Vagus nerve stimulation during rehabilitative training improves forelimb strength following ischemic stroke
Introduction
Stroke is the second most common cause of disability worldwide (Leary and Saver, 2003). Ischemic stroke causes neural death due to inadequate blood flow, often resulting in movement impairments on the opposite side of the body (Deb et al., 2010, Lo et al., 2003). Seventy-five percent of patients who survive an ischemic stroke continue to have significant weakness in the upper extremities even after extensive rehabilitative therapy (Harvey and Nudo, 2007, Kwakkel, 2009, Levine and Greenwald, 2009). Impaired limb function reduces the ability to perform activities of daily living, reduces the quality of life, and increases medical costs (King, 1996, Whyte et al., 2004). The development of an effective therapy to restore motor function would fulfill a large unmet clinical need.
Physical rehabilitation after stroke drives plasticity in the form of reorganization of cortical circuitry in the motor system (Johansson, 2000, Nudo, 2003, Rossini and Forno, 2004, Schaechter, 2004, Ward and Cohen, 2004). One common rehabilitative intervention, constraint induced movement therapy (CIMT) causes reorganization of the motor cortex map of arm movement (Sawaki et al., 2008, Schaechter et al., 2002). Additionally, new methods using virtual reality and electrical stimulation of motor cortex may also promote increased synaptic plasticity and cortical reorganization within the motor cortex (Adkins-Muir and Jones, 2003, Lindenberg et al., 2012, You et al., 2005). The development of additional methods to increase neural plasticity may lead to improved recovery of motor function (Hallett, 2001, Nudo, 2003). We have recently developed a method to induce specific and long-lasting cortical map plasticity by pairing vagus nerve stimulation (VNS) with movements or sensory stimuli in intact rats (Engineer et al., 2011, Porter et al., 2011). Repeatedly delivering VNS with forelimb movements resulted in movement-specific map plasticity within the primary motor cortex beyond training without VNS (Porter et al., 2011). We hypothesized that this enhancement in reorganization within the motor cortex may improve recovery of function after stroke.
Upper limb strength is one of the best prognostic indicators for arm function and chronic disability following stroke (Harris and Eng, 2007, Mercier and Bourbonnais, 2004, Sunderland et al., 1989). Here, we evaluated whether the delivery of VNS during rehabilitative training can enhance recovery of forelimb strength in a model of ischemic stroke. Rats were trained to perform an isometric force task that quantitatively measures forelimb force generation (Hays et al., 2012). This task is fully automated, allowing the experimenter to test several animals simultaneously and avoid the possibility of experimenter bias. Unilateral injections of a peptide vasoconstrictor, endothelin-1, into primary motor cortex caused an ischemic infarct and impaired function of the trained forelimb (Fang et al., 2010, Gilmour et al., 2004, Hays et al., 2012). Rats underwent rehabilitative training for five weeks with or without the delivery of VNS. No VNS was delivered on week six to allow evaluation of persistent effects. VNS delivered during rehabilitative training restored pull force generation back to pre-lesion levels, whereas extensive rehabilitative training without VNS failed to restore function. These findings suggest that VNS paired with physical rehabilitation may hold promise for enhancing recovery of upper extremity function after stroke.
Section snippets
Subjects
Nineteen adult female Sprague–Dawley rats, approximately 4 months old and weighing approximately 250 g when the experiment began, were used in this experiment. The rats were housed in a 12:12 h reversed light cycle environment so that behavioral testing took place during the dark cycle in order to increase daytime activity levels. Rats were food deprived to no less than 85% of their normal body weight during training as motivation for the food pellet rewards. This study was designed to take into
Rats acquire skilled performance of the isometric force task
To assess forelimb function in the context of stroke, rats were trained to perform the isometric force task, a behavioral test that quantitatively assesses multiple parameters of forelimb function (Hays et al., 2012). The task requires rats to reach out and grasp a handle attached to a force transducer and apply 120 g of force to receive a food reward (Fig. 1). Rats became highly proficient at the task in 10.1 ± 0.6 days. Early in training, rats were able to generate forces up to 400 g. Highly
Discussion
This study tested whether delivering VNS during rehabilitative training could improve recovery of forelimb motor function following cortical ischemic damage compared to rehabilitative training alone. Forelimb function was assessed using the automated isometric pull task with approximately 50,000 pull attempts collected per rat, resulting in unbiased data collection and high statistical power (Hays et al., 2012). Rats received rehabilitative training on an isometric force task (Hays et al., 2012
Conclusion/implications
This study provides a proof of concept demonstration that stimulation of the vagus nerve paired with rehabilitative training can improve recovery of forelimb function in a rat model of stroke. VNS delivered during rehabilitative training fully restored forelimb force generation to pre-lesion levels. A similar amount of rehabilitative training without VNS was insufficient to restore performance. These results suggest that VNS paired with physical rehabilitation is a potentially viable new
Funding
This work was supported by MicroTransponder, Inc.
Author contributions
N.K., S.A.H., and M.P.K. wrote the manuscript. N.K., M.P.K., R.L.R., and A.M.S. designed the study. N.K., S.A.H., D.R.H., A.R., and M.P. performed behavioral testing. N.K., S.A.H., and A.M.S. analyzed the data. A.M.S. and R.L.R. provided software and hardware support. All authors discussed the results and provided comments on the manuscript.
Acknowledgments
We would like to T. Fayyaz, N. Alam, F. Naqvi, D. Cao, R. Babu, R. Gattamaraju, V. Konduru, S. Burghul, and R. Joseph for help with behavioral training.
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