart rate from the peak exercise rate following the end of the exercise stress test is known as the heart rate recovery index (HRRI). Several methods have been utilized to assess myocardial repolarization, such as QT interval (QT), corrected QT interval (QTc), and T-wave peak-to-end interval (Tp-e interval). Based on a growing number of data a higher Tp-e/QT ratio is linked to malignant ventricular arrhythmias, and an increased Tp-e interval may correlate with the transmural dispersion of repolarization. Our hypothesis is that the use of chronic AAS was decrease HRRI during maximal exercise and increased risk of cardiac arrhythmias and sudden cardiac death. METHODS: This study included 44 male bodybuilders, with an average age of 29.7 ± 8.14 years, divided into AAS abuse [AAS users (n = 21) and AAS nonuser (n = 23)]. RESULTS: The first (p = 0.001) and second minute (p = 0.001) HRRI of the subjects with AAS users were significantly lower than those of the control group. Additionally, HRRI after the third (p = 0.004) and fifth minutes (p = 0.007) of the recovery period were significantly lower in AAS group compared with the control group. Who used AAS had significantly higher QT, QTc, Tp-e, Tp-e/QT, and Tp-e/QTc values than non-users (all p = 0.001). CONCLUSIONS: Chronic AAS use has been shown to cause sympathetic dominance, which may be a pro arrhythmic state.

Analysis of the Relationship between Recent Small Subcortical Infarcts and Autonomic Nervous Dysfunction.

OBJECTIVE: Autonomic Nervous System (ANS) dysfunction may be involved in the pathogenesis of Cerebral Small Vessel Disease (CSVD). The study aimed to explore the relationship between Recent Small Subcortical Infarct (RSSI) and Blood Pressure Variability (BPV), and Heart Rate Variability (HRV). METHODS: A total of 588 patients from the CSVD registration research database of Henan Province were included in this study, and were divided into two groups according to the presence of RSSI. Clinical data, including demographic characteristics, disease history, laboratory indexes, 24-hour ambulatory blood pressure and electrocardiogram indicators, and imaging markers of CSVD, were collected. Univariate and binary logistic regression analyses were used to study the relationship between RSSI and indicators of laboratory, HRV and BPV in the CSVD population. RESULTS: Multivariate analysis showed that higher 24-hour mean Diastolic Blood Pressure (DBP)[Odds Ratios (OR)=1.083,95% Confidence Intervals (CI)=(1.038,1.129), p < 0.001], Standard Deviation (SD) of 24-hour DBP [OR=1.059,95%CI=(1.000,1.121), p = 0.049], nocturnal mean Systolic Blood Pressure (SBP) [OR=1.020,95%CI=(1.004,1.035), p = 0.012], nocturnal mean DBP [OR=1.025,95%CI=(1.009,1.040), p = 0.002] were independent risk factors for RSSI. In contrast, the decrease of the standard deviation of N-N intervals (SDNN) [OR=0.994,95%CI=(0.989,1.000), p = 0.035] was beneficial to the occurrence of RSSI. In addition, neutrophil counts [OR=1.138,95%CI=(1.030,1.258), p = 0.011], total cholesterol (TC) [OR=1.203,95%CI=(1.008,1.437), p = 0.041] and High-Density Lipoprotein (HDL) [OR=0.391, 95%CI=(0.195,0.786), p = 0.008] were also independently associated with the occurrence of RSSI. After adjusting for confounding factors, except for TC, the other factors remained associated with the occurrence of RSSI. CONCLUSION: Increased 24-hour mean DBP, nocturnal mean SBP and DBP, SD of 24-hour DBP and decreased SDNN were independently correlated with RSSI occurrence, suggesting that sympathetic overactivity plays a role in the pathogenesis of RSSI.

Parasympathetic neurons derived from human pluripotent stem cells model human diseases and development.

Autonomic parasympathetic neurons (parasymNs) control unconscious body responses, including "rest-and-digest." ParasymN innervation is important for organ development, and parasymN dysfunction is a hallmark of autonomic neuropathy. However, parasymN function and dysfunction in humans are vastly understudied due to the lack of a model system. Human pluripotent stem cell (hPSC)-derived neurons can fill this void as a versatile platform. Here, we developed a differentiation paradigm detailing the derivation of functional human parasymNs from Schwann cell progenitors. We employ these neurons (1) to assess human autonomic nervous system (ANS) development, (2) to model neuropathy in the genetic disorder familial dysautonomia (FD), (3) to show parasymN dysfunction during SARS-CoV-2 infection, (4) to model the autoimmune disease Sjögren's syndrome (SS), and (5) to show that parasymNs innervate white adipocytes (WATs) during development and promote WAT maturation. Our model system could become instrumental for future disease modeling and drug discovery studies, as well as for human developmental studies.

Calcineurin regulates synaptic Ca2+-permeable AMPA receptors in hypothalamic presympathetic neurons via α2δ-1-mediated GluA1/GluA2 assembly.

Hypertension is a major adverse effect of calcineurin inhibitors, such as tacrolimus (FK506) and cyclosporine, used clinically as immunosuppressants. Calcineurin inhibitor-induced hypertension (CIH) is linked to augmented sympathetic output from the hypothalamic paraventricular nucleus (PVN). GluA2-lacking, Ca2+-permeable AMPA receptors (CP-AMPARs) are a key feature of glutamatergic synaptic plasticity, yet their role in CIH remains elusive. Here, we found that systemic administration of FK506 in rats significantly increased serine phosphorylation of GluA1 and GluA2 in PVN synaptosomes. Strikingly, FK506 treatment reduced GluA1/GluA2 heteromers in both synaptosomes and endoplasmic reticulum-enriched fractions from the PVN. Blocking CP-AMPARs with IEM-1460 induced a larger reduction of AMPAR-mediated excitatory postsynaptic current (AMPAR-EPSC) amplitudes in retrogradely labelled, spinally projecting PVN neurons in FK506-treated rats than in vehicle-treated rats. Furthermore, FK506 treatment shifted the current-voltage relationship of AMPAR-EPSCs from linear to inward rectification in labelled PVN neurons. FK506 treatment profoundly enhanced physical interactions of α2δ-1 with GluA1 and GluA2 in the PVN. Inhibiting α2δ-1 with gabapentin, α2δ-1 genetic knockout, or disrupting α2δ-1-AMPAR interactions with an α2δ-1 C terminus peptide restored GluA1/GluA2 heteromers in the PVN and diminished inward rectification of AMPAR-EPSCs in labelled PVN neurons induced by FK506 treatment. Additionally, microinjection of IEM-1460 or α2δ-1 C terminus peptide into the PVN reduced renal sympathetic nerve discharges and arterial blood pressure elevated in FK506-treated rats but not in vehicle-treated rats. Thus, calcineurin in the hypothalamus constitutively regulates AMPAR subunit composition and phenotypes by controlling GluA1/GluA2 interactions with α2δ-1. Synaptic CP-AMPARs in PVN presympathetic neurons contribute to augmented sympathetic outflow in CIH. KEY POINTS: Systemic treatment with the calcineurin inhibitor increases serine phosphorylation of synaptic GluA1 and GluA2 in the PVN. Calcineurin inhibition enhances the prevalence of postsynaptic Ca2+-permeable AMPARs in PVN presympathetic neurons. Calcineurin inhibition potentiates α2δ-1 interactions with GluA1 and GluA2, disrupting intracellular assembly of GluA1/GluA2 heterotetramers in the PVN. Blocking Ca2+-permeable AMPARs or α2δ-1-AMPAR interactions in the PVN attenuates sympathetic outflow augmented by the calcineurin inhibitor.

Ventricular response as a predictor of the termination of sustained paroxysmal atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is the most common sustained atrial arrhythmia. Accurate detection of the timing and possibility of AF termination is vital for optimizing rhythm and rate control strategies. The present study evaluated whether the ventricular response (VR) in AF offers a distinctive electrocardiographic indicator for predicting AF termination. METHODS: Patients experiencing sustained paroxysmal AF for more than 3 h were observed using 24-h ambulatory Holter monitoring. VR within 5 min before AF termination (VR 0-5 min, BAFT) was compared with VR observed during the 60th to 65th min (VR 60-65 min, BAFT) and the 120th to 125th min (VR 120-125 min, BAFT) before AF termination. Maximum and minimum VRs were calculated on the basis of the average of the highest and lowest VRs across 10 consecutive heartbeats. RESULTS: Data from 37 episodes of paroxysmal AF revealed that the minimum VR0-5 min, BAFT (64 ± 20 bpm) was significantly faster than both the minimum VR120-125 min, BAFT (56 ± 15 bpm) and the minimum VR60-65 min, BAFT (57 ± 16 bpm, p < .05). Similarly, the maximum VR0-5 min, BAFT (158 ± 49 bpm) was significantly faster than the maximum VR120-125 min, BAFT (148 ± 45 bpm, p < .05). In the daytime, the minimum VR0-5 min, BAFT (66 ± 20 bpm) was significantly faster than both the minimum VR60-65 min, BAFT (58 ± 17 bpm) and minimum VR120-125 min, BAFT (57 ± 15 bpm, p < .05). However, the mean and maximum VR0-5 min, BAFT in the daytime were similar to the mean and maximum VR120-125 min in the daytime, respectively. At night, the minimum, mean, and maximum VR0-5 min, BAFT were similar to the minimum, mean, and maximum VR120-125 min, respectively. CONCLUSIONS: Elevated VR rates during AF episodes may be predictors for the termination of AF, especially during the daytime and in patients with nondilated left atria. These findings may guide the development of clinical approaches to rhythm control in AF.