Exercise is Medicine: Spinal Cord Injury

EPHE 441 B02

Emilie Noble

December 2, 2016

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 Introduction

According to the Foundation for Spinal Cord Injury Prevention, Care & Cure (FSCIP,

2009), the United States sees 12,000 new cases of spinal cord injury (SCI) every year and over

40% of these are a result of motor vehicle accidents. Spinal cord injuries lead to varying degrees

of paralysis, loss of sensation and loss of some internal organ function. These consequences

result in a decreased mobility and functional independence and thus, a decrease in quality of life.

The purpose of this review is to note the physiological changes that occur in patients with SCI,

and the potential for rehabilitation through physical activity.

Physiology of SCI

In the simplest of terms, spinal cord injuries are characterised by mechanical trauma to

both grey and white matter (Nashmi & Fehlings, 2001). Nashmi & Fehlings conducted a study

using rats with a T7 lesion and found a reduced myelin thickness, swelling of the axon at the

location of the lesion, and disturbances in the propagation of action potentials. First, there is a

decreased action potential amplitude and an increased refractory period (Nashmi & Fehlings). An

increase in the number of potassium channels along the cell membrane of the axon was also

found, leading to a greater out flux of potassium and a net hyperpolarization. These factors result

in a decreased conduction velocity, reduced ability to propagate at high frequencies and an

increased threshold for activation. Thus, a stronger stimulus is required to reach threshold

potential and produce an action potential (Nashmi & Fehlings).

The musculoskeletal system is also a recipient of many repercussions post spinal cord

injury. A reduction in neural stimulation leads to contractile units becoming disorganized as

muscles begin to break down (Dolbow, 2015). Muscle cross sectional area decreases 45-80% in

the first 6 months along with a decrease in number of slow twitch fibers, resulting in the

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remaining muscle being more prone to fatigue (Dolbow). Concurrently, there are dramatic effects

on bone mineral density as muscle action is reduced. Dolbow states bone mineral density may

decrease up to 50% in the first 3 years post injury, and this is largely seen in the trabecular bone.

Acute Effects

Acute effects of exercise on patients with spinal cord injuries were addressed by looking

at serum concentration of neurotrophic factors brain-derived neurotrophic factor (BDNF) and

insulin-like growth factor 1 (IGF-1) in a study by Vega et al. (2008). These compounds are

known to promote neuroplasticity and neurogenesis. The study protocol involved 11 human

spinal cord injury patients who engaged in two days of exercise at different intensity levels. Data

was collected by drawing blood samples from each participants ear lobe and concentrations of

neurotropic factors were determined. Vega et al. found significantly elevated concentrations of

BDNF after the moderate intensity warm up (P<0.05), however after higher intensity exercise,

BDNF concentrations were no different from resting values. IGF-1, however was significantly

elevated after both warm up and high intensity exercise (p<0.01). Vega et al. postulate the lack of

circulating BDNF seen in high intensity exercise may be due to an increased uptake into the

central nervous system. These results demonstrate the direct relationship between single bouts of

exercise and elevation in serum concentrations of these important neurotrophic factors.

Chronic Effects of Exercise

At the Muscle.

To maintain the ability to conduct activities of daily living, it is vital for patients with SCI

to have functional strength of the upper limb. Such activities include transfers into or out of a

wheelchair, self care and household chores. A study by Hicks et al. (2003) looked at strength,

exercise capacity and quality of life in 23 spinal cord injury patents over a 9-month exercise

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training program. Participants engaged in two exercise sessions per week, which included both

aerobic and strength components. The aerobic component involved three 5-7 minute-long

workloads at intensity levels of 40, 60, and 80% of age predicted heart rate max. Participants

then trained chest press, elbow flexion and shoulder flexion strength, and were tested using one

repetition maximum. A number of questionnaires were used to assess quality of life. Results of

this study state significant improvements in submaximal arm ergometry power output (p<0.05),

upper body muscle strength (p<0.05), and overall quality of life (p<0.05) (Hicks et al., 2003).

Hicks et al. reports that participants also found activities of daily living to be much easier after 9

months of training and even suggest that subjects increased exercise capacity is due to

adaptations in peripheral circulation and increased muscular strength.

These findings are strongly supported by Hicks et al. (2011), who conducted an extensive

review of 82 studies on exercise and spinal cord injuries. They found that both exercise programs

with arm ergometry and mixed exercise programs including strength, aerobic and mobility

training resulted in significant improvements in muscular strength as well as power and

recommend patients should participate in a combined exercise program 2-3 times per week to see

benefits (Hicks et al., 2011).

More recently, Dost et al. (2014) compared endurance exercise to progressive resistance

training on overall strength as well as functional independence measures and found that while

both exercise methods improved functional independence, resistance training resulted in more

improvements in upper limb strength. Several studies report that insulin-like growth factor 1

(IGF-1) is responsible for the muscular hypertrophy observed due to its role in activating satellite

cells, which then proliferate and promote protein synthesis in the muscle (Vega et al., 2008;

Dupont-Versteegden et al., 2000; Zanou & Gailly, 2013).

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At the Lesion.

Dolbow (2015) states the ability of the nervous system to reorganize itself by forming

new neural connections, i.e. neuroplasticity, is driven by physical activity. A study by Ilha et al.

(2008) observed the effects of exercise training on recovery and regeneration in rats with sciatic

nerve lesion. The rats were given 2 weeks of recovery time post lesion, then began their

respective training programs. The 5 groups included the control with no lesion, sedentary group,

resistance training group, endurance training group, and concurrent training group (resistance

followed by endurance training). Ilha et al. found that endurance training resulted in the highest

degree of myelinated fiber maturation and promoted normalization of function in the hind limb

after only one week of training. All other groups, including resistance training and concurrent

training did not show the same adaptations. These results are depicted in Figure 1 below,

showing cross sections of the nerve fibers above and below the location of the lesion. The figure

shows the sedentary, resistance trained, and concurrent trained groups all had small, thinly

myelinated axons, while the endurance trained group showed larger axons with more mature

myelin. Ilha et al. attribute the results of the endurance trained group to an increased expression

of BDNF which perhaps occurs due to certain modalities of exercise and not others. This may

explain the lack of adaptation seen in the resistance and concurrent trained groups.

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Figure 1. Transverse sections of

regenerating sciatic nerves 5

weeks post exercise training. (A)

and (B): proximal and distal

portions of uninjured sciatic

nerve. (C) and (D): proximal and

distal portions from sedentary

group. (E) and (F): proximal and

distal from endurance trained

group. (G) and (H): resistance

trained group. (I) and (J):

concurrent group. (Ilha et al.,

2008).

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 Gazula et al. (2004) were concerned with the dendritic architecture of spinal motor

neurons in rats with a complete spinal cord transection at the T5-T6 level. The study included

three experimental groups: control (intact spinal cord), complete spinal cord transection (SCT),

and SCT + daily exercise. The exercise protocol involved a motorized device which simulated a

walking motion in the paralyzed hind limbs of the rats. These rats were exercised in 30 minute

bouts, two times per day for five days. Results were analyzed by mapping the dendritic

architecture of the lumbar motor neurons. The SCT group that did not engage in exercise showed

significant atrophy of dendrites due to a loss of descending excitatory drive (Gazula et al.). The

SCT + exercise group, however, displayed much larger dendritic trees than the just SCT group.

These were comparable to the control group on a number of factors including the number of

primary dendrites, branching, total arbor size, and length of longest dendrites. The results

indicate rapid and significant pruning occurs in motor neurons lacking descending input, but this

pruning could be prevented with hind limb exercise. Thus, aerobic exercise affects the growth

and maintenance of dendrites, which Gazula et al. report may be linked to the release of BDNF

following exercise. This proposition is supported by Vavrek et al. (2006), who injected BDNF

into animals at the location of cell bodies of lesioned neurons, and found a significant increase in

sprouting.

Brain Derived Neurotrophic Factor

Brain derived neurotrophic factor is expressed by a wide variety of cells in the human

body, including neurons of the central nervous system, immune inflammatory cells, vascular

epithelia, smooth muscle, muscle satellite cells and myoblasts (Vega et al., 2008). BDNF can

also be stored and transported by platelets, which appear to release it at the site of traumatic

injury. Thus, BDNF can reach an injury site both by transport in blood and by release by the

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neurons themselves. BDNF has been shown to protect motor neurons from degeneration and

promote axonal sprouting after injury (Vega et al.). Ilha et al. (2008) report that BDNF is also

responsible for enhancing the expression of myelin-associated glycoprotein, thus is important in

remyelination. One study even observed resting concentrations of BDNF in SCI patients to be

six times higher than in uninjured individuals (Vega et al.). Because exercise has been shown to

further elevate expression of BDNF, it can be concluded that exercise is incredibly important for

neurogenesis during the rehabilitation process following spinal cord injury.

The mechanisms involving BDNF remain mostly unknown, however there are a few

postulations as to how exercise and BDNF relate to neurogenesis. Firstly, exercise results in

elevated cardiac output, which in turn causes an increase in blood transportation. This may lead

to an increase in platelets arriving at the injury site, allowing more BDNF to be released. Another

possible mechanism may occur in the neurons themselves. In able bodied individuals, exercising

results in a high frequency of action potential propagation, but in SCI patients, such high

frequencies are unattainable. However, if there is a greater demand for high frequency action

potentials than there is supply, this may trigger the release of BDNF from neural cells and drive

neurogenesis. Furthermore, there may remain some neural connections crossing the injury site.

The more these neurons get activated, the stronger the connections will become. Thus, exercise

will promote use of those pathways and strengthen the neural connections.

Technological Interventions

Numerous studies have used exercise in conjunction with other forms of intervention,

two of which include transplantation and functional electrical stimulation. A study by Dupont-

Versteegden et al. (2000) looked at the mechanisms by which muscular cross sectional area of

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atrophied muscles could be increased by assessing the size of the plantaris and soleus muscles in

rats. The experimental groups included an endurance trained group, a group with transplantation

of fetal spinal cord tissue, and a combined transplant and endurance training group. The findings

of this study state that transplantation alone cannot restore cross sectional area of either muscle,

while exercise significantly increased the cross sectional area of plantaris, but not soleus.

However, exercise in conjunction with transplantation resulted in a significant increase in the

muscular size of both muscles. The study suggests the proliferation of satellite cells is required to

achieve muscle hypertrophy by fusing to myofibers and increasing the number of myofiber

nuclei (Dupont-Versteegden et al.).

Functional electrical stimulation (FES) is another therapeutic method often used in

conjunction with exercise. A case study on a 39-year-old motor complete spinal cord injury

patient looked at electrical stimulation and its effects on the skeletal muscles (Ryan, Erickson,

Young & McCully, 2013). The study involved 24 weeks of progressive electrical stimulation

while endurance training and measured skeletal muscle mitochondrial capacity. This was done by

measuring the rate of recovery of muscle oxygen consumption using near infra-red spectroscopy.

Results indicate a three-fold increase in mitochondrial oxidative capacity as a result of electrical

stimulation (Ryan et al.). The results of this study have limitations, however. Firstly, there was

only one participant, thus it was more exploratory than conclusive. Second, the methods give a

very poor description of how the participant was aerobically exercised, stating that he trained in

his wheelchair with both legs extended. This appears to indicate the participant trained by

wheeling the chair, but the electrodes were placed on his quadriceps muscles.

FES is commonly used in combination with an apparatus, such as cycling, whereby an

electrical stimulation is applied to the muscles of the lower limb to aid with activation, thus

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making it easier to perform the cycling motion. Johnston et al. (2015) discus numerous benefits

of using FES cycling. First, it can help reduce the amount of muscle atrophy and allows muscles

to maintain (or re-learn) the ability to activate to electrical stimulation (Johnston et al.). In some

cases, FES cycling may even promote muscle hypertrophy and enhance bone health. Lastly,

because FES is a method for aiding in aerobic exercise, it has been shown to benefit

cardiovascular fitness (Johnson et al.).

Contraindications

Although exercise has demonstrated countless positive effects in patients with spinal cord

injury, there remain several contraindications. First, tetraplegics often have difficulty

thermoregulating. Under conditions of complete transection of the spinal cord, there is reduced

afferent input to the thermoregulatory centre in the hypothalamus (Prince, 2012). This is paired

with reduced vasomotor control and disruption in ability to sweat (Prince). Studies show SCI

patients reach higher core temperatures in warm conditions than able bodied participants do, and

also have significantly lower metabolic rates (Prince). Thus, when exercising under warm or hot

conditions, affected individuals should take care not to over heat.

Second, the majority of SCI patients rely on wheelchairs, therefore the lower extremity

ceases to experience weight bearing. As a result of this sudden absence of loading, there is a

rapid loss in bone mineral density and increase in risk of osteoporosis (Dolbow, 2015). Fragility

fractures occur due to low trauma activities that would not normally result in fractures, and are

often seen in osteoporotic patients. Dolbow reports these types of injuries are commonly

observed in SCI patients as a result of every day activities, such as wheelchair transfers.

Accordingly, when exercising, individuals with SCI should take care to begin carefully and

increase intensity slowly. While weight bearing will help to improve bone mineral density,

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affected individuals should not use the standing frame for extended periods of time upon

initiation of their exercise program.

Finally, loss of sensation in limbs may result in injuries going unnoticed. Individuals with

SCI are highly susceptible to sores due to constant sitting or lying in the supine position. This

can be aggravated by doing exercises while seated, such as wheelchair based leg cycle or arm

crank exercises.

Conclusions

Research strongly supports the idea of exercise as medicine in the rehabilitation of spinal

cord injuries. As reported, exercise causes an increase in brain-derived neurotropic hormone and

insulin-like growth factor 1, which are key players in neuroplasticity and muscular adaptations

respectively. BDNF has been shown to increase connectivity and myelination and IGF-1 plays a

role in muscular hypertrophy, leading to improvements in strength and functionality, thus quality

of life. It seems that endurance training may be more useful for neurogenesis, while resistance

training is more useful for improving muscular strength. Persons with SCI are recommended to

engage in 2-3 exercise sessions every week of moderate to vigorous aerobic training, resistance

training, and functional electrical stimulation (Dolbow, 2015; Hicks et al., 2011). Future studies

should look further into the physiological effects of using functional electrical stimulation and

observe any changes in expression of neurotrophic factors.

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Neurorestoratology, 3: 133-139.

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Dupont-Vesteegden, E.E., Murphy, R.J.L., Houle, J.D., Gurley, C.M., & Peterson, C.A. (2000).
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