Exp Neurol. 2017 May;291:141-150. doi: 10.1016/j.expneurol.2017.02.006.

Electrical neuromodulation of the cervical spinal cord facilitates forelimb skilled function recovery in spinal cord injured rats.

Alam M1, Garcia-Alias G1, Jin B1, Keyes J1, Zhong H1, Roy RR2, Gerasimenko Y3, Lu DC4, Edgerton VR5.
1 Department of Integrative Biology and Physiology, University of California, Los Angeles, CA 90095, United States.
2 Department of Integrative Biology and Physiology, University of California, Los Angeles, CA 90095, United States; Brain Research Institute, University of California, Los Angeles, CA 90095, United States.
3 Department of Integrative Biology and Physiology, University of California, Los Angeles, CA 90095, United States; Pavlov Institute of Physiology, St. Petersburg 199034, Russia; Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan 420006, Russia.
4 Departments of Neurosurgery, University of California, Los Angeles, CA 90095, United States.
5 Department of Integrative Biology and Physiology, University of California, Los Angeles, CA 90095, United States; Brain Research Institute, University of California, Los Angeles, CA 90095, United States; Departments of Neurobiology, University of California, Los Angeles, CA 90095, United States; Departments of Neuroscience, University of California, Los Angeles, CA 90095, United States. Electronic address: vre@ucla.edu.

 

Abstract

Enabling motor control by epidural electrical stimulation of the spinal cord is a promising therapeutic technique for the recovery of motor function after a spinal cord injury (SCI). Although epidural electrical stimulation has resulted in improvement in hindlimb motor function, it is unknown whether it has any therapeutic benefit for improving forelimb fine motor function after a cervical SCI. We tested whether trains of pulses delivered at spinal cord segments C6 and C8 would facilitate the recovery of forelimb fine motor control after a cervical SCI in rats. Rats were trained to reach and grasp sugar pellets. Immediately after a dorsal funiculus crush at C4, the rats showed significant deficits in forelimb fine motor control. The rats were tested to reach and grasp with and without cervical epidural stimulation for 10weeks post-injury. To determine the best stimulation parameters to activate the cervical spinal networks involved in forelimb motor function, monopolar and bipolar currents were delivered at varying frequencies (20, 40, and 60Hz) concomitant with the reaching and grasping task. We found that cervical epidural stimulation increased reaching and grasping success rates compared to the no stimulation condition. Bipolar stimulation (C6- C8+ and C6+ C8-) produced the largest spinal motor-evoked potentials (sMEPs) and resulted in higher reaching and grasping success rates compared with monopolar stimulation (C6- Ref+ and C8- Ref+). Forelimb performance was similar when tested at stimulation frequencies of 20, 40, and 60Hz. We also found that the EMG activity in most forelimb muscles as well as the co-activation between flexor and extensor muscles increased post-injury. With epidural stimulation, however, this trend was reversed indicating that cervical epidural spinal cord stimulation has therapeutic potential for rehabilitation after a cervical SCI.

KEYWORDS: Cervical spinal cord injury; Corticospinal tract; Epidural electrical stimulation; Motor-evoked potentials; Reaching and grasping

PMID: 28192079

 

Supplement:

Restoration of arm and hand function is one of the highest priorities of individuals with a cervical SCI (Anderson, 2004). We had previously demonstrated that epidural electrical stimulation at cervical spinal cord segments improves grip strengths of cervical SCI rats (Alam et al., 2015) and humans (Lu et al., 2016). In the current study, we ask if similar stimulation with selected stimulation parameters can facilitate functional reaching and grasping movements in cervical SCI rats.

We had trained adult long-Evans rats to reach and grasp sugar pellets. After the rats mastered the reaching task, we had implanted intramuscular EMG electrodes in several forelimb muscles and epidural stimulation electrodes at the cervical spinal cord segments C6 and C8. After recovery, reaching scores were recorded along with baseline EMG patterns followed by a dorsal funiculi crush injury at C4 spinal cord. The rats showed significant deficits in forelimb fine-motor function due to this injury. The rats were tested to reach and grasp with and without epidural spinal cord stimulation during 10 weeks post-injury. The results suggest that reaching scores were higher during and post-stimulation compared to pre-stimulation as shown in Fig. 1. An important observation here is that not only does the stimulation have acute effects but there are chronic effects which result from repeated treatments. Further experiments will be necessary to determine how long the acute effects lasts after a single treatment session.

 

 

Fig. 1. Mean (± SEM) success rates for reaching and grasping of the rats before stimulation (gray bars), during epidural stimulation (red bar) and after epidural stimulation (orange bars). Pre-injury vs. post-injury before stimulation (†p < 0.05). Pre-stimulation vs. with stimulation (*p < 0.05) and post-stimulation (*p < 0.05).

 

The spinal injury resulted in an increase of EMG activities during reaching and grasping. The EMG amplitude continue to increase in the later weeks (as shown in Fig. 2) showing higher levels of excitation of each of the motor pools studied of spinal cord circuits with the loss of supraspinal inputs due to the cervical cord injury. The mechanism for this is unknown, but these results are consistent with an increase in aberrant connections leading to impaired coordination among motor pools. This phenomenon has been observed in several studies of motor function during the recovery process from spina cord injury.

 

 

Figure 2. Mean (± SEM) integrated EMG values during reaching and grasping without stimulation in intact and at different weeks post-injury. EMG activities of the muscles were significantly higher at post-injury compared to pre-injury when performing the task (*p < 0.05).

 

With cervical epidural stimulation, the EMG activity of the forelimb muscles decreased. Fig. 3 shows the effects of two bipolar stimulations (C6- C8+ and C6+ C8-) on EMG amplitudes during reaching and grasping task.

 

 

Figure 3. Mean (± SEM) integrated EMG values obtained before stimulation and during bipolar stimulations at 10 weeks post-injury.

 

Electrically enabling motor control (eEmc) via epidural stimulation of spinal cord is a promising therapeutic technique for the recovery of motor function after a spinal cord injury (Edgerton and Roy, 2012). While eEmc has already proven to be effective on recovering lower-limb functions for SCI paraplegics, our current data along with the previous finding (Alam et al., 2015) indicate that eEmc has therapeutic potential for rehabilitation after cervical SCI as well.

 

References:

Alam M, Garcia-Alias G, Shah PK, Gerasimenko Y, Zhong H, Roy RR, Edgerton VR (2015) Evaluation of optimal electrode configurations for epidural spinal cord stimulation in cervical spinal cord injured rats. Journal of Neuroscience Methods 247:50-57.

Anderson KD (2004) Targeting recovery: priorities of the spinal cord-injured population. J Neurotrauma 21:1371-1383.

Edgerton VR, Roy RR (2012) A new age for rehabilitation. Eur J Phys Rehabil Med 48:99-109.

Lu DC, Edgerton VR, Modaber M, AuYong N, Morikawa E, Zdunowski S, Sarino ME, Sarrafzadeh M, Nuwer MR, Roy RR, Gerasimenko Y (2016) Engaging cervical spinal cord networks to reenable volitional control of hand function in tetraplegic patients. Neurorehabilitation and Neural Repair.