A Novel Approach for Brain Stimulation in Severe Stroke
Phase: EARLY_PHASE1
Conditions: Stroke
Sponsor: The Cleveland Clinic

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SPECIFIC AIMS: Approx. 31%-64% of patients with stroke experience moderate to severe 
impairment of the upper limb, despite intensive rehabilitation. Upper-limb function may be 
improved by delivering rehabilitation in conjunction with a promising experimental approach 
known as brain stimulation, believed to affect excitability of cortical areas that contribute to plastic 
mechanisms in recovery. However, improvements observed in moderately/severely-affected 
patients remain limited. This is because stimulation is delivered using a generic approach, based 
on a concept about plasticity that is pertinent only to the recovery of mildly-affected patients [1, 
2]. Stimulation is delivered to always facilitate the excitability of the ipsilesional primary motor 
cortex (iM1) and suppress the excitability of the undamaged, contralesional motor cortices 
(“conventional approach”), based on the concept that the iM1 makes the most important 
contributions towards recovery, while the contralesional motor cortices exert excessive inter-
hemispheric inhibition (IHI) and limit paretic-limb movement. But ipsilesional corticospinal 
pathways are extensively damaged in moderately/severely-affected patients (58%-83% of 
patients in many studies). Therefore, these patients cannot experience facilitation of iM1 for 
return of paretic-limb function, evidence based on our AHA studies [3-5].  
In this Transformational Project Award (TPA), we take our exploratory AHA findings to the 2nd 
stage and test whether facilitating the intact, contralesional motor cortices would yield the 
maximum improvement in paretic-limb function in moderately/severely impaired patients, based 
on plastic mechanisms most pertinent to patients’ recovery (scientific premise) (Fig. 1). Our in-
progress AHA study and other studies have revealed that intact, contralesional motor cortices 
make functionally significant contributions to paretic-limb movement when there is extensive 
ipsilesional damage. Contralesional motor cortices reduce IHI and excite uncrossed output to 
support movements of the proximal and distal paretic-limb, including reaching and grasp/grip. 
Therefore, in our recent AHA study, facilitation of the contralesional motor cortices, particularly 
the contralesional dorsal premotor cortex (cPMd), given just for a single session, leads to 20% 
more improvement in paretic-limb reaching speed than the conventional approach facilitating 
iM1 in moderately/severely affected patients [3]. Here, we will test whether the promise and 
mechanisms of facilitating cPMd elicited within a single session in our recent AHA study can be 
consolidated to generate clinically meaningful improvements in function in moderately/severely-
affected patients by applying multiple sessions in rehabilitation.  
In a pilot, randomized controlled study, 24 patients will receive facilitation of cPMd or iM1 
(conventional approach) in conjunction with rehabilitation given for 2 days a week for 6 weeks. 
Moderately/severely-impaired patients with complete loss of ipsilesional corticospinal pathways 
will be selected, because these patients have been shown to have the best therapeutic response 
to cPMd facilitation in our in-progress AHA study [3, 6]. Primary outcome will be upper limb 
impairment, and secondary outcomes will be tests of functional abilities, proximal reaching 
performance and patient-reported disability. Associated neural mechanisms will also be studied 
using neurophysiological and functional connectivity MRI techniques. Damage to ipsilesional 
corticospinal pathways will be indexed with diffusion tensor imaging (DTI). 
AIM 1: Determine the effect of facilitating cPMd on upper-limb impairment, functional 
abilities, proximal control and patient-reported disability. Hyp 1: Facilitation of cPMd 
will lead to greater reduction in impairment and disability and to superior improvements 
in functional ability and proximal reaching control than facilitation of iM1. 
AIM 2: Investigate the effects of facilitating cPMd on inter-hemispheric connectivity. Hyp 
2: Facilitation of cPMd will lead to greater reduction of IHI imposed upon iM1 and a larger 
increase in cPMd-to-iM1 functional connectivity compared with facilitation of iM1. 

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AIM 3: Investigate the effects of facilitating cPMd on uncrossed output. Hyp 3: Facilitation 
of cPMd will lead to greater excitation of uncrossed output to the paretic upper limb 
compared with facilitation of iM1.  
AIM 4: Explore how ipsilesional corticospinal damage influences the response to 
facilitation of cPMd. Hyp 4: Improvements elicited with facilitation of cPMd vs. iM1 will 
vary as a function of the degree of damage to ipsilesional corticospinal pathways. 
IMPACT: In line with the mission of the AHA to build healthier lives for all, the proposed project 
will offer the most disadvantaged patients, those who typically cannot improve with conventional 
therapies, a unique opportunity to benefit from a novel brain stimulation approach tailored to 
their mechanism of plasticity. As such, the project will spearhead the development of targeted 
therapies to supplant generic approaches. In a broader sense, the project will revolutionize the 
understanding of stroke recovery in the fields of rehabilitation and neurology that generally have 
disparaged the potential of uninjured contralesional motor areas- neural resources consistently 
viable to support paretic-limb function in the most-affected patients. 
 SIGNIFICANCE 
Helping the most affected patients achieve the maximum improvement in function. Of the 
7 million stroke survivors living in the US, nearly three-fourths experience residual paresis of the 
upper limb [7]. Of them, approximately 31%-64% experience moderate to severe paresis, which 
limits participation in daily activities and self-care tasks, and increases reliance on caregivers for 
meeting every personal need. Patients with moderate/severe paresis generally do not benefit 
sufficiently from conventional or promising rehabilitation therapies, unlike the mildly-affected 
patients [6, 8-18]. Here, we aim to specifically help promote rehabilitation outcomes in 
moderately/severely-impaired patients to address an unmet clinical need and give these patients 
the same opportunities for recovery as those enjoyed by mildly-affected patients.  
 
Discarding one-type-suits-all approaches and adopting targeted therapies. Though 
several techniques have been developed to promote rehabilitation outcomes, such as peripheral 
electrical stimulation and robotics, the one technique that has gained widespread attention owing 
to its potential to directly tap into the plasticity of the recovering brain is brain stimulation [1, 19-
30]. Originally developed for use as a surgically implanted technique, brain stimulation became 
widely popular when noninvasive alternatives were introduced [20]. Commonly known as 
“transcranial” techniques, these alternatives deliver currents from atop the scalp/skull without 
requiring surgery. A typical example is transcranial magnetic stimulation (TMS), which delivers 
currents based on the principle of electromagnetic induction. TMS pulses applied in repeated 
Figure 1: Scientific Premise: Stimulation delivered to facilitate 
the excitability of the uninjured (contralesional) motor cortices 
will lead to improvement in proximal (e.g., reaching) and distal 
(e.g., grasp/grip) paretic-limb function in patients with extensive 
damage to ipsilesional pathways (Aim 1). Mechanisms will 
involve strengthening of inter-hemispheric connectivity (Aim 2) 
and excitation of uncrossed pathways (Aim 3). Improvements 
will vary as a function of the degree of ipsilesional damage (Aim 
4). 
Aim 2: Inter-Hemispheric Connectivity 
Aim 3:  
Uncrossed Output 
Aim 1:  
Upper Limb 
Function 
Theoretical Framework 
Aim 4: Influence of 
Corticospinal 
Damage 

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succession, known as repetitive TMS (rTMS), have the potential to modulate cortical excitability, 
thereby function, for long periods of time [1, 19-23, 25, 27, 31-35]. 
But improvements witnessed in moderately/severely-impaired patients remain limited [15, 25, 
28, 36-38]. We have explained based on AHA and NIH studies (Grant-in-Aid and Beginning 
Grant-in-Aid, K01) that stimulation is delivered using a generic approach, based on a concept 
about plasticity that is pertinent only to the recovery of mildly-affected patients [1, 2]. Stimulation 
is always delivered to facilitate iM1 and suppress contralesional motor cortices, based on the 
view that iM1 makes the most important contributions to recovery, while contralesional motor 
cortices exert excessive IHI and limit paretic-limb movement. But ipsilesional corticospinal 
pathways are damaged extensively in moderately/severely-affected patients (58%-83% of 
patients in many studies). Therefore, these patients cannot experience facilitation of iM1 for 
restoration of function of the paretic-limb [1, 6, 15, 27, 31]. Rather than perpetuate a one-type-
suits-all approach that is relevant only to the recovery of select few with minimal damage, here 
we offer a novel targeted approach meant to facilitate areas consistently viable to support 
recovery in the majority of patients with extensive damage. 
 
Targeting the long-disparaged contralesional motor areas - neural resources consistently 
viable to support recovery in patients with extensive damage. We premise that the uninjured, 
contralesional motor cortices would support maximum recovery of paretic-limb function in 
moderately/severely-impaired patients, based on plastic mechanisms most pertinent to patients’ 
recovery (Fig. 1). Evidence presented by our group and other groups has indicated that 
contralesional motor cortices make functionally relevant contributions to paretic-limb movement 
in patients with extensive ipsilesional damage [27, 39]. Functional MRI (fMRI) evidence shows 
that uninjured, contralesional motor cortices are more active than ipsilesional regions during 
paretic-limb movement in seriously affected patients [4, 5, 40-48]. Contralesional over-activation 
is essential to paretic-limb movement, because TMS-induced suppression of this activity, 
especially that of the contralesional dorsal premotor cortex (cPMd), leads to slowing of ongoing 
paretic-limb movement [3, 37, 49]. This means that cPMd is functionally significant to paretic-
limb movement in the more-affected patients [3, 37, 49]. Therefore, we recommend facilitating 
the cPMd instead of the conventional target- iM1- for generating the maximum improvement in 
paretic-limb function in moderately/severely-impaired patients (Aim 1). Our recommendation 
aligns with the contemporary view that contralesional not ipsilesional areas are functionally 
significant in the presence of extensive ipsilesional damage, but it contrasts with the 
conventional concept that a single area (iM1) is responsible for recovery. As such, our 
recommendation provides the impetus to supplant generic with targeted therapies for 
achievement of maximum recovery in every patient.  
Characterizing mechanisms by which contralesional motor cortices can contribute to 
recovery of the paretic-limb. We believe there are two key mechanisms by which uninjured 
contralesional motor cortices can contribute to paretic-limb recovery (Aims 2 and 3) (Fig. 1). 
(a) Strengthening of inter-hemispheric connectivity: Inter-hemispheric (callossal) connections 
offer a rich resource for information flow between hemispheres. It is thus conceivable that as 
iM1 is rendered less capable of controlling paretic-limb movement on account of extensive 
damage, intact contralesional motor cortices enhance their cooperation with weak iM1 to 
collectively control paretic-limb movement. Bestmann et al. [5] have tested this idea using a 
combination of TMS and fMRI. TMS was delivered to cPMd while fMRI was collected during 
the performance of paretic-limb movement. Targeting of cPMd led to an increase in fMRI 
activation of remote ipsilesional sensorimotor regions, which otherwise were inactive during 

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paretic-limb movement in moderately/severely-impaired patients. Therefore, we anticipate 
that rTMS-based targeting of cPMd delivered in conjunction with paretic-limb rehabilitation 
would lead to strengthening of inter-hemispheric connectivity with weak ipsilesional regions, 
amplifying the gain of residual ipsilesional signals conveyed to the paretic limb in patients 
with extensive damage (Aim 2) [5].  
(b) Unmasking of uncrossed (ipsilateral) pathways: Contralesional motor cortices can also 
support paretic-limb movement via evolutionarily conserved uncrossed pathways [50-55]. 
Morphologic evidence from animal studies has shown that in the presence of extensive 
ipsilesional corticospinal injury, sparse, but intact, uncrossed corticospinal and brainstem-
mediated reticulospinal pathways provide robust outgrowth to the affected spinal cord [52, 
56-59]. Facilitating cPMd could further excite these uncrossed pathways to promote paretic-
limb function in patients with extensive damage to ipsilesional pathways (Aim 3). 
INNOVATION 
Tapping into promising improvements elicited with a novel approach of brain stimulation. 
Based on an ongoing AHA award, we have conducted the first-in-human study to facilitate the 
undamaged, contralesional motor cortices [3]. In a crossover design, patients received 
facilitatiion of cPMd and iM1 (conventional approach) for a single session each. Facilitation of 
cPMd led to robust improvements in paretic-limb reaching spped in moderately/severely-affected 
patients who failed to improve with the conventional approach involving the facilitation of iM1 
(Aim 1) (Fig. 2A). Underlying mechanism involved strengthening of inter-hemispheric and 
uncrossed connectivity (Aims 2 and 3) (Fig. 2B) [3]. Here, we will test whether the promise and 
mechanisms of facilitating cPMd elicited within a single session can be consolidated to generate 
clinically meaningful improvements in function by applying multiple sessions in rehabilitation. 
This would make the proposed study the first-in-human study to deliver long-term facilitation to 
the undamaged, contralesional motor cortices.  
 
Unique opportunity to characterize neural mechanisms otherwise evidenced only in 
animal studies. Animal studies have demonstrated that intact contralesional motor cortices offer 
uncrossed pathways to support paretic-forelimb recovery when there is extensive damage to 
ipsilesional pathways (Fig. 1) [53-55]. There is anecdotal evidence to suggest a similar 
phenomenon occurs in humans. In patients with severe stroke, TMS applied to the contralesional 
motor cortex elicits muscle-evoked potentials (MEPs) in the paretic-limb. These MEPs, known 
as ipsilateral (same-side) MEPs (not to be confused with contralateral MEPs elicited with TMS 
delivered to the opposite motor cortex), represent unmasked uncrossed output [4, 52, 57, 58, 
60-73]. No study to date, however, has characterized the plasticity of this uncrossed output in 
humans. The proposed study will demonstrate for the first time recovery-associated gain in size 
of ipsilateral MEPs with facilitation of parent cPMd (Aim 3). This finding would offer concrete 
evidence of the existence of direct contribution from the intact hemisphere and its plasticity in 
support of paretic-limb recovery, a novel translational achievement. 
 
PRELIMINARY APPROACH 
Published and preliminary data acquired in our ongoing and recent AHA studies (Grant-in-Aid 
and Beginning Grant-in-Aid) and an NIH K01 study has provided support for our scientific 
premise. Data was acquired as part of short-term and long-term experiments.  
SHORT-TERM EXPERIMENT: Moderately/severely-impaired patients with extensive 
damage who fail to improve with the conventional approach show robust improvements 
in paretic-limb movement with novel approach involving facilitation of cPMd [3]: Fifteen 

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patients with mild to severe impairment after chronic stroke (≥6 months) received single sessions 
of facilitation of cPMd, facilitation of iM1 (conventional approach), and facilitation of a control 
region, contralesional M1 (cM1), in a randomized, sham-controlled, crossover study. Facilitation 
was delivered using rTMS. Sessions were separated by ≥1 week to allow for washout of effects. 
At baseline, impairment (Upper Extremity Fugl-Meyer, UEFM) and corticospinal damage 
(indexed using DTI as Fractional Anisotropy, FA) were measured. Outcomes included paretic-
limb reaching speed and IHI exerted from the contralesional upon the ipsilesional motor cortices 
(studied using TMS) [3].  
In line with findings of other studies, we observed that moderately/severely-impaired patients 
with extensive ipsilesional damage failed to achieve any improvement in paretic-limb reaching 
with facilitation of iM1 [15, 25, 28, 36-38]. But a unique finding was that these same patients 
achieved significant improvement with facilitation of cPMd (t13 =2.57; p =0.012; Fig. 2A). Effect 
of facilitating cPMd was related to a reduction in IHI; patients who became faster at paretic-limb 
reaching with cPMd facilitation experienced greater reduction in IHI from contralesional upon 
ipsilesional cortices, i.e., better inter-hemispheric connectivity (r=0.75, p <0.001, Fig. 2B).  
Effect of facilitating cPMd was more remarkable than effect of facilitating cM1. Facilitation of 
cPMd led to faster paretic-limb reaching (t4=3.479, p=0.025) and greatly reduced IHI compared 
to facilitation of iM1 (z=1.83, p=0.06) (Fig. 2D)[3]. This result aligns with findings of other studies, 
where transient suppression of cPMd leads to greater slowing of paretic-limb reaching than 
transient suppression of cM1 (Fig. 2C)[4, 5, 74]. Collectively, evidence from our work and 
previous work indicates that cPMd is more indispensible for paretic-limb movement than other 
contralesional areas. Bilateral organization and robust uncrossed connectivity likely affords 
cPMd the flexibility to control ipsilateral besides contralateral movements [5, 52, 64-67, 74-80].  
Overall, our short-term data has revealed that cPMd is a more promising target than iM1 or other 
contralesional regions for promoting paretic-limb function in the most-disadvantaged patients 
(Aim 1). cPMd contributes to paretic-limb movement by reducing IHI, i.e., strengthening inter-
hemispheric connectivity (Aim 2). Our short-term data has also helped stratify patients mostly 
likely to respond to cPMd facilitation. Using machine learning, co-I Dr. Wang [3, 34, 45, 81, 82] 
has identified that moderately/severely-impaired patients (UEFM ≤ 42 out of 66) with extensive 
damage to ipsilesional pathways [inability to elicit MEPs in paretic-muscle with TMS delivered to 
iM1 (MEP-) and FA values < 50% of normal white-matter integrity] show the best response to 
cPMd facilitation; mildly-affected patients show the poorest response [3]. Therefore, we will only 
Figure 2 (A) and (B). Adapted from our recent short-term study (Sanakarasubramanian, Plow et al. Clin Neurophysiol 2017). 
(A) Effect of our new approach of cPMd facilitation upon paretic-limb reaching speed is compared to the effect of the 
conventional approach of iM1 facilitation in patients with extensive damage (MEP-). (B) Improvement in paretic-limb reaching-
speed was related to reduction in IHI following cPMd (not iM1) facilitation. (C) Adaptation from Harris-Love et al. 2016, 2017 
comparing the effects of transiently suppressing the activity of cPMd and cM1 upon ongoing paretic-limb reaching. (D) 
Adaptation from our work comparing the effects of transiently facilitating the activity of cPMd and cM1 upon ongoing paretic-
limb reaching (Sanakarasubramanian, Plow et al. 2017). 
* 
A 
0 
250 
Conventional 
cPMd 
Faster Reaching (ms)à   
MEP- patients 
-40 
-20 
0 
20 
-80 
20 
120 
220 
320 
 ß Less IHI 
Faster Reaching (ms) à) 
r= 0.75* 
Reduction in IHI 
B 
C 
cPMd 
cM1 
% Slower  
In Reaching 
Slower 
-250 
0 
250 
500 
Faster Reaching 
(ms) à 
D 
Faster 
* 
* 
cPMd 
cM1 

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enroll the most-affected patients who fit criteria identified in our short-term study. Enrolling a 
homogeneous sample with high likelihood of response would contribute to scientific rigor and 
statistical power and improve the chances of success.  
 LONG-TERM EXPERIMENT: Moderately/severely-impaired patients with extensive 
damage achieve dramatic improvements in paretic-limb function with multiple sessions 
of cPMd facilitation: In line with the design of the proposed study, we conducted a pilot 
randomized controlled study. Three patients with moderate/severe-impairment and extensive 
damage to ipsilesional pathways, meeting criteria specified in our short-term study (UEFM ≤42, 
MEP-), were randomly assigned to receive facilitation of cPMd (n=2) or iM1 (conventional 
approach) (n=1) in conjunction with rehabilitation given for 3 days/wk for 5 wks. Facilitation was 
delivered using rTMS [3]. Outcomes included impairment (UEFM) and functional ability to 
perform paretic-limb tasks (Wolf Motor Function Test, WMFT) [83]. Neural metrics were also 
studied with TMS, including IHI and output of uncrossed pathways (ipsilateral MEPs).  
Our findings revealed that patients receiving cPMd facilitation achieved dramatic improvements 
upon UEFM (9-point gain from 30  8.4 to 39.0  9.90) that exceeded the minimal-clinically 
important difference (5.2-point gain [84]). This improvement also exceeded the gain witnessed 
in patients receiving iM1 facilitation by two-fold (4.3-point gain on UEFM from 31.4  11.07 to 
35.7  10.34) (Fig. 3A) [85, 86]. Improvements achieved upon UEFM translated to recovery of 
functional abilities. Patients receiving cPMd facilitation became 75% faster on WMFT 
(12.153.32 to 20.8114.24 movements per min), while the patient receiving iM1 facilitation 
became slower (17.20 to 13.30 movements per min).  
In association with recovery, patients receiving cPMd facilitation experienced a reduction in IHI 
from the contralesional motor cortices. IHI was studied here as suppression of ongoing voluntary 
paretic-muscle activity elicited with TMS given to the contralesional motor cortex (referred to as 
ipsilateral silent period or iSP) (Fig. 3B). Patients receiving cPMd facilitation showed 
considerable shortening of iSP (19.516.46ms to 11.75 3.89ms) compared to the patient 
receiving iM1 facilitation (12ms to 25.5ms), implying reduction in IHI and strengthening of inter-
hemispheric cooperation during paretic-muscle activity. Reduction in IHI offered iM1 a reprieve; 
a patient originally lacking MEPs (MEP-) showed restoration of MEPs in the paretic-muscle 
(MEP+) after receiving cPMd facilitation, indicating amplification (dis-inhibition) of residual 
signals to the paretic limb (Fig. 3C). MEPs were not restored after iM1 facilitation.  
Patients receiving cPMd facilitation also showed larger ipsilateral MEPs after treatment than the 
patient receiving iM1 facilitation (705.38V and 622.12V vs. 481.56 V) (Fig. 3D). Ipsilateral 
MEPs were already present in our sample though contralateral MEPs were lacking (MEP-). This 
means that intact motor cortices were already contributing to paretic-limb function via uncrossed 
Figure 3 (A) UEFM improvement; (B) IHI reduction: shortening of iSP duration; (C) restoration of MEPs in paretic muscle in 
a patient who could not elicit MEPs at baseline. (D) Increase in uncrossed or ipsilateral MEPs after cPMd facilitation. 

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pathways in the absence of ample ipsilesional pathways. Facilitation of cPMd further 
strengthened this uncrossed contribution to favor paretic-limb recovery [53-55]. 
 
Overall, our long-term data has revealed that cPMd facilitation can help generate clinically 
meaningful gains in function in moderately/severely-impaired patients who otherwise show 
limited improvement with conventional iM1 facilitation (Aim 1). cPMd facilitation strengthens 
inter-hemispheric and uncrossed connectivity, amplifying any descending signals to the paretic-
limb (Aims 2 and 3). In this study, we will also explore how response to cPMd facilitation varies 
as a function of ipsilesional damage (DTI) for responder stratification (Aim 4).  
APPROACH 
Study Design and Criteria: In a pilot, randomized-controlled, single-blind study, a target of 24 
patients will be assigned to either receive 
facilitation of cPMd or facilitation of iM1 
(conventional approach), delivered daily in 
conjunction with rehabilitation for 2 days/wk 
for 6 wks. They will be assigned to treatment 
groups using a stratified randomization 
scheme to minimize group imbalances on 4 
key patient characteristics: (1) time post-
stroke (<2 yrs vs. ≥2 yrs), (2) cortical vs. 
subcortical stroke, (3) presence of active wrist extension vs. no wrist extension, and (4) paretic 
side (dominant vs. non-dominant). Assessments will be completed at baseline and at the end of 
treatment after 6 wks, except assessments for Aim 1 that will also be completed at screening 
and at 3-month follow-up visit (Table 1). Ten age matched healthy controls, fifteen age matched 
mild, and up to 5 moderately impaired participants (who will undergo rTMS and CCFES based-
therapy) will also be enrolled to record comparative neural indices. The goal will be to establish 
age-based norms for healthy, mild, moderate, and severe neurophysiologic metrics related to 
EDC, FDI, Biceps, and Triceps muscles.  
 
Patients included will be (1) between the ages of 18 and 90 yrs; 2) in chronic phase (≥6 months) 
after index ischemic/hemorrhagic stroke; 3); moderate or severely impaired with extensive 
damage to ipsilesional pathways (MEP -) [note: patients meeting these criteria typically make up 
40%-83% of the sample in our studies and in other studies] or have <10° active wrist extension 
or <10° active thumb abduction/extension or <10° active extension in at least two additional 
digits (i.e., will not meet minimum CIMT criteria) [3, 6, 27, 69]; and 4) medically stable. Patients 
will be excluded if they have 1) brainstem stroke; 2) cerebellar stroke 3) bilateral strokes; 4) 
severe cognitive impairment; 5) substantially elevated tone/spasticity in wrist/hand (Modified 
Ashworth Scale >3); 6) severe contracture; 7) participation in OT or Botox therapy within 2 
months; 8) exclusion criteria for TMS and MRI (metal implant in head, H/O seizures, alcohol or 
substance abuse, intake of medications contraindicated with TMS [89], cardiac pacemaker or 
programmable implant). For healthy control and mild participants, the exclusionary criteria will 
be the same as mentioned above.  Healthy control inclusion criteria is age between 18-90 years 
old, without any diagnosis of neurological disease. Mild inclusion criteria includes age between 
18-90 years old and UEFM score of 47 or above. For moderate participants, the exclusion criteria 
will be the same as mentioned above. Moderate inclusion criteria include having >10° active 
wrist extension and >10° active thumb abduction/extension and >10° active extension in at least 
two additional digits (i.e., will meet minimum CIMT criteria) and adequate active movement of 

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shoulder and elbow to position the paretic hand on one’s lap for performance of functional task 
practice and CCFES-assisted hand opening exercises. 
 
Participants with multiple and/or bilateral strokes that meet the following criteria will be 
considered for eligibility based on study neurologists review of previous MRI/CT scans: 
1. The non-target infarct is not affecting sensorimotor structures and pathways 
2. The non-target infarct is not affecting both UE and does not impair study participation 
and assessment 
3. All strokes occurred over 6 months ago (chronic) 
 
 
Subject Recruitment: Cleveland Clinic logs >3200 annual visits for stroke, based on which 
>7975 patients have been included in an ongoing database created by the PI. Approx. 282 
patients from this database have been screened, and 80 have been enrolled in the past 5 years 
(~21% screen-in rate). This database will serve as the primary source for recruitment. In case 
more subjects are needed, referrals from stroke physicians (see Dr. Machado’s letter) and 
assistance from NINDS’ Regional Stroke Clinical Trials network will be sought. For this study we 
will contact subjects who previously completed the optional pilot testing protocol in the 16-128 
study, “Novel Brain Stimulation Therapies in Stroke Guided by Expressions of Plasticity”. The 
optional pilot testing these subjects completed was the exact protocol that we are performing in 
this current study protocol. We will ask them to allow us to use their data from the visits they 
completed in the 16-128 study, “Novel Brain Stimulation Therapies in Stroke Guided by 
Expressions of Plasticity”, in this current study.  
Once a potential subject is identified, an email or EPIC Messaging/MYCHART will be sent to their 
physician at the Cleveland Clinic, seeking permission to contact the subject. If permission is received, a 
letter or EPIC Messaging/MYCHART will be sent to the subject. The letter will briefly outline the 
procedures of the study and ask the subject to call if they are interested in participating. If the subject 
expresses interest, then a preliminary eligibility screening will be completed over the phone. If subjects 
do not call back within 2 weeks of the original date of mailing, then the study staff will call the subject to 
determine if they are interested in participating. Candidates who meet eligibility requirements over the 
phone call will be scheduled to come in for informed consent visit, interview and physician 
screening/examination. 
History, Physical and Neurologic Examination, and Screening/Eligibility Testing: Stroke 
physicians at Cleveland Clinic will screen patients at the beginning of the study to determine eligibility, 
either on-site or through a video screen for subjects who cannot reasonably make it to one of the sites. 
Therapists will also conduct a screening to assess upper limb functionality before subjects are enrolled. 
This is typically done on-site before or after the physician screening, unless participants are not within a 
reasonable distance to the Cleveland Clinic and a virtual visit is more appropriate. The therapists will 
assess active/passive range of motion, and determine the participant’s ability to move their upper limbs 
in a functional space. For interested candidates that would like to perform a video screen for eligibility 
they will provide a separate informed consent for the video screen. Given that the screening consent is 
meant to preclude the need for the patient to come for an on site visit, it will be completed online. Through 
secure Cleveland Clinic RedCap data management server, the participant receive an electronic mail (e-
mail) providing links the informed consent form that will also contain space for providing e-signature. The 
participant will be given few days to review the screening consent form and provide consent to undergo 

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eligibility assessments over video. The screening consent form would remind participants that they are 
not giving consent to undergo study procedures, but to be interviewed over video. After screening consent 
is obtained, research team, therapist and/or physician will perform video screening with the participant. 
The video screen will be conducted on CCF encrypted devices (ex: CCF computer, CCF phone) using 
CCF Skype for Business or ExpressCare.  
Stimulation: Stimulation will be delivered using rTMS, based on the expertise of the PI [3, 25, 
32, 45, 47, 81, 82, 90-93]. Facilitation will be achieved using 5Hz rTMS, capable of facilitating 
the excitability of both higher motor (PMC and adjoining SMA) and primary motor cortices (M1). 
In the cHMC facilitation group, a region 2 cm anterior and 1 cm medial to the contralesional 
motor hotspot will be targeted, corresponding to the location of premotor and adjoining SMA 
complex.Forty two 10-sec trains of 50 pulses each will be delivered over a period of 21.21 min 
(2100 pulses total).. Patients in the iM1 facilitation group will receive stimulation to the 
ipsilesional motor hotspot, unless the hotspot cannot be identified, in which case the mirror 
location of the contralesional hotspot will be targeted.  rTMS will be delivered at an intensity of 
90% Active Motor Threshold (AMT) based on the wrist extensor (extensor digitorum communis 
(EDC)) muscle (details later). Choice of EDC is driven by the clinical need for restoration of wrist-
extension, a key predictor of recovery [69, 87, 88]. 
Rehabilitation: Immediately after rTMS, patients will receive 1-hr of task- or goal-oriented 
training, optimized for use in moderately/severely-impaired patients by co-I Dr. Wolf’s group and 
other groups [45, 105-109]. rTMS and training will be delivered for 2 days/wk for 6 wks, a dose 
found to be sufficient for eliciting clinically-meaningful gains in function in our work [45]. 
AIM 1: Determine the effect of facilitating cPMd on upper-limb impairment, functional 
abilities, proximal control and patient-reported disability. At baseline, end-of-treatment and 
3-month follow-up, we will collect the following indices. Impairment will be measured using 
UEFM, one of the most widely used assessments in stroke [110]. UEFM will serve as our primary 
outcome because it is sensitive to discerning the effects of rTMS/rehabilitation [14, 45, 111-114], 
and has excellent reliability (ICC= 0.97), consistency (Cronbach’s α= 0.84) and validity [115-
120]. Functional ability to use the paretic upper limb in a variety of tasks will be assessed using 
WMFT (developed by co-I, Dr. Wolf). Time to complete each task will be noted and converted to 
rate (60/Performance Time (sec)), optimized for measurement in moderately/severely-impaired 
patients [83]. WMFT rate shows high validity and reliability in this population [83]. Grip strength 
will also be recorded with WMFT. Proximal motor control will be assessed using an upper 
extremity task. The task will characterize motor control in moderately/severely-impaired patients 
who typically lack adequate distal movements. Patient’s perceived disability related to physical 
function will be indexed using the Stroke Impact Scale (SIS-16), a reliable (ICC= 0.94) and valid 
index [127, 128].  
Expected outcomes and interpretations: Based on the findings of our AHA study, we expect that 
facilitation of cPMd will lead to greater improvement on UEFM, WMFT rate, grip strength, and 
SIS-16 than facilitation of iM1  (Fig. 3A). This finding would mean that facilitation of the intact 
hemisphere promotes paretic upper-limb recovery in patients who cannot rely on injured cortices 
due to extensive ipsilesional damage.  
AIM 2: Investigate the effects of facilitating cPMd upon inter-hemispheric connectivity. 
Inter-hemispheric connectivity will be characterized using IHI collected with TMS and functional 
connectivity collected with resting-state fMRI (rsfMRI). IHI will serve as the primary outcome 

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because it is sensitive to capturing the effects of rTMS [3, 45, 47, 125, 129-131]. Functional 
connectivity will complement IHI measurement as a secondary outcome because while IHI 
records neurophysiologic interactions between a contralesional and a weak ipsilesional region, 
functional connectivity defines “global” interactions across multiple regions.  
Before describing the measurement of IHI, it is important provide details about TMS procedures. 
Single-pulse TMS will be delivered using a figure-of-eight coil with stereotactic guidance from 
patient’s MRI. Surface EMG electrodes affixed to paretic and non-paretic EDC will measure 
TMS-evoked MEPs and “silence” of ongoing muscle-activity. At the screening visit, TMS will be 
delivered to iM1 to confirm the absence of ipsilesional MEPs in paretic EDC (MEP-) [69, 87, 88]. 
Patients showing ≥50μV MEPs in consistent trials (≥6 of 10) in resting paretic EDC (10%-20% 
contraction) will be excluded. Eligible participants will undergo repeat testing of TMS targeting 
iM1 at baseline and at end-of-treatment to identify restoration of ipsilesional MEPs, as seen in 
our pilot study (Fig. 3C). TMS will also be delivered to cM1. Motor hotspot will be identified as 
the site eliciting ≥100µV MEPs in consistent trials (≥6 of 10) in slightly contracted non-paretic 
EDC (10%-20% contraction). The lowest intensity required to elicit these criterion-level MEPs 
will be termed as AMT. TMS will be delivered at 100% MSO to cM1 and cPMd during voluntary 
paretic muscle-activity (50% contraction) for measurement of IHI. Silence elicited in muscle-
activity, called iSP, will be recorded (Fig. 3B) [45, 47, 132]. % EMG suppression during iSP 
(relative to pre-stimulus EMG) is labeled IHI.  
rsfMRI will denote temporal correlation between low-frequency Blood Oxygenation Level-
Dependent (BOLD) fluctuations occurring across different regions as intrinsic functional 
connectivity [133-136]. rsfMRI obviates the need for performance of a movement, offering an 
advantage over motor task-based fMRI for testing of moderately/severely impaired patients [133-
136]. Methods and analysis will follow steps outlined in our work with Dr. Sakaie [133, 134, 136-
143]. Based on this work, we have found that moderately/severely-impaired patients 
demonstrate an increase in functional connectivity between cPMd and iM1 in association with 
recovery (n=9) [142]. Here, we will examine whether this intrinsic connectivity strengthens with 
facilitation of cPMd. Temporal correlation between reference time series of cPMd, iM1 and 
different areas will be computed and converted to t- and z-score maps (Fig. 4A) [142, 143].  
Expected outcomes and interpretations: Based on our AHA studies, we expect that facilitation 
of cPMd will lead to a greater reduction of IHI and a larger increase in cPMd-to-iM1 functional 
connectivity than facilitation of iM1 (conventional approach) (Fig. 3B, 4A). This finding would 
mean that facilitation of the intact hemisphere helps strengthen inter-hemispheric connectivity 
with weak iM1 to promote paretic-limb recovery in patients with extensive ipsilesional damage. 
AIM 3: Evaluate the effects of facilitating cPMd upon uncrossed output to the paretic-
limb. Output of uncrossed pathways will be studied as ipsilateral MEPs elicited in the paretic-
muscle with TMS (Fig. 3D) [144]. During tonic contraction of the paretic-muscle (100% 
contraction), high-intensity TMS (100% of maximum device output) will be delivered to cM1 and 
cPMd (30 trials each) [144]. Ipsilateral MEPs will be identified as potentials exceeding pre-
stimulus EMG by >1SD at a latency ~6-15ms longer than the latency of contralateral MEPs 
elicited in the corresponding non-paretic muscle. Uncrossed pathways mainly supply spinal 
motor neurons of proximal and distal flexors, so we will record ipsilateral MEPs from flexor carpi 
radialis muscle as well as EDC and biceps [82, 93, 144]. Ipsilateral MEP area will be calculated 
as 100*area of rectified EMG in ipsilateral MEP/(avg pre-stimulus EMG* ipsilateral MEP). We 
will also use a clinical peripheral electrical stimulation technique called H-Reflex to study spinal 

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pathway excitability. H-reflex will be collected using a clinical grade neurostimulator used to 
collect H-reflex in the clinical setting along with sticker electrodes to record the stimulation 
readings in a muscle of the forearm.  
Expected outcomes and interpretations: Based on our AHA study, we expect that facilitation of 
cPMd will lead to larger gains in ipsilateral MEP area than facilitation of iM1 (Fig. 3D). This finding 
would mean facilitating the intact hemisphere strengthens its uncrossed contributions to favor 
paretic-limb recovery in patients who otherwise lack adequate ipsilesional contributions. 
AIM 4: Explore how ipsilesional corticospinal damage influences response to cPMd 
facilitation. At baseline, damage to ipsilesional corticospinal pathways will be indexed using 
DTI. DTI enables the investigation of structural integrity and orientation of pathways in vivo 
through the estimation of magnitude and directionality of water diffusion [69, 145-149]. DTI 
metrics can help quantitate damage even when patients show no response to TMS due to 
extensive damage (MEP-) (Fig. 4B) [3, 47, 69]. High angular resolution diffusion weighted 
images will be acquired and analyzed using steps outlined in our work with Dr. Sakaie [34, 47, 
91, 150-154]. Ipsilesional and contralesional corticospinal tracts will be reconstructed using 
probabilistic tractography [47, 91, 153, 155]. FA, a unit-less measure of white matter integrity, 
will be calculated [156, 157]. FAAsymmetry given by FAContralesional – FAIpsilesional/FAContralesional + 
FAIpsilesional, will be used to express integrity of ipsilesional vs. contralesional tracts. Higher values 
of FAAsymmetry indicate severe damage. Stroke neurologist, Dr. Conforto, will identify lesion 
location (posterior limb of internal capsule (PLIC) or non-PLIC) and volume (cm3) [158]. 
Expected outcomes and interpretations: Based on our AHA study, we expect that improvements 
associated with facilitation of cPMd will vary as a function of baseline corticospinal damage [3]. 
This would allow identification of a threshold level of damage, beyond which patients fail to show 
criterion-level improvement (5.2-point gain [84]) on UEFM, necessary for responder stratification 
for this new approach involving facilitation of intact areas.  
STATISITICAL ANALYSIS: For analysis of aims 1, 2 and 3, linear mixed effects models will be 
used to compare change in UEFM (primary endpoint), WMFT rate, functional ability, grip 
strength,  SIS, IHI, functional connectivity, and ipsilateral MEP area from baseline to end-of-
treatment (and 3-month follow-up) between groups. Models will account for spasticity, baseline 
wrist extension (none; ≤10°; >10°), lesion size/location, time post-stroke, side of paresis, biologic 
variables (e.g., sex) and handedness. Bivariate (Pearson’s) correlation will be used to explore 
relationships between change in function and change in IHI, functional connectivity and 
ipsilateral MEP area. Chi-square or Fisher’s Exact test will help compare the frequency of 
responders (those achieving ≥5.2-point UEFM gain [84]) and patients showing restoration of 
ipsilesional MEPs (MEP+) between groups. For aim 4, regression models will capture the 
influence of baseline FAAsymmetry upon improvements associated with facilitation of cPMd vs. iM1l, 
and separately the influence of baseline UEFM and wrist extension. 
Figure 4. (A) Group rsFMRI data from moderately/severely-
impaired patients (n=9) reveals areas in ipsilesional M1 and 
sensory cortices (S1) (MNI: X: 49 Y: 29 Z: 48) that show an increase 
in functional connectivity with cPMd (MNI: 26, -6, 53) (peak t-value= 
3.25) following rehabilitation. (B) Examples from our work 
demonstrating the feasibility of successfully generating FA maps 
(top) and reconstructing corticospinal tracts (bottom) in patients 
with severe (left panel) and mild damage (right panel).  

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Additional data analysis will be conducted using quantum machine learning (QML) to develop a 
classification model for assessing the functional capacity of stroke patients to use the affected 
upper extremity. We will utilize behavioral outcome measures signifying the functional capacity 
collected during this study. The ultimate goal of this analysis is to discern variations in functional 
capacity among individuals affected by stroke for tailoring rehabilitation interventions to each 
patient’s specific needs. 
Potential Pitfalls and Alternative Solutions: If not all patients can elicit ipsilateral MEPs in the 
paretic muscle, we will compare groups upon the frequency of evidence of these MEPs after 
treatment (Chi-square/Fisher’s Exact) [4, 52, 57, 58, 60-73]. If effects of cPMd facilitation are 
weak, we will perform sub-group analyses based on baseline wrist extension to determine which 
category of patients shows the best response. We will also determine what level of baseline 
FAAsymmetry, connectivity, impairment (UEFM) predicts response vs. non-response (based on 
attainment of 5.2-point UEFM gain [84]). Anticipating that cPMd facilitation may have effects on 
bilateral control, we will adopt bimanual test used in our recent study [159].  
Sample 
size 
Estimation 
and 
Power 
Analysis: Table 2 shows sample size 
estimations 
based 
on 
two-sample 
t 
conducted across difference scores between 
groups. We expect to enroll 22 subjects but in 
accounting for ~10% attrition, a total of 24 subjects will be enrolled.   
IMPACT: While greater damage produces greater impairment following stroke, it also generates 
a widespread plastic response involving the intact cortices in the contralesional hemisphere. 
Although this response may not be sufficient to support complete recovery, it is likely to support 
more recovery than what is otherwise possible to achieve [4]. Demonstrating that facilitating 
these intact areas can lead to restoration of paretic-limb function in patients who fail to benefit 
from any therapies on account of extensive damage will carry tremendous clinical impact, 
provide the impetus to develop targeted therapies and depart from conventional beliefs that have 
always disparaged the potential offered by the intact hemisphere.  
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