Restoring After Central Nervous System Injuries: Neural Mechanisms and Translational Applications of Motor Recovery

Abstract

Central nervous system (CNS) injuries, including stroke, traumatic brain injury, and spinal cord injury, are leading causes of long-term disability. It is estimated that more than half of the survivors of severe unilateral injury are unable to use the denervated limb. Previous studies have focused on neuroprotective interventions in the affected hemisphere to limit brain lesions and neurorepair measures to promote recovery. However, the ability to increase plasticity in the injured brain is restricted and difficult to improve. Therefore, over several decades, researchers have been prompted to enhance the compensation by the unaffected hemisphere. Animal experiments have revealed that regrowth of ipsilateral descending fibers from the unaffected hemisphere to denervated motor neurons plays a significant role in the restoration of motor function. In addition, several clinical treatments have been designed to restore ipsilateral motor control, including brain stimulation, nerve transfer surgery, and brain-computer interface systems. Here, we comprehensively review the neural mechanisms as well as translational applications of ipsilateral motor control upon rehabilitation after CNS injuries.

Keywords: Axon regrowth; Brain–computer interface system; Ipsilateral motor control; Neuroplasticity; Spinal cord injury; Stroke; Traumatic brain injury.

Fig. 1

Compensatory pathways during the acute stage after different CNS injuries. A1 After a local motor cortical lesion, significant reorganization occurs in the perilesional areas to compensate for the injured region. A2 The contralesional cortex controls the ipsilesional cortex by functional cortico-cortical connections to compensate for the lesion in a moderate cortical lesion. A3 A severe cortical lesion affects interhemispheric inhibition, while the cortex on the injured side completely loses its function, and the contralesional cortex directly controls the paretic side. B The cortico-rubro-spinal pathway is enhanced after damage to the internal capsule or brainstem pyramid. The reticulospinal tracts can be another compensatory pathway after pyramidal lesions. C After a DLF lesion, the spared propriospinal tract connecting different segments of the spinal cord plays an important role in functional recovery. D CST axons from the ipsilesional cortex sprout and cross below the lesion after hemisection of the spinal cord.

Fig. 2

The potential circuit basis and molecular mechanism for implementation of ipsilateral motor control and the cellular mechanism of axon regeneration. A Schematic organization of ipsilateral motor pathways. The mechanism of ipsilateral motor control may include the following possibilities: 1. The contralesional cortex controls the remaining CST in the impaired hemisphere by callosal fiber enhancement; 2. Synaptic connections between the contralesional cortex and the ipsilesional subcortical areas are increased; 3. The crossed CST originating from the contralesional cortex sprouts across the midline to the damage-denervated side of the spinal cord; 4. The number and activity of uncrossed CST fibers from the contralesional cortex to the affected spinal cord are increased. B Cartoon showing the difference between CST axonal sprouting and regeneration in the spinal cord. Axon growth including axon sprouting and axon regeneration. The sprouting refers to axon regrowth from intact neurons on the unaffected side, and regenerating axons arise from the cut ends of the transected axon of injured neurons. C Factors that enhance axon growth are shown in the yellow box, while factors that inhibit axon growth are shown in the blue box. Note that both CST regrowth (green) and spared CST axons (blue) aim to re-innervate the spinal cord of the affected side. D, There are two forms of axon regeneration in spinal cord injury, one in which regenerating axons cross through the glial scars, and one in which regenerating axons bypass the injury site. E Cellular mechanisms that facilitate the passage of regenerating axons across the astroglial scar. The neonatal microglia secrete fibronectin and their binding proteins to establish a bridge to the extracellular matrix and express various peptidase inhibitors to promote CST regrowth to pass through the injury site. Nerve/glial antigen 2 positive (NG2⁺) cells increase scar formation by secreting pro-inflammatory factors that impede the passage of regenerating axons through glial scars.

Fig. 3

Clinical advances for enhancing neuroplasticity to promote motor recovery. Schematic of brain stimulation systems for patients: A1 The noninvasive brain stimulation method TMS controls cortical activity via magnetic signals. A2 tES modulate the activation of cortex by low-intensity current. A3 In invasive brain stimulation systems, such as DBS, electrodes are implanted in a deep brain region and a generator is implanted in the upper chest. A4 The VNS system requires the implantation of electrodes into the vagus nerve in the left neck. B Targeted neurotechnologies for EES during overground walking in patients with SCI [187]. Upper: During training, the wireless communication environment ensures that the EES on the spinal cord can be independently adjusted in real time. An auxiliary device applies multidirectional forces to the trunk against gravity and a real-time processing system records the full-body movements, ground reaction forces, and the electrical activity of leg muscles. A 16-channels electrode paddle array with pulse generator is implanted in the lumbosacral dorsal roots that connect to specific motor neuron pools innervating different leg muscles. EES sequences under voluntary intention induce different lower extremity movements, such as hip flexors and ankle extensors. Lower: The study timeline of this system. C The mechanism and study methodology of IpsiHand [37]. Left: The EEG electrode placement strategy of IpsiHand. The recording electrodes are placed in the bilateral motor cortex (blue triangle in the contralesional motor cortex and yellow diamond in the ipsilesional motor cortex), a spatial control electrode (green pentagon) in the contralesional frontal lobe, and a spectral control electrode in the contralesional motor cortex (red dot). Right: The images above show how IpsiHand works. The exoskeleton is attached to a patient’s impaired forearm, palm, and intermediate phalanges of the index and middle finger. A microprocessor in the forearm controls the exoskeleton by an assembly that processes EEG signals. Based on the decoded EEG signals, a linear actuator drives fine hand movements in a 3-finger pinch grip.

Fig. 4

Crossing nerve transfer surgery to improve motor function by enhancing neuroplasticity in the contralesional hemisphere in patients with unilateral arm paralysis [41]. A Procedure of contralateral C7 nerve transfer surgery. After harvesting the bilateral C7 nerves in adequate sites, the C7 nerve on the non-paralyzed side (blue) is drawn behind the trachea and esophagus via a pre-spinal route to the paralyzed side (yellow) and coapted directly to the C7 nerve on the paralyzed side. B Functional MRI assessment in patients with CC7 surgery. The changes in brain activation on fMRI are evaluated during the 12 months after surgery. Left: Brain activation (yellow) during active extension of the paralyzed wrist. Before surgery, activation was only evident in the ipsilesional hemisphere. At month 8, activation began to appear in both hemispheres. Contralesional activation was enhanced and extended to a larger area than ipsilesional activation at 10 months after surgery, and it was weaker and covered a smaller region at month 12 than at month 10. Right: Brain activation (blue) during active extension of the non-paralyzed wrist. Brain activation associated with movements of the non-paralyzed wrist was stable in the contralesional hemisphere before and after surgery.

Fig. 5

A new rehabilitation strategy that integrates multiple technologies and integrates sensorimotor information to achieve ipsilateral motor control. In patients with unilateral CNS injury, sensory information from the paralyzed limb is increased by using sensors, electrical stimulation, and surgery, and specific sensory information is decoded. The decoded information is then directly transmitted to specific regions of the contralesional hemisphere by electrical stimulation. At the same time, the motor commands from the contralesional cortex are extracted, and the motor information is decoded according to the data set during training, and then the exoskeleton is directly controlled to drive the affected limb and complete the corresponding action.