Enhancing plasticity in central networks improves motor and sensory recovery after nerve damage

Eric C Meyers,Nimit Kasliwal,Seth A Hays,Abigail Berry,Elaine Lai,Bleyda R Solorzano,Mario Romero-Ortega,Robert L Rennaker,Geetanjali Bendale,Michael P Kilgard,Patrick D Ganzer

doi:10.1038/s41467-019-13695-0

Abstract

Nerve damage can cause chronic, debilitating problems including loss of motor control and paresthesia, and generates maladaptive neuroplasticity as central networks attempt to compensate for the loss of peripheral connectivity. However, it remains unclear if this is a critical feature responsible for the expression of symptoms. Here, we use brief bursts of closed-loop vagus nerve stimulation (CL-VNS) delivered during rehabilitation to reverse the aberrant central plasticity resulting from forelimb nerve transection. CL-VNS therapy drives extensive synaptic reorganization in central networks paralleled by improved sensorimotor recovery without any observable changes in the nerve or muscle. Depleting cortical acetylcholine blocks the plasticity-enhancing effects of CL-VNS and consequently eliminates recovery, indicating a critical role for brain circuits in recovery. These findings demonstrate that manipulations to enhance central plasticity can improve sensorimotor recovery and define CL-VNS as a readily translatable therapy to restore function after nerve damage.

Highlights

Nerve damage can cause chronic, debilitating problems including loss of motor control and paresthesia, and generates maladaptive neuroplasticity as central networks attempt to compensate for the loss of peripheral connectivity
Because closed-loop vagus nerve stimulation (CL-VNS) reduced the abnormal co-recruitment of digit flexion—elbow flexion movements resulting from nerve injury (Fig. 2c), we investigated whether an anatomical correlate could explain this finding
We evaluated plasticity and recovery after nerve damage in a group of rats treated with a celltype specific immunotoxin to deplete acetylcholine in the brain, a neuromodulator known to be required for CL-VNS-dependent plasticity[20]

Summary

Introduction

Nerve damage can cause chronic, debilitating problems including loss of motor control and paresthesia, and generates maladaptive neuroplasticity as central networks attempt to compensate for the loss of peripheral connectivity. Even after successful nerve regeneration, peripheral damage precipitates lasting changes throughout the central nervous system, as injured axons in the damaged nerve sprout, regrow, and establish new connections with both appropriate and aberrant targets[5,6] This includes extensive reorganization of synaptic connectivity in regions of the brain and spinal cord that control motor and sensory function. We observe that CL-VNS reverses the maladaptive expansion of cortical circuits resulting from nerve damage and restores the descending drive of injured networks in the absence of observable effects on peripheral nerve or muscle health. These changes are paralleled by the enhancement of motor and sensory recovery

Methods

Results

Conclusion