Over 2.5 million people around the world are currently suffering from chronic spinal cord injury (SCI) with over 130,000 newly diagnosed individuals each year. In the majority of cases, the damage results from physical trauma such as car accidents, falls, gunshot wounds and sports injuries, but it can also result from non-traumatic causes such as infection, insufficient blood flow, and tumours. Just over half of injuries affect the cervical spine, which is the upper part of the spinal column that corresponds to the area of the neck and shoulders.
These injuries often result in loss of muscle function, sensation, or autonomic function in the parts of the body nerved by the spinal cord below the level of the injury. A spinal cord injury can be complete, with a total loss of sensation and muscle function, or incomplete, with some nervous signals able to travel across the injured area of the spinal cord to the respective body areas. Depending on the location and severity of the damage, the symptoms may vary, from numbness to paralysis and chronic pain and control of body temperature. Some level of dysfunction occurs in every organ system, such as bowel or bladder incontinence and sexual function. Long-term outcomes after spinal cord injury also vary, from full recovery to permanent tetraplegia (permanent loss of the ability to move or feel all four limbs) or paraplegia (loss of the ability to move or feel the legs and lower part of the body). Spinal cord injuries specifically can result in full or partial tetraplegia, carrying a great significance, especially since most of the affected patients are aged 30 or younger.
The treatment of spinal cord injuries can in some cases involve early surgery. However, dealing with the complications often involves extended physiotherapy, occupational therapy, as well as social worker and psychologist input in order to help the patient set goals and develop a plan of discharge. It seems that regaining upper extremity and hand function is one of the most important goals for most patients with tetraplegia, since even a partial re-establishment of lost upper-limb function will significantly improve their quality of life.
Recently, there have been some promising results in a laboratory setting with the use of new methods, including medications, intense motor retraining and epidural spinal cord stimulation (using electrical currents on the lower spinal cord to stimulate the nerves directly by bypassing the traditional brain-to-spinal-cord pathways). Serotonin drugs (medications that modulate the function of the neurotransmitter serotonin in the body) have been shown to have positive effects on the recovery of mobility after SCI. The efficacy of epidural spinal cord stimulation has also been demonstrated in chronic paraplegic SCI patients, leading to the recovery of both lower-limb control as well as postural function.
The possibility that these methods might restore upper-extremity function has led Dr Reggie Edgerton and his team at UCLA to investigate the possibility of combination strategies – such as the pairing of electrical stimulation with pharmacological agents – in order to induce a synergistic, therapeutic effect on upper-extremity functional restoration. This approach has been demonstrated with the legs and control of the trunk, which provides stability when sitting.
Investigating the improvement of upper-limb function
Enabling motor control by epidural electrical stimulation of the spinal cord is a promising therapeutic technique for the recovery of motor function after an SCI. Although epidural electrical stimulation has resulted in improvement in hindlimb motor function, it has so far been unknown whether it has any therapeutic benefit for improving forelimb function after a cervical SCI.
The team at UCLA conducted an initial study on the properties of the spinal cord in response to epidural stimulation in rats, by testing whether electric pulses delivered at cervical spinal cord segments would facilitate the recovery of forelimb fine motor control after a cervical SCI. They also investigated how the neuromuscular system of the forelimbs reorganise and lead to improved function. The results showed that cervical epidural stimulation rapidly increased reaching and grasping success rates in rats compared to no stimulation.
In order to demonstrate the potential efficacy of epidural stimulation of the cervical spine in humans, the team initially tested the handgrip function in two severely injured tetraplegia patients (Lu et al 2016). This was the first demonstration that epidural stimulation could be used to enhance upper-limb function. A similar study conducted by the team showed for the first time that a non-invasive transcutaneous spinal stimulation technique (a less invasive method with access to the nerves through the skin) increased handgrip function by 300% in tetraplegic subjects within a four-week period, with just two hourly sessions per week (Gad et al 2018).
A later study included six tetraplegic patients in a study of upper-limb function in response to transcutaneous stimulation, combined with the administration of the drug buspirone. The results were not conclusive here, but it appeared that some of the participants benefited from buspirone and particularly from buspirone in combination with stimulation. Another interesting observation three months after the intervention was that several of the patients dramatically improved after the experiment, suggesting that they continued to regain function after the initial treatment and recovery.
This delayed finding suggests that the improved function is highly dependent on the use of the upper limbs. Specifically, as the subject regains new functional connections to the muscles, new opportunities arise to perform a wider range of movements and become more competent in performing different daily tasks. In their latest studies on humans, as well as in rats, the team has demonstrated some of the electrophysiological properties of the cervical spinal networks that have reorganised and formed new connections, demonstrating that there are multiple combinations of neural connections available to perform the same movement. This feature of our nervous system was demonstrated clearly over a century ago, resulting in the concept of ‘redundancy’ in the nervous system.
Buspirone facilitates forelimb recovery in rats
It is worth looking in more detail at one of the team’s studies on rats. In order to compare the beneficial effects of buspirone to the beneficial effects of fluoxetine (a medication commonly used as an antidepressant) on the improvement of forelimb motor function after an injury to the spinal cord at the level of the fourth vertebra, Dr Edgerton and his team organised an experimental study using rats.
The rats were initially trained on a reaching and grasping task before the experiment. The trained rats then underwent surgery to implant the necessary electrodes for the electrical stimulation and in order to record muscle activity patterns. Later, they had surgery in order to inflict an incomplete spinal cord injury at cervical level C4 (or bilateral dorsal funiculi crush).
The injury reduced the rat reaching and grasping performance as expected. There were a number of tests performed afterwards with the use of buspirone, fluoxetine or none of the two. The use of buspirone improved the forelimb performance in rats rapidly within only two weeks, however it was observed that their performance decreased after the discontinuation of the medication. The treatment with fluoxetine, on the other hand, revealed a more progressive improvement of performance over a longer period of eight weeks. Both medications showed promising results. The reorganisation of functionally available and novel connections improved food retrieval success rate after injury over time. These new neural networks allowed the brain and the spinal cord to perform similar movements as before injury by using different patterns of activation and combination of muscles. This experiment was important because it also gave the team significant information on the effective dosages of the medications required, in combination with electrical stimulation, in order to have optimal outcomes.
Improving handgrip in humans
As mentioned above, the team’s previous study on chronic SCI patients with tetraplegia, revealed that a combination of buspirone and non-invasive stimulation (small electrodes placed on the skin along the neck region of the spine) improved the sensation of temperature and touch, and strength and voluntary control of the upper limbs. These results confirmed that the cervical spinal networks can, as with the lower spinal cord circuits, be re-engaged and/or reformed through electrical and pharmacological stimulation in order to help the patient regain coordinated muscle functionality.
These initial hopeful results, in combination with the more detailed and accurate information obtained from the above experiment on rats, have given this team as well as other teams the confidence to take the next step and design future studies on humans which will include a larger number of participants. These studies will be necessary to support the already highly promising outcomes and to receive FDA approval of this new procedure. The priority focus will be the administration of more precise dosages of the serotonergic medication, something that will require careful examination of optimal dosage in humans, similar to how it was previously done in the animal model.
- Jin, B, Alam, M, Tierno, A, et al, (2021) Serotonergic Facilitation of Forelimb Functional Recovery in Rats with Cervical Spinal Cord Injury. Neurotherapeutics, 18, 1226–1243. doi.org/10.1007/s13311-020-00974-8
- Freyvert, Y, Yong, NA, Morikawa, E, et al, (2018). Engaging cervical spinal circuitry with non-invasive spinal stimulation and buspirone to restore hand function in chronic motor complete patients. Scientific Reports, 8, 15546. doi.org/10.1038/s41598-018-33123-5
- Gad, P, Lee, S, Terrafranca, N, et al, (2018) Non-Invasive Activation of Cervical Spinal Networks after Severe Paralysis. J Neurotrauma. 35(18), 2145–2158. doi.org/10.1089/neu.2017.5461
- Lu, DC, Edgerton, VR, Modaber, M, et al, (2016) Engaging Cervical Spinal Cord Networks to Reenable Volitional Control of Hand Function in Tetraplegic Patients. Neurorehabil Neural Repair. 30(10), 951–962. doi.org/10.1177/1545968316644344
Dr Reggie Edgerton and his team assess methods of regaining control in the mammalian spinal cord after injury.
Walkabout Foundation, Dana & Albert R Broccoli Charitable Foundation and Nanette and Burt Forester, including matching by PwC LLP, Roberta Wilson, BEL13VE in Miracles Jack Jablonski Foundation, Christopher and Dana Reeve Foundation, National Institute of Biomedical Imaging and Bioengineering (NIBIB) and National Institute of Neurological Disease and Stoke (NINDS).
The present findings are totally dependent on a long-term team of coworkers, particularly, Yury Gerasimenko, Parag Gad, Hui Zhong, Roland Roy, Dan Lu, and Niranjala Tillakaratne.
Dr Edgerton is a Professor in the Department of Neurobiology at UCLA, focusing on how neural networks in the mammalian spinal cord regain control of standing, stepping, and fine movements as well as bladder, bowel, and sexual functions after paralysis, and how these motor functions are modified by chronic activity-dependent interventions after spinal cord injury.
Dept of Neurobiology, 73210 CHS
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