The Human Thalamocortical Network in Tourette Syndrome
Phase: NA
Conditions: Tourette Syndrome
Sponsor: University of Florida

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Protocol with Statistical Analysis 
Plan Included 
 
 
Project Title:  The Human Thalamocortical 
Network in Tourette Syndrome 
 
 
ClinicalTrials.Gov NCT:02056873 
 
Date: 23September2019 
 
 
 

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IRB Protocol 
1) Project Title:  The Human Thalamocortical Network in Tourette Syndrome  
 
2)   Principal Investigators:  Dr. Michael Okun, Dr. Aysegul Gunduz (Co-PI, PI 
Proxy) 
 
3)   Abstract:  Deep brain stimulation (DBS) has emerged as a highly efficacious 
treatment for addressing basal ganglia disorders[14-16, 61] such as Parkinson disease, 
essential tremor, and dystonia. Recently, groups including the UF Center for 
Movement Disorders and Neurorestoration have applied DBS for the treatment of 
OCD and TS[10-12, 59]. Although three brain targets have been tested in open-label 
series, one, the centromedian (CM) thalamus-parafascicular complex, has to date the 
greatest number of documented cases revealing significant improvements in motor 
tics). The globus pallidus interna (GPi) and the anterior limb of the internal capsule 
(ALIC)/nucleus accumbens have also emerged as potentially effective areas for 
amelioration of medication refractory tics, however they have been less studied[24, 
49]. The CM target was chosen for this study as we believe it will have the greatest 
chance to yield positive efficacy and safety data (specific aim 1), and will also 
provide a target where physiological changes related to motor tics are likely to be 
discovered (specific aim 2)[59]. The University of Florida uses the CM thalamic 
region target for Tourette DBS.  The reason that this target was chosen for this 
protocol was that our center has used the target and developed preliminary safety and 
efficacy data.  This target also is the most commonly used worldwide, and we track 
all side effects of all global implants in the International Tourette Deep Brain 

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Stimulation public database at our institution and this is recently published in JAMA 
Neurology.  We have shown CM has the physiological signals that differentiate tic 
from voluntary movement and this makes it an ideal target.  Side effects depend on 
the contact chosen for programming and we can adjust the stimulation to avoid all 
side effects.  The side effects we encounter include paresthesia, dysarthria, dizziness, 
pulling (capsule) and blurry vision.  These are reversible with programming changes. 
We will assess the effectiveness of chronic (continuous) stimulation of the CM 
thalamic region for suppressing motor tics in TS (specific aim 1).  The Medtronic 
Summit RC+S device and cortical ECOG strips (Model 09130) can record local field 
potentials (LFPs), and can be programmed to detect specific electrographic patterns. 
The device allows physiology to be recorded even after internalization of the 
hardware. The physiology underlying TS will be examined in specific aim 2. 
Additionally, in specific aim 2 we will be able to record from electrocorticography 
(ECOG) leads (Medtronic Model 09130 cortical strip) which will be placed over the 
pre-motor and motor cerebral cortex.  These studies will enhance our understanding 
of the pathophysiology of the disease and will help in developing better rationales for 
future studies.  The experimental design will facilitate stimulation in the CM region, 
and recording from the ECOG.  The presence of a detectable physiological change in 
CM or from the ECOG (specific aim 2) will allow for the experimental use of a 
closed loop DBS system, where a tic is detected on the ECOG, and a stimulation 
pulse is delivered in the CM region (specific aim 3).  
4)   Background:  Tourette syndrome (TS) is a chronic neurodevelopmental disorder 

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characterized by motor and phonic tics, typically occurring with childhood onset[1-5].  
The syndrome is commonly associated with other neuropsychiatric comorbidities (e.g. 
attention deficit hyperactivity disorder (ADHD), obsessive compulsive features (OCD), 
and other behavioral manifestations). In the majority of TS cases the motor 
manifestations can be managed using a combination of TS education, comprehensive 
behavioral intervention for tics (CBIT), and/or a variety of medications, and behavioral 
therapy[5, 6]. The natural history of TS has revealed that most patients will experience 
significant improvement of tics in late adolescence or early adulthood[5, 6].  However, 
experts now recognize that there is a subset of patients who will continue to experience 
disabling tics despite optimal medication and behavioral management.  For these 
severely affected patients, deep brain stimulation (DBS) has the potential to improve 
refractory and disabling tics[7]. 
DBS has been well established as a treatment for Parkinson’s disease, essential 
tremor, dystonia, and OCD, and has achieved full approval, or a humanitarian device 
exemption for each of these indications.[8-18]  There have been many DBS studies 
and position papers detailing careful and meticulous techniques for screening 
patients[19-21].    
DBS, though a minimally invasive therapy, still has associated risks, and DBS failure 
can result in medical complications and this endpoint can have economic 
consequences[22]. Patient selection and management can likely improve the risk-
benefit ratio for individual sufferers and this will likely apply to TS DBS[23]. The 
importance of pre-operative assessment, patient selection, DBS team expertise, DBS 
team experience, and post-operative management has been shown to be important, 

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especially when groups have studied cohorts of patients that have been DBS 
failures[22, 23].  Since TS is a childhood onset disorder, often with complex clinical 
features, a waxing and waning course, and frequent neuropsychiatric 
comorbidities[5], the evaluation of patients has a level of complexity greater than 
many of the other current DBS indications[23]. During the evaluation period there is 
also a risk that tics may be falsely under- or over-quantified due to frequent changes 
in tic manifestations, and effects of social context. The first attempted surgeries for 
TS were ablations (i.e. lesions) placed in the thalamus and these were performed by 
Hassler and Dieckmann[24]. In 1999, Visser-Vandewalle reported the first case of 
thalamic DBS for TS[25]. Since this report, multiple groups have observed 
improvement with DBS despite utilizing many brain targets and many approaches[25-
43].  
Most early TS DBS studies consisted of either single case reports or small case series 
(Level of Evidence IV), and these reports had widely variable methodological and 
outcome reporting[23]. Since the initial reports and guidelines there has been an 
explosion in the field of international publications reporting both DBS successes and 
failures.. In 2005, the TSA hosted a meeting of internationally recognized experts to 
develop recommendations to guide research and early use of DBS in TS[44].    
Additionally, a collaborative international network of investigators was established, 
and in 2010-11 the TSA commissioned an International Database of Deep Brain 
Stimulation Studies in Tourette Syndrome (TSA DBS Registry, http://tsa-
usa.org/dbs/), which has been recently launched.  The major update since 2006 has 
been the relaxing of the recommendation that all patients be 25 years of age or older.  

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Tourette, has now followed all of the other DBS indications which use age as a 
relative factor in the decision by a multidisciplinary team.  There is no standard 
accepted age for DBS surgery, and there have been many reported successful cases 
below the age of 25[37, 42]. 
5)   Purpose:  The purpose of this research study is to evaluate the effectiveness and 
safety of a possible new treatment for TS. The Medtronic Summit RC+S device and 
cortical ECOG strips (Medtronic Model 09130 cortical strip) can be programmed to 
record physiology and to provide chronic (continuous stimulation), or alternatively 
responsive stimulation to deep brain structures.  
 
Specifically, this investigation will: 
(1)  Test the hypothesis that centromedian (CM) continuous brain stimulation 
will be an effective and safe method for the treatment of tics in medication 
refractory TS. There is now a growing body of evidence supporting the use of DBS 
for tic suppression. Implantable brain stimulators provide a reversible and 
programmable solution to neuromodulation which are safer (no tissue destruction) 
and potentially more effective than ablative techniques such as thalamotomy, 
capsulotomy, and cingulotomy, especially because they can be performed 
bilaterally[62]. There are however important issues that may limit standard DBS 
effectiveness in this population including specific problems unique to this group of 
patients including the paroxysmal nature of the disorder. It would be desirable to 
design a therapy such as the one proposed in this grant application to neuromodulate 
only when needed (closed loop or responsive therapy). We plan to implant CM 

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thalamus and cortical ECOG bilaterally in 10 medication refractory TS subjects. We 
will employ a prospective blinded staggered onset design. We hypothesize that by 
using a chronic (continuous) stimulation strategy we will be able to achieve a greater 
than 40% reduction (over 6 months) in total tics (motor and phonic on the YGTSS) in 
more than ½ of our subjects (6/10). We will in this study assess safety and also 
employ stopping rules to ensure subject safety. 
(2)  Define the intra-operative and post-operative physiological changes seen in 
TS. We hypothesize that there will be rate and pattern changes in the physiology that 
will correlate with the clinical manifestation of motor and phonic tics. Following 
implantation and internalization of hardware, the device used in this study will be 
able to record physiology (i.e. the LFP). This unique feature is not currently available 
for other FDA approved brain stimulation devices (Medtronic PC and SC, 
Minneapolis, Minn), and the option will allow our team to document physiology, and 
to measure, using videotape analysis, electromyogram, and position sensors placed on 
muscles and areas of the body that exhibit tics, and we will attempt physiological 
correlation using LPS’s from the CM region and from ECOGs. We have recently 
discovered band specific frequencies[59] in thalamic LFPs, and these frequencies 
emerged after therapeutic DBS in a small cohort of human TS subjects. We quantified 
increases in gamma oscillations and their correlations with improvement of TS 
symptomatology, and found that those subjects obtaining the best clinical outcome 
from thalamic DBS exhibited the greatest gamma power changes[59]. Thus, the 
correlation between gamma band activity and clinical tic scores supports the theory 
that thalamic gamma band dynamics[59] are correlated with improved 

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symptomatology in TS. Because synchronized gamma oscillations are a fundamental 
property of thalamocortical communication and DBS therapy, we will perform a 
comprehensive study of the modulations to define the relationship between gamma 
oscillations and tic expression in cortical and subcortical targets. In order to 
accomplish this goal, we will use a DBS system that utilizes an implanted 
programmable neurostimulator that will allow for synchronized recording of cortical 
and subcortical LFPs, and consequently enable the investigation of tic-related brain 
oscillation dynamics. This avenue of research is the first critical step in neurosensing 
and responsive neuromodulation. The neurostimulator (Medtronic Summit RC+S 
device and cortical ECOG strips (Model 09130) is novel in that it can be can be 
programmed to provide continuous or responsive stimulation. Both deep brain and 
cortical ECOG strips will be placed as part of this system. We will collect real time, 
local field potentials (LFPs) that are time synchronized with clinical behavior, and we 
will collect these from both the CM region and from pre-motor and motor cortex in 
order to study thalamocortical interactions in the context of human TS. The collection 
of these potentials will allow us to better understand the fundamental neural activity 
important to tic generation (specific aim 2), and to attempt responsive stimulation 
approach (specific aim 3). Our proposal will uncover the neuronal activity inherent to 
CM and from cerebral cortex, and will reveal how DBS affects this activity in the 
human TS patient. 
(3)  Test the hypothesis that responsive brain stimulation will provide an 
alternative to chronic deep brain stimulation in TS. We hypothesize that we will 
be able to use physiological changes collected in Specific Aim 2 to tailor a responsive 

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therapy for TS patients. This paradigm is preferable to chronic stimulation for its 
potential to reduce stimulation-related side effects. Outcomes will be measured by 
comparing the results of chronic continuous stimulation (Specific Aim 1) to an acute 
test of responsive stimulation (Specific Aim 3). Responsive stimulation parameters 
will be identical to chronic continuous stimulation parameters and will strictly be 
within safety ranges. If acute responsive stimulation leads to low side effects and 
comparable clinical outcomes for a patient, we will test chronic responsive 
stimulation for one week at a time, up to four weeks in total.  This procedure will be 
performed at an appropriate time point (approved by the Principal Investigator) after 
the 6 month primary endpoint is reached but prior to Month 36 (study completion) 
(see visits 6.1-6.4 in schedule of events).  The patient programmer will allow patients 
to turn off responsive stimulation and switch back to standard continuous therapy. A 
firmware update from Medtronic will allow the Summit RC+S internal signal sensing 
and processing units to communicate with the stimulation unit. Outcomes for chronic 
responsive stimulation will also be measured by comparing the results of chronic 
continuous stimulation. 
Duration of the Investigation: We expect the duration of this investigation will be 
five years. In the first year we plan to implant and follow the first two subjects. In 
Year 2 we will plan to implant and follow the third, fourth, and fifth subjects while 
we continue to follow the first two subjects. In Year 3 we plan to implant and follow 
the sixth and seventh, and eighth subjects while we continue to follow the first five 
subjects. In Year 4 we plan to implant and follow the ninth and tenth subject, but also 
to continue to follow the other eight subjects.  In Year 5 we will complete follow-up 

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and data analysis and submit publications for peer review.  These time estimations are 
plans that could be subject to change based on a number of external factors that may 
be out of our control.  We plan to follow each subject clinically for a minimum of 24 
months following implant, and to follow them for 12 more months for a minimum of 
2 and a maximum of 4 research visits, and then clinically each year as long as they 
wish to remain implanted, and to assess needs for battery replacement.  We plan to 
apply to CMS and Medicare for insurance coverage of the device implantation and 
battery replacement costs, and to apply to Medtronic for device donation (Medtronic 
has already reviewed this proposal in their scientific grants committee and approved 
donation of the devices and replacement devices). 
6)   Protocol:  Methodology to be used - The study will be a prospective blinded 
design. Subjects will include ten individuals with medication refractory and severely 
disabling TS. We expect to consent and screen 50 individuals in order to enroll ten. A 
total of 6/10 subjects (60%) will need to be “responders” as a result of the 
intervention (YGTSS motor tic subscale reduction of >40%) for this study to reach 
effectiveness criteria. 
Inclusion Criteria 
• The diagnosis of TS must be made by both a fellowship-trained movement 
disorders neurologist and a psychiatrist and must meet Diagnostic and Statistical 
Manual of Mental Disorders (DSM-V) criteria for a diagnosis of TS. 
• 
Yale Global Tic Severity Scale (YGTSS; 100) must be >35/50 for at least 12 
months and the motor tic subscore >15. The TS must be causing incapacitation 
with severe distress, self-injurious behavior, and/or quality of life disruption. 

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OCD, Depression, and ADHD are not exclusionary[63-65] provided tics are the 
major difficulty requiring surgical intervention. 
• 
There are no gender criteria for this study. 
• The subject’s TS symptoms must be medication refractory. To meet the 
medication refractory criteria, subjects must have been treated by a psychiatrist or 
neurologist experienced in TS with therapeutic doses (doses adapted from 
Scahill’s recommendations of at least three dopamine blocking drugs) either 1-4 
mg/day of haloperidol or 2-8 mg/day of pimozide, risperidone (1-3 mg/day), and 
aripiprazole (2.5-5 mg/day)]. There must be at a minimum[66] single trial with an 
alpha-2 adrenergic agonist (0.1-0.3 mg/day).  In summary, we will use exact 
criteria stated by Mink et. al. TSA DBS Guidelines published in 2006, to 
determine if subjects are medication refractory. 
• Clinically relevant depression must be pharmacologically treated and deemed 
stable (by the study psychiatrist).  
• Must have been stabilized for one month on TS medication without a dose change 
prior to surgical intervention. If medication trials resulted in discontinuation of TS 
medications the subject must be stabilized for three months off TS medicines. 
• Must be willing to keep TS related medications stable and unchanged throughout 
the trial.  
• Must have been offered habit reversal therapy/cognitive behavioral intervention 
therapy (HRT) if a subject did not have it prior to enrollment. Subjects are not 
required to participate in HRT but it will be highly encouraged, and must be 
completed prior to the start of the protocol. Those who improve significantly with 

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HRT will be excluded from receiving surgery. 
• If the tic is focal or addressable by botulinum toxin treatment, the study 
neurologist will offer to administer a trial of botulinum toxin prior to 
consideration of surgical therapy. If the subject chooses not to have the treatment, 
they cannot participate in the study. If the patient responds satisfactorily to 
botulinum toxin, and their quality of life significantly improves, they will be 
excluded. 
• Must be 21 years of age or older (noting that the TSA recommendations for DBS 
have been revised and now remove the strict age criteria[49] (TSA DBS Working 
Group and International Database on TS DBS, Chair is the PI of this FDA IDE, 
Dr. Okun). 
• Patient and/ or caregiver should be able to recharge the system as needed.  
Patients should be cognitively able to understand battery charging and status. 
Exclusion Criteria 
• Any previous neurosurgical intervention including DBS or ablative brain lesions, 
any metal in the head and any type of implanted stimulator. 
• Untreated or unstable anxiety, depression, bipolar disorder or other Axis I 
psychiatric disorder. 
• Presence of psychotic features. 
• Significant psychosocial factors that can cause increased risk. 
• The presence of only simple motor tics, a movement disorder other than TS, or 
medication related movement disorders from TS medications. 
• The presence of drug-induced tics (potentially associated with the use of stimulant 

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medications, anticonvulsant drugs, etc). 
• Severe medical co-morbidity including cardiovascular disorder, lung disorder, 
kidney disease, chronic neurological disease, hematological disease, or frailty that 
impact tolerability of the surgery as judged by the screening physicians. 
• Abnormal brain magnetic resonance imaging (MRI) scan including 
hydrocephalus, stroke, structural lesions, demyelinating lesions, or infectious 
lesions that would potentially confound the outcome or safety of the surgery as 
judged by the study neurosurgeon. Also excluded if severe atrophy is present. 
• Dementia or cognitive dysfunction that will place the subject at risk for worsening 
cognition, and/or may impact the ability to cooperate with tasks involved in the 
study. 
• Any attempt or intent of suicide in the last six months. 
• Significant substance abuse or dependence (e.g., stimulants, alcohol, opiates, 
benzodiazepines) within the past six months. 
• Multiple failed medication treatments of inadequate dose or duration. 
• History of noncompliance with previous medical and psychosocial treatment 
efforts. 
• Severe head banging tics (any tics which have the potential to result in damage to 
the DBS). 
• Women of child-bearing potential who are pregnant or who wish to become 
pregnant during the study (a urine pregnancy screen required). 
• A positive urine drug screen for illicit substances (a urine drug screen is required), 
not to include marijuana/cannabinoid use. 

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• History of multiple surgical procedures with poor outcomes. 
• Unexplained gaps in medical history. 
• Pending lawsuits or other legal action. 
• Patients who expect or are likely to require a future MRI. 
• Patients who do not have access to a site that can program the device if they 
cannot come to UF for clinical re-programming followup. 
Recruitment: There are approximately 600 TS patients actively followed with yearly 
appointments at the UF Psychiatry and Movement Disorders clinics. An average of 
three new TS patients are evaluated each week for diagnosis and treatment options, 
and many are now referred to our institution for DBS based on our experiences with 
OCD and movement disorders. It is unknown how many TS patients are medication-
refractory. However, if we conservatively assume that 2.5-5% of existing patients will 
be eligible for the study, that will result in a pool of approximately 20-40 patients, 
plus an additional 4-6 patients a year from referrals of new patients during the life of 
the grant. From this pool, we anticipate being able to recruit 10 patients (2-3 per year) 
over 5 years to complete this study.  Subjects will be paid a $200 stipend, to be paid 
after each visit is complete, per visit (with exception of the post-implant visits, as it 
does not require a separate trip to our center) to help compensate for time and travel.  
Unscheduled visits will be compensated if requested by the study team.  One 
unscheduled visit per calendar year will be compensated for patient-requested 
unscheduled visits, though there is no limit to how many they may request.  
Additionally, the PI of this protocol is also the PI for the International Tourette 
Syndrome DBS database project, and receives TS DBS referrals from all over the 

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world, which will also aid in study recruitment. 
Subjects will be recruited in one of three ways: 1) the neurology clinic, 2) the 
psychiatry clinic, or 3) through referral by the Tourette Syndrome Association and 
their TSA DBS database project. We will also utilize an IRB (Institutional Review 
Board) approved database to recruit eligible patients from the TS population who are 
followed in the Movement Disorders Clinic at UF.  
Obtaining Informed Consent: Prior to any intervention, the principal investigator 
(PI), along with the neuropsychiatric study coordinator, will explain the protocol and 
study procedures as well as the risks and benefits of the surgical procedure, device 
related complications, medical related complications, and the risk of not obtaining the 
“perceived benefit” from surgery. The PI will explain what choices the subject will 
have at the conclusion of the study (if the subject consents and is implanted), 
including the alternatives of 1) continuing active stimulation at current settings, 2) 
continuing active stimulation but searching for new settings, 3) discontinuing 
stimulation, and 4) discontinuing stimulation and removing the device. If a subject 
continues to receive active stimulation at the conclusion of the study, the subject will 
be followed clinically by the PI and seen at yearly intervals until the device receives 
FDA approval, or alternatively until the device is no longer available. The Summit 
programmer is unique to the device under study.  Commercially available 
programmers do not support the Summit system.  Therefore, at the conclusion of the 
subject’s participation, he or she will be limited in clinical programming follow-up to 
institutions (such as UF) who have the Summit programmer.  The PI will follow each 
patient enrolled for the entire battery life of the RC+S, due to the limited availability 

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of the research programmer.  These visits beyond the study duration will be standard 
yearly routine DBS programming checks.  The PI will explain the time commitments 
for each study visit, as well as potential time commitments for any study related 
adverse events. Finally, the PI will discuss alternatives to participating in the study 
including 1) continuing medical therapy, 2) entering a TS drug trial, 3) seeking 
behavioral interventions (HRT, etc.), and 4) entering other device related studies for 
TS that may be available such as for transcranial magnetic stimulation (TMS).  
7)   Research Plan:  This study will assess the safety and effectiveness of bilateral 
simultaneous implantation of CM DBS and ECOG for medication refractory TS. The 
primary effectiveness outcome variable for each subject will be a YGTSS total tic 
subscale reduction of >40%, and the primary safety outcome will be defined as the 
serious adverse event (SAE) rate using historical data published from Parkinson’s 
disease randomized trials[13, 67-71]. The study will also examine the physiology 
associated with TS and tics, as well as explore the possibility of the effectiveness of 
responsive stimulation.  
The study will follow a prospective blinded design. Effectiveness, tolerability, and 
safety will be assessed and the study will allow for exploration of appropriate 
programming parameters and physiology.  
Multidisciplinary Pre-Operative Screening and Evaluation: The multidisciplinary 
pre-operative screening and evaluation will include four specialties: 1) movement 
disorders neurology, 2) psychiatry, 3) neurosurgery, and 4) neuropsychology. Details 
of the steps in the multidisciplinary pre-operative screening and evaluation are 
provided below.  

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The potential study subject will be evaluated by a neurologist and a psychiatrist, and 
each will perform a complete medical history.  The subject will be asked to provide 
medical records as applicable from previous medical providers, and complete a 
medical history form.  The subject will be asked to “sign off” that this medical history 
form is accurate and complete, to the best of his/her knowledge, so that the study 
team can ensure that medical history-related eligibility criteria have been assessed.  
The PI and study coordinator will perform urine pregnancy screening, and physical 
examination. The diagnosis of TS will be made based on strict DSM-V criteria, and 
will be confirmed by the study neurologist and psychiatrist. A psychiatrist will 
perform a psychiatric history and will be assisted by the study coordinator in 
collection of scales and questionnaires. The data and measures collected are listed 
below. 
General Demographics Sheet: Each subject will be assigned an independent ID 
number (assigned by the study coordinator). The following information will be 
collected: age, disease duration, all medical comorbidities, all medications and 
dosages, family history, smoking history, alcohol history and substance abuse history.  
Mini International Neuropsychiatric Interview (MINI): The MINI will be used to 
provide DSM-V diagnoses. This is a clinician-administered comprehensive 
psychiatric assessment based on DSM-V criteria. This tool will provide a pre-
operative diagnosis of DSM-V Axis I disorders. The MINI is a brief structured 
diagnostive interview for the major psychiatric disorders that will typically last 20 to 
30 minutes. The MINI will be used for screening purposes to ensure that all patients 
have met inclusion criteria (i.e., all psychiatric co-morbidities identified and treated 

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prior to DBS surgery), and will be used to assess whether pre-operative psychiatric 
diagnoses impart risk for post-operative mood changes.  
Columbia Suicide Severity Rating Scale (C-SSRS): The C-SSRS is a 
questionnaire that uses a rating scale assessment to determine if there is a risk of 
or presence of suicidal ideation or behavior. 
Quality of Life Assessment Scale (QOLAS): The QOLAS is a 10-item interview 
designed to assess quality of life in 5 domains: physical, psychological, social/family, 
work, and cognitive.  The participant is asked to rate quality of life in each domain at 
the beginning of the study, and these ratings are compared to those later in the study 
to measure change in quality of life. 
Yale Global Tic Severity Scale (YGTSS): The YGTSS is a semi-structured 
interview designed to assess tic presence and severity. Current motor and phonic tics 
are then rated separately according to number, frequency, intensity, complexity and 
interference on a 6-point ordinal scale. The YGTSS has excellent inter-rater 
agreement, good psychometric properties, and is recommended for use in the Tourette 
Syndrome Association (TSA) DBS guidelines. 
Modified Rush Tic Rating Scale (MRTRS): The MRTRS is a validated measure 
that examines five domains of impairment in TS. The scale allows for a videotape 
protocol, in which an independent blinded reviewer assesses tics by video when the 
examiner has left the room. Ratings of 0-4 can be assigned on five disability 
categories: number of body areas, frequency of motor tics, frequency of phonic tics, 
severity of motor tics, and severity of phonic tics. The sum of these ratings yields a 
total score of overall tic disability (0-20). The videotapes for this study will be rated 

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by an independent, blinded movement disorders neurologist. 
SF-36: The SF-36 is a validated 36 question quality of life measure. The results will 
give an 8-scale profile of functional health and well-being. The SF-36 is a generic 
measure that does not target a specific disease.  
Hamilton Depression Rating Scale (HAM-D): The HAM-D is a semi-structured 
clinician administered interview designed to measure a range of symptoms. The 
HAM-D consists of a 17-item questionnaire designed to evaluate depressed mood, the 
cognitive symptoms of depression, as well as the co-morbid symptoms of anxiety. 
Yale-Brown Obsessive Compulsive Scale (Y-BOCS): The Y-BOCS provides a 
quantitative measure of the symptoms of OCD. The Y-BOCS is a widely used and 
psychometrically sound clinician-rated, semi-structured interview assessing the OCD 
symptom severity. The Y-BOCS rates the severity of obsessions and compulsions 
across five items and provides a total severity score. We will be using the 10-item 
version which uses 5 items each for obsessive thoughts and compulsive behavior. 
This scale provides a quantitative measure of the severity of OCD on a scale of 0 to 
40. 
Young Mania Rating Scale (YMRS): The YMRS is one of the most frequently 
utilized rating scales to assess manic symptoms. The scale has 11 items and is based 
on the patient’s subjective report of his or her clinical condition over the previous 48 
hours. Additional information is based upon clinical observations made during the 
course of the clinical interview. Items specifically assess the following symptoms: 
elevated mood, elevated energy, increased sexuality, decrease in sleep, irritable and 
aggressive behavior, increased rate and amount of speech, language and thought 

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disorders, appearance, and grandiose or paranoid ideation. This scale will provide a 
quantitative measure of the symptoms of mania on a scale of 0 to 60. 
Conner’s Short Version ADHD Scale Adults (CAARS) short form: This is a 
multimodal assessment of the ADHD behaviors and problems in adults.  This is a 
short form survey that will take 10 minutes to administer and it will provide a 
baseline of ADHD symptoms including Inattention/Memory Problems, 
Impulsivity/Emotional Lability, Hyperactivity/Restlessness and Problems with Self-
Concept. 
Premonitory Urge for Tics Scale (PUTS): This is a ten-item questionnaire to assess 
how much a Tourette patient feels an urge to tic and the intensity of the urge.  It takes 
about 7 minutes to administer.  Scores range from nine to thirty-six (item ten is not 
scored), with higher scores indicating higher intensity of urge.   
Multidisciplinary Evaluation: Evaluation by Neurosurgeon: A DBS fellowship-
trained neurosurgeon (Dr. Kelly Foote) will perform a complete history and a 
physical examination, evaluate medical co-morbidities, obtain or examine a recent 
brain MRI scan, and clinically assess all medical co-morbidities and potential risks of 
TS surgery. 
Evaluation by Neuropsychologist: All potential participants will undergo a 
neuropsychological evaluation in order to screen for potential attention, memory, 
and/or other cognitive deficits that might potentially interfere with their participation 
in this protocol. The specific measures will provide broad-based coverage of the 
major cognitive domains and include validated measures routinely given to our DBS 
patients (pre and post-surgery), as well as those recommended by the TSA in their 

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general guidelines[44]. 
 
 

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Table 1. Neuropsychological Measures 
 
Cognitive 
Construct  & 
Estimated Time 
Measures - The neuropsychological measures have been chosen for sensitivity, resistance 
to practice effects and/or availability of equivalent parallel forms.  
* Denotes that parallel forms will be used. 
General Intellect 
(Total Time=30’) 
Weschler Abbreviated Scale of Intelligence (WASI-II) - A quick, reliable measure of 
intellect yielding verbal, performance and full scale IQ estimate. The 4 WASI-II subscales 
include Vocabulary, Similarities, Block Design, and Matrix Reasoning. It is nationally 
standardized. Individuals who score below the 5th percentile will not be enrolled in this 
study. Administered only during the initial screening.  
Attention & 
Working Memory  
(Total time = 10’) 
*Digit span and Spatial Span from Weschler Memory Scale-IV - both span measures 
involve immediate retention of sequences, both forwards and backwards. One is verbal 
(digit span) and the other is visual (spatial span).  
Episodic Memory 
(Total time=45’)  
*California Verbal Learning Test-2  - A sensitive verbal memory test that involves 
immediate and delayed recall of a list of words. Cued recall and recognition is also tested. 
There are 2 different forms with strong consistency and agreement.  
 Story (Logical Memory) and Face Memory (Visual Reproductions) subtests from the 
Weschler Memory Scale-IV - Involves learning and remembering meaningful information, 
including stories and unfamiliar faces 
Visuospatial 
(Total time=15’) 
 *Judgment of Line Orientation. Consists of 30 items, each showing pairs of angled lines 
to be matched to the display cards. Two equivalent forms are available. 
Executive & 
Mental Efficiency  
(Total time = 12’) 
 Trail Making Test  - A timed measure of set shifting, visual search, and flexibility. Scores 
will be based on time to completion.  
*Stroop Interference Procedure - A reliable measure assessing the ability to inhibit 
prepotent response; sensitive to fronto-striatal dysfunction.  
*Word Fluency (phonemic and category) – involves speeded generation of words 
beginning with target letters (i.e., F, A, S) or from designated semantic categories.  
Motor 
(Total time=10’) 
Grooved Pegboard - A measure of fine motor coordination and processing speed. Each 
hand is tested separately. 
Mood Measures 
Beck Depression Inventory-2 (BDI-II) - A brief self-report scale of depression. 
State Trait Anxiety Inventory (STAI; 124) - A 40 item scale assessing state & trait 
anxiety. 
 
 
 
Following the multidisciplinary screening, the neurologist, psychiatrist, 
neurosurgeon, and neuropsychologist will meet to discuss the findings and confirm 
inclusion/exclusion criteria are all adequate. The multidisciplinary team must be 
convinced that there are no significant cognitive deficits in any potential study 
subjects, and they must agree that the risk-benefit ratio is appropriate to proceed with 
DBS surgery.  
8)   Schedule of Assessments:  
In addition to screening measures, assessments will be made throughout the course of 

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the study. Data on complications and possible side effects of surgery will be collected 
in an on-going manner by the study coordinator. The following schedule of 
assessments is a summary of the assessments that will occur during the study. 
Schedule of Assessments (Pre-operative includes screening and baseline.)* 
*visits will occur +/- 14 days from target date, except for the Month 1 visit which will occur +/- 7 days 
from target date 
** Visits 6.1-6.4 will be up to one month at a time (+/- 14 days), for up to 4 months, at a time point 
approved by the Principal Investigator between Month 6 and Month 36, based on the individual’s response 
to acute responsive stimulation.  If they occur beyond month 24, they make take the place of the follow up 
visits. 
 
This schedule is a guideline for which questionnaires/ assessments will be 
administered during the study. The principal investigator may decide all items 
VISIT* 
MINI 
YGT
SS 
MRTR
S 
SF-
36 
HAM
-D 
Y-
BOC
S 
QOL
AS 
YMR
S/ 
CAA
RS 
Neuro
-
psych
ology 
Batte
ry 
C-
SSRS 
Pre-operative 
X 
X  
X 
X 
X 
X 
X 
X 
X 
X 
Month 1 (day 30) 
  
X 
X 
X 
 
 
  
  
 
X 
Month 2 (day 60) 
  
X 
X 
X 
 
 
  
  
 
X 
Month 3 (day 90) 
  
X 
X 
X 
 
 
  
  
 
X 
Month 4 (day 120) 
  
X 
X 
X 
 
 
  
  
 
X 
Month 5 (day 150) 
  
X 
X 
X 
 
 
  
  
 
X 
Month 6 (day 180)  
X 
X 
X 
X 
X 
X 
X 
 
X 
Month 12  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Month 18  
  
X 
X 
X 
X 
X 
X 
X 
 
X 
Month 24  
  
X 
X 
X 
X 
X 
X 
X 
 
X 
Followup visits (2-
4 visits within a 12 
month period) 
 
X 
X 
 
 
 
 
 
 
X 
Visits 6.1-6.4** 
  
X 
X 
 
 
 
  
  
 
X 

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listed in the schedule of assessments are not necessary at every visit, with the 
exception of the C-SSRS.  Subjects will be interviewed using the YGTSS at 
screening and one day prior to implantation we will recheck YGTSS to be sure 
they continue to meet eligibility criteria. The MRTRS will be videotaped, and 
blinded review will be performed by two movement disorders neurologists at 
baseline and at 6 months. The blinded reviewers will examine videotapes from 
baseline and six months in chronic continuous stimulation, OFF DBS, and 
responsive conditions. Additionally the study psychiatrist, assisted by the study 
coordinator, will perform baseline, Month 6, Month 12, Month 18 and Month 24 
follow-up visits including the HAM-D, Y-BOCS, YMRS, QOLAS, SF-36, C-
SSRS and CAARS (as necessary) (follow-ups to be performed +/- 14 days). The 
neuropsychology battery will also be obtained by the study neuropsychologist 
pre-surgery and approximately one year post-surgery. The C-SSRS will be 
administered at each study visit by the study neurologist or psychiatrist to monitor 
for suicidal ideation and/or intent.  Along with these assessments, there will be 
careful documentation of all adverse events and concomitant medications therapy 
(reporting any medications the patients may have taken that were not allowed by 
protocol). At any time, participants may request to be seen for an “unscheduled 
visit,” for example, to assess programming parameters or address an adverse 
event.  It will be up to the principal investigator’s discretion which assessments to 
perform at unscheduled visits.  For an overview of the study procedures and 
timepoints, the Schedule of Events is included below.  

 
Schedule of Events 
Study Events per ICF and Protocol (monthly visits 
to occur +/- 14 days, except month 1, which will 
occur +/- 7 days) ** 
Screening Baseline  
Bilateral 
Lead Implants*** 
IPG 
Implant
*** 
Thresh
olds 
Month 
1 
Month 
2 
Month 
3 
Month 
4 
Month 
5 
Month 
6 
Visits 
6.1 -
6.4* 
Month 
12 
Month 
18 
Month 
24 
Follo
w up 
visits 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History (included in each consult as 
applicable) 
X 
X**** 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neurology Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam ( (included in each consult as 
applicable) 
X 
X**** 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
Vital Signs 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Collection of Urine Samples  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Test 
X 
X**** 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug Test 
X 
X**** 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Psychiatric Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neuropsychologist Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Demographics (age, disease duration, family history, 
smoking history, alcohol history and substance abuse 
history) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Structured Clinical Interview for DSM-V (MINI) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Yale Global Tic Rating Scale (YGTSS)  
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blinded Yale Global Tic Rating Scale (YGTSS)  
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Pre-Implant Modified Rush Tic Rating Scale (MRTS)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Modified Rush Tic Rating Scale (MRTS) with device 
turned on, off, and "responsive" setting 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blinded Rating Modified Rush Tic Rating Scale 
(MRTS) 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
SF-36® Health Survey  
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Hamilton Rating Scale for Depression (HAM-D)  
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
 
Yale-Brown Obsessive-Compulsive Scale (Y-BOCS)  
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
 
Young Mania Rating Scale (YMRS) 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
 
The Conner's Attention Deficit Questionnaire 
(CAARS) 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
 

 
Neuropsychological Battery (Weschler abbreviated 
scale of intelligence, digit span and spatial span, 
California Verbal Learning Subtest, Story and Face 
Memory Subtest of WMS-III, Judgement of Line 
Orientation, Stroop Test, Trailmaking Test, Word 
Fluency Test, Grooved Pegboard, State Trait Anxiety 
Inventory, Beck Depression Inventory II) 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Premonitory Urge for Tics Scale (PUTS) 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Columbia Suicide Severity Rating Scale (C-SSRS)  
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physiology Collection 
 
- 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Quality of Life Assessment Schedule (QOLAS) 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
 
Review of Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review by multi-disciplinary DBS panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neurosurgical Exam, including co-morbidities, risk 
assessment  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRI brain w/dye 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT scan for localization 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Anesthesia 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hospitalization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Device Activation 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Device Programming 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Explant 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Replacement procedure (either new battery or non-IDE 
DBS) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Concomitant Medication Log 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Adverse Event Log 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
* Visits 6.1-6.4 will be up to one month at a time (+/- 14 days),  for up to 4 months, at a time point approved by the Principal Investigator between Month 6 and Month 36, based on the individual’s 
response to acute responsive stimulation.  If they occur beyond month 24, they make take the place of the follow up visits. 
** Patients will receive a $200 stipend per visit to help compensate for time and travel, with the exception of “post implant,” as it is typically done during the same trip as the IPG implant visit. 
*** Lead and IPG implant will be completed within 30 days  
**** Only done at baseline if screening visit assessment is over 30 days before surgery 

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9)   Surgical Procedure:  A high resolution, volumetric, three tesla MRI scan will be 
obtained prior to the surgical procedure. On the morning of the procedure, a Cosman-
Roberts-Wells (CRW) head ring will be applied under local anesthesia and a high-
resolution stereotactic head Computed Tomography (CT) scan will be obtained. 
Using software developed at UF, the CT and MRI images will be fused and 
stereotactic targeting will be carried out using the high quality MRI images. Only 
imaging procedures that adhere to the DBS manufacturer’s guidelines will be used in 
this study. This software facilitates navigation in “AC-PC space” (a computationally 
reformatted MRI with a three-dimensional, orthogonal Cartesian coordinate system 
centered on the patient’s mid-commissural point), which is readily defined by 
identifying the anterior and posterior commissures and a non-colinear midline point 
in the patient’s brain. The initial target and trajectory will be selected in AC-PC space 
and the corresponding CRW coordinates will be automatically generated and used to 
set the stereotactic frame. Detailed microelectrode recording will confirm the location 
of CM prior to implantation. 
CM Location: The stereotactic target of CM will be defined anatomically utilizing 
lateral, antero-posterior, and midline points of reference. The anterior commissure, 
posterior commissure, and midline points will be defined on our computer software. 
The antero-posterior coordinate will be defined relative to the midcommissural point. 
The CM target will be stereotactically targeted at 5 mm lateral, and 4 mm posterior to 
the midcommissural point. A trajectory will be chosen to avoid blood vessels and the 
base of sulci. A dime to nickel sized burr hole will be placed and a microelectrode 
recording apparatus set up on the head frame. The CM thalamus will be located by 

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recording cells in the dorsal thalamic tier using microelectrode recording, and by fusion 
to our 3-dimensional atlas which can be morphed to the subject’s MRI and then the 
target located by superimposing microelectrode recordings (3 passes) on the morphed 
atlas. The physiological recordings will be utilized to define 10 mm above CM 
thalamus, delineate the dorsal border, and record through the length of the nucleus 
(approximately 10 mm), and into ventral thalamus (approximately 10 mm). 
Additionally, the ventral thalamic border will be delineated by the microelectrode 
recording. The study PI is experienced in microelectrode mapping (over 900 DBS 
cases) and will determine the correct location and depth of the final lead. The subject 
will have position sensors placed on the extremities with motor tics. Recording of cells 
and position sensors will be synchronously obtained, along with a videotape to 
correlate tics. Once the pattern of physiological signal has been verified, the final lead 
will be placed to cover both the dorsal and ventral extent of CM. Contacts 1 and 2 (of 0, 
1, 2, 3 ventral to dorsal configuration) will be placed in the center of the target. The 
lead will be tested by macro-stimulation to obtain thresholds for benefit and side 
effects. A fluoroscopic X-ray will then be obtained and the lead secured using the 
plastic cap provided in the DBS kit (Medtronic, Minneapolis, Minn) 
After placement of each CM DBS lead, a cortical ECOG strip on each side will be 
placed through a second small burr hole to reach the desired pre-motor and motor 
cortical strip region.  A Medtronic Summit RC+S device which is a new 
neurostimulator that has the ability to acquire, process, and store neural activity from 
ECOG and deep brain LFP leads will be placed subclavicularly within 30 days of lead 
implant (and tunneled and connected by a lead extension as is standard in DBS 

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operations). The lead configuration is connected directly to the battery source which 
will be placed in a subclavicular pocket and will consist of the following: lead 1 – left 
CM depth electrode, lead 2 – left cortical ECoG strip for pre-motor and primary 
motor, lead 3 – right CM depth electrode, and lead 4 – right cortical ECoG strip for 
pre-motor and primary motor. Lead 1 and lead 2 will be connected via a Y-connector 
(Medtronic 37082) provided by Medtronic to form a single channel 8-contact 
connector because Summit RC+S only allows 2 8-contacts leads instead of 4 4-
contact leads. The same will be done to lead 3 and lead 4. There will be one 
neurostimulator (Summit RC+S) implanted within the chest connected to all four 
leads. 
The placement of the Medtronic Model 09130 cortical strip will target M1 at a point 
on M1 approximately 3 cm from the midline.  This targeting will be based on the 
anatomic identification of the central sulcus and by using the method described by 
Shimamoto e.a.[72], we will use these authors’ published procedure to place and 
verify the ECOG lead[72]. Once the new burr hole is drilled, the dura matter will be 
opened and the Medtronic Model 09130 cortical strip will be placed over pre-motor 
and motor hand/arm regions. The "hand bump" is an easily identifiable landmark on 
the stereotactic MRI.  We will also check the "phase reversal" on somato-sensory 
evoked potential which will assist in confirming the electrode position is over the M1 
hand/arm area. A small notch will be placed on the burr hole to help hold the cortical 
strip in place, and the burr hole will be sealed with a fibrin sealant. Post-implantation, 
subjects will be comprehensively evaluated for any untoward symptom and will 
receive the appropriate treatment as necessary. Subjects will continue to be evaluated 

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throughout the study for any significant health changes and referred accordingly for 
clinical care as needed. 
10)   Description of the Hardware:  The system that will be used includes the 
neurostimulator itself; the implantable leads; a programmer that includes a wand and 
telemetry interface; a recharging coil and controller for recharging Summit RC+S 
neurostimulator; and a patient remote control to check battery status and whether the 
device is on or off. These devices are called the Recharge Therapy Manager (RTM, 
Model 97755) and Patient Therapy Manager (PTM, Model 4NR009), respectively. 
The patients will receive training from the research group, and will be given written 
instructions to take home. The Clinician Telemetry Module (CTM, Model 4NR011) 
is used to set up the device  stimulation. The sensing parameters will be setup through 
the Summit RC+S Research Development Kits. The depth leads for CM have a 
flexible, isodiametric lead body that encloses four insulated wires, and have four 
cylindrical electrodes at the distal end. The proximal end has four contacts adapted 
for connecting to the neurostimulator device (Medtronic lead models 3387). The 
depth lead is implanted into the brain to provide an interface through which 
stimulation can be delivered, or the activity of the brain can be monitored by the 
device or observed by a clinician using a programmer. The model 3387 DBS lead has 
four electrodes with 1.5mm contacts and 1.5mm spacing.  The RC+S stimulator is 
rated for 9 years and is rechargeable.  Patients will be required to charge as needed to 
maintain device functionality.  
The Medtronic Model 09130 cortical strip has a flexible, isodiametric lead body that 
encloses four insulated wires, and has four disk electrodes within a paddle at its distal 

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end. The proximal end has four contacts adapted for connecting to the 
neurostimulator device. The strip lead is implanted into the brain to provide an 
interface through which stimulation can be delivered or activity of the brain can be 
monitored by the device, or observed by a clinician using a programmer.   
There will thus, in summary, be two CM thalamic leads (one in each brain 
hemisphere) and two ECOG strips (one in each brain hemisphere), and one 
neurostimulator (Summit RC+S) implanted in the chest. 
Subjects will have a post-operative CT scan for lead location and to assess for 
intracranial air and hemorrhage. The CT scan will be fused back to the MRI.  Each of 
the four contacts on each deep DBS lead will be measured, and localized on an atlas to 
confirm the correct lead position. In the future if an experimental fMRI or MRI is 
considered, FDA and IRB approval will be sought.  The Summit system has not been 
evaluated for MR compatibility. 
11)   Specific Approaches for Specific Aim 1 Overview:  The study will follow a 
prospective blinded design (see Figure 1 below). Effectiveness, tolerability, and safety 
will be assessed, and the study will allow for exploration of appropriate programming 
parameters. 
12)   Study Summary:  Once subjects have been consented, baseline measures must 
be collected within two weeks of the surgery.  Subjects will be followed with 
standardized measures for a minimum of 24 months (+/- 14 days) post-DBS 
implantation and a maximum of 36 months (+/- 14 days) post-DBS implantation for 
the research study.  The main outcomes will be measured at 6 months post-DBS (+/- 

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14 days). There will then be three additional days of data collection where subjects will 
be either “on” DBS, “off DBS” or “on DBS responsive mode (Figure 1 and 2).”  
MRTRS scales will be collected in each mode for an independent video review.  
Stimulators will be blindly set to the “mode” for the day and left in that mode for one 
hour prior to data collection which will include MRTS and also physiology as recorded 
by the neurostimulator. 
 
Figure 1. Study design 
• Following recruitment and multidisciplinary screening, candidates will receive 
bilateral CM DBS plus bilateral ECOG strips, and bilateral chest implanted 
neurostimulators. 
• Prior to implantation, primary outcome and secondary outcome variables will 
be assessed. A blinded videotape will be obtained of the MRTRS. The blinded 
videotapes will be evaluated by two blinded movement disorders neurologists 
who will score the MRTRS’s at baseline and 6 months (+/- 14 days). 
• Implantation will be accomplished by a neurosurgeon and neurologist, both of 
whom will not participate in the blinded evaluations of subjects. 
• The primary effectiveness outcome for the study will be >40% reduction on 

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the blindly rated YGTSS total motor/phonic tic sub-scale at six months on 
DBS as compared to pre-op baseline. The secondary effectiveness variable 
will be assessed by the MRTRS blinded ratings. 
• The primary safety outcome will be defined as the serious adverse event 
(SAE) rate in patients compared to the SAE rate in patients implanted with the 
Medtronic DBS device for treatment of Parkinson’s disease as drawn from 
published randomized studies[13, 67-71].  The intent is to show that the 
serious adverse event rate will not exceed the 95th percent confidence interval 
for the historical experience with the Medtronic DBS for Parkinson’s disease. 
A 95% confidence interval for the SAE rate will be utilized for an analysis of 
data for 10 subjects at their three month visits due to the small sample size.  
• The secondary outcome measure will consist of a review of the types, duration 
and frequency of non-serious adverse events.  Therefore, all adverse events 
will be used as an additional measure in determining safety outcomes. 
• The safety experience will be reviewed approximately every 6 months by the 
Data Safety Monitoring Board (DSMB). The DSMB will be informed of all 
serious adverse events and all mild adverse events which are potentially 
device related. The DSMB will designate each AE as mild or severe; as device 
related, uncertain to be device related or not device related; and as anticipated 
or unanticipated. The DSMB may employ a stopping rule for greater than 1 
device related death or completed suicide. 
Details of the Protocol: 
• Following consent, subjects will be screened by the multidisciplinary team 

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and ethics panel to be certain all inclusion and exclusion criteria are met.  
• Following approval by the multidisciplinary and ethics panel, subjects will 
undergo baseline studies and within four weeks will receive bilateral CM 
devices and bilateral ECOG devices. 
• Stimulation will be turned on within one week (+/- 7 days) after the implant 
completion which will be approximately one month post lead implantation. 
• All subjects will undergo once a month programming visits for months 1-6 
(+/- 14 days, with the exception of Month 1, which has a +/- 7 day window).  
Additional visits may be needed to obtain optimization of settings. 
Physiological data will be collected from both the CM thalamus and the 
ECOG strips during all protocol visits, and responsive parameters will also be 
tested.  Subjects may also choose to come to the clinic for “unscheduled 
visits” as they deem necessary.  The activities done at these visits will be at 
the discretion of the principal investigator. 
• Physiology data beyond month 12, and the chronic stimulation titration (visits 
6.1-6.4), may be performed at the participant’s home as necessary rather than 
at the University of Florida.  The equipment used are all mobile as shown in 
the RC+S system configuration as explained in Section 18 (refer to Figure 3).  
• Details of physiology collection procedure: The subject will be asked to put 
on EMG sensors and signals from this device will stream into the research 
host computer (RHC). The signals from the Summit RC+S device will also be 
downloaded onto the RHC, which will have the Summit Research 

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Development Kit (RDK) installed (refer to Section 19). Stimulation and brain 
activity data since the previous visit can then be reviewed and analyzed on an 
individual basis. 
• The CM neurostimulators will be programmed in an outpatient setting to 
deliver only chronic continuous stimulation in all patients. Stimulation 
parameters will be adjusted as necessary to provide maximal tic reduction.  
The cortical strips will be chronically set to record mode for data collection 
only, until the acute Aim 3 responsive trial. 
• The neurologist and DBS programmer will be allowed to adjust stimulation 
parameters during months 1-5 to achieve maximal tic suppression and 
minimal to no side effects.  The programming that will be employed will be 
identical to that used for Parkinson’s disease randomized trials[13, 67-71]. 
• At day 180 (6 months +/- 14 days), the primary and secondary outcome 
variables will collected, as will all scales.  If optimization is not achieved at 
Month 6, Month 6 data collection may be postponed as deemed necessary by 
the Principal Investigator (with the exception of the C-SSRS), up to 12 
months (+/- 14 days) past the first programming visit (Month 1).  However, 
there must be a 30 period of stable stimulation settings before primary 
outcomes are assessed. 
• Primary and secondary outcomes and physiology collection will be assessed 
over approximately 3 outpatient days. The “on” DBS condition will be used 
and compared to the pre-operative baseline for the primary outcome (specific 
aim 1). The other conditions will be used for secondary analyses, and the on 

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responsive stimulation response will be compared to the pre-operative 
baseline (specific aim 3). 
• 
Beyond the 36 month study period, the Principal will continue to follow and provide 
standard of care visits to subject throughout the duration of battery life (labeled to 
last 9 years).  These visits will be treated and billed as routine DBS checks. 
Algorithm for CM Thalamus Device Programming: Programming to be performed 
for this study by the device programmer under the supervision of the PI.  
Prior to programming sessions each month, there will be a one to two hour 
physiology data collection session (specific aim 2). Fifteen minutes of real time 
physiological baseline monitoring will be recorded from the device (this will be 
videotaped and motion sensors will be applied to capture tics and correlate with 
physiology).  Responsive settings will be checked each month and any improvement 
in tics noted. 
• Each of the four thalamic contacts on the DBS lead will be checked for 
benefits and side effects of stimulation using the identical paradigm employed 
by our clinic for subjects receiving best clinical care with Parkinson’s disease 
DBS[73]. The initial programming paradigm is designed to help the clinician 
choose the best stimulation contact by first identifying thresholds and side 
effects for each lead while holding frequency and pulse width constant. 
• A baseline MRTRS will be recorded prior to each programming session. 
• Electrical impedances and battery life will be checked to ensure the integrity 
of the device. Any anomalies will require immediate referral to the implanting 

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neurosurgeon for evaluation and potential correction. 
• High frequency stimulation will be held constant at 130Hz, and pulse width 
held constant at 90μs during the duration of the initial programming session.  
• Each lead contact (0, 1, 2, 3) will be independently tested on each of the two 
CM leads. The voltage will be increased by .1-.5 volts until a side effect is 
encountered or alternatively until 7 volts is reached. Any side effect lasting 
>30 seconds or that is uncomfortable for the subject will be immediately acted 
upon by the programmer by decreasing the current to a tolerable level or 
turning the device to an off position. The current setting evoking a side effect 
will be documented so that it will not be used for future programming at that 
contact. We will record data during the different stimulation settings to 
investigate the induced changes in the brain signals that may provide 
signatures of optimal stimulation settings. 
• The benefits on visible tic suppression will be subjectively assessed at each 
contact and each setting; the contact providing the most improvement will be 
chosen for chronic monopolar stimulation. 
• A concluding MRTRS will be recorded at the conclusion of this initial 
programming session, following a 20 minute period at the chronically chosen 
settings. 
• Each month the programmer will have the latitude to change the contact, 
frequency, or pulse width of stimulation liberally, and as often as needed until 
optimal settings are discovered for visible tic suppression.  

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• There must be a 30 day period where no changes are made to the final DBS 
parameters prior to the examination of the primary outcome measure.  
• All scales and a blinded videotape will be obtained of the MRTRS at 6 months 
in the on, off and at responsive stimulation settings will be performed.  
• The MRTRS videotapes will be scrambled by the statistician for all conditions 
and time intervals so the videotape review will not be biased. 
A summary of Month 6 data collection is provided below (Figure 2), note these 
conditions will be presented blindly to the patient, and then performed over 3 separate 
days of testing.  The order of the three conditions will be set by the statistician and 
counterbalanced across all 10 patients (figure 2 below): 
 
Figure 2. Timeline of clinical scales for reporting study outcomes.  
Specific Approaches for Specific Aim 2: The information obtained in specific aim 1 
during each data collection session will be sorted, and correlations between 
physiology and tics, urge to tic, or behavioral abnormality will be sought. The signal-
processing tools that will be utilized for this task will include established spectral 
analysis methods, namely: 
• Power changes in the time and frequency domains 

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• Changes in inter-channel coherence and/or cross-correlation 
• Fractal dimension and line length 
• Presence of phase amplitude coupling between gamma band activity and other 
oscillations 
The combination of these analysis techniques in multiple brain regions (cortical and 
thalamic) allows for detection of thalamocortical interaction. Endogenous modulation 
of thalamocortical rhythmicity occurs during specific cognitive processes, several of 
which (e.g. sensorimotor gating, and focused motor action) have been implicated in 
the pathophysiology of TS[57]. This analysis will be performed for two reasons. First, 
these analyses may yield triggers detectable by the device by utilizing detection and 
signal analysis tools (i.e. spectral power estimation). This analysis will be performed 
for two reasons. First, these analyses may yield predictors detectable by the device by 
utilizing detection and signal analysis tools: line length trending, area-under-the-curve 
trending, and half-wave detection, applied in various logical combinations on single 
or multiple channels. Second, using an a priori limit on the multiple analysis methods 
will aid in assigning significance to any changes observed. This analysis will also 
allow us to conclude the total number of subjects in our cohort with gamma or other 
band oscillations.  The analysis will allow us to examine whether there is an ECOG 
motor or pre-motor signal that can be used for responsive stimulation (detect in the 
ECOG and respond with DBS from the CM). 
Specific Approaches for Aim 3: If an electrophysiological change or set of changes 
from baseline can be observed to preferentially accompany motor tics, across a given 
subject’s data, with significance p < 0.1, it will be defined as a predictor for that 

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subject. Note that we do not require a high level of significance here; nor do we 
require the predictor to be entirely absent from baseline data. We assume that the 
consequences of a false positive (i.e., detection of the predictor without 
accompanying tics) are negligible. This is justified since the amount of stimulation 
that will be delivered responsively will in any case be less than that which would be 
delivered by their regular continuous stimulation.  We will utilize available analysis 
tools to examine outcomes, but we will also report to the FDA on any new responsive 
stimulation detection and programming tools that may become available during the 
course of this protocol, and request permission to use them if appropriate. 
Subjects for whom predictors can be identified during acute physiological data 
collections in Months 1-5, as described above, will have a responsive DBS setting 
programmed for their six-month outcome testing. In responsive mode, the device may 
titrate the amplitude of stimulation within previously set comfort and safety levels, if 
tic signatures are not suppressed (i.e., until non-symptomatic brain signals are 
attained). If patients respond favorably during acute responsive testing, we will test 
chronic responsive stimulation for one month at a time (+/- 14 days), at some time 
point approved by the Principal Investigator between Month 6 and Month 36 (see 
visits 6.1-6.4 in schedule of events). The stimulation amplitude will be set to its 
optimal setting for chronic stimulation. The new patient programmer will allow 
patients to turn off responsive stimulation and switch back to standard continuous 
therapy.  Subjects without a predictor will not have a chronic responsive setting. 
Options for the Subject Once Specific Aims are Complete: Subjects may at any 
time during the study opt to terminate their participation and may also opt for 

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hardware removal. The investigator may continue to empirically adjust stimulation 
settings based on patient tolerance, and both short-term and long-term response. As 
long as the RC+ S batteries are implanted, all subjects implanted will have the option 
for chronic or responsive stimulation depending on their individual preference and 
effectiveness of each technique. For subjects not under optimal control following 6 
months of DBS therapy, we will offer open-label programming to search for the best 
parameters. Subjects who continue to receive active stimulation, will be followed by 
the PI and seen at yearly intervals.  Patients will be able to be implanted with the 
standard Medtronic device after the study period once the RC+S is depleted.  
However, only the RC+S allow closed loop stimulation. As long as the subject is 
implanted with the RC+S device, the Principal Investigator will continue to follow 
and provide standard of care visits to subject throughout the duration of its battery life 
(labeled to last  9 years).  These annual visits will be treated and billed as routine 
DBS checks.  We will discuss with the subject the option of explanting their devices 
and pursuing insurance authorization to implant a standard Medtronic DBS device in 
CM for control of tic as needed. 
13)   Description of Power Analysis and Statistical Methods:   
Power Analysis: We will determine the effectiveness of DBS by comparing total tic 
score (YGTSS) at the six month time point to the pre-operative value for each 
subject. A 40% or greater reduction will be considered a successful response. The 
power to detect a statistical significance between a null proportion of 0.10 (this 
assumes that the true proportion of successful responders is 10%). The power analysis 
revealed that for an alternative proportion of .60 (i.e., 6 of 10 patients will show a 

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40% or greater reduction in motor tics at six months) there is a statistical power of 
0.80 at an alpha level of .05. Therefore, we anticipate ten participants will be required 
for this study. The power procedure in Statistical Analysis Software (SAS), version 
9.1 was used to conduct the power analysis. Data collected from this study will 
provide additional and currently unavailable data to inform power analysis of 
subsequent studies in Table 2 below. 
 

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Table 2. Power Analysis for Sample Size Effects 
 
General Analysis Approaches: The Wilcoxon signed rank test will be used to test for 
significant pre-post changes in numerical measures (e.g., YGTSS). Spearman 
correlations will be used to test relationships among numerical measures (e.g., 
neurocognitive measures, severity of tics and quality of life measures). Both the 
Wilcoxon signed rank and Spearman correlation tests are nonparametric procedures 
that are robust from data departures from normality and appropriate in the case of 
small sample sizes. All statistical tests will be two-sided and will be considered 
significant if p-values are less than 0.05. SAS software will be used to conduct all 
data analysis. 
Specific Analysis Approach for Aim 1: We will determine the effectiveness of the 
“on condition” of DBS by comparing motor tic score (YGTSS) at the six month 
evaluation to the pre-operative value for each subject. A 40% or greater reduction will 
be considered a successful response. We will then test the hypothesis that the 
proportion of successful responders is greater or equal to (6/10) using the exact 

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binomial test. We will compare the baseline motor YGTSS to the on DBS condition 
at six months (primary outcome). We will also perform comparisons of baseline to 
on/off/responsive conditions, and also comparisons of on/off conditions at six months 
as secondary analyses. To compare on versus off condition, we will form paired 
difference scores of YGTSS (YGTSS on minus YGTSS off) at six months and test for 
significance using the Wilcoxon signed rank test.  
Specific Analysis Approach for Aim 2: We will first investigate rate and pattern 
changes in physiology and the possible correlation with clinical manifestation of 
motor tics by using exploratory data analysis techniques that will be graphical in 
nature. These exploratory techniques will include spectrograms and event related 
potentials. We will then conduct a preliminary time series analysis estimating fractal 
dimension, line length, and area-under-the-curve of the raw signal. The data obtained 
from these analyses will inform subsequent analysis and guide the development of 
statistical methods to analyze these types of data streams. Subsequent analysis will be 
more comprehensive, and will include time-frequency analysis of specific frequency 
bands, measures of coherence between channels containing movement related activity, 
and quantification of phase-amplitude coupling between frequency bands of interest. 
Any of these techniques has the potential to identify candidate predictors of tic onset. 
Specific Analysis Approach for Aim 3: This protocol calls for testing an acute 
responsive DBS condition in subjects who reveal physiological predictors that can be 
set to sense tic by ECOG, and to respond to tic on the CM implanted device. It may 
also be possible to both sense and deliver stimulation from the CM DBS lead.  Data 
will be analyzed using the Wilcoxon signed rank test. We will collect physiology 

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data and analyze the data, and test chronic responsive stimulation settings one 
month at a time for those subjects that respond well to the acute testion after 
Month 3.   
Risk Analysis: The Medtronic Activa RC+S device and Medtronic Model 09130 
cortical strip system represents a new therapeutic approach to treating TS. As such, 
the probable risks and anticipated benefits of this treatment approach must be 
considered based on information from the literature of deep brain stimulation. This 
experience suggests that deep brain stimulation has an acceptable risk profile and that 
anticipated benefits outweigh the probable risks. Kimmelman and colleagues in a 
recent meta-analysis of deep brain surgery for Parkinson’s disease revealed a 
favorable risk-benefit ratio with the estimated intracerebral hemorrhage rate of 1.57% 
(95% confidence interval, 1.26%-1.95%), and the proportion of trajectories associated 
with serious neurological deficits was only 0.41% (0.28%-0.60%)[74]. 
14) Safety Studies and Potential Risks with the Investigational Device: 
Experience with the Medtronic RC+S device and Cortical Strips:  
There are currently no human patients implanted with the Medtronic Activa RC+S 
along with the Medtronic Model 09130 cortical strip for TS. 
Safety of Chronically Implanted Neurostimulators: Probable risks associated with 
chronically implanted neurostimulators and of devices implanted in the cranium 
include the risks of surgery-related adverse events such as hemorrhage and infection, 
chronic implantation adverse events such as infection, erosion and necrosis, 
stimulation-related side effects or discomfort, and stimulation associated brain injury. 
Experience from randomized DBS studies for Parkinson’s disease suggest a low 

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overall risk[13, 67-71].  Additionally, a recent expert consensus led by Bronstein et 
al. reviewed DBS complications[75].  The rates of surgical complications depended 
on the team and experience and included intracranial hemorrhage, stroke, infection, 
lead erosion without infection, lead fracture, lead migration, and death.  These were 
all rare complications and the most worrisome overall complication was the 
possibility of symptomatic intracerebral hemorrhage which was less than 2% at 
experienced medical centers. Hardware infection was the most commonly reported 
serious adverse effect and ranged from approximately 5% to 20% among reports in 
the literature[75]. 
Safety Experience with Medtronic Summit RC+S device and Cortical Strips in 
TS 
There are no human cases published of the use of this device in TS DBS. 
Perception of Neurostimulation: Stimulation of the brain has the potential to 
produce sensations that are noxious or disturbing.  Any stimulation related side 
effects can be alleviated by re-programming or turning the device to an off position, 
which we plan to do during this study. 
Other Medtronic Summit RC+S and Cortical Strip System Potential Risks:  
The following adverse events have been reported with deep brain stimulation: 
dysaesthesias, speech disorders, headache, abnormal thinking, abnormal vision, 
double vision, abnormal dreams, difficulty swallowing, paresis/paralysis, pneumonia, 
CNS depression, hostility, personality disorder, confusion, paresthesia, anxiety, chest 
pain, hallucination, drowsiness, amnesia, nausea, vomiting, dizziness, walking 
difficulty, postural hypotension, increased salivation, agitation, delusions, difficult 

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breathing, fainting, sleep disorder, rapid heart rate and deep thrombophlebitis[74, 76-
78].  
If the patient is not satisfied with the programming stimulation options at home and 
would like them to be revised outside of the standard clinical study visits, 
reprogramming can only be performed at UF. This is because standard Medtronic 
stimulation programmers that can interface with standard Medtronic 
neurostimulators, which can be found at other institutions, do not interface with the 
Summit RC+S.  
Summary of the Most Serious Medtronic Summit RC+S and Cortical Strip 
Risks: 
There are no human cases published on this device in TS DBS and therefore there is 
no summary data available except what can be referenced in the Device Masterfile 
#2010. 
Some medical procedures such as diathermy, electroconvulsive therapy, and 
transcranial magnetic stimulation are prohibited because the amount of energy 
coupled into the implanted lead system can result in heating and neural tissue 
damage. Any medical procedure that delivers energy to an implanted lead system has 
the potential to cause tissue damage by induced heating. Therapeutic radiation to the 
head should be avoided due to potential damage to the Medtronic Summit RC+S and 
Medtronic Model 09130 cortical strip system. This is included in the labeling 
appendix which we include in this IDE. 
Treatment with therapeutic ultrasound to the head and neck should not be performed 
since energy may be sent thorough the leads resulting in brain damage. The effects of 

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therapeutic ultrasound treatment below the head and neck on the System are unknown 
and should be avoided unless the risk of not using the treatment outweigh the risks of 
using it. However, imaging with diagnostic ultrasound to any part of the body is safe 
and will not interfere with the System.  
Magnetic Resonance Imaging: The Summit system has not been evaluated for 
MRI safety.  Therefore, subjects will be asked to carefully consider whether they 
anticipate future MRI scans.  This is a risk-benefit trade-off that will be 
discussed prior to study participation.  If necessary, a CT scan will follow device 
implantation.   Images of the brain produced using ultrasound or magnetic resonance 
imaging (MRI), may be compromised by a cranially implanted medical device. In 
addition, there are risks associated with neuroimaging that require following safety 
guidelines; failure to do so may result in serious injury to the patient. 
The high magnetic field associated with MR imaging may cause induced currents 
and/or mechanical forces on the pulse generator and/or lead(s); these may be 
perceived by the patient and could result in dislodgement of a pulse generator and/or 
the lead(s). In addition, the radio frequency (RF) fields used in MR imaging may 
cause induced currents and heating of the pulse generator and/or lead(s); these may 
cause damage to the surrounding tissue. 
MR imaging of patients implanted with a neurostimulator device may be safe under 
certain conditions (see labeling appendix), however failure to follow MR safety 
guidelines may result in injury. While the number of incidences has been low, there 
have been two reported cases of severe injury resulting from MR imaging of patients 
implanted with deep brain stimulators. In one case, a patient who was implanted 

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bilaterally with DBS electrodes for treatment of PD experienced dystonia 
immediately following an MRI procedure. In this case, it is thought that the heating in 
the leads may have caused thermal tissue damage. In the second case, a patient with 
bilaterally implanted neurostimulation systems developed a neurologic deficit 
following an MR procedure. In both incidences the scans were performed using 
parameters that deviated from the manufacturer recommended safety guidelines[79, 
80]. 
System Replacements, Lead Connection Changes, and Explants 
Battery Depletion: In the event of battery depletion (whether due to a pre-mature 
failure or following the labeled 9 year lifetime), an additional surgical procedure will 
be required to replace the Neurostimulator, assuming that the System functionality is 
still desired.  
The risks posed by a Neurostimulator replacement or explant procedure are expected 
to be lower than those of the initial implant. During a replacement procedure, there is 
no need to create a new craniectomy, resulting in a much shorter procedure time. The 
previously implanted leads are attached to the new neurostimulators or are 
abandoned. Therefore, neurostimulator replacements does not require penetration of 
the dura.  
When the RC+S battery is depleted, the patients will be given the option of 
replacement or explantation. For the former, the depleted device, will be replaced by 
either an RC+S (with 4 electrode array inputs) or one commercially available RC 
device (with 2 electrode array inputs). In the latter case, the cortical leads will be left 
in place, disconnected proximally, with the thin proximal end of the extension 

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exposed and buried deep to the IPG. This will avoid the risk of inadvertent delivery of 
unintended cortical stimulation as a potential programming error. Only continuous 
(conventional) DBS can be delivered from the RC devices. If the study doctor 
determines it is necessary to remove the device, or if the patients request that the 
device be removed, the cost of removal will be billed to the insurance company. The 
patients will be responsible for paying any deductible, co-insurance, or co-payments 
for these explant services, and for any non-covered or out-of-network services. 
Patients will be informed that DBS electrode removal involves substantial risk of 
reversible and irreversible harms, such as requiring additional brain interventions, 
further hospitalizations, long-term use of antibiotics or other medications, possible 
loss of the benefits of future stimulation and psychological distress.  
 
Summary of Risks to Subjects: Though there is no safety data in humans specific to 
the devices used in this study, the safety experience of DBS systems in the literature 
has been reassuring[75]. Significant adverse events associated with implantation of 
the neurostimulator and leads, such as hemorrhage, CNS infection and poor wound 
healing can occur with DBS. Subjects have tolerated DBS devices well, both in terms 
of comfort with the cranial implant as well as with stimulation. And the common side 
effects encountered that are unique to TS CM DBS have been a subjective sensation 
of eye pulling/twitching, sensory phenomenon, nausea, and dizziness.  All of these 
common side effects with CM DBS are reversible by changing the stimulation setting 
or turning the device off. [37, 38, 59, 75, 76, 78, 81-83].  
Procedures for Protecting Against or Minimizing Risks:  We plan to follow the 

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Tourette Syndrome Association’s recommendations and only enroll adults with TS 
whose tics are severe and intractable to medical therapy[44]. Our investigation will 
use rigorous inclusion and exclusion criteria, pre- and post-operative assessments 
using standardized rating scales and comprehensive post-operative assessments 
including neurological, psychiatric, and neuropsychological evaluations. Study 
subjects will be assessed by a psychiatrist or neurologist using the C-SSRS at each 
study visit to monitor for suicidal ideation and/or intent. In addition, the UF 
Movement Disorders Center has expertise in diagnosing and treating TS in a 
multidisciplinary manner. 
Effective screening and the neurological/psychiatric evaluation will rule out other 
conditions that may prevent subjects from participating in these studies. Once the 
subject enters the study, s/he will be closely followed by an experienced clinical 
research team. Careful monitoring of all subjects via phone contacts and clinical 
management throughout the study will help minimize risk. The clinical research team 
has developed considerable expertise in monitoring the safety of subjects 
participating in research studies. There is an experienced research 
neurologist/psychiatrist available 24 hours a day, seven days a week. 
After the neurostimulator is programmed to provide stimulation, subjects can suspend 
stimulation by application of a remote device. The remote device can be held over the 
chest neurostimulator and used to turn the device off. 
The protocol includes exit criteria for those who believe their condition is worsening 
during any particular phase of the study, and participants can withdraw at any time. 
Subjects may also wish to discontinue stimulation for any reason and we will support 

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this decision. Symptom worsening to the point that the subject becomes actively 
suicidal or requires hospitalization will prompt immediate assessment by an 
unblinded investigator of whether the subject should continue in their current study 
phase. Deterioration in symptoms, mood, anxiety, cognition, or in general level of 
functioning noted by the subject, family members, study physician or other research 
staff will also prompt assessment by an unblinded investigator of whether the subject 
should continue in their current study phase.  
If determined by the investigators and/or the subject that it is in their best medical 
interest to have the device removed, it will be done expeditiously. In the event a 
problem develops after one month post-surgery, the neurostimulator can be removed 
leaving the leads in place. In the past, subjects that have the leads left in place have 
not experienced adverse advents except for the restriction on future MRI scans. This 
restriction may affect the participants’ ability to thoroughly evaluate other conditions 
should they develop in the future. The procedure would not restrict the participant 
from future neurosurgical procedures.  
Risks to privacy are negligible in this protocol, since subjects will not be identified by 
name or by any personal health information in any summary reports or publications. 
Anticipated Benefits:  The primary anticipated benefit to subjects receiving an 
implanted Medtronic Summit RC+S and Medtronic Model 09130 cortical strip is the 
potential for a significant reduction in the symptoms of TS that would not be 
reasonably possible with further trials of medications and other approved treatment 
options. Experience in deep brain stimulation for the treatment of psychiatric 
disorders reported in the literature suggest that deep brain stimulation can benefit 

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patients by reducing symptoms without significant stimulation-related adverse 
events[11, 26, 37, 84].  The subjects will also have the benefit of the RC+S’s 9-year 
rated battery life, resulting in the likelihood of fewer battery replacement surgeries, 
thereby reducing medical risk and financial commitments.  The RC+S is the only 
rechargeable system with closed loop capability. 
15)   Justification for the Investigation:  This study will provide important safety, 
targeting, and effectiveness data for the treatment of medication refractory TS. The 
device and methodology are novel, and this study can provide potentially important 
experience for expanding stimulation options beyond standard chronic high frequency 
DBS. The study allows for “tailoring” of therapy to individual patient needs in a 
disorder that is known for its paroxysmal nature. Low duty cycle stimulation, 
particularly responsive stimulation, may have therapeutic advantages beyond what is 
currently available and this may allow further expansion to treatment of other 
neurological and neuropsychiatric disorders. This device may have added benefits in 
saving battery life, and preventing tolerance. Finally, this study will offer 
physiological data from deep brain thalamic structures in the human. Such 
information is conspicuously lacking from current literature, and has the potential to 
corroborate current models of TS pathophysiology. Furthermore, physiology may 
enhance our basic understanding of the circuitry involved in this disorder and help us 
to develop better, more focused hypothesis driven studies. 
16)   Patient Population, including number, age, sex and condition:  A total of ten 
subjects, 21 years and older with TS.  Subjects must not have an active diagnosis of 
DSM-V major depression or other active and disabling psychiatric disorders. There 

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are no restrictions on ethnicity, social background, or gender. Only subjects who are 
able to give full informed consent would be accepted. Subjects who currently meet 
DSM-V criteria for: Bipolar or Psychotic Depression, Organic Mental Disorder, 
Schizophrenia, Schizoaffective Disorder, Delusional Disorder, or Psychotic Disorder 
Not Otherwise Specified will be excluded from this study. 
17)   Monitoring Procedures:  This project entails substantial risk to subjects. 
Therefore, we have established the following monitoring procedures. 
Multidisciplinary Pre-Operative Screening and Evaluation: The multidisciplinary 
pre-operative screening and evaluation will include four specialties: 1) movement 
disorders neurology, 2) psychiatry, 3) neurosurgery, and 4) neuropsychology.  
Data Safety Monitoring Board (DSMB): This study will have a designated DSMB 
composed of three members (A neurologist, a psychiatrist, and a non-neurological 
physician) without ties to the current study or any conflicts of interest. The DSMB 
will be charged with the duty of meeting every 6 months to discuss all of the AE’s for 
the study.  
The safety experience will be frequently reviewed by the Data Safety Monitoring 
Board (DSMB). The DSMB will be informed of all serious adverse events and all 
mild adverse events which are potentially device related in the opinion of the 
investigator. The DSMB will designate each AE as mild or severe; as device related, 
uncertain to be device related or not device related; and as anticipated or 
unanticipated. 
Once the first subject is enrolled, the DSMB will meet approximately every 6 months 
in person, via teleconference, or electronically until all subjects have completed the 6 

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month primary outcome. The DSMB has the authority to suspend further enrollment 
pending investigation of safety concerns raised by SAEs occurring in the trial.  The 
DSMB has a stopping rule for more than one death or more than 1 suicide deemed to 
be device related. The DSMB stopping rule for an individual subject would be a 
suicide attempt deemed potentially device related. 
Adverse Event Reporting: Once a subject is enrolled into the study, continuous 
close monitoring will be conducted by the Principal Investigator (PI) in conjunction 
with the neurosurgeon and other investigators as well as the University of Florida’s 
Institutional Review Board (IRB), through annual reports of progress and by 
immediate notification of serious and unanticipated adverse events by the PI to the 
IRB. 
Stopping rules for the study have been established: This study will be suspended by 
the DSMB only if an unexpected and severe psychiatric or neurological complication 
occurs and they deem suspending or stopping the study appropriate. Specific 
examples that would warrant suspending the study include the following, only in the 
event that they do not reverse with adjustment or discontinuation of the DBS device: 
• Severe worsening of symptoms 
• Induction of severe difficult to treat depression 
 
Additionally, the DSMB has a firm stopping rule for more than a single death or 
suicide attempt in the cohort during the 6 month post-operative period. 
18) 
Device 
Description 
Summary: 
The 
Summit 
RC+S 
system 
is 
a 
multiprogrammable device that both delivers electrical stimulation and records 

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bioelectric data through one or two leads implanted in the brain. Summit RC+S 
electrical stimulation is based on the RC neurostimulator but adds the functionality of 
bioelectrical data recording (sensing). There are no new tissue contacting materials in 
Summit RC+S. 
Stimulation is provided by controlled delivery of current from a battery in an 
implantable neurostimulator (INS) to metal electrodes surgically implanted in the 
brain in the same manner as previous Activa RC. The INS is typically placed in the 
pectoral location. Current is conducted to the electrodes via electrical conduits, 
including extensions and leads, which are tunneled subdermally through the neck, 
travel through the skull, and terminate in a neural structure appropriate to the 
neurological disease being treated. 
Like Activa RC, the Summit RC+S system is capable of providing stimulation to 2 
leads, each with 4 electrode contacts. Stimulation parameters are adjusted to optimize 
therapy for the patient. They can be independently controlled and include the 
following: active electrode(s), electrode polarity, pulse width, amplitude, and 
frequency. The stimulation settings are stored in programs. A program is a specific 
combination of pulse width, rate, and amplitude settings acting on a specific electrode 
combination on a lead, or on a lead and the INS, in unipolar mode. Up to four 
programs can be combined into a group. 
Pulse width, amplitude, and electrode polarity are independently programmed for 
each program within a group. Rate, rate limits and cycling for each program within a 
group must have the same values. 
Stimulation is delivered to a maximum of two implanted leads (one lead per 

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hemisphere), with a maximum of 4 electrodes per lead. Rate is limited to 250 Hz, 
pulse width is limited to 450 μsec, amplitude is limited to 10.5 V (or 25.5 mA) and 
the charge density warning threshold is 30 μC/cm2/phase.  The RC+S is a 
rechargeable device.  Patients must charge the device as often as needed to maintain 
its functionality.  This could be as often as daily.  Failure to properly recharge the 
stimulator will result in loss of stimulation. The patients will receive training from the 
research group on how to recharge the device, and will be given written instructions 
to take home. They can reach out to the research team whenever they encounter any 
issues.  
Stimulation programs are controlled by the clinician via the unique Summit 
programmer and cannot be controlled by commercially available programmers.. 
Sensing functions, the recording of bioelectric data, is controlled by a separate 
sensing clinician programmer. 
19)   System Overview: 
The system block diagram of the Summit RC+S is given below in Figure 3. This 
investigational system is being provided to investigator-clinicians as part of the NIH 
BRAIN Initiative Public-Private Partnership with institutional and FDA 
investigational device exemptions.  

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• 
 Summit RC+S implantable pulse 
generator (IPG), Model B35300R 
• 
Research Lab Programmer (RLP), 
Model 4NR010 
• 
Clinician Telemetry Module 
(CTM), Model 4NR011 
• 
Lead extension Model 37087 
• 
Research Software Development 
Kit (RDK), Model 4NR013 
• 
Patient Therapy Manager (PTM), 
Model 4NR009  
• 
Recharge Therapy Manager 
(RTM), Model 97755 
Figure 3. Block diagram the Summit RC+S. 
RC+S communicates with peripheral devices via the Clinician Therapy Module 
(CTM), which must be within 2 meters of RC+S during communications. For clinical 
programming of the device, the research lab programmer (RLP) is linked to RC+S via 
the CTM. Most research related uses of RC+S are programmed on an investigator’s 
windows-based host computer using the Research Development Kit (RDK).  The 
RDK is an application programming interface (API) that can be programmed to 
establish a data and command conduit between a host computer and RC+S. This 
conduit can be utilized by researchers to receive sensing data and also send low-
latency stimulation update commands back to the neurostimulator, via the CTM. The 
patient recharges the device using the Rechargeable Therapy Monitor (RTM), and can 
interrogate it to check its function using the Patient Therapy Manager (PTM). The 
patients will receive training from the research group on how to use these devices, 
and will be given written instructions to take home. They can reach out to the study 
group whenever they encounter issues.  
 
The RDK is designed for rapid, automated closed-loop algorithm prototyping. This 

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programming interface provides for a low-latency bi-directional data port between an 
implantable device and an external computer that processes data and algorithms.  The 
RDK includes software that resides on the host computer to enable a variety of 
software programs (e.g., Java programs, Matlab® scripts, and graphical Matlab 
Simulink® models) to communicate with RC+S. This architecture allows algorithms 
to be both flexible and safe: flexibility is enabled because algorithms on the host 
computer can be as complex as needed and also utilize data from sensors connected to 
the external computer (e.g, wearable accelerometers, gait and posture sensors, etc.); 
safety is ensured because updates to the implantable stimulator are limited to those 
permissible by the patient programmer and thereby constrained to ranges set by a 
clinician. With Summit RC+S demo units and the Summit RDK, we will first design 
toolboxes for the algorithms we currently use in our projects with the Activa PC+S. 
Since we have data collected with 6 TS patients, we will utilize these datasets and 
input them into the Summit RDK as if they are being received from the RC+S 
implant. This rich dataset will allow us to learn how to program the SDK for real-time 
analysis. Since the RC+S allows for data streaming of brain signals in real time 
without any signal degradation, next steps would be to implement more sophisticated 
machine learning and data mining algorithms on our computers. More importantly, 
we can connect a demo unit RC+S to external signal generators to program sensing 
algorithms and understand the ADC conversion processes within the RC+S. Finally, 
we can also connect the RC+S to oscilloscopes to study the stimulator outputs and 
stimulator output timings.  
 

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Prior to the Medtronic PC+S and RC+S devices there was only one FDA-approved, totally 
implantable neuromodulation device that has the capability of sensing brain activity and 
delivering therapeutic stimulation: The Responsive Neurostimulation (RNS) device from 
Neuropace Inc. RNS is FDA-approved for the treatment of epilepsy. It has the capability to 
deliver short stimulation trains in the presence of epileptic activity and is designed to deliver 
a few pulse trains a day (5 minutes of stimulation a day). The very short battery life of this 
device precludes the delivery of constant or near-constant stimulation, as is the contemporary 
standard for movement disorders. A second platform, from Medtronic Inc. that allows 
adaptive stimulation paradigms was also recently introduced. The first-generation device, the 
Activa PC+S, has been available under physician-sponsored investigational device 
exemptions since 2013 and was the device we used for the current FDA IDE G130253. 
Several groups worldwide have begun to utilize this device in a variety of brain disorders, for 
sensing subcortical LFPs or cortical ECoG potentials to advance understanding of disease 
pathophysiology. Our team at UF has extensive experience with PC+S in the context of our 
current study focusing on multi-site brain recordings during Tourette deep brain stimulation. 
Recently, several add-ons to the basic PC+S platform were developed to prototype promising 
adaptive control algorithms. Although we and others have learned much from this 
experience, some problems with the first-generation PC+S platform have limited full testing 
of adaptive control. Its signal-to-noise ratio may preclude detection of high frequency (>100 
Hz) cortical activity, fully internalized adaptive control strategies are limited, and its lack of 
recharging capability has raised concern for battery drainage when testing adaptive 
algorithms. Additionally, since Medtronic is phasing out the PC+S there is a risk that their 
device supply will not be able to support the remaining implants in our IDE protocol and 

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therefore we will very likely need to switch to Summit RC+S eventually; this second-
generation bidirectional (sense and stimulate) interface has a rechargeable battery, and an 
improved signal to noise ratio allowing detection of high frequency brain signals. It also has 
a greater flexibility in the implementation of adaptive algorithms. The RC+S can be 
considered an “upgrade” to the PC+S, as it still provides closed loop stimulation, but also is 
rechargeable, providing a much longer battery life (labeled as 9 years vs. approx. 2-3 years). 
 
Adaptive stimulation with RC+S can occur in one of two modes: Distributed, in which the 
control algorithm resides on the researcher host computer (RHC), or embedded, in which 
control is accomplished within RC+S according to a preprogrammed algorithm.  For in-clinic 
testing we will primarily use the distributed mode. During in clinic testing, ECoG and Cm-Pf 
LFP data will be streamed to the RHC to verify that neural correlates of tics can be detected.  
These detected events will then be used to responsively deliver DBS. We will also study 
markers of clinically optimized settings, by comparing signals to charge balanced stimulation 
settings that we know will not provide clinical benefit.  
An adaptive control algorithm is embedded in RC+S. Prior to home use of adaptive 
stimulation, patients will be given and instructed on how to use the Clinician Therapy 
Module (CTM) and a tablet computer provided by the lab to interface with the CTM device 
which in turn communicates with the Summit RC+S. These devices allow switching off 
adaptive DBS and returning to open loop DBS.  
Adaptive control algorithms: We will develop adaptive control algorithms using the 
Medtronic Research Development Kit. Since control algorithms will be based on each 
subjects’ personalized neural signatures of tic symptomology, we cannot specify exact 

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algorithms prior to obtaining recordings from RC+S. In general, we expect the controller to 
utilize spectral power from one or more frequency bands extracted from cortical and/or 
thalamic recordings. Our initial data points to significant deviations from baseline data 
during tics in the Cm-Pf that is not present during voluntary movements (see Figure 4). These 
features can be captured using power bands of low frequencies up to 8Hz. 
 
Figure 4. Differentiating tics and volitional movements. Shown is the time series and 
spectrogram for each condition. (A,B,C,D) correspond to TS01, Images (E,F,G,H) correspond to 
TS02. (B,F) Increases in CM low frequency LFP are concurrent with (A,E) motor cortex beta 
desynchronization LFP at the onset of tics. (D,H) No increases in low frequency CM LFP are 

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observed during volitional movements, such as grasping (shown), but (C,G) motor cortex beta 
desychronization is still observed. (I) Data from follow up visit month 2. Subject TS01 was 
instructed to tic freely. Tic onset denoted by red dotted line:  (1) A neck wrenching tic (simple), 
(2)  Rapid arm throwing tic (complex long), (3) Arm wrenching tic (complex), (4) Arm throwing 
and neck twisting tic (complex long). In a separate trial the subject was asked to perform a series 
of volitional movements. Movement onset denoted by red dotted line: (5) Talking and 
opening/closing hands rapidly, (6,7) Opening/closing hands, (8,9) Rapidly shaking hands. No tics 
were observed during the volitional movement condition. 
 
The controller will be based on threshold crossings in this frequency range or possibly 
multiple frequency ranges, and will change stimulation current between a low-therapeutic 
level and a high-therapeutic level. For each proposed control algorithm, we will test the 
performance of the algorithm using an external RC+S and the RDK prior to implementing 
adaptive control in the patient. System integration will be checked by connecting the demo 
RC+S unit to signal generators to verify sensing algorithms, and by connecting the demo 
RC+S unit to oscilloscopes to verify stimulation delivery is consistent with algorithm outputs 
using previously collected neural data from PC+S devices. Testing and documentation of 
system integration for sensing and stimulation will comply with FDA CFR 820.30 on design 
controls for implanted devices. 
 
Safety of adaptive stimulation: During adaptive stimulation, several safety features protect 
patients from the potential from uncomfortably high stimulation settings or from prolonged 
periods with clinically inadequate settings. Stimulation parameters that can be implemented 
by the control algorithm are preselected by clinicians to avoid the possibility of producing 
major stimulation-induced adverse effects.  No possible combination of stimulation stetting 
will exceed the upper charge density limit of 30 microcoulombs per centimeter squared per 

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phase. Prior to home testing, patients will be instructed on how to exit adaptive mode at any 
time and return to open-loop mode should excessive discomfort occur, but are encouraged to 
consult with study staff if possible prior to doing so. 
 
Summit RC+S sensing malfunction or premature battery drainage: Should the sensing 
capability of Summit RC+S fail, without failure of the therapeutic stimulation function, we 
will attempt to restore it by noninvasive restoration of the software (see design master file for 
Summit RC+S referenced in this application). Should the sensing function be permanently 
lost with no compromise of the therapeutic function, no specific treatment is needed, and the 
patient would exit from the study.  Regarding the possibility of premature depletion of 
battery life due to use of the sensing function in addition to the neurostimulation function, 
this risk is mitigated by the fact that the sensing function utilizes relatively little energy 
(compared to therapeutic stimulation). Within its lifetime labeled for 9 years, RC+S has no 
known limit to the number of times it can be recharged.  
 
Manufacturing Information: Please reference Medtronic MAF 2978, PMA P960009 and 
P840001 for information on these devices.  
 
Device Charges: The Investigational Device, including the Summit RC+S system, will be 
provided by Medtronic.