By: Catherine Gooch
Background
Spinal cord injury (SCI) is a neurological condition caused by damage to the spinal cord, the long column of nervous tissue running from the low back up to the brainstem. SCI prevents motor signals that originate in the brain from reaching muscles below the injury. This leads to permanent paralysis based on the location of the injury. Injuries in the thoracic or lumbar spine can cause paralysis of the legs, known as paraplegia, while injuries in the cervical spine can cause paralysis of both the arms and legs, known as tetraplegia. The extent of the loss in muscle function also depends on the severity of the injury, so less severe injuries that leave some of the nerves intact may not cause complete paralysis. But even incomplete injuries do still impair muscle function to some extent.
Because motor function is essential for maintaining independence and quality of life, many researchers are exploring ways to promote the recovery of motor function after SCI. While there are a variety of perspectives from which to approach this problem, such as pharmacological interventions or exercise therapy (Dietz 2021), this article will focus on an exciting avenue of research that uses electrical stimulation to promote functional recovery in people with SCI.
Action Potentials
The brain communicates with the body via electrical signals called action potentials. This allows electrical stimulation to have an effect on muscle activity.
Motor signals originate in an area of the brain called the motor cortex. When neurons in this area receive a stimulus, ions such as sodium and potassium begin to rapidly flow in and out of the cell. Ions are charged particles, and their flow represents a change in the electrical potential of the neuron. During this process, the membrane potential, or the difference in electrical potential on both sides of the cell membrane, quickly depolarizes, meaning it becomes less negative. It then repolarizes once potassium flows back into the cell, and returns to its resting membrane potential of around -70 mV. This whole process of the membrane potential rapidly depolarizing and then repolarizing constitutes an action potential.
Action potentials travel along the length of the neuron, called the axon, and reach the point where the end of one neuron is just a small distance away from the beginning of another. This small space between neurons is called the synaptic cleft. Once an action potential reaches the end of a neuron, the neuron will release certain chemicals called neurotransmitters into the synaptic cleft. These neurotransmitters cause the next neuron to experience an action potential just as the one before did. This process of action potentials essentially traveling from one neuron to another is how the nervous system uses electricity to send signals throughout the body.
Motor Pathways
Once an action potential begins in the motor cortex, it needs to reach the muscles. To do this, it travels along the corticospinal pathway. This pathway takes the action potential from the motor cortex, through the brain, and then through the spinal cord. Different regions of the spinal cord control different muscles, with the cervical spine controlling the arms and hands while the lumbar spine controls the leg muscles. After reaching the appropriate spinal level, the action potential synapses with a motor neuron, sending the signal directly to the muscle and causing it to contract.
Since motor signals travel through the spinal cord, damage to the spinal cord will impair the ability for these signals to reach areas below the level of injury. As such, someone with a spinal cord injury in their lumbar or thoracic spine will still be able to use their arms and hands, but will be paralyzed below the waist, while someone who injures their cervical spine will lose function in all four limbs.
Approximate map depicting a variety of upper-limb muscles and the vertebral levels at which their motor neurons originate. Based on data from McIntyre et al., 2002.
Spinal cord stimulation
Because muscle activity is caused by electrical impulses, scientists have been able to use various types of electrical stimulation to induce motor responses, with significant clinical implications. One type of stimulation is transcutaneous spinal stimulation, or TSS. With TSS, small electrodes are placed over the skin at specific levels of the spinal cord. When the stimulation is turned on, the electricity initiates action potentials at the spinal level where the electrodes were placed. These action potentials are then conducted along motor neurons and then initiate muscle contraction.
In addition to being placed over the skin, electrodes can also be surgically implanted into the epidural space within the spinal column. This form of stimulation is known as epidural spinal stimulation, or ESS. Placing the electrodes directly adjacent to the spinal cord, rather than over the skin itself, allows stimulation to be more precise. One benefit of ESS compared to TSS is that the stimulation can be more specific. This is because epidural electrode paddles contain many very small electrodes which can be individually turned on or off. And since the paddles are implanted right next to the spinal cord, researchers can use lower intensities of stimulation compared to TSS because the signals don’t have to pass through the skin to reach their destination. But since ESS requires surgery, it is considerably less easily accessible and carries more risk than TSS, which is completely non-invasive.
Effects of stimulation on people with SCI
Although some implantable spinal cord stimulators are FDA-approved for pain management, the use of spinal cord stimulation for motor recovery in people with SCI is still experimental. Recent studies have found promising results, though.
One such study involved a 23-year old man who had lost all of his motor function in the trunk and legs after being hit by a car (Harkema et al., 2011). More than two years of physical therapy focused on walking led to no improvements, so he opted to have an electrode array implanted in his lumbar spine. After recovering from the surgery, he underwent experimental sessions where he received electrical stimulation while trainers manually helped him move his legs in a walking pattern on a treadmill, and while he practiced standing with support from hand rails. After 80 sessions, he was able to stand for more than four minutes with just ESS and no other assistance. Although he was not able to fully walk, ESS did allow the subject to move his legs in a stepping-like pattern, which was a huge improvement.
Similarly promising results have also been found using non-invasive TSS to elicit movement in the lower limbs. One study that investigated this recruited fifteen individuals with SCI and assigned them to either a real TSS group or a sham TSS group (Sayenko et al., 2019). The sham TSS mimicked the experience of real TSS, but didn’t actually elicit any motor responses in participants’ legs. In this way, it functioned as a placebo.
During the initial session, all fifteen participants practiced standing with and without continuous stimulation. Six participants then returned for twelve more sessions of stand training, three times per week over the course of four weeks. Each session lasted for two hours and involved two exercises, performed both with and without continuous TSS. In the “Circle” exercise, participants stood on a force plate and shifted their bodyweight while trying to follow a circular pattern displayed on a screen in front of them. In the “Basketball” exercise, the screen showed targets and baskets, and the participants shifted their bodyweight left and right to make the targets land in the baskets. Participants were told to try to maximize their score in these games, giving them motivation to try their best during the experimental sessions. In addition to training for the participants, these exercises also gave the researchers data about participants’ center of pressure.
The study found that without TSS, the participants required assistance in order to stand upright; but when TSS was applied, the level of assistance needed to maintain upright posture decreased significantly. No such result was found in the sham TSS group. This, combined with higher muscle recordings in the leg muscles during stimulation, indicates that non-invasive TSS was able to activate the neurons below the injury and cause the muscle contractions needed to support participants’ bodyweight during upright standing. The intensity of stimulation required to reach motor threshold and make upright standing easier also decreased throughout the duration of the study. This could indicate that damaged connections between neurons near the injury were being reconfigured via Hebbian neuroplasticity. This is the hypothesis that ‘neurons that fire together wire together’ (other research on SCI recovery has found support for this idea, see Jo et al., 2023).
Interestingly, the study by Sayenko et al. found motor-function improvements in all participants after their sessions, including those in the sham group. This is an important finding because it shows that there is some capability for functional improvements after task-specific training, even without electrical stimulation. The improvements were, however, much stronger in the real TSS group. This indicates that neuromodulation is crucial for facilitating these improvements and maximizing people’s ability to recover function after SCI.
In addition to the research on lower-limb recovery, there has also been investigation on the effects of electrical spinal stimulation on upper-limbs. One such study involved two people with cervical SCI who had an epidural electrode array implanted in their cervical spine (Lu et al., 2016). Both subjects had severe injuries, with very little motor function in their upper limbs and no motor function at all in their lower limbs. The researchers measured the amount of force the participants of the study produced in their hand muscles before, during, and after continuous stimulation, and did this both while they were at rest and while they were trying to squeeze their fist. They did this repeatedly for eight weeks after the implant.
The researchers found that the participants’ force generation in their hands gradually increased over the course of the stimulation sessions. By the end of the study, both participants’ muscle contractions without stimulation were even stronger than their initial contractions with stimulation. They also had more control over the timing of these muscle contractions, and the results appeared to last long-term. Interestingly, increases in muscle activity were mostly found when the participants were not only receiving stimulation, but when they were actively trying to grip.
A similar study explored the effects of stimulation on upper-limb motor recovery, but used TSS instead of ESS (Inancini et al., 2021). This study had six participants with cervical SCI, and began with four weeks of training specific functional tasks, such as moving individual fingers or pinching small coins. The participants then underwent another four weeks of the same training, but while receiving cervical TSS. Participants then returned for monthly follow-up visits to assess whether any improvements in motor performance were retained.
The results of this intervention were very impressive. One participant who had complete paralysis in his hands, which did not improve after the first four weeks of training, was able to move his fingers for the first time since his injury once he began receiving TSS. Other participants who had some ability to move their hands saw large improvements as well. While the training alone led to slight improvements in each measured task, training with stimulation led to larger functional improvements in every subject.
Based on these results, the authors asserted that “Stimulation allowed the participants to engage more fully in the training exercises by permitting activation of previously weak or paralyzed muscles” (314), leading to functional improvements that remained for three to six months after the intervention ended. The fact that these results lasted for months after the participants stopped receiving any form of stimulation is important because it demonstrates that some degree of neuroplasticity is retained after SCI.
Future directions
The overall body of literature on this topic points toward a promising line of research that can hopefully lead to improvements in motor function and quality of life for people living with SCI. However, it is important to keep in mind that the outcomes of ESS and TSS, so far, have been quite modest. Participants in these studies have been able to regain certain functions such as standing and moving previously paralyzed limbs, but more complex movements and fine motor control are still beyond what spinal cord stimulation, even when combined with physical and occupational therapy, can recover. More comprehensive recovery will likely require neuromodulation in combination with other treatments, such as drug treatments. It is also important to keep in mind that every individual and every injury is different, and as such, treatments will need to be tailored specifically to the person receiving them. This presents a methodological challenge for researchers.
There are many questions that will need to be better understood before spinal cord stimulation can become a widespread treatment option. For one, it is not yet entirely clear what neural mechanisms are responsible for the observed improvements in motor function after stimulation. There is also a large correlation between severity of the injury and recovery outcomes, which raises the question of to what extent people with more severe SCI are capable of recovering voluntary motor control (Seáñez and Capogrosso, 2021).
It has also been well-established that neuromodulation works best in combination with training activities, but it is not entirely clear what specific activities should be used to maximize recovery. Similarly, it is not yet understood how best to incorporate spinal cord stimulation into clinical rehabilitation programs. How frequently should patients attend stimulation sessions? How long should these sessions last? The answers to these questions are not yet known. It is also not clear whether TSS or ESS should be used in combination with other types of neuromodulation such as peripheral nerve stimulation or transcranial magnetic stimulation; and if so, how should they be combined?
These are questions that are actively being investigated by researchers all over the world. Hopefully in the coming decades, their work can create a more thorough understanding of how neuromodulation works to improve motor function and how to apply this knowledge in the clinical setting, and can be used to develop new and improved treatment options for people living with SCI.
Sources
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