Res Sq [Preprint]. 2024 May 2:rs.3.rs-4295137. doi: 10.21203/rs.3.rs-4295137/v1.

ABSTRACT

Vagus Nerve Stimulation (VNS) was the first FDA-approved stimulation therapy to treat patients with refractory epilepsy and remains widely used. The mechanisms behind the therapeutic effect of VNS remain unknown but are thought to involve afferent-mediated modulation to cortical circuits ¹ . In this work, we use a coherent holographic imaging system to characterize vagus nerve evoked potentials (VEPs) in the cortex in response to typical VNS stimulation paradigms, which does not require electrode placement nor any genetic, structural, or functional labels. We find that stimulation amplitude strongly modulates VEPs response magnitude (effect size 0.401), while pulse width has a moderate modulatory effect (effect size 0.127) and frequency has almost no modulatory effect (effect size 0.009) on the evoked potential magnitude. We find mild interaction between pulse width and frequency. This non-contact label-free functional imaging technique could serve as a non-invasive rapid feedback tool to quantify VEPs and could increase the efficacy of VNS in patients with refractory epilepsy.

PMID:38746403 | PMC:PMC11092866 | DOI:10.21203/rs.3.rs-4295137/v1

medRxiv [Preprint]. 2024 May 1:2024.04.29.24306598. doi: 10.1101/2024.04.29.24306598.

ABSTRACT

BACKGROUND: Inflammation contributes to morbidity following subarachnoid hemorrhage (SAH). Transauricular vagus nerve stimulation (taVNS) offers a noninvasive approach to target the inflammatory response following SAH.

METHODS: In this prospective, triple-blinded, randomized, controlled trial, twenty-seven patients were randomized to taVNS or sham stimulation. Blood and cerebrospinal fluid (CSF) were collected to quantify inflammatory markers. Cerebral vasospasm severity and functional outcomes (modified Rankin Scale, mRS) were analyzed.

RESULTS: No adverse events occurred. Radiographic vasospasm was significantly reduced (p = 0.018), with serial vessel caliber measurements demonstrating a more rapid return to normal than sham (p < 0.001). In the taVNS group, TNF-α was significantly reduced in both plasma (days 7 and 10) and CSF (day 13); IL-6 was also significantly reduced in plasma (day 4) and CSF (day 13) (p < 0.05). Patients receiving taVNS had higher rates of favorable outcomes at discharge (38.4% vs 21.4%) and first follow-up (76.9% vs 57.1%), with significant improvement from admission to first follow-up (p = 0.014), unlike the sham group (p = 0.18). The taVNS group had a significantly lower rate of discharge to skilled nursing facility or hospice (p = 0.04).

CONCLUSION: taVNS is a non-invasive method of neuro- and systemic immunomodulation. This trial supports that taVNS following SAH can mitigate the inflammatory response, reduce radiographic vasospasm, and potentially improve functional and neurological outcomes. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT04557618.

PMID:38746275 | PMC:PMC11092685 | DOI:10.1101/2024.04.29.24306598

Neurogastroenterol Motil. 2024 May 12:e14815. doi: 10.1111/nmo.14815. Online ahead of print.

ABSTRACT

OBJECTIVE: There has been recent clinical interest in the use of vagus nerve stimulation (VNS) for treating gastrointestinal disorders as an alternative to drugs or gastric electrical stimulation. However, effectiveness of burst stimulation has not been demonstrated. We investigated the ability of bursting and continuous VNS to influence gastric and pyloric activity under a range of stimulation parameters and gastric pressures. The goals of this study were to determine which parameters could optimally excite or inhibit gastric activity.

MATERIALS AND METHODS: Data were collected from 21 Sprague-Dawley rats. Under urethane anesthesia, a rubber balloon was implanted into the stomach, connected to a pressure transducer and a saline infusion pump. A pressure catheter was inserted at the pyloric sphincter and a bipolar nerve cuff was implanted onto the left cervical vagus nerve. The balloon was filled to 15 cmH₂O. Stimulation trials were conducted in a consistent order; the protocol was then repeated at 25 and 35 cmH₂O. The nerve was then transected and stimulation repeated to investigate directionality of effects.

RESULTS: Bursting stimulation at the bradycardia threshold caused significant increases in gastric contraction amplitude with entrainment to the bursting frequency. Some continuous stimulation trials could also cause increased contractions but without frequency changes. Few significant changes were observed at the pylorus, except for frequency entrainment. These effects could not be uniquely attributed to afferent or efferent activity.

SIGNIFICANCE: Our findings further elucidate the effects of different VNS parameters on the stomach and pylorus and provide a basis for future studies of bursting stimulation for gastric neuromodulation.

PMID:38735698 | DOI:10.1111/nmo.14815

Neurotherapeutics. 2024 Apr;21(3):e00371. doi: 10.1016/j.neurot.2024.e00371.

NO ABSTRACT

PMID:38734464 | DOI:10.1016/j.neurot.2024.e00371

Int J Surg. 2024 May 9. doi: 10.1097/JS9.0000000000001592. Online ahead of print.

ABSTRACT

Currently, clinical practice and scientific research mostly revolve around a single disease or system, but the single disease-oriented diagnostic and therapeutic paradigm needs to be revised. This review describes how transcutaneous auricular vagus nerve stimulation (taVNS), a novel noninvasive neuromodulation approach, connects the central and peripheral systems of the body. Through stimulation of the widely distributed vagus nerve from the head to the abdominal cavity, this therapy can improve and treat central system disorders, peripheral system disorders, and central-peripheral comorbidities caused by autonomic dysfunction. In the past, research on taVNS has focused on the treatment of central system disorders by modulating this brain nerve. As the vagus nerve innervates the heart, lungs, liver, pancreas, gastrointestinal tract, spleen and other peripheral organs, taVNS could have an overall modulatory effect on the region of the body where the vagus nerve is widespread. Based on this physiological basis, we summarize the existing evidence of the taVNS ability to regulate cardiac function, adiposity, glucose levels, gastrointestinal function, and immune function, among others, to treat peripheral system diseases, and complex diseases with central and peripheral comorbidities. This review shows the successful examples and research progress of taVNS using peripheral neuromodulation mechanisms from more perspectives, demonstrating the expanded scope and value of taVNS to provide new ideas and approaches for holistic therapy from both central and peripheral perspectives.

PMID:38729100 | DOI:10.1097/JS9.0000000000001592

Cells. 2024 Apr 30;13(9):770. doi: 10.3390/cells13090770.

ABSTRACT

Parkinson’s disease (PD) is recognized as the second most prevalent primary chronic neurodegenerative disorder of the central nervous system. Clinically, PD is characterized as a movement disorder, exhibiting an incidence and mortality rate that is increasing faster than any other neurological condition. In recent years, there has been a growing interest concerning the role of the gut microbiota in the etiology and pathophysiology of PD. The establishment of a brain-gut microbiota axis is now real, with evidence denoting a bidirectional communication between the brain and the gut microbiota through metabolic, immune, neuronal, and endocrine mechanisms and pathways. Among these, the vagus nerve represents the most direct form of communication between the brain and the gut. Given the potential interactions between bacteria and drugs, it has been observed that the therapies for PD can have an impact on the composition of the microbiota. Therefore, in the scope of the present review, we will discuss the current understanding of gut microbiota on PD and whether this may be a new paradigm for treating this devastating disease.

PMID:38727306 | PMC:PMC11083070 | DOI:10.3390/cells13090770

Psychosom Med. 2024 May 1;86(4):342-348. doi: 10.1097/PSY.0000000000001302. Epub 2024 Mar 4.

ABSTRACT

OBJECTIVE: Vagus nerve functioning, as indexed by high-frequency heart rate variability (HF-HRV), has been implicated in a wide range of mental and physical health conditions, including sleep complaints. This study aimed to test associations between HF-HRV measured during sleep (sleep HF-HRV) and subjective sleep complaints 4 years later.

METHODS: One hundred forty-three healthy employees (91% male; MAge = 47.8 years [time 2], SD = 8.3 years) of an industrial company in Southern Germany completed the Jenkins Sleep Problems Scale, participated in a voluntary health assessment, and were given a 24-hour ambulatory heart rate recording device in 2007. Employees returned for a health assessment and completed the Jenkins Sleep Problems Scale 4 years later.

RESULTS: Hierarchical regression analyses showed that lower sleep HF-HRV measured in 2007 was associated with higher self-reported sleep complaints 4 years later after controlling for covariates (rab,c = -0.096, b = -0.108, 95% CI, -0.298 to 0.081, ΔR2 = 0.009, p = .050).

CONCLUSIONS: These data are the first to show that lower sleep HF-HRV predicted worse sleep 4 years later, highlighting the importance of vagus nerve functioning in adaptability and health.

PMID:38724040 | DOI:10.1097/PSY.0000000000001302

Eur Heart J Case Rep. 2024 Apr 23;8(5):ytae214. doi: 10.1093/ehjcr/ytae214. eCollection 2024 May.

ABSTRACT

BACKGROUND: Vagus nerve stimulation (VNS) is an established therapy for drug-resistant epilepsy and depression. While VNS co-existence with cardiac pacemakers is considered safe, its interaction with implantable cardioverter defibrillators (ICDs) remains poorly understood. The concern revolves around the potential for VNS stimulation to interfere with ICD function, potentially resulting in inappropriate therapy or changes in cardiac pacing.

CASE SUMMARY: We present the case of a 50-year-old woman with drug-resistant epilepsy who underwent VNS device implantation and subsequent transvenous ICD placement for primary prevention post-myocardial infarction. These devices were thoughtfully situated contralaterally, with a minimum 10 cm separation. Comprehensive testing and follow-up demonstrated no interactions during device programming or serial assessments. Simultaneous interrogation of both devices with their respective telemetry wands caused chaotic artefacts in all channels on the ICD, likely due to electromagnetic interference. Importantly, this interference did not affect ICD sensing.

DISCUSSION: The co-existence of VNS and ICD in a patient is an emerging scenario with limited previous reports, yet our findings align with prior cases involving VNS and pacemakers. Emphasizing the need for optimal device separation and meticulous evaluation, particularly at maximum VNS output and ICD sensitivity settings, ensures their safe and feasible co-existence. As the use of VNS alongside cardiac implantable electronic devices becomes more common, a diligent evaluation for potential interactions is imperative. Our case highlights the successful co-existence of VNS and ICD, underscoring the importance of careful monitoring and evaluation to guarantee the safe utilization of these two devices.

PMID:38721251 | PMC:PMC11078306 | DOI:10.1093/ehjcr/ytae214

Front Endocrinol (Lausanne). 2024 Apr 24;15:1381093. doi: 10.3389/fendo.2024.1381093. eCollection 2024.

ABSTRACT

Vagal paraganglioma (VPGL) is a rare neuroendocrine tumor that originates from the paraganglion associated with the vagus nerve. VPGLs present challenges in terms of diagnostics and treatment. VPGL can occur as a hereditary tumor and, like other head and neck paragangliomas, is most frequently associated with mutations in the SDHx genes. However, data regarding the genetics of VPGL are limited. Herein, we report a rare case of a 41-year-old woman with VPGL carrying a germline variant in the FH gene. Using whole-exome sequencing, a variant, FH p.S249R, was identified; no variants were found in other PPGL susceptibility and candidate genes. Loss of heterozygosity analysis revealed the loss of the wild-type allele of the FH gene in the tumor. The pathogenic effect of the p.S249R variant on FH activity was confirmed by immunohistochemistry for S-(2-succino)cysteine (2SC). Potentially deleterious somatic variants were found in three genes, SLC7A7, ZNF225, and MED23. The latter two encode transcriptional regulators that can impact gene expression deregulation and are involved in tumor development and progression. Moreover, FH-mutated VPGL was characterized by a molecular phenotype different from SDHx-mutated PPGLs. In conclusion, the association of genetic changes in the FH gene with the development of VPGL was demonstrated. The germline variant FH: p.S249R and somatic deletion of the second allele can lead to biallelic gene damage that promotes tumor initiation. These results expand the clinical and mutation spectra of FH-related disorders and improve our understanding of the molecular genetic mechanisms underlying the pathogenesis of VPGL.

PMID:38721148 | PMC:PMC11076847 | DOI:10.3389/fendo.2024.1381093

J Neurosci. 2024 May 7:e0107242024. doi: 10.1523/JNEUROSCI.0107-24.2024. Online ahead of print.

ABSTRACT

Drugs of abuse cause changes in the prefrontal cortex (PFC) and associated regions that impair inhibitory control over drug-seeking. Breaking the contingencies between drug-associated cues and the delivery of the reward during extinction learning reduces relapse. Vagus nerve stimulation (VNS) has previously been shown to enhance extinction learning and reduce drug-seeking. Here we determined the effects of VNS-mediated release of brain-derived neurotrophic factor (BDNF) on extinction and cue-induced reinstatement in male rats trained to self-administer cocaine. Pairing 10 days of extinction training with VNS facilitated extinction and reduced drug-seeking behavior during reinstatement. Rats that received a single extinction session with VNS showed elevated BDNF levels in the medial PFC as determined via an enzyme-linked immunosorbent assay (ELISA). Systemic blockade of Tropomyosin receptor kinase B (TrkB) receptors during extinction, via the TrkB antagonist ANA-12, decreased the effects of VNS on extinction and reinstatement. Whole-cell recordings in brain slices showed that cocaine self-administration induced alterations in the ratio of AMPA and NMDA receptor-mediated currents in layer 5 pyramidal neurons of the infralimbic cortex (IL). Pairing extinction with VNS reversed cocaine-induced changes in glutamatergic transmission by enhancing AMPAR currents, and this effect was blocked by ANA-12. Our study suggests that VNS consolidates extinction of drug-seeking behavior by reversing drug-induced changes in synaptic AMPA receptors in the IL, and this effect is abolished by blocking TrkB receptors during extinction, highlighting a potential mechanism for the therapeutic effects of VNS in addiction.Significance Statement Extinction training can reverse maladaptive neuroplasticity induced by drugs of abuse, but adjunct treatments are sought that can facilitate the process and consolidate the newly formed memories. Pairing extinction training with vagus nerve stimulation (VNS) facilitates extinction and reduces drug-seeking behavior during reinstatement. Here, we show that rats receiving a single extinction session with VNS exhibit elevated brain-derived neurotrophic factor (BDNF) levels in the medial prefrontal cortex (mPFC). We also demonstrate that VNS consolidates the extinction of drug-seeking behavior by reversing cocaine-induced changes in synaptic AMPA receptors in the infralimbic cortex (IL) of the mPFC. This effect is blocked by the TrkB antagonist ANA-12, emphasizing the role of BDNF and TrkB receptors in the therapeutic effects of VNS in addiction.

PMID:38719446 | DOI:10.1523/JNEUROSCI.0107-24.2024