Repetitive Transcranial Magnetic Stimulation (rTMS) to Contralesional Hemisphere in Patients With Stroke for Upper Limb Recovery

PRIMARY OBJECTIVES To determine whether NBS guided 1Hz rTMS targeting the motor
representation areas of hand muscles on the healthy brain hemisphere has a beneficial effect
on the motor recovery of the corresponding stroke-affected muscles when combined with
standardized task-oriented motor rehabilitation.

SECONDARY OBJECTIVES

1. To determine whether motor evoked potentials (MEPs) can be elicited from paretic and/or
plegic muscles in patients with stroke using navigated TMS (eXimia NBS) and targeting
the anatomical cortical areas representing the affected muscles.

2. To determine the correlation between existing MEPs, other TMS parameters and the
clinical deficits of limb function.

3. To determine the prognostic value of MEPs and other TMS parameters in predicting motor
recovery after stroke

4. To determine the diagnostic value of MEPs and other TMS parameters in monitoring the
response to rehabilitation

5. To assess safety by capturing all Serious Adverse Events during both single pulse and
rTMS delivery

STUDY PROCEDURES

The purpose of the study including risks and benefits will be explained to potential
participants who will then be asked to sign an informed consent form. Potential
participants will be screened for inclusion and exclusion criteria

The study will be performed in 2 parts. In part 1 Nexstim eXimia NBS will be utilized for
neuronavigation and a third party TMS will be used for delivering the rTMS. In part 2
Nexstim eXimia NBS will be utilized together with Nexstim eXimia TMS for delivering the
rTMS. Part 2 will commence once the patients participating in Part 1 have undergone the
study visit 22 (see 5.1 below).

15 patients will be recruited to part 1 and 15 patients for part 2 (6 additional subjects
will be recruited assuming a 20% drop out rate)

In part 1 of the study 10 subjects will be randomized to rTMS treatment and 5 subjects will
be randomized to sham rTMS. Of the 10 rTMS treatment subjects, 5 will be given stimulation
protocol A and 5 will be given stimulation protocol B, described below. In part 2, either
stimulation protocol A or B will be chosen for continue study based on predetermined outcome
criteria. In part 2, 10 subjects will receive this chosen rTMS treatment and 5 subjects
will receive sham rTMS.

The study will consist of 24 study visits with the addition of 4 additional visits as needed
to complete outcome assessments.

VISIT SCHEDULE

The study will be performed over 24 to 28 sessions:

1. Visit 1(Screening visit): Baseline = 3-9 months after the stroke. The purpose of this
visit is to obtain informed consent for the study (if not previously obtained) and to
screen subjects for inclusion and exclusion criteria.

2. Visit 2: Baseline assessment. The purpose of this visit is to establish the baseline of
injury, motor status and NBS parameters (Hand motor mapping and motor tract integrity,
both hemispheres - see appendix A). Subjects will also undergo a structural MRI. The
subject will then be randomized to either rTMS or to sham treatment. The baseline visit
may if necessary take place on 2 separate days.

3. Visits 3-21: During these visits the patient will undergo standardized task-oriented
motor rehabilitation of the hand. In addition the patient will receive the rTMS therapy
according to the protocol of the group she/he was randomized into during visit 1. The
visits will take place during a 6 week period, three visits per week. During each week
the visits will take place each on a separate day and a maximum of two visits will take
place on consecutive days. During the first visit of each week (visits 3, 6, 9, 12, 15
and 18) in addition to the rTMS and task-oriented motor rehabilitation, the patient
will undergo measurement of NBS parameters (Motor tract integrity, both hemispheres).

4. Visit 22: End of the task-oriented motor rehabilitation. The purpose of the visit is to
establish the extent of recovery that has occurred during the rehabilitation. The visit
will take place 3-5 days after the last rTMS/rehabilitation session and includes
functional motor testing and evaluation of NBS parameters (Hand motor mapping and motor
tract integrity, both hemispheres). 1-2 visits may be needed to complete assessment.

5) Visit 23: 1 month after the end of the rehabilitation therapy. The purpose of the visit
is to determine whether any changes in motor function or NBS parameters have occurred within
1 month of ending therapy. The assessment includes functional motor testing and evaluation
of NBS parameters (Hand motor mapping and motor tract integrity, both hemispheres). 1-2
visits may be needed to complete assessment.

6) Visit 24: 6 months after end of the rehabilitation therapy. The purpose of this visit is
to determine the long-term rehabilitation success. The assessment includes functional motor
testing and evaluation of NBS parameters (Hand motor mapping and motor tract integrity, both
hemispheres. In patients experience a new stroke or TIA during this time, only the data
prior to the event will be used in the analysis. 1-2 visits may be needed to complete
assessment.

Inclusion Criteria:

- ≥ 18 years of age

- An ischemic or hemorrhagic stroke suffered 3-9 months prior to the study

- no other known brain abnormalities by history or by structural MRI

- A one-sided stroke resulting in upper extremity paresis

- A Chedoke Arm and Hand Activity Inventory score of 3-6 for the affected limb

Exclusion Criteria:

- Implanted metallic parts of implanted electronic devices, including pacemakers,
defibrillators, or implant medication pump

- Pregnant or trying to become pregnant

- History of alcohol abuse, illicit drug use or drug abuse or significant mental
illness

- any history of epilepsy

- Any condition that would prevent the subject from giving voluntary informed consent

- An implanted brain stimulator

- Aneurysm clip or other metal in body

- Enrolled or plans to enroll in an interventional trial during this study

- Scalp wounds or infections

- Claustrophobia precluding MRI

- A fixed contraction deformity in the affected limb

- Excessive spasticity as indicated by the Modified Ashworth Spasticity (MAS) Scale
>2/4 in the affected limb

- previous stroke with residual deficits (TIAs not a reason for exclusion)

- premorbid (retrospective) modified Rankin Scale (mRS) score ≥2 of any aetiology

- a concurrent progressive neurologic disorder, acute coronary syndrome, severe heart
disease (NYHA Classification > 3), or other major medical condition

- confirmed or suspected lower-limb fracture preventing mobilization

- patients requiring palliative care

- patients undergoing any other occupational therapy than what is provided in the study

- A recent injection of botulinum toxin to the affected upper limb in the last 3
months, or the need of an injection of botulinum toxin anytime during the study
period and follow up

- Ataxia as measured by a score > 1 on item 7 (limb ataxia) of the NIH stroke scale

- Severe aphasia as measured by a score of > 2 on item 9 (best language) of the NIH
stroke scale

- Severe neglect as measured by a score of 2 on item 11 (extinction and inattention) of
the NIH stroke scale