Restoring Sensorimotor Function Through Neuromodulation After Spinal Cord Injury: Progress and Remaining Challenges

Abstract

Spinal cord injury (SCI) is a major disability that results in motor and sensory impairment and extensive complications for the affected individuals which not only affect the quality of life of the patients but also result in a heavy burden for their families and the health care system. Although there are few clinically effective treatments for SCI, research over the past few decades has resulted in several novel treatment strategies which are related to neuromodulation. Neuromodulation-the use of neuromodulators, electrical stimulation or optogenetics to modulate neuronal activity-can substantially promote the recovery of sensorimotor function after SCI. Recent studies have shown that neuromodulation, in combination with other technologies, can allow paralyzed patients to carry out intentional, controlled movement, and promote sensory recovery. Although such treatments hold promise for completely overcoming SCI, the mechanisms by which neuromodulation has this effect have been difficult to determine. Here we review recent progress relative to electrical neuromodulation and optogenetics neuromodulation. We also examine potential mechanisms by which these methods may restore sensorimotor function. We then highlight the strengths of these approaches and remaining challenges with respect to its application.

Keywords: electrical stimulation modulation; neural circuits; neuromodulation; optogenetics; sensorimotor function; spinal cord injury.

Figure 1

Neuromodulation approaches for restoring function after spinal cord injury. Neuromodulation includes pharmacological modulation, electrical modulation and optogenetics modulation. Electrical modulation approaches are grouped by the stimulation location, including brain stimulation (deep brain stimulation, direct motor cortex stimulation), spinal cord stimulation (epidural electrical stimulation), peripheral stimulation (functional electrical stimulation) and brain-machine interface.

Figure 2

Mechanisms of electrical modulation and optogenetics modulation in the treatment of spinal cord injury. (A) There are three potential mechanisms by which electrical stimulation regulation promotes sensorimotor function repair after spinal cord injury: (1) cortical stimulation promotes regeneration of the free ends of the CST; (2) spinal cord stimulation can promote the formation and activation of circuits established by spared PNs that lead to the re-emergence of locomotion and sensation when SCI results in disruption of the flow of motor instructions from the brain and brainstem to the spinal motor circuits; and (3) electrical modulation can recruit proprioceptive afferents, which have been proposed to be the most influential in regaining volitional control of affected muscles, and rebuild the sensorimotor circuits which were disruption when spinal cord injury. PNs, propriospinal neurons; INs, interneurons; MNs, motoneurons. S, sensory neurons. The blue and green dotted lines show the rebuild of neuronal connections after electrical modulation. (B) Overview of the optogenetics system. The implanted optical fiber is guided to the target tissue, and the target neuron is activated or inhibited by illumination with blue or yellow light. Specific neurons in the cerebral cortex or spinal cord are simplified into two green neuron patterns in the figure. Blue light (470-nm wavelength) changes the conformation of the transmembrane ion channel protein ChR2, allowing positively charged ions to flow into the cytoplasm, leading to depolarization of neurons. Yellow light (580-nm wavelength) alters the conformation of the transmembrane ion pump protein HR, which allows negatively charged ions to enter the cytoplasm, leading to hyperpolarization of neurons.