Reorganization of Motor Cortex by Vagus Nerve Stimulation Requires Cholinergic Innervation

Abstract

Background Vagus nerve stimulation (VNS) paired with forelimb training drives robust, specific reorganization of movement representations in the motor cortex. The mechanisms that underlie VNS-dependent enhancement of map plasticity are largely unknown. The cholinergic nucleus basalis (NB) is a critical substrate in cortical plasticity, and several studies suggest that VNS activates cholinergic circuitry. Objective We examined whether the NB is required for VNS-dependent enhancement of map plasticity in the motor cortex. Methods Rats were trained to perform a lever pressing task and then received injections of the immunotoxin 192-IgG-saporin to selectively lesion cholinergic neurons of the NB. After lesion, rats underwent five days of motor training during which VNS was paired with successful trials. At the conclusion of behavioral training, intracortical microstimulation was used to document movement representations in motor cortex. Results VNS paired with forelimb training resulted in a substantial increase in the representation of proximal forelimb in rats with an intact NB compared to untrained controls. NB lesions prevent this VNS-dependent increase in proximal forelimb area and result in representations similar to untrained controls. Motor performance was similar between groups, suggesting that differences in forelimb function cannot account for the difference in proximal forelimb representation. Conclusions Together, these findings indicate that the NB is required for VNS-dependent enhancement of plasticity in the motor cortex and may provide insight into the mechanisms that underlie the benefits of VNS therapy.

Vagus nerve stimulation paired with tactile training improved sensory function in a chronic stroke patient

“…Repeatedly pairing brief bursts of VNS with sensory or motor events drives robust, event-specific plasticity in neural circuits Porter, 2012). Lesion of the cholinergic neurons in the basal forebrain is sufficient to prevent the cortical motor map plasticity caused by VNS-movement pairing, highlighting the role of neuromodulatory systems in VNSdependent enhancement of plasticity (Hulsey, 2016). These studies suggest that it will be important to pay careful attention to patient medication and comorbid conditions that might interfere with neuromodulator function.…”

“…VNS is used to reduce seizure frequency in some patients with epilepsy (Howland, 2014) with a 30 seconds on, 5 minutes off stimulation paradigm. Animal research indicates that brief, 0.5 second bursts of 0.8 mA VNS triggers release of norepinephrine and acetylcholine in the cerebral cortex, which can restore synaptic connectivity after brain injury and improve function if delivered during rehabilitative training , 2014, Hulsey, 2016, 2017, Khodaparast, 2013Nichols, 2011;Porter, 2012;Pruitt, 2016). It is not yet known, whether brief bursts of VNS paired with tactile discrimination training can improve the recovery of sensory function after stroke.…”

Vagus nerve stimulation during rehabilitative training enhances recovery of forelimb function after ischemic stroke in aged rats

“…Stimulation of the vagus nerve increases levels of these neuromodulators, as well as brain derived neurotrophic factor, providing a clear link to plasticity and recovery after injury (Conner et al, 2005; Follesa et al, 2007; Furmaga et al, 2012; Roosevelt et al, 2006). A reduction in either noradrenergic or cholinergic function prevents the effects of VNS on the central nervous system, including VNS-dependent enhancement of cortical plasticity (Hulsey et al, 2016; Krahl et al, 1998; Nichols et al, 2011). Temporal dissociation of VNS delivery and rehabilitative training significantly decreases VNS-dependent recovery after stroke, providing further indication that enhanced-plasticity underlies recovery (Khodaparast et al, 2014, 2015).…”

Forelimb training drives transient map reorganization in ipsilateral motor cortex

“…After the completion of training, standard short-duration ICMS [21,22] was performed in the right hemisphere, and both left-side (contralateral) and right-sided (ipsilateral) movements were evaluated by an experimenter blinded to the rat’s experimental condition. Rats were anesthetized with a cocktail of ketamine hydrochloride (50 mg/kg), xylazine (20 mg/kg), and acepromazine (5 mg/kg) injected intramuscularly.…”

“…Stimulation sites were chosen randomly, with an effort made to ensure that each site was at least 1 mm in distance from the immediately previous penetration. Each stimulation consisted of a 40 ms pulse train of ten 200-µs monophasic cathodal pulses delivered at 286 Hz [21,22]. A maximum stimulation intensity of 300 µA was used to determine the presence of any ipsilateral (right) forelimb response to stimulation.…”