Biology (Basel). 2024 Apr 16;13(4):266. doi: 10.3390/biology13040266.

ABSTRACT

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.

PMID:38666878 | PMC:PMC11047897 | DOI:10.3390/biology13040266

Sci Adv. 2024 Apr 26;10(17):eadn3760. doi: 10.1126/sciadv.adn3760. Epub 2024 Apr 26.

ABSTRACT

Acetylcholine is produced in the spleen in response to vagus nerve activation; however, the effects on antibody production have been largely unexplored. Here, we use a chronic vagus nerve stimulation (VNS) mouse model to study the effect of VNS on T-dependent B cell responses. We observed lower titers of high-affinity IgG and fewer antigen-specific germinal center (GC) B cells. GC B cells from chronic VNS mice exhibited altered mRNA and protein expression suggesting increased apoptosis and impaired plasma cell differentiation. Follicular dendritic cell (FDC) cluster dispersal and altered gene expression suggested poor function. The absence of acetylcholine-producing CD4⁺ T cells diminished these alterations. In vitro studies revealed that α7 and α9 nicotinic acetylcholine receptors (nAChRs) directly regulated B cell production of TNF, a cytokine crucial to FDC clustering. α4 nAChR inhibited coligation of CD19 to the B cell receptor, presumably decreasing B cell survival. Thus, VNS-induced GC impairment can be attributed to distinct effects of nAChRs on B cells.

PMID:38669336 | PMC:PMC11051663 | DOI:10.1126/sciadv.adn3760

Brain Behav Immun. 2024 Apr 24:S0889-1591(24)00376-3. doi: 10.1016/j.bbi.2024.04.027. Online ahead of print.

ABSTRACT

BACKGROUND: The vagus nerve plays an important role in neuroimmune interactions and in the regulation of inflammation. A major source of efferent vagus nerve fibers that contribute to the regulation of inflammation is the brainstem dorsal motor nucleus of the vagus (DMN) as recently shown using optogenetics. In contrast to optogenetics, electrical neuromodulation has broad therapeutic implications. However, the anti-inflammatory effectiveness of electrical stimulation of the DMN (eDMNS) and the possible heart rate (HR) alterations associated with this approach have not been investigated. Here, we examined the effects of eDMNS on HR and cytokine levels in mice administered with lipopolysaccharide (LPS, endotoxin) and in mice subjected to cecal ligation and puncture (CLP) sepsis.

METHODS: Anesthetized male 8-10-week-old C57BL/6 mice on a stereotaxic frame were subjected to eDMNS using a concentric bipolar electrode inserted into the left or right DMN or sham stimulation. eDMNS (500, 250 or 50 μA at 30 Hz, for 1 min) was performed and HR recorded. In endotoxemia experiments, sham or eDMNS utilizing 250 μA or 50 μA was performed for 5 mins and was followed by LPS (0.5 mg/kg) i.p. administration. eDMNS was also applied in mice with cervical unilateral vagotomy or sham operation. In CLP experiments sham or left eDMNS was performed immediately post CLP. Cytokines and corticosterone were analyzed 90 mins after LPS administration or 24 h after CLP. CLP survival was monitored for 14 days.

RESULTS: Either left or right eDMNS at 500 μA and 250 μA decreased HR, compared with baseline pre-stimulation. This effect was not observed at 50 μA. Left side eDMNS at 50 μA, compared with sham stimulation, significantly decreased serum and splenic levels of the pro-inflammatory cytokine TNF and increased serum levels of the anti-inflammatory cytokine IL-10 during endotoxemia. The anti-inflammatory effect of eDMNS was abrogated in mice with unilateral vagotomy and was not associated with serum corticosterone alterations. Right side eDMNS in endotoxemic mice suppressed serum TNF and increased serum IL-10 levels but had no effects on splenic cytokines. In mice with CLP, left side eDMNS suppressed serum IL-6, as well as splenic IL-6 and increased splenic IL-10 and significantly improved the survival rate of CLP mice.

CONCLUSIONS: For the first time we show that a regimen of eDMNS which does not cause bradycardia alleviates LPS-induced inflammation. These eDMNS anti-inflammatory effects require an intact vagus nerve and are not associated with corticosteroid alterations. eDMNS also decreases inflammation and improves survival in a model of polymicrobial sepsis. These findings are of interest for further studies exploring bioelectronic anti-inflammatory approaches targeting the brainstem DMN.

PMID:38670240 | DOI:10.1016/j.bbi.2024.04.027

Cureus. 2024 Apr 25;16(4):e59009. doi: 10.7759/cureus.59009. eCollection 2024 Apr.

ABSTRACT

Inflammatory bowel disease (IBD) refers to two chronic conditions of the digestive tract: ulcerative colitis (UC) and Crohn’s disease (CD), representing a progressive inflammatory process that mainly occurs in the gut, with frequent extra-intestinal manifestations. Even if remission is periodically obtained for some patients, the histological activity and digestive symptoms may continue, maintaining a persistent systemic inflammation that could induce further extra-intestinal complications and contribute to the development of neurodegenerative disease. C-reactive protein (CRP) is an acute-phase reactant that is widely accepted as a dominant serum biomarker in IBD. CRP consequently activates the complement cascade, supports the release of pro-inflammatory cytokines, and the clearance of microbial pathogens. All these processes facilitate further processes, including atherosclerosis and hypercoagulability, alteration of the intestinal microbiota, and the increased permeability of the intestinal barrier for neurotoxic substances produced by gut microorganisms, due to the presence of a high level of lipopolysaccharides. For IBD, the connection between intestinal inflammation and central nervous system inflammation could be explained through the activity of the vagus nerve, a carrier of cytokines, CRP, and toxic materials to the brain, potentially inducing vascular lesions and damage of the glial vascular unit, with further risk for degeneration within the central nervous system. CRP is a key marker for IBD pathogenesis and is able to dissociate into its monomeric form, mCRP, on contact with activated cell and tissue components via the systemic circulation. We hypothesize that the chronic inflammatory process within IBD could initiate neuroinflammation and neurodegeneration, and therefore, further investigation of the significance of chronically raised plasma of CRP and mCRP in patients with IBD is warranted, as it may represent a critical predictive factor associated with a later neurodegenerative risk. Any future initiative aimed at pharmacologic modulation of CRP (e.g., blocking CRP-mCRP dissociation), could represent a new therapeutic approach protecting against intestinal inflammation and concomitantly reducing the risk of neuroinflammation, neurodegeneration, and cognitive decline.

PMID:38665135 | PMC:PMC11045161 | DOI:10.7759/cureus.59009

JAAPA. 2024 May 1;37(5):1-7. doi: 10.1097/01.JAA.0000000000000014. Epub 2024 Apr 25.

ABSTRACT

Migraine headache is a common and potentially debilitating disorder often treated by physician associates/assistants (PAs) and other providers. With the recent advances in new drugs and device technology for the treatment of migraine, the American Headache Society has released a consensus statement on both preventive and acute strategies for clinical practice. The US FDA has recently approved various types of medications and devices for the treatment and prevention of migraine attacks including several calcitonin gene-related peptide (CGRP) receptor inhibitors, a selective serotonin receptor agonist (SSRA), noninvasive vagus nerve stimulation (nVNS), external trigeminal nerve stimulation (e-TNS), and external concurrent occipital and trigeminal neurostimulation (eCOT-NS), among other pharmacologic and nonpharmacologic options. This article provides a review of migraine prevention and acute treatment protocol, highlighting new approaches to both.

PMID:38662902 | DOI:10.1097/01.JAA.0000000000000014

Brain Behav Immun. 2024 Apr 23:S0889-1591(24)00382-9. doi: 10.1016/j.bbi.2024.04.034. Online ahead of print.

ABSTRACT

The vagus nerve, a pivotal link within the gut-brain axis, plays a critical role in maintaining homeostasis and mediating communication between the gastrointestinal tract and the brain. It has been reported that gastrointestinal infection by Salmonella typhimurium (S. typhimurium) triggers gut inflammation and manifests as anxiety-like behaviors, yet the mechanistic involvement of the vagus nerve remains to be elucidated. In this study, we demonstrated that unilateral cervical vagotomy markedly attenuated anxiety-like behaviors induced by S. typhimurium SL1344 infection in C57BL/6 mice, as evidenced by the open field test and marble burying experiment. Furthermore, vagotomy significantly diminished neuronal activation within the nucleus of the solitary tract and amygdala, alongside mitigating aberrant glial cell activation in the hippocampus and amygdala. Additionally, vagotomy notably decreases serum endotoxin levels, counters the increase in splenic Salmonella concentration, and modulates the expression of inflammatory cytokines-including IL-6, IL-1β, and TNF-α-in both the gastrointestinal tract and brain, with a concurrent reduction in IL-22 and CXCL1 expression. This intervention also fostered the enrichment of beneficial gut microbiota, including Alistipes and Lactobacillus species, and augmented the production of gamma-aminobutyric acid (GABA) in the gut. Administration of GABA replicated the vagotomy’s beneficial effects on reducing gut inflammation and anxiety-like behavior in infected mice. However, blockade of GABA receptors with picrotoxin abrogated the vagotomy’s protective effects against gut inflammation, without influencing its impact on anxiety-like behaviors. Collectively, these findings suggest that vagotomy exerts a protective effect against infection by promoting GABA synthesis in the colon and alleviating anxiety-like behavior. This study underscores the critical role of the vagus nerve in relaying signals of gut infection to the brain and posits that targeting the gut-brain axis may offer a novel and efficacious approach to preventing gastrointestinal infections and associated behavioral abnormalities.

PMID:38663772 | DOI:10.1016/j.bbi.2024.04.034

Seizure. 2024 Feb 19;117:298-304. doi: 10.1016/j.seizure.2024.02.011. Online ahead of print.

ABSTRACT

BACKGROUND: Right-sided vagus nerve stimulation (RS-VNS) is indicated when the procedure was deemed not technically feasible or too risky on the indicated left side.

OBJECTIVE: The present study aims to systematically review the literature on RS-VNS, assessing its effectiveness and safety.

METHODS: A systematic review following PRISMA guidelines was conducted: Pubmed/MEDLINE, The Cochrane Library, Scopus, Embase and Web of science databases were searched from inception to August 13th,2023. Gray literature was searched in two libraries. Eligible studies included all studies reporting, at least, one single case of RS-VNS in patients for the treatment of drug-resistant epilepsy.

RESULTS: Out of 2333 initial results, 415 studies were screened by abstract. Only four were included in the final analysis comprising seven patients with RS-VNS for a drug-resistant epilepsy. One patient experienced nocturnal asymptomatic bradycardia whereas the other six patients did not display any cardiac symptom. RS-VNS was discontinued in one case due to exercise-induced airway disease exacerbation. Decrease of epileptic seizure frequency after RS-VNS ranged from 25 % to 100 % in six cases. In the remaining case, VNS effectiveness was unclear. In one case, RS-VNS was more efficient than left-sided VNS (69 % vs 50 %, respectively) whereas in another case, RS-VNS was less efficient (50 % vs 95 %, respectively).

CONCLUSION: Literature on the present topic is limited. In six out of seven patients, RS-VNS for drug-resistant epilepsy displayed reasonable effectiveness with a low complication rate. Further research, including prospective studies, is necessary to assess safety and effectiveness of RS-VNS for drug-resistant epilepsy patients.

PMID:38615369 | DOI:10.1016/j.seizure.2024.02.011

J Transl Gastroenterol. 2023 Oct-Dec;1(2):94-100. doi: 10.14218/jtg.2023.00098. Epub 2023 Dec 25.

ABSTRACT

BACKGROUND AND OBJECTIVES: In this systematic review, we assessed the efficacy, potential mechanisms, and safety of two neuromodulation therapies in patients with inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis. The first therapy is vagus nerve stimulation (VNS) utilizing implantable or transcutaneous electrodes, and the second is sacral nerve stimulation (SNS) using implantable or percutaneous electrodes.

METHODS: We conducted a systematic literature review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The PubMed database was comprehensively searched, and studies were rigorously assessed for inclusion and exclusion criteria.

RESULTS: Our analysis encompassed five clinical studies, three on VNS and two on SNS. Most investigated studies demonstrated significant beneficial effects on IBD symptoms, including disease activity, severity of intestinal lesions, and intestinal pain. When evaluating the impact on key IBD pathophysiologies, both VNS and SNS exhibited trends toward reducing biomarkers of intestinal mucosal inflammation and mitigating sympathetic dominance. Importantly, none of the evaluated neuromodulation methods resulted in long-term adverse effects.

CONCLUSIONS: Cumulative evidence from the evaluated studies indicates that VNS and SNS therapies effectively alleviate IBD symptoms and may hold promise in addressing the underlying pathophysiologies of IBD, including intestinal mucosal inflammation and sympathetic dominance. Consequently, they represent valuable options for individualized IBD treatment.

PMID:38606364 | PMC:PMC11007757 | DOI:10.14218/jtg.2023.00098

Biochem Pharmacol. 2024 Apr 10:116201. doi: 10.1016/j.bcp.2024.116201. Online ahead of print.

ABSTRACT

Intestinal barrier dysfunction, leaky gut, is implicated in various diseases, including irritable bowel syndrome (IBS) and neurodegenerative conditions like Alzheimer’s disease. Our recent investigation revealed that basal forebrain cholinergic neurons (BFCNs), critical for cognitive function, receive signals from butyrate and orexin, playing a role in regulating intestinal barrier function through adenosine A2B signaling and the vagus. This study explores the involvement and function of brain histamine, linked to BFCNs, in the regulation of intestinal barrier function. Colonic permeability, assessed by quantifying absorbed Evans blue in rat colonic tissue, showed that histamine did not affect increased colonic permeability induced by LPS when administered subcutaneously. However, intracisternal histamine administration improved colonic hyperpermeability. Elevating endogenous histamine levels in the brain with SKF91488, a histamine N-methyltransferase inhibitor, also improved colonic hyperpermeability. This effect was abolished by intracisternal chlorpheniramine, an histamine H1 receptor antagonist, not ranitidine, an H2 receptor antagonist. The SKF91488-induced improvement in colonic hyperpermeability was blocked by vagotomy, intracisternal pirenzepine (suppressing BFCNs activity), or alloxazine (an adenosine A2B receptor antagonist). Additionally, intracisternal chlorpheniramine injection eliminated butyrate-induced improvement in colonic hyperpermeability. These findings suggest that brain histamine, acting via the histamine H1 receptor, regulates intestinal barrier function involving BFCNs, adenosine A2B signaling, and the vagus. Brain histamine appears to centrally regulate intestinal barrier function influenced by butyrate, differentiating its actions from peripheral histamine in conditions like IBS, where mast cell-derived histamine induces leaky gut. Brain histamine emerges as a potential pharmacological target for diseases associated with leaky gut, such as dementia and IBS.

PMID:38608783 | DOI:10.1016/j.bcp.2024.116201

Front Cardiovasc Med. 2024 Mar 27;11:1384637. doi: 10.3389/fcvm.2024.1384637. eCollection 2024.

ABSTRACT

The non-neuronal cholinergic system of the cardiovascular system has recently gained attention because of its origin. The final product of this system is acetylcholine (ACh) not derived from the parasympathetic nervous system but from cardiomyocytes, endothelial cells, and immune cells. Accordingly, it is defined as an ACh synthesis system by non-neuronal cells. This system plays a dispensable role in the heart and cardiomyocytes, which is confirmed by pharmacological and genetic studies using murine models, such as models with the deletion of vesicular ACh transporter gene and modulation of the choline acetyltransferase (ChAT) gene. In these models, this system sustained the physiological function of the heart, prevented the development of cardiac hypertrophy, and negatively regulated the cardiac metabolism and reactive oxygen species production, resulting in sustained cardiac homeostasis. Further, it regulated extra-cardiac organs, as revealed by heart-specific ChAT transgenic (hChAT tg) mice. They showed enhanced functions of the blood-brain barrier (BBB), indicating that the augmented system influences the BBB through the vagus nerve. Therefore, the non-neuronal cardiac cholinergic system indirectly influences brain function. This mini-review summarizes the critical cardiac phenotypes of hChAT tg mice and focuses on the effect of the system on BBB functions. We discuss the possibility that a cholinergic signal or vagus nerve influences the expression of BBB component proteins to consolidate the barrier, leading to the downregulation of inflammatory responses in the brain, and the modulation of cardiac dysfunction-related effects on the brain. This also discusses the possible interventions using the non-neuronal cardiac cholinergic system.

PMID:38601043 | PMC:PMC11004362 | DOI:10.3389/fcvm.2024.1384637