Effectiveness and neural mechanisms associated with tDCS delivered to premotor cortex in stroke rehabilitation: study protocol for a randomized controlled trial
Effectiveness and neural mechanisms associated with tDCS delivered to premotor cortex in stroke rehabilitation: study protocol for a randomized controlled trial
Ela B Plow 0 1
David A Cunningham 1
Corin Bonnett 1
Guang H Yue
0 Department of Physical Medicine & Rehab, Neurological Instt., Cleveland Clinic , Cleveland, OH 44195 , USA
1 Department of Biomedical Engineering, Lerner Research Instt., Cleveland Clinic , 9500 Euclid Avenue, ND20, Cleveland, OH 44195 , USA
Background: More than 60% of stroke survivors experience residual deficits of the paretic upper limb/hand. Standard rehabilitation generates modest gains. Stimulation delivered to the surviving Primary Motor Cortex in the strokeaffected hemisphere has been considered a promising adjunct. However, recent trials challenge its advantage. We discuss our pilot clinical trial that aims to address factors implicated in divergent success of the approach. We assess safety, feasibility and efficacy of targeting an alternate locus during rehabilitation- the premotor cortex. In anticipating variance across patients, we measure neural markers differentiating response from non-response. Methods/Design: In a randomized, sham-controlled, double-blinded pilot clinical study, patients with chronic stroke (n = 20) are assigned to receive transcranial direct current stimulation delivered to the premotor cortex or sham during rehabilitation of the paretic arm/hand. Patients receive the designated intervention for 30 min, twice a day for 3 days a week for 5 weeks. We assess hand function and patients' reports of use of paretic hand. A general linear mixed methods model will analyze changes from pre- to post-intervention. Responders and non-responders will be compared upon baseline level of function, and neural substrates, including function and integrity of output tracts, bi-hemispheric balance, and lesion profile. Incidence of adverse events will be compared using Fisher's Exact test, while rigor of blinding will be assessed with Chi-square analysis to ascertain feasibility. Discussion: Variable success of cortical stimulation in rehabilitation can be related to gaps in theoretical basis and clinical investigation. Given that most patients with severe deficits have damage to the primary motor cortex or its output pathways, it would be futile to target stimulation to this site. We suggest targeting premotor cortex because it contributes substantially to descending output, a role that is amplified with greater damage to the motor cortex. With regards to clinical investigation, paired cortical stimulation in rehabilitation has been compared to rehabilitation alone in unblinded trials or to unconvincing sham conditions. Transcranial direct current stimulation, a noninvasive technique of brain stimulation, which offers a more effective placebo and has a favorable safety-feasibility profile, may improve scientific rigor. Neural markers of response would help inform patient selection for future clinical trials so we can address limitations of recent negative studies. Trial registration: http://clinicaltrials.gov/ct2/show/NCT01539096 (Continued on next page)
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Keywords: Stroke, Rehabilitation, Brain stimulation, Motor cortex (M1), Premotor cortex (PMC), Diffusion tensor imaging
(DTI), Functional magnetic resonance imaging (fMRI), Resting state functional magnetic resonance imaging (rs-fMRI),
Transcranial magnetic stimulation (TMS), Transcranial direct current stimulation (tDCS)
Arm/hand deficits post-stroke: evidence regarding
adjunctive cortical stimulation
Stroke is the leading cause of long-term disability in
adults . More than 60% of survivors experience
residual deficits of the paretic upper limb [2,3], where
standard rehabilitation generates only modest gains .
A promising new approach involves delivering
adjunctive stimulation to the brain. Early studies show that
electrical stimulation delivered to the surviving primary
motor cortex (M1) in the stroke-affected hemisphere in
conjunction with rehabilitation facilitates outcomes of
the paretic extremity [5-14]. Translational models
suggest the effect is synergistic and emerges from
augmented activity within targeted, residual M1 [5-7].
Despite its preliminary success, recent clinical trials have
failed to witness an advantage of the paired approach in
comparison to rehabilitation delivered alone [15-19].
Gaps in the theoretical basis and variability of
experimental design are implicated [4,19].
Gaps in the theoretical basis and variability in
Studies have invariably targeted M1 in the
strokeaffected hemisphere [8-10,15]. Given that M1 and its
output pathways are spared only in few patients with
focal lesions [20,21], targeting M1 may be ineffective
across most. It is thus important to deviate from the
classical strategy of stimulating M1 while still realizing
that effectiveness may vary depending upon who is
enrolled. Well recovered patients demonstrate promise of
additive stimulation [14,22], but disappointing results
are observed in patients with severe impairments
[16,18]. The obvious theoretical questions remain - are
the effects of adjuvant cortical stimulation favorable for
some versus others, and why?
The clinical utility of paired stimulation in
rehabilitation is also marred by variability in design. The paired
approach has been compared to either rehabilitation
alone in unblinded trials [8-10] or to unconvincing sham
stimulation [16,23] or to no control conditions at all
[24,25]. Approaches of stimulation are extremely
variable too, with little information about why one method
may have greater utility than another. Invasive
techniques (intracranial stimulation of residual M1) carry
serious postsurgical risks , but even noninvasive
methods (delivered from over the scalp and skull), such
as repetitive transcranial magnetic stimulation, rTMS,
may induce acute seizures . Plus, rTMS is
nonportable, and impractical to apply in chronic rehabilitation
, unlike invasive stimulation [8-10]. Modes of
stimulation are distinct too, with some facilitating activity of
stroke-affected hemisphere, and others downregulating
that of the unaffected .
Rehabilitation strategies are inconsistent; some groups
employ laboratory-based training paradigms [13,14,22,29],
whereas others use standard [8-10,16,17,23-25,30] or newer
methods of rehabilitation [12,18,31]. It is critical to
understand that the type of training that is combined with
stimulation determines how generalizable the benefits would be.
Improvements are specific for tasks that are strategically
paired with stimulation [7,29,32], thus, choosing a
rehabilitative intervention/paradigm that is applicable across most
activities of daily living would indeed be more meaningful.
Additionally, duration is important because singular
sessions of paired stimulation and training tend to be positive
[13,14] and hence, popular, but they may inflate and contort
the clinical advantage that is truly offered by stimulation.
Rationale for our approach
In addressing theoretical gaps in the present literature,
we propose that premotor cortex (PMC) could serve as
an alternate locus in the stroke-affected hemisphere. As
a higher-order motor region, it contributes substantially
(approximately 60%) and independently to descending
motor tracts, plays a superior role in dexterity [33-35],
and contributes more strongly with increasing damage
to M1 [36,37]. Descending motor output from PMC has
as strong a predictive power in prognosticating recovery
as output from M1 [38,39]. However, in anticipating that
effects of stimulation can vary across patients, we
propose to assess pathologic and neural markers of
individual recovery [4,19] to inform design of future trials.
Since variability in design, choice of stimulation and
its mode, and type of rehabilitative strategy have
impacted interpretation of the utility of paired stimulation
in stroke rehabilitation, here, we suggest design-related
modifications for upcoming trials. When selecting
between methods of cortical stimulation, an alternative
non-invasive technique may involve transcranial direct
current stimulation (tDCS), which with passage of
lowlevel current alters cortical excitability. tDCS may
provide a better safety-feasibility ratio than intracranial and
rTMS methods because it induces minimal risks, offers
effective placebo and is low cost and easy to administer
in patients with chronic conditions with concurrent
therapies [14,18,22,40]. With respect to rehabilitation
protocols, adopting a paradigm that is standardized yet
customizable to patients goals and objectives would be
more effective in promoting generalizability; an
example is modified constraint-induced movement therapy
(CIMT) , involving use of paretic limb in
patientspecific tasks simulating activities of daily living during
constraint of the unaffected limb. CIMT may also be
effective as a paired rehabilitation technique because it is
shown to facilitate activity in targeted, residual M1 and
restore inter-hemispheric balance ; delivering adjunctive
tDCS could then amplify its neural basis and effectiveness
. Long-term rather than short-term pairing with
rehabilitation may carry greater utility. This is because the
effects of short-term tDCS are transient , but longer
staggered paradigms generate greater retention [42,43].
Incorporating extended treatment paradigms [16-18,24,44]
would also be important for making decisions about
longterm clinical relevance [13,14,22,29,45] of paired cortical
stimulation and rehabilitation.
Objectives and hypotheses
In line with our rationale, the objectives of the present
pilot clinical study are to: 1) examine the safety,
feasibility and effectiveness of CIMT paired with tDCS
targeting PMC, versus CIMT delivered alone in
alleviating impairments of the paretic hand in patients with
chronic stroke; and 2) assess neural markers associated
with response to paired paradigm versus CIMT alone.
We hypothesize that the paired approach involving
stimulation of PMC in the stroke-affected hemisphere will
be more effective than CIMT in improving hand function
in chronic stroke. The paired approach will facilitate the
individuals specific neural substrates of recovery and will
be safe to employ throughout the length of the study.
We use a pilot, randomized, sham-controlled,
doubleblind clinical study design. Twenty patients are being
randomly assigned to PMC tDCS plus CIMT or sham
tDCS plus CIMT groups. All outcomes are collected at
pretest and at post-test after 5 weeks of intervention. At
3-month follow up, outcomes of hand function are
collected to examine retention.
Participants and recruitment
We are enrolling patients with chronic stroke with
mild-tomoderate impairments in upper limb function [46,47], who
fulfill the following prerequisites:
20 years post-stroke; ability to extend fingers or thumb
or wrist 10 and chief complaint of inadequate ability
to use the paretic hand compared to its use prior to a
single (ischemic or hemorrhagic) stroke.
The exclusionary criteria relate to contraindications of
cortical stimulation [48,49] and imaging [36,37]. These
include: cardiac pacemaker; metallic implant in the head;
seizure disorder; medication-resistant epilepsy in a
firstdegree relative; use of any neuro- or psycho-active
medications as published in recommendations ; history of
fainting spells of undetermined etiology; pregnancy;
implanted pumps/stimulators/shunts; any other neurological
condition affecting sensorimotor systems, such as brain
tumor, dementia, or substance abuse; severe cognitive
deficits (mini-mental state exam score  <18);
ongoing/recent (within 2 months) rehabilitation for upper limb.
This is a single-center pilot clinical study. Patients with
chronic stroke are being recruited from nine area
hospitals within the Cleveland Clinic health system through
outpatient and community-based stroke programs,
referrals from providers, medical chart review, liaison with
local support groups, and spontaneous demand through
newspaper, radio and website advertisements.
Ethics, consent, study organization and registration
The study is being conducted in agreement with the
principles of the Declaration of Helsinki, and with the
guidelines of Good Clinical Practice (GCP) of the
International Conference on Harmonization of Technical
Requirements for Registration of Pharmaceuticals for
Human Use (ICH). The study protocol has been
approved by the local and independent Ethics Committee
of the Cleveland Clinic (Institutional Review Board). The
study is also registered as a pilot clinical trial on
clinicaltrials.gov (NCT01539096). Extramural funding
for the present study is provided by the National
Institutes of Health (NIH) for EP.
During the consent process, the investigator explains
the benefits and risks of participation in the study and
provides an informed consent form approved by the
Institutional Review Board. To gauge whether subjects
have sufficiently understood the study processes so as to
make an informed decision, the investigator probes by
asking open-ended questions about details contained in
the consent form. Only patients who respond correctly
and provide written informed consent by signing the
consent document are enrolled in the study. Results will
be published only with de-identified data.
Inclusion and exclusion criteria
The inclusion criteria are: age 21 years; chronic phase
of recovery (>6 months) after first-ever stroke up to
Patients are initially screened by telephone, followed by
thorough chart review. The physical therapist, principal
investigator and study coordinator evaluate subjects,
who provide written informed consent in person, to
ensure eligibility. Diagnosis and eligibility are confirmed at
screening by a neurologist. Screening for neuroimaging
and brain stimulation is repeated at each of these levels.
Following confirmation of eligibility, the pretest is
scheduled over 2 days, and involves evaluation of upper limb
function and neural markers of change. Post-test,
following 5 weeks of the assigned intervention, is similar to
Outcomes of hand function: the detailed timeline is
presented in Figure 1. Our primary outcome of hand
function is the upper extremity Fugl-Meyer (UEFM)
assessment, which measures impairments of the upper
limb/hand . It is commonly used in studies pairing
cortical stimulation with rehabilitation [8-10]. It includes
33 items that provide a gross indication of overall
functional status of an individual. It is rated on an ordinal
scale (0 to 2, maximum score 66) by an investigator .
Secondary outcomes of function include: 1) the motor
activity log , which is a self-report assessment of the
patients own perception of degree and quality of use of
their affected hand in daily activities; 2) the Action
Research arm test, which is a performance-oriented test
that rates function across grasp, grip, pinch, and gross
movement ; 3) the nine-hole peg test, which is a
performance-oriented test of dexterity measuring
timeto-place individual pegs consecutively into spaces and
removing them as promptly as possible ; 4) isometric
finger-abduction strength measured as force exerted
during maximum isometric abduction; and 5) spasticity
of finger and wrist flexors measured with the modified
Ashworth scale , which ranges from 0 (no change in
muscle tone upon quick stretch) to 4 (most severe
spasticity, where the hand is rigid in flexion). All outcomes
of hand function are repeated at a 3-month follow-up
Markers of neural recovery
Neuroimaging and tests of cortical neurophysiology are
being conducted at pretest and at post-test to identify
predictors and correlates of response, compare which
substrates are adaptive in one individual versus another,
and discern the potential underlying reason for variance.
Predictors of response: diffusion tensor imaging defines
the structural patency of white matter tracts . Using
this method, we evaluate the integrity of corticospinal
tracts, which are considered most critical to dexterity
. We anticipate that PMC-based tracts will be more
predictive of recovery with tDCS than those emerging
Mechanisms of response: functional neuroimaging is the
most important assay to measure changes in the brain
occurring in recovery in stroke. By measuring changes in
Evaluation by neurologist, physical therapist
Assessment of qualifying stroke affecting upper limb
CIMT selection criteria
9 Hole Peg Test Isometric Force of Finger Abduction
Randomization and double blinding
3 month Follow Up Evaluation
Figure 1 Overview of study procedures. CIMT, constraint-induced movement therapy; tDCS, transcranial direct current stimulation; MRI,
magnetic resonance imaging.
Transcranial magnetic stimulation & Neuroimaging:
Functional MRI and Diffusion Tensor Imagining
perfusion or blood oxygenation during movement of the
paretic hand, one can infer the association of activity of
a region with its role in dexterity. Functional
neuroimaging, such as functional MRI (fMRI), has demonstrated
that damage due to stroke downregulates activity in
stroke-affected versus intact hemispheres. As recovery
occurs, the balance in activity (as seen using fMRI)
between bilateral hemispheres, returns [37,41]. We are
exploring whether delivering tDCS to PMC in the
strokeaffected hemisphere helps restore this balance. Another
form of functional neuroimaging, called resting-state fMRI
, is critical in identifying how, over the course of stroke
recovery, functional connectivity (fc) evolves between
widespread networks . We investigate whether fc is
strengthened, particularly between PMC and M1, with
application of tDCS in CIMT.
Substrates of response: transcranial magnetic stimulation
(TMS) noninvasively measures cortical and corticospinal
neurophysiology . In the present pilot trial, TMS
defines efficiency of conduction via residual corticospinal
tracts , the structural integrity of which is outlined with
diffusion tensor imaging. TMS also measures conduction
between both hemispheres relayed via transcallosal
pathways; this conduction is normally inhibitory, that is, one
hemisphere exerts inhibition upon another, and that in
return exerts counter-inhibition. In stroke, balance of such
inhibition is disrupted. Whereas inhibition from the intact
stroke-affected hemisphere is exaggerated, that in the
opposite direction is diminished . We explore whether
tDCS delivered to PMC in the stroke-affected hemisphere
improves the efficiency of corticospinal conduction and
helps rebalance inhibition exerted between the intact and
We are using randomization blocks in sizes of four,
where two patients in a block are assigned to PMC tDCS
plus CIMT and the other two to the sham tDCS plus
CIMT group. Such block randomization prevents the
possibility that several patients in a row would get
randomized to tDCS or sham tDCS groups in the early part
of the study. The order of patients in blocks is random,
generated using an online tool. Allocations are concealed
in an opaque envelope and hidden in a locked cabinet
with restricted access; they are opened by an investigator
not involved in data collection or analysis before the first
day of treatment.
supervision of the study principal investigator and
physical therapist (EP) in an outpatient setting at the
Cleveland Clinic main campus. All patients receive
CIMT for 30 minutes, twice a day, 3 days a week for
5 weeks. It includes massed (intensive) functional
exercises for the paretic upper limb guided by the principle
of shaping , which involves a graded, regimented,
feedback-driven approach to achieving impairment- and
patient-specific goals. Tasks focus upon transfer to
realworld activities, including activities like grooming,
making a telephone call, et cetera. The protocol of CIMT
discussed here differs slightly from the modified version
of the program that is generally employed . Instead
of one 30-minute session, we deliver two 30-minute
sessions; rather than 10 weeks, we deliver CIMT for
5 weeks, at the same frequency, that is, three times a
week. We have incorporated this frequency and length
to improve compliance, as patients are required to visit
the outpatient clinic 15 times over 5 weeks rather than
30 times over 10 weeks. Patients use of the non-paretic
upper limb is restrained by placing it in a mitt, which
they are asked to maintain for 2 hrs every weekday
during peak times of activity, instead of 5 hrs.
The tDCS of anodal polarity is delivered to PMC in the
stroke-affected hemisphere to potentially raise its activity
: it is delivered using a constant current
batterydriven (9-V) stimulator (Soterix, NY, New York, USA)
connected to conductive rubber electrodes (5 7 cm )
placed in saline-soaked sponges . The anodal
electrode is placed on the scalp site corresponding to PMC
[34,61], guided by MRI-based stereotaxy. Specifically, the
center of the anode is 3 cm anterior to the locus in the
stroke-affected hemisphere that evokes the best and
most consistent responses with TMS in a muscle of the
paretic hand . The reference (cathodal) electrode is
placed above the contralateral orbit. Electrodes are
secured using Velcro bands. Direct current is delivered at
a dose of 1 mA during rehabilitation in patients in the
tDCS plus CIMT group. For patients in the sham tDCS
plus CIMT group, the 1 mA current is delivered
transiently (30 to 60 seconds) at outset, and then slowly turned
off after habituation. For all patients, the current is
ramped up slowly at the onset of intervention to minimize
excessive tingling and maintain blinding. This is a valid
method for placebo as patients receiving tDCS become
habituated to its sensation within a short time .
Patients and investigators assessing outcomes are blinded
to the group assignment. Double blinding is intended
to minimize bias that could emerge from participants
perceptions of treatment and therapeutic confusion or
observer bias within the investigative team about the
benefits of the approach. To quantify the success of double
blinding, we ask patients at the end of the study whether
they believed they received tDCS or sham tDCS, or
whether they did not have reason to believe one way or
another. A similar questionnaire is completed with the
investigators who assess outcomes.
A report on side effects is completed at every visit. At
every treatment visit, the report documents whether or
not subjects experienced side effects related to tDCS,
such as tingling, headache, itching, fatigue, pain and
problems concentrating. On days of testing with TMS,
the report also documents whether subjects experienced
side effects related to TMS, such as seizure, loss of
consciousness or hearing difficulties. Transient side effects
are documented separately from serious events that are
categorized as related or unrelated to interventions.
Serious adverse events include those that may require
inpatient hospitalization. Adverse event reporting follows
guidelines set by the local Institutional Review Board.
To ensure safety in case of seizure or any unrelated
serious medical issues, provisions include an on-call
medical response team and clinical research nursing support
that work closely with the physician on the study (AM).
We are defining attrition as a lapse in treatment >1 week,
inability to complete post-test or follow up, or exclusion
or withdrawal in the case of a serious adverse event or
development of a condition that is a contraindication to
participation in the study.
Sample size estimation
The sample size has been estimated based on previous
studies that have paired invasive or noninvasive
stimulation with rehabilitation [8,9,12,17,31]. Because UEFM
has been most commonly investigated across the
majority of studies, we used the effect sizes calculated across
these studies to generate several permutations of sample
size and the corresponding extent of change in the
UEFM score (Figure 2) to estimate power. Using a
method of simulations  where 500 simulations were
performed, we estimated sample sizes that would
generate significant differences upon the UEFM based on a
mixed-effects model. From this method, we have found
that a sample size of 10 per group would yield 83%
power (95% CI 79.41 to 86.19%) to detect differences
between groups (PMC tDCS plus CIMT sham tDCS plus
CIMT group), 99.6% power to note differences across
time (95% CI 98.56 to 99.95%) and 97% power (95% CI
95.35 to 99.46%) to observe a group X time interaction
Figure 2 Power analysis: power was determined by simulation.
Lower and upper lines define exactly the 95% CI for power,
calculated based on the binomial distribution. N is the total sample
size. The analysis was performed at a 0.05 significance level
considering 2 2 factorial analysis of variance (ANOVA) (tDCS plus
CIMT and sham tDCS plus CIMT from pretest to post-test). Power
has been estimated here for an interaction term (A *C).
Although the estimated sample size appears small, it is
commensurate with the pilot exploratory nature of our
study. Pilot studies involving brain stimulation generally
use smaller sample sizes compared to rehabilitation trials
 because contraindications to brain
stimulation/imaging are constraining. Still, we anticipate having
adequate statistical power based on prior evidence where
despite enrolling a total of 14 to 30 subjects, several
studies report significant benefit of adjunctive
stimulation [8,30,44]. Additionally, use of a repeated-measures
design further provides greater power. Studying neural
mechanisms with fMRI and tractography in limited
sample sizes is challenging. Given the exploratory nature of
our pilot study, we would be able to highlight elemental
neural mechanisms of recovery. Previously, in a
threegroup, randomized controlled study design with a small
sample of 20, we deciphered correlates of fMRI .
Recently too, Stagg et al.  show differences in fMRI
activation across varying types of tDCS interventions in 11
patients with stroke. Without overemphasizing the
importance of small pilot studies, we stress instead the
significance of large-scale studies in generating clear
evidence of efficacy. Our current pilot exploratory study
is a step in that direction as it would offer estimates of
effect size related to PMC tDCS and neural markers that
can serve as entry criteria.
Statistical and data analyses
Feasibility: analysis of feasibility includes investigating
the rigor of experimental blinding and determining
compliance with the 5-week outpatient rehabilitation
program. A chi-square analysis will determine whether
patients in one group versus another estimate their
group assignment correctly. Investigators also complete
a similar questionnaire at the end of the study. While
patient responses will indicate the rigor of the blinding
procedures, responses from investigators will ensure
investigator equipoise, preventing observer bias. Attrition
or missing data will be analyzed using a strategy known
as multiple imputations , where each missing value
is replaced with a set of plausible values that represent
the uncertainty about the true value. The multiple
imputed data sets are analyzed using standard procedures
used for complete datasets and by combining results
from these analyses. The method of multiple
imputations does not attempt to estimate each missing value
through simulated values, but rather represents a
random sample of missing values. This process results in
valid statistical inferences that properly reflect the
uncertainty due to missing values.
Safety: the incidence of adverse events in each group
will be computed as a proportion of individuals in each
group who experienced side effects. We will be using the
Fisher exact test to contrast the incidence of side effects
between both groups.
Efficacy and markers of recovery: our primary
endpoint of efficacy is the UEFM. Secondary outcomes
include nine-hole peg test, Action Research arm test,
motor activity log, finger abduction strength and the
modified Ashworth scale of spasticity. A general linear
mixed-model approach will be followed to analyze
functional outcomes across three levels of time (pre, post,
and follow-up). Significant two-way interaction,
whenever present, will be explored using the Tukey honestly
significant difference (HSD) test. Non-parametric tests
will be used if the distribution is not normal.
To assess neural substrates of recovery, both groups will
be compared for change in inter-hemispheric balance
(fMRI), fc and transcallosal inhibition and corticospinal
conduction (TMS) from pretest to post-test. To
understand whether effects of interventions vary across patients
and factors explaining such variance, an ideal method
would have involved identifying clinical, pathologic and
neural factors that would predict the change in UEFM.
However, since the statistical power of the study may be
inadequate to pursue this analysis, we will follow an
alternative method. Patients who achieve 3.5 gain in the
UEFM score (criterion of clinical improvement defined in
a previous clinical trial of invasive cortical stimulation) 
after 5 weeks of the intervention would be called
responders. We will investigate whether the proportion of
responders versus nonresponders includes a greater
majority of patients from the tDCS group (Chi-square
analysis). More importantly, we will compare clinical,
pathologic and neural indicators between responders and
nonresponders (independent samples t-test). These will
include: baseline UEFM, location of disease (Oxford
Stroke classification: total anterior circulation or partial
anterior circulation or lacunar strokes) , residual
function and integrity of corticospinal tracts on the
strokeaffected side measured with TMS and diffusion tensor
We have described the protocol of our ongoing pilot
clinical study in chronic stroke, where we test safety,
feasibility, efficacy and neural markers of upper limb
rehabilitation combined with stimulation targeting the
PMC in the affected hemisphere. Evidence on the value
of paired cortical stimulation in rehabilitation is divided
due to theoretical and design-related issues. Stimulating
peri-lesional and affected M1 without knowing the
individual substrates of recovery creates variability in
response [4,19,67]. Differences in design, such as type of
control, blinding and safety-feasibility trade off of
varying types of stimulation have further added confusion to
evidence of efficacy. Recent trials have also failed at the
phase III level due to poor estimation of the magnitude
of the placebo effect [19,68]. Therefore, to prepare for
future trials, we propose targeting the PMC in the
affected hemisphere with the rationale that it may serve as
an alternative locus of recovery. We employ tDCS,
which may be safer and feasible to apply online during
long-term outpatient rehabilitation; based on its ability
to provide a more effective placebo, it permits us to
adopt double blinding and sham control, helping
estimate the magnitude of placebo. Finally, we identify
patient-specific indicators of recovery to stratify
responders for design of future investigations.
Knowing markers of response versus non-response to
brain stimulation in rehabilitation would not only
harmonize evidence in the field, but will also help us select
candidates for subsequent trials. Early clinical trials of
invasive stimulation showed greater promise of adjuvant
stimulation [8-10] than recent phase III [15,19], potentially
since patients in earlier trials possessed functioning
corticospinal pathways  unlike only a few in phase III
. Similarly, rehabilitative outcomes are invariably
successful for well-recovered patients [14,22], unlike for those
with moderate/severe paresis [16,18,31]. Subcortical
lesions respond better [13,29] than massive infarcts of total
anterior circulation . If we find that responsive patients
show distinctive characteristics, such as patent and
functioning white matter tracts et cetera, then these would
serve as entry criteria for the future. Unfortunately it may
also mean that stimulation may be more fruitful only for a
limited few, but this information would optimize resource
allocation. For patients showing limited to no response,
we would identify whether functioning of alternate areas
(as identified on fMRI) and patency of tracts from other
regions (from tractography) may hold greater meaning. A
patient-guided approach to utilizing such residual
resources will then be created, employing alternate
rehabilitation methods and/or stimulating patient-specific loci.
Knowing mechanisms of long-term pairing can help
address why chronic effects are not as robust. Even though
singular sessions or short-term paradigms show benefit
[11,13,16,22,29,30], trials incorporating long-term training
have failed to witness an advantage [15-19]. Divergent
success across short- and long-term studies may also be an
effect of dosage. Stimulation may have an initial accelerative
effect [25,32] manifested in the short term, but over the
long term, the effect of rehabilitation itself may become
robust [37,70], diminishing the comparative effect size.
[15-19]. Confounding from individual variance may also
factor in; if stimulation in rehabilitation were truly
effective, its differences from rehabilitation would evolve over
time; on the flip side, if all gains were solely related to
variance across individuals, then a long-term study would
show no difference, and short-term studies would be easily
confounded. Short-term designs also have the added
advantage of higher treatment fidelity; standardized
laboratory-based paradigms can be delivered in short-term
approaches more easily [13,14,22,29,45], whereas longer
protocols of clinical rehabilitation suffer from variance in
treatment delivery [8-10,16,17,23-25,30,44]. However,
exploring stimulation delivered with long-duration
rehabilitation still carries greater clinical utility, despite challenges
to adherence and fidelity, because short-term paradigms,
though invariably positive, do not correlate with
longterm outcomes [13,14,22,23,29-31,45].
Use of chronic paradigms offers another important
advantage, namely, retention. Besides the primary endpoint,
we have built a delayed follow up. Initial clinical trials note
that groups receiving cortical stimulation retain benefits
whereas the ones receiving rehabilitation alone show a dip
in performance after the end of training [8,9]. These
delayed benefits, maintained post-stimulation, may be
indicative of a neuro-protective effect  that we may be able
to infer by completing our 3-month follow up.
Besides duration and retention, we suggest other
potential advancements that could help improve the rigor
of study design in the field. Creating a sham-controlled,
double-blinded approach remains ethically and
technically challenging with invasive stimulation [8-10], and
sham conditions created with noninvasive rTMS have
not been strongly convincing either [24,25]. Using tDCS
may offer a unique opportunity to create a more valid
sham for effective blinding  and provide a better
estimation of the placebo effect. Caveats remain to be
addressed, however. Is it possible that what is gained in
safety-feasibility with tDCS is lost in effectiveness, when
relating to more focal methods such as rTMS and
invasive cortical stimulation .
Overall, the strengths of our pilot protocol include 1)
examining a novel target of stimulation that differs from
the classical and contemporary approach; 2) use of a
generalizable rehabilitation paradigm that is delivered
over the long term to generate true estimates of efficacy,
adherence, and retention, thence, utility of brain
stimulation; 3) use of a method of stimulation that is low cost,
safe, feasible and allows estimation of the magnitude of
the placebo effect; and 4) characterization of structural,
pathologic, neurophysiologic and functional predictors
of response. Despite these strengths, we anticipate
challenges. The estimated sample size may be limited.
Because others have noted significant effects with similar
repeated-measures designs with a total of 14  to 24
 patients, we anticipate our pilot exploratory study
may generate comparable effects. Nevertheless, we do
not wish to undermine the significance of large-scale
studies. In fact, our current exploratory study is a step in
the direction. The resources of our study and its
singlecenter nature, though, are restrictive in addressing
efficacy at that level at this time. Combining imaging and
stimulation makes enrollment increasingly difficult and
adds greater measurement burden. Also, since the
intervention can only be delivered in a hospital setting, poor
compliance can affect feasibility. To mitigate such
threats, a contracted treatment schedule for CIMT is
being followed. If a greater and/or accelerated benefit were
to be achieved with tDCS, then the utility of abridged
CIMT would be established. Our rationale is derived
from our work where tDCS paired with contracted
vision rehabilitation promoted gains equivalent to a
traditional, longer paradigm [32,40,71]. Ultimately, our pilot
clinical study carries important implications for future
trials; utility of an alternate cortical target would inform
future transcranial research and investigation of markers
of recovery would inform invasive (intracranial)
applications of subcortical/deep brain structures that are in
translational stages [72,73].
CIMT: Constraint-induced movement therapy; Fc: Functional connectivity;
fMRI: Functional magnetic resonance imaging; GCP: Good clinical practice;
M1: Primary motor cortex; NIH: National Institutes of Health; PMC: Premotor
cortex; rTMS: Repetitive transcranial magnetic stimulation; tDCS: Transcranial
direct current stimulation; TMS: Transcranial magnetic stimulation;
UEFM: Upper extremity Fugl-Meyer.
All authors made significant intellectual contributions. EP is the initiator and
principal investigator. DC has developed data collection and the analysis
scheme for TMS. GY created the clinical trial design with EP. AW and CB are
trial managers and research coordinators. EB, KS and ML have helped
develop the imaging measurement scheme for diffusion tensor imaging, fc
and fMRI. SJ has helped develop fMRI analysis and lesion profile for stroke.
XW is the trial statistician. AM developed the approach and protocol with EP
and edited and helped draft the manuscript. EP created the first draft that
was reviewed and edited critically by all other authors, and their revisions
were included by EP. All authors read and approved the final manuscript.
Study Statistician: Xiao-Feng Wang.
The study is funded by the NIH Career Development Award (1K01HD069504
to EP) and the investigator role of EP is also supported by American Heart
Association (13BGIA17120055). Contribution by GY, AW, CP, DC was
supported by NIHs R01HD061363 to GY, while contribution of AM was
supported by grants from NIH, including New Innovator Award
(1DP2OD006469) and R01HD061363. The authors would like to acknowledge
Ms Nicole Varnerin, Mr Daniel Janini and Ms Sarah Roelle for their
contribution towards data collection and analysis.
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