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Vagus Nerve Stimulation Reduces Indomethacin-Induced Small Bowel Inflammation.

ABSTRACT: Crohn's disease is a chronic, idiopathic condition characterized by intestinal inflammation and debilitating gastrointestinal symptomatology. Previous studies of inflammatory bowel disease (IBD), primarily in colitis, have shown reduced inflammation after electrical or pharmacological activation of the vagus nerve, but the scope and kinetics of this effect are incompletely understood. To investigate this, we studied the effect of electrical vagus nerve stimulation (VNS) in a rat model of indomethacin-induced small intestinal inflammation. 1 min of VNS significantly reduced small bowel total inflammatory lesion area [(mean ± SEM) sham: 124 ± 14 mm², VNS: 62 ± 14 mm², p = 0.002], intestinal peroxidation and chlorination rates, and intestinal and systemic pro-inflammatory cytokine levels as compared with sham-treated animals after 24 h following indomethacin administration. It was not known whether this observed reduction of inflammation after VNS in intestinal inflammation was mediated by direct innervation of the gut or if the signals are relayed through the spleen. To investigate this, we studied the VNS effect on the small bowel lesions of splenectomized rats and splenic nerve stimulation (SNS) in intact rats. We observed that VNS reduced small bowel inflammation also in splenectomized rats but SNS alone failed to significantly reduce small bowel lesion area. Interestingly, VNS significantly reduced small bowel lesion area for 48 h when indomethacin administration was delayed. Thus, 1 min of electrical activation of the vagus nerve reduced indomethacin-induced intestinal lesion area by a spleen-independent mechanism. The surprisingly long-lasting and spleen-independent effect of VNS on the intestinal response to indomethacin challenge has important implications on our understanding of neural control of intestinal inflammation and its potential translation to improved therapies for IBD.

SUBMITTER: Caravaca AS

PROVIDER: S-EPMC8789651 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Introduction: VNS is an adjunctive neuromodulation therapy for patients with drug-refractory epilepsy. The antiseizure effect of VNS is thought to be related to a diffuse modulation of functional connectivity but remains to be confirmed. Aim: To investigate electroencephalographic (EEG) metrics of functional connectivity in patients with drug-refractory epilepsy treated by vagus nerve stimulation (VNS), between VNS-stimulated "ON" and nonstimulated "OFF" periods and between responder (R) and nonresponder (NR) patients. Methods: Scalp-EEG was performed for 35 patients treated by VNS, using 21 channels and 2 additional electrodes on the neck to detect the VNS stimulation. Patients were defined as VNS responders if a reduction of seizure frequency of ∼50% was documented. We analyzed the synchronization in EEG time series during "ON" and "OFF" periods of stimulation, using average phase lag index (PLI) in signal space and phase-locking value (PLV) between 10 sources. Based on graph theory, we computed brain network models and analyzed minimum spanning tree (MST) for responder and nonresponder patients. Results: Among 35 patients treated by VNS for a median time of 7 years (range 4 months to 22 years), 20 were R and 15 were NR. For responder patients, PLI during ON periods was significantly lower than that during OFF periods in delta (p = 0.009), theta (p = 0.02), and beta (p = 0.04) frequency bands. For nonresponder patients, there were no significant differences between ON and OFF periods. Moreover, variations of seizure frequency with VNS correlated with the PLI OFF/ON ratio in delta (p = 0.02), theta (p = 0.04), and beta (p = 0.03) frequency bands. Our results were confirmed using PLV in theta band (p < 0.05). No significant differences in MST were observed between R and NR patients. Conclusion: The correlation between VNS-induced interictal EEG time-series desynchronization and decrease in seizure frequency suggested that VNS therapeutic impact might be related to changes in interictal functional connectivity. Impact statement Electroencephalography (EEG) desynchronization has been proposed to be a mechanism for antiepileptic effect of vagus nerve stimulation (VNS). We measured interictal EEG time-series synchronization during stimulated (ON) and nonstimulated (OFF) periods in epileptic patients treated by VNS. Phase lag index differences between ON and OFF periods were measured in delta, theta, and beta bands only in responder patients. To our knowledge, our study is the first to statistically correlate interictal cortical desynchronization during ON periods with reduction in seizure frequency. Our result supports the hypothesis that the antiseizure effect of VNS is mediated by cortical desynchronization.

Project description:BackgroundAutonomic nerve stimulation is used as a treatment for a growing number of diseases. We have previously demonstrated that application of efferent vagus nerve stimulation (eVNS) has promising glucose lowering effects in a rat model of type 2 diabetes. This paradigm combines high frequency pulsatile stimulation to block nerve activation in the afferent direction with low frequency stimulation to activate the efferent nerve section. In this study we explored the effects of the parameters for nerve blocking on the ability to inhibit nerve activation in the afferent direction. The overarching aim is to establish a blocking stimulation strategy that could be applied using commercially available implantable pulse generators used in the clinic.MethodsMale rats (n = 20) had the anterior abdominal vagus nerve implanted with a multi-electrode cuff. Evoked compound action potentials (ECAP) were recorded at the proximal end of the electrode cuff. The efficacy of high frequency stimulation to block the afferent ECAP was assessed by changes in the threshold and saturation level of the response. Blocking frequency and duty cycle of the blocking pulses were varied while maintaining a constant 4 mA current amplitude.ResultsDuring application of blocking at lower frequencies (≤ 4 kHz), the ECAP threshold increased (ANOVA, p < 0.001) and saturation level decreased (p < 0.001). Application of higher duty cycles (> 70%) led to an increase in evoked neural response threshold (p < 0.001) and a decrease in saturation level (p < 0.001). During the application of a constant pulse width and frequency (1 or 1.6 kHz, > 70% duty cycle), the charge delivered per pulse had a significant influence on the magnitude of the block (ANOVA, p = 0.003), and was focal (< 2 mm range).ConclusionsThis study has determined the range of frequencies, duty cycles and currents of high frequency stimulation that generate an efficacious, focal axonal block of a predominantly C-fiber tract. These findings could have potential application for the treatment of type 2 diabetes.

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Vagus Nerve Stimulation Reduces Indomethacin-Induced Small Bowel Inflammation.

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