Over the years, many questions recur repeatedly every few days. Let me try to recap some of these questions to stimulate discussion. Please ask and comment...
1. Will there be a cure for spinal cord injury?
• The answer to this question of course depend on one's definition of a cure. If a cure means eradication of spinal cord injury, I think that it is unlikely in my lifetime. If a cure means complete restoration of all function to "normal" or pre-injury levels for all people with spinal cord injury, I think that that this is unlikely because we probably will not have therapies that can completely reverse aging and changes of the body due to the injury. On the other hand, I believe that there will be effective therapies that will restore function to people with spinal cord injury, including touch and pain sensations, bladder and bowel function, erection and ejaculation, and motor control including long-distance walking. Several years ago, I tried to get around the problem of the definition of "cure" by proposing that a person would be cured if a well-informed observer cannot tell that a person has had spinal cord injury. This does not necessarily mean that the person has been completely restored to pre-injury levels or all functions are normal.
2. When will a cure be available?
• Some therapies are restoring substantial function to some people. These are what I call the first generation therapies which include treatments like weight-supported treadmill ambulation training, decompression and untethering of a spinal cord that is compressed. Some preliminary data suggest that certain cell transplants such as olfactory ensheathing glia transplants will restore 4-8 levels of sensory function and 1-2 levels of motor function. None of these therapies can be construed as a cure. Second generation therapies are beginning to come into clinical trial and should be available in a few years. These include nasal mucosa olfactory ensheathing glia, Schwann cell transplants, and perhaps even embryonic stem cells. The latter unfortunately have been mired in political debate and has already been delayed by 4 years. In addition, several therapies such as Nogo receptor blockers and Nogo antibodies, glial-derived neurotrophic factor, chondroitinase, and other treatments are being developed for clinical trial and may come on line within a year or two. The timing of such treatments depends on the availability of funding for clinical trials. But, if sufficient funding were available, I think that some of these treatments will be shown to be effective and will be available in 4 years. Finally, third generation therapies will be closer to the "cure". These include possible combination cell transplant therapies with growth factors and other treatments that stimulate regeneration of the spinal cord. These should produce more recovery in more people. For example, cell transplants combined with drugs such as glial-derived neurotrophic factor, chondroitinase ABC, and cAMP/rolipram have been reported to produce significantly better regeneration in rats compared to individual treatments. The rate at which these treatments get into clinical trial depend on the amount of funding available for clinical trial. If funding were made available, I think that some of third generation therapies will be available as soon as 8 years from now.
3. Will a cure work for chronic spinal cord injury?
• Yes, I believe so for the following reasons. First, much animal and human data suggest that regeneration of relatively few axons can restore function such as walking, bladder function, and sexual function. This is because the spinal cord contains much of the circuitry necessary to execute and control these functions. Probably about 10% of the axons in the spinal cord are necessary and sufficient to restore some of these functions. Second, animal studies suggest that axons continue to try to regrow for long periods of time after injury. Treatments that provide a path for growth, that negate some of the factors that inhibit growth, and that stimulate axonal growth can restore function. Third, while chronic spinal cord injury studies in animals are still very limited, the fact that many people continue to recover some function years after injury provide hope that these therapies will also work in chronic spinal cord injury. However, it is important to provide some caveats concerning recovery. Recovery may be limited by muscle atrophy and other changes in the body. Likewise, there is a phenomenon called "learned non-use" where neural circuits may turn off after prolonged periods of non-use. Intensive exercise and physical therapy will be necessary to reverse these changes.
4. What can I do now to be ready for the cure?
• The first and foremost concern of people with spinal cord injury should be to take care of their body and try to prevent muscle and bone atrophy and other changes that may prevent recovery of function. This is difficult but people need to engage in disciplined exercise that maintains their muscle and bone, take care of their skin, bladder, and bowels. People should avoid procedures that cause irreversible loss of peripheral nerve and other functions. On the other hand, it is important to weigh the benefits of procedures such as tendon transfers which can provide greater functionality and independence for people with weak hands. Likewise, certain procedures such as Mitrofanoff and bladder augmentation to reduce bladder spasticity may provide greater independence but may not be easily reversible. Finally, many studies have shown that people with the highest levels of education after injury are more likely to have better quality of life and health. It is important that people do not neglect their brain, the most important part of their body.
5. What can I do about spasticity, spasms, and neuropathic pain?
• Many people suffer from spasticity (increased tone), spasms (spontaneous movements), and pain or abnormal sensations (in areas below the injury site where there is diminished or absent sensation). These problems arise from disconnection of the brain from the body. Neurons in the spinal cord that have been disconnected tend to become hyperexcitable. Spasticity is the most common manifestation. Several treatments will reduce spasticity. The most commonly used drug is baclofen (a drug that stimulates GABA-B receptors in the spinal cord). Oral doses of baclofen up to 120 mg/day will reduce spasticity for most people. However, due to side-effects, some people cannot tolerate high oral doses and must take combinations of drugs, including clonidine or tizanidine which activate alpha-adrenergic receptors. In general, while these drugs reduce spasticity, they are typically not effective in preventing spasms without causing significant weakness. Taking too much anti-spasticity drug may reduce the muscle tone to the extent that muscle atrophy will occur. So, people should titrate the dose of anti-spasticity drugs so that they continue to have some tone. Few drugs are effective against spasms. One possible drug is neurontin (gabapentin) which is an anti-epileptic drug. Neuropathic pain probably results from increased excitability of spinal neurons that have been disconnected from sensory signals and may manifest in "burning", "freezing", or "pressure" type pain, usually in areas where normal sensation is absent or greatly diminished. Neurontin is reduces neuropathic pain in some people but people generally accomodate to the drug and higher doses are necessary over time. In some people, low doses (20 mg/day) of the anti-depressant drug amitryptaline (Elavil) may be useful in taking the edge off neuropathic pain. However, for many people, none of the oral drugs are sufficient to control spasticity, spasms, or neuropathic pain. For people with severe spasticity, a pump that delivers baclofen directly to the spinal cord through an implanted catheter may be effective and necessary. In about 15% of people, however, none of these therapies are sufficient to control spasms and neuropathic pain.
6. How can I exercise and will it do any good?
• Exercise in a paralyzed person is difficult and some specialized equipment may be necessary and useful for exercising the muscles. First, most people have standing frames where they can stand for an hour or two every day. Second, functional electrical stimulation (FES) can be used to activate their leg muscles and the legs can be stimulated to pedal an exercise bike. Third, standing and walking in a swimming pool is the cheapest and possibly most cost-effective way for a person to stand and walk. Fourth, weight-supported treadmill ambulation training has been shown to improve walking recovery. Finally, people should think about setting aside a month or two every year where they would essentially engage in full-time training. During the rest of the year, they need to maintain the gains that they have achieved by spending an hour or so per day on exercising. Although there have been few formal studies of the subject, many people with spinal cord injury have reported significant increases in the girth of their legs when they use FES regularly.
7. What is osteoporosis, its mechanisms and consequences, and ways to reverse it?
• Osteoporosis is loss of calcium in bone that occur throughout the skeletal system, particularly in the pelvis and legs below the injury site. The mechanism is not understood but appears to be related to disuse and the loss of gravitational and other stresses on the bone. In acute spinal cord injury, bone begins to decalcify within days after spinal cord injury, with significant increases in calcium in the urine (hypercalciuria) within 10 days. The pattern of bone loss is 2-4 times greater those seen in people on prolonged bedrest without spinal cord injury, similar to the bone loss seen in postmenopausal women. The loss of bone is not effectively reversed by increased dietary calcium intake alone. Parathyroid hormone level is generally low in the first year but increases above normal after the first year. Substantial (25-43%) decreases in bone mineral densities occur in the leg bones occur within a year and may exceed 50% loss by 10 years while bone density may increase in the arms after 4 months in paraplegic patients, compared to tetraplegics. Some studies suggest that people with spasticity have less bone loss than those who are flaccid. Losses in bone result in increased fracture rates. The Model Spinal Cord Injury System, for example, reported a 14% incidence of fracture by 5 years after injury, 28% and 39% by 10 and 15 years, usually in the most demineralized bone. People with complete spinal cord injury and paraplegia have 10 times greater fracture rates than those with incomplete injury or tetraplegia. Weight-bearing and bicycling with functional electrical stimulation will reverse osteoporosis when started within 6 weeks after injury. However, such programs are less effective in people with chronic spinal cord injury. Some preliminary studies suggest that treatment bisphosphonates (Pamidronate) and parathyroid hormone (Teriparatide) can prevent or reduce osteoporosis and fracture rates in people with chronic spinal cord injury. http://www.emedicine.com/pmr/topic96.htm
8. What is autonomic dysreflexia, its mechanisms and consequences, and treatments?
• Autonomic dysreflexia (AD) refers to increased activity of the sympathetic nervous system, associated with profuse sweating, rash, elevated blood pressure, and vasodilation above the injury level. People with AD commonly develop a headache caused by vasodilation of brain blood vessels. Heart rate falls and vision may be blurred. Nasal congestion may be present. Between 40-90% of people with spinal cord injury suffer from AD and is more severe in people with spinal cord injury above T6. AD can be triggered by many potential causes, including bladder distension, urinary tract infection, and manipulation of the bowel and bladder system, pain from any source, menstruation, labor and delivery, sexual intercourse, temperature changes, constrictive clothing, sunburns, and insect bites. When AD occurs, doctors usually catheterize the bladder to ensure adequate urinary drainage, check for fecal impaction manually using lidocaine jelly as a lubricant, and eliminate all other potential causes of irritation to the body. Treatment includes use of calcium channel blocker Nifedipine (Procardia 10 mg capsule) to reduce blood pressure or adrenergic alpha-receptor blocking agent phenoxybenzamine (10 mg twice a day), mecamylamine (Inversine 2.5 mg orally). Diazoxide (Hyperstat 1-3 mg/kg). Often doctors in emergency room may not know how to handle AD crises in people with spinal cord injury and therefore it is important for people to know the treatments. http://www.emedicine.com/pmr/topic217.htm
9. What is syringomyelia, its mechanisms and consequences, and treatments?
• Syringomyelia is the presence of a cyst in the spinal cord, resulting from enlargement of the central canal. The central canal is typically tiny and not visible on magnetic resonance images (MRI) of the spinal cord. As many as 15% of people develop a syringomyelic cyst in their spinal cords with perhaps 5% showing symptoms of pain and loss of function associated with cyst enlargement, beginning as early as one month to as late as 45 years after injury. Pain is the most commonly reported symptom associated with syringomyelia. Other symptoms include increased weakness, loss of sensation, greater spasticity, and increased sweating. The symptoms can be aggravated by postural changes, Valsalva manuever (increasing pressure in the chest). It may also be associated with changes in bladder reflexes, autonomic dysreflexia, painless joint deformity or swelling, increased spasticity, dissociation of sensation and temperature, respiratory impairment. The cyst can be observed with MRI scans. It is usually associated with scarring of the meninges or arachnoid membranes of the spinal cord, observable with CT-scan with myelography. Surgical intervention is recommended when there is progressive neurological loss. Traditionally, syringomyelia has been treated with shunting of the cyst by placement of a catheter between the cyst and the subarachnoid space or pleural cavity. But shunting alone is frequently associated with shunt blockade within a year. More recent studies suggest that meticulous removal of adhesions with duroplasty (increasing the dura by grafting membrane) to re-establish subarachnoid cerebrospinal fluid flow is more effective and may result in elimination of the cyst in 80% of cases. One study has shown that transplantation of fetal tissues into the cyst can eliminate the cyst. http://www.emedicine.com/pmr/topic115.htm
10. What is the effect of spinal cord injury on sexual function and what can be done to improve such function?
• Most people with spinal cord injury above the T10 will continue to have reflex erections associated with stimulation. Some people may have prolonged erections called priapism. A majority can have ejaculation although increased stimulation including vibration may be required. In many people, ejaculation may be retrograde, i.e. the ejaculate goes into the bladder rather comes out, because the external sphincter may be open. Retrograde ejaculation should not be harmful or cause urinary tract infections. A serious associated complication of sexual intercourse in both men and women is the occurrence of autonomic dysreflexia (AD) with orgasm, with associated headaches and other symptoms of AD. These can be treated with drugs to lower blood pressure (see answer to AD above). In addition, sexual intercourse may be associated with increased spasticity and spasms. People with injuries below T10 may have damage to the spinal cord centers responsible for erection and ejaculation. Many techniques are available to increase erection, including drugs such as Sildenafil (Viagra), vacuum pumps, cock rings, and penile prostheses. Several studies have reported that women with "complete" spinal cord injury can achieve orgasms, possibly through neural pathways outside of the spinal cord.
1. Will there be a cure for spinal cord injury?
• The answer to this question of course depend on one's definition of a cure. If a cure means eradication of spinal cord injury, I think that it is unlikely in my lifetime. If a cure means complete restoration of all function to "normal" or pre-injury levels for all people with spinal cord injury, I think that that this is unlikely because we probably will not have therapies that can completely reverse aging and changes of the body due to the injury. On the other hand, I believe that there will be effective therapies that will restore function to people with spinal cord injury, including touch and pain sensations, bladder and bowel function, erection and ejaculation, and motor control including long-distance walking. Several years ago, I tried to get around the problem of the definition of "cure" by proposing that a person would be cured if a well-informed observer cannot tell that a person has had spinal cord injury. This does not necessarily mean that the person has been completely restored to pre-injury levels or all functions are normal.
2. When will a cure be available?
• Some therapies are restoring substantial function to some people. These are what I call the first generation therapies which include treatments like weight-supported treadmill ambulation training, decompression and untethering of a spinal cord that is compressed. Some preliminary data suggest that certain cell transplants such as olfactory ensheathing glia transplants will restore 4-8 levels of sensory function and 1-2 levels of motor function. None of these therapies can be construed as a cure. Second generation therapies are beginning to come into clinical trial and should be available in a few years. These include nasal mucosa olfactory ensheathing glia, Schwann cell transplants, and perhaps even embryonic stem cells. The latter unfortunately have been mired in political debate and has already been delayed by 4 years. In addition, several therapies such as Nogo receptor blockers and Nogo antibodies, glial-derived neurotrophic factor, chondroitinase, and other treatments are being developed for clinical trial and may come on line within a year or two. The timing of such treatments depends on the availability of funding for clinical trials. But, if sufficient funding were available, I think that some of these treatments will be shown to be effective and will be available in 4 years. Finally, third generation therapies will be closer to the "cure". These include possible combination cell transplant therapies with growth factors and other treatments that stimulate regeneration of the spinal cord. These should produce more recovery in more people. For example, cell transplants combined with drugs such as glial-derived neurotrophic factor, chondroitinase ABC, and cAMP/rolipram have been reported to produce significantly better regeneration in rats compared to individual treatments. The rate at which these treatments get into clinical trial depend on the amount of funding available for clinical trial. If funding were made available, I think that some of third generation therapies will be available as soon as 8 years from now.
3. Will a cure work for chronic spinal cord injury?
• Yes, I believe so for the following reasons. First, much animal and human data suggest that regeneration of relatively few axons can restore function such as walking, bladder function, and sexual function. This is because the spinal cord contains much of the circuitry necessary to execute and control these functions. Probably about 10% of the axons in the spinal cord are necessary and sufficient to restore some of these functions. Second, animal studies suggest that axons continue to try to regrow for long periods of time after injury. Treatments that provide a path for growth, that negate some of the factors that inhibit growth, and that stimulate axonal growth can restore function. Third, while chronic spinal cord injury studies in animals are still very limited, the fact that many people continue to recover some function years after injury provide hope that these therapies will also work in chronic spinal cord injury. However, it is important to provide some caveats concerning recovery. Recovery may be limited by muscle atrophy and other changes in the body. Likewise, there is a phenomenon called "learned non-use" where neural circuits may turn off after prolonged periods of non-use. Intensive exercise and physical therapy will be necessary to reverse these changes.
4. What can I do now to be ready for the cure?
• The first and foremost concern of people with spinal cord injury should be to take care of their body and try to prevent muscle and bone atrophy and other changes that may prevent recovery of function. This is difficult but people need to engage in disciplined exercise that maintains their muscle and bone, take care of their skin, bladder, and bowels. People should avoid procedures that cause irreversible loss of peripheral nerve and other functions. On the other hand, it is important to weigh the benefits of procedures such as tendon transfers which can provide greater functionality and independence for people with weak hands. Likewise, certain procedures such as Mitrofanoff and bladder augmentation to reduce bladder spasticity may provide greater independence but may not be easily reversible. Finally, many studies have shown that people with the highest levels of education after injury are more likely to have better quality of life and health. It is important that people do not neglect their brain, the most important part of their body.
5. What can I do about spasticity, spasms, and neuropathic pain?
• Many people suffer from spasticity (increased tone), spasms (spontaneous movements), and pain or abnormal sensations (in areas below the injury site where there is diminished or absent sensation). These problems arise from disconnection of the brain from the body. Neurons in the spinal cord that have been disconnected tend to become hyperexcitable. Spasticity is the most common manifestation. Several treatments will reduce spasticity. The most commonly used drug is baclofen (a drug that stimulates GABA-B receptors in the spinal cord). Oral doses of baclofen up to 120 mg/day will reduce spasticity for most people. However, due to side-effects, some people cannot tolerate high oral doses and must take combinations of drugs, including clonidine or tizanidine which activate alpha-adrenergic receptors. In general, while these drugs reduce spasticity, they are typically not effective in preventing spasms without causing significant weakness. Taking too much anti-spasticity drug may reduce the muscle tone to the extent that muscle atrophy will occur. So, people should titrate the dose of anti-spasticity drugs so that they continue to have some tone. Few drugs are effective against spasms. One possible drug is neurontin (gabapentin) which is an anti-epileptic drug. Neuropathic pain probably results from increased excitability of spinal neurons that have been disconnected from sensory signals and may manifest in "burning", "freezing", or "pressure" type pain, usually in areas where normal sensation is absent or greatly diminished. Neurontin is reduces neuropathic pain in some people but people generally accomodate to the drug and higher doses are necessary over time. In some people, low doses (20 mg/day) of the anti-depressant drug amitryptaline (Elavil) may be useful in taking the edge off neuropathic pain. However, for many people, none of the oral drugs are sufficient to control spasticity, spasms, or neuropathic pain. For people with severe spasticity, a pump that delivers baclofen directly to the spinal cord through an implanted catheter may be effective and necessary. In about 15% of people, however, none of these therapies are sufficient to control spasms and neuropathic pain.
6. How can I exercise and will it do any good?
• Exercise in a paralyzed person is difficult and some specialized equipment may be necessary and useful for exercising the muscles. First, most people have standing frames where they can stand for an hour or two every day. Second, functional electrical stimulation (FES) can be used to activate their leg muscles and the legs can be stimulated to pedal an exercise bike. Third, standing and walking in a swimming pool is the cheapest and possibly most cost-effective way for a person to stand and walk. Fourth, weight-supported treadmill ambulation training has been shown to improve walking recovery. Finally, people should think about setting aside a month or two every year where they would essentially engage in full-time training. During the rest of the year, they need to maintain the gains that they have achieved by spending an hour or so per day on exercising. Although there have been few formal studies of the subject, many people with spinal cord injury have reported significant increases in the girth of their legs when they use FES regularly.
7. What is osteoporosis, its mechanisms and consequences, and ways to reverse it?
• Osteoporosis is loss of calcium in bone that occur throughout the skeletal system, particularly in the pelvis and legs below the injury site. The mechanism is not understood but appears to be related to disuse and the loss of gravitational and other stresses on the bone. In acute spinal cord injury, bone begins to decalcify within days after spinal cord injury, with significant increases in calcium in the urine (hypercalciuria) within 10 days. The pattern of bone loss is 2-4 times greater those seen in people on prolonged bedrest without spinal cord injury, similar to the bone loss seen in postmenopausal women. The loss of bone is not effectively reversed by increased dietary calcium intake alone. Parathyroid hormone level is generally low in the first year but increases above normal after the first year. Substantial (25-43%) decreases in bone mineral densities occur in the leg bones occur within a year and may exceed 50% loss by 10 years while bone density may increase in the arms after 4 months in paraplegic patients, compared to tetraplegics. Some studies suggest that people with spasticity have less bone loss than those who are flaccid. Losses in bone result in increased fracture rates. The Model Spinal Cord Injury System, for example, reported a 14% incidence of fracture by 5 years after injury, 28% and 39% by 10 and 15 years, usually in the most demineralized bone. People with complete spinal cord injury and paraplegia have 10 times greater fracture rates than those with incomplete injury or tetraplegia. Weight-bearing and bicycling with functional electrical stimulation will reverse osteoporosis when started within 6 weeks after injury. However, such programs are less effective in people with chronic spinal cord injury. Some preliminary studies suggest that treatment bisphosphonates (Pamidronate) and parathyroid hormone (Teriparatide) can prevent or reduce osteoporosis and fracture rates in people with chronic spinal cord injury. http://www.emedicine.com/pmr/topic96.htm
8. What is autonomic dysreflexia, its mechanisms and consequences, and treatments?
• Autonomic dysreflexia (AD) refers to increased activity of the sympathetic nervous system, associated with profuse sweating, rash, elevated blood pressure, and vasodilation above the injury level. People with AD commonly develop a headache caused by vasodilation of brain blood vessels. Heart rate falls and vision may be blurred. Nasal congestion may be present. Between 40-90% of people with spinal cord injury suffer from AD and is more severe in people with spinal cord injury above T6. AD can be triggered by many potential causes, including bladder distension, urinary tract infection, and manipulation of the bowel and bladder system, pain from any source, menstruation, labor and delivery, sexual intercourse, temperature changes, constrictive clothing, sunburns, and insect bites. When AD occurs, doctors usually catheterize the bladder to ensure adequate urinary drainage, check for fecal impaction manually using lidocaine jelly as a lubricant, and eliminate all other potential causes of irritation to the body. Treatment includes use of calcium channel blocker Nifedipine (Procardia 10 mg capsule) to reduce blood pressure or adrenergic alpha-receptor blocking agent phenoxybenzamine (10 mg twice a day), mecamylamine (Inversine 2.5 mg orally). Diazoxide (Hyperstat 1-3 mg/kg). Often doctors in emergency room may not know how to handle AD crises in people with spinal cord injury and therefore it is important for people to know the treatments. http://www.emedicine.com/pmr/topic217.htm
9. What is syringomyelia, its mechanisms and consequences, and treatments?
• Syringomyelia is the presence of a cyst in the spinal cord, resulting from enlargement of the central canal. The central canal is typically tiny and not visible on magnetic resonance images (MRI) of the spinal cord. As many as 15% of people develop a syringomyelic cyst in their spinal cords with perhaps 5% showing symptoms of pain and loss of function associated with cyst enlargement, beginning as early as one month to as late as 45 years after injury. Pain is the most commonly reported symptom associated with syringomyelia. Other symptoms include increased weakness, loss of sensation, greater spasticity, and increased sweating. The symptoms can be aggravated by postural changes, Valsalva manuever (increasing pressure in the chest). It may also be associated with changes in bladder reflexes, autonomic dysreflexia, painless joint deformity or swelling, increased spasticity, dissociation of sensation and temperature, respiratory impairment. The cyst can be observed with MRI scans. It is usually associated with scarring of the meninges or arachnoid membranes of the spinal cord, observable with CT-scan with myelography. Surgical intervention is recommended when there is progressive neurological loss. Traditionally, syringomyelia has been treated with shunting of the cyst by placement of a catheter between the cyst and the subarachnoid space or pleural cavity. But shunting alone is frequently associated with shunt blockade within a year. More recent studies suggest that meticulous removal of adhesions with duroplasty (increasing the dura by grafting membrane) to re-establish subarachnoid cerebrospinal fluid flow is more effective and may result in elimination of the cyst in 80% of cases. One study has shown that transplantation of fetal tissues into the cyst can eliminate the cyst. http://www.emedicine.com/pmr/topic115.htm
10. What is the effect of spinal cord injury on sexual function and what can be done to improve such function?
• Most people with spinal cord injury above the T10 will continue to have reflex erections associated with stimulation. Some people may have prolonged erections called priapism. A majority can have ejaculation although increased stimulation including vibration may be required. In many people, ejaculation may be retrograde, i.e. the ejaculate goes into the bladder rather comes out, because the external sphincter may be open. Retrograde ejaculation should not be harmful or cause urinary tract infections. A serious associated complication of sexual intercourse in both men and women is the occurrence of autonomic dysreflexia (AD) with orgasm, with associated headaches and other symptoms of AD. These can be treated with drugs to lower blood pressure (see answer to AD above). In addition, sexual intercourse may be associated with increased spasticity and spasms. People with injuries below T10 may have damage to the spinal cord centers responsible for erection and ejaculation. Many techniques are available to increase erection, including drugs such as Sildenafil (Viagra), vacuum pumps, cock rings, and penile prostheses. Several studies have reported that women with "complete" spinal cord injury can achieve orgasms, possibly through neural pathways outside of the spinal cord.
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