Review Article

Emerging Therapies in
Address correspondence
to Dr Mary L. Dombovy,
Unity Health System,
Dept of Physical Medicine
and Rehabilitation,
89 Genesee St, Rochester, Neurorehabilitation
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NY 14611-3201,
mdombovy@unityhealth.org.
Mary L. Dombovy, MD, MHSA, FAAN
Relationship Disclosure:
Dr Dombovy’s institution
is compensated for her
litigation and testimony. ABSTRACT
Unlabeled Use of
Products/Investigational
Just as advancing technology has furthered our understanding of how the nervous
Use Disclosure: system recovers, technology also enables the development of novel approaches to
Dr Dombovy discusses treatment. Because nervous system disease and injury often lead to severely impaired
the unlabeled use of
pharmaceuticals and
function, patients and families are willing to try anything, so therapies are often
information on adopted with little evidence that they actually work. Evidence shows that compre-
investigational treatments. hensive rehabilitation programs produce better outcomes, but it is still not understood
Copyright * 2011, what components of these multifaceted programs are critical to their success. Func-
American Academy of
Neurology. All rights tional neuroimaging and other modalities now allow monitoring of neurophysiologic
reserved. changes that can be paired with assessments detailing clinical changes, furthering our
understanding of the factors that influence the recovery process. This article discusses
several novel and emerging therapies in neurorehabilitation as well as recent multi-
study reviews of selected treatments.

Continuum Lifelong Learning Neurol 2011;17(3):530–544.

THERAPIES IN THE EARLY be beneficial and deserves additional

POSTINJURY PERIOD
Hypothermia
Evidence from animal models supports
the neuroprotective effects of hypo-
thermia in global cerebral ischemia
(postYcardiac arrest), traumatic brain
injury (TBI), spinal cord injury (SCI),
and stroke.1 Hypothermia has become
the standard of care postYcardiac
arrest.2 Although clinical evidence sug-
gests a benefit in TBI,3 evidence is
conflicting for both SCI and stroke.
Povlischock and Wei suggest that evi-
dence points to slow rewarming com-
bined with immunophilin ligands such
as cyclosporine A as a key to improved
results. The Brain Trauma Foundation
and the American Association of Neuro-
logical Surgeons guidelines task force
issued a Level III recommendation for
optional use of hypothermia for adults
with TBI.4 Recent evidence suggests
that the combination of neuroprotec-
tive medications with hypothermia may
study.5 Zhao and colleagues6 provide a
review of the benefits and limitations of
hypothermic intervention, highlighting
the effects on biochemical and patho-
logic processes.
Pharmacologic Interventions
TBI, SCI, and stroke are all associated
with a period of secondary injury that
evolves over hours to days resulting from
a cascade of biochemical and physiologic
events. Several biochemical derange-
ments are responsible for secondary
injury and include changes in calcium
homeostasis, increased free radical pro-
duction, lipid peroxidation, mitochon-
drial dysfunction, inflammation, and
apoptosis. This time period provides a
window of opportunity for therapeutic
intervention, with the potential to re-
duce secondary damage and thus im-
prove long-term clinical outcomes.
Many preclinical studies in both TBI
and stroke suggest that compounds that

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target mechanisms involved in second-
ary injury both salvage brain tissue
and improve function. Yet all of the ap-
proaches that have been tested in phase
III clinical trials have failed to clearly
demonstrate efficacy.7,8 Table 7-1 shows
a synopsis of clinical neuroprotective
trials in stroke. Some therapies, such
as the use of corticosteroids post-TBI,
should be abandoned, as a recent multi-
trial review demonstrated increased
mortality and disability in patients with
TBI receiving corticosteroids.9 Evidence
points to the pathophysiologic hetero-
geneity of TBI and stroke, inadequate
information to determine optimal dos-
ing and timing, as well as suboptimal
clinical and statistical design.10,11
Numerous trials remain ongoing and
involve known compounds such as pro-
gesterone, erythropoietin, statins, and
KEY POINTS
phosphodiesterase inhibitors. Other h Hypothermia shows
early strategies, such as decompressive promise as an acute
craniectomy, show promise in selected treatment for cerebral
patients. Approaches combining several ischemia and traumatic
therapies and improved research design brain injury.
may be critical to success.5,7,12 h Clinical trials of
neuroprotection have
failed to demonstrate
THERAPIES IN THE efficacy.
POSTACUTE PERIOD
Pharmacologic Therapies
Drugs enhancing neurotrophins.
Brain-derived neurotrophic factor (BDNF),
among other neurotrophins, has emerged
as a major modulator of both synaptic
transmission and plasticity in many re-
gions of the CNS. BDNF has been shown
to increase the survival of neurons, to
increase synaptic transmission,13 and to
enhance long-term potentiation along
with short-term synaptic plasticity.14,15

TABLE 7-1 Clinical Trials of Neuroprotectants in Acute Ischemic Stroke

Neuroprotectant Number of Trials

Calcium channel blocker 16
Free radical scavenger-antioxidant 9
Hemodilution 9
Hypothermia (brain cooling) 9
Serotonin antagonist 7
Sodium channel blocker 7
Blood pressureYrelated strategy 6
Glutamate antagonist: NMDA receptor blockade 6
at glycine site
Phosphatidylcholine precursor 6
Hemicraniectomy 5
Magnesium 5
Osmotic agent 5
Temperature control 5
Neutrophil adhesion molecule antagonist 4
Albumin 3
Calcium chelator 3

continued on next page

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 Emerging Therapies

TABLE 7-1 Continued

Neuroprotectant Number of Trials

Corticosteroid 3
Fibroblast growth factor 3
GABA agonist 3
Ganglioside 3
Glutamate antagonist: AMPA antagonist 3
Glutamate antagonist: noncompetitive NMDA 3
channel blocker
Glycemic control strategy 3
Opioid antagonist 3
Prostanoid 3
Statin 3
Antibiotic 2
Combination of agents 2
GABA derivative 2
Glutamate antagonist: competitive NMDA 2
receptor blocker
Hyperbaric oxygen 2
Oxygenated fluorocarbon, oxygen supplementation 2
Volume expansion 2
Astrocyte modulator 1
Beta-blocker 1
CNS stimulant 1
Flow enhancer 1
Glutamate antagonist: NMDA polyamine site blocker 1
Glycine (NMDA co-agonist) 1
Interleukin-1 receptor antagonist 1
Iron chelator 1
Laser system 1
Oxygenated fluorocarbon 1
Potassium channel opener 1
Serotonin receptor agonist 1
Serotonin uptake inhibitor 1
Traditional Chinese medicine 1
Vasodilator 1
Other 2
GABA = +-aminobutyric acid; AMPA = !-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid.
Adapted from Ginsberg MD. Neuroprotection for ischemic stroke: past, present and future. Neuropharmacology
2008;55(3):363Y389. Copyright B 2008, with permission from Elsevier.

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Secondary brain injury after ischemic and
traumatic insults results from a combina-
tion of cytotoxic, inflammatory, ischemic,
and apoptotic processes. Several lines of
evidence indicate that BDNF may play a
role in limiting the secondary injury that
occurs after TBI and stroke by altering
gene expression in injured cells.16 Ad-
ministration of BDNF after TBI, stroke,
and SCI in animals has been shown to
be neuroprotective and promote plastic-
ity and recovery.17,18
Selective serotonin reuptake inhibi-
tors (SSRIs), tricyclic antidepressants,
and monoamine oxidase inhibitors all
increase BDNF levels in the frontal
cortex.19 Statins upregulate BDNF, in-
crease neurogenesis, and are associ-
ated with improvement after TBI and
ischemia.7,20 Compounds that alter his-
tones, thereby altering gene expression
through chromatin remodeling, increase
BDNF expression and promote neuro-
genesis.21 Although no clinical recom-
mendations can yet be given, additional
animal studies and early clinical inves-
tigations are underway.
Amphetamine. Over the past 50
years, numerous animal studies have
shown that amphetamine combined
with task-relevant training improves out-
comes following TBI and ischemia.22 A
small double-blind, placebo-controlled
clinical trial provided evidence that d-
amphetamine combined with physical
therapy improved short-term motor
function after stroke.23 Another placebo-
controlled study in patients with sub-
acute stroke evaluated d-amphetamine
administration combined with 1 hour of
speech therapy 3 times per week for
a total of 10 sessions. Patients receiving
d-amphetamine improved significantly,
and at 6 months they still demonstrated
a persistent positive trend despite no ad-
ditional drug or therapy.24 Results of
clinical trials since have been variable.
This variability can possibly be attributed
to study design issues such as stroke
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KEY POINTS
size and location; dosing and timing of h Brain-derived
drug; and timing, type, and intensity of neurotrophic factor
physical therapy. Despite concerns modulates synaptic
about the potential negative cardiovas- transmission and
cular effects of amphetamine, studies to plasticity in the CNS.
date have not shown a difference in h Amphetamine may
adverse events between drug and pla- improve recovery after
cebo in subjects given amphetamine stroke when combined
within 1 week following stroke.22 The with a therapy program.
NIH-sponsored Amphetamine-Enhanced h Dopaminergic drugs
Stroke Recovery (AESR) study is evalu- improve arousal
ating the impact of the timing and and attention
duration of therapy. after traumatic
Dopaminergic drugs. Several stud- brain injury.
ies have looked at the effects of other
dopaminergic agents, such as levodopa,
bromocriptine, amantadine, and meth-
ylphenidate, on promoting recovery and
improving alertness, attention, memory,
and initiation. These studies were gen-
erally small, producing variable results.
The most convincing evidence supports
the use of amantadine at doses of 200 mg
to 400 mg per day to improve arousal
and executive functioning in patients
with TBI.25,26 In one study showing
improvements in executive function-
ing after administration of amantadine,
PET revealed an increase in glucose
metabolism in the left prefrontal cortex.27
The magnitude of the increase in glu-
cose metabolism correlated with the
degree of improvement in executive
function.
Studies evaluating methylphenidate
after brain injury and stroke have
shown mostly positive results. Methyl-
phenidate appears to have its greatest
effect on improving speed of mental
processing, tests of attention, and mo-
tor performance.28,29 Administration of
methylphenidate to patients with mod-
erate to severe TBI while they are still in
the intensive care unit may reduce length
of stay.30 In 2006, the Neurobehavioral
Guidelines Working Group recom-
mended the use of methylphenidate in
patients with TBI with impairments in
attentional skills and processing speed.31
www.aan.com/continuum 533
 Emerging Therapies
KEY POINTS
h Acetylcholinesterase
inhibitors improve
memory after traumatic
brain injury.
h Benzodiazepines and
antipsychotics appear to
slow recovery from
traumatic brain injury
and stroke.
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Adverse reactions to these dopami-
nergic medications are rare at the
doses used in clinical practice but may
include paranoia, anxiety, agitation,
increases in heart rate and blood
pressure, and lowering of the seizure
threshold.
Piracetam. After reviewing several
studies involving more than 220 stroke
patients with aphasia, a Cochrane Re-
view concluded that piracetam may be
effective as an adjunct to therapy in the
treatment of aphasia after stroke.32
Piracetam’s mechanism of action is not
clear. It is not available in the United
States at the time of this writing.
Acetylcholinesterase inhibitors.
Because TBI commonly affects the basal
frontal lobes, cholinergic deficit is com-
mon. Patients with TBI also frequently
have impairments in memory. In clinical
trials, the effects of donepezil and riva-
stigmine are consistently positive, im-
proving memory, attention, and speed
of processing.28,33 The Neurobehavioral
Guidelines Working Group and a recent
comprehensive review33 both recom-
mend the use of donepezil and riva-
stigmine in patients with moderate to
severe TBI during the subacute and
chronic periods of recovery. Side effects
include nausea, diarrhea, vomiting, mus-
cle cramping, and fatigue, but these can
often be minimized by slowly escalating
the dose. Anticholinesterase inhibitors
should not be used in patients with
symptomatic bradycardia or atrioven-
tricular block. There are no reports that
anticholinesterase inhibitors lower the
seizure threshold.
Selective serotonin reuptake inhib-
itors. Ample evidence exists that
depression adversely affects functional
recovery following stroke and TBI and
that treating depression improves
recovery. 34 Only limited evidence
exists that SSRIs may improve function-
ing following stroke or TBI indepen-
dent of their effects on depression.28
Modafinil. Modafinil is approved to
improve wakefulness in adults with nar-
colepsy, obstructive sleep apnea, and
shift work disorder. It is frequently used
in clinical settings to improve arousal
and attention following TBI and stroke
with few reported significant side ef-
fects and the clinical impression that it
is beneficial in selected patients. The
mechanism of action is unclear. Cur-
rently, few studies exist to either refute
or support its use.33
Polypharmacy. In clinical practice,
various combinations of pharmacologic
agents are frequently used in patients
with TBI and stroke. This is particularly
true for those patients with severe de-
ficits, especially impairments of arousal,
attention, initiation, and impulsivity. In
some situations, patients may be on
more than three psychoactive agents, at
times including both dopaminergic and
antidopaminergic drugs. Each practi-
tioner or institution appears to have a
unique approach. Pharmacologic treat-
ment will be reviewed from a clinical
perspective in the article ‘‘Traumatic
Brain Injury.’’
Medications with Adverse
Effects on Recovery
Agitation, anxiety, insomnia, and sleep-
wake cycle disturbance are all common
following TBI and stroke, resulting in
disruption of the rehabilitation pro-
gram as well as inappropriate behav-
ior. Strong evidence from both animal
and human studies demonstrates that
typical +-aminobutyric acid agonists
(benzodiazepines) produce residual
cognitive and behavioral effects that
outlast their duration in the blood-
stream.35,36 There have also been long-
standing concerns that the use of anti-
psychotics after TBI and stroke may
reinstate deficits that had abated as well
as delay recovery.37,38 Although imme-
diate control of dangerous behaviors is
June 2011

sometimes urgently needed (see the
article ‘‘Traumatic Brain Injury’’), other
environmental and pharmacologic
interventions should be considered for
management of agitation, impulsivity,
and sleep disruption.39
Nonpharmacologic Therapies
Constraint-induced movement ther-
apy. Constraint-induced movement
therapy (CIMT) involves restraining the
unaffected extremity during therapy ses-
sions with the affected extremity and
for several hours or constantly at other
times for periods of several weeks to
over a month (Case 7-1). In addition to
involving repetitive massed practice
(which mounting evidence shows is
critical to motor skill recovery), CIMT
reduces sensory input to the uninvolved
extremity. CIMT has been shown to pro-
duce clinical improvement and changes
in fMRI in both acute and chronic pa-
tients poststroke.40,41 In a recent re-
view, Wittenberg and Schaechter42
noted that both fMRI and transcranial
magnetic stimulation (TMS) demon-
KEY POINT
strated changes in brain activation that h Constraint-induced
correlated with CIMT. The changes movement therapy
were variable and likely correlated with improves upper
the extent of stroke-induced damage extremity function in
to the descending corticospinal tract. conjunction with
A recent review43 of CIMT for the cortical reorganization.
upper extremity poststroke concluded
that disability is moderately improved
immediately following the interven-
tion. Although additional information
is needed to assess long-term benefit, a
recent reexamination of the data from
the Extremity Constraint Induced Ther-
apy Evaluation (EXCITE) trial noted
that subjects needed to perform above
a functional threshold in order to
maintain gains or continue to improve
after the CIMT ceased.44 Another re-
cent study45 compared CIMT to bilat-
eral arm training in patients with
stroke and found better functional use
of the affected extremity after CIMT
for patients with mild to moderate
stroke. Proximal arm motor impair-
ment improved more after bilateral
training. CIMT has also been used with
success in patients with cerebral palsy46
and TBI.47

Case 7-1
An 18-month-old girl with cerebral palsy and a left hemiparesis presented
to the clinic. She ambulated with an ankle-foot orthosis and had
reasonable gross motor function in every muscle group in her left upper
extremity. She tended not to use the arm in any activity. Her parents were
very motivated and supportive.
She was referred to occupational therapy for constraint-induced
movement therapy and underwent periodic casting of her unimproved
right upper extremity for 3 weeks at a time with 3 weeks off. During this
time she also received intensive therapy, partly with a therapist and also
through a home program. The initial attempts were difficult, with much
crying and difficulties with cooperation, but her parents and occupational
therapist persisted over a 2-year period.
At the end of 2 years, she was using her left upper extremity
spontaneously in general activities and had individual finger control.
Comment. This case illustrates the potential impact of constraint-induced
movement therapy on upper extremity function given a long span of time
and a consistent approach.

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 Emerging Therapies

KEY POINTS
h Reducing activation
of the ipsilateral
hemisphere improves
motor function in both
healthy individuals and
those with traumatic
brain injury or stroke.
h Transcranial magnetic
stimulation and
transcranial direct
current stimulation
produce cortical
activation changes and
may evolve into useful
therapy adjuncts.
Clinical implementation of CIMT
is limited for several reasons. To parti-
cipate, patients need active wrist and
hand movement, including at least
10 degrees of wrist and finger extension,
which limits its application to patients
with mild to moderate motor impair-
ment. Additionally, patients with TBI
with cognitive-behavioral impairments
and children may not be receptive to
wearing a cast or other restraint on the
uninvolved extremity, which may re-
duce cooperation with therapies or
cause anxiety in caregivers and parents.
Finally, CIMT repetitive practice sessions
are time intensive (which can increase
costs), can be frustrating, and require a
high degree of motivation.
Transcranial magnetic stimulation
and transcranial direct current stim-
ulation. The theory behind CIMT is that
in addition to forced use of the involved
extremity, thus increasing input to the
involved hemisphere, input from the
uninvolved extremity to the uninvolved
hemisphere is reduced.48 fMRI studies
show increased activation of motor
areas in both hemispheres when the
affected extremity is moved soon after
stroke.49,50 Concentration of activity
within the motor areas correlates with
good recovery, while persistence of
activation in the contralesional hemi-
sphere correlates with less recovery.49,51
In addition, the lateralization of neural
activity during unimanual activity is, in
part, related to interhemispheric inhibi-
tion between motor areas exerted via
transcallosal connections that are dis-
rupted following stroke.52 In theory,
persisting activation of the unaffected
hemisphere may limit activation of the
involved hemisphere, thus limiting post-
injury recovery. Even in healthy sub-
jects, inhibition of the ipsilateral motor
cortex or facilitation of the contralateral
motor cortex by TMS improves upper
extremity motor speed and motor task
acquisition.53,54
After extensive review of studies em-
ploying either TMS or transcranial direct
current stimulation (tDCS) in patients
with stroke, Nowak and colleagues55
concluded that evidence strongly sug-
gests that TMS and tDCS are both be-
neficial and safe in promoting motor
recovery following stroke. Improve-
ment was noted following inhibition
of the uninvolved hemisphere as well
as stimulation of the involved hemi-
sphere. The beneficial effects of TMS
and tDCS on cortical excitability outlast
the stimulus for minutes to hours and
thus may be paired with poststimula-
tion therapy. Repeated activation over
several days or weeks and in combina-
tion with training appears to enhance
both the effect size and duration of
improvement.
Currently, TMS and tDCS are not part
of the therapeutic regimen following
stroke or TBI, as many questions still
exist regarding these therapies, such as
the optimal frequency and intensity of
the stimulation, the appropriate timing
and duration of the program postinjury,
and the appropriate patient selection in
terms of severity and location of injury.
Although studies are underway, the ef-
fects of pairing either TMS or tDCS with
standard rehabilitation approaches,
CIMT, or robot-assisted therapy are
largely unknown.
Robot-assisted therapy. After stroke
and TBI, many patients have little or
no ability to use their upper extremity.
Robotic devices are able to deliver high-
intensity, reproducible therapy and may
be useful in those with little voluntary
movement as well as those with greater
ability. A review56 of 11 trials with a
total of 328 patients compared robot-
assisted training with either standard
therapy or no therapy. They concluded
that robot-assisted training produces
greater improvement in arm strength
and motor function but not in activities
of daily living. Considerable variation

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existed in the type, timing, frequency,
and duration of training.
In a multicenter randomized con-
trolled trial involving 127 patients more
than 6 months poststroke who had mod-
erate to severe upper extremity impair-
ment, Lo and colleagues57 compared
intensive robot-assisted therapy to
intensive conventional therapy and to
limited therapy. No difference existed
at 12 weeks immediately following the
intervention. At 36 weeks, both the
robot-assisted group and those receiv-
ing intensive conventional therapy
showed significant improvements in mo-
tor function compared to those receiv-
ing more limited therapy. In another
multicenter study, this one involving
109 patients 3 to 9 months poststroke,
Kutner and colleagues58 compared
therapist-supervised repetitive task
practice to robot-assisted therapy. Both
produced significant and equivalent
improvements in upper extremity func-
tion. The investigators concluded that
robotics may reduce therapist labor, re-
duce costs, and foster acceptance of ap-
proaches that involve repetitive practice,
such as CIMT.
Body weightYsupported treadmill
training. Body weightYsupported tread-
mill training (BWSTT) involves com-
pensating for a percentage of the
subject’s body weight, usually via sus-
pension with a harness over a treadmill.
The subject then walks on the tread-
mill at varying speeds and with varying
percentages of body-weight support. In
addition, one or more therapists may
assist by advancing a paretic leg or pro-
viding tactile or verbal cues. Working
on a treadmill facilitates an even gait
speed and provides more gait cycles and
repetition than could occur over ground,
while reducing the need for trunk con-
trol by displacing weight through the
harness suspension. As noted above,
research has shown that repetition is
critical to skill acquisition. See Video
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KEY POINTS
Segments 19 through 22 for an exam- h Robot-assisted
ple of BWSTT in a patient with intra- therapy may assist
cerebral hemorrhage. with implementation of
Patients with hemiparesis, ataxia, par- repetitive training tasks.
tial spinal cord injury, and cerebral h Body weightYsupported
palsy may all benefit from this approach treadmill training
(Case 7-2). Preliminary research has promotes gait
demonstrated improvements in mea- improvement following
sured gait parameters after BWSTT traumatic brain injury,
in stroke,59Y61 spinal cord injury,62Y64 stroke, and partial
multiple sclerosis,65 and pediatric spinal cord injury.
patients.66,67 Yen and colleagues61 were
also able to demonstrate changes in
cortical excitability that correlated
with functional improvement follow-
ing BWSTT but not after general phys-
ical therapy.
The practical efficacy of BWSTT has
been limited by the physical and time
demands placed on therapists who
must manually facilitate stepping dur-
ing the early phases of therapy in some
patients. It was hypothesized that a
robotic device that facilitates stepping
might enhance the adoption of BWSTT.
Unfortunately, Hornby and colleagues60
demonstrated that therapist-assisted
BWSTT was superior to robotic-assisted
BWSTT in a group of patients with
chronic stroke. A recent Cochrane Re-
view68 of studies on overground gait
training was unable to determine whether
overground physical therapy gait training
improves gait function in patients with
chronic stroke but concluded that it did
produce an improvement in walking
speed. In addition to potentially enhanc-
ing functional and neurologic recovery of
gait, BWSTT may also serve to provide
general aerobic exercise in patients with
neurologic impairments at a level that
they would not be able to achieve
through other means.
Exercise. General aerobic exercise
improves cardiorespiratory function and
plays a role in reducing risk for vascular
diseases, including stroke. New evidence
is emerging that aerobic exercise may
also enhance neural plasticity, cognitive
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 Emerging Therapies

KEY POINT
h General exercise
programs promote
Case 7-2
A 45-year-old woman had an ‘‘over the handlebars’’ bicycle accident
fitness and appear to
during a race while going downhill at about 45 miles per hour. She
enhance CNS plasticity.
sustained a C4-C5 fracture dislocation and had only minimal motor
function with considerable preserved sensation. Acutely she required a
tracheostomy and ventilation but was weaned from the ventilator at
2 months. At that time she had 3/5 strength in her legs, 4/5 proximal arm
strength, and 2/5 hand strength. Proprioception was seriously impaired
in both lower extremities.
After inpatient rehabilitation she required minimal assistance with
activities of daily living and was ambulating short distances with a walker
and minimal assistance, albeit with a very irregular gait.
She began a body weightYsupported treadmill training (BWSTT) program
for 1 hour a day 5 days a week. After 2 months her gait had noticeably
improved, and she was ambulating in the community with a cane.
Beginning 9 months postinjury her walking began to decline because
of increased pain and stiffness. MRI was negative for syrinx. She was
started on baclofen and duloxetine. Therapy was intensified. After
the addition of tizanadine and gabapentin, she resumed physical
therapy in a therapy pool with a treadmill floor. She improved partially,
but she never returned to the level she had achieved at 6 months
postinjury.
She is awaiting an intrathecal baclofen trial and is hopeful that it will
both improve her spasticity and provide additional pain control.
Comment. Reinnervation in partial spinal cord injury can lead to
devastating neuropathic pain and spasticity. BWSTT is a useful therapy
because it delivers repetitive, consistent walking. The intense repetition
appears important to the process of recovery.

function, and motor recovery. Physical task-specific training resulted in mean-

activity increases neurogenesis in the
hippocampus, directly affects synaptic
plasticity, and increases angiogenesis,69,70
at least in part through increasing levels
of BDNF.
Saunders and colleagues71 reviewed
24 trials involving 1147 patients with
stroke that included cardiorespiratory,
strength, and mixed exercise programs.
Training improved fitness but not nec-
essarily functional activities. The only
consistent effect observed was that
cardiorespiratory training involving walk-
ing improved a wide range of walking
parameters and reduced dependence
on others during walking. After review-
ing 14 trials with 659 patients, French
and colleagues72 found that repetitive,
ingful functional gains when compared
with usual care. No significant adverse
effects were noted. Evidence was insuf-
ficient to demonstrate maintenance of
gains at 6 to 12 months after the train-
ing ended. The role of exercise does not
seem surprising. Healthy subjects need
to continue to exercise to maintain
fitness levels, so one could assume that
the same is likely true for persons with
neurologic injuryVpotentially even
more so. Experienced clinicians know
the deleterious effects of even a rela-
tively short period of immobility during
an illness or after an injury in patients
with neurologic impairment.
Physical exercise in humans appears
to protect against the development of

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dementia.73Y75 Devine and Zafonte76
reviewed numerous animal and hu-
man studies and reached the following
conclusions: (1) strong evidence from
animal models of stroke and TBI dem-
onstrates that physical exercise promotes
neurocognitive recovery; (2) physical
exercise programs appear to be safe in
the subacute and chronic phase after
stroke and TBI; and (3) preliminary
evidence from widely varying human
studies suggests a neurocognitive bene-
fit, but more studies are needed.
Fitness exercise programs could be
a simple, effective adjunct to promote
brain plasticity following TBI and
stroke. This intervention is noninvasive,
generally safe, and also benefits gen-
eral health and performance of daily
activities. Functional neuroimaging
may help shed light on the neurophysi-
ology underlying the beneficial effects
of exercise.
Peripheral stimulation techniques.
Peripheral stimulation approaches in-
clude muscle vibration and peripheral
nerve stimulation. For patients with se-
vere paralysis, these techniques are an
adjunct to facilitating movement. So-
phisticated functional electrical stimula-
tion devices provide a means for those
with SCI to use their paralyzed extrem-
ities to walk and accomplish other
tasks.77 Advances in mechanical engi-
neering, nanotechnology, and nervous
system interfaces, in collaboration with
knowledgeable clinicians, will hope-
fully further advance these devices.
In addition to facilitating muscle con-
traction, peripheral stimulation pro-
vides input to the paretic extremity,
altering the excitability of the cortico-
spinal pathway via modulation of motor
cortex activity.78,79 Numerous recent
reports show functional benefit when
muscle vibration and peripheral nerve
stimulation are applied to the affected
extremities in conjunction with a therapy
program.80Y85 It remains unclear what
Continuum Lifelong Learning Neurol 2011;17(3):530–544
Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
KEY POINT
frequency, intensity, duration, and tim- h Functional electrical
ing postinjury produce the best results. stimulation enhances
Most reports show a drop-off in benefit somatosensory input
after 2 to 6 months, but it is not known to the brain.
how many subjects were continuing to
participate in activities using the affected
extremities. Popović and colleagues86
published a review of this topic.
Electrical stimulation of paralyzed
muscles, particularly after SCI, reduces
muscle atrophy and helps slow bone
mineral density decline.87 Cost of equip-
ment, frequency of application, and
practicality limit clinical and ongoing
application.
Mental practice. Mental practice with
motor imagery is commonly used in
athletic skill training. Studies of patients
with stroke suggest that mental prac-
tice may be useful as an adjunct to CIMT
or other repetitive therapies in improv-
ing motor skills.88,89 Cortical reorgan-
ization was also noted. Evidence from
TMS studies demonstrates that ‘‘mirror
neurons’’ found in the premotor and
parietal cortex are activated during mo-
tor imagery, action observation, and
imitation.90
Mental practice can be carried out
independent of therapy sessions and
may help to moderate physical demands
and allow patients to rehearse a skill
when therapy assistance is not available.
Constraint-induced language ther-
apy. Based on the principles of other
constraint-induced therapy programs,
constraint-induced language therapy
(CILT) uses a physical barrier between
participants who are given tasks that
require communication, thus forcing
verbal communication. Members of
the control group were allowed to use
any means of communication during
the task. Although the ability to com-
municate improved in both the control
and CILT groups, the CILT subjects
used more words, whereas the control
subjects used more gestures.91 Addi-
tionally, improvement correlated with
www.aan.com/continuum 539
 Emerging Therapies
KEY POINT
h Continued activity
and training after
formal therapy is likely
necessary to preserve
functional gains.
540 www.aan.com/continuum
Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
increased activation of the left hemi-
sphere, previously noted to accom-
pany better recovery from aphasia.92
CONCLUSION
The past decade has seen an incredible
leap in our understanding of how the
injured nervous system responds to
drugs, central and peripheral stimu-
lation, as well as other therapy ap-
proaches. In many situations, definitive
conclusions remain elusive owing to
heterogeneity in research design, sub-
jects, and timing. Clinical implementa-
tion lags because of lack of time, limited
funding and reimbursement, large
required effort, and limited communi-
cation among the various disciplines
involved in neurorehabilitation. Inten-
sive rehabilitation is physically and
mentally demanding for patients, many
of whom have other active medical
problems. It is tedious to work over
and over again on tasks that one once
took for granted.
The foundation supporting the con-
cept that repetitive practice produces
functional improvement and nervous
system reorganization can be used in
combination with emerging cellular and
pharmacologic approaches. Coordina-
tion between research scientists and
clinicians will improve study design as
well as include more subjects.
More widespread clinical implemen-
tation of approaches known to produce
superior outcomes needs to occur. The
future holds great promise for restor-
ative therapies.
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