Nat Commun. 2024 Jul 20;15(1):6119. doi: 10.1038/s41467-024-50523-6.

ABSTRACT

Bioelectronic therapies modulating the vagus nerve are promising for cardiovascular, inflammatory, and mental disorders. Clinical applications are however limited by side-effects such as breathing obstruction and headache caused by non-specific stimulation. To design selective and functional stimulation, we engineered VaStim, a realistic and efficient in-silico model. We developed a protocol to personalize VaStim in-vivo using simple muscle responses, successfully reproducing experimental observations, by combining models with trials conducted on five pigs. Through optimized algorithms, VaStim simulated the complete fiber population in minutes, including often omitted unmyelinated fibers which constitute 80% of the nerve. The model suggested that all Aα-fibers across the nerve affect laryngeal muscle, while heart rate changes were caused by B-efferents in specific fascicles. It predicted that tripolar paradigms could reduce laryngeal activity by 70% compared to typically used protocols. VaStim may serve as a model for developing neuromodulation therapies by maximizing efficacy and specificity, reducing animal experimentation.

PMID:39033186 | DOI:10.1038/s41467-024-50523-6

J Physiol. 2024 Jul 19. doi: 10.1113/JP286680. Online ahead of print.

ABSTRACT

Transcutaneous auricular vagus nerve stimulation (taVNS) targets subcutaneous axons in the auricular branch of the vagus nerve at the outer ear. Its non-invasive nature makes it a potential treatment for various disorders. taVNS induces neuromodulatory effects within the nucleus of the solitary tract (NTS), and due to its widespread connectivity, the NTS acts as a gateway to elicit neuromodulation in both higher-order brain regions and other brainstem nuclei (e.g. spinal trigeminal nucleus; Sp5). Our objective was to examine stimulation parameters on single-neuron electrophysiological responses in α-chloralose-anaesthetized Sprague-Dawley rats within NTS and Sp5. taVNS was also compared to traditional cervical VNS (cVNS) on single neuronal activation. Specifically, electrophysiological extracellular recordings were evaluated for a range of frequency and intensity parameters (20-250 Hz, 0.5-1.0 mA). Neurons were classified as positive, negative or non-responders based on increased activity, decreased activity or no response during stimulation, respectively. Frequency-dependent analysis showed that 20 and 100 Hz generated the highest proportion of positive responders in NTS and Sp5 with 1.0 mA intensities eliciting the greatest magnitude of response. Comparisons between taVNS and cVNS revealed similar parameter-specific activation for caudal NTS neuronal populations; however, individual neurons showed different activation profiles. The latter suggests that cVNS and taVNS send afferent input to NTS via different neuronal pathways. This study demonstrates differential parameter-specific taVNS responses and begins an investigation of the mechanisms responsible for taVNS modulation. Understanding the neuronal pathways responsible for eliciting neuromodulatory effects will enable more tailored taVNS treatments in various clinical disorders. KEY POINTS: Transcutaneous auricular vagus nerve stimulation (taVNS) offers a non-invasive alternative to invasive cervical vagus nerve stimulation (cVNS) by activating vagal afferents in the ear to induce neuromodulation. Our study evaluated taVNS effects on neuronal firing patterns in the nucleus of the solitary tract (NTS) and spinal trigeminal nucleus (Sp5) and found that 20 and 100 Hz notably increased neuronal activity during stimulation in both nuclei. Increasing taVNS intensity not only increased the number of neurons responding in Sp5 but also increased the magnitude of response, suggesting a heightened sensitivity to taVNS compared to NTS. Comparisons between cVNS and taVNS revealed similar overall activation but different responses on individual neurons, indicating distinct neural pathways. These results show parameter-specific and nuclei-specific responses to taVNS and confirm that taVNS can elicit responses comparable to cVNS at the neuronal level, but it does so through different neuronal pathways.

PMID:39031516 | DOI:10.1113/JP286680

Eur J Neurol. 2024 Jul 19:e16398. doi: 10.1111/ene.16398. Online ahead of print.

ABSTRACT

BACKGROUND AND PURPOSE: Cervical artery dissection (CAD) represents a leading cause of unilateral lower cranial nerve IX-XII palsy, known as Collet-Sicard syndrome (CSS). High-resolution magnetic resonance imaging (HR-MRI) is widely used in the evaluation of patients with CAD, providing information regarding vessel wall abnormalities and intraluminal thrombus.

METHODS: We present a patient with palsy of multiple lower cranial nerves in the context of CSS, attributed to unilateral spontaneous internal carotid artery dissection.

RESULTS: We describe a 68-year-old man with unremarkable previous history, who presented with subacute, gradually worsening dysphagia and hoarse voice. Clinical examination revealed right-sided palsy of cranial nerves IX-XII. Three-dimensional fat-saturated black-blood T1-weighted high-resolution vessel wall imaging disclosed spontaneous dissection with intramural hematoma along the distal right internal carotid artery. Neck MRI showed inward displacement of right aryepiglottic fold, right pyriform sinus dilatation, and right true vocal cord in middle position, indicative of right vagus nerve palsy, atrophy of right trapezius and sternocleidomastoid muscles, due to right spinal accessory nerve palsy, and unilateral tongue atrophy with fatty infiltration, characteristic for right hypoglossal nerve palsy.

CONCLUSIONS: This case highlights the utility of high-resolution vessel wall imaging and especially fat-saturated T1-weighted black-blood SPACE (sampling perfection with application-optimized contrast using different flip-angle evolutions) sequences in the accurate diagnosis of CAD, revealing the characteristic mural hematoma and intimal flap. HR-MRI is also valuable in the recognition of indirect signs of lower cranial nerve compression.

PMID:39030970 | DOI:10.1111/ene.16398

J Neurol Phys Ther. 2024 Jul 19. doi: 10.1097/NPT.0000000000000488. Online ahead of print.

ABSTRACT

BACKGROUND AND PURPOSE: Implantable vagus nerve stimulation (VNS) paired with volitional upper extremity rehabilitation can improve impairment and function among moderately to severely impaired, chronic stroke survivors. This study is a retrospective analysis of the in-clinic rehabilitation phase of the blinded, placebo-controlled, randomized pivotal VNS-REHAB trial to determine whether dosing parameters during in-clinic paired VNS therapy were associated with responder status and whether covariates might impact that determination.

METHODS: Data were limited to 53 participants in the active VNS group who had received VNS implants prior to undergoing 6 weeks of in-clinic rehabilitation paired with VNS. Tasks were standardized across all participants. Dosing parameters included number of stimulations and task time. The primary outcome was the Fugl-Meyer Upper Extremity Assessment (FMA-UE), evaluated at the end of 6 weeks (Post-1). Participants were classified a priori as responders based on an improvement of ≥6 points on the FMA-UE from baseline to Post-1.

RESULTS: Dosing parameters were not associated with FMA-UE responder status at the end of 6 weeks. Covariates including age, gender, paretic hand, baseline severity, and chronicity of stroke were also not significant associations of response.

DISCUSSION AND CONCLUSIONS: While responders to VNS could be defined, therapy dosing and participant attributes did not provide greater specification for association of responder status. Limitations of this study include small sample size and non-linearity of the FMA-UE. Future studies will include reassessing responder categorization using more linear scales and examining stroke lesion characteristics to determine whether these measures are more sensitive to dosing parameters.

VIDEO ABSTRACT AVAILABLE: for more insights from the authors (see the Video, Supplemental Digital Content 1, available at: http://www.w3.org/1999/xlink).

PMID:39028576 | DOI:10.1097/NPT.0000000000000488

Heliyon. 2024 Jun 27;10(13):e33840. doi: 10.1016/j.heliyon.2024.e33840. eCollection 2024 Jul 15.

ABSTRACT

BACKGROUND: Our previous studies have demonstrated that the activated Cholinergic Anti-inflammatory Pathway (CAP) effectively suppresses systemic inflammation and immunity in early sepsis. Some parameters of Heart Rate Variability (HRV) could be used to reflect the regulatory activity of CAP. However, in the early stages of severe sepsis of some patients, the inflammatory storm can still result in multiple organs dysfunction and even death, suggesting they lose CAP’s modulation ability. Since CAP is part of the vagus nerve and is directly innervated by the Medullary Visceral Zone (MVZ), we can reasonably concluded that pathological changes induced by MVZ’s neuroinflammation should be responsible for CAP’s dysfunction in modulating systemic inflammation in early sepsis.

METHODS: We conducted two independent septic experiments, the sepsis model rats were prepared by cecum ligation and puncture (CLP) method. In the first experiment, A total of 64 adult male Sprague-Dawley rats were included. Under the condition of sepsis and CAP’s pharmacological activation or blockade, we investigated the MVZ’s pathological changes, the functional state of key neurons including catecholaminergic and cholinergic neurons, key genes’ expression such as Oligodendrocyte Transcription Factor 2 (Olig-2) mRNA, glial fibrillary acidic protein (GFAP) mRNA, and matrix metalloprotein (MMP) -9 mRNA, and CAP’s activities reflected by HRV. The second experiment involved in 56 rats, through central anti-inflammation by feeding with 10 mg/ml minocycline sucrose solution as the only water source, or right vagus transection excepting for central anti-inflammation as a mean of the CAP’s functional cancel, we confirmed that the neuroinflammation in MVZ affected systemic inflammation through CAP in sepsis.

RESULTS: In the first experiment, cholinergic and catecholaminergic neurons showed significant apoptosis with reduced expressions of TH, but the expression of CHAT remained relatively unaffected in MVZ in sepsis. HRV parameters representing the tone of the vagus nerve, such as SDNN, RMSSD, HF, SD1, and SD2, did not show significant differences among the three Septic Groups, although they all decreased significantly compared to the Control Group. The expressions of GFAP mRNA and MMP-9 mRNA were up-regulated, while the expression of Olig-2 mRNA was down-regulated in the Septic Groups. Intervention of CAP had a significant effect on cholinergic and catecholaminergic neurons’ apoptosis, as well as the expressions of TH/CHAT and these key genes, but had little effect on HRV in sepsis. In the second experiment, the levels of TNF-α, IL-6, in serum and MVZ were significantly increased in sepsis. Central anti-inflammatory treatment reversed these changes. However, right vagotomy abolished the central anti-inflammatory effect.

CONCLUSIONS: Our study uncovered that MVZ’s neuroinflammation may play a crucial role in the uncontrolled systemic inflammation through inflammatory demyelination in MVZ, which disrupts CAP’s modulation on the systemic inflammation in early sepsis.

PMID:39027552 | PMC:PMC11255576 | DOI:10.1016/j.heliyon.2024.e33840

Front Neurosci. 2024 Jul 4;18:1405310. doi: 10.3389/fnins.2024.1405310. eCollection 2024.

ABSTRACT

Tinnitus, characterized by phantom sound perception, is a highly disruptive disorder lacking definitive and effective treatments. Its intricate neural mechanisms are not fully understood. Transcutaneous auricular vagus nerve stimulation (taVNS) has demonstrated potential as a substitute or supplementary treatment by activating central vagal pathways. However, standardized therapeutic protocols and objective tests to assess efficacy are lacking. Therefore, taVNS shows promise as a therapy for tinnitus, and treatment protocols should be optimized in future clinical trials.

PMID:39027324 | PMC:PMC11254635 | DOI:10.3389/fnins.2024.1405310

Surgery. 2024 Jul 17:S0039-6060(24)00368-4. doi: 10.1016/j.surg.2024.05.037. Online ahead of print.

ABSTRACT

BACKGROUND: This study analyzed all reported cases of painful traumatic neuromas to better understand their anatomic distribution, etiologies, and surgical treatment.

METHODS: PubMed, Embase, Cochrane, and Web of Science were searched in October 2023 for articles describing painful traumatic neuromas.

RESULTS: In total, 414 articles reporting 5,562 neuromas were included and categorized into head/neck, trunk, upper extremity, lower extremity, and autonomic nerves. Distribution was as follows: Head/neck: 82 articles reported on 393 neuromas (93.2% iatrogenic) most frequently involving the lingual (44.3%), cervical plexus (14.9%), great auricular (8.5%), inferior/superior alveolar (8.3%), and occipital (7.2%) nerves. Trunk: 47 articles reported on 554 neuromas (92.9% iatrogenic) most commonly involving the intercostal (35.4%), genitofemoral (14.3%), and pudendal (12.9%) nerves. Upper extremity: 159 articles reported on 2079 neuromas (53.3% after amputation) most frequently involving the digital (46.9%), superficial radial (18.3%), and median (7.0%) nerves. Lower extremity: 128 articles reported on 2,531 neuromas (53.0% after amputation) most commonly involving the sural (17.9%), superficial peroneal (17.3%), and saphenous (16.0%) nerves. Autonomic nerves: 15 articles reported on 53 neuromas (100% iatrogenic) most frequently involving the biliary tract (73.9%) and vagus nerve (14.9%). Compared with the extremities, neuromas in the head/neck and trunk had significantly longer symptom duration before surgical treatment and the nerve end was significantly less frequently reconstructed after neuroma excision.

CONCLUSION: Painful neuromas are predominantly reported in the extremities yet may occur throughout the body primarily after iatrogenic injury. Knowledge of their anatomic distribution from head to toe will encourage awareness to avoid injury and expedite diagnosis to prevent treatment delay.

PMID:39025690 | DOI:10.1016/j.surg.2024.05.037

Neurobiol Dis. 2024 Jul 15:106606. doi: 10.1016/j.nbd.2024.106606. Online ahead of print.

ABSTRACT

The gut microbiota produces metabolites that enrich the host metabolome and play a part in host physiology, including brain functions. Yet the biological mediators of this gut-brain signal transduction remain largely unknown. In this study, the possible role of the gut microbiota metabolite indole, originating from tryptophan, was investigated. Oral administration of indole to simulate microbial overproduction of this compound in the gut consistently led to impaired locomotion and anxiety-like behaviour in both C3H/HeN and C57BL/6 J mice. By employing c-Fos protein expression mapping in mice, we observed a noticeable increase in brain activation within the dorsal motor nucleus of the vagus nerve (DMX) and the locus coeruleus (LC) regions in a dose-dependent manner. Further immune co-labelling experiments elucidated that the primary cells activated within the LC were tyrosine hydroxylase positive. To delve deeper into the mechanistic aspects, we conducted chemogenetic activation experiments on LC norepinephrine neurons with two doses of clozapine N-oxide (CNO). Low dose of CNO at 0.5 mg/kg induced no change in locomotion but anxiety-like behaviour, while high dose of CNO at 2 mg/kg resulted in locomotion impairment and anxiety-like behaviour. These findings support the neuroactive roles of indole in mediating gut-brain communication. It also highlights the LC as a novel hub in the gut-brain axis, encouraging further investigations.

PMID:39019292 | DOI:10.1016/j.nbd.2024.106606

Physiol Meas. 2024 Jul 17;45(7). doi: 10.1088/1361-6579/ad5ef6.

ABSTRACT

Objective.To determine the optimal frequency and site of stimulation for transcutaneous vagus nerve stimulation (tVNS) to induce acute changes in the autonomic profile (heart rate (HR), heart rate variability (HRV)) in healthy subjects (HS) and patients with heart failure (HF).Approach.We designed three single-blind, randomized, cross-over studies: (1) to compare the acute effect of left tVNS at 25 Hz and 10 Hz (n= 29, age 60 ± 7 years), (2) to compare the acute effect of left and right tVNS at the best frequency identified in study 1 (n= 28 age 61 ± 7 years), and (3) to compare the acute effect of the identified optimal stimulation protocol with sham stimulation in HS and HF patients (n= 30, age 59 ± 5 years, andn= 32, age 63 ± 7 years, respectively).Main results.In study 1, left tragus stimulation at 25 Hz was more effective than stimulation at 10 Hz in decreasing HR (-1.0 ± 1.2 bpm,p< 0.001 and -0.5 ± 1.6 bpm, respectively) and inducing vagal effects (significant increase in RMSSD, and HF power). In study 2, the HR reduction was greater with left than right tragus stimulation (-0.9 ± 1.5 bpm,p< 0.01 and -0.3 ± 1.4 bpm, respectively). In study 3 in HS, left tVNS at 25 Hz significantly reduced HR, whereas sham stimulation did not (-1.1 ± 1.2 bpm,p< 0.01 and -0.2 ± 2.9 bpm, respectively). In HF patients, both active and sham stimulation produced negligible effects.Significance.Left tVNS at 25 Hz is effective in acute modulation of cardiovascular autonomic control (HR, HRV) in HS but not in HF patients (NCT05789147).

PMID:39016202 | DOI:10.1088/1361-6579/ad5ef6

CNS Neurosci Ther. 2024 Jul;30(7):e14751. doi: 10.1111/cns.14751.

ABSTRACT

AIMS: To predict the vagus nerve stimulation (VNS) efficacy for pediatric drug-resistant epilepsy (DRE) patients, we aim to identify preimplantation biomarkers through clinical features and electroencephalogram (EEG) signals and thus establish a predictive model from a multi-modal feature set with high prediction accuracy.

METHODS: Sixty-five pediatric DRE patients implanted with VNS were included and followed up. We explored the topological network and entropy features of preimplantation EEG signals to identify the biomarkers for VNS efficacy. A Support Vector Machine (SVM) integrated these biomarkers to distinguish the efficacy groups.

RESULTS: The proportion of VNS responders was 58.5% (38/65) at the last follow-up. In the analysis of parieto-occipital α band activity, higher synchronization level and nodal efficiency were found in responders. The central-frontal θ band activity showed significantly lower entropy in responders. The prediction model reached an accuracy of 81.5%, a precision of 80.1%, and an AUC (area under the receiver operating characteristic curve) of 0.838.

CONCLUSION: Our results revealed that, compared to nonresponders, VNS responders had a more efficient α band brain network, especially in the parieto-occipital region, and less spectral complexity of θ brain activities in the central-frontal region. We established a predictive model integrating both preimplantation clinical and EEG features and exhibited great potential for discriminating the VNS responders. This study contributed to the understanding of the VNS mechanism and improved the performance of the current predictive model.

PMID:39015946 | PMC:PMC11252558 | DOI:10.1111/cns.14751