REVIEW URRENT C OPINION
Motor rehabilitation in stroke and traumatic brain injury: stimulating and intense Erika Y. Breceda a,b and Alexander W. Dromerick a,b
Purpose of review The purpose of this review is to provide an update on the latest neurorehabilitation literature for motor recovery in stroke and traumatic brain injury to assist clinical decision making and assessing future research directions. Recent findings The emerging approach to motor restoration is now multimodal. It engages the traditional multidisciplinary rehabilitation team, but incorporates highly structured activity-based therapies, pharmacology, brain stimulation and robotics. Clinical trial data support selective serotonin reuptake inhibitors and amantadine to assist motor recovery poststroke and traumatic brain injury, respectively. Similarly, there is continued support for intensity as a key factor in activity-based therapies, across skilled and nonskilled interventions. Aerobic training appears to have multiple benefits; increasing the capacity to meet the demands of hemiparetic gait improves endurance for activities of daily living while promoting cognition and mood. At this time, the primary benefit of robotic therapy lies in the delivery of highly intense and repetitive motor practice. Both transcranial direct current and magnetic stimulation therapies are in early stages, but have promise in motor and language restoration. Summary Advancements in neurorehabilitation have shifted treatment away from nonspecific activity regimens and amphetamines. As the body of knowledge grows, evidence-based practice using interventions targeted at specific subgroups becomes progressively more feasible. Keywords brain injuries, cerebrovascular disease, motor recovery, neuronal plasticity, rehabilitation
INTRODUCTION As the world population ages and medical advancements improve survival rates after stroke and traumatic brain injury (TBI), improving the lives of survivors assumes greater importance. Stroke remains a leading cause of long-term disability with only 45% of individuals discharged directly home [1,2]. Current projections from the American Heart Association forecast total US direct stroke costs to increase from $71.55 billion to $183.13 billion in 2030, adjusted for inflation [3]. The estimated direct and indirect cost for TBI is $76.5 billion in the USA [4,5]. Motor deficits are present in 30 and 80% of survivors in TBI and stroke, respectively [6,7]. Emerging evidence suggests that the optimal approach may be multimodal, still founded on manipulation of motor practice, but incorporating other interventions such as drugs or brain stimulation. Evolving rehabilitation clinical trial methods can now support the empiric demonstration of
optimal intervention content, dosage and timing. We will discuss recent advances in neurorehabilitation with respect to motor recovery and identify directions for future research.
PHARMACOLOGICAL AGENTS TO SUPPORT MOTOR RECOVERY Motor recovery has been targeted using several classes of pharmacological agents. Recent studies a
Washington DC Veterans Affairs Medical Center and bMedstar National Rehabilitation Hospital, Georgetown University Department of Rehabilitation Medicine, Washington, District of Columbia, USA Correspondence to Alexander W. Dromerick, MD, Medstar National Rehabilitation Hospital, Georgetown University Department of Rehabilitation Medicine, 102 Irving Street NW, Washington, DC 20010, USA. Tel: +1 202 877 1932; fax: +1 202 726 7521; e-mail: Alexander.W. [email protected] Curr Opin Neurol 2013, 26:595–601 DOI:10.1097/WCO.0000000000000024
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KEY POINTS A multimodal approach to motor restoration following stroke and TBI that encompasses interventions from all members of the interdisciplinary team is needed. Intensity of training appears to be a key factor in motor restoration. Dosing of therapeutic interventions needs to be better understood and examined for feasibility in the clinic. Fluoxetine and aerobic exercise have great promise; multicentre RCTs are now needed. Clinical trial designs that identify subgroups are now available to provide a more tailored approach to rehabilitation.
survivors did not find significantly improved motor performance [13]. A review by Martinsson et al. [14] found no significant effect of amphetamines on motor or neurological function at follow up and raised a question of increased mortality. Newer trials are investigating dosage and age differences that may explain negative trial results [15,16]. A recent small RCT found that dextroamphetamine initiated within 14–60 days improved activities of daily living (ADLs) and arm function when given twice weekly, 1 h prior to therapy sessions [17]. These small studies need to be replicated before amphetamines can be accepted as a treatment to improve motor recovery.
Cerebrolysin have been successful in repurposing drugs such as antidepressants and antiparkinsonian drugs for motor recovery. Below is a discussion of the current status of popular motor enhancement agents.
Fluoxetine Selective serotonin reuptake inhibitors (SSRIs) are being evaluated; a recent multicentre randomized controlled trial (RCT) has shown promising benefits for fluoxetine. Chollet et al. [8] investigated the addition of daily fluoxetine 5–10 days poststroke and found greater motor improvements after 90 days than in the placebo group. There was no follow-up beyond 90 days. Several possible mechanisms of SSRI effects are under investigation. These include upregulation of brain-derived neurotrophic factor (BDNF), a protein important during activity-dependent remodelling. Improved serotonergic transmission and increased cortical activation [9–11] are also possible. In addition to improved motor performance, SSRIs have demonstrated improved recall when administered in the subacute phase of stroke recovery [12]. Future trials that include prolonged monitoring and larger sample sizes are now needed.
Amphetamines Amphetamines may still be the most popular ‘recovery-enhancing’ drug, but clinical trial data are lacking. Amphetamine treatment is based on promising animal studies in the 1970s. Human trials have been overall disappointing, and there is debate whether these findings are due to inadequate trial design or intrinsic ineffectiveness of the drug. The largest RCT of amphetamine in acute stroke 596
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Cerebrolysin is a neuropeptide and free amino acid combination with neuroprotective and neurorestorative properties. It was promising in animal models and small-scale RCTs, but recent trials have not been as successful. A Phase III clinical trial yielded an increased survival rate after severe stroke, but no significant effects on motor improvement [18]. Posthoc comparisons did demonstrate motor benefits in the moderate stroke subgroup. Although initial data from Lang et al. [19] suggested that cerebrolysin facilitated improvement on the National Institutes of Health Stroke Scale at 30 days, by day 90 the outcomes resembled those of controls. Further trials may be needed to identify potential subgroups.
Amantadine for traumatic brain injury In moderate and severe TBI, amantadine trials have been encouraging. Giacino et al. [20 ] found a significant improvement in the Disability Rating Scale in minimally conscious TBI patients when given amantadine vs. placebo at 4 weeks postinitiation of treatment. The dosage was gradually increased from 100 mg/day to 200 mg twice a day for 4 weeks. Amantadine also improved consciousness in children with subacute brain injury undergoing traditional rehabilitation for a 3-week period [21]. In this randomized, double-blind crossover trial, participants were given amantadine twice daily. As impaired consciousness delays rehabilitation, this could help to reduce the consequences of prolonged bed rest, which include 1–1.5% muscle strength loss per day, decrease cardiac output and other metabolic changes [22,23]. It should be noted that this clinical trial experience with amantadine in TBI relates to patients with impaired consciousness or vegetative state and this does not necessarily generalize to mild or moderate TBI. &
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ACTIVITY-BASED INTERVENTIONS THAT PROMOTE MOTOR RECOVERY Activity-based interventions hope to maximize neural plasticity, a factor believed to be important in recovery. Optimal doses and schedules of training have not been adequately established. Current animal studies of forelimb motor practice involve 400–600 repetitions per session. In contrast, two multisite studies assessing US rehabilitation found that stroke and TBI survivors receive an average of 32–50 repetitions of upper extremity active and passive movement per session [24,25]. Similarly, patients received an average of 249–357 steps, compared with the 1000–2000 steps used in animal studies. Repetition is one parameter important for experience-dependent neural plasticity [26]. Kleim and Jones [26] notes other influential factors for neural plasticity, including specificity, salience, time, age, transference, ‘use it or lose it’, interference and intensity; there are no clear recommendations for rehabilitation. How the use of compensatory strategies that emphasize quick independence in ADLs affects motor restoration efforts is unclear; restoration-based approaches are generally favoured [27].
Constraint-induced movement therapy Constraint-induced movement therapy (CIMT) consists of paretic limb motor training using a shaping paradigm while constraining the nonparetic limb to encourage use of the paretic arm for functional tasks. It has been investigated in both chronic and acute stages of recovery poststroke. A study by Dromerick et al. [28] examined the effects of CIMT delivered at an average of 9.65 days poststroke and found no significant benefit over traditional therapy. The EXCITE trial examined CIMT delivery in the subacute phase (3–9 months) and demonstrated greater motor improvement in the CIMT group versus customary care that was not dose matched [29]. However, the CIMT group may have received more hours of training than the observation control group, and it is not clear whether the treatment effect was due to the CIMT approach, or simply more training. A metaanalysis and systematic review suggest that CIMT may be better suited to improve motor function in patients greater than 6 months poststroke [30]. Given the review contained several nondose-matched control group studies of primarily neuro-developmental treatment therapy, further studies are needed.
Interdisciplinary comprehensive arm rehabilitation evaluation Interdisciplinary comprehensive arm rehabilitation evaluation (ICARE) is an ongoing large RCT testing
skill acquisition, capacity building and motivational enhancement to improve upper extremity motor function after stroke [31]. The Accelerated Skill Acquisition Program is the experimental intervention, which emphasizes rehabilitation principles thought to be essential: challenging and meaningful practice tasks; addressing interfering impairments; overload and specificity of practice; goal directedness; avoidance of artificial task breakdown; self-directed therapy; balance of immediate and future needs; and increasing self-confidence.
Body weight supported treadmill training Trials demonstrate that body weight supported treadmill training (BWSTT) improves disability, gait speed, gait symmetry and cardiovascular health in stroke and TBI populations [32–34]. Patients walk on a treadmill with a portion of their body weight unloaded by an overhead harness system. A recent large clinical trial, Locomotor Experience Applied Post-Stroke (LEAPS), failed to show significant differences between home therapy and treadmill training, but it did show improvement in gait speed across all groups [34]. However, all study groups received greater than normal quantities of physical therapy that may account for the improvement seen across all groups. BWSTT provides a means to perform safe, high-intensity gait training that is difficult to achieve overground. Current studies are examining the use of BWSTT while providing percutaneous electrical stimulation at the T11–T12 spinal region [35] in persons with complete spinal cord injuries. The findings suggest that stimulation can modulate firing patterns in muscles that lack supraspinal input; there may be implications for restoration in stroke and TBI.
Accelerating progress in activity-based interventions Perhaps the most important question is still unanswered; how much and when should we initiate activity-based interventions? Answering this question is essential. With regard to how much, intensity appears to be the resounding theme among recent studies, whether a measure of total therapy volume or metabolic cost. Current best practice guidelines in Canada and the USA call for a minimum of 1 h, 5 days per week, of each therapy during a standard inpatient stay. A recent study of 123 patients found that stroke survivors in Canada received an average of 37 min/day of combined physical and occupational therapy [36].
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Is more intense therapy always beneficial regardless of the stage of recovery? There is conflicting evidence surrounding the specific benefits of physical and occupational therapy in stroke and TBI survivors [36–39]. More focused multicenter studies involving 116 stroke survivors with moderate to severe strokes found that the minutes spent in gait training during the first block of inpatient therapy predicted outcomes regardless of therapy rendered over the course of treatment [37]. However, when inpatient rehabilitation was compared with no rehabilitation care, no significant difference was found in upper extremity functional outcomes, global improvement and ADL function at 6 months [40].
ADJUNCT MODALITIES FOR ASSISTING IN MOTOR RECOVERY Although most stroke and TBI survivors benefit from traditional therapy, it is clear that more is needed to attain full recovery, especially with the severely affected population. Various technologies to supplement therapy are being investigated and will be described below.
Brain stimulation Transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) are noninvasive, well tolerated and painless approaches. TMS works via magnetic induction and tDCS works via low-voltage direct electrical current [41]. Two approaches are being tested to enhance neurorehabilitation poststroke using these types of brain stimulation. One is to increase lesioned hemisphere activity, which has been shown to correlate with improved motor performance, grip force, reading efficiency and aphasia, depending on the brain location stimulated [42–45]. Another approach is to alter the stimulation parameters to suppress or inhibit specific brain regions. The brain has strong inter-hemispheric inhibitory connections. Stroke patients have a greater inhibitory drive from the nonlesioned hemisphere to the lesioned hemisphere that is associated with poor motor performance of the hand [46]. Thus, inhibiting the nonlesioned hemisphere via tDCS or high-frequency rTMS should result in motor improvements. Randomized, placebocontrolled trials that modulate the inhibition of the nonlesioned hemisphere over the motor cortex demonstrate an improvement in motor performance [47,48 ]. The benefits of the stimulation are greater when done as a priming activity to therapy, thus augmenting the benefits of activity-dependent &
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plasticity. Now, there is a need for larger RCTs to validate the use of these modalities and determine their utility in clinical practice. Epidural cortical stimulation using electrodes placed over the motor cortex is another approach. A preliminary feasibility study of 24 patients demonstrated improved arm function in stroke survivors at a 6-month follow-up after having received the implanted cortical stimulation and combined rehabilitation therapy that was not seen in the rehabilitation control group [49]. The result of a large multicentre RCT is not formally published [50].
Robotic therapy As technology advances, robotic therapy is entering neurorehabilitation. Robotic therapy can manipulate different practice variables, including intensity, repetition and specificity. It also holds the potential to deliver engaging high-intensity and high repetition therapy without the burden of direct one-to-one therapy; if combined with a virtual reality or reward-based interface, it can also create an engaging and motivational environment for the right patient. Recent RCTs have found that robotassisted therapy improves functional outcomes and upper extremity function in stroke patients when given at a high intensity [51,52,53 ,54]. Although robotics such as the InMotion2 (Interactive Motion Technologies Inc. Watertown, MA, USA) or the MIME (Mirror Image Movement Enabler) can elicit gains in motor performance postintervention that are maintained at follow up; these gains are statistically nonsignificant when compared with those elicited by dose-matched therapeutic interventions [54]. One of the prominent barriers in incorporating the aforementioned robots into rehabilitation clinics is cost. If these devices can be mass-produced, they may be a means to provide an adjunct highintensity, task-specific and low-cost intervention. &&
Functional electrical stimulation Functional electrical stimulation (FES) uses a stimulator to activate skeletal muscle to accomplish a functional goal. A recent study [55] found that FES does contribute to neural plasticity by increasing motor-evoked potentials, a measure of cortical excitability of the muscles, which may account for the gains seen in muscle strength. Multicentre RCTs examining the effects of FES via devices such as the WalkAide (Innovative Neurotronics Inc., Austin, TX, USA) and L300 (Bioness Inc., Valencia, CA, USA) have shown significant improvement in gait speed, but no greater benefit than the traditional Volume 26 Number 6 December 2013
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ankle–foot orthosis (AFO) [55–57]. These data and the additional cost suggest why FES is likely to have limited use.
Cardiovascular exercise Perhaps the most supported treatment recommendation is participation in aerobic exercise. The benefits of an intense aerobic exercise program are well documented [58,59,60 ,61], and go beyond general cardiovascular health. Studies show improved gait velocity, gait endurance and improved VO2 peak in stroke survivors who participated in a progressively graded aerobic treadmill exercise program, and results were retained 1 year postintervention regardless of continuation of the exercise program [58,59,60 ]. The frequency in the treatments ranged from two to three times per week for 3–6 months. Although the benefit of cardiovascular exercise may come as no surprise, clinicians are often reluctant to recommend strenuous activity in the absence of physiological monitoring in a nonclinical setting. In the studies noted above, participants of all ages were trained, with had a range of baselines measures, but were cleared from cardiac illness prior to initiating the program. Intensity was graded on the basis of heart rate reserve and training was increased to 50–80% as able. Higher intensity aerobic exercise was also associated with improved depression scores in patients with a TBI [61]. Thus, intensity seems to be a key factor in obtaining measurable results and we should encourage patients to participate in an exercise program [62]. Van de Port et al. [63] found that 90 min of circuit training demonstrated a small but significant improvement in gait speed and walking distance versus controls. Gait speed has also been correlated with predicted life expectancy [64]. In fact, using age, sex and gait speed was as accurate in predicting survival rates as a more complex model that utilizes age, sex, chronic conditions, blood pressure, BMI and hospitalization. This suggests a target walking speed of 1–1.4 m/s, the rate required to cross a street. &&
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Stem cells/cellular therapy Stem cell therapies are under investigation for stroke and TBI. Although the interventional approach for neurorehabilitation of stroke and brain injury is still primarily in animal models, there are a few Phase I and II human trials. Three main approaches for cellular therapies exist: stimulating neurogenesis, minimizing inflammation and neuroprotection [65]. Current trials in animal models of stroke demonstrated early success in increasing angiogenesis
in vivo and in vitro [66]. Lee et al. [67] studied the safety of injecting stem cells intravenously in humans postischemic stroke, and found it to be well tolerated when compared with a sham group. Although they did show a significant improvement in modified Rankin Scale (mRS), evaluations were taken at different time points for both groups. Other randomized double-blind studies have also demonstrated safety, but sample sizes were too small to evaluate effectiveness [68].
CONCLUSION Neurorehabilitation may eventually resemble other treatments, wherein a combination of approaches yields the best outcome. Fluoxetine and aerobic training to improve motor recovery are the most promising newer standalone motor interventions; both warrant definitive clinical trials. The consistent findings that robotic therapy is equivalent (’noninferior’) to traditional therapy suggests that robots can increase accessibility and deliver large volumes of training. Identifying appropriate subgroups during clinical trials, including severity, cognitive function and lesion location, may lead to more individualized successful rehabilitation treatment. Likewise, Bayesian or other study designs may increase the efficiency and reduce the costs of rehabilitation trials. Given these advances and increased effort in neurorehabilitation research, there is great promise for improving the lives of people with stroke and TBI. Acknowledgements This work was supported in part by the Department of Veterans Affairs Office of Academic Affiliations (OAA). Conflicts of interest Dr Alexander W. Dromerick has served as a site investigator for the VECTOR, WalkAide and ICARE trials.
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Motor rehabilitation Breceda and Dromerick 58. Macko RF, Ivey FM, Forrester LW, et al. Treadmill exercise rehabilitation improves ambulatory function and cardiovascular fitness in patients with chronic stroke: a randomized, controlled trial. Stroke 2005; 36:2206–2211. 59. Luft AR, Macko RF, Forrester LW, et al. Treadmill exercise activates subcortical neural networks and improves walking after stroke: a randomized controlled trial. Stroke 2008; 39:3341–3350. 60. Globas C, Becker C, Cerny J, et al. Chronic stroke survivors benefit from high&& intensity aerobic treadmill exercise: a randomized control trial. Neurorehabil Neural Repair 2012; 26:85–95. This study investigated the effects of high-intensity aerobic training in the older population (>60 years old) poststroke and found that training improved gait endurance and VO2 peak; this supports finding from previous studies that also found similar improvements in the younger population. The benefits were observable 1 year after and were not associated with higher adverse events. 61. Hoffman JM, Bell KR, Powell JM, et al. A randomized controlled trial of exercise to improve mood after traumatic brain injury. PM R 2010; 2:911–919. 62. Lam JM, Globas C, Cerny J, et al. Predictors of response to treadmill exercise in stroke survivors. Neurorehabil Neural Repair 2010; 24:567–574.
63. van de Port IG, Wevers LE, Lindeman E, et al. Effects of circuit training as alternative to usual physiotherapy after stroke: randomised controlled trial. BMJ 2012; 344:e2672. 64. Studenski S, Perera S, Patel K, et al. Gait speed and survival in older adults. JAMA 2011; 305:50–58. 65. Lindvall O, Kokaia Z. Stem cells in human neurodegenerative disorders: time for clinical translation? J Clin Invest 2010; 120:29–40. 66. Hicks SD, Middleton FA, Miller MW. Ethanol-induced methylation of cell cycle genes in neural stem cells. J Neurochem 2010; 114:1767– 1780. 67. Lee JS, Hong JM, Moon GJ, et al. A long-term follow-up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke. Stem Cells 2010; 28:1099–1106. 68. Sprigg N, Bath PM, Zhao L, et al. Granulocyte-colony-stimulating factor mobilizes bone marrow stem cells in patients with subacute ischemic stroke: the Stem cell Trial of recovery EnhanceMent after Stroke (STEMS) pilot randomized, controlled trial (ISRCTN 16784092). Stroke 2006; 37:2979– 2983.
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Motor rehabilitation in stroke and traumatic brain injury: stimulating and intense Erika Y. Breceda a,b and Alexander W. Dromerick a,b
Purpose of review The purpose of this review is to provide an update on the latest neurorehabilitation literature for motor recovery in stroke and traumatic brain injury to assist clinical decision making and assessing future research directions. Recent findings The emerging approach to motor restoration is now multimodal. It engages the traditional multidisciplinary rehabilitation team, but incorporates highly structured activity-based therapies, pharmacology, brain stimulation and robotics. Clinical trial data support selective serotonin reuptake inhibitors and amantadine to assist motor recovery poststroke and traumatic brain injury, respectively. Similarly, there is continued support for intensity as a key factor in activity-based therapies, across skilled and nonskilled interventions. Aerobic training appears to have multiple benefits; increasing the capacity to meet the demands of hemiparetic gait improves endurance for activities of daily living while promoting cognition and mood. At this time, the primary benefit of robotic therapy lies in the delivery of highly intense and repetitive motor practice. Both transcranial direct current and magnetic stimulation therapies are in early stages, but have promise in motor and language restoration. Summary Advancements in neurorehabilitation have shifted treatment away from nonspecific activity regimens and amphetamines. As the body of knowledge grows, evidence-based practice using interventions targeted at specific subgroups becomes progressively more feasible. Keywords brain injuries, cerebrovascular disease, motor recovery, neuronal plasticity, rehabilitation
INTRODUCTION As the world population ages and medical advancements improve survival rates after stroke and traumatic brain injury (TBI), improving the lives of survivors assumes greater importance. Stroke remains a leading cause of long-term disability with only 45% of individuals discharged directly home [1,2]. Current projections from the American Heart Association forecast total US direct stroke costs to increase from $71.55 billion to $183.13 billion in 2030, adjusted for inflation [3]. The estimated direct and indirect cost for TBI is $76.5 billion in the USA [4,5]. Motor deficits are present in 30 and 80% of survivors in TBI and stroke, respectively [6,7]. Emerging evidence suggests that the optimal approach may be multimodal, still founded on manipulation of motor practice, but incorporating other interventions such as drugs or brain stimulation. Evolving rehabilitation clinical trial methods can now support the empiric demonstration of
optimal intervention content, dosage and timing. We will discuss recent advances in neurorehabilitation with respect to motor recovery and identify directions for future research.
PHARMACOLOGICAL AGENTS TO SUPPORT MOTOR RECOVERY Motor recovery has been targeted using several classes of pharmacological agents. Recent studies a
Washington DC Veterans Affairs Medical Center and bMedstar National Rehabilitation Hospital, Georgetown University Department of Rehabilitation Medicine, Washington, District of Columbia, USA Correspondence to Alexander W. Dromerick, MD, Medstar National Rehabilitation Hospital, Georgetown University Department of Rehabilitation Medicine, 102 Irving Street NW, Washington, DC 20010, USA. Tel: +1 202 877 1932; fax: +1 202 726 7521; e-mail: Alexander.W. [email protected] Curr Opin Neurol 2013, 26:595–601 DOI:10.1097/WCO.0000000000000024
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KEY POINTS A multimodal approach to motor restoration following stroke and TBI that encompasses interventions from all members of the interdisciplinary team is needed. Intensity of training appears to be a key factor in motor restoration. Dosing of therapeutic interventions needs to be better understood and examined for feasibility in the clinic. Fluoxetine and aerobic exercise have great promise; multicentre RCTs are now needed. Clinical trial designs that identify subgroups are now available to provide a more tailored approach to rehabilitation.
survivors did not find significantly improved motor performance [13]. A review by Martinsson et al. [14] found no significant effect of amphetamines on motor or neurological function at follow up and raised a question of increased mortality. Newer trials are investigating dosage and age differences that may explain negative trial results [15,16]. A recent small RCT found that dextroamphetamine initiated within 14–60 days improved activities of daily living (ADLs) and arm function when given twice weekly, 1 h prior to therapy sessions [17]. These small studies need to be replicated before amphetamines can be accepted as a treatment to improve motor recovery.
Cerebrolysin have been successful in repurposing drugs such as antidepressants and antiparkinsonian drugs for motor recovery. Below is a discussion of the current status of popular motor enhancement agents.
Fluoxetine Selective serotonin reuptake inhibitors (SSRIs) are being evaluated; a recent multicentre randomized controlled trial (RCT) has shown promising benefits for fluoxetine. Chollet et al. [8] investigated the addition of daily fluoxetine 5–10 days poststroke and found greater motor improvements after 90 days than in the placebo group. There was no follow-up beyond 90 days. Several possible mechanisms of SSRI effects are under investigation. These include upregulation of brain-derived neurotrophic factor (BDNF), a protein important during activity-dependent remodelling. Improved serotonergic transmission and increased cortical activation [9–11] are also possible. In addition to improved motor performance, SSRIs have demonstrated improved recall when administered in the subacute phase of stroke recovery [12]. Future trials that include prolonged monitoring and larger sample sizes are now needed.
Amphetamines Amphetamines may still be the most popular ‘recovery-enhancing’ drug, but clinical trial data are lacking. Amphetamine treatment is based on promising animal studies in the 1970s. Human trials have been overall disappointing, and there is debate whether these findings are due to inadequate trial design or intrinsic ineffectiveness of the drug. The largest RCT of amphetamine in acute stroke 596
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Cerebrolysin is a neuropeptide and free amino acid combination with neuroprotective and neurorestorative properties. It was promising in animal models and small-scale RCTs, but recent trials have not been as successful. A Phase III clinical trial yielded an increased survival rate after severe stroke, but no significant effects on motor improvement [18]. Posthoc comparisons did demonstrate motor benefits in the moderate stroke subgroup. Although initial data from Lang et al. [19] suggested that cerebrolysin facilitated improvement on the National Institutes of Health Stroke Scale at 30 days, by day 90 the outcomes resembled those of controls. Further trials may be needed to identify potential subgroups.
Amantadine for traumatic brain injury In moderate and severe TBI, amantadine trials have been encouraging. Giacino et al. [20 ] found a significant improvement in the Disability Rating Scale in minimally conscious TBI patients when given amantadine vs. placebo at 4 weeks postinitiation of treatment. The dosage was gradually increased from 100 mg/day to 200 mg twice a day for 4 weeks. Amantadine also improved consciousness in children with subacute brain injury undergoing traditional rehabilitation for a 3-week period [21]. In this randomized, double-blind crossover trial, participants were given amantadine twice daily. As impaired consciousness delays rehabilitation, this could help to reduce the consequences of prolonged bed rest, which include 1–1.5% muscle strength loss per day, decrease cardiac output and other metabolic changes [22,23]. It should be noted that this clinical trial experience with amantadine in TBI relates to patients with impaired consciousness or vegetative state and this does not necessarily generalize to mild or moderate TBI. &
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ACTIVITY-BASED INTERVENTIONS THAT PROMOTE MOTOR RECOVERY Activity-based interventions hope to maximize neural plasticity, a factor believed to be important in recovery. Optimal doses and schedules of training have not been adequately established. Current animal studies of forelimb motor practice involve 400–600 repetitions per session. In contrast, two multisite studies assessing US rehabilitation found that stroke and TBI survivors receive an average of 32–50 repetitions of upper extremity active and passive movement per session [24,25]. Similarly, patients received an average of 249–357 steps, compared with the 1000–2000 steps used in animal studies. Repetition is one parameter important for experience-dependent neural plasticity [26]. Kleim and Jones [26] notes other influential factors for neural plasticity, including specificity, salience, time, age, transference, ‘use it or lose it’, interference and intensity; there are no clear recommendations for rehabilitation. How the use of compensatory strategies that emphasize quick independence in ADLs affects motor restoration efforts is unclear; restoration-based approaches are generally favoured [27].
Constraint-induced movement therapy Constraint-induced movement therapy (CIMT) consists of paretic limb motor training using a shaping paradigm while constraining the nonparetic limb to encourage use of the paretic arm for functional tasks. It has been investigated in both chronic and acute stages of recovery poststroke. A study by Dromerick et al. [28] examined the effects of CIMT delivered at an average of 9.65 days poststroke and found no significant benefit over traditional therapy. The EXCITE trial examined CIMT delivery in the subacute phase (3–9 months) and demonstrated greater motor improvement in the CIMT group versus customary care that was not dose matched [29]. However, the CIMT group may have received more hours of training than the observation control group, and it is not clear whether the treatment effect was due to the CIMT approach, or simply more training. A metaanalysis and systematic review suggest that CIMT may be better suited to improve motor function in patients greater than 6 months poststroke [30]. Given the review contained several nondose-matched control group studies of primarily neuro-developmental treatment therapy, further studies are needed.
Interdisciplinary comprehensive arm rehabilitation evaluation Interdisciplinary comprehensive arm rehabilitation evaluation (ICARE) is an ongoing large RCT testing
skill acquisition, capacity building and motivational enhancement to improve upper extremity motor function after stroke [31]. The Accelerated Skill Acquisition Program is the experimental intervention, which emphasizes rehabilitation principles thought to be essential: challenging and meaningful practice tasks; addressing interfering impairments; overload and specificity of practice; goal directedness; avoidance of artificial task breakdown; self-directed therapy; balance of immediate and future needs; and increasing self-confidence.
Body weight supported treadmill training Trials demonstrate that body weight supported treadmill training (BWSTT) improves disability, gait speed, gait symmetry and cardiovascular health in stroke and TBI populations [32–34]. Patients walk on a treadmill with a portion of their body weight unloaded by an overhead harness system. A recent large clinical trial, Locomotor Experience Applied Post-Stroke (LEAPS), failed to show significant differences between home therapy and treadmill training, but it did show improvement in gait speed across all groups [34]. However, all study groups received greater than normal quantities of physical therapy that may account for the improvement seen across all groups. BWSTT provides a means to perform safe, high-intensity gait training that is difficult to achieve overground. Current studies are examining the use of BWSTT while providing percutaneous electrical stimulation at the T11–T12 spinal region [35] in persons with complete spinal cord injuries. The findings suggest that stimulation can modulate firing patterns in muscles that lack supraspinal input; there may be implications for restoration in stroke and TBI.
Accelerating progress in activity-based interventions Perhaps the most important question is still unanswered; how much and when should we initiate activity-based interventions? Answering this question is essential. With regard to how much, intensity appears to be the resounding theme among recent studies, whether a measure of total therapy volume or metabolic cost. Current best practice guidelines in Canada and the USA call for a minimum of 1 h, 5 days per week, of each therapy during a standard inpatient stay. A recent study of 123 patients found that stroke survivors in Canada received an average of 37 min/day of combined physical and occupational therapy [36].
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Is more intense therapy always beneficial regardless of the stage of recovery? There is conflicting evidence surrounding the specific benefits of physical and occupational therapy in stroke and TBI survivors [36–39]. More focused multicenter studies involving 116 stroke survivors with moderate to severe strokes found that the minutes spent in gait training during the first block of inpatient therapy predicted outcomes regardless of therapy rendered over the course of treatment [37]. However, when inpatient rehabilitation was compared with no rehabilitation care, no significant difference was found in upper extremity functional outcomes, global improvement and ADL function at 6 months [40].
ADJUNCT MODALITIES FOR ASSISTING IN MOTOR RECOVERY Although most stroke and TBI survivors benefit from traditional therapy, it is clear that more is needed to attain full recovery, especially with the severely affected population. Various technologies to supplement therapy are being investigated and will be described below.
Brain stimulation Transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) are noninvasive, well tolerated and painless approaches. TMS works via magnetic induction and tDCS works via low-voltage direct electrical current [41]. Two approaches are being tested to enhance neurorehabilitation poststroke using these types of brain stimulation. One is to increase lesioned hemisphere activity, which has been shown to correlate with improved motor performance, grip force, reading efficiency and aphasia, depending on the brain location stimulated [42–45]. Another approach is to alter the stimulation parameters to suppress or inhibit specific brain regions. The brain has strong inter-hemispheric inhibitory connections. Stroke patients have a greater inhibitory drive from the nonlesioned hemisphere to the lesioned hemisphere that is associated with poor motor performance of the hand [46]. Thus, inhibiting the nonlesioned hemisphere via tDCS or high-frequency rTMS should result in motor improvements. Randomized, placebocontrolled trials that modulate the inhibition of the nonlesioned hemisphere over the motor cortex demonstrate an improvement in motor performance [47,48 ]. The benefits of the stimulation are greater when done as a priming activity to therapy, thus augmenting the benefits of activity-dependent &
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plasticity. Now, there is a need for larger RCTs to validate the use of these modalities and determine their utility in clinical practice. Epidural cortical stimulation using electrodes placed over the motor cortex is another approach. A preliminary feasibility study of 24 patients demonstrated improved arm function in stroke survivors at a 6-month follow-up after having received the implanted cortical stimulation and combined rehabilitation therapy that was not seen in the rehabilitation control group [49]. The result of a large multicentre RCT is not formally published [50].
Robotic therapy As technology advances, robotic therapy is entering neurorehabilitation. Robotic therapy can manipulate different practice variables, including intensity, repetition and specificity. It also holds the potential to deliver engaging high-intensity and high repetition therapy without the burden of direct one-to-one therapy; if combined with a virtual reality or reward-based interface, it can also create an engaging and motivational environment for the right patient. Recent RCTs have found that robotassisted therapy improves functional outcomes and upper extremity function in stroke patients when given at a high intensity [51,52,53 ,54]. Although robotics such as the InMotion2 (Interactive Motion Technologies Inc. Watertown, MA, USA) or the MIME (Mirror Image Movement Enabler) can elicit gains in motor performance postintervention that are maintained at follow up; these gains are statistically nonsignificant when compared with those elicited by dose-matched therapeutic interventions [54]. One of the prominent barriers in incorporating the aforementioned robots into rehabilitation clinics is cost. If these devices can be mass-produced, they may be a means to provide an adjunct highintensity, task-specific and low-cost intervention. &&
Functional electrical stimulation Functional electrical stimulation (FES) uses a stimulator to activate skeletal muscle to accomplish a functional goal. A recent study [55] found that FES does contribute to neural plasticity by increasing motor-evoked potentials, a measure of cortical excitability of the muscles, which may account for the gains seen in muscle strength. Multicentre RCTs examining the effects of FES via devices such as the WalkAide (Innovative Neurotronics Inc., Austin, TX, USA) and L300 (Bioness Inc., Valencia, CA, USA) have shown significant improvement in gait speed, but no greater benefit than the traditional Volume 26 Number 6 December 2013
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ankle–foot orthosis (AFO) [55–57]. These data and the additional cost suggest why FES is likely to have limited use.
Cardiovascular exercise Perhaps the most supported treatment recommendation is participation in aerobic exercise. The benefits of an intense aerobic exercise program are well documented [58,59,60 ,61], and go beyond general cardiovascular health. Studies show improved gait velocity, gait endurance and improved VO2 peak in stroke survivors who participated in a progressively graded aerobic treadmill exercise program, and results were retained 1 year postintervention regardless of continuation of the exercise program [58,59,60 ]. The frequency in the treatments ranged from two to three times per week for 3–6 months. Although the benefit of cardiovascular exercise may come as no surprise, clinicians are often reluctant to recommend strenuous activity in the absence of physiological monitoring in a nonclinical setting. In the studies noted above, participants of all ages were trained, with had a range of baselines measures, but were cleared from cardiac illness prior to initiating the program. Intensity was graded on the basis of heart rate reserve and training was increased to 50–80% as able. Higher intensity aerobic exercise was also associated with improved depression scores in patients with a TBI [61]. Thus, intensity seems to be a key factor in obtaining measurable results and we should encourage patients to participate in an exercise program [62]. Van de Port et al. [63] found that 90 min of circuit training demonstrated a small but significant improvement in gait speed and walking distance versus controls. Gait speed has also been correlated with predicted life expectancy [64]. In fact, using age, sex and gait speed was as accurate in predicting survival rates as a more complex model that utilizes age, sex, chronic conditions, blood pressure, BMI and hospitalization. This suggests a target walking speed of 1–1.4 m/s, the rate required to cross a street. &&
&&
Stem cells/cellular therapy Stem cell therapies are under investigation for stroke and TBI. Although the interventional approach for neurorehabilitation of stroke and brain injury is still primarily in animal models, there are a few Phase I and II human trials. Three main approaches for cellular therapies exist: stimulating neurogenesis, minimizing inflammation and neuroprotection [65]. Current trials in animal models of stroke demonstrated early success in increasing angiogenesis
in vivo and in vitro [66]. Lee et al. [67] studied the safety of injecting stem cells intravenously in humans postischemic stroke, and found it to be well tolerated when compared with a sham group. Although they did show a significant improvement in modified Rankin Scale (mRS), evaluations were taken at different time points for both groups. Other randomized double-blind studies have also demonstrated safety, but sample sizes were too small to evaluate effectiveness [68].
CONCLUSION Neurorehabilitation may eventually resemble other treatments, wherein a combination of approaches yields the best outcome. Fluoxetine and aerobic training to improve motor recovery are the most promising newer standalone motor interventions; both warrant definitive clinical trials. The consistent findings that robotic therapy is equivalent (’noninferior’) to traditional therapy suggests that robots can increase accessibility and deliver large volumes of training. Identifying appropriate subgroups during clinical trials, including severity, cognitive function and lesion location, may lead to more individualized successful rehabilitation treatment. Likewise, Bayesian or other study designs may increase the efficiency and reduce the costs of rehabilitation trials. Given these advances and increased effort in neurorehabilitation research, there is great promise for improving the lives of people with stroke and TBI. Acknowledgements This work was supported in part by the Department of Veterans Affairs Office of Academic Affiliations (OAA). Conflicts of interest Dr Alexander W. Dromerick has served as a site investigator for the VECTOR, WalkAide and ICARE trials.
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Volume 26 Number 6 December 2013
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Motor rehabilitation Breceda and Dromerick 58. Macko RF, Ivey FM, Forrester LW, et al. Treadmill exercise rehabilitation improves ambulatory function and cardiovascular fitness in patients with chronic stroke: a randomized, controlled trial. Stroke 2005; 36:2206–2211. 59. Luft AR, Macko RF, Forrester LW, et al. Treadmill exercise activates subcortical neural networks and improves walking after stroke: a randomized controlled trial. Stroke 2008; 39:3341–3350. 60. Globas C, Becker C, Cerny J, et al. Chronic stroke survivors benefit from high&& intensity aerobic treadmill exercise: a randomized control trial. Neurorehabil Neural Repair 2012; 26:85–95. This study investigated the effects of high-intensity aerobic training in the older population (>60 years old) poststroke and found that training improved gait endurance and VO2 peak; this supports finding from previous studies that also found similar improvements in the younger population. The benefits were observable 1 year after and were not associated with higher adverse events. 61. Hoffman JM, Bell KR, Powell JM, et al. A randomized controlled trial of exercise to improve mood after traumatic brain injury. PM R 2010; 2:911–919. 62. Lam JM, Globas C, Cerny J, et al. Predictors of response to treadmill exercise in stroke survivors. Neurorehabil Neural Repair 2010; 24:567–574.
63. van de Port IG, Wevers LE, Lindeman E, et al. Effects of circuit training as alternative to usual physiotherapy after stroke: randomised controlled trial. BMJ 2012; 344:e2672. 64. Studenski S, Perera S, Patel K, et al. Gait speed and survival in older adults. JAMA 2011; 305:50–58. 65. Lindvall O, Kokaia Z. Stem cells in human neurodegenerative disorders: time for clinical translation? J Clin Invest 2010; 120:29–40. 66. Hicks SD, Middleton FA, Miller MW. Ethanol-induced methylation of cell cycle genes in neural stem cells. J Neurochem 2010; 114:1767– 1780. 67. Lee JS, Hong JM, Moon GJ, et al. A long-term follow-up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke. Stem Cells 2010; 28:1099–1106. 68. Sprigg N, Bath PM, Zhao L, et al. Granulocyte-colony-stimulating factor mobilizes bone marrow stem cells in patients with subacute ischemic stroke: the Stem cell Trial of recovery EnhanceMent after Stroke (STEMS) pilot randomized, controlled trial (ISRCTN 16784092). Stroke 2006; 37:2979– 2983.
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