Fig. 6: Proposed mechanism underlying VNS-mediated enhanced plasticity and recovery after nerve damage.

a Prior to injury, the majority of motor cortex evokes movements of the digit flexors through the median and ulnar nerves, and a small area evokes movements of the extensor muscles through the radial nerve. Subjects are able to grasp and pull a handle to generate around 150 g of force. b Damage to the median and ulnar nerves generates maladaptive changes in central networks. Cortical drive and synaptic connectivity within the injured digit flexion networks is reduced. In conjunction, networks innervated through the spared radial nerve demonstrate a pathological cortical expansion. Despite reinnervation and rehabilitative training, subjects continue to exhibit maladaptive central changes and long-term deficits in force generation. c Closed-loop VNS paired with forelimb movement during rehabilitation generates timed activation of neuromodulatory networks, including the cholinergic nucleus basalis (NB). This precisely timed neuromodulation enhances synaptic connectivity and cortical drive to increase output to muscles via the reinnervated median and ulnar nerves. Correspondingly, CL-VNS reverses the pathological expansion of extensor networks controlled via the spared radial nerve. Motor function is recovered in the absence of large scale peripheral changes in the nerves or muscle, indicating that central changes can compensate and restore function. d Lesion of the nucleus basalis (NB) prevents acetylcholine release and consequently CL-VNS-dependent central plasticity. No reorganization of central networks was observed in subjects with NB lesions that received CL-VNS. NB lesions prevented the enhanced recovery seen with CL-VNS, providing a causal link between enhanced central reorganization and improved recovery after nerve damage. e CL-VNS is based on precise timing between the activation of neuromodulatory networks and neural activity during rehabilitation. A matched amount of VNS delayed by 2 h from equivalent rehabilitation degrades the temporal association and prevents CL-VNS-dependent plasticity in central networks. Consequently, subjects that receive Delayed VNS fail to demonstrate enhanced recovery of function. This illustrates that timing-independent effects of VNS cannot account for enhanced recovery, and reinforces the notion that plasticity in central networks directed by CL-VNS supports the recovery of motor and sensory function after nerve damage.