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The effect of right vagus nerve stimulation on focal cerebral ischemia: an experimental study in the rat - PubMed

The effect of right vagus nerve stimulation on focal cerebral ischemia: an experimental study in the rat

Zhenghui Sun et al. Brain Stimul. 2012 Jan.

Abstract

Background: The aim of this study was to determine the effect of vagus nerve stimulation (VNS) on infarct size after transient and after permanent focal cerebral ischemia in rats and to test the hypothesis that VNS-induced neuroprotection is due to changes in cerebral blood flow.

Methods: Ischemia was produced by either temporary proximal middle cerebral artery occlusion (TMCAO) or permanent distal middle cerebral artery occlusion (PMCAO). Stimulating electrodes were implanted on the cervical part of the right vagus nerve, and electrical stimulation was initiated 30 minutes after the induction of ischemia and delivered for 30 seconds every 5 minutes for 1 hour. All the procedures were duplicated but no stimulus was delivered in control groups. Cerebral blood flow in the MCA territory was continuously monitored with laser speckle contrast imaging. A neurologic evaluation was undertaken after 24 hours of ischemia, and animals were euthanized and neuronal damage evaluated.

Results: Ischemic lesion volume was smaller in VNS-treated animals in both the temporary and permanent ischemic groups (P<.01). VNS-treated animals in TMCAO had better functional scores at 24 hours as compared with control animals (P<.01), but there were no statistically significant differences in the neurobehavioral scores in PMCAO (P=.089). Cerebral blood flow changes in the MCA territory during ischemia did not differ between the VNS-treated animals and control animals in either group.

Conclusions: VNS offers neuroprotection against stroke in both temporary and permanent ischemia. Although the precise mechanism of this effect remains to be determined, alterations in cerebral blood flow do not appear to play a role. VNS could readily be translated to clinical practice.

Copyright © 2012 Elsevier Inc. All rights reserved.

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Figures

Figure 1
Figure 1

Schematic of experimental protocol for the temporary middle cerebral artery occlusion (TMCAO) studies which involved filament occlusion along with right common carotid occlusion (rCCAO) (A) and the permanent middle cerebral artery occlusion (PMCAO) studies produced by photothrombosis along with rCCAO (B). Changes in regional cerebral blood flow (CBF) were monitored with laser speckle contrast imaging. Over the first 30 minutes following MCA occlusion, the vagal nerve was not stimulated, with vagal nerve stimulation (VNS) starting 30 minutes into ischemia and lasting for 60 minutes.

Figure 2
Figure 2

Systemic arterial pressure (SAP) (A, C) and heart rate (HR) (B, D) for the TMCAO (A, B) and PMCAO (C, D) studies. For the first 30 minutes following MCA occlusion the vagus nerve was not stimulated (NS1), for the next 60 minutes the vagus nerve was stimulated (Stim); physiological parameters are shown for the 30 minutes after the end of stimulus (NS2). In panels B and D the heart rate is shown during the four minutes immediately preceding each pulse train (Pre-VNS) and for the 30 seconds of stimulation (VNS). Blood pressure increased equally with MCA occlusion, independent of VNS stimulation. Vagal nerve stimulation did produce a significant decrease in heart rate in both the transient and permanent studies. * p<0.05 in comparison to baseline; † p<0.02, # p<0.005 in comparison to no VNS stimulation. Data are shown as mean ± SEM. There were eight animals in each of the four groups (TMCAO control, TMCAO VNS, PMCAO control, PMCAO VNS).

Figure 3
Figure 3

Cerebral blood flow in the MCA territory (circles) and in the boundary zone (triangles) as determined from laser speckle contrast imaging during and following temporary MCA occlusion. Changes in flow are shown as a fraction of the baseline (pre-ischemia) flow. The open symbols are from the groups not receiving vagus nerve stimulation and the close symbols are from stimulated animals. VNS did not produce any change in blood flow. Data are shown as mean ± SEM. The symbols are slightly time-shifted so as to more easily visualize the data. There were eight animals in each group.

Figure 4
Figure 4

Speckle images showing changes in cerebral blood flow (CBF) with respect to blood flow just prior to filament occlusion of the MCA. The image on the left (A) was obtained following MCA occlusion but prior to start of vagus nerve stimulation, while the image on the right (B) was obtained during a 30 second train of stimulation pulses to the vagus nerve. There is a dramatic decrease in CBF in the MCA territory. Note the similarity of the two images with no apparent increase in CBF due to stimulation. The numbers on the color scale are fractions of the pre-occlusion CBF and the scale bar in panel A is 1 mm.

Figure 5
Figure 5

Cerebral blood flow in the MCA territory (circles) and in the peri-infarct territory (triangles) as determined from laser Doppler flowmetry (LDF) during and following permanent MCA occlusion. Changes in flow are shown as a fraction of the baseline (pre-ischemia) flow. The open symbols are from the groups not receiving vagus nerve stimulation and the close symbols are from stimulated animals. VNS did not produce any change in blood flow. Data are shown as mean ± SEM. There were eight animals in each group.

Figure 6
Figure 6

Infarct volume in animals in the transient ischemia study with (closed circles) and without (open circles) vagus nerve stimulation (VNS) in the cerebral cortex (left panel), the striatum (center panel), and in the total brain (right panel). * p<0.005 with respect to unstimulated group. There were eight animals in each group.

Figure 7
Figure 7

Infarct volume in animals in the permanent ischemia study with (closed circles) and without (open circles) vagus nerve stimulation (VNS). * p<0.02 with respect to unstimulated group. There were eight animals in each group.

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