Langenbecks Arch Surg. 2024 Apr 27;409(1):138. doi: 10.1007/s00423-024-03323-x.

ABSTRACT

PURPOSE: Treating an infiltration of the recurrent laryngeal nerve (RLN) by thyroid carcinoma remains a subject of ongoing debate. Therefore, this study aims to provide a novel strategy for intraoperative phenosurgical management of RLN infiltrated by thyroid carcinoma.

METHODS: Forty-two patients with thyroid carcinoma infiltrating the RLN were recruited for this study and divided into three groups. Group A comprised six individuals with medullary thyroid cancer who underwent RLN resection and arytenoid adduction. Group B consisted of 29 differentiated thyroid cancer (DTC)patients who underwent RLN resection and ansa cervicalis (ACN)-to-RLN anastomosis. Group C included seven patients whose RLN was preserved.

RESULTS: The videostroboscopic analysis and voice assessment collectively indicated substantial improvements in voice quality for patients in Groups A and B one year post-surgery. Additionally, the shaving technique maintained a normal or near-normal voice in Group C one year post-surgery.

CONCLUSION: The new intraoperative phonosurgical strategy is as follows: Resection of the affected RLN and arytenoid adduction is required in cases of medullary or anaplastic carcinoma, regardless of preoperative RLN function. Suppose RLN is found infiltrated by well-differentiated thyroid cancer (WDTC) during surgery, and the RLN is preoperatively paralyzed, we recommend performing resection the involved RLN and ACN-to-RLN anastomosis immediately during surgery. If vocal folds exhibit normal mobility preoperatively, the MACIS scoring system is used to assess patient risk stratification. When the MACIS score > 6.99, resection of the involved RLN and immediate ACN-to-RLN anastomosis were performed. RLN preservation was limited to patients with MACIS scores ≤ 6.99.

PMID:38676783 | DOI:10.1007/s00423-024-03323-x

Ann N Y Acad Sci. 2024 Apr 27. doi: 10.1111/nyas.15138. Online ahead of print.

ABSTRACT

With age, parasympathetic activity decreases, while sympathetic activity increases. Thus, the typical older adult has low heart rate variability (HRV) and high noradrenaline levels. Younger adults with this physiological profile tend to be unhappy and stressed. Yet, with age, emotional experience tends to improve. Why does older adults’ emotional well-being not suffer as their HRV decreases? To address this apparent paradox, I present the autonomic compensation model. In this model, failing organs, the initial phases of Alzheimer’s pathology, and other age-related diseases trigger noradrenergic hyperactivity. To compensate, older brains increase autonomic regulatory activity in the pregenual prefrontal cortex (PFC). Age-related declines in nerve conduction reduce the ability of the pregenual PFC to reduce hyperactive noradrenergic activity and increase peripheral HRV. But these pregenual PFC autonomic compensation efforts have a significant impact in the brain, where they bias processing in favor of stimuli that tend to increase parasympathetic activity (e.g., stimuli that increase feelings of safety) and against stimuli that tend to increase sympathetic activity (e.g., threatening stimuli). In summary, the autonomic compensation model posits that age-related chronic sympathetic/noradrenergic hyperactivity stimulates regulatory attempts that have the side effect of enhancing emotional well-being.

PMID:38676452 | DOI:10.1111/nyas.15138

Int J Mol Sci. 2024 Apr 22;25(8):4564. doi: 10.3390/ijms25084564.

ABSTRACT

Loewi’s discovery of acetylcholine (ACh) release from the frog vagus nerve and the discovery by Dale and Dudley of ACh in ox spleen led to the demonstration of chemical transmission of nerve impulses. ACh is now well-known to function as a neurotransmitter. However, advances in the techniques for ACh detection have led to its discovery in many lifeforms lacking a nervous system, including eubacteria, archaea, fungi, and plants. Notably, mRNAs encoding choline acetyltransferase and muscarinic and nicotinic ACh receptors (nAChRs) have been found in uninnervated mammalian cells, including immune cells, keratinocytes, vascular endothelial cells, cardiac myocytes, respiratory, and digestive epithelial cells. It thus appears that non-neuronal cholinergic systems are expressed in a variety of mammalian cells, and that ACh should now be recognized not only as a neurotransmitter, but also as a local regulator of non-neuronal cholinergic systems. Here, we discuss the role of non-neuronal cholinergic systems, with a focus on immune cells. A current focus of much research on non-neuronal cholinergic systems in immune cells is α7 nAChRs, as these receptors expressed on macrophages and T cells are involved in regulating inflammatory and immune responses. This makes α7 nAChRs an attractive potential therapeutic target.

PMID:38674149 | DOI:10.3390/ijms25084564

Int J Mol Sci. 2024 Apr 10;25(8):4196. doi: 10.3390/ijms25084196.

ABSTRACT

Vagus nerve stimulation (VNS) represents a long-term adjunctive treatment option in patients with difficult-to-treat depression (DTD). Anti-inflammatory effects have been discussed as a key mechanism of action of VNS. However, long-term investigations in real-world patients are sparse. In this naturalistic observational study, we collected data on cytokines in peripheral blood in n = 6 patients (mean age 47.8) with DTD and VNS treatment at baseline and at 6 months follow-up. We have identified clusters of peripheral cytokines with a similar dynamic over the course of these 6 months using hierarchical clustering. We have investigated cytokine changes from baseline to 6 months as well as the relationship between the cytokine profile at 6 months and long-term response at 12 months. After 6 months of VNS, we observed significant correlations between cytokines (p < 0.05) within the identified three cytokine-pairs which were not present at baseline: IL(interleukin)-6 and IL-8; IL-1β and TNF-α; IFN-α2 and IL-33. At 6 months, the levels of all the cytokines of interest had decreased (increased in non-responders) and were lower (5-534 fold) in responders to VNS than in non-responders: however, these results were not statistically significant. VNS-associated immunomodulation might play a role in long-term clinical response to VNS.

PMID:38673781 | DOI:10.3390/ijms25084196

J Clin Med. 2024 Apr 20;13(8):2399. doi: 10.3390/jcm13082399.

ABSTRACT

Background: The primary purpose of this study was to preliminarily examine the effects of autonomic nervous system activity on the dorsolateral prefrontal cortex. Recent studies have examined approaches to modulating autonomic activity using invasive and non-invasive methods, but the effects of changes in autonomic activity during cognitive tasks on the dorsolateral prefrontal cortex have not been fully investigated. The purpose of this preliminary investigation was to examine changes in autonomic activity and blood oxygen saturation in the dorsolateral prefrontal cortex during reading tasks induced by vagus nerve stimulation using a microcone patch. Methods: A cohort of 40 typically developing adults was enrolled in this study. We carefully examined changes in autonomic nervous system activity and blood oxygen saturation in the dorsolateral prefrontal cortex during a reading task in two conditions: with and without microcone patch stimulation. Results: Significant changes in brain activation in the dorsolateral prefrontal cortext due to microcone patch stimulation were confirmed. In addition, hierarchical multiple regression analysis revealed specific changes in reading task-related blood oxygen saturation in the dorsolateral prefrontal region during microcone patch stimulation. Conclusions: It should be recognized that this study is a preliminary investigation and does not have immediate clinical applications. However, our results suggest that changes in autonomic nervous system activity induced by external vagal stimulation may affect activity in specific reading-related regions of the dorsolateral prefrontal cortex. Further research and evaluation are needed to fully understand the implications and potential applications of these findings.

PMID:38673672 | DOI:10.3390/jcm13082399

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

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

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

Int J Clin Health Psychol. 2024 Apr-Jun;24(2):100462. doi: 10.1016/j.ijchp.2024.100462. Epub 2024 Apr 17.

ABSTRACT

BACKGROUND: Inhibitory control represents a core executive function that critically facilitates adaptive behavior and survival in an ever-changing environment. Non-invasive transcutaneous auricular vagus nerve stimulation (taVNS) has been hypothesized to improve behavioral inhibition performance, however the neurocomputational mechanism of taVNS-induced neuroenhancement remains elusive.

METHOD: In the current study, we investigated the efficacy of taVNS in a sham-controlled between-subject functional near infrared spectroscopy (fNIRS) experiment with an emotional face Go/No-Go paradigm in ninety healthy young adults.

RESULTS: After a data quality check, eighty-two subjects were included in the final data analysis. Behaviorally, the taVNS improved No-Go response accuracy, together with computational modeling using Hierarchical Bayesian estimation of the Drift Diffusion Model (HDDM) indicating that it specifically reduced the information accumulation rate for Go responses, and this was negatively associated with increased accuracy of No-Go responses. On the neural level, taVNS enhanced engagement of the bilateral inferior frontal gyrus (IFG) during inhibition of angry expression faces and modulated functional couplings (FCs) within the prefrontal inhibitory control network. Mediation models revealed that taVNS-induced facilitation of inhibitory control was critically mediated by a decreased information accumulation for Go responses and concomitantly enhanced neurofunctional coupling between the inferior and orbital frontal cortex.

DISCUSSION: Our findings demonstrate a potential for taVNS to improve emotional inhibitory control via reducing pre-potent responses and enhancing FCs within prefrontal inhibitory control networks, suggesting a promising therapeutic role in treating specific disorders characterized by inhibitory control deficits.

PMID:38665809 | PMC:PMC11044052 | DOI:10.1016/j.ijchp.2024.100462

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