Effects of Neuromodulation and Rehabilitation of the Locomotor Network in Freezing of Gait
Phase: NA
Conditions: Parkinson Disease With Freezing of Gait
Sponsor: Medical University of South Carolina

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PI Name:  Gonzalo J. Revuelta, DO 
 
 
Study Title:  Effects of Neuromodulation and Rehabilitation of the Locomotor Network in Freezing of 
Gait 
 
TABLE OF CONTENTS –  
 
A. Specific Aims, page 1 
B. Background and Significance, page 1-2 
C. Preliminary Studies, page 2 
D. Research design and methods, page 2 
E. Protection of Human Subjects, page 3 
F. References, page 8 
G. Consultants, page 8 
H. Facilities Available, page 8 
I. Investigator Brochure, page 10 
J. Appendix, page 10 
 
A. SPECIFIC AIMS 
 
Aim 1: To determine the effects of supplementary motor area low frequency repetitive transcranial 
magnetic stimulation (SMA LF-rTMS) + rehabilitation compared to rehabilitation alone on the locomotor 
network in patients with PD and FoG.  
Hypothesis: SMA LF-rTMS followed by rehabilitation will decrease connectivity between mesencephalic 
locomotor region (MLR) and SMA more so than rehabilitation alone. 
Aim 2: To determine the effects of SMA LF-rTMS + rehabilitation compared to rehabilitation alone on 
FoG severity in patients with PD and FoG. 
Hypothesis:  SMA LF-rTMS followed by rehabilitation will improve FoG severity (as measured by 
objective and subjective markers of FoG severity) more so than rehabilitation alone.  
 
B. BACKGROUND AND SIGNIFICANCE 
 
FoG is a debilitating condition, which occurs in the majority of patients with PD1-3.  FoG often leads to 
falls, hospitalizations, or nursing home placement and has been found to be the most important predictor 
of poor health-related quality of life2, 4-6. Current treatment strategies aim to optimize response to available 
medical or surgical therapies; however, responses are limited, inconsistent and short lived.  Previous 
rehabilitation strategies have yielded only modest improvements in gait parameters not FoG specifically, 
and there is no evidence of sustained efficacy.  As our knowledge of the pathophysiology grows, we 
begin to understand that FoG is not purely a dopaminergic circuit phenomenon.  Preliminary evidence 
from our group and others support the notion that FoG is a network dysfunction with significant 
contribution from cortical structures.  Our observation of the reversibility of FoG following immobilization 
supports the plausibility of network modulation and rehabilitation as a therapeutic approach.   
By characterizing locomotor network dysfunction in FoG before and after cortical inhibition and 
rehabilitation we can provide further evidence of increased cortical governance as a major contributor to 
Medical University of South Carolina 
Protocol 

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the pathophysiology of FoG.  Furthermore, the pilot data gathered here will not only support the feasibility 
of neuromodulation of the locomotor network, but will support the use of cortical inhibition as a therapeutic 
approach to FoG.  We believe that with our current understanding of the locomotor network, we can 
target the supplementary motor area (SMA) in a non-invasive way with rTMS, and normalize locomotor 
network activity.  This approach will mimic the immobilization periods, releasing cortical control in a 
targeted manner.  Once this maladaptive process is removed, patients will be primed to walk without 
cortical interference.  This provides a therapeutic window where rehabilitative approaches designed to 
increase automatic gait.  By performing this combined cortical inhibition and gait training repeatedly we 
propose we will achieve network normalization and reverse FoG while gaining considerable knowledge 
regarding FoG pathophysiology, neuromodulation and rehabilitation.  
 
C. PRELIMINARY STUDIES 
Preliminary Studies:  We performed functional and diffusion MRI on 
46 patients with PD, 22 patients with FoG and 24 PD controls.  There 
was increased functional connectivity between PPN and multiple 
structures (including the SMA) within the motor network in FoG 
compared to PD-controls (see figure 1).  We also found a significantly 
increased fiber count with diffusional kurtosis imaging (DKI) based 
tractography on tracts originating in the left PPN and ending in the 
SMA (see figure 2). Overall our data demonstrates the feasibility of the 
use of functional and structural MRI for evaluating these networks in 
our hands, as well as supporting the central hypothesis of increased 
cortical control.   
We looked at dual task interference for velocity, step length, time to 
turn and overall task time on 23 subjects from our cohort that had full 
set of gait analysis data.  We found dual task interference to be greater 
in patients with FoG compared to PD controls, particularly in the off 
medication state, and for the overall task and turning task (see Figure 
3).  This data supports the notion that dual task interference, 
particularly for turning is an important marker for FoG severity, and can 
be used as an effective outcome measure in our study.    
D. RESEARCH DESIGN AND METHODS (including data 
analysis)  
Imaging Protocol: Subjects will undergo identical imaging protocols 
before and after intervention.  For structural imaging deterministic 
fiber-tracking algorithm based on DKI will be used, with a seeding 
region placed at the PPN to the ending region at the SMA.  The 
anisotropy threshold for all subjects will be set at 0.20, angular 
threshold at 40 degrees, and step size at 1.5 mm. Tracks with length 
less than 60 mm were discarded and a total of 10000 seeds were 
placed.  For fMRI, subjects will have eyes closed at rest (resting state 
or RS fMRI). BOLD time series will be extracted via SPM 12’s marsbar toolbox from predetermined 
regions of interest (ROIs) including the left PPN, STN, pallidum, cerebellum, putamen, caudate, primary 
motor cortex, SMA, and thalamus.  Time course correlations will be performed to determine a correlation 
coefficient between the PPN and locomotor network ROIs.  For the interleaved TMS/BOLD protocol 
patients will lay supine in the MRI scanner with a TMS coil mounted in the MR head coil.  Resting motor 
threshold (RMT) will be obtained, and the coil will be adjusted from the motor cortex to the SMA.  
Participants will then receive a run of TMS/BOLD (12 single pulses with 12 second interpulse interval at 
110% RMT).  
0
200
400
600
800
1000
Left
Right
Non-Freezers
Freezers
p = 0.05
Figure 2. 
-0.1
0.1
0.3
0.5
0.7
0.9
PPN-M1
PPN-Caud
PPN-Put
PPN-Thal
PPN-Cereb
PPN-SMA
PPN-STN
Correlation Coefficient
Non- Freezers
Freezers
Figure 1. 
-80.00
-60.00
-40.00
-20.00
0.00
20.00
40.00
Velocity
(cm/sec)
Average
Step
Length
(cm)
M2 Time
to Turn
(sec)
Overall
Task Time
(sec)
Control
OFF
ON
Figure 3. 

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Patient Selection:  Subjects meeting diagnostic criteria for PD 
and documented FoG will be recruited from the MUSC 
Movement Disorder Clinic by clinical staff.  Subjects with 
contraindications to MRI, or TMS (no history of seizures, no 
metal implants in head, no pregnancy) dementia, or inability to 
complete the walk 30 feet in the off state without assistance will 
be excluded.  Questionnaires to assess cognitive, quality of life 
(PDQ39) and FoG assessments (nFOG-Q7) will be administered 
at screening visit and post intervention.  Standard motor (Unified 
PD rating scale; UPDRS) assessments will be performed at the 
time of gait analysis (see Table 1).  Women of childbearing 
potential will have a urine pregnancy test.  
rTMS Protocol: Active rTMS will be delivered to the bilateral SMA 
region at the following parameters: 1 Hz, 1200 total pulses, 110% 
resting motor threshold (rMT), 20 minutes total for ten total 
sessions.  Sham stimulation will be administered using the 
Magventure B-65 placebo system in which the sham side of the 
coil was placed over the pre-SMA (no magnetism delivered) and 
electricity is delivered to scalp stimulating electrodes in the same 
pulse sequence as active stimulation replicating stimulation 
sensation.  This device is FDA approved for Depression.  
Participants will be given a questionnaire to complete about their 
thoughts on the treatment.  This will occur on the last day of the 
intervention period (10th day of intervention).  
Rehabilitation Protocol:  Subjects will undergo ten, 20 minute, 
dual task training sessions immediately following each rTMS session.  Dual task training will consist of 
repetitive trials of straightaway walking and turning while adding increasingly difficult concurrent cognitive 
tasks (working memory language and calculation).  Subjects will be instructed to focus on the cognitive 
task, not on their gait with the goal of improving gait without increasing error rate on the cognitive task.  
Variations of this protocol have been successfully implemented in this patient population8, 9.    
Trial Design and outcomes: Subjects will be randomized to either active rTMS + rehabilitation or 
rehabilitation alone at a 2:1 ratio (10 active: 5 control).  An additional 6 patients will be randomized to 
either active rTMS + rehabilitation or rehabilitation alone at a 1:2 ratio (2 active: 4 control).  This will bring 
total number of subjects to 12 active and 9 control. The primary outcome measure will be dual task 
interference for turning.   
Gait Assessment/Analysis Protocol:  Gait is assessed at baseline and post intervention.  Subjects will 
walk on an electronic walkway (GaitRite + M2) which will capture straightaway walking and turning, in the 
off medication and on medication state, under single and dual task conditions (2 trials each), capturing 
multiple spatiotemporal parameters.  Dual task interference for overall task time (timed up and go), step 
length, velocity and nFOG-Q scores will be secondary outcomes.  Gait assessment will be videotaped.  
Statistical analyses:  The sample size estimation is based on the primary (mechanistic) aim (Aim 1), 
since the effect size of the clinical aim (Aim 2) has not yet been established.  A two group t-test with a 
0.05 two-sided significance level will have 80% power to detect the difference between a treatment 
group mean of 0.11 and a control group mean of -0.06 assuming that the standard deviation is 0.10, 
when the sample sizes in the two groups are 12 and 9, respectively (a total sample size of 21). The 
mean and standard deviation estimates are based upon the functional connectivity strength for the 
FOG+ and combined control groups as reported in Fling et al 201410.  The observed treatment effects 
on FoG severity of the treatment group, as compared to the control group, will be used to determine the 
effect size of this therapy, and estimate the sample size for future trials aiming to determine efficacy.  
Table 1 
Summary of Activities: 
Screening Visit 
Cognitive Assessment 
Questionnaires 
Baseline Gait Analysis  
Baseline MRI Visit 
RS fMRI 
Diffusion MRI 
Interleaved TMS/BOLD 
Intervention x 10 days 
1Hz rTMS 
Dual task training 
Treatment questionnaire (day 10 only) 
Post-Tx Gait Analysis 
Post-Tx MRI Visit 
Phone assessments 
(nFOGQ 1, 2 & 3 months) 

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E. PROTECTION OF HUMAN SUBJECTS 
 
1.  RISKS TO THE SUBJECTS  
a.  Human Subjects Involvement and Characteristics  
 
Participants will range in age from 18-80 years of age.  Patients will be recruited from the Movement 
Disorders clinic at MUSC.  The subject population will consist of people with a diagnosis of Parkinson’s 
disease, as defined by UK Brain Bank diagnostic criteria for Parkinson’s disease that have FOG as 
identified by item 14 of the UPDRS.    Parkinson’s disease commonly affects both men and women of 
all ages.  Since Parkinson’s disease does not discriminate gender or age, subjects classified as 
“vulnerable” may be included.  Our study population reflects the demographics of this population and 
area that meet the inclusion criteria. 
As subjects are seen for their medical treatment in the Movement Disorders Clinic, we will request their 
consideration to participate in the study.  We will review the premise of the study as well as consent 
form and address any questions or concerns to the subject’s satisfaction assuring them that 
participation will not affect their current or future medical care.  The subjects will be given a copy of the 
consent in clinic to read.  If the subject is interested in participating, they will be scheduled for a 
screening visit.  If the subject has not had an opportunity to read the consent at home, they will be 
given the opportunity to do so at screening and again the study protocol will be explained, and 
questions will be answered.  If the subject decides to participate they will sign the written institutional 
IRB approved consent form as well as the HIPAA authorization at that time.  All information and data 
will be stored in a locked office in the Movement Disorders Office, only accessible by the study staff. 
In some cases, there may be some subjects that do not have a scheduled appointment during the 
months designated for the study and we will need to contact the subjects by telephone to offer the 
opportunity to participate in the study.  They will be contacted by the treatment team first, if interested 
they will then be contacted by the study team.  If the subject is interested, we will schedule a screening 
visit (as described above) in order to review the study in person with the subject. If the subject wishes 
to proceed then we will complete and sign the consent form and HIPAA authorization and proceed with 
the remaining study visits.   
Our only “vulnerable” population that will be sampled in this study is the elderly with the concern of co-
morbid conditions that may affect their ability to participate; however, the inclusion criteria specifies that 
they will be able to physically participate in the study.  We will not be excluding any gender or 
race/ethnic population that fits the inclusion criteria.  Our sampling will reflect the population of the 
Movement Disorders clinic.  No children are involved in this study.  There will be no collaborating sites 
involved. 
b.  Sources of Materials  
Once potential subjects are identified and agree to enroll in the study they will be requested to sign the 
HIPAA authorization and informed consent. They will be assigned a sequential subject number for 
identification purposes and all subsequent materials collected will contain only their subject number.  
The research material that will be obtained during the study is noted above and will be kept in individual 
data binders assigned to each subject. 
c.  Potential Risks  
The subject may voluntarily withdraw from the study at any time.  This decision will have no impact 
upon their current or future medical care in our facility.   
The physical risks to the subjects related to the Gait Assessment protocol are similar to those risks 
present when walking down the sidewalk.  Subjects that are asked to delay the time they take their 

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morning medications or turn off their DBS device may feel their Parkinson’s symptoms for a longer 
period of time on the morning of that visit.  Patients are often asked to delay their morning medications 
when evaluated in our clinics as part of standard practice.  In order to minimize this delay these visits 
are scheduled first thing in the morning.  Physical risks would include musculoskeletal injury due to fall 
or overexertion.  A harness will be used when subjects walk on the treadmill and a physical therapist 
will be walk along side the patient when subjects are walking on the electronic walkway or hallway.  
Loss of Confidentiality Risk: There is a potential risk of loss of confidentiality with this study.  The video 
will show your face as you walk. The videotape will be stored on a secure, password-protected server 
at MUSC, and only MUSC staff will have access to it. 
The physical risks to the subjects related to the MRI are primarily related to movement of any iron 
containing items in the MRI room, or of any iron containing implant.  Patients with iron containing 
implants are excluded from the study.  Precautions have been taken to eliminate this risk.  Iron 
containing items are not allowed in the MRI room.  Patients may also experience discomfort or 
emontional stress related to the MRI.  These discomforts are primarily related to the feelings of 
claustrophobia or loud noise generated by the MRI scanner.  Patients are provided with ear plugs and 
are educated about the procedure beforehand to reduce discomfort.  
The following is a summary of TMS related risks: 
 
Physical: There are minimal risks associated with rTMS, which are further minimized when proper 
screening is completed. Nonetheless, there are several physical risks associated with rTMS. In very 
rare circumstances seizures can be induced by TMS but all instances of TMS induced seizures were 
isolated and no long term inducement of seizures has resulted from TMS. There are also a host of 
physical side effects associated with rTMS, which vary drastically by location of stimulation. These 
include but are not limited to: headaches; scalp soreness; ear discomfort; hearing loss; fainting or 
faintness; and muscle pains. Among published rTMS studies that targeted the pre-SMA or vertex, no 
seizures have been reported. Previous research has reported that rTMS to the pre-SMA is well 
tolerated. Fainting may also occur during exposure therapy, although this is rarely reported.  
 
Potential risk of a seizure: In designing this experiment, we have followed the latest safety guidelines 
for TMS. Despite these precautions, there is a very small chance that you could have a seizure as a 
result of rTMS. Eight seizures have been noted in previous studies, with six of them occurring in healthy 
volunteers without any history of seizures, brain tumors or traumatic brain injuries. All of these seizures 
have occurred during rTMS with the participant in the treatment chair and a trained operator on hand. 
All seizures have stopped by themselves without any medication. No participants have had any 
problems after the seizures. MUSC has a plan for dealing with fainting and seizures, and every TMS 
researcher is familiar with it. If you have a seizure, you will be made to lie down with your legs elevated. 
An emergency response team will be called. Most seizures, including those caused by rTMS, last less 
than 60 seconds and do not require any medication. A neurologist will evaluate you once you recover 
from the seizure. Any participant who has a seizure cannot continue with the study.  
Potential for scalp discomfort and headaches: Some people report mild discomfort when the 
magnetic pulses are applied over the scalp. A small number of people (~5%) report headache following 
rTMS. However, the headaches are temporary and manageable with common over-the-counter pain 
remedies. 
Potential worsening of mood with TMS: rTMS is an FDA-approved therapy for treatment-resistant 
depression. There is no evidence that rTMS causes depression or worsens mood. We will work closely 
with you to familiarize you with the TMS equipment and setup to help with anxiety you may have about 

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the procedures. The Brain Stimulation Laboratory team members at MUSC are experienced with the 
proposed procedures and are among the leading experts in the field of brain stimulation and TMS. 
Other potential effects of TMS on brain tissue: TMS is thought to be safe, with no brain damage, 
despite extensive use in humans and other animals. We have reported a safety study looking at the 
MRI scans before and after 2 weeks of daily left prefrontal TMS for depression. No structural changes 
were found in left prefrontal lobe of patients who received active TMS compared to placebo. We have 
also performed an MRI diffusion imaging study before and after TMS/fMRI and found no deleterious 
effect of TMS on brain tissue at the site of stimulation. 
Potential hearing loss: The TMS coil generates a high-energy click that may cause hearing damage. 
Humans exposed to TMS have shown temporary increases in auditory threshold (especially at high 
frequencies) lasting at least 5 minutes and less than 4 hours. Foam earplugs can protect against these 
changes and will be worn during TMS sessions. 
Potential changes in cognitive function: There have been no reports of long-term changes (more 
than a minute) in cognitive function (memory, attention, etc.) in TMS studies. Safety studies specifically 
looking for these changes did not find any effects of TMS with the exception of one open study in which 
healthy volunteers were exposed to 150 trains of TMS at different site of stimulation in an experiment 
that lasted more than 3 hours. There was a significant decrease in scores on a logical memory test. 
The stimulation parameters exceeded the recommended safety range and there was no control for 
patient fatigue or other non-specific effects.  
Safety in case of pregnancy: This protocol will exclude pregnant women. The risks of using TMS with 
pregnant women are currently unknown. Please inform the research team if you are pregnant or think 
that you might have become pregnant during the study. A pregnancy test will be performed before the 
experiment begins. 
Unknown Risks: TMS is an experimental procedure that has not been approved by the FDA as 
anything other than a therapy for treatment-resistant depression. The Principal Investigator will let you 
know if they learn anything that might make you change your mind about participating in the study. 
Social and Economic: The treatment design will require that all participants attend daily, 1 hour 
treatment sessions for 3 concurrent weeks during each work day (Mon. - Fri.). This may cause 
disruption of normal social and work schedules and may even result in work hours lost. To minimize 
this potential problem, sessions will be scheduled around the participant’s personal schedule. 
 
2.  ADEQUACY OF PROTECTION AGAINST RISKS  
 
a. Recruitment and Informed Consent 
Subjects who meet the inclusion/exclusion criteria will be recruited from the Movement Disorders Clinic.  
Consent will be obtained by the study personnel.  All research data and informed consents will be 
collected and stored in a locked office in the Movement Disorders office only accessible to the study 
staff. A source document worksheet will be utilized to document the consent process including HIPAA 
authorization and ensure each patient has been cleared medically by their treating physician and 
specialist if deemed necessary. A copy of the informed consent and HIPAA authorization will be given 
to the subject for their personal records. 
b. Protection against Risk 
The participation of human subjects in research falls under the jurisdiction of federal regulations (45 
CFR 46 and 21 CFR 50 and 56).  MUSC investigators are granted the privilege of working with human 

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subjects under normal assurance to the government that such research complies with regulations 
protecting human subjects.  The university has a federal-wide assurance for research with human 
subjects (FWA 00001888, Feb 2002), and is in compliance with federal policy governing use of human 
subjects.  Individuals involved in human subject research at MUSC are required to complete the 
Collaborative IRB Training Initiative (CITI) offered on-line by the University of Miami.  All human subject 
protocols are reviewed through an academic Institutional Review Board (IRB) process.  The Office of 
Research Integrity coordinates the activities of three IRB committees.  The MUSC IRB is accredited by 
the Association for the Accreditation of Human Research Protection Programs.   
This study does not require subjects to exercise or exert themselves in any way, the gait training 
protocol expects patients to maintain self selected speed, however it does challenge their gait by 
having them perform cognitive tasks while walking, always accompanied by a therapist. Patients will be 
monitored throughout the study for the development of any adverse events.  An adverse event related 
to study procedures would be the development of new onset symptom directly related to the gait 
analysis or MRI procedures.  A serious adverse event would be defined as any event that jeopardizes 
the subject’s health, requiring hospitalization, resulting in significant, persistent disability, birth defects, 
congenital anomaly or resulting in a life threatening event or death.  Should any medical complications 
arise during active testing, the test will be stopped and immediate medical care will be rendered. The 
subject could be directed to one of our on-campus emergency rooms to further administer care if 
needed. Additionally, the subject will have the ability to stop active testing (ie the treadmill or MRI) at 
any point during the testing (treadmill has an emergency stop button and patients can communicate 
with MRI technician) and would be able to dis-enroll from the study altogether at any point during the 
time of the study. To protect confidentiality, subjects will be assigned a unique study identifier. This is in 
order to eliminate identifying Protected Health Information (PHI) on all data collection sheets, including 
participant diaries and investigator records.  All signed consents and source document worksheets 
pertaining to the study will be stored in a locked office in the Movement Disorders Research Office.  
During the course of the study, user access to this information and participant identifiers will be 
restricted to staff associated with the study.  Computerized data will be stored on a secure, password 
protected, network. 
Participants must meet specific medical and historical screenings (e.g., no history of seizures, no metal 
implants in head, no pregnancy) to minimize risks associated with repetitive transcranial magnetic 
stimulation (rTMS).  Participants will complete a TMS safety screening that includes a series of basic 
health and history questions that are used to thoroughly mitigate risk of injury from TMS. The TMS 
safety screening is based on internationally agreed upon standards of safety. The screening will be 
administered in interview format to candidate participants and to enrolled participants.  
 
3.  POTENTIAL BENEFITS OF THE PROPOSED RESEARCH TO THE SUBJECTS AND OTHERS  
 
By completing this study subjects will be able to understand better the severity of the freezing of gait, 
how the currently prescribed medications and stimulation affects it, and will also have information about 
their cognitive abilities.  This information can be provided to their treating physicians to help guide 
treatment decisions.  Furthermore, the proposed intervention may be of benefit for their walking.  
 
4.  IMPORTANCE OF THE KNOWLEDGE TO BE GAINED  
 
Identifying an effective means of measuring FoG severity will make it possible to test the efficacy of 
multiple potentially effective therapeutic agents.  Understanding the pathways most related to FoG via 
our imaging protocols would yield potential therapeutic targets for this condition.  Finally, collecting pilot 
data on this specific intervention may yield sufficient data to justify a larger trial.  
 

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5.  SUBJECT SAFETY AND MINIMIZING RISKS (Data and Safety Monitoring Plan) 
The participant is at minimal risk during the intervention; however, safety precautions will be taken by 
securing medical clearance for all participants.  During the Motion Analysis and gait training portion of 
the study, subjects will be attended by the research therapist at all times. We do not anticipate any 
cardiovascular discomfort since subjects will not be asked to exert themselves in any way.  Lab 
technician will take all necessary precautions including the use of a harness to avoid falls.  Additionally, 
the participant will be aware that they may discontinue the study at any time.  Subjects will be aware of 
all possible side effects at the time of screening and will be instructed to notify the PI or Co-PI 
immediately if they experience a side effect. 
Internationally recommended TMS screening procedures will be completed prior to in person screening, 
during in person screening/enrollment, and prior to each rTMS session to minimize the chance that 
participants are at risk for severe risks associated with rTMS (e.g., seizures). Short term side effects 
such as migraine headaches can be minimized by recommending that participants take an OTC pain 
killer (e.g., Ibuprofen) on their own volition. 
If an emergency should present, the facility is located on the MUSC campus with 24-hour access to the 
MUSC Emergency Room that is staffed by an emergency response team.  
If during assessment of a subject’s UPDRS score, the subject is found to be severely depressed or 
suicidal, the investigator will verify the patient's current mental health status and ensure the patient is 
directed and transported to the nearest psychiatric emergency services immediately or arrange for 
expedited evaluation by psychiatric services if the patient is not actively suicidal. 
Data will be kept stored in a locked office in the Movement Disorders Research Office.  During the 
course of the study, user access to this information and participant identifiers will be restricted to staff 
associated with the study.  Computerized data will be stored on a secure, password protected, 
institutional approved database. 
F. REFERENCES/LITERATURE CITATIONS 
 
1. 
Forsaa EB, Larsen JP, Wentzel-Larsen T, Alves G. A 12-year population-based study of 
freezing of gait in Parkinson's disease. Parkinsonism Relat Disord 2015;21(3):254-258. 
2. 
Perez-Lloret S, Negre-Pages L, Damier P, et al. Prevalence, determinants, and effect on quality 
of life of freezing of gait in Parkinson disease. JAMA neurology 2014;71(7):884-890. 
3. 
Nieuwboer A, Giladi N. Characterizing freezing of gait in Parkinson's disease: Models of an 
episodic phenomenon. Mov Disord 2013;28(11):1509-1519. 
4. 
Moore O, Peretz C, Giladi N. Freezing of gait affects quality of life of peoples with Parkinson's 
disease beyond its relationships with mobility and gait. Mov Disord 2007;22(15):2192-2195. 
5. 
Grimbergen YA, Munneke M, Bloem BR. Falls in Parkinson's disease. Curr Opin Neurol 
2004;17(4):405-415. 
6. 
Walton CC, Shine JM, Hall JM, et al. The major impact of freezing of gait on quality of life in 
Parkinson's disease. J Neurol 2015;262(1):108-115. 
7. 
Nieuwboer A, Rochester L, Herman T, et al. Reliability of the new freezing of gait questionnaire: 
agreement between patients with Parkinson's disease and their carers. Gait Posture 2009;30(4):459-
463. 
8. 
Brauer SG, Morris ME. Can people with Parkinson's disease improve dual tasking when 
walking? Gait Posture 2010;31(2):229-233. 
9. 
Schabrun SM, Lamont RM, Brauer SG. Transcranial Direct Current Stimulation to Enhance 
Dual-Task Gait Training in Parkinson's Disease: A Pilot RCT. PLoS One 2016;11(6):e0158497. 

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10. 
Fling BW, Cohen RG, Mancini M, et al. Functional reorganization of the locomotor network in 
Parkinson patients with freezing of gait. PLoS One 2014;9(6):e100291. 
G. CONSULTANTS 
n/a 
 
H. FACILITES AVAILABLE 
 
The Center for Rehabilitation Research in Neurological Conditions houses two separate laboratories for 
assessing gait, and has facilities in the third floor hallway that are typically used for gait training.  The 
lab is equipped with state of the art equipment capable of various measures of gait and movement.  
The clinical research program is housed in 208B Rutledge Avenue at the Murray Center for Research 
in Parkinson’s Disease, together with clerical support personnel and office machinery.  The Program 
also sees outpatients in the Rutledge Tower, a 158,000 sq foot modern complex for ambulatory care.  
The clinical laboratory is also house in the building with a staff experienced in the performance of 
clinical trials, under the direction of a Clinical Research Coordinator.  Portable digital video recording is 
present in the Neurology Clinic as well as video studio in the research facility.  The performance site 
complies with regulations cited in 45 CFR Part 46. 
3T MRI scanners are available in the Center for Biomedical Imaging at 30 Bee Street or Rutledge 
tower. 
 
The Brain Stimulation Lab (BSL) is a series of labs and offices (>3000 square feet) primarily located on 
the 5th floor of the Institute of Psychiatry (IOP). BSL studies use electromagnetic approaches as either 
research tools investigating neuroscience questions or as investigational or FDA approved treatments 
for brain diseases. Techniques actively being used by BSL researchers and their collaborators include: 
transcranial magnetic stimulation (TMS), vagus nerve stimulation (VNS), transcranial direct current 
stimulation (tDCS), electroconvulsive therapy (ECT), deep brain stimulation (DBS) and epidural cortical 
stimulation (epCS). TMS is a non-invasive technique for mapping brain functions and possibly treating 
neurospychiatric disorders such as Parkinson's disease, chronic pain and depression. MUSC’s BSL 
team has been a world leader in TMS research since 1995, performing basic research studies using 
TMS as well as using TMS in clinical trials, such as an NIMH-sponsored study of depression (OPT-
TMS) and studies of TMS to inhibit pain, determine if TMS can change food cravings, and determine if 
TMS can help modify symptoms in stroke patients. ECT, VNS and TMS are clinical services offered 
within the BSL. BSL researchers at MUSC were the first in the world (in 1998) to implant VNS devices 
in patients with major depression who had not adequately responded to traditional antidepressants. 
DBS and epCS are more invasive than TMS or VNS, but are less invasive than traditional brain 
surgery, where the brain is permanently lesioned. DBS of the thalamus is approved for the treatment of 
Parkinson's disease and the BSL has studies underway using DBS or epCS for treatment resistant 
depression. Members of the BSL team overlap and collaborate with the Center for Advanced Imaging 
Research (CAIR). In some instances, brain stimulation techniques are delivered in conjunction with 
fMRI studies to examine relevant circuitry. 
Current equipment in the BSL includes 14 TMS machines, some of which are historical display pieces: 
a 1993 Cadwell® High Speed MES-10 (with a water-cooled figure-8 coil), a Dantec® MagPro (with a 
figure-8 and a round coil) and newer Dantec machine, four NeoPulse Neotonus® Model 3600 
stimulators (with solid focal coils and sham coils), a Magstim® Rapid, Super-Rapid and Bistim 
machines (with figure-8 and double- cone coils). We also have a new Brainsway H-coil device and a 
Neuronetics Neurostar machine. For determining motor thresholds, the BSL has a Dantec® Cantata 
EMG machine and a laptop computer with MacCRO Spike software and Colborne amplifiers. The ECT 
suite has two MECTA Spectrum 5000Q machines and a Thymotron IV. Desktop computers with 22” 

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LCD monitors run Brainsight®, a software program for frameless stereotaxy used for image-guided 
targeted TMS. 
The laboratory also contains a resting ECG analysis system, phlebotomy chair, exam table refrigerator, 
automated blood pressure monitor, ophthalmoscope, and an L-shaped counter with two sinks. There is 
a nasal oxygen supply and an emergency cart. The BSL has 3 image analysis workstations networked 
directly to the Center for Advanced Imaging Research (CAIR) for rapid image data analysis and transfer 
of functional imaging data needed to guide TMS placement using Brainsight. The BSL psychometrician 
utilizes a designated neuropsychological testing room containing desktop and laptop computers to run 
neurocognitive and attention test software such as the CPT, PsyScope.1.2.1, visual working memory 
task, WCST, etc. 
Previous studies in the BSL have ranged from clinical trials in unipolar depression, bipolar affective 
disorders, borderline personality disorder (BOPD), chronic pain and acute laboratory pain, to challenge 
studies in generalized anxiety disorder, post-stroke aphasia, Tourette’s syndrome, Parkinson’s disease 
and schizophrenia. There are numerous studies as well integrating TMS with functional imaging 
(SPECT tracers injected in this lab or interleaved TMS/fMRI studies in the CAIR). Additionally the BSL 
was funded through the Defense Advanced Research Projects Agency (DARPA) to perform sleep-
deprivation studies in healthy adults and use within-individual fMRI-guided TMS to determine if TMS 
can produce improvements in performance. 
Inter-TMS-administrator reliability is established across all clinicians and scientists involved in studies to 
insure safety and standardization of TMS delivery and minimal, standardized interaction with research 
patients during TMS delivery. TMS treatment is logged in terms of the number of magnetic stimuli 
exposure for both study patients and researchers present in the room. Weekly meetings are held to 
discuss clinical and research related issues as well as to share the latest scientific findings and to 
discuss future projects related to the field. The BSL also serves as the international editorial office 
headquarters of Brain Stimulation, Basic, Translational and Clinical Research in Neuromodulation, 
published by Elsevier 
 
I. INVESTIGATOR BROCHURE ____________________________________________________ 
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