[18F]FEOBV positron emission tomography may not be a suitable method to measure parasympathetic denervation in patients with Parkinson's disease.

INTRODUCTION: The peripheral autonomic nervous system may be involved years before onset of motor symptoms in some patients with Parkinson's disease (PD). Specific imaging techniques to quantify the cholinergic nervous system in peripheral organs are an unmet need. We tested the hypothesis that patients with PD display decreased [18F]FEOBV uptake in peripheral organs - a sign of parasympathetic denervation. METHODS: We included 15 PD patients and 15 age- and sex matched healthy controls for a 70 min whole-body dynamic positron emission tomography (PET) acquisition. Compartmental modelling was used for tracer kinetic analyses of adrenal gland, pancreas, myocardium, spleen, renal cortex, muscle and colon. Standard uptake values (SUV) at 60-70 min post injection were also extracted for these organs. Additionally, SUVs were also determined in the total colon, prostate, parotid and submandibular glands. RESULTS: We found no statistically significant difference of [18F]FEOBV binding parameters in any organs between patients with PD and healthy controls, although trends were observed. The pancreas SUV showed a 14% reduction in patients (P = 0.021, not statistically significant after multiple comparison correction). We observed a trend towards lower SUVs in the pancreas, colon, adrenal gland, and myocardium of PD patients with versus without probable REM sleep behavior disorder. CONCLUSION: [18F]FEOBV PET may not be a sensitive marker for parasympathetic degeneration in patients with PD.

Unilateral Dry Eye Due to Possible Isolated Parasympathetic Denervation of the Lacrimal Gland in a Woman With Hypothyroidism.

PURPOSE: The aim of this study was to report a unique case of unilateral neurogenic dry eye disease (DED) secondary to isolated parasympathetic denervation of the lacrimal gland along with a literature review. METHOD: This is a case report and literature review on neurogenic DED discussing its clinical presentation, etiology, and treatment options. RESULTS: A 32-year-old woman with hypothyroidism presented with pain and a burning sensation in her left eye and dry nares for 1 week. Ocular examination revealed conjunctival congestion and inferior superficial punctate fluorescein staining in the left eye. Her unanesthetized Schirmer values were 24 and 01 mm in the right and left eyes, respectively, with no secretory activity noted in the left lacrimal gland on direct assessment. A detailed neurologic examination, autoimmune panel, and neuroimaging were unremarkable except for the dry left nasal cavity. She is currently using lubricants and did not consent to pilocarpine therapy. Her lacrimal gland activity was unchanged till 3 months of follow-up. The most common cause of neurogenic DED is idiopathic, followed by trauma. Pilocarpine therapy, in oral, topical, or combined form, has improved tear secretion in 63% of neurogenic DED seen in animal cohort. CONCLUSIONS: Unilateral neurogenic DED can occur as an isolated parasympathetic denervation of the lacrimal glands. Pilocarpine therapy has shown some efficacy in animal cohort of neurogenic DED; however, it needs to be explored for human eyes.

New insights in diagnostics and therapies in syncope: a novel approach to non-cardiac syncope.

This article aims to give advice on how to identify and manage patients with syncope who are at risk of severe outcomes, that is, at risk of trauma, potentially life-threatening episodes or frequent recurrences reducing quality of life. The first step of syncope diagnostic assessment is to identify patients with cardiac syncope, and once established, these patients must receive the adequate mechanism-specific treatment. If cardiac syncope is unlikely, reflex (neurally mediated) syncope and orthostatic hypotension are the most frequent causes of transient loss of consciousness. For these presentations, efficacy of therapy is largely determined by the mechanism of syncope rather than its aetiology or clinical features. The identified mechanism of syncope should be carefully assessed and assigned either to hypotensive or bradycardic phenotype, which will determine the choice of therapy (counteracting hypotension or counteracting bradycardia). The results of recent trials indicate that 'mechanism-specific therapy' is highly effective in preventing recurrences. Established mechanism-specific treatment strategies include withdrawal of hypotensive drugs, applying fludrocortisone and midodrine for the hypotensive phenotype and cardiac pacing in the bradycardic phenotype.

The role of autonomic pathways in peripheral apelin-induced gastrointestinal dysmotility: involvement of the circumventricular organs.

NEW FINDINGS: What is the central question of this study? Are central autonomic pathways and circumventricular organs involved in apelin-induced inhibition of gut motility? What is the main finding and its importance? Peripherally administered apelin-13 inhibits gastric and colonic motor functions through sympathetic and parasympathetic autonomic pathways, which seems to be partly mediated by the apelin receptor in circumventricular organs. ABSTRACT: Peripheral administration of apelin-13 has been shown to inhibit gastrointestinal (GI) motility, but the relevant mechanisms are incompletely understood. This study aimed to investigate (i) whether the apelin receptor (APJ) is expressed in circumventricular structures involved in autonomic functions, (ii) whether they are activated by peripherally administered apelin, (iii) the role of autonomic pathways in peripheral exogenous apelin-induced GI dysmotility, and (iv) the changes in apelin levels in the extracellular environment of the brain following its peripheral application. Ninety minutes after apelin-13 administration (300 µg kg-1 , i.p.), gastric emptying (GE) and colon transit (CT) were measured in rats that underwent parasympathectomy and/or sympathectomy. Plasma and cerebrospinal fluid (CSF) samples were also collected from another group of rats that received apelin-13 or vehicle injection. The immunoreactivities for APJ and c-Fos in circumventricular organs (CVOs) were evaluated by immunohistochemistry. Compared with vehicle-treated rats, GE and CT were inhibited significantly by apelin-13 treatment, and were completely restored in animals that underwent the combination of parasympathectomy and sympathectomy and sympathectomy alone, respectively. Apelin concentrations were elevated in both plasma and CSF following peripheral administration of apelin-13. APJ expression was detected in area postrema (AP), subfornical organ and organum vasculosum of lamina terminalis, and c-Fos expression was observed in response to apelin injection. Apelin-induced c-Fos expression in AP was partially attenuated by pretreatment with the cholecystokinin-1 receptor antagonist lorglumide, whereas it was completely abolished in vagotomized rats. The present data suggest that APJ in CVOs could indirectly contribute to the inhibitory action of peripheral apelin on GI motor functions.

Deep Dive into Denervation: Institutional Experience with Selective Denervation in Nonflaccid Facial Palsy.

Background: Selective denervation of facial nerve branches ("Modified Selective Neurectomy") improves smile dynamics in patients with nonflaccid facial palsy, but functional morbidity such as oral incompetence has been reported. A comprehensive outcomes assessment of selective denervation will help clinicians educate patients regarding risks and benefits, and improve decision making as they incorporate this procedure into treatment algorithms. Methods: Retrospective review identified selective denervation cases performed by the senior author between February 2019 and February 2020. Pre- and postoperative outcomes were assessed using chart review, the facial clinimetric evaluation (FaCE), the electronic clinician-graded facial function tool (eFACE), and an automated computer-aided facial assessment tool (Emotrics). Results: Twenty consecutive selective denervation procedures were performed in 19 patients. Review of patient-reported outcome measures demonstrated mixed results. Favorably, patients reported smile improvement (13/17, 76.5%) and improvements in facial tightness/discomfort (8/17, 47.1%). Seven patients (41.2%) had worse drooling and five patients (29.4%) had increased difficulty chewing after surgery. Clinician-graded evaluation revealed statistically significant improvements in nasolabial fold depth at rest, oral commissure (OC) position at rest, and OC movement with smile. Total, static, and dynamic eFACE scores all demonstrated significant improvements. Computer-aided facial assessment revealed a significant increase in dental display, and an increase in OC excursion that trended toward significance. Conclusions: Selective denervation improves patient-reported, clinician-graded, and automated smile metrics, but some patients experience exacerbations in oral incompetence and articulation difficulties, and must be counseled regarding these possibilities.

Safety and Dose Study of Targeted Lung Denervation in Moderate/Severe COPD Patients.

RATIONALE: Targeted lung denervation (TLD) is a novel bronchoscopic treatment for the disruption of parasympathetic innervation of the lungs. OBJECTIVES: To assess safety, feasibility, and dosing of TLD in patients with moderate to severe COPD using a novel device design. METHODS: Thirty patients with COPD (forced expiratory volume in 1 s 30-60%) were 1:1 randomized in a double-blinded fashion to receive TLD with either 29 or 32 W. Primary endpoint was the rate of TLD-associated adverse airway effects that required treatment through 3 months. Assessments of lung function, quality of life, dyspnea, and exercise capacity were performed at baseline and 1-year follow-up. An additional 16 patients were enrolled in an open-label confirmation phase study to confirm safety improvements after procedural enhancements following gastrointestinal adverse events during the randomized part of the trial. RESULTS: Procedural success, defined as device success without an in-hospital serious adverse event, was 96.7% (29/30). The rate of TLD-associated adverse airway effects requiring intervention was 3/15 in the 32 W versus 1/15 in the 29 W group, p = 0.6. Five patients early in the randomized phase experienced serious gastric events. The study was stopped and procedural changes made that reduced both gastrointestinal and airway events in the subsequent phase of the randomized trial and follow-up confirmation study. Improvements in lung function and quality of life were observed compared to baseline values for both doses but were not statistically different. CONCLUSIONS: The results demonstrate acceptable safety and feasibility of TLD in patients with COPD, with improvements in adverse event rates after procedural enhancements.

Parasympathectomy increases resting secretion of the submandibular gland in minipigs in the long term.

Parasympathectomy leads to retrogressive alteration and dysfunction of the submandibular gland (SMG) within 1 month, but its long-term effect is unclear. Excessive secretion is observed in half of the patients 4-6 months after SMG transplantation, which completely denervates the gland. Here, we investigated the long-term effect of parasympathectomy on the secretion of SMGs in minipigs. The results showed that the resting salivary secretion of SMGs decreased by 82.9% of that in control at 2 months after denervation, but increased by 156% at 6 months. Although experiencing an atrophic period, the denervated glands regained their normal morphology by 6 months. The expression of the function-related proteins, including muscarinic acetylcholine receptor (mAChR) 3, aquaporin 5 (AQP5), tight junction protein claudin-3, and claudin-4 was decreased at 2 months after denervation. Meanwhile, the protein expression of stem cell markers, including sex-determining region Y-box 2 and octamer-binding transcription factor 4, and the number of Ki67+ cells were significantly increased. However, at 6 months after denervation, the expression of mAChR3, AQP5, claudin-1, claudin-3, and claudin-4 was significantly raised, and the membrane distribution of these proteins was increased accordingly. The autonomic axonal area of the glands was reduced at 2 months after denervation but returned to the control level at 6 months, suggesting that reinnervation took place in the long term. In summary, parasympathectomy increases resting secretion of the SMGs in the long term with a possible mechanism involving improved transepithelial fluid transport. This finding may provide a new strategy for xerostomia treatment.

Preganglionic Parasympathetic Denervation Rabbit Model for Innervation Studies.

PURPOSE: Tear secretion from the main lacrimal gland (LG) is mainly regulated by parasympathetic nerves. We performed several innervation studies to investigate lacrimation. METHODS: In male rabbits, we performed a retrograde dye-tracing study of LG innervation, evaluated preganglionic parasympathetic denervation, and administered glial cell-derived neurotrophic factor (GDNF) in the surgical area after parasympathetic denervation. RESULTS: Accumulation of fluorescent dye was observed in the pterygopalatine ganglion cells on the same side as the dye injection into the main LG. Fewer stained cells were observed in the cervical and trigeminal ganglia. After parasympathetic denervation surgery, tear secretion was decreased, and fluorescein and rose bengal staining scores were increased at day 1 after surgery and remained increased for 3 months on the denervated side only. Most of the effects in rabbits with parasympathetic denervation were not recovered by administration of GDNF. CONCLUSIONS: The main LG is primarily innervated by parasympathetic nerves to stimulate tear secretion. After preganglionic parasympathetic denervation, lacrimation was decreased, resulting in dry eyes, and this was maintained for at least 3 months. Administration of GDNF only minimally altered the effects of denervation.

Long-term safety of bilateral targeted lung denervation in patients with COPD.

Background: Targeted lung denervation (TLD) is a novel bronchoscopic therapy for COPD which ablates parasympathetic pulmonary nerves running along the outside of the two main bronchi with the intent of inducing permanent bronchodilation. The goal of this study was to evaluate the feasibility and long-term safety of bilateral TLD during a single procedure. Patients and methods: This prospective, multicenter study evaluated 15 patients with moderate-to-severe COPD (forced expiratory volume in 1 s [FEV1] 30%-60%) who underwent bilateral TLD treatment following baseline assessment without bronchodilators. The primary safety end point was freedom from documented and sustained worsening of COPD directly attributable to TLD up to 1 year. Secondary end points included technical feasibility, change in pulmonary function tests, exercise capacity, and health-related quality of life. Follow-up continued up to 3 years for subjects who reconsented for longer-term follow-up. Results: A total of 15 patients (47% male, age 63.2±4.0 years) underwent TLD with a total procedure time of 89±16 min, and the total fluoroscopy time was 2.5±2.7 min. Primary safety end point of freedom from worsening of COPD was 100%. There were no procedural complications reported. Results of lung function analysis and exercise capacity demonstrated similar beneficial effects of TLD without bronchodilators, when compared with long-acting anticholinergic therapy at 30 days, 180 days, 365 days, 2 years, and 3 years post-TLD. Five of the 12 serious adverse events that were reported through 3 years of follow-up were respiratory related with no events being related to TLD therapy. Conclusion: TLD delivered to both lungs in a single procedure is feasible and safe with few respiratory-related adverse events through 3 years.

Catheter Ablation of Bradyarrhythmia: From the Beginning to the Future.

Enhanced parasympathetic tone may cause sinus bradycardia or pauses, transient or permanent atrioventricular block, with resultant vasovagal syncope. A substantial portion of these patients may be highly symptomatic and refractory to the conventional therapies and may require cardiac pacemaker implantation. Cardioneuroablation is a little known technique for management of patients with excessive vagal activation based on radiofrequency catheter ablation of main parasympathetic autonomic ganglia around the heart. Due to complicated inclusion criteria, ganglia detection methods, and ablation endpoints, routine usage of the procedure cannot be recommended at this time. In this comprehensive review, we aimed to discuss all aspects of cardioneuroablation procedure in bradyarrhythmias.

Long-term effect of parasympathetic or sympathetic denervation on intestinal epithelial cell proliferation and apoptosis.

Intestinal epithelial tissue is constantly regenerated as a means to maintain proper tissue function. Previous studies have demonstrated that denervation of the parasympathetic or sympathetic nervous system to the intestine alters this process. However, results are inconsistent between studies, showing both increases and decreases in proliferation after denervation of the parasympathetic or sympathetic. The effect appears to correlate with (1) the timing post-denervation, (2) denervation-induced changes in food intake, (3) the denervation technique used, and (4) which intestinal segment is investigated. Thus, we proposed that parasympathetic or sympathetic denervation does not have an effect on intestinal epithelial regeneration when you (1) evaluate denervation after long-term denervation, (2) control for post-surgical changes in food intake, (3) use minimally invasive surgical techniques and (4) include a segmental analysis. To test this, adult male Sprague Dawley rats underwent parasympathetic denervation via subdiaphragmatic vagotomy, sympathetic denervation via celiacomesenteric ganglionectomy, a parasympathetic denervation sham surgery, or a sympathetic denervation sham surgery. Sham surgery ad libitum-fed groups and sham surgery pair-fed groups were used to control for surgically induced changes in food intake. Three weeks post-surgery, animals were sacrificed and tissue from the duodenum, jejunum, and ileum was excised and immunohistochemically processed to visualize indicators of proliferation (bromodeoxyuridine-positive cells) and apoptosis (caspase-3-positive cells). Results showed no differences between groups in proliferation, apoptosis, or total cell number in any intestinal segment. These results suggest that parasympathetic or sympathetic denervation does not have a significant long-term effect on intestinal epithelial turnover. Thus, intestinal epithelial regeneration is able to recover after autonomic nervous system injury. Impact statement This study investigates the long-term effect of autonomic denervation on intestinal epithelial cell turnover, as measured by proliferation, apoptosis, and total cell number. Although previous research has established that autonomic denervation can alter intestinal epithelial turnover under short-term conditions, here we establish for the first time that these changes do not persist long-term when you control for surgical-induced changes in food intake and use targeted denervation procedures. These findings add to the base of knowledge on autonomic control of tissue turnover, highlight the ability of the intestinal epithelium to recover after autonomic injury and reveal possible implications of the use of ANS denervation for disease treatment in humans.

Parasympathectomy increases resting salivary secretion in normal and irradiated submandibular glands of rats.

Fluid and ion secretion from the submandibular gland (SMG) is mainly regulated by parasympathetic nerves. This study evaluated the effect of parasympathectomy on salivary secretion from normal and irradiated rat SMGs from 1 to 24 wk after denervation. Although stimulated salivary secretion was significantly lower in denervated SMGs compared with contralateral self-controls, the resting salivary flow rates were markedly higher in the denervated SMGs at 1, 12, and 24 wk after denervation. The levels of muscarinic acetylcholine M1 and M3 receptors, as well as of aquaporin 5, were up-regulated. Notably, although irradiated SMGs showed significantly lower resting and stimulated salivary secretion rates than non-irradiated SMGs, the resting salivary secretion rates of the irradiated and denervated SMGs were markedly higher than seen in the irradiated self-control SMGs at 1, 12, and 24 wk after parasympathectomy, and were even higher than seen in the non-irradiated sham-operated rats. The expression of M1 and M3 receptors was similarly elevated. Taken together, our results suggest that parasympathetic denervation increases resting salivary secretion of both normal and irradiated SMGs. This approach might provide a potential modality for relieving radiation-induced xerostomia, which is a common complication following treatment of head and neck cancer.

Atrioventricular Node Slow-Pathway Ablation Reduces Atrial Fibrillation Inducibility: A Neuronal Mechanism.

BACKGROUND: Radiofrequency ablation (RFA) for atrioventricular nodal reentrant tachycardia appears to reduce atrial tachycardia, which might relate to parasympathetic denervation at cardiac ganglionated plexuses. METHODS AND RESULTS: Compared to 7 control canines without RFA, in 14 canines, RFA at the bottom of Koch's triangle attenuated vagal stimulation-induced effective refractory periods prolongation in atrioventricular nodal and discontinuous atrioventricular conduction curves but had no effect on the sinoatrial node. RFA attenuated vagal stimulation-induced atrial effective refractory periods shortening and vulnerability window of atrial fibrillation widening in the inferior right atrium and proximal coronary sinus but not in the high right atrium and distal coronary sinus. Moreover, RFA anatomically impaired the epicardial ganglionated plexuses at the inferior vena cava‒inferior left atrial junction. This method was also investigated in 42 patients who had undergone ablation of atrioventricular nodal reentrant tachycardia, or 12 with an accessory pathway (AP) at the posterior septum (AP-PS), and 34 patients who had an AP at the free wall as control. In patients with atrioventricular nodal reentrant tachycardia and AP-PS, RFA at the bottom of Koch's triangle prolonged atrial effective refractory periods and reduced vulnerability windows of atrial fibrillation widening at the inferior right atrium, distal coronary sinus and proximal coronary sinus but not the high right atrium. In patients with AP-free wall, RFA had no significant atrial effects. CONCLUSIONS: RFA at the bottom of Koch's triangle attenuated local autonomic innervation in the atrioventricular node and atria, decreased vagal stimulation-induced discontinuous atrioventricular nodal conduction, and reduced atrial fibrillation inducibility due to impaired ganglionated plexuses. In patients with atrioventricular nodal reentrant tachycardia or AP-PS, RFA prolonged atrial effective refractory periods, and narrowed vulnerability windows of atrial fibrillation.

The morphological substrate for Renal Denervation: Nerve distribution patterns and parasympathetic nerves. A post-mortem histological study.

BACKGROUND: Renal Denervation as a possible treatment for hypertension has been studied extensively, but knowledge on the distribution of nerves surrounding the renal artery is still incomplete. While sympathetic and sensory nerves have been demonstrated, there is no mention of the presence of parasympathetic nerve fibers. OBJECTIVES: To provide a description of the distribution patterns of the renal nerves in man, and, in addition, provide a detailed representation of the relative contribution of the sympathetic, parasympathetic and afferent divisions of the autonomic nervous system. METHODS: Renal arteries of human cadavers were each divided into four longitudinal segments and immunohistochemically stained with specific markers for afferent, parasympathetic and sympathetic nerves. Nerve fibers were semi-automatically quantified by computerized image analysis, and expressed as cross-sectional area relative to the distance to the lumen. RESULTS: A total of 3372 nerve segments were identified in 8 arteries of 7 cadavers. Sympathetic, parasympathetic and afferent nerves contributed for 73.5% (95% CI: 65.4-81.5%), 17.9% (10.7-25.1%) and 8.7% (5.0-12.3%) of the total cross-sectional nerve area, respectively. Nerves are closer to the lumen in more distal segments and larger bundles that presumably innervate the kidney lie at 1-3.5mm distance from the lumen. The tissue-penetration depth of the ablation required to destroy 50% of the nerve fibers is 2.37 mm in the proximal segment and 1.78 mm in the most distal segments. CONCLUSION: Sympathetic, parasympathetic and afferent nerves exist in the vicinity of the renal artery. The results warrant further investigation of the role of the parasympathetic nervous system on renal physiology, and may contribute to refinement of the procedure by focusing the ablation on the most distal segment.