Development and regeneration of the vagus nerve.

The vagus nerve, with its myriad constituent axon branches and innervation targets, has long been a model of anatomical complexity in the nervous system. The branched architecture of the vagus nerve is now appreciated to be highly organized around the topographic and/or molecular identities of the neurons that innervate each target tissue. However, we are only just beginning to understand the developmental mechanisms by which heterogeneous vagus neuron identity is specified, patterned, and used to guide the axons of particular neurons to particular targets. Here, we summarize our current understanding of the complex topographic and molecular organization of the vagus nerve, the developmental basis of neuron specification and patterned axon guidance that supports this organization, and the regenerative mechanisms that promote, or inhibit, the restoration of vagus nerve organization after nerve damage. Finally, we highlight key unanswered questions in these areas and discuss potential strategies to address these questions.

Vagal pathways for systemic regulation of glucose metabolism.

Maintaining blood glucose at an appropriate physiological level requires precise coordination of multiple organs and tissues. The vagus nerve bidirectionally connects the central nervous system with peripheral organs crucial to glucose mobilization, nutrient storage, and food absorption, thereby presenting a key pathway for the central control of blood glucose levels. However, the precise mechanisms by which vagal populations that target discrete tissues participate in glucoregulation are much less clear. Here we review recent advances unraveling the cellular identity, neuroanatomical organization, and functional contributions of both vagal efferents and vagal afferents in the control of systemic glucose metabolism. We focus on their involvement in relaying glucoregulatory cues from the brain to peripheral tissues, particularly the pancreatic islet, and by sensing and transmitting incoming signals from ingested food to the brain. These recent findings - largely driven by advances in viral approaches, RNA sequencing, and cell-type selective manipulations and tracings - have begun to clarify the precise vagal neuron populations involved in the central coordination of glucose levels, and raise interesting new possibilities for the treatment of glucose metabolism disorders such as diabetes.

Molecular cell types as functional units of the efferent vagus nerve.

The vagus nerve vitally connects the brain and body to coordinate digestive, cardiorespiratory, and immune functions. Its efferent neurons, which project their axons from the brainstem to the viscera, are thought to comprise "functional units" - neuron populations dedicated to the control of specific vagal reflexes or organ functions. Previous research indicates that these functional units differ from one another anatomically, neurochemically, and physiologically but have yet to define their identity in an experimentally tractable way. However, recent work with genetic technology and single-cell genomics suggests that genetically distinct subtypes of neurons may be the functional units of the efferent vagus. Here we review how these approaches are revealing the organizational principles of the efferent vagus in unprecedented detail.

Cholinergic Neurotransmission Controls Orexigenic Endocannabinoid Signaling in the Gut in Diet-Induced Obesity.

The brain bidirectionally communicates with the gut to control food intake and energy balance, which becomes dysregulated in obesity. For example, endocannabinoid (eCB) signaling in the small-intestinal (SI) epithelium is upregulated in diet-induced obese (DIO) mice and promotes overeating by a mechanism that includes inhibiting gut-brain satiation signaling. Upstream neural and molecular mechanism(s) involved in overproduction of orexigenic gut eCBs in DIO, however, are unknown. We tested the hypothesis that overactive parasympathetic signaling at the muscarinic acetylcholine receptors (mAChRs) in the SI increases biosynthesis of the eCB, 2-arachidonoyl-sn-glycerol (2-AG), which drives hyperphagia via local CB1Rs in DIO. Male mice were maintained on a high-fat/high-sucrose Western-style diet for 60 d, then administered several mAChR antagonists 30 min prior to tissue harvest or a food intake test. Levels of 2-AG and the activity of its metabolic enzymes in the SI were quantitated. DIO mice, when compared to those fed a low-fat/no-sucrose diet, displayed increased expression of cFos protein in the dorsal motor nucleus of the vagus, which suggests an increased activity of efferent cholinergic neurotransmission. These mice exhibited elevated levels of 2-AG biosynthesis in the SI, that was reduced to control levels by mAChR antagonists. Moreover, the peripherally restricted mAChR antagonist, methylhomatropine bromide, and the peripherally restricted CB1R antagonist, AM6545, reduced food intake in DIO mice for up to 24 h but had no effect in mice conditionally deficient in SI CB1Rs. These results suggest that hyperactivity at mAChRs in the periphery increases formation of 2-AG in the SI and activates local CB1Rs, which drives hyperphagia in DIO.

An adeno-associated viral labeling approach to visualize the meso- and microanatomy of mechanosensory afferents and autonomic innervation of the rat urinary bladder.

The urinary bladder is supplied by a rich network of sensory and autonomic axons, commonly visualized by immunolabeling for neural markers. This approach demonstrates overall network patterning but is less suited to understanding the structure of individual motor and sensory terminals within these complex plexuses. There is a further limitation visualizing the lightly myelinated (A-delta) class of sensory axons that provides the primary mechanosensory drive for initiation of voiding. Whereas most unmyelinated sensory axons can be revealed by immunolabeling for specific neuropeptides, to date no unique neural marker has been identified to immunohistochemically label myelinated visceral afferents. We aimed to establish a non-surgical method to visualize and map myelinated afferents in the bladder in rats. We found that in rats, the adeno-associated virus (AAV), AAV-PHP.S, which shows a high tropism for the peripheral nervous system, primarily transduced myelinated dorsal root ganglion neurons, enabling us to identify the structure and regional distribution of myelinated (mechanosensory) axon endings within the muscle and lamina propria of the bladder. We further identified the projection of myelinated afferents within the pelvic nerve and lumbosacral spinal cord. A minority of noradrenergic and cholinergic neurons in pelvic ganglia were transduced, enabling visualization and regional mapping of both autonomic and sensory axon endings within the bladder. Our study identified a sparse labeling approach for investigating myelinated sensory and autonomic axon endings within the bladder and provides new insights into the nerve-bladder interface.

T cells at the interface of neuroimmune communication.

The immune system protects the host from infection and works to heal damaged tissue after infection or injury. There is increasing evidence that the immune system and the nervous system work in concert to achieve these goals. The sensory nervous system senses injury, infection, and inflammation, which results in a direct pain signal. Direct activation of peripheral sensory nerves can drive an inflammatory response in the skin. Immune cells express receptors for numerous transmitters released from sensory and autonomic nerves, which allows the nervous system to communicate directly with the immune system. This communication is bidirectional because immune cells can also produce neurotransmitters. Both innate and adaptive immune cells respond to neuronal signaling, but T cells appear to be at the helm of neuroimmune communication.

Nitrergic inhibition of sympathetic arteriolar constrictions in the female rodent urethra.

During the urine storage phase, tonically contracting urethral musculature would have a higher energy consumption than bladder muscle that develops phasic contractions. However, ischaemic dysfunction is less prevalent in the urethra than in the bladder, suggesting that urethral vasculature has intrinsic properties ensuring an adequate blood supply. Diameter changes in rat or mouse urethral arterioles were measured using a video-tracking system. Intercellular Ca2+ dynamics in arteriolar smooth muscle (SMCs) and endothelial cells were visualised using NG2- and parvalbumin-GCaMP6 mice, respectively. Fluorescence immunohistochemistry was used to visualise the perivascular innervation. In rat urethral arterioles, sympathetic vasoconstrictions were predominantly suppressed by α,ß-methylene ATP (10 µM) but not prazosin (1 µM). Tadalafil (100 nM), a PDE5 inhibitor, diminished the vasoconstrictions in a manner reversed by N-ω-propyl-l-arginine hydrochloride (l-NPA, 1 µM), a neuronal NO synthesis (nNOS) inhibitor. Vesicular acetylcholine transporter immunoreactive perivascular nerve fibres co-expressing nNOS were intertwined with tyrosine hydroxylase immunoreactive sympathetic nerve fibres. In phenylephrine (1 µM) pre-constricted rat or mouse urethral arterioles, nerve-evoked vasodilatations or transient SMC Ca2+ reductions were largely diminished by l-nitroarginine (l-NA, 10 µM), a broad-spectrum NOS inhibitor, but not by l-NPA. The CGRP receptor antagonist BIBN-4096 (1 µM) shortened the vasodilatory responses, while atropine (1 µM) abolished the l-NA-resistant transient vasodilatory responses. Nerve-evoked endothelial Ca2+ transients were abolished by atropine plus guanethidine (10 µM), indicating its neurotransmitter origin and absence of non-adrenergic non-cholinergic endothelial NO release. In urethral arterioles, NO released from parasympathetic nerves counteracts sympathetic vasoconstrictions pre- and post-synaptically to restrict arteriolar contractility. KEY POINTS: Despite a higher energy consumption of the urethral musculature than the bladder detrusor muscle, ischaemic dysfunction of the urethra is less prevalent than that of the bladder. In the urethral arterioles, sympathetic vasoconstrictions are predominately mediated by ATP, not noradrenaline. NO released from parasympathetic nerves counteracts sympathetic vasoconstrictions by its pre-synaptic inhibition of sympathetic transmission as well as post-synaptic arteriolar smooth muscle relaxation. Acetylcholine released from parasympathetic nerves contributes to endothelium-dependent, transient vasodilatations, while CGRP released from sensory nerves prolongs NO-mediated vasodilatations. PDE5 inhibitors could be beneficial to maintain and/or improve urethral blood supply and in turn the volume and contractility of urethral musculature.

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.

Site-specific autonomic vasomotor responses and their interactions in rat gingiva.

Blood flow in the gingiva, comprising the interdental papilla as well as attached and marginal gingiva, is important for maintaining of gingival function and is modulated by risk factors such as stress that may lead to periodontal disease. Marked blood flow changes mediated by the autonomic (parasympathetic and sympathetic) nervous system may be essential for gingival hemodynamics. However, differences in autonomic vasomotor responses and their functional significance in different parts of the gingiva are unclear. We examined the differences in autonomic vasomotor responses and their interactions in the gingiva of anesthetized rats. Parasympathetic vasodilation evoked by the trigeminal (lingual nerve)-mediated reflex elicited frequency-dependent blood flow increases in gingivae, with the increases being greatest in the interdental papilla. Parasympathetic blood flow increases were significantly reduced by intravenous administration of the atropine and VIP antagonist. The blood flow increase evoked by acetylcholine administration was higher in the interdental papilla than in the attached gingiva, whereas that evoked by VIP agonist administration was greater in the attached gingiva than in the interdental papilla. Activation of the cervical sympathetic nerves decreased gingival blood flow and inhibited parasympathetically induced blood flow increases. Our results suggest that trigeminal-parasympathetic reflex vasodilation 1) is more involved in the regulation of blood flow in the interdental papilla than in the other parts of the gingiva, 2) is mediated by cholinergic (interdental papilla) and VIPergic systems (attached gingiva), and 3) is inhibited by excess sympathetic activity. These results suggest a role in the etiology of periodontal diseases during mental stress.

Increased cardiac vagal tone in childhood-only, adolescent-only, and persistently antisocial teenagers: the mediating role of low heart rate.

BACKGROUND: Cardiac vagal tone is an indicator of parasympathetic nervous system functioning, and there is increasing interest in its relation to antisocial behavior. It is unclear however whether antisocial individuals are characterized by increased or decreased vagal tone, and whether increased vagal tone is the source of the low heart rate frequently reported in antisocial populations. METHODS: Participants consisted of four groups of community-dwelling adolescent boys aged 15.7 years: (1) controls, (2) childhood-only antisocial, (3) adolescent-only antisocial, and (4) persistently antisocial. Heart rate and vagal tone were assessed in three different conditions: rest, cognitive stressor, and social stressor. RESULTS: All three antisocial groups had both lower resting heart rates and increased vagal tone compared to the low antisocial controls across all three conditions. Low heart rate partially mediated the relationship between vagal tone and antisocial behavior. CONCLUSIONS: Results indicate that increased vagal tone and reduced heart rate are relatively broad risk factors for different developmental forms of antisocial behavior. Findings are the first to implicate vagal tone as an explanatory factor in understanding heart rate - antisocial behavior relationships. Future experimental work using non-invasive vagus nerve stimulation or heart rate variability biofeedback is needed to more systematically evaluate this conclusion.

Systemic Glucose Regulation by a Hindbrain Inhibitory Circuit in a Mouse Model of Type 1 Diabetes.

INTRODUCTION: Previous work showed that increasing the electrical activity of inhibitory neurons in the dorsal vagal complex (DVC) is sufficient to increase whole-body glucose concentration in normoglycemic mice. Here we tested the hypothesis that deactivating GABAergic neurons in the dorsal hindbrain of hyperglycemic mice decreases synaptic inhibition of parasympathetic motor neurons in the dorsal motor nucleus of the vagus (DMV) and reduces systemic glucose levels. METHODS: Chemogenetic activation or inactivation of GABAergic neurons in the nucleus tractus solitarius (NTS) was used to assess effects of modulating parasympathetic output on blood glucose concentration in normoglycemic and hyperglycemic mice. Patch-clamp electrophysiology in vitro was used to assess cellular effects of chemogenetic manipulation of NTS GABA neurons. RESULTS: Chemogenetic activation of GABAergic NTS neurons in normoglycemic mice increased their action potential firing, resulting in increased inhibitory synaptic input to DMV motor neurons and elevated blood glucose concentration. Deactivation of GABAergic DVC neurons in normoglycemic mice altered their electrical activity but did not alter systemic glucose levels. Conversely, stimulation of GABAergic DVC neurons in mice that were hyperglycemic subsequent to treatment with streptozotocin changed their electrical activity but did not alter whole-body glucose concentration, while deactivation of this inhibitory circuit significantly decreased circulating glucose concentration. Peripheral administration of a brain impermeant muscarinic acetylcholine receptor antagonist abolished these effects. CONCLUSION: Disinhibiting vagal motor neurons decreases hyperglycemia in a mouse model of type 1 diabetes. This inhibitory brainstem circuit emerges as a key parasympathetic regulator of whole-body glucose homeostasis that undergoes functional plasticity in hyperglycemic conditions.

Preliminary evidence of transcutaneous vagus nerve stimulation effects on sleep in veterans with post-traumatic stress disorder.

Sleep problems are common among veterans with post-traumatic stress disorder and closely associated with hyperarousal symptoms. Transcutaneous vagus nerve stimulation (tVNS) may have potential to improve sleep quality in veterans with PTSD through effects on brain systems relevant to hyperarousal and sleep-wake regulation. The current pilot study examines the effect of 1 h of tVNS administered at "lights out" on sleep architecture, microstructure, and autonomic activity. Thirteen veterans with PTSD completed two nights of laboratory-based polysomnography during which they received 1 h of either active tVNS (tragus) or sham stimulation (earlobe) at "lights out" with randomised order. Sleep staging and stability metrics were derived from polysomnography data. Autonomic activity during sleep was assessed using the Porges-Bohrer method for calculating respiratory sinus arrhythmia (RSAP-B ). Paired t-tests revealed a small decrease in the total sleep time (d = -0.31), increase in N3 sleep (d = 0.23), and a small-to-moderate decrease in REM sleep (d = -0.48) on nights of active tVNS relative to sham stimulation. tVNS was also associated with a moderate reduction in cyclic alternating pattern (CAP) rate (d = -0.65) and small-to-moderate increase in RSAP-B during NREM sleep. Greater NREM RSAP-B was associated with a reduced CAP rate and NREM alpha power. This pilot study provides preliminary evidence that tVNS may improve sleep depth and stability in veterans with PTSD, as well as increase parasympathetically mediated nocturnal autonomic activity. These results warrant continued investigation into tVNS as a potential tool for treating sleep disturbance in veterans with PTSD.

Evidence of deviant parasympathetic response to social exclusion in women with borderline personality disorder.

Stressful social situations like social exclusion are particularly challenging for patients with borderline personality disorder (BPD) and often lead to dysfunctional reactive behaviour of aggression and withdrawal. The autonomous signature of these core symptoms of BPD remains poorly understood. The present study investigated the parasympathetic response to social exclusion in women with BPD (n = 62) and healthy controls (HC; n = 87). In a between-subjects design, participants experienced objective social exclusion or overinclusion in the Cyberball task, a virtual ball-tossing game. Need threat scores served as individual measures of perceived exclusion and the resulting frustration of cognitive-emotional needs. Five-minute measurements of high-frequency heart rate variability (HF-HRV) at three time points (before, during, after Cyberball) indicated parasympathetic tone and regulation. We observed a trend towards lowered baseline HF-HRV in BPD vs. HC in line with previous findings. Interestingly, the parasympathetic response of patients with BPD to objective and perceived social exclusion fundamentally differed from HC: higher exclusion was associated with increased parasympathetic activation in HC, while this autonomic response was reversed and blunted in BPD. Our findings suggest that during social stress, the parasympathetic nervous system fails to display an adaptive regulation in patients with BPD, but not HC. Understanding the autonomous signature of the stress response in BPD allows the formulation of clinically relevant and biologically plausible interventions to counteract parasympathetic dysregulation in this clinical group.

Vagus nerve stimulation as a therapeutic option in inflammatory rheumatic diseases.

The vagus nerve forms intricate neural connections with an extensive number of organs, particularly the digestive system. The vagus nerve has a pivotal role as a fundamental component of the autonomic nervous system, exhibiting an essential effect. It establishes a direct link with the parasympathetic system, consequently eliciting the synaptic release of acetylcholine. Recent studies have revealed the potential anti-inflammatory function of the vagus nerve. The activation of the hypothalamic system through the stimulation of vagal afferents is fundamentally involved in regulating inflammation. This activation process leads to the production of cortisol. The other mechanism, defined as the cholinergic anti-inflammatory pathway, is characterized by the involvement of vagal efferents. These fibers release the neurotransmitter acetylcholine at particular synaptic connections, involving interactions with macrophages and enteric neurons. The mechanism under consideration is ascribed to the α-7-nicotinic acetylcholine receptors. The fusion of acetylcholine receptors is responsible for the restricted secretion of inflammatory mediators by macrophages. A potential mechanism for anti-inflammatory effects involves the stimulation of the sympathetic system through the vagus nerve, leading to the control of immunological responses within the spleen. This article offers an extensive summary of the present knowledge regarding the therapeutic effectiveness of stimulating the vagus nerve in managing inflammatory rheumatic conditions based on the relationship of inflammation with the vagus nerve. Furthermore, the objective is to present alternatives that may be preferred while applying vagus nerve stimulation approaches.

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

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

Validity of Ultra-Short-Term Heart Rate Variability Derived from Femoral Arterial Pulse Waveform in a British Military Cohort.

Various non-electrocardiogram (ECG) based methods are considered reliable sources of heart rate variability (HRV) measurement. However, the ultra-short recording of a femoral arterial waveform has never been validated against the gold-standard ECG-based 300s HRV and was the aim of this study.A validity study was conducted using a sample from the first follow-up of the longitudinal ADVANCE study UK. The participants were adult servicemen (n = 100); similar in age, rank, and deployment period (Afghanistan 2003-2014). The femoral arterial waveforms (14s) from the pulse wave velocity (PWV) assessment, and ECG (300s) were recorded at rest in the supine position using the Vicorder™ and Bittium Faros™ devices, respectively, in the same session. HRV analysis was performed using Kubios Premium. Resting heart rate (HR) and root mean square of successive differences (RMSSD) were reported. The Bland-Altman %plots were constructed to explore the PWV-ECG agreement in HRV measurement. A further exploratory analysis was conducted across methods and durations.The participants' mean age was 38.0 ± 5.3 years. Both PWV-derived HR (r = 0.85) and RMSSD (rs=0.84) showed strong correlations with their 300s-ECG counterparts (p < 0.001). Mean HR was significantly higher with ECG than PWV (mean bias: -12.71 ± 7.73%, 95%CI: -14.25%, -11.18%). In contrast, the difference in RMSSD between the two methods was non-significant [mean bias: -2.90 ± 37.82% (95%CI: -10.40%, 4.60%)] indicating good agreement. An exploratory analysis of 14s ECG-vs-300s ECG measurement revealed strong agreement in both RMSSD and HR.The 14s PWV-derived RMSSD strongly agrees with the gold-standard (300s-ECG-based) RMSSD at rest. Conversely, HR appears method sensitive.

Effects of hand catalepsy on subjective trance perception and relative parasympathetic tone in healthy volunteers during pleasant hypnotic session: a randomized controlled study.

This study was designed to evaluate the effects on hand catalepsy on parasympathetic tone assessed using Analgesia/Nociception Index (ANI) and on subjective rating of absorption, dissociation, and time perception among healthy volunteers. This was a randomized controlled trial including participants to a medical hypnosis congress in France. Ninety volunteers were randomized in two arms, all receiving a fifteen-minute positive hypnotic trance, with or without hand catalepsy. The relative parasympathetic tone assessed by ANI (Analgesia/Nociception Index), heart rate and respiratory rate were recorded at different times of the study protocol. The actual duration of the hypnotic session, calculated from eye closing to eye opening, was also recorded. At the end of the hypnotic trance, participants subjectively rated their level of absorption and dissociation on a 0-10 scale. They were also asked to estimate the duration of the hypnotic session from eye closing to eye opening. In total, ninety subjects were included in the study. One subject was excluded because of deviation in the protocol standard, leaving eighty-nine subjects for analysis. Subject characteristics were similar between groups. There was a statistically different increase in ANI and decrease in both heart rate and respiratory rate over time with no difference with or without hand catalepsy. There was no statistically significant difference in absorption and dissociation subjective scales between groups. The median [Q1-Q3] actual duration of hypnotic sessions was similar between the catalepsy and the control groups (9 [8-10] min vs. 8 [7-10] min, respectively). However, subjects in the catalepsy group estimated a longer duration of the hypnotic session (12 [10-15] min) than in the control group (10 [5-10] min) with a mean ± SD overestimation of 3 ± 4 min (p < 0.001). Parasympathetic comfort increased during the hypnotic trance with no difference between groups. However, adding hand catalepsy to a pleasant hypnotic trance did not appear to increase feelings of absorption or dissociation but created time distortion on the longer side that could be useful in some clinical settings. Nevertheless, further study is still needed to determine more precisely the physiological and psychological effects on hand catalepsy during the hypnotic trance.

Does Parasympathetic Nervous System Activity Exacerbate Depressive Symptoms in College Students Who Experienced Parent-Child Separation? A Longitudinal Examination.

Childhood separation caused by parental migration increases the risk of suffering depressive symptoms among college students. However, most studies in this field have focused on environmental factors and largely ignored the role of physiological reactivity to stress (e.g., parasympathetic nervous system activity) in this process. The present study examined the long-term effects of the parent-child separation experience on depressive symptoms in college students, and explored the moderating role of parasympathetic nervous system (PNS) activity in these relationships. The participants were 242 college students (Mage = 18.74 years, SD = 0.79; 32.2% male), including 149 college students who experienced parent-child separation and 93 college students without this experience. Using a three-wave longitudinal design, participants completed the measures of the parent-child separation experience, PNS activity (measured via respiratory sinus arrhythmia, RSA), and depressive symptoms at Time 1 (T1, before the COVID-19 lockdown). Their depressive symptoms were again measured at Time 2 (T2, during the COVID-19 lockdown) and Time 3 (T3, after the COVID-19 lockdown). The results showed that the parent-child separation experience positively predicted depressive symptoms in college students at three time points. Moreover, the parent-child separation experience positively predicted depressive symptoms at T2 among males with less and average RSA suppression but positively predicted depressive symptoms at T2 among females with greater RSA suppression. These findings indicate a long-term effect of parent-child separation on depressive symptoms in college students that still exist after they entered university, and that the effect varies depending on PNS activity and gender.

Stimulation of the vagus nerve as a therapeutic principle.

Modulation of the parasympathetic tone leads to extensive physiological reactions at several levels, including the decreased production of proinflammatory cytokines. Many studies have demonstrated that chronic inflammatory diseases are associated with reduced parasympathetic and increased sympathetic activities. Moreover, it was demonstrated that a low parasympathetic and a high sympathetic activity in patients with rheumatoid arthritis (RA) predicts a poor therapeutic response to anti-tumor necrosis factor (TNF) treatment compared to RA patients with a more balanced autonomic nervous system. The autonomic equilibrium could be restored by electrical stimulation of the vagus nerve. Considering the patients who do not sufficiently respond to the available drugs, patients for whom the effectiveness of the drugs wanes over time, or have drug-related adverse events, a nonpharmacological approach such as bioelectronics might be a useful supplement as an instrument in the successful extension of the therapeutic armamentarium for rheumatic diseases; however, there is a great need for further studies and the development of novel therapeutic strategies in the field of neuroimmunology.