Behavioral, Temporal, and Spatial Targets for Cellular Transplants as Adjuncts to

Rehabilitation for Stroke

Bruce H. Dobkin

Stroke. 2007;38:832-839
doi: 10.1161/01.STR.0000248408.49398.9c
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2007 American Heart Association, Inc. All rights reserved.
Print ISSN: 0039-2499. Online ISSN: 1524-4628

The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://stroke.ahajournals.org/content/38/2/832

Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Stroke can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office.
Once the online version of the published article for which permission is being requested is located, click
Request Permissions in the middle column of the Web page under Services. Further information about this
process is available in the Permissions and Rights Question and Answer document.

Reprints: Information about reprints can be found online at:

http://www.lww.com/reprints

Subscriptions: Information about subscribing to Stroke is online at:

http://stroke.ahajournals.org//subscriptions/

Downloaded from http://stroke.ahajournals.org/ by guest on February 23, 2013

 Behavioral, Temporal, and Spatial Targets for Cellular
Transplants as Adjuncts to Rehabilitation for Stroke
Bruce H. Dobkin, MD

Abstract—Stem cell and more differentiated neural cell transplantation strategies are an intriguing approach for neural
repair to augment rehabilitation interventions after stroke. In the cortex, exogenous cells could create, augment, or
extend in time endogenous peri-infarct and remote molecular signals, such as those for neurogenesis, cell differentiation,
axonal and dendritic sprouting, network connectivity, and long-term potentiation, as well as deliver engineered genes
and provide replacement cells in a network. If demyelinated axons exist in the periphery of an infarct, they could be
targets for remyelination to reestablish conductivity. Much is unknown, however, about the mechanisms by which
pluripotent embryonic and multipotent neural stem cells serve as agents of therapeutic plasticity. The robustness of their
effects on neuromodulation, reorganization, regeneration, and behavioral recovery is a work in progress. Invasive
interventions may have adverse effects not appreciated in preclinical testing. These should initially be offered only to
patients with specific profound impairments after it is clinically certain that major disabilities will not improve. If a
cellular strategy is very safe, it may be offered to subjects with moderate impairments when they are no longer likely
to make further functional gains. Clinical trial designs are suggested that take into account the optimal timing after stroke
and specific targets for cellular therapies to foster repair, remapping, and modulation of neural circuits. Cell-mediated
rehabilitation would then use task-specific therapies in an optimal dose to maximize training-induced reorganization and
learning and, most important, reduce unwanted disability. (Stroke. 2007;38[part 2]:832-839.)
Key Words: brain recovery 䡲 cell transplantation 䡲 clinical trials 䡲 ethics 䡲 functional recovery 䡲 neural stem cells
䡲 neuroregeneration 䡲 outcomes 䡲 rehabilitation 䡲 stroke recovery 䡲 transcranial magnetic stimulation 䡲 trophic factors

R ehabilitation is concerned with addressing impairments

such as leg weakness, daily activities such as independence
in walking and self-care, and participation in usual roles such as
bined with in situ microstimulation studies in animals, have
revealed how activity-dependent plasticity induces greater syn-
aptic efficacy.5,6 These adaptations evolve over the course of
walking quickly and safely enough to enable socialization in the skills learning within, eg, sensorimotor representational maps for
home and community.1 Measures of impairment, activities of voluntary movements, as well as in other components of the
daily living, and participation in home and community life must networks that contribute to skills.7
be incorporated into the design of assessments, targets for Cellular therapies, then, and perhaps other types of bio-
therapy, and outcomes for trials that inject or implant embryonic, logic and pharmacological interventions, could serve as
hematopoietic, and adult stem cells and more differentiated adjuncts to the neurorehabilitation program of highly im-
neural precursors into patients disabled by stroke.2 paired subjects. Therapeutic cells may be capable of enhanc-
Cell-mediated strategies seek to partially restore the neural ing fundamental mechanisms for learning within circuits that
controls for complex cognitive, sensory, or motor functions. they reconstruct or modulate, as well as by inducing, deliv-
The acquisition of skills ordinarily evolves through progres- ering, or extending in time peri-infarct and more distant
sive practice that draws on declarative and procedural mecha- molecular signals for neurogenesis, cell differentiation, ax-
nisms of learning and memory. The fundamental neurobiology onal and dendritic sprouting, network connectivity, and long-
of learning underlies the essential components of strategies for term potentiation. These gene-induced, biochemical, physio-
neurorehabilitation as well.3 Indeed, animal models of normal logical, and morphological modulations may be especially
learning and for recovery of function after stroke reveal that important for optimizing the function of spared pathways.
repetitive practice, exercise, or an enriched environment can Each cellular strategy must be proven in preclinical models
evoke endogenous neurogenesis and the expression of signaling and phase 1 and 2 clinical trials to be safe from inducing
molecules such as brain-derived neurotrophic factor and modu- hemorrhage, infection from a virus or other organism, inflam-
late other molecular pathways for experience-induced learning.4 mation, tumorigenesis, epilepsy, and aberrant plasticity that
Functional neuroimaging studies in patients after stroke, com- increases disability. The method of delivery of cells will also

Received May 22, 2006; final revision received September 21, 2006; accepted September 25, 2006.
From the Reed Neurologic Research Center, Geffen School of Medicine, University of California–Los Angeles, Los Angeles, Calif.
Correspondence to Bruce H. Dobkin, MD, Reed Neurologic Research Center, Geffen School of Medicine, University of California–Los Angeles, 710
Westwood Plaza, Los Angeles, CA 90095. E-mail [email protected]
© 2007 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org DOI: 10.1161/01.STR.0000248408.49398.9c

832
Downloaded from http://stroke.ahajournals.org/ by guest on February 23, 2013
 Dobkin Cell Transplants as Adjunctive Stroke Treatment 833

impact safety issues. Intravenous, intrathecal, intraventricu- scales, however, do not measure the degree of weakness or
lar, and direct injection into brain parenchyma near a cystic sensory loss of the affected extremities or require their use.
cavity are all viable,8,9 each with possible side effects. The The initial degree of impairment, according to the National
effectiveness of the route may be limited by the receptivity of Institutes of Health Stroke Scale (NIHSS), may be a useful
the cerebral milieu over the time after stroke as to how well marker for predicting very high and very low levels of
cells penetrate, migrate, survive, differentiate, and integrate subsequent function. An NIHSS at 1 week after stroke of ⬍10
to make connections or produce modulating substances in an predicts a 20% chance of an excellent outcome (BI ⱖ95),
optimal distribution. If safe, interventions for profoundly whereas a score ⬎17 to 19 is a predictor of poor outcomes
impaired subjects may also be applied to patients with fixed, with a BI ⬍65 and Glasgow Outcome Score ⱖ3 or death.16,17
moderate impairments to enhance defined functions, such as An Orpington Prognostic score ⬎5 is also associated with
greater use of a paretic hand. Unfortunately, a tendency to poor functional outcomes. The combination of severe senso-
overly interpret the robustness of the results of cellular rimotor impairment and hemianopia predicts that only ap-
strategies in animal models has led to questionably ethical proximately one third of patients will walk without physical
practices by some clinicians who are already injecting cells help by 6 months.18 Thus, by 2 weeks after stroke, clinicians
into patients without following the standards of a clinical can anticipate which patients are least likely to recover the
trial. Investigators in poststroke studies must shun the unsci- ability to care for themselves.
entific designs used, eg, in patients with spinal cord injury Kwakkel and colleagues19 and Kollen et al20 examined in
and amyotrophic lateral sclerosis in China10 and other coun- greater detail at trying to predict when gains may slow in their
tries, as well as false starts such those that occurred in early longitudinal study of 100 patients who had a first stroke in the
treatments of Parkinson’s disease with implants of adrenal middle cerebral artery distribution. Subjects were tested weekly
cells. on 18 variables from weeks 1 to 10 after onset, biweekly from
weeks 10 to 20, and at weeks 26, 38, and 52. The subjects had
Temporal and Behavioral Targets participated in a randomized trial for intensity of treatment of an
The timing for a biologic intervention for the neural repair of arm or leg intervention.21 The investigators used random coef-
specific deficits ought to take into account both the state of the ficient modeling of change scores to examine the impact of
injury milieu and clinical criteria. The timing of transplantation improvements on walking, upper extremity dexterity, and func-
of stem cells or neural precursors for repair, rather than for tional independence. At 6 months, some dexterity in the paretic
neuroprotection, after stroke will depend on the readiness of the arm was found in 38%, and complete functional recovery was
peri-infarct milieu11 into which cells are exposed, including the seen in 12% of the patients. Infarcts of two thirds of the
effects of inflammation, reactive astrocytes, macrophages, local hemisphere, a right hemisphere stroke, a homonymous hemi-
gene expression and signaling, architectural barriers to migra- anopia, visual gaze deficit and visual inattention, and the severity
tion, and others. For example, during the first 2 to 3 weeks and of paresis were significantly associated with poor arm func-
probably longer after an experimental stroke, the peri-infarct tion.19 In other observational studies, these factors had also
cortex expresses a rise or fall in a range of neuronal growth- tended to predict poorer outcomes for ADL.2 Motricity Index
promoting and growth-inhibiting genes that affect the making of scores of leg movement and strength of at least 25 points in the
cytoskeletal proteins, direct axon growth cones, and produce first week and Fugl-Meyer arm scores of 11 points in the second
angiogenesis and other molecular signals for the proliferation week that increased to 19 points in the fourth week raised the
and migration of endogenous stem cells from the subventricular probability of developing some dexterity of the hand from 74%
zone.12,13 Exogenous stem cell interventions, including bone to 94% at 6 months, based on the Action Research Arm Test
marrow stromal cells, may be most useful within this time frame (dexterity was captured by a score ⱖ10 points). The investiga-
to extend and sculpt these mechanisms for axonal regeneration, tors found no significant change in the probabilities for regaining
cellular signaling, and synaptogenesis.14 hand dexterity based on measures taken after 4 weeks. Lack of
Timing must also account for the point at which clinicians voluntary motor control of the leg in the first week with no
can state with some confidence that further measurable emergence of synergistic flexor or extensor arm movements by
recovery of an impairment is unlikely. An entry requirement 4 weeks was also associated with poor outcome at 6 months for
for initial clinical trials may be that subjects have no ability to the upper extremity. This finding suggests profound loss of the
grasp or pinch objects and perform no more than a few descending corticospinal and corticoreticulospinal projections.
degrees of voluntary flexion and extension at the elbow, Compatible with other studies, the absence of wrist and finger
wrist, and fingers. How soon after stroke can clinicians extension or a persistently flaccid arm at 2 to 4 weeks after
predict that the rate of gains has reached a plateau? The stroke stroke predicts no functional use of the arm and hand at 6
outcomes literature suggests that the rate of increase in months.15 If some finger flexion and extension are present within
functional improvement in the majority of survivors peaks by 4 weeks of stroke onset, however, progress may continue toward
12 weeks for activities of daily living (ADL) with some gains the ability to grasp and release items held in the palm, possibly
that continue out to 24 weeks.15 On admission for inpatient followed by development of a key pinch, 3-finger pinch, and
rehabilitation at ⬇2 weeks after a stroke, poor function by the finer individuation of finger and wrist movements. Initial cellu-
Barthel Index (BI ⬍45/100) and Functional Independence lar implant studies that focus on restoration of a functional hand
Measure motor score (⬍27/90) each anticipate dependence in will, therefore, want to include patients who have minimal or no
ADL at discharge.2 Week-to-week improvements stop sooner wrist and finger extension that persists at least 2 and preferably
for patients with the most severe impairments. These ADL 4 weeks after the stroke.
Downloaded from http://stroke.ahajournals.org/ by guest on February 23, 2013
834 Stroke February 2007 Part II

Time-dependent covariates for gains in the level of inde- Stroke Rehabilitation Practices for Sensorimotor-Related
pendence for walking (by the functional ambulation index, or Impairments and Disabilities to Drive the Functional Effects of
FAC, with its 6 categories) were more difficult to determine Cellular Transplants
in the studies by Kwakkel and colleagues. They found that Evidence-Based Practices Evidence-Evolving Practices
postural control for standing balance (by the Timed Balance
● Bobath and neurodevelopmental ● Increase cortical excitation
Test) was most important, followed by a higher change score therapy approaches by transcranial magnetic,
on the Fugl-Meyer Motor Assessment for selective move- direct motor cortex, or
ments, fewer omissions on a letter cancellation task, and ● Correct qualitative deviations in peripheral nerve
greater strength (measured by the Motricity Index).20 The kinematics, kinetics, and stimulation
temporospatial components of
explained variance, however, was only 18%, and the regres- ● Repetitive practice with
functional movements, such as
sion coefficients were rather low. Thus, recovery of walking feedback in a virtual
sitting balance, reach, grasp,
is more difficult to predict than recovery of hand dexterity, reality environs
pinch, or walk
probably because less readily measurable behavioral adapta- ● Shaping: practice with feedback ● Simultaneous bimanual
tions may enable walking despite marked loss of selective leg to gradually incorporate simple, practice of similar
movements. Some general rules for inclusion of patients for then more complex, multijoint movements
cellular implant trials to aid the recovery of walking can be components of task-specific
movements ● Combinational
offered, however. Subjects should not have hip flexor or knee interventions: eg,
extensor strength against gravity or resistance, if the inter- ● Task-oriented massed practice: robotics-assisted treadmill
vention is being offered within the first 2 to 3 months after treadmill training of gait with training of walking in a
partial body weight support;
onset. If a cell strategy is attempted for subjects who are able virtual environment
constrain unaffected arm to
to walk, walking speed should probably be ⬍0.3 m/s for a encourage use of affected one;
15-m walk and associated primarily with poor motor con- robotics-assistive arm and leg ● Pharmacotherapy: replace
trol,22 not due to comorbid conditions such as joint pain and devices depleted neurotransmitters
deconditioning. Finer assessment of outcomes beyond and modulators, enhance
● Electromyographic or joint angle
strength, speed, and endurance for trials of repair can include neuronal excitability or
biofeedback to increase joint
long-term potentiation to
temporal and spatial measures of the pattern of gait, such as motion or induce electrical
enhance learning
the equality of single-limb support times for the legs and the stimulation of a muscle
stride length, which may better reflect fine neural changes in ● Functional electrical stimulation ● Spinal cord electrical
motor control.23 of single or sequential muscles stimulation to drive
Stroke may, of course, induce more than motor impairments. for grasp or foot clearance flexor-extensor
● Increase strength (resistance movements, such as
Aphasia occurs in up to 30% of patients after stroke, but only
exercises), endurance (treadmill stepping
about half of these patients still have impaired language 1 month
walking or recumbent pedaling), ● Biologic neural repair
later. Global aphasia for ⱖ1 month has a poor prognosis for
speed (feedback about time to strategies
functional communication, but language gains in specifically perform task), and accuracy
trained aspects of aphasia can occur in patients even with (visual feedback)
chronic stroke.24,25 The temporal window for reaching a plateau
in patients with mild to moderate impairments, then, is wide.
The types of linguistic impairment must be well defined before Table). Indeed, the optimal intensity and duration of therapy to
trying to intervene to attain measurable changes in outcome. maximize gains are almost never determined even within clini-
Hemispatial neglect often improves by 4 months after stroke in cal trials.28 Most studies of augmented practice have offered
all but the most impaired hemiplegic subjects, who initially have ⬇16 hours of additional treatment for a specified problem in
anosognosia.2 Aspects of spatial inattention may persist, how- patients with mild to moderate impairments or disabilities, and
ever, so measures of change must be comprehensive.26 As many most of these trials have revealed less than a 10% improvement
as 50% of patients with a homonymous hemianopia have with that modest increment in treatment time.29 Thus, the
improved within the first month after onset, and up to 20% may maximal level of recovery over time for a specific impairment or
improve for 3 to 6 months.27 Gains are due to compensation, disability with conventional rehabilitation techniques in patients
early restitution of conduction along the involved optic radia- with severe stroke, the type most likely to be considered for
tions, and perhaps neural plasticity. The timing for a cellular invasive cellular implantation, cannot be calculated with
intervention for a specific impairment, then, ought to be as soon certainty.
as a high threshold for further clinically meaningful gains has A brief pulse of a task-oriented therapy (the Table) can lead
been reached. to rapid changes in function in subacute and chronically
Several potential confounders make temporal and behavioral disabled patients who retain some motor control. Much of the
data about recovery after stroke somewhat unreliable. The gain found for patients with chronic hemiparesis who have at
rehabilitation experience of patients in most observational stud- least 20 degrees of residual voluntary wrist and finger
ies was usually left open ended. Evidence-based therapy ap- extension, for example, has occurred within the first few days
proaches and strategies best suited for an individual’s impair- of a 2-week course of therapy that constrained the use of the
ments and disabilities may not have been used.1,15 For example, unaffected hand and pushed 6 hours of daily therapy with the
task-specific practice to improve reaching and pinching or for affected one.15 Improvements that are elicited by brief train-
walking may have led to better gains had it been tried (the ing, from 6 to 18 hours of focused therapy, could confound
Downloaded from http://stroke.ahajournals.org/ by guest on February 23, 2013
 Dobkin Cell Transplants as Adjunctive Stroke Treatment 835

efforts to interpret the effects of an implant. To lessen the extremity and for walking monitored by repeated fMRI or
impact of early rapid improvement related to rehabilitation, a transcranial magnetic stimulation at regular intervals during
phase-in of therapy for the targeted behavioral outcomes, therapy suggest that this approach may give insight into gradu-
before a cellular implant, should be part of experimental ally adapting brain-behavior and dose-response relation-
protocols. Another concern in trials for cell-mediated repair is ships.28,34,35–37 Although a strategy of serial clinical and neuro-
that the clinical science of cellular transplants may benefit imaging probes to ascertain whether therapies produce ongoing
from success in restoration of hand movement, even if this cerebral reorganization may oversimplify the neurobiologic
provides no gain in function, but patients would not benefit. processes involved in neural connectivity and synaptic efficacy,
Improvement in voluntary wrist extension of the hemiplegic it aims to find a clinical means to address whether the subject has
arm without the ability to grasp and release for holding and any spared and responsive capacity before transplantation and
manipulating objects will have little impact on the daily whether the cells may be involved in augmenting recovery of
activities of the patient with stroke, because the subject will function after transplantation. For example, a trial of implanta-
have to continue to use the unaffected hand for all gross and tion of a human teratoma (NT-2) cell line of neurons into the
dexterous actions. An intervention that carries risk, such as region of the basal ganglia in patients with deep infarcts found
invasive cell implantation, must aim to enable better function. metabolic activity for labeled glucose at the graft site in some of
the subjects, which may reflect functioning cells or local inflam-
Spatial Targets mation.38 Metabolic activity that increased transsynaptically
Anatomic and functional neuroimaging may help determine beyond the implant would be a more convincing demonstration
the site for an implant, the intactness of residual pathways, of functional inclusion of the graft.
and the physiological incorporation and actions of the new
cells. Insights into the physiological effects of cellular trans- Targets in Gray Matter
plants may be revealed in vivo by functional magnetic Specific anatomic sites for transplanted cells will depend, of
resonance imaging (fMRI) during a passive or voluntary course, on the functional properties of the cells and their
movement, by positron emission tomography (PET) with a ability to migrate and survive to contribute to the actions of
glucose or oxygen radionucleotide during rest or with an the residual network. The tissue immediately surrounding an
activation paradigm, and by PET with a marker for a specific infarction, which includes the ischemic penumbra, has been
ligand or neurotransmitter function, such as [18F]fluorodopa characterized by the expression of cytotoxic and cytoprotec-
and [11C]raclopride for dopamine activity. These techniques tive molecules that may trigger repair processes and serve as
have revealed patterns of cerebral reorganization after stroke a milieu that supports learning by exciting long-term poten-
and during task-oriented rehabilitation suggesting that best tiation.39,40 These processes could be amplified or sustained
clinical recovery occurs when the primary regions that beyond their usual temporal course with intravenous injection
represent a motor or language task are activated.30 Indeed, the of exogenous cells that produce a neurotrophic factor.41
anatomic volume of a cortical infarct may not predict recov- Cellular gene delivery to the intact cortex could amplify the
ery of the hand as well as the percentage of functionally intact production of neurotrophins, neurotransmitters, and other
tissue in M1, as determined by fMRI.31 Most of the imaging modulators involved in learning,42 as well as genes to drive
studies, however, were performed on patients who evolved axonal regeneration and augment corticocortical dendritic
good motor recovery, so past patterns of activation may not and axonal sprouting.43,44 These new connections, however,
be relevant to studies of highly impaired subjects.32 Still, the may not contribute to clinically useful sensorimotor activity
observation in animal models and in human studies that without rehabilitative training. New sprouts may also create
peri-infarct tissue plays a critical role in clinical recovery aberrant connections that either have no effect or even lessen
makes this area, defined by anatomic and functional imaging, function in the newly modulated circuit and the patient. For
a region of interest for implantation.33 example, the new axons that arose after a microinfarction of
Functional neuroimaging could be a tool to explore other the primary motor cortex forelimb region of a monkey
locations for a cell implant, to determine whether the motor revealed the capacity for a regenerative axonal response from
network is engaged by task-specific rehabilitation, and to mon- the ventral premotor region into the primary sensory cortex,
itor the dose of therapy needed to maximize cerebral reorgani- but it is not clear how this input would affect recovery,
zation after cell therapy.28,34 For example, if ipsilesional M1 or because it is a unique pathway.43
secondary motor areas were active during an fMRI task, the In the gray matter, cells could serve as a synaptic bridge that
subject may be a better candidate for restoration of functional reunites dendrites within a disrupted intracortical pathway, a site
movements than the patient who exhibited no residual function that especially lends itself to monitoring by functional neuroim-
in critical pathways. In a related strategy, if the fMRI activation aging techniques. Given the complexities of the signaling cas-
pattern evolved in response to a brief trial of therapy, the cades that lead to functional circuits during development, how-
investigators would have evidence to suspect that the sensori- ever, an attempt to recreate a circuit seems more formidable than
motor network was accessible and intact enough to be a reservoir to use repair techniques to increase the efficacy of a surviving
for motor learning.35 The network, then, might be responsive to circuit. For example, some experiments reveal that adult hip-
cell implantation at a critical site as an adjunct to task-specific pocampal neural stem cells can integrate into neuronal networks
rehabilitation to help drive partial anatomic or physiological and make functional synapses.45 Most studies of adult bone
reconstruction of the network and enhance motor skill learning. marrow– derived stem cells reveal morphological and marker
Several small studies of rehabilitation interventions for the upper genes of neurons but not clearly functional neurons.46 Neuro-
Downloaded from http://stroke.ahajournals.org/ by guest on February 23, 2013
836 Stroke February 2007 Part II

nally restricted precursors, however, may be more likely to through white matter to their targets. Axon extension beyond
survive to make synaptic connections, at least in rodent the lesion site has been accomplished in select experimental
models.47 conditions in animal models, however.63,64
An increase in the descending motor command by a modest
amount, even oligosynaptically via reticulospinal pathways to Rehabilitation Designs for
propriospinal projections and then to spinal motoneurons,48 Cell-Mediated Trials
could have a large functional benefit. In another potential To successfully sow rewards from seeding the brain, specific
approach, stem cells that reach into homologous M1 of the neurorehabilitation strategies will be needed to propagate the
unaffected hemisphere may theoretically enhance or sustain functional effects of implants (the Table). Given what is
endogenous growth programs triggered by the stroke.49,50 The known about the temporal course of endogenous peri-infarct
corticospinal tract has projections that either remain uncrossed or gene expression in animal models and the course for recovery
recross under the central canal of the spinal cord51,52 and may of hand function, the earliest time point for an intervention
sprout within the cord after injury.53 Cell modulation of unaf- aimed at recovery of functional use of the hand, as noted, will
fected M1 could, then, augment the local increase in dendritic be 2 to 4 weeks after hemiplegic stroke. Investigators who
spines that have been reported in animal models49 and augment test cell-mediated interventions for other behavioral targets
input into subcortical and spinal targets. and at later times may want to take the following approach
until more is understood about when and how each biologic
Targets in White Matter intervention may best be deployed to enhance recovery.
White matter lesions that cause paralysis may be confined to the Once subjects are entered into a trial for neural repair, they
centrum semiovale, internal capsule, or pons or extend from the could be given 6 therapy sessions over 2 weeks with 12 hours
periphery of a cortical infarction or intracerebral hemorrhage. of therapist contact for progressive task-oriented treatment
White matter lesions may disrupt association, commissural, aimed at the impairments and functional outcomes designated
fascicular, and other projection fibers. Pathological studies of for the trial (the Table). Where evidence-based practices
cavitated infarcts usually describe severed axons and wallerian exist, these rehabilitation interventions can be incorporated
degeneration. If demyelination exists among spared axons, a into the therapy regimen.15 Therapies with a strong concep-
remyelination strategy with stem cells or oligodendrocyte pre- tual basis that are applicable to the behavioral and network
cursors to rescue axons becomes of interest.54 In addition to targets for the cellular intervention should also be incorpo-
the goal of restoration of a small percentage of nonconducting rated into the rehabilitation component of the trial (the
motor and sensory projections, cortical language areas dis- Table).65 The subjects would then be reassessed on the
connected within the superior arcuate fasciculus and visual study’s motor and functional scales, if better use of the arm or
field impairments from lesions in the optic radiations could walking were the goal. These scores become the new base-
be improved modestly by remyelination that restores the line. If change exceeds a predefined level on any of the
transmission of action potentials, perhaps enough for patients primary outcome assessments, eg, ⱖ10% better, the rehabil-
to respond to rehabilitation training. Remyelination strategies itation intervention should continue for 6 additional sessions.
for spinal cord injury have been proposed on the basis of If no further change occurs and the subject still meets the
autopsy findings of intact axons in the surrounds of cystic entry criteria for impairment and disability, the transplant (or
lesions.55 In animal models, short segments of axons appear placebo) proceeds and progressive practice is continued for at
to have been remyelinated by stem cells, olfactory ensheath- least 3 contact hours per week for 24 weeks, along with a
ing glia,56,57 and endogenous and exogenous oligodendrocyte daily home program. This approach minimizes the experi-
progenitors.58 No reports, however, have described intact mental “noise” of gains that are unlikely to be related to the
axons that have been stripped of myelin for short segments cellular intervention. A stable behavioral baseline may also
around a stroke in autopsy tissue. It will be important for decrease the number of subjects needed to power a random-
pathology studies to determine whether axon markers in the ized clinical trial. Most important, this strategy aims to
absence of myelin markers near a cavitation can be found maximize the potential benefits of cell-based therapy as an
after stroke in patients. Recent MR sequences such as adjunct to rehabilitation for stroke.
diffusion tensor imaging,59 perhaps combined with magnetic
resonance spectroscopy,60 may also become useful for deter- Deployment of Cellular Strategies in Patients
mining whether remyelination of spared axons is a potential Preclinical studies that reveal positive results for an experi-
target and whether the cellular strategy is successful.61 mental intervention for neuroprotection or neural repair have
Cellular transplants could modulate the sprouting of spared an enormous impact on the expectations of clinicians, dis-
axons and the regeneration of disrupted axons by providing abled patients, and the media. Animal experiments after
neurotrophins or acting on axon growth cone inhibitors, such stroke have led to several reasonably well-designed safety
as Nogo-A.62 Cells with or without gene modifications for trials in patients, in that the cell types were characterized, an
producing trophic or tropic substances could be placed into estimate of the optimal volume of cells and their survival
the perilesional or distal milieu to augment axon growth were determined, cell placement procedures were standard-
through white matter. The complexity of long distance (ⱖ1 ized, the patient population was defined, valid measures of
cm) axonal regeneration is formidable, however. The archi- behavior were obtained, a prospective search for adverse
tectural barriers and the balance of progrowth and inhibitory effects was made, and standard statistical analyses were
molecules in the milieu must be managed to guide axons presented. The safety trials included intravenous injection of
Downloaded from http://stroke.ahajournals.org/ by guest on February 23, 2013
 Dobkin Cell Transplants as Adjunctive Stroke Treatment 837

autologous mesenchymal stem cells ⬇40 days after a hemi- Preclinical experiments that best inform the design of
spheric stroke66 and implantation of human neuronal cells human trials ideally include a lesion of etiology, volume, and
derived from a teratocarcinoma cell line (NT-2 cells; LBS- location that parallels 1 of the varieties of stroke in patients;
Neurons, Layton Bioscience, Inc) into the edge of chronic examine changes induced by injury and by repair procedures
deep infarcts near the basal ganglia.38 Any positive note of both near and remote from the lesion; distinguish between
efficacy was imputed from secondary analyses of the small reactive molecular and histological changes versus changes
sample sizes. Safety studies in spinal cord injury have critical to repair cascades; include explicit training paradigms
proceeded with injection of human fetal spinal cord tissue for the reacquisition of testable skills; correlate morphologi-
into a syrinx,67 autologous activated macrophage injections cal and physiological measures of repair with behavioral
into the acute injury (Proneuron Biotechnologies, Israel), and measures of task reacquisition; and reproduce key results in
porcine oligodendrocyte progenitors (www.diacrin.com) and ⬎1 laboratory, in different strains or species of rodent, and in
autologous olfactory ensheathing glia into chronic injuries a larger mammal such as a nonhuman primate.72
without any efficacy noted.68 A biased interpretation of the The capacity of stem cells to adapt their fate and function
animal preclinical literature has also led to commercial to a changing pathological environment after ischemia and
infusions of cells, presumably of hematopoietic or neural anatomic disconnection is the basis for transplantation and for
origin, that are marketed for whatever neurological disease manipulating proliferating endogenous cells to achieve ther-
and deficit the recipient wishes to mollify (eg, see http:// apeutic plasticity.73 So far, the quest for human interventions
stemedica.com, www.stemcellschina.com). No knowledge of has been built primarily on conjecture and modest demon-
course can be gained from this misuse of a new technology. strations of cell activities and altered sensorimotor behaviors
Do the cells survive, act in some way on neural tissue, or in rodents, rather than on a clear definition of cell capabilities
lessen specified and carefully assessed impairments and and physiological and morphological objectives for repair by
disabilities? Disabled patients are ready, but are cellular a specific cell line. More preclinical work is indicated.
strategies ready for clinical efficacy trials? Guidelines for safety and efficacy in preclinical and clinical
Adult autologous neural stem cells, endogenous cells from trials67,74 may help investigators learn as much as possible, in
the subventricular zone, hematopoietic and umbilical stem the inevitable absence of full understanding, about their
cells, embryonic stem cells, and lines developed from these experimental intervention. In promoting clinical trials, inves-
types hold promise, but their characteristics and specific tigators must protect highly disabled persons from lightly
actions, the specific goals for deployment, and their effects on interpreted preclinical results, as well as from physical and
behavior in animal models need ongoing development. The emotional harm. Patients weigh uncertain risks and benefits
scientific investigations behind manipulating cells to carry against the hope for extraordinary new therapies that easily
out recognizable functions that significantly augment behav- capture the imagination.
ioral recovery are hopeful, but they have not yet created a
“road map” toward safely helping patients. The modulation of Disclosures
None.
neuroprotection, neural reorganization, and regeneration is
reasonably apparent in published experiments in animal References
models; eg, when intraparenchymal and intravenous trans- 1. Dobkin B. Strategies for stroke rehabilitation. Lancet Neurol. 2004;3:
plants survive and migrate in modest numbers, stimulate or 528 –536.
produce growth factors, alter proteins in the microenviron- 2. Dobkin B. The Clinical Science of Neurologic Rehabilitation. New York:
Oxford University Press; 2003.
ment, make regenerative substances, or possibly integrate 3. Ziemann U, Meintzschel F, Korchounov A, Ilic T. Pharmacological
with other neurons or with demyelinated axons. Behavioral modulation of plasticity in the human motor cortex. Neurorehabil Neural
gains, however, appear modest in animal models of stroke. Repair. 2006;20:243–251.
Even when care has been taken to try to define the effects of 4. Vaynman S, Gomez-Pinilla F. License to run: exercise impacts functional
plasticity in the intact and injured CNS by using neurotrophins. Neuro-
cellular manipulations on a behavioral scale to assess out- rehabil Neural Repair. 2005;19:283–295.
comes, the gains seem less than robust.13,69 Often, the relation 5. Kleim JA, Barbay S, Cooper NR, Hogg TM, Reidel CN, Remple MS,
between an increase in behavioral function on a simple scale Nudo RJ. Motor learning– dependent synaptogenesis is localized to func-
tionally reorganized motor cortex. Neurobiol Learn Mem. 2002;77:63–77.
and the presumed biologic effects of the cell transplantation 6. Ramanathan D, Conner J, Tuszynski M. A form of motor cortical plas-
compared with placebo lacks a demonstrated neurophysio- ticity that correlates with recovery of function after brain injury. Proc
logical or morphological correlation. In the modeling and Natl Acad Sci U S A. 2006;103:11370 –11375.
treatment of any neurological disease, making brain-behavior 7. Paz R, Natan C, Boraud T, Bergman H, Vaadia E. Emerging patterns of
neuronal responses in supplementary and primary motor areas during
correlations owing to injury or gains is challenging. Thera- sensorimotor adaptation. J Neurosci. 2005;25:10941–10951.
peutic trials in neurorehabilitation that have been built on a 8. Jin K, Sun Y, Xie L, Mao XO, Childs J, Peel A, Logvinova A, Banwait
strong basic science foundation and animal modeling often S, Greenberg DA. Comparison of ischemia-directed migration of neural
precursor cells after intrastriatal, intraventricular, or intravenous trans-
prove no better than what is already available,70,71 in part plantation in the rat. Neurobiol Dis. 2005;18:366 –374.
because of the many biologic and behavioral differences 9. Ikeda R, Kurokawa MS, Chiba S, Yoshikawa H, Ide M, Tadokoro M,
between humans and rodents in health and disease. Indeed, Nito S, Nakatsuji N, Kondoh Y, Nagata K, Hashimoto T, Suzuki N.
Transplantation of neural cells derived from retinoic acid-treated cyno-
the animal models of injury and repair for stroke and spinal
molgus monkey embryonic stem cells successfully improved motor
cord injury have inherent limitations for their applicability to function of hemiplegic mice with experimental brain injury. Neurobiol
human interventions.72 Dis. 2005;20:38 – 48.

Downloaded from http://stroke.ahajournals.org/ by guest on February 23, 2013

838 Stroke February 2007 Part II

10. Dobkin BH, Curt A, Guest J. Cellular transplants in China: observational 33. Butefisch C, Kleiser R, Seitz R. Post-lesional cerebral reorganisation:
study from the largest human experiment in chronic spinal cord injury. evidence from functional neuroimaging and transcranial magnetic stim-
Neurorehabil Neural Repair. 2006;20:5–13. ulation. J Physiol Paris. 2006;99:437– 454.
11. Weller P, Wittsack H-J, Siebler M, Homberg V, Seitz R. Motor recovery 34. Dobkin B, Firestine A, West M, Saremi K, Woods R. Ankle dorsiflexion
as assessed with isometric finger movements and perfusion magnetic as an fMRI paradigm to assay motor control for walking during rehabil-
resonance imaging after acute ischemic stroke. Neurorehabil Neural itation. Neuroimage. 2004;23:370 –381.
Repair. 2006;20:390 –397. 35. Dong Y, Dobkin BH, Cen SY, Wu AD, Winstein CJ. Motor cortex
12. Carmichael S. Cellular and molecular mechanisms of neural repair after activation during treatment may predict therapeutic gains in paretic hand
stroke: making waves. Ann Neurol. 2006;59:735–742. function after stroke. Stroke. 2006;37:1552–1555.
13. Zhang RL, Zhang ZG, Chopp M. Neurogenesis in the adult ischemic 36. Koski L, Mernar T, Dobkin B. Immediate and long-term changes in
brain: generation, migration, survival, and restorative therapy. Neurosci- corticomotor output response to rehabilitation: correlation with functional
entist. 2005;11:408 – 416. improvements in chronic stroke. Neurorehabil Neural Repair. 2004;18:
14. Zhang C, Li Y, Chen J, Gao Q, Zacharek A, Kapke A, Chopp M. Bone 230 –249.
marrow stromal cells upregulate expression of bone morphogenetic 37. Ward N, Brown M, Thompson A, Frackowiak R. Longitudinal changes in
proteins 2 and 4, GAP junction protein connexin-43 and synaptophysin cerebral response to proprioceptive input in individual patients after
after stroke in rats. Neuroscience. 2006;141:687– 695. stroke: an fMRI study. Neurorehabil Neural Repair. 2006;20:398 – 405.
15. Dobkin B. Rehabilitation after stroke. N Engl J Med. 2005;352: 38. Kondziolka D, Steinberg G, Wechsler L, Meltzer CC, Elder E, Gebel J,
1677–1684. Decesare S, Jovin T, Zafonte R, Lebowitz J, Flickinger JC, Tong D,
16. Johnston K, Wagner D, Haley E, Connors AF Jr; RANTIAS Investi- Marks MP, Jamieson C, Luu D, Bell-Stephens T, Teraoka J. Neurotrans-
gators. Combined clinical and imaging information as an early stroke plantation for patients with subcortical motor stroke: a Phase 2 ran-
outcome measure. Stroke. 2002;33:466 – 472. domized trial. J Neurosurg. 2005;103:38 – 45.
17. Frankel MR, Morgenstern LB, Kwiatkowski T, Lu M, Tilley BC, 39. Hagemann G, Redecker C, Neumann-Haefelin T, Freund H-J, Witte O.
Broderick JP, Libman R, Levine SR, Brott T. Predicting prognosis after Increased long-term potentiation (LTP) in the surround of experimentally
stroke: a placebo group analysis from the National Institute of Neuro- induced focal cortical infarction. Ann Neurol. 1998;44:255–258.
logical Disorders and Stroke rt-PA stroke trial. Neurology. 2000;55: 40. Tsai P, Ohab J, Kertesz N, Groszer M, Matter C, Gao J, Liu X, Wu H,
952–959. Carmichael ST. A critical role of erythropoietin receptor in neurogenesis
18. Patel A, Duncan P, Lai S, Studenski S. The relation between impairments and post-stroke recovery. J Neurosci. 2006;26:1269 –1274.
and functional outcomes poststroke. Arch Phys Med Rehabil. 2000;81: 41. Nomura T, Honmou O, Harada K, Houkin K, Hamada H, Kocsis JD. IV
1357–1363. infusion of brain-derived neurotrophic factor gene-modified human mes-
19. Kwakkel G, Kollen BJ, van der Grond J, Prevo AJ. Probability of enchymal stem cells protects against injury in a cerebral ischemia model
regaining dexterity in the flaccid upper limb: impact of severity of paresis in adult rat. Neuroscience. 2005;136:161–169.
42. Conner JM, Chiba AA, Tuszynski MH. The basal forebrain cholinergic
and time since onset in acute stroke. Stroke. 2003;34:2181–2186.
system is essential for cortical plasticity and functional recovery fol-
20. Kollen B, van de Port I, Lindeman E, Twisk J, Kwakkel G. Predicting
lowing brain injury. Neuron. 2005;46:173–179.
improvement in gait after stroke: a longitudinal prospective study. Stroke.
43. Dancause N, Barbay S, Frost SB, Plautz EJ, Chen D, Zoubina EV, Stowe
2005;36:2682–2686.
AM, Nudo RJ. Extensive cortical rewiring after brain injury. J Neurosci.
21. Kwakkel G, Wagenaar R, Twisk J, Lankhorst G, Koetsier J. Intensity of
2005;25:10167–10179.
leg and arm training after primary middle cerebral artery stroke: a ran-
44. Carmichael S, Wei L, Rovainen C, Woolsey T. New patterns of intra-
domised trial. Lancet. 1999;354:191–196.
cortical projections after focal cortical stroke. Neurobiol Dis. 2001;8:
22. Dobkin BH. Short-distance walking speed and timed walking distance:
910 –922.
redundant measures for clinical trials? Neurology. 2006;66:584 –586.
45. Song H, Kempermann G, Wadiche LO, Zhao C, Schinder AF,
23. Saremi K, Marehbian J, Regnaux JP, Elashoff R, Bussel B, Dobkin BH.
Bischofberger J. New neurons in the adult mammalian brain: synapto-
Reliability and validity of bilateral thigh and foot accelerometry measures
genesis and functional integration. J Neurosci. 2005;25:10366 –10368.
of walking in healthy and hemiparetic subjects. Neurorehabil Neural
46. Lu P, Tuszynski MH. Can bone marrow-derived stem cells differentiate
Repair. 2006;20:297–305. into functional neurons? Exp Neurol. 2005;193:273–278.
24. Bhogal SK, Teasell R, Speechley M. Intensity of aphasia therapy, impact 47. Lepore AC, Neuhuber B, Connors TM, Han SS, Liu Y, Daniels MP, Rao
on recovery. Stroke. 2003;34:987–993. MS, Fischer I. Long-term fate of neural precursor cells following trans-
25. Pulvermuller F, Hauk O, Zohsel K, Neininger B, Mohr B. Therapy- plantation into developing and adult CNS. Neuroscience. 2006;139:
related reorganization of language in both hemispheres of patients with 513–530.
chronic aphasia. Neuroimage. 2005;28:481– 489. 48. Mazevet D, Meunier S, Pradat-Diehl P, Marchand-Pauvert V, Pierrot-
26. Corbetta M, Kincade MJ, Lewis C, Snyder AZ, Sapir A. Neural basis and Deseilligny E. Changes in propriospinally mediated excitation of upper
recovery of spatial attention deficits in spatial neglect. Nat Neurosci. limb motoneurons in stroke patients. Brain. 2003;126:988 –1000.
2005;8:1603–1610. 49. Bury S, Jones T. Unilateral sensorimotor cortex lesions in adult rats
27. Zhang X, Kedar S, Lynn MJ, Newman NJ, Biousse V. Natural history of facilitate motor skill learning with the ‘unaffected’ forelimb and training-
homonymous hemianopia. Neurology. 2006;66:901–905. induced dendritic structural plasticity in the motor cortex. J Neurosci.
28. Dobkin BH. Rehabilitation and functional neuroimaging dose-response 2002;22:8597– 8606.
trajectories for clinical trials. Neurorehabil Neural Repair. 2005;19: 50. Carmichael ST, Chesselet MF. Synchronous neuronal activity is a signal
276 –282. for axonal sprouting after cortical lesions in the adult. J Neurosci. 2002;
29. Kwakkel G, van Peppen R, Wagenaar RC, Wood Dauphinee S, Richards 22:6062– 6070.
C, Ashburn A, Miller K, Lincoln N, Partridge C, Wellwood I, Langhorne 51. Ralston D, Ralston H. The terminations of corticospinal tract axons in the
P. Effects of augmented exercise therapy time after stroke: a meta-anal- macaque monkey. J Comp Neurol. 1985;242:325–337.
ysis. Stroke. 2004;35:2529 –2539. 52. Lacroix S, Havton LA, McKay H, Yang H, Brant A, Roberts J, Tuszynski
30. Baron J-C, Cohen L, Cramer SC, Dobkin BH, Johansen-Berg H, MH. Bilateral corticospinal projections arise from each motor cortex in
Loubinoux I, Marshall RS, Ward NS; First International Workshop on the macaque monkey: a quantitative study. J Comp Neurol. 2004;473:
Neuroimaging and Stroke Recovery. Neuroimaging in stroke recovery: a 147–161.
position paper from the First International Workshop on Neuroimaging 53. Tuszynski MH, Grill R, Jones LL, McKay HM, Blesch A. Spontaneous
and Stroke Recovery. Cerebrovasc Dis. 2004;18:260 –267. and augmented growth of axons in the primate spinal cord: effects of local
31. Crafton K, Mark A, Cramer S. Improved understanding of cortical injury injury and nerve growth factor-secreting cell grafts. J Comp Neurol.
by incorporating measures of functional anatomy. Brain. 2003;126: 2002;449:88 –101.
1650 –1659. 54. Tanaka K, Nogawa S, Suzuki S, Dembo T, Kosakai A. Upregulation of
32. Gerloff C, Bushara K, Sailer A, Wassermann EM, Chen R, Matsuoka T, oligodendrocyte progenitor cells associated with restoration of mature
Waldvogel D, Wittenberg GF, Ishii K, Cohen LG, Hallett M. Multimodal oligodendrocytes and myelination in peri-infarct area in the rat brain.
imaging of brain reorganization in motor areas of the contralesional Brain Res. 2003;989:172–179.
hemisphere of well recovered patients after capsular stroke. Brain. 2006; 55. Kakulas B. A review of the neuropathology of human spinal cord injury
129:791– 808. with emphasis on special features. J Spinal Cord Med. 1999;22:119 –124.

Downloaded from http://stroke.ahajournals.org/ by guest on February 23, 2013

 Dobkin Cell Transplants as Adjunctive Stroke Treatment 839

56. Li Y, Field P, Raisman G. Regeneration of adult rat corticospinal axons 65. Kimberley T, Khandekar G, Skraba L, Spencer J, Van Gorp E, Walker S.
induced by transplanted olfactory ensheathing cells. Neuroscience. 1998; Neural substrates for motor imagery in severe hemiparesis. Neurorehabil
18:10514 –10524. Neural Repair. 2006;20:268 –277.
57. Keirstead HS, Nistor G, Bernal G, Totoiu M, Cloutier F, Sharp K, 66. Bang O, Lee J, Lee P, Lee G. Autologous mesenchymal stem cell
Steward O. Human embryonic stem cell-derived oligodendrocyte pro- transplantation in stroke patients. Ann Neurol. 2005;57:874 – 882.
genitor cell transplants remyelinate and restore locomotion after spinal 67. Anderson D, Beattie M, Blesch A, Bresnahan J, Bunge M, Dietrich D,
cord injury. J Neurosci. 2005;25:4694 – 4705. Dietz V, Dobkin B, Fawcett J, Fehlings M, Fischer I, Grossman R, Guest
58. Penderis J, Shields SA, Franklin RJ. Impaired remyelination and J, Hagg T, Hall ED, Houle J, Kleitman N, McDonald J, Murray M, Privat
depletion of oligodendrocyte progenitors does not occur following A, Reier P, Steeves J, Steward O, Tetzlaff W, Tuszynski MH, Waxman
repeated episodes of focal demyelination in the rat central nervous SG, Whittemore S, Wolpaw J, Young W, Zheng B. Recommended
system. Brain. 2003;126:1382–1391. guidelines for studies of human subjects with spinal cord injury. Spinal
59. Newton JM, Ward NS, Parker GJ, Deichmann R, Alexander D, Friston K, Cord. 2005;43:453– 458.
Frackowiak R. Non-invasive mapping of corticofugal fibres from 68. Feron F, Perry C, Cochrane J, Licina P, Nowitzke A, Urquhart S,
multiple motor areas—relevance to stroke recovery. Brain. 2006;129: Geraghty T, Mackay-Sim A. Autologous olfactory ensheathing cell trans-
809 – 819.
plantation in human spinal cord injury. Brain. 2005;128:2951–2960.
60. Reddy H, Narayanan S, Matthews P, Hoge R, Pike G, Duquette P.
69. Lu M, Krams M, Zhang L, Zhang ZG, Chopp M. Assessing combination
Relating axonal injury to functional recovery in MS. Neurology. 2000;
treatments in acute stroke: preclinical experiences. Behav Brain Res.
54:236 –239.
2005;162:165–172.
61. Jiang Q, Zhang ZG, Ding GL, Zhang L, Ewing JR, Wang L, Zhang R, Li
70. Dobkin B, Apple D, Barbeau H, Basso M, Behrman A, Deforge D,
L, Lu M, Meng H, Arbab AS, Hu J, Li QJ, Pourabdollah Nejad DS,
Ditunno J, Dudley G, Elashoff R, Fugate L, Harkema S, Saulino M, Scott
Athiraman H, Chopp M. Investigation of neural progenitor cell induced
angiogenesis after embolic stroke in rat using MRI. Neuroimage. 2005; M. Methods for a randomized trial of weight-supported treadmill training
28:698 –707. versus conventional training for walking during inpatient rehabilitation
62. Papadopoulos CM, Tsai SY, Cheatwood JL, Bollnow MR, Kolb BE, after incomplete traumatic spinal cord injury. Neurorehabil Neural
Schwab ME, Kartje GL. Dendritic plasticity in the adult rat following Repair. 2003;17:153–167.
middle cerebral artery occlusion and Nogo-a neutralization. Cereb 71. Dobkin B, Barbeau H, Deforge D, et al. The evolution motor function for
Cortex. 2006;16:529 –536. walking over the first 12 weeks of rehabilitation for incomplete traumatic
63. Chen P, Goldberg D, Kolb B, Lanser M, Benowitz L. Inosine induces spinal cord injury: the SCILT multicenter randomized trial. Neurorehabil
axonal rewiring and improves behavioral outcome after stroke. Proc Natl Neural Repair. 2007; 21:In press.
Acad Sci U S A. 2002;99:9031–9036. 72. Dobkin B. Curiosity and cure: translational research strategies for neural
64. Steinmetz M, Horn K, Tom V, Miller JH, Busch SA, Nair D, Silver DJ, repair-mediated rehabilitation. J Neurobiol. 2007; In press.
Silver J. Chronic enhancement of the intrinsic growth capacity of sensory 73. Martino G, Pluchino S. The therapeutic potential of neural stem cells. Nat
neurons combined with the degradation of inhibitory proteoglycans Rev Neurosci. 2006;7:395– 406.
allows functional regeneration of sensory axons through the dorsal root 74. Steeves J, Lammertse D, Curt A, et al. Guidelines for the conduct of
entry zone in the mammalian spinal cord. J Neurosci. 2005;25: clinical trials for spinal cord injury as developed by the ICCP panel.
8066 – 8076. Spine. 2007; In press.

Downloaded from http://stroke.ahajournals.org/ by guest on February 23, 2013