Stroke Ex

Introduction

Following a stroke, declines occur throughout the body including decreased cardiovascular fitness, decreased aerobic capacity and endurance, muscle atrophy, and diminished ability to complete ADLs with greater energy expenditure required to complete everyday tasks. Insulin resistance and increased amount of fat percentage also commonly occur. Stroke also leads to declines in mobility, balance, and strength, often leading to a sedentary lifestyle for stroke survivors. Many of these factors contribute to a high incidence and increased risk of having a subsequent stroke, highlighting the importance of regular exercise after stroke. [1] [2]

Exercise Types in Animal Experiments

Most animal experiments regarding the effects of exercise on cerebral ischemia have utilized either voluntary or forced exercise protocols [3]. Voluntary exercise permits the subjects to exercise at levels which will simulates normal human daily activity or manual labor [3]. Forced exercise on the other hand, demands the subjects exercise on a treadmill, typically for 30-60 minutes 5-7 days per week [3]. This type of exercise simulates gym exercise or in the context of stroke rehabilitation, body-weight support treadmill training or riding a bicycle ergometer [3][4].

Excitotoxicity

A stroke can cause death in many cells, but some cells that are injured can recover. It is important when beginning exercise following stroke to avoid excessive activity while the injury is still acute. In a study by Kozlowski et al, [5] constraint induced movement of an impaired limb immediately after an experimental cerebral stroke in adult rats has been shown to dramatically increase neuronal injury and result in long-lasting deficits in limb placement, decreased response to stimulation, and defective use of the limb for postural support and reactions. Furthermore, the sensorimotor cortices of these animals showed large increases in the volume of the lesions, and an absence of dendritic growth and sprouting. Thus, during intense activity in an acute injury the cells will be stressed and the extracellular environment will become toxic, leading to death of cells that were injured but could have been recovered. Animal studies show that an extreme level of activity in the first week following a stroke can lead to an even larger lesion. [5] However, these harmful effects only occur with extreme overuse of the limbs and intense exercise immediatly after the lesion. [6]This form of excitotoxicity can be avoided with self paced activity in the early periods following stroke. Studies have shown that intensive activity to tolerance after a week or so does not increase lesion size or worsen behavioral outcomes, and is beneficial to the patient. [7]

Glutamate

One form of excitotoxicity present following an ischemic stroke is the activation of the glutamate system. Studies have shown that cerebral ischemia can lead to the uncontrolled release of glutamate [8]. Overactivation or misuse of glutamate and its receptors has been shown to increase injury following cerebral ischemia, especially in neurons of the hippocampus [3]. However, glutamate levels typically return to normal 24 hours after an ischemic insult at which time, they can act to aid in brain recovery [9]. Studies indicate that exercise preconditioning may decrease the expression of glutamate and positively effect glutamate receptors, leading to a reduced amount of brain damage following stroke [3]. Research by Soriano et al. has also shown that an increase in NMDA receptor activity positively correlates with cell survival and ischemic tolerance in neurons [10]. Because of this, it is probable that exercise preconditioning may regulate the gultamate system and increase ischemic tolerance in neuronal tissues. Several studies have examined the potentially beneficial effects of exercise, both before and after stroke, on glutamate levels and functional outcomes.

Exercise Prior to Stroke

Glutamate receptor antagonists, such as those that target NR2B and mGluR5 have been shown to reduce brain damage after stroke [11]. Research has suggested that exercise prior to a stroke can affect glutamate receptors, possibly promoting a resistance to ischemic stroke [11]. This is especially evident in the striatum as it is especially vulnerable to ischemic insult and enriched in glutamatergic neurons [11].

In a study conducted on rats, NR2B and mGluR5 expression in the striatum was significantly lower in the group that received an exercise intervention consisting of treadmill training (moderate intensity – 30 min/day, 6 days/week for 4 weeks) compared to those rats that did not exercise [11]. Rats in the exercise group also demonstrated a significantly reduced ischemic area and fewer neurological deficits following a stroke [11]. The results of this study indicate that those rats that received exercise prior to a stroke had better functional outcomes following stroke compared to those rats that did not exercise.

A study conducted by Jia et. al. [8] found similar results utilizing treadmill training (moderate intensity – 30 min/day, 5 days/week for 2 weeks) prior to the onset of stroke. They found that the rats in the exercise group pre-stroke demonstrated a decrease in infarct volume and fewer neurological deficits compared to those rats that did not exercise [8]. The authors suggested this may be due to the down-regulation of mGluR-1 mRNA and inhibition of the excessive release of glutamate resulting from cerebral ischemia [8].

Exercise Following Stroke

Following stroke, it was found that rats that began a treadmill exercise protocol (moderate intensity – 30 min/day for 2 weeks) 24 hours after stoke had significantly higher scores on several motor function tests compared to rats that did not exercise after a stroke [9]. Moreover, when compared to rats that did not experience a stroke but followed the same exercise protocol, it was found that the rates of improvement between the two groups did not differ significantly [9]. Treadmill training increased striatal extracellular glutamate, BDNF, and p-synapsin I (a protein involved in the regulation of neurotransmission) levels in both the normal rats and rats post-stroke [9]. Based on these results, treadmill exercise 24 hours after stroke resulted in greater functional improvements, possibly due to an increase in glutamate release via the enhanced expression of BDNF [9].

Other studies have also documented the benefits of exercise after stroke stating that brain infarct volume was reduced in rats with early treadmill training (moderate intensity – 30 min/day, 5 days/week for 2 weeks initiated 24 hours post stroke) after stroke [12]. These studies also supported the notion that glutamate may play a role in the recovery of motor function following stroke [12]. While increased glutamate levels were noted with treadmill exercise in rats, this increase was only temporary and did not exacerbate brain injury [12]. Furthermore, increased levels of glutamate in the hippocampus may facilitate neuroplasticity and thus, help facilitate motor recovery after stroke [12].

Exercise Summary

Moderate aerobic exercise for 30 min/day, 5-6 days per week prior to a stroke can help promote a resistance to ischemic stroke and lead to better functional outcomes following stroke should it occur [11][8]. Moderate aerobic exercise initiated 24 hours post-stroke 5 days/week has also been linked to greater functional improvements and increased motor recovery in rats [9][12]. Aerobic exercise prior to a stroke can include biking, jogging, walking, etc. while following a stroke, body-weight support treadmill training or the use of a bicycle ergometer may be necessary.

Apoptosis

Following an ischemic event, apoptosis has been shown to occur in peripheral areas for a defined period, eventually leading to cell death [3]. Proposed mechanisms for decreasing apoptosis following cerebral ischemia include promotion of heat shock proteins (HSP-70) and extracellular signal-related kinases 1 and 2 (ELK1/2).

HSP-70

Hsp-70 facilitates optimum folding of proteins during normal and stressful conditions including ischemia, oxidative stress, glucose deprivation and exposure to toxins [14]. HSP-70 is thought to function by inhibiting apoptosis inducing factor (AIF), as well as promoting anti-apoptotic proteins such as the Bcl-2 family. More information regarding the involvement of AIF (caspase-independent apoptosis) and the Bcl-2 family of proteins involvement in apoptotic pathways can be found here (Bcl-2). HSP-70 has not only been identified in cells following ischemia, but has also been proven to increase in neurons following physical exercise [14]. In a study conducted by Zhan, [13] rats that were injected with HSP-70 at 2 1/4 and 3 hours following ischemic MCAO showed a decrease in infarction size by 68% when compared with control groups. These rats also showed increased neurological function based on a forelimb-placement test, in which response to whisker stimulation was measured and compared to control groups [13]. The results of this test showed that rats treated with IV HSP-70 had a 31% success rate with forelimb placement, compared to 5% with a saline-treated control group (non-MCAO rats measured at 97.8%).[13]))] One interesting aspect found in this study was that the injectable HSP-70 treatment led to a decrease in natural HSP-70 production[13]. This was proposed to occur due to binding to heat shock factor 1, not allowing the promotion of HSP-70.[13]

ERK1/2

Extracellular signal-related kinases 1 and 2 operate in the MAPK pathway and play a pivotal role in signal transduction following ischemic injury in the adult brain [15]. Activation of ERK1/2 is an important defense mechanism against ischemia or hypoxia by counteracting cell death and enabling damage repair [14]. The ERK-mediated signals have been shown to play a major role in ischemia-induced apoptosis by regulating Bax/Bcl-2 expression [14] [3]. ERK1/2 has also been shown to play a role in the release of apoptosis inhibiting factor (AIF)[3].

Exercise Effects

In a study conducted by Liebelt in 2010, preconditioning of rats with moderate intensity treadmill training (30 m/min) for 30 minutes a day and 5 days per week over a 3-week period led to a reduction in neuronal apoptosis and brain infarction volume [14]. This type of training was shown to increase the amount of HSP-70 and ERK ½ in neurons, however, significant improvements were only seen following 3 weeks of exercise (and not in 1- or 2-week exercise groups)[14]. In addition to this, brain infarct volume was shown to be significant less in the 3-week exercise group in comparison to the 1- or 2-week groups [14]. Also, this study showed that inhibiting both HSP-70 and ERK1/2 reduced the neuroprotective effects that were shown following exercise [14]. The beneficial effects were hypothesized to occur due to a measured increase in anti-apoptotic proteins (Bcl-xl) and a decrease in pro-apoptotic proteins (Bax, AIF) [14]. This would suggest that this type of exercise preconditioning not only promotes cellular survival signals but also interrupts cell death signals after an ischemic event.

Angiogenesis

A series of studies have demonstrated that physical exercise may be a promising preconditioning method to induce brain ischemic tolerance through the promotion of angiogenesis. [3] Angiogenesis, the growth of new capillary blood vessels in the body, has been shown to lead to a better outcome in stroke surviviors.[16] In a study conducted in 1994, Krupinski et al. [16] demonstrated that patients with a higher blood count in infarcted brain tissue (via angiogenesis) had fewer lasting deficitis and longer survival rate than those patients with a lower blood count in the infarcted hemisphere.

Studies using magnetic resonance angiography have provided evidence that physical exercise and rehabilitation promote cerebral angiogenesis in healthy subjects. [17] Other studies have gone on to show that physical exercise prior to an ischemic event imrpoved cerebral blood flow during the period of reperfusion in transient ischemic stroke in a rat.[18]

Angiogenesis associated with exercise is heavily linked to vascular endothelial growth factor(VEGF). VEGF is an important regulator of angiogenesis and vascular survival.[19] Recent research has also suggested that VEGF has properties that additionally promote neural survival and neurogenesis.[19] VEGF has several members but VEGF-A is focused on.[19] It is a stimulator of endothelial cell proliferation, migration, and survival.[19] The main receptor that VEGF exerts its angiogenic effect on is VEGFR-2.[19] Additionally, VEGF promotes axonal outgrowth of dorsal root ganglion, cervical ganglion, and primary cortical neurons.[19] Following an ischemic stroke VEGF has the ability to reduce death in primary cortical cells.[19] VEGF has two possible mechanisms in promoting recovery following ischemic stroke. First, it has a direct potential for neural protection and regeneration by directly influencing neural survival and neurogenesis.[19] Second, VEGF has pro-angiogenic effects that would promote revascularization in the area of infarct and consequently leading to enhanced perfusion.[19] The literature does not recommend concise parameters regarding the exercise dosage that ideally induces increases in VEGF. However, Swain et al.[20] found that voluntary exercise over a 30 day period (with the average distance covered at 36 miles) induced significant angiogenesis in the motor regions of the cerebral cortex. Research has additionally shown that angiogenesis and neurogenesis have an promoting relationship between one another in the brain.[19] Areas of angiogenic activity are many times spatially associated with increased neurogenesis—neuroblasts migrate to areas of newly forming microvessels.[19]

Physical exercise has been demonstrated to increase the level of VEGF mRNA and protein in the hippocampus of mice.[21] Increased VEGF can promote angiogenesis of cerebal vasculature, thus promoting the theory that exercise may lead to brain ischemic tolerance and better outcomes following stroke.[22]

Inflammation

It is known that an inflammatory response occurs following stroke and is linked to patient outcome [23]. Research has also demonstrated that infections may contribute to inflammation thereby affecting stroke risk and outcomes as well [23]. Exercise has been shown to have an effect on the inflammatory process via cytokine levels and HPA-axis activation.

Cytokines

It has been established that cerebral ischemia induces an inflammatory response via the activation of cytokines such as IL-1β, IL-6, TNF-α, and IFN-γ [3]. Research has also shown that post-ischemic inflammation can facilitate infarct progression and neurological deficits thereby contributing to further brain injury [3]. Increased levels of pro-inflammatory cytokines such as IL-1β, IL-6, TNF-α, and IFN-γ, have been linked to increased activity of the HPA-axis and to immune function following stroke [24][25]. Several studies have demonstrated that cytokine levels are constantly changing in response to exercise [4].

IL-1β

Research has demonstrated that IL-1β is down-regulated with exercise [4]. Studies on rats showed that up-regulation of IL-1β had a detrimental effect following cerebral ischemia and that using a receptor antagonist to block IL-1β resulted in neuroprotective effects by reducing brain edema, decreasing the number of neutrophils in ischemic areas, and reducing the interaction between neutrophils and endothelial cells [4].

IL-6

IL-6 levels are elevated in muscles of persons with Type II diabetes, a common condition in persons following stroke. Exercising can help balance the levels of IL-6 to improve insulin sensitivity and decrease the incidence and risk of of diabetes in this population[26]. While IL-6 is generally thought of as a pro-inflammatory cytokine it has been suggested recently that it may have anti-inflammatory effects as well [4][25]. These anti-inflammatory effects depend on the inhibition of IL-1 and TNF-α production and stimulation of the production of their circulating antagonists [4]. There is some evidence that exercise-induced increases in IL-6 acted to prevent increases in TNF-α [25]. It has also been noted that exercise leads to significant increases in plasma IL-6 concentrations, as much as 100 times normal levels following a marathon, but decreases of IL-6 in the brain [4]. Therefore, exercise may facilitate a neuroprotective effect by increasing plasma IL-6 concentrations which acts to reduce TNF-α and decreasing IL-6 levels in the brain.

TNF-α

Following a stroke, levels of TNF-α mRNA are increased in skeletal thigh muscle of the both the nonparetic and the paretic side compared to controls without neurologic injury or gait impairments, with a greater increase shown in muscles of the paretic side of the body. The paretic thigh muscles demonstrated a 2.8fold increase while the nonparetic thigh muscles showed a 1.6fold increase compared to the control subjects. [2][26] TNF-a down-regulates slow twitch muscle fiber protein synthesis following stroke and enhances slow twitch protein degradation. It also activates NF-kB transcription factor. This has Musculoskeletal consequences.[26] There is a down-regulation of TNF-α following exercise which has been shown to have a neuroprotective function following stroke [4]. This down-regulation allows for gains in muscle protein and muscle strength with resistance exercise. [2] It also improves metabolism and insulin sensitivity. Type II diabetes commonly occurs in persons following a stroke, so exercise and decreasing TNF-a levels is key to prevent or manage this issue.[26]

IFN-γ

Following exercise, plasma IFN-γ levels appear to be unaffected but INF-γ levels in the brain are down-regulated [4]. As IFN-γ is known to have pro-inflammatory effects and therefore, can be detrimental following cerebral ischemia, decreased IFN-γ in the brain following exercise could be beneficial in an individual’s recovery following stroke.

HPA-axis

Increased HPA-axis activation is associated with increased levels of pro-inflammatory cytokines and poor functional outcomes following stroke [27]. Studies have demonstrated that increased aerobic fitness is associated with a lower HPA-axis response to stress [25]. Studies on humans and rats have shown that aerobic exercise resulted in decreased HPA-axis activity and subsequent stress response [25]. The authors suggested this effect may be due to adaptations in peripheral sympathetic nerve synthesis/release rates, increases in endogenous antioxidant defenses, and increased expression of heat shock proteins [25]. These findings suggest that aerobic exercise prior to the occurrence of a stroke could potentially lead to a decreased stress response and therefore, better functional outcomes following stroke.

Exercise Summary

Exercise following stroke, such as body-weight support treadmill training or riding a bicycle ergometer, can have a beneficial effect on pro-inflammatory cytokine levels and thus, help reduce brain damage associated with inflammation post-stroke [4]. Regular participation in an aerobic exercise program prior to a stroke can potentially lead to better outcomes following stroke by facilitating decreased HPA-axis activation in response to stress [25].

Oxidative stress

Reactive oxygen species (ROS) are normal products of aerobic metabolism, and when they are produced in excess, they may cause cell apoptosis and necrosis.[28] The central nervous system (CNS) is particularly sensitive to ROS due to the interaction of iron and highly reactive hydroxyl radicals which can cause damage to DNA and proteins.[29] Due to this heightened sensitivity to ROS in the CNS, it is highly important to maintain the redox state in different types of neuro cells. In recent years, it has become clear that regular exercise beneficially affects brain function and could play an important preventative and therapeutic role in stroke, among other neurological diseases.[30]

Oxidative damage has been associated with poor physiological function of the brain. In rat models, beneficial effects on brain function and lowered accumulation of ROS occurred with moderate training, very hard training, and even overtraining.[31] The findings of several studies indicate that regular exercise acts as a preconditioner against oxidative stress.[28] In a study by Ding et al.[32], trained rats suffered less damage during stroke or other oxidative stress related challenges. Rat studies in which young and middle aged rats were subjected to 60-90 minutes of swimming 5 days a week showed improved cognitive function in passive and active avoidance tests after 9 weeks of regular exercise.[33] These functional changes were accompanied by a decrease in protein carbonyl in the brain extracts, possibly due to mild oxidative stress upregulating of proteasome activity in the brain as an adaptive response.[33] This suggests that a modest increase in ROS in the brain would constitute a mechanism for beneficial consequences in brain function by regular exercise.[33]

The relationship between ROS concentrations and brain function can be characterized by a typical bell-shaped curve.[28] Radak et al.[28] suggest that both low and high levels of ROS, as represented in the bell-curve, could impair cell function. Low levels of ROS might cause insufficient gene expression for redox homeostasis and therefore impair the responses to oxidative challenge, eventually leading to increased vulnerability.[28] High levels of ROS exceed the adaptive tolerance of cells, resulting in significant oxidative damage, apoptosis and necrosis.[28] Exercise training likely increases the window between low and high levels of ROS, resulting in increased resistance and tolerance to oxidative challenges.[28] Exercise can influence the ROS generation in the brain via calcium dependent pathways, which may be linked to the activity of neurons.[28]

Exercise, Oxidative Stress, and the Role of PGC-1a

PGC-1a promotes the expression of a number of antioxidant genes through the coactivation of the transcription factors that regulate them, which include nuclear respiratory factors and nuclear receptors.[34] PGC-1a is strongly neuroprotective against oxidative insults as well as excitotoxicity. PGC-1a is induced as part of several behaviors that induce adaptive stress response programs, such as exercise or caloric restriction.[35] There is now growing evidence that caloric restriction, exercise, and cognitive stimulation reduce the risk of neurogenerative disease like stroke.[35] Exericse will promote neuronal health in part through enhanced resistance to oxidative stress, potentially through up-regulation of PGC-1a, among other mechanisms like neurotrophin expression and synaptic activity.[35]

Exercise and Antioxidants in the Brain

Current evidence suggests that exercise training selectively regulates the activity of antioxidant enzymes in different brain regions.[28] The activity response of antioxidant enzymes in the brain, with exercise, is probably dependent of the type of physical activity, the intensity and duration of exercise training, and the age, sex, and strain of rats used in the experiment.[28] For example, in certain brain parts such as the stem and corpus striatum, exercise training resulted in increased activities of superoxide dismutase (SOD) and GPX.[36]

Clinical Relevance

Regular physical exercise that produces smaller to moderate increases in ROS may be beneficial by enabling the preparation of cells for higher levels of oxidative stress encountered in the future.[33]

Neurogenesis

Studies have linked exercise to improved neurogensis following stroke [4]. Neurogensis and synaptic reorganization are key events in an individual's functional recovery following stroke.[37] These improvements may be due to the action that exercise has on the signaling mechanisms associated with the action of neurotrophins such as NGF and BDNF [4]. Additionally, a positive feedback loop is created because it has been shown that increases in synaptic activity then induced compensatory angiogenesis.[37]

NGF, BDNF, NO, and BrdU +

Nerve growth factor (NGF) and brain derived nerve factor (BDNF) are neurotrophins that function to support growth, survival, and differentiation of certain neuronal cells in the nervous system [4]. NGF has been reported to prevent neuronal cell death after brain injury and provide neuroprotection by guarding neurons against hypoglycemia and excitotoxicity via stabilizing intracellular calcium [4]. BDNF is a key protein that plays a significant role in regulating maintenance, growth, and survival of neurons.[38] It influences the regulation of axonal and dendritic branching and remodeling, helps increase the efficacy of synaptic transmission, has been shown to be highly neuroprotective and reduce neuronal cell death in a number of brain injury models, and promotes motor recovery after stroke [39][4][40][41]. BDNF synthesis is mediated centrally and has been shown to be activity dependent.[38] Specifically, exercise has been shown to increase BDNF transcription, as well as, increasing the uptake of insulin-like growth factor I—which is a precursor to the elevation in BDNF mRNA expression.[42] BDNF and NGF have also been shown to increase the activity of free-radical scavengers thus helping to protect the neurons against free-radical damage [4]. BrdU + has been used to measure survival and the phenotype of proliferating and newly generated cells in the peri-infarct region. Specifically it labels neural progenitor cells born after a stroke, and was used in a study with rats that underwent focal cortical ischemia via the vasoconstrictor endothelin. [43]

Nitric oxide is a reactive molecule produced by endothelial nitric oxide synthase (eNOS).[44] eNOS influences systemic blood pressure, vascular tone, vascular remodeling, and angiogensis.[44] The phosphorylation of eNOS has been shown to have neuroprotective qualities following stroke.[44] NO has recently been shown to play a crucial role in the expression of BDNF.[44] It mediates BDNF-induced growth-associated protein 43 (GAP-43) mRNA expression.[44] Exercise has been shown to upregulate eNOS expression and thus be protective against ischemic stroke.[44] An exercise regimen in human CABG patients shown that eNOS mRNA expression, eNOS protein, and phosphorylated eNOS were all higher in an exercise group that performed 10 minutes of row ergometer and 10 minutes of bicycle ergometer 3 times daily.[45] In a knock-out study in mice it was shown that eNOS deficient mice had increased neurological functional deficit after stroke.[44] eNOS has been shown to have a crucial role in in both angiogenesis and neurogenesis.[44]

Effects of Exercise on NGF and BDNF

Studies have shown that exercise can up-regulate neurotrophins such as NGF and BDNF endogenously. Thus, exercise can help facilitate recovery from a brain injury, such as stroke, via up-regulation of NGF and BDNF [4]. A study conducted by Ploughman et. al. found that a single, short 30 minute walk performed 4 days after stroke increased BDNF levels in the intact sensorymotor cortex more than longer distance walks or higher intensity runs in rats following ischemic stroke [40]. The authors stated that increased levels of BDNF, in addition to insulin-like growth factor (IFG-1) (mediates exercise-induced neurogenesis in the rat hippocampus) and synapsin-I (a protein implicated in neuroplasticity), in the intact hemisphere may set the stage for neuronal remodeling after stroke [40]. They also stated that exercise above a moderate intensity or for a longer distance were associated with increased levels of corticosteroids which could lead to worse functional outcomes following stroke [40]. A later study conducted by Ploughman et. al. found that reach training (10 minutes of reaching for pellets on a tray progressed over the course of 5 weeks to 60 minutes reaching to a higher tray, performed daily) preceded with an endurance training protocol initiated 5 days post-stroke (30 minutes at a slow pace progressed to 60 minutes at a mild to moderate pace over 5 weeks, performed daily) in rats led to an enhanced recovery of skilled reaching ability, potentially due to increased levels of BDNF following the endurance training [46]. The authors noted that clinically, endurance training could consist of body-weight support treadmill training or an arm and leg bicycle ergometer [46]. Research has also demonstrated that exercise induced NGF was capable of reducing infarct size following a middle cerebral artery occlusion in the rodent model [4].
BrdU + levels were elevated in the peri-infarct region following ischemic stroke in greater levels in younger versus older rats. Proliferation of BrdU cells were seen in the ipsilesional dentate gyrus of animals that exercised following stroke compared to those who did not perform any exercise.[43]

Exercise Summary

The above evidence suggests that endurance activities, such as riding a bicycle ergometer or body-weight support treadmill training, performed at no greater than a moderate intensity (walking pace) for a short duration (around 30 minutes) can lead to increased functional improvements following a stroke [40][46]. Also, these improvements may be due, at least in part, to the upregulation NGF and BDNF following exercise [4]. Additionally, modest improvements can be seen in both a younger and older population with a ligth intensity walking program. [43]

Plasticity

Exercise and stroke plasticity post CVA

Neural plasticity is the tendency of synapses and neuronal circuitry in the brain to change.[47][48] Genes and proteins responsible for plasticity are expressed at high levels during early brain development and decline in levels with ageing.[49] Because of these decreased levels plasticity was originally thought to occur only during early brain development and not in the adult brain, but recently, it has been determined that plasticity can play a role the adult brain as well and plays an important role in neural recovery after strokes.[47]

Cellular components such as Brain-derived neurotrophic factor (BNDF), GAP43 (neuromodulin), MARCKS, and CAP23 (also known as BASP1) play an important role in brain plasticity after stroke.[50] [49] Through increased gene expression and protein synthesis, recovery is promoted through increased neuronal growth, new axon sprouting, increasing elaboration of dendrites and spines, and long-term potentiation.[50] [49] [48] Through this process, long term cortical reorganization in the brain occurs.

During the first few weeks following ischemic stroke, dendritic arborization, synaptogenesis, astrocytes and fibroblast growth factors (FGF), which are neurotrophic growth factors, proliferate throughout both hemispheres of the brain. It has been suggested that these positive plastic changes in the brain shortly after stroke can be initiated and enhanced through exercise training. Specific motor training, such as contraint induced movement therapy, has proven to increase levels of FGF bilaterallyand BDNF in the injured hemisphere. [39]

After ischemia, exercise has been shown to increase stress and heat shock protein chaperones, which are highly neuroprotective, in addition to other plasticity-promoting factors. [39] Additionally, increased levels of BDNF, phosphorylated cAMP response-element binding protein (pCREB), IGF-1, and synapsin-I are seen, each of which are thought to play a part in increasing neuroplasticity following ischemia.[46] Increased levels of these proteins have been found in the hippocampus and sensorimotor cortex ipsilateral to the ischemic region in rat’s with middle cerebral artery occlusions immediately following exercising at a fast walking, 2 weeks after ischemia.[46] These levels were maintained for 30 minutes after a 60 minute bout of continuous walking but were maintained for 2 hours when the rats voluntarily selected walking time and speeds (shorter, less intense, but more frequent exercise) over a 12 hour period.[46] Based on these results, the authors concluded that plasticity after ischemia may be improved by more frequent, less intense exercise interventions which allow for the maintenance of higher levels of proteins which are responsible for producing changes in the plasticity of neural tissues.

Exercise and the enriched environment

An enriched environment, consisting of a variety of new challenges and experiences, has been demonstrated to be beneficial for increasing plastic changes in the brain after an ischemic stroke. Rats with an ischemic lesion immediately moved to housing in an enriched environment with more rats in larger cages, introduction of novel objects for manipulation with varying arrangements and changing, complex toys to interact with, demonstrated a variety of plastic neural changes that were not seen in rats housed in non-enriched environments. [51] The rats in the enriched group demonstrated increased brain weight, increased cortical and hippocampal thickness, increased neuronal cell body and nucleus size, increased dendritic branching, increased dendritic spine density in cortical pyramidal cells, increased number of glial cells, improved contact of astrocytes with neuronal synapses.[51] A change was also demonstrated in gene-expression with increased trophic factors including as BDNF, glial cell line-derived neurotrophic factor and nerve growth factor.[51] These factors assist to increase plasticity in the brain and produce functional changes through improving sensorimotor functions. It is thought that these changes in the cellular structure of brain cells after ischemic stroke are caused by the effect of learning of new tasks.[51]

Time window for plastic changes post CVA

Immediately after and during the first week following a stroke, intense motor rehabilitation can benefit the contralesional hemisphere while excessive forced exercise can cause increased damage in the injured hemisphere. Therefore, a gradual increase in motor rehabilition will be less detrimental during this vulnerable period. [39] However, after this initial period of protection, there has been show to be a brief period of increased expression of genes responsible for neural plasticity, leading to a brief period of increased neuroplasticity.[49] One study exposed rats to an enriched rehabilitation environment, running exercise and reaching training for 5 weeks, starting 5, 14, or 30 days after a middle cerebral artery occlusion.[49][7] Rats given rehab at 5 or 14 days demonstrated improved functional recovery while the rats that began treatment 30 days post stroke demonstrated little improvement in function.[7] Rats in the 5 and 14 day groups were found to have increased dendritic branching in the layer V cortical neurons while there was no effect on neuron growth in the 30 day group.[7] This indicates that the window for optimal neural plastic occurs early after the initial ischemic event and diminishes with time although precise timing of the window may be different in human models where spontaneous recovery post CVA has been observed at 90 days post ischemic events and does not consider other mechanisms of neural recovery.[49] [47] This is consistent with studies of human models which have associated poorer outcomes and longer hospital lengths of stay for patients who have had delays in the initiation of rehabilitation.[52]

Musculoskeletal Changes

Common musculoskeletal changes following a stroke include decreased lean muscle mass, increased body fat percentage and intramuscular fat, and increased reliance on anaerobic metabolism with greater lactic acid buildup. Additionally, an increased amount of fast twitch muscle fibers can be seen with a decreased amount of slow twitch or fatigue resistant muscle fibers. The proportion of fast twitch muscle fibers is negatively correlated with walking speed and can predict severity of gait deficits. TNF-a levels are also increased, which leads to activation of NF-kB transcription factor. This may in turn increase ROS, oxidative injury, and muscle atrophy. ROS can also increase muscle fatigue and injury during ADLs and mobility. [26]

The hindlimb muscles of rats induced with MCAO stroke, the most relevant to the human stroke, were analyzed for changes in muscle mass, fiber type, and protein content following low-intensity exercise. Exercise protocol simulated low-intensity exercise following acute stroke: rats ran on a treadmill for 6 days starting 2 days after stroke for 20 minutes/day at 10 meters per minute.
The affected soleus and affected/unaffected gastrocnemius muscles all demonstrated a significant treatment effect in regards to muscle weight. The affected soleus muscle had a significant increase in Type I fiber cross-sectional area (CSA), and Type II cross-sectional area of the unaffected soleus increased significantly. For the affected and unaffected plantaris muscle, there was a significant treatment effect on Type II CSA. The affected and unaffected gastrocnemius muscle demonstrated a significant treatment effect of Type I and Type II fiber CSA.
The myofibrillar protein content showed significant treatment effects of the affected and unaffected soleus muscles.[53]
This study indicates in rats following acute stroke, low intensity exercise can increase the amount of contractile protein available to generate force in addition to increasing both slow twitch and fast twitch fiber types. Importantly, it can attenuate some of the muscle atrophy that occurs within the first week following a stroke.

Aerobic and resistance exercise have both been shown to have positive effects on the musculoskeletal system. Some examples include treadmill walking, robot assisted walking, and strength training. Treadmill walking is generally considered the best exercise to convert fast to slow twitch muscle fibers in order to improve mobility, gait, and muscle performance.[26]

Conclusion/Exercise Recommendations

Exercise can have both positive and negative effects after stroke, dependent upon the duration, intensity, and frequency of exercise applied. During the first 3-5 days, high intensity exercise can produce excitotoxic effects in neural cells, inhibiting recovery. Early, frequent exercise at mild to moderate intensities, however, has been shown to have a positive effect on plastic changes in the brain after stroke, especially within the first few weeks after ischemic stroke. Lower intensity exercise is also beneficial for preventing increased oxidative stress within neural cells after ischemic stroke while moderate intensity exercise has also been shown to produce beneficial effects on glutamate receptor function post stroke. Moderate exercise prior to stroke has also demonstrated a positive effect on glutamate receptors and decreased apoptosis after a stroke does occur, a consideration for patients who have had a previous transient ischemic attack, which increases the risk for future strokes. Exercise has a therapeutic basis following stroke because it has been shown to promote neuroprotective qualities and neurogenesis through the upregulation of NGF, BDNF, nitric oxide synthase (NOS), and VEGF. Additionally the increase in VEGF and NOS leads to increased angiogenesis improving reperfusion at the infarcted area. With exercise promoting neurogensis and angiogensis better functional outcomes are seen following stroke. Based on these findings, optimal exercise recommendations would include early exercise at low intensities. This exercise intensity can be gradually increased over time but emphasis should be placed on less intense, more frequent treatments, especially in the acute and subacute phases of stroke recovery. This exercise plan should be modified to fit each patient’s specific needs.

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