Short-term effects of transcutaneous auricular vagus nerve stimulation on T-wave alternans in people with focal epilepsy – An exploratory pilot study

Epilepsy Behav Rep. 2024 Mar 5;26:100657. doi: 10.1016/j.ebr.2024.100657. eCollection 2024.


High levels of T-wave alternans (TWA) are linked to an increased risk of sudden cardiac death. People with epilepsy display elevated TWA levels that are decreased by chronic vagus nerve stimulation via implanted devices after 2-4 weeks or later. Our objective was to explore short-term effects of transcutaneous auricular vagus nerve stimulation (tVNS) on TWA. Five patients (3 female) with focal epilepsy undergoing video-EEG monitoring were included. TWA levels were determined using a one-channel modified lead I ECG via an open-source TWA-algorithm on two consecutive days, 1 h before, during and after tVNS via the left auricle. Data are given as mean ± SE. Mean TWA at baseline was 3.8 ± 0.4 µV and 3.0 ± 0.6 µV during stimulation on day 2. Stimulations on the second day were associated with TWA reductions by 22 ± 13 % that exceeded stimulation effects on the first day relative to baseline (p < 0.05). Linear mixed-models revealed effects of both stimulation (p < 0.05) and stimulation number (p < 0.005). Normalized TWA showed reproducible peak reductions at both days within 35 min after the initiation of tVNS (p < 0.05). Our observations suggest that tVNS has short-term effects on TWA, supporting the notion that vagus nerve stimulation has a beneficial impact on electrical cardiac properties.

PMID:38495402 | PMC:PMC10940126 | DOI:10.1016/j.ebr.2024.100657

Chronic Abdominal Discomfort Syndrome (CADS): Defining and Discussing a Novel Diagnosis

J Pain Res. 2024 Mar 11;17:975-979. doi: 10.2147/JPR.S450008. eCollection 2024.


In this article, we propose a new diagnostic paradigm known as Chronic Abdominal Discomfort Syndrome (CADS). Patient’s presentation centers around chronic abdominal pain not explained by acute pathology with or without accompanying dyspepsia, bloating, nausea and vomiting among other symptoms. The pathophysiology is noted to be neurogenic, possibly stemming from visceral sympathetic nerves or abdominal wall afferent nerves. Diagnosis is supported by signs or symptoms traversing clinical, diagnostic and functional criteria. Included is a tool which can assist clinicians in diagnosing patients with CADS per those domains. We hope to facilitate primary care physicians’ and gastroenterologists’ utilization of our criteria to provide guidance for selecting which patients may benefit from further interventions or evaluation by a pain physician. The pain physician may then offer interventions to provide the patient with relief.

PMID:38496342 | PMC:PMC10943270 | DOI:10.2147/JPR.S450008

Feasibility study of microburst VNS therapy in drug-resistant focal and generalized epilepsy

Brain Stimul. 2024 Mar 16:S1935-861X(24)00046-9. doi: 10.1016/j.brs.2024.03.010. Online ahead of print.


BACKGROUND: Vagus nerve stimulation (VNS) at low frequencies (≤30 Hz) has been an established treatment for drug-resistant epilepsy (DRE) for over 25 years.

OBJECTIVE: To examine the initial safety and efficacy performance of an investigational, high-frequency (≥250 Hz) VNS paradigm herein called “Microburst VNS” (μVNS). μVNS consists of short, high-frequency bursts of electrical pulses believed to preferentially modulate certain brain regions.

METHODS: Thirty-three (33) participants were enrolled into an exploratory feasibility study, 21 with focal-onset seizures and 12 with generalized-onset seizures. Participants were titrated to a personalized target dose of μVNS using an investigational fMRI protocol. Participants were then followed for up to 12 months, with visits every 3 months, and monitored for side-effects at all time points. This study was registered as NCT03446664 on February 27th, 2018.

RESULTS: The device was well-tolerated. Reported adverse events were consistent with typical low frequency VNS outcomes and tended to diminish in severity over time, including dysphonia, cough, dyspnea, and implant site pain. After 12 months of μVNS, the mean seizure frequency reduction for all seizures was 61.3% (median reduction: 70.4%; 90% CI of median: 48.9%-83.3%). The 12-month responder rate (≥50% reduction) was 63.3% (90% CI: 46.7%-77.9%) and the super-responder rate (≥80% reduction) was 40% (90% CI: 25.0%-56.6%). Participants with focal-onset seizures appeared to benefit similarly to participants with generalized-onset seizures (mean reduction in seizures at 12 months: 62.6% focal [n = 19], versus 59.0% generalized [n = 11]).

CONCLUSION: Overall, μVNS appears to be safe and potentially a promising therapeutic alternative to traditional VNS. It merits further investigation in randomized controlled trials which will help determine the impact of investigational variables and which patients are most suitable for this novel therapy.

PMID:38499287 | DOI:10.1016/j.brs.2024.03.010

Unraveling the gut-brain axis: the impact of steroid hormones and nutrition on Parkinson’s disease

Neural Regen Res. 2024 Oct 1;19(10):2219-2228. doi: 10.4103/1673-5374.391304. Epub 2023 Dec 21.


This comprehensive review explores the intricate relationship between nutrition, the gut microbiome, steroid hormones, and Parkinson’s disease within the context of the gut-brain axis. The gut-brain axis plays a pivotal role in neurodegenerative diseases like Parkinson’s disease, encompassing diverse components such as the gut microbiota, immune system, metabolism, and neural pathways. The gut microbiome, profoundly influenced by dietary factors, emerges as a key player. Nutrition during the first 1000 days of life shapes the gut microbiota composition, influencing immune responses and impacting both child development and adult health. High-fat, high-sugar diets can disrupt this delicate balance, contributing to inflammation and immune dysfunction. Exploring nutritional strategies, the Mediterranean diet’s anti-inflammatory and antioxidant properties show promise in reducing Parkinson’s disease risk. Microbiome-targeted dietary approaches and the ketogenic diet hold the potential in improving brain disorders. Beyond nutrition, emerging research uncovers potential interactions between steroid hormones, nutrition, and Parkinson’s disease. Progesterone, with its anti-inflammatory properties and presence in the nervous system, offers a novel option for Parkinson’s disease therapy. Its ability to enhance neuroprotection within the enteric nervous system presents exciting prospects. The review addresses the hypothesis that α-synuclein aggregates originate from the gut and may enter the brain via the vagus nerve. Gastrointestinal symptoms preceding motor symptoms support this hypothesis. Dysfunctional gut-brain signaling during gut dysbiosis contributes to inflammation and neurotransmitter imbalances, emphasizing the potential of microbiota-based interventions. In summary, this review uncovers the complex web of interactions between nutrition, the gut microbiome, steroid hormones, and Parkinson’s disease within the gut-brain axis framework. Understanding these connections not only offers novel therapeutic insights but also illuminates the origins of neurodegenerative diseases such as Parkinson’s disease.

PMID:38488556 | DOI:10.4103/1673-5374.391304

Lateral medullary vascular compression manifesting as paroxysmal hypertension

Acta Neurochir (Wien). 2024 Mar 15;166(1):139. doi: 10.1007/s00701-024-06032-y.


Neurovascular compression of the rostral ventrolateral medulla (RVLM) has been described as a possible cause of refractory essential hypertension. We present the case of a patient affected by episodes of severe paroxysmal hypertension, some episodes associated with vago-glossopharyngeal neuralgia. Classical secondary forms of hypertension were excluded. Imaging revealed a neurovascular conflict between the posterior inferior cerebellar artery (PICA) and the ventrolateral medulla at the level of the root entry zone of the ninth and tenth cranial nerves (CN IX-X REZ). A MVD of a conflict between the PICA and the RVLM and adjacent CN IX-X REZ was performed, resulting in reduction of the frequency and severity of the episodes. Brain MRI should be performed in cases of paroxysmal hypertension. MVD can be considered in selected patients.

PMID:38488893 | PMC:PMC10943153 | DOI:10.1007/s00701-024-06032-y

Vagus Nerve Stimulation Modulates Inflammation in Treatment-Resistant Depression Patients: A Pilot Study

Int J Mol Sci. 2024 Feb 26;25(5):2679. doi: 10.3390/ijms25052679.


Vagal neurostimulation (VNS) is used for the treatment of epilepsy and major medical-refractory depression. VNS has neuropsychiatric functions and systemic anti-inflammatory activity. The objective of this study is to measure the clinical efficacy and impact of VNS modulation in depressive patients. Six patients with refractory depression were enrolled. Depression symptoms were assessed with the Montgomery-Asberg Depression Rating, and anxiety symptoms with the Hamilton Anxiety Rating Scale. Plasmas were harvested prospectively before the implantation of VNS (baseline) and up to 4 years or more after continuous therapy. Forty soluble molecules were measured in the plasma by multiplex assays. Following VNS, the reduction in the mean depression severity score was 59.9% and the response rate was 87%. Anxiety levels were also greatly reduced. IL-7, CXCL8, CCL2, CCL13, CCL17, CCL22, Flt-1 and VEGFc levels were significantly lowered, whereas bFGF levels were increased (p values ranging from 0.004 to 0.02). This exploratory study is the first to focus on the long-term efficacy of VNS and its consequences on inflammatory biomarkers. VNS may modulate inflammation via an increase in blood-brain barrier integrity and a reduction in inflammatory cell recruitment. This opens the door to new pathways involved in the treatment of refractory depression.

PMID:38473935 | PMC:PMC10931975 | DOI:10.3390/ijms25052679

Clinical safety and feasibility of a novel implantable neuroimmune modulation device for the treatment of rheumatoid arthritis: initial results from the randomized, double-blind, sham-controlled RESET-RA study

Bioelectron Med. 2024 Mar 13;10(1):8. doi: 10.1186/s42234-023-00138-x.


BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that causes persistent synovitis, bone damage, and progressive joint destruction. Neuroimmune modulation through electrical stimulation of the vagus nerve activates the inflammatory reflex and has been shown to inhibit the production and release of inflammatory cytokines and decrease clinical signs and symptoms in RA. The RESET-RA study was designed to determine the safety and efficacy of an active implantable device for treating RA.

METHODS: The RESET-RA study is a randomized, double-blind, sham-controlled, multi-center, two-stage pivotal trial that enrolled patients with moderate-to-severe RA who were incomplete responders or intolerant to at least one biologic or targeted synthetic disease-modifying anti-rheumatic drug. A neuroimmune modulation device (SetPoint Medical, Valencia, CA) was implanted on the left cervical vagus nerve within the carotid sheath in all patients. Following post-surgical clearance, patients were randomly assigned (1:1) to active stimulation or non-active (control) stimulation for 1 min once per day. A predefined blinded interim analysis was performed in patients enrolled in the study’s initial stage (Stage 1) that included demographics, enrollment rates, device implantation rates, and safety of the surgical procedure, device, and stimulation over 12 weeks of treatment.

RESULTS: Sixty patients were implanted during Stage 1 of the study. All device implant procedures were completed without intraoperative complications, infections, or surgical revisions. No unanticipated adverse events were reported during the perioperative period and at the end of 12 weeks of follow-up. No study discontinuations were due to adverse events, and no serious adverse events were related to the device or stimulation. Two serious adverse events were related to the implantation procedure: vocal cord paresis and prolonged hoarseness. These were reported in two patients and are known complications of surgical implantation procedures with vagus nerve stimulation devices. The adverse event of vocal cord paresis resolved after vocal cord augmentation injections with filler and speech therapy. The prolonged hoarseness had improved with speech therapy, but mild hoarseness persists.

CONCLUSIONS: The surgical procedures for implantation of the novel neuroimmune modulation device for the treatment of RA were safe, and the device and its use were well tolerated.

TRIAL REGISTRATION: NCT04539964; August 31, 2020.

PMID:38475923 | PMC:PMC10935935 | DOI:10.1186/s42234-023-00138-x

Transcutaneous vagus nerve stimulation: a new strategy for Alzheimer’s disease intervention through the brain-gut-microbiota axis?

Front Aging Neurosci. 2024 Feb 27;16:1334887. doi: 10.3389/fnagi.2024.1334887. eCollection 2024.


Transcutaneous vagus nerve stimulation (tVNS) is an emerging non-invasive technique designed to stimulate branches of the vagus nerve distributed over the body surface. Studies suggest a correlation between the brain-gut-microbiota (BGM) axis and the pathogenesis of Alzheimer’s disease (AD). The BGM axis represents a complex bidirectional communication system, with the vagus nerve being a crucial component. Therefore, non-invasive electrical stimulation of the vagus nerve might have the potential to modify-most of the time probably in a non-physiological way-the signal transmission within the BGM axis, potentially influencing the progression or symptoms of AD. This review explores the interaction between percutaneous vagus nerve stimulation and the BGM axis, emphasizing its potential effects on AD. It examines various aspects, such as specific brain regions, gut microbiota composition, maintenance of intestinal environmental homeostasis, inflammatory responses, brain plasticity, and hypothalamic-pituitary-adrenal (HPA) axis regulation. The review suggests that tVNS could serve as an effective strategy to modulate the BGM axis and potentially intervene in the progression or treatment of Alzheimer’s disease in the future.

PMID:38476661 | PMC:PMC10927744 | DOI:10.3389/fnagi.2024.1334887

Online Bayesian optimization of vagus nerve stimulation

J Neural Eng. 2024 Mar 13. doi: 10.1088/1741-2552/ad33ae. Online ahead of print.


In bioelectronic medicine, neuromodulation therapies induce neural signals to the brain or organs, modifying their function. Stimulation devices capable of triggering exogenous neural signals using electrical waveforms require a complex and multi-dimensional parameter space to control such waveforms. Determining the best combination of parameters (waveform optimization or dosing) for treating a particular patient’s illness is therefore challenging. Comprehensive parameter searching for an optimal stimulation effect is often infeasible in a clinical setting due to the size of the parameter space. Restricting this space, however, may lead to suboptimal therapeutic results, reduced responder rates, and adverse effects.&#xD;&#xD;Approach. As an alternative to a full parameter search, we present a flexible machine learning, data acquisition, and processing framework for optimizing neural stimulation parameters, requiring as few steps as possible using Bayesian optimization. This optimization builds a model of the neural and physiological responses to stimulations, enabling it to optimize stimulation parameters and provide estimates of the accuracy of the response model. The vagus nerve innervates, among other thoracic and visceral organs, the heart, thus controlling heart rate, making it an ideal candidate for demonstrating the effectiveness of our approach.&#xD;&#xD;Main results. The efficacy of our optimization approach was first evaluated on simulated neural responses, then applied to vagus nerve stimulation intraoperatively in porcine subjects. Optimization converged quickly on parameters achieving target heart rates and optimizing neural B-fiber activations despite high intersubject variability. &#xD;&#xD;Significance. An optimized stimulation waveform was achieved in real time with far fewer stimulations than required by alternative optimization strategies, thus minimizing exposure to side effects. Uncertainty estimates helped avoiding stimulations outside a safe range. Our approach shows that a complex set of neural stimulation parameters can be optimized in real-time for a patient to achieve a personalized precision dosing. &#xD.

PMID:38479016 | DOI:10.1088/1741-2552/ad33ae