Brain Repair after Stroke

Stroke is the second leading cause of death worldwide. A majority of patients survive
stroke, however, making this disorder a major source of human disability. Although most
patients have some spontaneous behavioral improvements after a stroke, the recovery is
generally incomplete. Compounding this burden of disability is the fact that one in four
patients who have a stroke is under 65 years of age.
An emerging approach to reducing the degree of disability after a stroke focuses on brain
repair. Repair therapies aim to restore the brain, a goal that differs from that of
neuroprotection therapies, in which the aim is to limit acute stroke injury. A number of
repair-related therapies have been defined in preclinical studies. Such therapies can
produce enduring behavioral gains when introduced days to months after the onset of
stroke. Several classes of therapy are under study for brain repair, including the use of
stem cells, growth factors, small molecules, electromagnetic stimulation, and intensive
physiotherapy.1 Many of these therapies, including robot-based physiotherapy,2 are
already in human trials.
It is in this context that Lo et al.3 describe a multicenter, randomized, controlled trial to
evaluate the effect of robotic therapy on motor status in people with long-term disability
after stroke. As reported in this issue of the Journal, the primary study hypothesis was
that robotic therapy, when compared with intensive comparison therapy or usual care,
would lead to greater improvements in upper-limb function at 12 weeks, as measured by
the change in score on the Fugl-Meyer scale. Patients were randomly assigned to one of
three types of treatment: robot-assisted therapy, which consisted of high-intensity,
repetitive movements of the proximal and distal arm; intensive comparison therapy,
which matched the robotic therapy in schedule, form, and intensity but did so with the
use of conventional rehabilitation techniques; or usual care, which may have included
various types of physical and occupational therapy. Subjects in the two intensive-therapy
groups received three sessions (each approximately 1 hour in duration) per week over 12
weeks. Patients in the trial varied widely in the time since the onset of stroke (6 months to
24 years), had multiple coexisting illnesses (including mental health conditions and
previous strokes), and were receiving multiple medications.
The investigators' results did not support their study hypothesis. When robot-assisted
therapy was compared with either intensive comparison therapy or usual care, no
significant differences in the change in the Fugl-Meyer score were seen. There were no
safety concerns. In secondary analyses extending to 24 weeks after treatment, robotbased therapy was better than usual care but was not better than intensive comparison
therapy. However, since function had improved in patients in the two active treatment
groups, these findings reaffirm the idea that motor status can be improved in patients with
long-term disability after stroke.

Lo et al. successfully completed a difficult study and achieved a high rate of compliance,
a low dropout rate, an extended follow-up period, and careful matching of therapy details
across the two active treatment groups. But some basic facts of the chronic phase of
stroke can frustrate hypothesis testing in clinical trials. Behavioral gains in the activetreatment groups were smaller than anticipated in power calculations, possibly because
the average baseline motor deficits in patients were severe, and severe deficits are harder
to improve. Finding a treatment difference between groups also might have been
hampered by recruitment of highly motivated patients in all three study groups, since
patients who had had a stroke sometimes many years earlier had to agree to leave home
for 36 visits to a research laboratory.
Other features of the patients also may have influenced study outcomes. Patients had a
substantial number of coexisting illnesses in multiple domains. For example, depression
might have influenced results, given that 38% of patients were taking antidepressants. In
addition, 73% of all study enrollees were receiving some form of rehabilitation therapy at
baseline a very high rate for patients with long-term disability after stroke4 and this
proportion changed little throughout the study. The high rate of rehabilitation therapy
outside study protocol but concomitant with study interventions, as observed by Lo et al.,
is similar to previous experience in patients months or years after stroke5 and
complicates hypothesis testing. What else did subjects practice during the other 165 hours
per week? The experience of Lo et al. reminds us that many factors can have a substantial
effect on studies involving patients after stroke and prompts conservative power
calculations for future repair-based trials.
In the bigger picture, the potential for robotic therapy after stroke remains enormous.
Robotic devices can provide therapy in different functional modes, a point that was not
examined by Lo et al. Robots work in a consistent and precise manner and over long
periods without fatigue.6 They can modulate timing, content, and intensity of training in
reproducible ways, with a reduced need for human oversight.2 Robotic devices can also
measure the performance of patients during therapy. In addition, robot-based therapy can
interface with computers in brain-stimulation treatment or to provide simultaneous
cognitive training.
The findings of Lo et al. are of broad value to planning repair-based trials. Movement
training, at the heart of the current study, stands on its own as a means of improving
behavior in the stroke-injured brain, as shown by Wolf et al. in a phase 3 trial.7 But
movement training will also be of critical value as an adjunctive therapy to other
treatments that target brain repair, such as the use of growth factors or stimulants. Repairbased therapies drive maximum brain plasticity and achieve best behavioral gains when
they are shaped by training and experience.8 Thus, the findings in the active treatment
groups in the study by Lo et al. will be instructive in future trials.
These results challenge us to better stratify patients with long-term disabilities after
stroke. Such patients are generally selected on the basis of behavioral status. Functional
neuroimaging studies have clearly shown that a single behavioral phenotype can arise on
the basis of many different brain states. Anatomical and physiological testing might assist

in the identification of patients whose brains have sufficient biologic substrate to improve
in response to therapy. Toward this end, recent studies suggest that measures of injury to
the central nervous system9 or of brain function10 can help predict a patient's capacity
for treatment gains after stroke. Many different neurobiologic states can produce a
particular impairment, but only some of these states are likely to yield improved behavior
in response to a repair-based therapy.
Studies such as that by Lo et al. reinforce the theory that the adult brain has the capacity
for clinically relevant plasticity even in the chronic phase after a stroke. The future holds
great hope for the development of brain-repair protocols to greatly reduce the degree of
disability after stroke.
Disclosure forms provided by the author are available with the full text of this article at
NEJM.org.
This article (10.1056/NEJMe1003399) was published on April 16, 2010, at NEJM.org.

Source Information
From the Departments of Neurology and Anatomy and Neurobiology, University of
California, Irvine.

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