Skip to main content
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2016 Oct 1.
Published in final edited form as: Stroke. 2015 Aug 11;46(10):2998–3005. doi: 10.1161/STROKEAHA.115.007433

Drugs to Enhance Motor Recovery After Stroke

Steven C Cramer 1
PMCID: PMC4589468  NIHMSID: NIHMS708600  PMID: 26265126

Abstract

Among the therapeutic strategies under study to improve long-term outcome after stroke are drugs targeting events that underlie recovery. Drugs that enhance recovery are separate from those that promote neuroprotection or reperfusion in patients with stroke. Recovery-based drugs have distinct therapeutic targets that are related to plasticity and growth following stroke, and in general, improvements in behavioral outcome are not accompanied by a reduction in infarct volume. Interventions targeting recovery have a time window measured in days or sometimes weeks-months, suggesting potential utility for a large percentage of patients with stroke. Currently, among drugs that enhance motor recovery after stroke in humans, the strongest evidence exists for serotonergic and dopaminergic agents. Restorative therapies generally target the brain directly, in contrast to approved stroke therapeutics that target arteries, clots, platelets, glucose, or cholesterol. Targeting the brain has wide-ranging implications, for example, in relation to drug delivery. In addition, because restorative drugs aim to change brain structure and function, their effects are influenced by concomitant behavioral experience, a finding that informs selection of entry criteria, outcome measures, and biomarkers in a clinical trial setting. These points underscore the importance of a neural systems approach in studying stroke recovery.

Keywords: stroke, recovery, motor system, drugs, outcomes

Introduction

A new stroke activates several biological pathways, including those related to the ischemic cascade, immunological response, and restorative response. These constitute distinct therapeutic targets for stroke therapy. Reperfusion therapies are effective when given during the early hours following stroke onset, when regions of ischemic penumbra remain salvageable. As a result of this narrow therapeutic time window, a minority of patients with stroke currently receives a reperfusion-based therapy acutely post-stroke. Restorative therapies have a much wider time window, some being introduced during the days-weeks of spontaneous growth seen in the brain after stroke, and others introduced months later in an effort to stimulate neuroplasticity. Because of this wider time window, a large fraction of patients with stroke could potentially be eligible to receive a restorative therapy.

The current review focuses on drugs, specifically small molecules, which are commonly used in neurologic practice and which have advantages compared to some treatment approaches in terms of drug delivery and access to the brain1. Many types of restorative therapy besides small drugs are under study, including large molecules such as growth factors or monoclonal antibodies, biological agents such as stem cells, brain stimulation, robotics, and activity-based therapies2; ultimately the value of any drug must be measured in relation to the risk/benefit performance of all candidate restorative therapies. The current focus is on a mono-therapy approach, but increasing evidence will likely foster studies evaluating poly-therapy approaches.

The current review is focused on the motor system. A systems approach is central to many aspects of restorative neuroscience. The brain is in many ways an amalgam of many different systems operating in parallel. For a stent retriever placed in the MCA, the therapeutic target is a hemisphere full of at-risk brain systems. For a restorative therapy, however, only one or a few neural systems are likely to be viable therapeutic targets, as many systems may be either decimated beyond repair or little affected. Adoption of a systems-level approach has immediate implications for clinical trials in relation to topics such as entry criteria, endpoints, biomarkers, and the concomitant training that is important to shaping the effects of a restorative therapy.

The current focus on the motor system reflects the fact that motor deficits are common after stroke (82% of patients3) and are linked with reduced quality of life4, 5. At 6 months after stroke, 65% of patients are unable to incorporate a paretic hand effectively into daily activities6, which affects subjective well-being7. Moreover, even when neurological exam declares the patient wholly recovered, 71% of patients report persistent motor deficits when studied using patient-reported outcomes8. Lower extremity motor status is also linked with disability level9. Only 37% of persons with stroke can walk after the first week post-stroke, after which gait improvement is linked to better quality of life. Hemiplegic patients rank recovery of gait as their top priority10, 11.

Current status

There are no drugs approved in the U.S. to enhance motor recovery after stroke.

However, the recent approval by the U.S. FDA of a 4-aminopyridine preparation as a treatment to improve walking in patients with multiple sclerosis12 sounds a hopeful note for stroke.

Drugs with strongest evidence to date

For at least two classes of drug, serotonergic and dopaminergic, both of which are monoaminergic, existing evidence from human studies supports the possibility for enhancing motor outcome after stroke.

Serotonergic drugs

Serotonin normally plays in a role in modulating multiple cognitive functions, particularly response inhibition and memory consolidation, and modulates the impact of punishment-related signals on learning and emotion1315. Recent reports suggest potential clinical utility of selective serotonin reuptake inhibitor (SSRI) drugs for promoting improved motor outcome after stroke. Building on several prior smaller studies1619, the Fluoxetine for Motor Recovery After Acute Ischemic Stroke (FLAME) study20 was a double blind, placebo-controlled trial that enrolled non-depressed hemiplegic/hemiparetic patients within 10 days of ischemic stroke onset. Patients were randomized to 3 months of oral fluoxetine (20 mg/day) or placebo. Patients randomized to fluoxetine showed significantly greater gains on the primary endpoint, change in the arm/leg Fugl-Meyer motor score to day 90 (p=0.003), a remarkable difference of 9.7 points on this 100-point scale. Other human trials have reported favorable effects of SSRI drugs on recovery of non-motor behaviors after stroke 2123, increasing confidence in the results of the FLAME study. The importance of these findings is underscored by the substantial clinical experience with SSRI drugs (hundreds of millions of humans have been treated) and their generally strong safety record, in the broad population as well as in patients with cerebrovascular disease24, 25.

Several different mechanisms might account for these findings. The central mechanism of action for SSRI drugs in the treatment of major depression is via their high affinity for the serotonin transporter; drug binding to the transporter inhibits serotonin removal from the synaptic cleft, with long-term SSRI administration down-regulating and desensitizing key serotonin receptors thereby dampening negative feedback on serotonin release26. While it is true that the FLAME study excluded subjects with depression, these SSRI mechanisms might nonetheless have contributed to the findings in the FLAME study. Although depression is often classified dichotomously, i.e., as present or absent, evidence suggests that depressive symptoms impact brain function along a continuum, with increasing levels of depressive symptoms associated with larger effects even when restricting analysis to subjects who do not meet criteria for major depression27, 28, including after stroke29, 30. Consistent with this, better functional recovery after stroke is associated with lower depressive symptoms and with greater improvement of depressive symptoms over time31.

Other suggested mechanisms of action for SSRI drugs include reducing neural inflammation32, enhancing neurotrophin activity33, and increasing neurogenesis34. Chronic SSRI dosing increases intra-cortical facilitation35 and reduces intra-cortical inhibition36, and these changes have been compared to reinstating conditions of developmental critical periods36, 37. In addition, serotonin modulates spinal motor control through multiple effects on spinal motor circuits, including regulation of rhythmic activity and control of excitability, by acting on intrasynaptic and extrasynaptic receptors; this may help locomotor function but can also worsen spasticity38.

Dopaminergic drugs

Dopamine regulates many aspects of neural functioning, including excitability, synaptic transmission, plasticity, protein trafficking, and gene transcription39. Not surprisingly, therefore, dopamine has a key role in wide-ranging brain processes such as movement, reward, learning, and plasticity40. The role of this neurotransmitter is movement is well established: dopaminergic terminals in motor cortex contribute to cortical plasticity and indeed are necessary for motor skill learning41, 42. A randomized, double blind, placebo-controlled study of 53 patients within 6 months of stroke onset found that 100 mg L-Dopa/day, given as Sinemet and combined with physical therapy, was significantly better than placebo plus physical therapy on motor recovery after three weeks measured using the Rivermead Motor Assessment43. These effects were very likely attributable to dopamine, as studies in rodents, sub-human primates, and humans indicate that systemic administration of L-Dopa increases the brain concentration of dopamine but not norepinephrine--dopamine is the predominant brain metabolite formed from systemic L-Dopa4447.

Large studies of drugs that modulate dopamine neurotransmission after stroke continue to be needed but lacking48. Smaller studies that have examined a range of dopaminergic drugs in patients with stroke at varying time points post-onset have been inconsistent, with motor learning and plasticity improved in some studies49 but not others5052. For example, a placebo-controlled, double-blind study of 33 patients 1–12 months post-stroke did not find a difference between a 9 week course of ropinirole + physiotherapy compared to placebo + physiotherapy on gait velocity50. These differences might reflect small sample sizes. Some evidence suggests that genetic factors may be relatively important in modulating dopamine neurotransmission in humans5355.

Additional insight into divergent findings across studies of dopaminergic drugs might stem from the fact that a large number of environmental, cognitive, psychological, and other factors are important cofactors in the expression of dopamine effects. Dopamine is a central player in the limbic reward system, where, adding to the complexity, its neurotransmission is under the influence of numerous other transmitters56. Reward significantly influences long-term motor learning57. Dopamine is also important to motivation58, action learning59, action selection60, and in the control of voluntary exercise61. Thus, as with serotonergic drugs, dopaminergic drugs might influence motor recovery after stroke indirectly, through their action on any of several different non-motor neural systems.

Other drugs that might have important effects on recovery

Noradrenergic drugs

Noradrenergic neurotransmission broadly amplifies neuronal activity, increases the general level of excitability, and selectively amplifies activities evoked by unexpected inputs62. This effect of norepinephrine on regulating overall arousal levels has a modulatory effect on executive function14. To date there has been only a handful of studies of noradrenergic drugs to promote stroke recovery. These have been small in size but show promising results6365.

Cholinergic drugs

In the cortex, acetylcholine inputs positively enable plasticity by (a) selectively amplifying only anticipated (“selectively attended”) and (b) selectively weakening non-anticipated inputs62. Modulation of nicotinic cholinergic neurotransmission alters attention, while muscarinic receptors play a greater role in cognitive flexibility14. Luria long ago advocated for cholinergic therapies to enhance recovery66, yet very few controlled studies in humans with stroke have been published to date. Limited data in non-motor aspects of stroke recovery are promising6769, and a recent study in 33 patients found that donepezil to be safe when initiated within 24 hours of stroke onset68.

Amphetamine

Amphetamines increase neurotransmission in several monoamine systems. Initial studies of amphetamine to enhance post-stroke motor70, 71 or language 72 recovery were small but promising. A subsequent randomized, double blind, placebo-controlled trial of amphetamine in 71 patients with sub-acute stroke did not show a drug-related benefit73. At 5–10 days after stroke onset, patients were randomized to 10 sessions of either physiotherapy + amphetamine (10 mg) or physiotherapy + placebo, twice per week for five weeks. No difference between treatment groups was found for the primary outcome, Fugl-Meyer motor score. The subgroup with milder deficits might have derived the greatest drug-related gain, a possibility that requires further study. The optimal dose and administration schedule for amphetamine has not been rigorously studied and it remains to be definitively evaluated in human patients with stroke74.

Drugs that impede recovery

For a number of drugs, particularly neuroleptic or antiepileptic drugs, some evidence suggests that administration after stroke can impede motor recovery and thereby reduce motor outcome 7578. Such findings could potentially provide insights into the mechanisms of stroke recovery, and might also inform strategic planning in the design of pharmacological approaches to improving motor recovery after stroke.

Experiences such as those summarized above have identified a number of important issues in the design of clinical trials of brain repair after stroke79. These are considered below.

How does time since stroke onset affect a restorative therapy?

Time is a major factor. As with many CNS diseases, stroke evolves over time, and biological targets shift. The initial hyper-acute injury period is followed by a several week period throughout which repair-related events spontaneously increase in the brain8082, and during which the brain is galvanized for growth in a manner resembling normal development83. A critical window for therapeutic effectiveness has been defined during this period for several restorative interventions in preclinical studies8486. Drugs that promote recovery one week may be inert or even harmful the next8790. Importantly, because restorative therapies are generally introduced at a time when stroke injury is fixed, behavioral outcomes are improved after stroke without affecting final infarct volume. The period of spontaneous growth resolves over the ensuing weeks-months, but even in the chronic phase, clinically important gains may be seen for some therapies that aim to promote neural repair91, 92.

How do a patient’s activity, training, and experience after stroke affect a restorative therapy?

These are key considerations. When introducing a drug to promote plasticity after neural injury, the best behavioral recovery requires rehabilitation in order to mold new connections93 --neural repair after stroke occurs on the basis of experience-dependent plasticity94. In a landmark study, Feeney et al75 found that in rodents with an experimental stroke, amphetamine improved motor outcome, but only if drug dosing was paired with training. Subsequent studies have confirmed this principle across many other classes of post-stroke restorative therapy9599. This issue is not a consideration in acute stroke and preventative stroke studies, where treatment generally targets clots, platelets, arteries, the heart, or serum glucose or cholesterol levels. However, in stroke recovery studies, treatment often directly targets the brain, and retraining the brain is dependent on repeated behavioral reinforcement. Thus the patient need not engage in any particular behavioral regimen to enable tPA effectiveness, but available data indicate that such activity is central to realizing maximal effects of restorative drugs after stroke. These data are largely from preclinical studies, and so further studies in humans are needed to better understand the impact of post-stroke activity and training as adjuvants to recovery drugs. Similarly, evidence suggests that the psychosocial milieu in which patients experience post-stroke recovery is also a critically important experiential covariate100.

Given these many influences on stroke recovery, how can the target patient population be defined for a drug designed to enhance recovery after stroke?

Several techniques show promise to identify target populations. Stroke is a very heterogeneous condition. Just as no single drug is appropriate to treat all patients with cancer or pneumonia, so it is that no one therapy is likely to be useful to enhance recovery across all patients with stroke. Patients differ tremendously before the stroke, and infarcts are highly variable across subjects. Numerous measures have been studied for their ability to understand and to measure variance in behavioral recovery after stroke. Results have implications for patient selection and stratification in clinical trials of drugs targeting recovery. For example, in a study of 23 patients with chronic stroke undergoing robotic therapy to improve arm motor deficits, extent of stroke injury to the corticospinal tract accounted for approximately one third of the variance in treatment response101. These results remain to be confirmed in a study using a drug to enhance motor recovery after stroke, but likely results will generalize across treatment categories. This is an example of an imaging-based approach to identify the target population--extent of corticospinal tract injury substantially informs which patients are most likely to benefit from a recovery-based intervention. Further work remains to maximize the robustness of this approach, and this is a fervent area of investigation. Recent models emphasizing an interaction between neural function and neural injury102, 103. For some therapies, including serotonergic104, 105 and dopaminergic53 drugs, measures of genetic variability might also inform the likelihood that a patient will benefit from a drug.

For some therapies, preclinical findings may provide specific guidance for defining the target human population. For example, in a phase III clinical trial of epidural motor cortex stimulation in patients with chronic stroke, rodent and primate studies showing efficacy required preserved motor evoked responses98, 106108 but the trial109 did not did not. A post-hoc analysis found that trial enrollees randomized to epidural motor cortex stimulation who (like preclinical subjects) had preserved motor evoked responses were 2.5 times more likely (p<0.05) to achieve the primary efficacy endpoint as compared to enrollees lacking such responses110.

How do these issues affect selection of endpoints in trials of drugs aiming to enhance recovery after stroke?

As above, a systems approach is often important to therapeutic studies of stroke recovery. A therapy that improves outcome by promoting neuroplasticity might have maximum effect in a neural system that has sustained subtotal injury, but show no effect in a system that has been utterly obliterated by stroke. As such, a restorative drug given to a patient with dense aphasia but moderate hemiparesis might provide useful gains in motor function but not in language function. In such a context, drug effects would likely be more apparent using an outcome measure that has the granularity to detect differential effects across neural systems of the brain.

These points suggest the potential utility of modality-specific outcome measures to capture effects of treatments that target stroke recovery111. Global endpoints that capture many aspects of human behavior and summarize a person’s outcome using a single number (often a single digit) have established value in stroke clinical trials, but their value may be greatest for acute treatments that aim to salvage a large volume of threatened brain. On the other hand, for drugs that aim to enhance stroke recovery by improving function in specific neural systems that have been injured by survived, global endpoints might lack granularity and thus be insensitive; endpoints that are linked to the target neural system might provide a more accurate measure of drug effects. For example, a restorative therapy that significantly improves the modality-specific outcome measure “gait velocity” may or may not have a significant effect on the global outcome measure “modified Rankin scale score,” but improved gait might nonetheless be associated with improved quality of life112 and social participation113.

How do these issues affect interpretation of animal models and translation of preclinical stroke recovery studies?

The limits of preclinical models for stroke recovery remain to be completely defined. For studies focused on molecular responses to specific perturbations, rodent models offer great potential. Humans and rodents shared a common ancestor approximately 80–100 million years ago. Most genes are shared, and tissue-specific transcriptional responses have been highly conserved114, 115. However, as a human recovers during the weeks-months following a stroke, psychological issues such as mood, hopelessness, resilience, anxiety, and caregiver support may have important effects on outcomes, as might marital, religious, occupational, fiscal, litigational, and other social issues. Many patients at my institution struggle with insurance copayments, alcoholism, adjustments in retirement plans, power of attorney, and immigration status. Such factors of human life after stroke may be incompletely modeled in a study of rodents housed in an 18” cage with solitary (or single cellmate) confinement. A rat brain weighs 2 gm, has one third the proportional white matter volume of a human brain, is perfused by a pulse >250 beats/min, and has had a distinct trajectory of psychosocial and cultural evolution since the common mammalian ancestor, as compared to humans116. Thus for studies focused on the net effect of a drug on behavioral recovery after stroke, rodent models may have critical limitations. Given that regulatory agencies emphasize the importance of clinically meaningful endpoints in human trials117, rodent studies might be seen as providing the greatest insight at the molecular or tissue level rather than at the behavioral level.

Is there a role for biomarkers?

Definitely--this is a major unmet need that when robustly addressed could massively impact this field. A biomarker is an indicator of disease state118 that provides information on key molecular/cellular events that may be difficult to measure directly. Examples of biomarkers commonly used in clinical practice include plasma RNA levels in the setting of HIV infection, and intraocular pressure in the setting of glaucoma. A good biomarker must be in the causal pathway of the disease process and fully capture the net effect of treatment on the clinical outcome119, 120. Biomarkers are particularly useful in phase II trials, for example, to probe biological activity of a proposed therapy or to inform the decision whether or not to proceed to phase III119. A valid biomarker for a drug aiming to enhance stroke recovery could improve decision-making regarding timing, duration, frequency, or intensity with which treatment is prescribed for individual subjects, and could generate an improved understanding as to how findings in rodents relate to findings in humans121. There have been important advances in the study of biomarkers of stroke recovery in humans. Evidence suggests that the optimal choice of biomarker likely varies according to degree of injury and may differ across neural systems. Numerous candidate biomarkers have been proposed including blood-based tests, measures of brain structure and injury, and functional neuroimaging measures77, 122, 123. However, valid biomarkers of motor recovery after stroke in human, and the effects of drug targeting motor recovery, remain to be established.

How do current systems of care affect the study of drugs to enhance motor recovery after stroke?

Current patterns of care delivery may be important in several regards. Concomitant experience and training is a key factor when studying stroke recovery (see above). Provision of healthcare, including post-stroke rehabilitation therapy, differs substantially across countries and insurance plans and should be considered in the design of restorative trials. Even in optimal settings the dose of rehabilitation therapy may be lower than desired124. In the absence of approved therapies, clinicians prescribe unapproved drugs in the hopes that they can give patients some potential advantage, a fact that adds complexity to trials and so is worthy of note in the study of recovery-related drugs125. In many U.S. healthcare systems, a patient may be transferred to several care settings, under the care of several different physicians, during the critical month of brain repair following stroke onset, a fact that can also complicate clinical trials in stroke recovery.

Are there data that a restorative therapy can enhance motor outcome after stroke in humans, and are such effects clinically meaningful?

Several key trials have described effects that readily meet the definition of clinically meaningful. The 9.7 point Fugl-Meyer motor scale score found with fluoxetine in the FLAME study20 readily meets most definitions of minimum clinically important difference for this scale in patients recovering from stroke126. The same can be said for the 51.8% reduction in time to complete the Wolf Motor Function Test found one year after constraint induced therapy in the “Extremity Constraint Induced Therapy Evaluation” study91, a prospective, single-blind, randomized, clinical trial of 222 patients with arm motor deficits 3–9 months after stroke. Similarly, the “Locomotor Experience Applied Post-Stroke” trial92 found that 52% of enrollees receiving locomotor training shifted up an entire category of functional walking ability at one year post-stroke, a remarkable therapeutic achievement.

Conclusions

In selected instances, solid evidence exists that a restorative therapy, introduced long after injury is fixed, can improve behavioral outcome after stroke127. The largest trials to date have examined behavioral interventions such as constraint induced therapy or locomotor training. Regarding trials of drugs to enhance motor recovery, exciting results have been found in phase II studies of SSRI’s and of L-Dopa. This review considered several factors important to stroke recovery trials.

Acknowledgments

Funding Sources

This work was supported by NIH grants K24 HD074722 and 5M011 RR-00827.

Footnotes

Disclosures

Dr. Cramer has served as a consultant for GlaxoSmithKline, MicroTransponder, Dart Neuroscience, Roche, and RAND Corporation.

References

  • 1.Pardridge WM. Drug targeting to the brain. Pharmaceutical research. 2007;24:1733–1744. doi: 10.1007/s11095-007-9324-2. [DOI] [PubMed] [Google Scholar]
  • 2.Cramer SC. An overview of therapies to promote repair of the brain after stroke. Head Neck. 2011;(33 Suppl 1):S5–S7. doi: 10.1002/hed.21840. [DOI] [PubMed] [Google Scholar]
  • 3.Rathore S, Hinn A, Cooper L, Tyroler H, Rosamond W. Characterization of incident stroke signs and symptoms: Findings from the atherosclerosis risk in communities study. Stroke; a journal of cerebral circulation. 2002;33:2718–2721. doi: 10.1161/01.str.0000035286.87503.31. [DOI] [PubMed] [Google Scholar]
  • 4.Gresham G, Duncan P, Stason W, Adams H, Adelman A, Alexander D, et al. Post-stroke rehabilitation. Rockville, MD: U.S. Department of Health and Human Services. Public Health Service, Agency for Health Care Policy and Research; 1995. [Google Scholar]
  • 5.Saposnik G, Levin M. Virtual reality in stroke rehabilitation: A meta-analysis and implications for clinicians. Stroke; a journal of cerebral circulation. 2011;42:1380–1386. doi: 10.1161/STROKEAHA.110.605451. [DOI] [PubMed] [Google Scholar]
  • 6.Winstein CJ, Wolf SL, Dromerick AW, Lane CJ, Nelsen MA, Lewthwaite R, et al. Interdisciplinary comprehensive arm rehabilitation evaluation (icare): A randomized controlled trial protocol. BMC neurology. 2013;13:5. doi: 10.1186/1471-2377-13-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Wyller TB, Sveen U, Sodring KM, Pettersen AM, Bautz-Holter E. Subjective well-being one year after stroke. Clinical rehabilitation. 1997;11:139–145. doi: 10.1177/026921559701100207. [DOI] [PubMed] [Google Scholar]
  • 8.Stewart JC, Cramer SC. Patient-reported measures provide unique insights into motor function after stroke. Stroke; a journal of cerebral circulation. 2013;44:1111–1116. doi: 10.1161/STROKEAHA.111.674671. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Perera S, Mody SH, Woodman RC, Studenski SA. Meaningful change and responsiveness in common physical performance measures in older adults. J Am Geriatr Soc. 2006;54:743–749. doi: 10.1111/j.1532-5415.2006.00701.x. [DOI] [PubMed] [Google Scholar]
  • 10.Fritz S, Lusardi M. White paper: "Walking speed: The sixth vital sign". J Geriatr Phys Ther. 2009;32:46–49. [PubMed] [Google Scholar]
  • 11.Miller EL, Murray L, Richards L, Zorowitz RD, Bakas T, Clark P, et al. Comprehensive overview of nursing and interdisciplinary rehabilitation care of the stroke patient: A scientific statement from the american heart association. Stroke; a journal of cerebral circulation. 2010;41:2402–2448. doi: 10.1161/STR.0b013e3181e7512b. [DOI] [PubMed] [Google Scholar]
  • 12.Traynor K. Dalfampridine approved for ms. Am J Health Syst Pharm. 2010;67:335. doi: 10.2146/news100015. [DOI] [PubMed] [Google Scholar]
  • 13.Cools R, Roberts AC, Robbins TW. Serotoninergic regulation of emotional and behavioural control processes. Trends Cogn Sci. 2008;12:31–40. doi: 10.1016/j.tics.2007.10.011. [DOI] [PubMed] [Google Scholar]
  • 14.Logue SF, Gould TJ. The neural and genetic basis of executive function: Attention, cognitive flexibility, and response inhibition. Pharmacol Biochem Behav. 2014;123:45–54. doi: 10.1016/j.pbb.2013.08.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Cowen P, Sherwood AC. The role of serotonin in cognitive function: Evidence from recent studies and implications for understanding depression. J Psychopharmacol. 2013;27:575–583. doi: 10.1177/0269881113482531. [DOI] [PubMed] [Google Scholar]
  • 16.Dam M, Tonin P, De Boni A, Pizzolato G, Casson S, Ermani M, et al. Effects of fluoxetine and maprotiline on functional recovery in poststroke hemiplegic patients undergoing rehabilitation therapy. Stroke; a journal of cerebral circulation. 1996;27:1211–1214. doi: 10.1161/01.str.27.7.1211. [DOI] [PubMed] [Google Scholar]
  • 17.Miyai I, Reding R. Effects of antidepressants on functional recovery following stroke. J Neuro Rehab. 1998;12:5–13. [Google Scholar]
  • 18.Pariente J, Loubinoux I, Carel C, Albucher J, Leger A, Manelfe C, et al. Fluoxetine modulates motor performance and cerebral activation of patients recovering from stroke. Annals of neurology. 2001;50:718–729. doi: 10.1002/ana.1257. [DOI] [PubMed] [Google Scholar]
  • 19.Fruehwald S, Gatterbauer E, Rehak P, Baumhackl U. Early fluoxetine treatment of post-stroke depression--a three-month double-blind placebo-controlled study with an open-label long-term follow up. Journal of neurology. 2003;250:347–351. doi: 10.1007/s00415-003-1014-3. [DOI] [PubMed] [Google Scholar]
  • 20.Chollet F, Tardy J, Albucher JF, Thalamas C, Berard E, Lamy C, et al. Fluoxetine for motor recovery after acute ischaemic stroke (flame): A randomised placebo-controlled trial. Lancet neurology. 2011;10:123–130. doi: 10.1016/S1474-4422(10)70314-8. [DOI] [PubMed] [Google Scholar]
  • 21.Robinson RG, Jorge RE, Moser DJ, Acion L, Solodkin A, Small SL, et al. Escitalopram and problem-solving therapy for prevention of poststroke depression: A randomized controlled trial. Jama. 2008;299:2391–2400. doi: 10.1001/jama.299.20.2391. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Jorge RE, Acion L, Moser D, Adams HP, Jr, Robinson RG. Escitalopram and enhancement of cognitive recovery following stroke. Archives of general psychiatry. 2010;67:187–196. doi: 10.1001/archgenpsychiatry.2009.185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Mikami K, Jorge RE, Moser DJ, Arndt S, Jang M, Solodkin A, et al. Prevention of post-stroke generalized anxiety disorder, using escitalopram or problem-solving therapy. J Neuropsychiatry Clin Neurosci. 2014;26:323–328. doi: 10.1176/appi.neuropsych.11020047. [DOI] [PubMed] [Google Scholar]
  • 24.Aarts N, Akoudad S, Noordam R, Hofman A, Ikram MA, Stricker BH, et al. Inhibition of serotonin reuptake by antidepressants and cerebral microbleeds in the general population. Stroke. 2014;45:1951–1957. doi: 10.1161/STROKEAHA.114.004990. [DOI] [PubMed] [Google Scholar]
  • 25.Hankey GJ. Selective serotonin reuptake inhibitors and risk of cerebral bleeding. Stroke. 2014;45:1917–1918. doi: 10.1161/STROKEAHA.114.005844. [DOI] [PubMed] [Google Scholar]
  • 26.Walker FR. A critical review of the mechanism of action for the selective serotonin reuptake inhibitors: Do these drugs possess anti-inflammatory properties and how relevant is this in the treatment of depression? Neuropharmacology. 2013;67:304–317. doi: 10.1016/j.neuropharm.2012.10.002. [DOI] [PubMed] [Google Scholar]
  • 27.Kessler RC, Zhao S, Blazer DG, Swartz M. Prevalence, correlates, and course of minor depression and major depression in the national comorbidity survey. J Affect Disord. 1997;45:19–30. doi: 10.1016/s0165-0327(97)00056-6. [DOI] [PubMed] [Google Scholar]
  • 28.Cukrowicz KC, Schlegel EF, Smith PN, Jacobs MP, Van Orden KA, Paukert AL, et al. Suicide ideation among college students evidencing subclinical depression. J Am Coll Health. 2011;59:575–581. doi: 10.1080/07448481.2010.483710. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.da Rocha e Silva CE, Alves Brasil MA, Matos do Nascimento E, de Braganca Pereira B, Andre C. Is poststroke depression a major depression? Cerebrovasc Dis. 2013;35:385–391. doi: 10.1159/000348852. [DOI] [PubMed] [Google Scholar]
  • 30.Spalletta G, Ripa A, Caltagirone C. Symptom profile of dsm-iv major and minor depressive disorders in first-ever stroke patients. Am J Geriatr Psychiatry. 2005;13:108–115. doi: 10.1176/appi.ajgp.13.2.108. [DOI] [PubMed] [Google Scholar]
  • 31.Saxena SK, Ng TP, Koh G, Yong D, Fong NP. Is improvement in impaired cognition and depressive symptoms in post-stroke patients associated with recovery in activities of daily living? Acta Neurol Scand. 2007;115:339–346. doi: 10.1111/j.1600-0404.2006.00751.x. [DOI] [PubMed] [Google Scholar]
  • 32.Maes M, Leonard B, Fernandez A, Kubera M, Nowak G, Veerhuis R, et al. (neuro)inflammation and neuroprogression as new pathways and drug targets in depression: From antioxidants to kinase inhibitors. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35:659–663. doi: 10.1016/j.pnpbp.2011.02.019. [DOI] [PubMed] [Google Scholar]
  • 33.Duman RS, Monteggia LM. A neurotrophic model for stress-related mood disorders. Biol Psychiatry. 2006;59:1116–1127. doi: 10.1016/j.biopsych.2006.02.013. [DOI] [PubMed] [Google Scholar]
  • 34.Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science. 2003;301:805–809. doi: 10.1126/science.1083328. [DOI] [PubMed] [Google Scholar]
  • 35.Gerdelat-Mas A, Loubinoux I, Tombari D, Rascol O, Chollet F, Simonetta-Moreau M. Chronic administration of selective serotonin reuptake inhibitor (ssri) paroxetine modulates human motor cortex excitability in healthy subjects. NeuroImage. 2005;27:314–322. doi: 10.1016/j.neuroimage.2005.05.009. [DOI] [PubMed] [Google Scholar]
  • 36.Maya Vetencourt JF, Sale A, Viegi A, Baroncelli L, De Pasquale R, O’Leary OF, et al. The antidepressant fluoxetine restores plasticity in the adult visual cortex. Science. 2008;320:385–388. doi: 10.1126/science.1150516. [DOI] [PubMed] [Google Scholar]
  • 37.Guirado R, Perez-Rando M, Sanchez-Matarredona D, Castren E, Nacher J. Chronic fluoxetine treatment alters the structure, connectivity and plasticity of cortical interneurons. Int J Neuropsychopharmacol. 2014;17:1635–1646. doi: 10.1017/S1461145714000406. [DOI] [PubMed] [Google Scholar]
  • 38.Perrier JF, Cotel F. Serotonergic modulation of spinal motor control. Curr Opin Neurobiol. 2014;33C:1–7. doi: 10.1016/j.conb.2014.12.008. [DOI] [PubMed] [Google Scholar]
  • 39.Tritsch NX, Sabatini BL. Dopaminergic modulation of synaptic transmission in cortex and striatum. Neuron. 2012;76:33–50. doi: 10.1016/j.neuron.2012.09.023. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.McAllister TW. Polymorphisms in genes modulating the dopamine system: Do they influence outcome and response to medication after traumatic brain injury? The Journal of head trauma rehabilitation. 2009;24:65–68. doi: 10.1097/HTR.0b013e3181996e6b. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Molina-Luna K, Pekanovic A, Rohrich S, Hertler B, Schubring-Giese M, Rioult-Pedotti MS, et al. Dopamine in motor cortex is necessary for skill learning and synaptic plasticity. PLoS One. 2009;4:e7082. doi: 10.1371/journal.pone.0007082. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Hosp JA, Pekanovic A, Rioult-Pedotti MS, Luft AR. Dopaminergic projections from midbrain to primary motor cortex mediate motor skill learning. J Neurosci. 2011;31:2481–2487. doi: 10.1523/JNEUROSCI.5411-10.2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Scheidtmann K, Fries W, Muller F, Koenig E. Effect of levodopa in combination with physiotherapy on functional motor recovery after stroke: A prospective, randomised, double-blind study. Lancet. 2001;358:787–790. doi: 10.1016/S0140-6736(01)05966-9. [DOI] [PubMed] [Google Scholar]
  • 44.Nutt J, Fellman J. Pharmacokinetics of levodopa. Clin Neuropharmacol. 1984;7:35–49. doi: 10.1097/00002826-198403000-00002. [DOI] [PubMed] [Google Scholar]
  • 45.Firnau G, Sood S, Chirakal R, Nahmias C, Garnett ES. Cerebral metabolism of 6-[18f]fluoro-l-3,4-dihydroxyphenylalanine in the primate. J Neurochem. 1987;48:1077–1082. doi: 10.1111/j.1471-4159.1987.tb05629.x. [DOI] [PubMed] [Google Scholar]
  • 46.Doshi PS, Edwards DJ. Effects of l-dopa on dopamine and norepinephrine concentrations in rat brain assessed by gas chromatography. J Chromatogr. 1981;210:505–511. doi: 10.1016/s0021-9673(00)80342-8. [DOI] [PubMed] [Google Scholar]
  • 47.Everett GM, Borcherding JW. L-dopa: Effect on concentrations of dopamine, norepinephrine, and serotonin in brains of mice. Science. 1970;168:849–850. doi: 10.1126/science.168.3933.849. [DOI] [PubMed] [Google Scholar]
  • 48.Small S. Pharmacotherapy of aphasia A critical review. Stroke; a journal of cerebral circulation. 1994;25:1282–1289. doi: 10.1161/01.str.25.6.1282. [DOI] [PubMed] [Google Scholar]
  • 49.Floel A, Hummel F, Breitenstein C, Knecht S, Cohen LG. Dopaminergic effects on encoding of a motor memory in chronic stroke. Neurology. 2005;65:472–474. doi: 10.1212/01.wnl.0000172340.56307.5e. [DOI] [PubMed] [Google Scholar]
  • 50.Cramer SC, Dobkin BH, Noser EA, Rodriguez RW, Enney LA. Randomized, placebo-controlled, double-blind study of ropinirole in chronic stroke. Stroke; a journal of cerebral circulation. 2009;40:3034–3038. doi: 10.1161/STROKEAHA.109.552075. [DOI] [PubMed] [Google Scholar]
  • 51.Restemeyer C, Weiller C, Liepert J. No effect of a levodopa single dose on motor performance and motor excitability in chronic stroke A double-blind placebo-controlled cross-over pilot study. Restorative neurology and neuroscience. 2007;25:143–150. [PubMed] [Google Scholar]
  • 52.Sonde L, Lokk J. Effects of amphetamine and/or l-dopa and physiotherapy after stroke - a blinded randomized study. Acta Neurol Scand. 2007;115:55–59. doi: 10.1111/j.1600-0404.2006.00728.x. [DOI] [PubMed] [Google Scholar]
  • 53.Pearson-Fuhrhop KM, Minton B, Acevedo D, Shahbaba B, Cramer SC. Genetic variation in the human brain dopamine system influences motor learning and its modulation by l-dopa. PloS one. 2013;8:e61197. doi: 10.1371/journal.pone.0061197. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Pearson-Fuhrhop KM, Dunn EC, Mortero S, Devan WJ, Falcone GJ, Lee P, et al. Dopamine genetic risk score predicts depressive symptoms in healthy adults and adults with depression. PLoS One. 2014;9:e93772. doi: 10.1371/journal.pone.0093772. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Pearson-Fuhrhop KM, Cramer SC. Pharmacogenetics of neural injury recovery. Pharmacogenomics. 2013;14:1635–1643. doi: 10.2217/pgs.13.152. [DOI] [PubMed] [Google Scholar]
  • 56.Sesack SR, Grace AA. Cortico-basal ganglia reward network: Microcircuitry. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2010;35:27–47. doi: 10.1038/npp.2009.93. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Abe M, Schambra H, Wassermann EM, Luckenbaugh D, Schweighofer N, Cohen LG. Reward improves long-term retention of a motor memory through induction of offline memory gains. Current biology : CB. 2011;21:557–562. doi: 10.1016/j.cub.2011.02.030. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Salamone JD, Correa M. The mysterious motivational functions of mesolimbic dopamine. Neuron. 2012;76:470–485. doi: 10.1016/j.neuron.2012.10.021. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59.Costa RM. Plastic corticostriatal circuits for action learning: What's dopamine got to do with it? Annals of the New York Academy of Sciences. 2007;1104:172–191. doi: 10.1196/annals.1390.015. [DOI] [PubMed] [Google Scholar]
  • 60.Surmeier DJ, Plotkin J, Shen W. Dopamine and synaptic plasticity in dorsal striatal circuits controlling action selection. Current opinion in neurobiology. 2009;19:621–628. doi: 10.1016/j.conb.2009.10.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61.Garland T, Jr, Schutz H, Chappell MA, Keeney BK, Meek TH, Copes LE, et al. The biological control of voluntary exercise, spontaneous physical activity and daily energy expenditure in relation to obesity: Human and rodent perspectives. J Exp Biol. 2011;214:206–229. doi: 10.1242/jeb.048397. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.Merzenich MM, Van Vleet TM, Nahum M. Brain plasticity-based therapeutics. Front Hum Neurosci. 2014;8:385. doi: 10.3389/fnhum.2014.00385. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Beltran EJ, Papadopoulos CM, Tsai SY, Kartje GL, Wolf WA. Long-term motor improvement after stroke is enhanced by short-term treatment with the alpha-2 antagonist, atipamezole. Brain Res. 2010;1346:174–182. doi: 10.1016/j.brainres.2010.05.063. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64.Zittel S, Weiller C, Liepert J. Reboxetine improves motor function in chronic stroke A pilot study. J Neurol. 2007;254:197–201. doi: 10.1007/s00415-006-0326-5. [DOI] [PubMed] [Google Scholar]
  • 65.Wang LE, Fink GR, Diekhoff S, Rehme AK, Eickhoff SB, Grefkes C. Noradrenergic enhancement improves motor network connectivity in stroke patients. Annals of neurology. 2011;69:375–388. doi: 10.1002/ana.22237. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 66.Luria A. The Restoration of Motor Functions after Brain Injury. In: Luria A, editor. Restoration of function after brain injury. New York, NY: The Macmillan Company; 1963. pp. 78–116. [Google Scholar]
  • 67.Whyte EM, Lenze EJ, Butters M, Skidmore E, Koenig K, Dew MA, et al. An open-label pilot study of acetylcholinesterase inhibitors to promote functional recovery in elderly cognitively impaired stroke patients. Cerebrovascular diseases. 2008;26:317–321. doi: 10.1159/000149580. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 68.Barrett KM, Brott TG, Brown RD, Jr, Carter RE, Geske JR, Graff-Radford NR, et al. Enhancing recovery after acute ischemic stroke with donepezil as an adjuvant therapy to standard medical care: Results of a phase iia clinical trial. J Stroke Cerebrovasc Dis. 2011;20:177–182. doi: 10.1016/j.jstrokecerebrovasdis.2010.12.009. [DOI] [PubMed] [Google Scholar]
  • 69.Berthier ML, Green C, Higueras C, Fernandez I, Hinojosa J, Martin MC. A randomized, placebo-controlled study of donepezil in poststroke aphasia. Neurology. 2006;67:1687–1689. doi: 10.1212/01.wnl.0000242626.69666.e2. [DOI] [PubMed] [Google Scholar]
  • 70.Crisostomo E, Duncan P, Propst M, Dawson D, Davis J. Evidence that amphetamine with physical therapy promotes recovery of motor function in stroke patients. Annals of neurology. 1988;23:94–97. doi: 10.1002/ana.410230117. [DOI] [PubMed] [Google Scholar]
  • 71.Walker-Batson D, Smith P, Curtis S, Unwin H, Greenlee R. Amphetamine paired with physical therapy accelerates motor recovery after stroke Further evidence. Stroke; a journal of cerebral circulation. 1995;26:2254–2259. doi: 10.1161/01.str.26.12.2254. [DOI] [PubMed] [Google Scholar]
  • 72.Walker-Batson D, Curtis S, Natarajan R, Ford J, Dronkers N, Salmeron E, et al. A double-blind, placebo-controlled study of the use of amphetamine in the treatment of aphasia. Stroke; a journal of cerebral circulation. 2001;32:2093–2098. doi: 10.1161/hs0901.095720. [DOI] [PubMed] [Google Scholar]
  • 73.Gladstone DJ, Danells CJ, Armesto A, McIlroy WE, Staines WR, Graham SJ, et al. Physiotherapy coupled with dextroamphetamine for rehabilitation after hemiparetic stroke: A randomized, double-blind, placebo-controlled trial. Stroke; a journal of cerebral circulation. 2006;37:179–185. doi: 10.1161/01.STR.0000195169.42447.78. [DOI] [PubMed] [Google Scholar]
  • 74.Walker-Batson D, Mehta J, Smith P, Johnson M. Amphetamine and other pharmacological agents in human and animal studies of recovery from stroke. [Accessed July 11, 2015];Progress in neuro-psychopharmacology & biological psychiatry. doi: 10.1016/j.pnpbp.2015.04.002. [published online ahead of print 18 April 2015]. Progress in neuro-psychopharmacology & biological psychiatry. 2015. http://www.sciencedirect.com/science/article/pii/S0278584615000688. [DOI] [PubMed] [Google Scholar]
  • 75.Feeney D, Gonzalez A, Law W. Amphetamine, halperidol, and experience interact to affect the rate of recovery after motor cortex injury. Science. 1982;217:855–857. doi: 10.1126/science.7100929. [DOI] [PubMed] [Google Scholar]
  • 76.Goldstein L. Sygen in Acute Stroke Study Investigators Common drugs may influence motor recovery after stroke. Neurology. 1995;45:865–871. doi: 10.1212/wnl.45.5.865. [DOI] [PubMed] [Google Scholar]
  • 77.Butefisch C, Davis B, Wise S, Sawaki L, Kopylev L, Classen J, et al. Mechanisms of use-dependent plasticity in the human motor cortex. Proceedings of the National Academy of Sciences of the United States of America. 2000;97:3661–3665. doi: 10.1073/pnas.050350297. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 78.Conroy B, Zorowitz R, Horn SD, Ryser DK, Teraoka J, Smout RJ. An exploration of central nervous system medication use and outcomes in stroke rehabilitation. Archives of physical medicine and rehabilitation. 2005;86:S73–S81. doi: 10.1016/j.apmr.2005.08.129. [DOI] [PubMed] [Google Scholar]
  • 79.Cramer SC. Issues in clinical trial methodology for brain repair after stroke. In: Cramer SC, Nudo RJ, editors. Brain repair after stroke. Cambridge, UK: Cambridge University Press; 2010. pp. 173–182. [Google Scholar]
  • 80.Overman JJ, Carmichael ST. Plasticity in the injured brain: More than molecules matter. The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry. 2014;20:15–28. doi: 10.1177/1073858413491146. [DOI] [PubMed] [Google Scholar]
  • 81.Cramer SC. Repairing the human brain after stroke: I Mechanisms of spontaneous recovery. Annals of neurology. 2008;63:272–287. doi: 10.1002/ana.21393. [DOI] [PubMed] [Google Scholar]
  • 82.Li S, Carmichael ST. Growth-associated gene and protein expression in the region of axonal sprouting in the aged brain after stroke. Neurobiol Dis. 2006;23:362–373. doi: 10.1016/j.nbd.2006.03.011. [DOI] [PubMed] [Google Scholar]
  • 83.Cramer S, Chopp M. Recovery recapitulates ontogeny. Trends in neurosciences. 2000;23:265–271. doi: 10.1016/s0166-2236(00)01562-9. [DOI] [PubMed] [Google Scholar]
  • 84.Biernaskie J, Chernenko G, Corbett D. Efficacy of rehabilitative experience declines with time after focal ischemic brain injury. J Neurosci. 2004;24:1245–1254. doi: 10.1523/JNEUROSCI.3834-03.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 85.Chen J, Li Y, Wang L, Zhang Z, Lu D, Lu M, et al. Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats. Stroke; a journal of cerebral circulation. 2001;32:1005–1011. doi: 10.1161/01.str.32.4.1005. [DOI] [PubMed] [Google Scholar]
  • 86.Ren J, Kaplan P, Charette M, Speller H, Finklestein S. Time window of intracisternal osteogenic protein-1 in enhancing functional recovery after stroke. Neuropharmacology. 2000;39:860–865. doi: 10.1016/s0028-3908(99)00261-0. [DOI] [PubMed] [Google Scholar]
  • 87.Green AR, Hainsworth AH, Jackson DM. Gaba potentiation: A logical pharmacological approach for the treatment of acute ischaemic stroke. Neuropharmacology. 2000;39:1483–1494. doi: 10.1016/s0028-3908(99)00233-6. [DOI] [PubMed] [Google Scholar]
  • 88.Kozlowski D, Jones T, Schallert T. Pruning of dendrites and restoration of function after brain damage: Role of the nmda receptor. Restorative neurology and neuroscience. 1994;7:119–126. doi: 10.3233/RNN-1994-7207. [DOI] [PubMed] [Google Scholar]
  • 89.Narasimhan P, Liu J, Song YS, Massengale JL, Chan PH. Vegf stimulates the erk 1/2 signaling pathway and apoptosis in cerebral endothelial cells after ischemic conditions. Stroke; a journal of cerebral circulation. 2009;40:1467–1473. doi: 10.1161/STROKEAHA.108.534644. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 90.Zhao BQ, Tejima E, Lo EH. Neurovascular proteases in brain injury, hemorrhage and remodeling after stroke. Stroke; a journal of cerebral circulation. 2007;38:748–752. doi: 10.1161/01.STR.0000253500.32979.d1. [DOI] [PubMed] [Google Scholar]
  • 91.Wolf SL, Winstein CJ, Miller JP, Taub E, Uswatte G, Morris D, et al. Effect of constraint-induced movement therapy on upper extremity function 3 to 9 months after stroke: The excite randomized clinical trial. JAMA. 2006;296:2095–2104. doi: 10.1001/jama.296.17.2095. [DOI] [PubMed] [Google Scholar]
  • 92.Duncan PW, Sullivan KJ, Behrman AL, Azen SP, Wu SS, Nadeau SE, et al. Body-weight-supported treadmill rehabilitation after stroke. The New England journal of medicine. 2011;364:2026–2036. doi: 10.1056/NEJMoa1010790. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 93.Garcia-Alias G, Barkhuysen S, Buckle M, Fawcett JW. Chondroitinase abc treatment opens a window of opportunity for task-specific rehabilitation. Nature neuroscience. 2009;12:1145–1151. doi: 10.1038/nn.2377. [DOI] [PubMed] [Google Scholar]
  • 94.Cramer SC, Sur M, Dobkin BH, O'Brien C, Sanger TD, Trojanowski JQ, et al. Harnessing neuroplasticity for clinical applications. Brain : a journal of neurology. 2011;134:1591–1609. doi: 10.1093/brain/awr039. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 95.Fang PC, Barbay S, Plautz EJ, Hoover E, Strittmatter SM, Nudo RJ. Combination of nep 1–40 treatment and motor training enhances behavioral recovery after a focal cortical infarct in rats. Stroke; a journal of cerebral circulation. 2010;41:544–549. doi: 10.1161/STROKEAHA.109.572073. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 96.Starkey ML, Schwab ME. Anti-Nogo-A and training: Can one plus one equal three? Experimental neurology. 2012;235:53–61. doi: 10.1016/j.expneurol.2011.04.008. [DOI] [PubMed] [Google Scholar]
  • 97.Hovda D, Feeney D. Amphetamine with experience promotes recovery of locomotor function after unilateral frontal cortex injury in the cat. Brain Res. 1984;298:358–361. doi: 10.1016/0006-8993(84)91437-9. [DOI] [PubMed] [Google Scholar]
  • 98.Adkins-Muir D, Jones T. Cortical electrical stimulation combined with rehabilitative training: Enhanced functional recovery and dendritic plasticity following focal cortical ischemia in rats. Neurological research. 2003;25:780–788. doi: 10.1179/016164103771953853. [DOI] [PubMed] [Google Scholar]
  • 99.Adkins DL, Hsu JE, Jones TA. Motor cortical stimulation promotes synaptic plasticity and behavioral improvements following sensorimotor cortex lesions. Experimental neurology. 2008;212:14–28. doi: 10.1016/j.expneurol.2008.01.031. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 100.Johansson B. Brain plasticity stroke rehabilitation The willis lecture. Stroke; a journal of cerebral circulation. 2000;31:223–230. doi: 10.1161/01.str.31.1.223. [DOI] [PubMed] [Google Scholar]
  • 101.Riley JD, Le V, Der-Yeghiaian L, See J, Newton JM, Ward NS, et al. Anatomy of stroke injury predicts gains from therapy. Stroke; a journal of cerebral circulation. 2011;42:421–426. doi: 10.1161/STROKEAHA.110.599340. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 102.Stinear CM, Barber PA, Petoe M, Anwar S, Byblow WD. The prep algorithm predicts potential for upper limb recovery after stroke. Brain : a journal of neurology. 2012;135:2527–2535. doi: 10.1093/brain/aws146. [DOI] [PubMed] [Google Scholar]
  • 103.Burke Quinlan E, Dodakian L, See J, McKenzie A, Le V, Wojnowicz M, et al. Neural function, injury, and stroke subtype predict treatment gains after stroke. Annals of neurology. 2015;77:132–145. doi: 10.1002/ana.24309. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 104.Kato M, Serretti A. Review and meta-analysis of antidepressant pharmacogenetic findings in major depressive disorder. Molecular psychiatry. 2010;15:473–500. doi: 10.1038/mp.2008.116. [DOI] [PubMed] [Google Scholar]
  • 105.Kohen R, Cain KC, Buzaitis A, Johnson V, Becker KJ, Teri L, et al. Response to psychosocial treatment in poststroke depression is associated with serotonin transporter polymorphisms. Stroke; a journal of cerebral circulation. 2011;42:2068–2070. doi: 10.1161/strokeaha.110.611434. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 106.Kleim J, Bruneau R, VandenBerg P, MacDonald E, Mulrooney R, Pocock D. Motor cortex stimulation enhances motor recovery and reduces peri-infarct dysfunction following ischemic insult. Neurological research. 2003;25:789–793. doi: 10.1179/016164103771953862. [DOI] [PubMed] [Google Scholar]
  • 107.Plautz E, Barbay S, Frost S, Friel K, Dancause N, Zoubina E, et al. Post-infarct cortical plasticity and behavioral recovery using concurrent cortical stimulation and rehabilitative training: A feasibility study in primates. Neurological research. 2003;25:801–810. doi: 10.1179/016164103771953880. [DOI] [PubMed] [Google Scholar]
  • 108.Teskey G, Flynn C, Goertzen C, Monfils M, Young N. Cortical stimulation improves skilled forelimb use following a focal ischemic infarct in the rat. Neurological research. 2003;25:794–800. doi: 10.1179/016164103771953871. [DOI] [PubMed] [Google Scholar]
  • 109.Levy RM, Harvey RL, Kissela BM, Winstein CJ, Lutsep HL, Parrish TB, et al. Epidural electrical stimulation for stroke rehabilitation: Results of the prospective, multicenter, randomized, single-blinded everest trial. [Accessed July 11, 2015];Neurorehabil Neural Repair. doi: 10.1177/1545968315575613. [published online ahead of print Mar 6, 2015.] Neurorehabil Neural Repair. 2015. http://nnr.sagepub.com/content/early/2015/03/06/1545968315575613.long. [DOI] [PubMed] [Google Scholar]
  • 110.Nouri S, Cramer SC. Anatomy and physiology predict response to motor cortex stimulation after stroke. Neurology. 2011;77:1076–1083. doi: 10.1212/WNL.0b013e31822e1482. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 111.Cramer SC, Koroshetz WJ, Finklestein SP. The case for modality-specific outcome measures in clinical trials of stroke recovery-promoting agents. Stroke; a journal of cerebral circulation. 2007;38:1393–1395. doi: 10.1161/01.STR.0000260087.67462.80. [DOI] [PubMed] [Google Scholar]
  • 112.Salbach NM, Mayo NE, Higgins J, Ahmed S, Finch LE, Richards CL. Responsiveness and predictability of gait speed and other disability measures in acute stroke. Archives of physical medicine and rehabilitation. 2001;82:1204–1212. doi: 10.1053/apmr.2001.24907. [DOI] [PubMed] [Google Scholar]
  • 113.Perry J, Garrett M, Gronley J, Mulroy S. Classification of walking handicap in the stroke population. Stroke; a journal of cerebral circulation. 1995;26:982–989. doi: 10.1161/01.str.26.6.982. [DOI] [PubMed] [Google Scholar]
  • 114.Prasad A, Kumar SS, Dessimoz C, Bleuler S, Laule O, Hruz T, et al. Global regulatory architecture of human, mouse and rat tissue transcriptomes. BMC genomics. 2013;14:716. doi: 10.1186/1471-2164-14-716. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 115.Chan ET, Quon GT, Chua G, Babak T, Trochesset M, Zirngibl RA, et al. Conservation of core gene expression in vertebrate tissues. Journal of biology. 2009;8:33. doi: 10.1186/jbiol130. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 116.Cramer SC. Repairing the human brain after strokes. Ii. Restorative therapies. Annals of neurology. 2008;63:549–560. doi: 10.1002/ana.21412. [DOI] [PubMed] [Google Scholar]
  • 117.U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER). Guidance for industry. [Accessed July 11, 2015];Clinical studies section of labeling for human prescription drug and biological products — content and format. 2006 http://www.Fda.Gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm075059.Pdf.
  • 118.Temple R. A regulatory authority's opinion about surrogate endpoints. In: Nimmo W, Tucker G, editors. Clinical measurement in drug evaluation. New York: J. Wiley; 1995. pp. 3–22. [Google Scholar]
  • 119.Fleming T, DeMets D. Surrogate end points in clinical trials: Are we being misled? Ann Intern Med. 1996;125:605–613. doi: 10.7326/0003-4819-125-7-199610010-00011. [DOI] [PubMed] [Google Scholar]
  • 120.Bucher H, Guyatt G, Cook D, Holbrook A, McAlister F. Users' guides to the medical literature: Xix. Applying clinical trial results. A. How to use an article measuring the effect of an intervention on surrogate end points Evidence-based medicine working group. Jama. 1999;282:771–778. doi: 10.1001/jama.282.8.771. [DOI] [PubMed] [Google Scholar]
  • 121.Dijkhuizen RM, van der Marel K, Otte WM, Hoff EI, van der Zijden JP, van der Toorn A, et al. Functional mri and diffusion tensor imaging of brain reorganization after experimental stroke. Transl Stroke Res. 2012;3:36–43. doi: 10.1007/s12975-011-0143-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 122.Tardy J, Pariente J, Leger A, Dechaumont-Palacin S, Gerdelat A, Guiraud V, et al. Methylphenidate modulates cerebral post-stroke reorganization. NeuroImage. 2006;33:913–922. doi: 10.1016/j.neuroimage.2006.07.014. [DOI] [PubMed] [Google Scholar]
  • 123.Burke E, Cramer SC. Biomarkers and predictors of restorative therapy effects after stroke. Current neurology and neuroscience reports. 2013;13:329. doi: 10.1007/s11910-012-0329-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 124.Lang CE, Macdonald JR, Reisman DS, Boyd L, Jacobson Kimberley T, Schindler-Ivens SM, et al. Observation of amounts of movement practice provided during stroke rehabilitation. Archives of physical medicine and rehabilitation. 2009;90:1692–1698. doi: 10.1016/j.apmr.2009.04.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 125.Zorowitz RD, Smout RJ, Gassaway JA, Horn SD. Neurostimulant medication usage during stroke rehabilitation: The post-stroke rehabilitation outcomes project (psrop) Topics in stroke rehabilitation. 2005;12:28–36. doi: 10.1310/2403-B0CY-1UDN-4B6D. [DOI] [PubMed] [Google Scholar]
  • 126.See J, Dodakian L, Chou C, Chan V, McKenzie A, Reinkensmeyer DJ, et al. A standardized approach to the fugl-meyer assessment and its implications for clinical trials. Neurorehabilitation and neural repair. 2013;27:732–741. doi: 10.1177/1545968313491000. [DOI] [PubMed] [Google Scholar]
  • 127.Hermann DM, Chopp M. Promoting brain remodelling and plasticity for stroke recovery: Therapeutic promise and potential pitfalls of clinical translation. Lancet neurology. 2012;11:369–380. doi: 10.1016/S1474-4422(12)70039-X. [DOI] [PMC free article] [PubMed] [Google Scholar]

RESOURCES