CT-DBS for Traumatic Brain Injury Using the Medtronic Activa PC+S System
Phase: NA
Conditions: TBI (Traumatic Brain Injury)
Sponsor: Jaimie M. Henderson

 
 
 
 
CT-DBS for Traumatic Brain Injury Using the Medtronic Activa PC+S 
System   
Study Protocol and Statistical Analysis Plan 
NCT02881151 
January 30, 2020 

CONFIDENTIAL 
 
Page 1 of 39 
Study Protocol 
 
Title:  
CT-DBS for Traumatic Brain Injury Using 
Medtronic Activa PC and Percept PC 
Type and Phase:  
Single arm, single center feasibility study 
Study Product:  
Medtronic Activa PC system, Medtronic Percept PC 
system and Medtronic Nexus-E system for central 
thalamic deep brain stimulation (CT-DBS) 
Sponsor/Investigator 
Jaimie M. Henderson, MD 
Department of Neurosurgery 
Stanford University School of Medicine 
300 Pasteur Dr. 
Edwards Bldg/R-227 
Stanford, CA  94305 
Phone: 650.723.5574 
Fax: 650.725.8279 
henderj@stanford.edu 
 
Protocol Rev 
Issue Date 
1.0 
January 28, 2016 
2.0 
February 21, 2017 
3.0 
June 15, 2017 
4.0 
December 18, 2017 
5.0 
June 5, 2018 
6.0 
June 17, 2019 
7.0 
Jan 30, 2020 
8.0 
TBD 
 
 
 
 

CT-DBS Clinical Protocol, Ver 7 
 
 
CONFIDENTIAL 
 
Page 2 of 39 
TABLE OF CONTENTS 
TABLE OF CONTENTS ..............................................................................................................2 
LIST OF ABBREVIATIONS .......................................................................................................4 
1. 
SYNOPSIS ............................................................................................................................5 
2. 
INTRODUCTION ................................................................................................................7 
2.1. Traumatic Brain Injury ......................................................................................................8 
2.2. Rationale for Proposed Study ............................................................................................9 
2.3. Rationale for CT/DBS .....................................................................................................10 
2.4. Neuropsychological impairment following moderate to severe TBI: Target 
patient population .....................................................................................................11 
2.5. Role of frontostriatal systems in supporting sustained attention, working 
memory and processing speed ..................................................................................11 
2.6. Role of central thalamus in pathophysiology of moderate to severe TBI .......................12 
3. 
STUDY OBJECTIVES ......................................................................................................12 
4. 
STUDY DESIGN ................................................................................................................12 
5. 
STUDY DEVICE ................................................................................................................12 
6. 
STUDY PLAN ....................................................................................................................13 
6.1. Study Population .............................................................................................................14 
6.1.1. Inclusion Criteria .................................................................................................14 
6.1.2. Exclusion Criteria ................................................................................................15 
6.1.3. Concomitant Medications ....................................................................................15 
6.2. Informed Consent ............................................................................................................16 
6.3. Randomization to Multiple Baseline Condition and Treatment Withdrawal ..................16 
6.4. Screening Imaging ...........................................................................................................17 
6.5. Screening and Preoperative Baseline Evaluation ............................................................17 
6.6. Inpatient Hospital Stay ....................................................................................................17 
6.6.1. Stage I:  Bilateral DBS Lead Implantation ..........................................................17 
6.6.2. Stage II .................................................................................................................19 
6.7. Post-Surgical Washout Phase ..........................................................................................20 
6.8. DBS Stimulation Titration/Optimization ........................................................................20 
6.9. Unblinded Treatment Phase ............................................................................................20 
6.10. DBS Stimulation Long-term Continuation .................................................................20 
6.11. Six Month Open Label Follow-Up Period ..................................................................20 
6.12. Unscheduled Visits: ....................................................................................................21 
7. 
DESCRIPTION OF OUTCOME ASSESSMENTS ........................................................21 
7.1. Measures of Cognition ....................................................................................................21 
7.2. Physical Symptoms (self-report) .....................................................................................21 
7.3. Psychological Health (self-report) ...................................................................................22 
7.4. Quality of Life (self-report) .............................................................................................22 
7.5. Global Functional Outcome Measure ..............................................................................22 
7.6. Participant Interview .......................................................................................................23 
7.7. Exploratory Measures ......................................................................................................23 
7.7.1. Electrophysiological ............................................................................................23 

CT-DBS Clinical Protocol, Ver 7 
 
 
CONFIDENTIAL 
 
Page 3 of 39 
8. 
EARLY WITHDRAWAL OR TERMINATION ............................................................24 
9. 
ADVERSE EVENTS ..........................................................................................................24 
9.1. Adverse Event Identification and Assessment ................................................................24 
9.2. Adverse Device Effect .....................................................................................................24 
9.3. Serious Adverse Events (SAEs) ......................................................................................25 
9.4. Anticipated & Unanticipated (UADEs) Adverse Device Effects ....................................25 
9.4.1. Anticipated Adverse Events ................................................................................25 
9.4.2. Unanticipated adverse device effects (UADEs) ..................................................28 
9.5. Adverse Event Reporting ................................................................................................28 
9.5.1. Reporting Serious Adverse Events ......................................................................29 
9.5.2. Reporting UADEs ...............................................................................................29 
9.5.3. Stopping Rules .....................................................................................................29 
9.5.4. Reporting Deaths and Suicides ............................................................................29 
10. 
CLINICAL OVERSIGHT COMMITTEE ......................................................................29 
10.1. Medical Monitor .........................................................................................................30 
11. 
STATISTICAL PLAN .......................................................................................................30 
12. 
RISK ASSESSMENT AND MITIGATION ....................................................................30 
12.1. Known and Anticipated Surgical Risks ......................................................................30 
12.2. Device-Related and Therapy-Related Risks ...............................................................31 
12.3. Protocol for Managing Suicidal Ideation and Intent ...................................................31 
13. 
ADMINISTRATIVE REQUIREMENTS, INCLUDING INVESTIGATOR 
RESPONSIBILITIES ...............................................................................................33 
13.1. Good Clinical Practice (GCP) ....................................................................................33 
13.2. Ethical Considerations ................................................................................................33 
13.3. Subject Information and Informed Consent ...............................................................33 
13.4. Subject Confidentiality ...............................................................................................33 
13.5. Protocol Compliance ..................................................................................................33 
13.6. Maintenance of Study Records ...................................................................................34 
13.7. Study Monitoring ........................................................................................................34 
13.8. On-Site Audits ............................................................................................................34 
13.9. Case Report Form Completion ...................................................................................34 
13.10. 
Study Product Accountability ..................................................................................35 
14. 
REFERENCES ...................................................................................................................35 
APPENDIX 1. 
DEVICE PROGRAMMING SOP ..........................................................38 
 
 
 
 

CT-DBS Clinical Protocol, Ver 7 
 
 
CONFIDENTIAL 
 
Page 4 of 39 
LIST OF ABBREVIATIONS 
Abbreviation  
Definition  
AE 
Adverse Event 
SAE 
Serious Adverse Event 
UADE 
Unanticipated Device Event 
CT-DBS 
Central Thalamus-Deep Brain Stimulation 
GOSE 
Glasgow Outcome Scale-Extended 
MCS 
Minimally Conscious State 
IPG 
Implantable Pulse Generator 
EMCS 
Emergence from Minimally Conscious State 
SMTBI 
Moderate to severe Traumatic Brain Injury 
GPi 
Internal Globus Pallidus 
STN  
Subthalamic Nucleus 
VPM 
Ventral Posterior Medial 
CRF 
Case Report Form 
eCRF 
Electronic Case Report Form 
INS 
Implantable Neurostimulator 
IC 
Integrated Circuit 
PIC 
Algorithm Microprocessor 
ANT 
Attention Network Test 
PRO 
Patient-Reported Outcomes 
 
 
 
 

CT-DBS Clinical Protocol, Ver 7 
 
 
CONFIDENTIAL 
 
Page 5 of 39 
1. 
SYNOPSIS 
Table 1: 
Protocol Synopsis 
Title 
Central Thalamic Deep Brain Stimulation for the Treatment of Traumatic Brain 
Injury 
Study Groups 
Single arm study of 6 subjects  
Study Objective 
Pilot study to inform the safety and efficacy of central thalamic-deep brain 
stimulation (CT-DBS) in the treatment of chronic cognitive impairment and 
residual disability caused by traumatic brain injury (TBI). 
Study Device 
Medtronic Percept PC system for central thalamic deep brain stimulation (CT-
DBS) 
Clinical 
Hypothesis 
CT-DBS will be safe in the study population and will enhance cognitive function 
as indexed by the primary outcome measure 
Study Population 
Adult patients with a history of moderate to severe TBI (GCS ≤12) who continue 
to demonstrate neuropsychological impairment and functional disability 
(Glasgow Outcome Scale- Extended = 5-7) at least 24 months post-injury. The 6 
participants will be separated into three pairs. 
Study Design  
Single arm, open-label, sponsor-investigator study  
Number of Sites 
1 site 
Total Number of 
Subjects 
18 subjects screened with a total of 6 subjects enrolled for randomization and 
implantation 
Duration of Study 
The total duration of the study is 12 to 14 months depending on cohort. 
Inclusion Criteria 
• 
History of  moderate to severe  TBI based on worst GCS score within first 48 
hours of injury (acceptable GCS range = 3-12) 
• 
Age 22-60 
• 
At least 24 months from date of onset  
• 
Fluent in English and able to independently provide consent 
• 
Retains decision-making capacity and is able to function independently (i.e., 
unsupervised) in the home setting 
• 
Multiple unsuccessful attempts to sustain competitive employment or 
complete an academic degree-granting program of study 
• 
Either receives no CNS stimulants or other medications known to affect 
cognitive function, or on stable doses of these medications for the last three 
months (see additional information regarding concomitant medications 
below) 

CT-DBS Clinical Protocol, Ver 7 
 
 
CONFIDENTIAL 
 
Page 6 of 39 
Exclusion Criteria 
• 
History of major developmental, neurologic, psychiatric or substance use 
disorder with evidence of disability prior to onset of TBI 
• 
Major medical co-morbidities including: end stage renal failure, severe heart 
failure, coagulopathy, severe respiratory problems, severe liver failure, 
uncontrolled hypertension or other significant medical co morbidities 
• 
Have had a documented seizure within 3 months of study screening (subjects 
may re-screen if seizure free after initial screen failure) 
• 
Malignancy with < 5 years life expectancy 
• 
Untreated / uncontrolled (severe at the time of enrollment) depression or 
other psychiatric disorder 
• 
Women of childbearing age who do not regularly use an accepted 
contraceptive method 
• 
Inability to stop anticoagulation therapy or platelet anti-aggregation therapy 
before, during and after surgery 
• 
Previous DBS or other brain implants 
• 
Previous ablative intracranial surgery 
• 
Implantable hardware not compatible with MRI 
• 
Condition requiring diathermy after DBS implantation 
• 
Hardware, lesions or other factors limiting placement of electrodes in optimal 
target location in the judgment of the operating surgeon 
• 
Concurrent enrollment in any other clinical trial 
• 
Any condition or finding that, in the judgment of the PI, significantly 
increases risk or significantly reduces the likelihood of benefit from DBS 
Main Study 
Phases/Activities 
• 
Pre-screening Evaluation and Informed Consent 
• 
Randomization to 1of 3 baseline conditions lasting 30, 44 or 58 days.  Each 
participant will also be randomly assigned to a treatment withdrawal or 
continuation condition for 21 days following the 90-day unblinded treatment 
phase 
• 
Baseline physical and neurological pre-operative examinations 
• 
Hospitalization and surgical implantation of DBS system 
• 
Post-operative washout (30-day surgical washout for resolution of any 
transient physiological or behavioral effects of surgery) 
• 
DBS Stimulation Titration/Optimization (14 days, optimize settings to be 
used during treatment phase) 
• 
Unblinded Treatment Phase (90 days) 
• 
Randomization to treatment withdrawal or continuation  
• 
6-month open label follow up 
Outcome 
Measures 
Primary outcome measure: 
o Trail Making test 
Secondary outcome measures include: 
• 
Measures of Cognition 
o Ruff 2 & 7 
• 
Physical Symptoms (self-report) 

CT-DBS Clinical Protocol, Ver 7 
 
 
CONFIDENTIAL 
 
Page 7 of 39 
o Rivermead Post-Concussion Symptom Questionnaire (RPQ) 
• 
Psychological Health (Self-report) 
o Patient Health Questionnaire-9 (PHQ-9) 
o Columbia Suicide Severity Rating Scale (C-SSRS) 
• 
Quality of Life 
o Traumatic Brain Injury Quality of Life (TBI-QoL subscales) 
• 
Measure of Global Function 
o Glasgow Outcome Scale – Extended (GOSE) 
Safety Endpoints 
Rate of adverse events, serious adverse events and adverse device effects 
Statistical 
Methods and 
Sample Size 
Determination  
This is a single center, feasibility study to be performed by a sponsor investigator 
at an academic institution.  All baseline, procedural, and safety and effectiveness 
follow-up data will be summarized with appropriate descriptive statistics.  For 
continuous variables, we will summarize data by the mean, median, standard 
deviation, minimum and maximum.  For non-continuous variables we will 
summarize by percentages and frequency distributions.  We will tabulate data for 
all enrolled patients. 
2. 
INTRODUCTION  
This study involves the treatment of cognitive impairment secondary to traumatic brain injury 
(TBI) using the Medtronic  Percept PC for central thalamic deep brain stimulation (CT-DBS).  
The proposed study, if successful, will provide supporting evidence for the development of a 
novel therapeutic approach utilizing CT-DBS to improve these enduring cognitive impairments 
arising in persons with multi-focal structural brain injuries.  This research will address the critical 
gap of the lack of any available treatments.  CT-DBS targets well-defined neuronal populations 
within the central thalamus that have known anatomical and physiological specializations, which 
not only provide a key role in arousal regulation during cognitively-mediated behaviors, but also 
exhibit a particular vulnerability to dysfunction in the setting of multi-focal, non-selective brain 
injuries. 
The proposed study builds on a previous clinical study of CT-DBS in subjects with very severe 
traumatic brain injuries (Schiff et al. 2007 [22]; Giacino et al. 2012 [10]).  In the preliminary 
clinical and preclinical studies, we have identified that CT/DBS acts through specific circuit and 
cellular mechanisms that counter the effects of deafferentation and impaired cellular function 
across long-range cortico- cortical connections and modulatory cortico-striato-pallidal-
thalamocortical pathways following brain injuries by direct activation of the frontostriatal 
network.  We have further identified a strategic location within the three-dimensional confines of 
the central thalamus that provides an optimal means for facilitating arousal, attention, executive 
function and motivation. 
Our proposed study aims to support development of CT-DBS as a novel therapeutic avenue for 
accessing cognitive reserve in patients with acquired brain injuries.  In the proposed feasibility 
study of 6 subjects at a single investigational site, we will test the safety of CT-DBS in the 
moderate to severe traumatic brain injury (SMTBI) population with GOSE 5-7 level recovery 
and collect data to establish the translation of preclinical studies into human application of CT-
DBS.  We estimate a screen failure rate of 3:1 for this study. 

CT-DBS Clinical Protocol, Ver 7 
 
 
CONFIDENTIAL 
 
Page 8 of 39 
This is a single-site feasibility study being conducted by a sponsor-investigator.  There have been 
no changes made to the Medtronic Percept PC for use in this study. 
2.1. 
Traumatic Brain Injury 
TBI is a leading cause of death and long-term disability in the United States as well as worldwide 
(Murray and Lopez 1997 [19]).  Significant attention has been given to TBI in recent years, 
particularly due to significant numbers of military personnel who have suffered TBI in combat 
since 2000.  According to the Defense and Veterans Brain Injury Center, there were 212,742 
TBIs between 2000-2011Q1 in all Armed Forces and 2,235 of these were severe TBIs.  
Additionally, the statistics of TBI are even more concerning in the civilian population.  In 
addition to 50,000 TBI-related deaths in the US civilian population, there are over 1 million 
Americans treated in emergency departments every year and 235,000 hospital admissions 
(Corrigan et al. 2010 [4]).  It is estimated that 43% of those discharged from hospital admissions 
(124,000 patients per year) will develop long-term disability due to TBI (Selassie et al. 2008 
[27]).  Thus, TBI disproportionately affects young and otherwise healthy individuals who could 
contribute to the work force.  The intervention proposed here is aimed at providing functional 
improvements that may produce social and vocational reentry and improved vocational 
performance.  Successful treatment of individuals in this disability range thus has the potential 
for tremendous impact, both for the individual and for society. 
Deep brain stimulation is a standard FDA approved treatment for advanced movement disorders 
and holds great promise for other neurologic disorders, including TBI because of its distinct 
mechanism of action that can produce control of axonal action potential generation.  The safety 
and feasibility of DBS for patients in chronic post- traumatic injury who fulfilled the behavioral 
criteria for the minimally conscious state (MCS) and emergence from minimally conscious state 
(MCS and EMCS) has been demonstrated in a previous IDE and we have provided the proof-of-
concept that cognitively-mediated functions can be facilitated in chronic brain injury with DBS 
directed into the central thalamus (Schiff et al. 2007 [22]).  The scientific basis for the CT/DBS 
approach taken here has evolved over a 20-year period of study of the pathophysiology of 
impaired consciousness in human subjects and the physiological investigations of the role of the 
central thalamus in forebrain arousal regulation (Purpura and Schiff 1997 [20]; Schiff and Plum 
2000 [21]; Shirvalkar et al. 2006 [28]; Schiff et al. 2007 [22]; Smith et al. 2009 [29]; Schiff 2008 
[23], 2009 [24], 2010 [25], 2012 [26]).  These studies are described in more detail in the section 
that follows. 
Approximately 70% of persons who sustain moderate to severe TBI experience chronic cognitive 
impairments (TBI Model Systems National Data and Statistical Center [31]) that disrupt 
vocational, social and emotional functioning.  This is due, in part, to diffuse axonal injury which 
results in widespread disconnection across the cerebrum, leading to secondary neuronal death 
concentrated in the intralaminar nuclei of the central thalamus.  After one year, one-third of these 
individuals remain unemployed and nearly 40% continue to require supervision (TBI Model 
Systems National Data and Statistical Center [31]).  After five years, more than 30% still require 
some level of supervised care, and 29% report dissatisfaction with life (Corrigan 2014 [5]).  Self-
report and neuropsychometric findings suggest that slowing in processing speed, mental fatigue 
and deficient mental control contribute significantly to residual disability following TBI.  We 
have established that CT-DBS can significantly modulate and facilitate performance across a 
wide range of executive function tasks in the non-human primate (Baker et al. 2011 [1]; 2012 
[2]) and in a pilot human study (Schiff et al. 2007 [22]), including tasks involving sustained 

CT-DBS Clinical Protocol, Ver 7 
 
 
CONFIDENTIAL 
 
Page 9 of 39 
attention, working memory and complex visual pattern recognition.  We postulate based on our 
prior investigation that the effects of CT-DBS are mediated by activation of downregulated 
frontocentral cortical regions and will produce improvements in processing speed and executive 
functions as measured by standardized neuropsychometric measures (Trails B, continuous 
performance tasks) and customized behavioral tasks assaying sustained attention and working 
memory.  We also anticipate that these changes in cognitive efficiency will facilitate 
improvements in vocational productivity, psychological health and self-reported quality of life. 
2.2. 
Rationale for Proposed Study 
In the proposed feasibility study of six subjects, we plan to evaluate the safety and efficacy of 
CT/DBS in patient subjects who have recovered from a moderate or severe brain injury (initial 
GCS 12 or lower) to an outcome level ranging from GOSE 5 to the lower half of GOSE 7.  As 
briefly outlined below and based on our pre-clinical studies of CT/DBS in intact non-human 
primates and rodents with and without TBI, and our clinical experience with CT/DBS in 
MCS/EMCS subjects, we outline the rationale that this new patient TBI population is optimally 
matched to obtain clinically meaningful benefits from CT/DBS (see Figure 1).  We are targeting 
a collection of well-defined neuronal populations within the central thalamus that have known 
anatomical and physiological specializations that both provide a key role in arousal regulation 
during cognitively- mediated behaviors and are particularly vulnerable to dysfunction in the 
setting of multi- focal, non-selective brain injuries.  
As per Figure 1, an optimal benefit of CT/DBS in patients recovering from moderate to severe 
traumatic brain injury is proposed for the functional outcomes captured across the GOSE level 5 
to 7 range on this scale.  The conceptual basis for targeting this population includes evidence that 
CT/DBS can have a significant behavioral facilitation effect across the range of minimally 
conscious state (Schiff et al. 2007) to executive function in the intact mammalian forebrain 
(Baker et al. 2011, 2012, 2013).  Patients with initial moderate to severe brain injury (GCS<12) 
and recovery to GOSE level 5 to lower 7 are anticipated to demonstrate significant cerebral 
deafferentation leading to a large population of neocortical, striatal and thalamic neurons that do 
not reach their full potential dynamic range as a result of deafferentation but could under 
conditions of sufficiently increased background synaptic activity. 

CT-DBS Clinical Protocol, Ver 7 
 
 
CONFIDENTIAL 
 
Page 10 of 39 
Figure 1: 
Effects of CT/DBS are Present across the Continuum from MCS to Healthy Intact 
Brain 
 
2.3. 
Rationale for CT/DBS 
The fundamental rationale for CT/DBS as a therapeutic modality in the SMTBI patient 
population with recoveries in the range of GOSE 5-7 targeted here is based on several 
considerations:  
• the frequent observation of a specific clustering of neuropsychological impairments in 
this patient population 
• the specific role of frontostriatal systems in establishing these specific 
neuropsychological functions in the brain 
• the functional role of the central thalamus in supporting frontostriatal systems and 
regulating activity across frontostriatal neuronal populations in response to cognitive 
demands 
• the common pathology of deafferentation of the central thalamus arising across all 
moderate to severe brain injuries with a maximal predicted preservation of neuronal 
cell types in the GOSE 5-7 level recovery from STBI patient population 
• clinical and pre-clinical studies demonstrating that CT-DBS can facilitate behaviors in 
humans and rodents with TBI, and that these specific neuropsychological functions 
affected in the SMTBI patient population can be significantly facilitated by CT-DBS 
in a human subject with very severe brain injury, as well as in intact non-human 
primates. 

CT-DBS Clinical Protocol, Ver 7 
 
 
CONFIDENTIAL 
 
Page 11 of 39 
2.4. 
Neuropsychological impairment following moderate to severe TBI: 
Target patient population 
Diffuse traumatic brain injuries produce a very wide range of neuropsychological deficits that 
associate with distinct injury patterns but have considerable overlap (Levin et al. 2013).  Several 
studies, however, have characterized common symptom clusters which do show clear 
consistency across large population cohorts of patients with both moderate to severe and mild 
traumatic brain injuries (Levin et al. 2013 [14]; Dikmen et al. 2003 [6]).  A larger proportion of 
the STBI patient population targeted here is known to suffer significant ongoing morbidity due to 
cognitive impairment (Dikmen et al. 2003 [6]).  A systematic relationship has been established 
between the severity of initial deafferentation (as assessed by clinical variables) and 
neuropsychological measures of working memory, learning, attention, and information 
processing speed (Dikmen et al. 2003 [6]).  Detailed evaluation of a cohort of 500 patients 
suffering STBI provides additional population data supporting both the uniqueness and the 
specificity of measures of working memory, attention and processing speed in the STBI patient 
population that identify the sub-cohort we plan to target in this study (Dikmen, unpublished 
studies).  Specifically, population data show clear separation of performance of the Trails B test 
(TMT-B) in the group of symptomatic patients with GOSE 5-7 level recovery from those in the 
Upper Good recovery range (GOSE 8).  These population-based data show a marked difference 
in median completion time on the TMT-B between patients functioning in the Lower or Upper 
Moderate (UM=76s) to Lower Good (LG=75s) outcome categories of the GOSE, as compared to 
those functioning in the Upper Good (UG=52s) range.  A primacy of these symptoms in the 
STBI group is further identified in studies of outcomes of mild TBI supporting the biological 
continuity of the effects of TBI and linkage of the primary neuropsychological functions targeted 
for support here using CT-DBS.  In mild TBI subjects, processing speed deficits are identified as 
the first principal component of measurable deficits, followed by an index of visual working 
memory (Levin et al. 2013 [14]).  These measurements are consistent with the hypothesis that the 
anterior forebrain is the area most sensitive to deafferentation injuries associated with TBI of all 
types (Schiff 2010 [25]).  
2.5. 
Role of frontostriatal systems in supporting sustained attention, 
working memory and processing speed 
Human neuroimaging and studies in non-human primate provide a convergence of evidence that 
frontostriatal systems organize and support the neurophysiological substrate underpinning a 
group of psychological capacities collectively described as executive functions (Stuss and Knight 
2013 [30]).  At the core of this wide-ranging set of capacities are the neuropsychological 
functions of sustaining attention; holding instructions or briefly presented information in 
memory; and processing information quickly ahead of executing a variety of motor responses 
such as gestures and spoken language.  Persistent activity in specialized neuronal populations in 
frontal cortex, striatum and thalamus has been consistently identified as supporting sustained 
attention, working memory, and processing speed (McCormick et al. 2003 [18]).  The loss of 
dynamic range of activation of frontostriatal systems in response to demands on executive 
function systems can thus be understood as the result of deafferentation of these neurons 
resulting from brain injuries and of their main source of activation in the central thalamus (see 
below).  The dominance of psychological effects of STBI by the cluster of impaired sustained 
attention, working memory, and cognitive processing speed deficits is the direct result of the 

CT-DBS Clinical Protocol, Ver 7 
 
 
CONFIDENTIAL 
 
Page 12 of 39 
graded impact in those patients remaining functionally affected by their injuries of the loss of this 
general purpose base function of frontostriatal systems (Duncan and Owen 2003 [7]). 
2.6. 
Role of central thalamus in pathophysiology of moderate to severe 
TBI 
The central thalamus is anatomically specialized to provide strong synaptic drive across the 
frontal and prefrontal cortices and rostral striatum in response to cognitive demands (reviewed in 
Schiff 2008 [23]; Mair and Hembrook 2012 [16]).  Control of the activation of central thalamus 
in response to these demands emanates from medial frontal cortex and is modulated by the full 
set of brainstem ‘arousal system’ inputs from cholinergic, noradrenergic, and other monoamine 
pathways.  Diffuse axonal injury results in widespread disconnection across the cerebrum with 
secondary neuronal death of these central thalamic neurons arising as a common pathology; the 
concentration of damage in the central thalamus (intralaminar) and related association nuclei 
indexes the severity of outcome (Maxwell et al. 2006 [17]).  These nuclei show a greater 
vulnerability to multifocal brain injury because of their widespread projections that lead to their 
disproportionate deafferentation that is associated with diffuse injuries.  Loss of input from these 
neurons secondary to this deafferentation leads to a failure to maintain sufficient membrane 
depolarization to produce or sustain action potential firing rates typical of frontocortical and 
striatal neuronal populations in the wakeful state; in studies of severely brain injured human 
subjects who remain within the very severely impaired categories of minimally conscious state 
and confusional state this effect can be measured in differences in regional cerebral metabolic 
rates (Fridman et al. 2014 [9]); the level of recovery of central thalamic metabolism in these 
studies grades level of recovered behavioral function. Several circuit- level specializations of the 
central thalamus underlie dysfunction of the forebrain after STBI and deafferentation of the 
central thalamus (Schiff 2010 [25]). 
3. 
Study Objectives  
This is a feasibility study to inform the safety and efficacy of central thalamic-deep brain 
stimulation (CT-DBS) in the treatment of chronic cognitive impairment and residual disability 
caused by traumatic brain injury (TBI). 
4. 
Study Design 
This is a single arm, sponsor-investigator feasibility study to be conducted at a single 
investigational site. 
5. 
Study Device 
This study utilizes the Medtronic Percept PC Deep Brain Stimulation system. The Percept PC 
has been approved by the FDA for Bilateral stimulation of the internal globus pallidus (GPi) or 
the subthalamic nucleus (STN) as an adjunctive therapy in reducing some of the symptoms of 
advanced, levodopa-responsive Parkinson's disease that are not adequately controlled with 
medication.  The device is being provided by the manufacturer, Medtronic, and no changes have 
been made to the device for use in this study. 

CT-DBS Clinical Protocol, Ver 7 
 
 
CONFIDENTIAL 
 
Page 13 of 39 
The Percept PC system consists of the neurostimulator, leads, extensions and clinician and 
patient programmers. As shown in Figure 2 below, there are separate programmers for the 
clinician and the patient.   
Figure 2: 
Percept PC System  
 
 
6. 
STUDY PLAN 
The research plan is organized around the central aim of acquiring pilot clinical data that will 
inform the safety and efficacy of central thalamic-deep brain stimulation (CT-DBS) in the 
treatment of chronic cognitive impairment and residual disability caused by TBI.  We intend to 
recruit 6 adults with a history of moderate to severe TBI (GCS = 3-12) who continue to 
demonstrate neuropsychological impairment and functional disability at least 24 months post-
injury (Glasgow Outcome Scale- Extended = 5-7) {Wilson, 1998, Structured interviews for the 
Glasgow Outcome Scale and the extended Glasgow Outcome Scale: guidelines for their use}.   
Following study enrollment, participants will be randomly assigned to 1 of 3 baseline conditions 
lasting 30, 44, or 58 days.  Two participants will be assigned per condition.  The staggered 
baseline schedule will enable assessment of CT-DBS effects within individual subjects and 
across subject pairs.  Each participant will also be randomly assigned to a treatment withdrawal 
or continuation condition.  This process is explained in detail in Section 6.3 of this document. 
Following a 30 to 60-day presurgical baseline phase to ensure surgical readiness and establish 
current level of function across multiple domains, participants will undergo implantation of a 
deep brain stimulator in the central lateral nucleus of the thalamus.  Implantation of the 
stimulator will be followed by a staggered post-surgical baseline that will increase progressively 
for each pair of participants.  After a 14-day stimulation titration phase, CT-DBS will be 

CT-DBS Clinical Protocol, Ver 7 
 
 
CONFIDENTIAL 
 
Page 14 of 39 
administered for 90 consecutive days.  Following the unblinded stimulation phase, participants 
will enter a 21-day double-blinded treatment withdrawal phase.  The study will formally 
conclude at the end of the withdrawal phase.  Participants will be given the option to continue to 
use the device following study termination, if they are receiving benefit. 
The study design includes 3 unique features that were incorporated to detect treatment effects, 
reduce sources of bias and estimate generalizability: 
• Subject pairs will be randomized to one of 3 progressively-increasing baseline 
observation periods.  Should treatment be effective, improvements in performance on 
the outcome measures will occur in temporal contiguity to the onset of CT-DBS.  
This design element will help differentiate the effects of CT-DBS from random 
fluctuations in function. 
• Treatment will be withdrawn in a double-blinded manner- neither the investigators 
nor the subjects will have knowledge of when CT-DBS is discontinued.  This feature 
will minimize the influence of examiner and subject bias on the outcomes of interest. 
• Outcome assessment across multiple subjects following establishment of a stable 
baseline will enable identification of a significant treatment effect and permit 
inferences to be drawn concerning generalizability of results (Schiff, 2007 [22], 
Behavioral improvements with thalamic stimulation after severe traumatic brain 
injury). 
Study Operations:  This is a single site study.  All procedures, assessments and follow-up care 
will be take place at Stanford University under the leadership of Jaimie Henderson, MD.  The 
study co-investigators from Weill-Cornell, Spaulding Rehabilitation/Harvard, Cleveland Clinic 
and University of Utah will travel to Stanford for procedures.  Two additional Weill-Cornell 
faculty members will travel to Stanford to do EEG testing and other data collection.  Dr. 
Nicholas Schiff at Weill-Cornell will lead the data analysis.  
The members of the team have had successful remote collaborations for over a decade.  The 
project has adequate funding for remote collaboration tools for conference calling and document 
sharing, travel for in-person meetings and a project manager.   
6.1. 
Study Population 
6.1.1. 
Inclusion Criteria 
• History of moderate to severe TBI based on worst GCS score within first 48 hours of 
injury (acceptable GCS range = 3-12) 
• Age 22-60 
• At least 24 months from date of onset  
• Fluent in English and able to independently provide consent 
• Retains decision-making capacity and is able to function independently (i.e., 
unsupervised) in the home setting 
• Multiple unsuccessful attempts to sustain competitive employment or complete an 
academic degree-granting program of study 

CT-DBS Clinical Protocol, Ver 7 
 
 
CONFIDENTIAL 
 
Page 15 of 39 
• Either receives no CNS stimulants or other medications known to affect cognitive 
function, or on stable doses of these medications for the last three months (see 
additional information regarding concomitant medications below) 
6.1.2. 
Exclusion Criteria 
• History of major developmental, neurologic, psychiatric or substance use disorder 
with evidence of disability prior to onset of TBI 
• Major medical co-morbidities including: end stage renal failure, severe heart failure, 
severe congestive heart disease, coagulopathy severe respiratory problems, severe 
liver failure, uncontrolled hypertension or other significant medical co morbidities 
• Have had a documented seizure within 3 months of study screening (subjects may re-
screen if seizure free after initial screen failure 
• Malignancy with < 5 years life expectancy 
• Untreated / uncontrolled (severe at the time of enrollment) depression or other 
psychiatric disorder 
• Women of childbearing age who do not regularly use an accepted contraceptive 
method   
• Inability to stop anticoagulation or platelet anti-aggregation therapy before, during 
and after surgery 
• Previous DBS or other brain implants 
• Previous ablative intracranial surgery 
• Implantable hardware not compatible with MRI 
• Condition requiring diathermy after DBS implantation 
• Hardware, lesions or other factors limiting placement of electrodes in optimal target 
location in the judgment of the operating surgeon 
• Concurrent enrollment in any other clinical trial 
• Any condition or finding that, in the judgment of the PI, significantly increases risk or 
significantly reduces the likelihood of benefit from DBS 
6.1.3. 
Concomitant Medications 
Subjects who are on centrally-acting medications will remain eligible for enrollment as long as 
the dose of the medication has been stable for at least three months prior to the date of 
enrollment.  All concomitant medication and concurrent therapies will be documented during the 
Baseline Visit, and at every subsequent study visit.  At each study visit, the Study Coordinator 
will review and print the list of concomitant medications that were completed at the participant’s 
prior visit in order to accurately review and document changes in the participant’s concomitant 
medications or concurrent therapies.  The generic name of the drug, presence/absence of the drug 
at the time of randomization, date started, dose, route, unit frequency of administration (i.e., 
schedule) and the date stopped or changed will be recorded.  We will also record whether the 
medication was prescribed to treat an AE (and, if so, the date of the AE form) or a new clinical 

CT-DBS Clinical Protocol, Ver 7 
 
 
CONFIDENTIAL 
 
Page 16 of 39 
problem that arose after enrollment.  The same information will be recorded for non-
pharmacologic therapies, with the exception of dose and route of administration.  
If there are any changes in a centrally-acting medication, or if a new centrally-acting medication 
is added following randomization, the Study Coordinator will apprise the Sponsor and a protocol 
violation will be recorded.  The Sponsor will evaluate the potential influence of the new 
medication on the study treatment and will make a disposition regarding continued participation 
in the trial.  Any disposition recommending withdrawal from the trial will be reviewed by the 
Clinical Oversight Committee (see Section 10 below) before any action is taken.  
6.2. 
Informed Consent  
If no exclusion criteria are identified during the pre-screening interview, the 
investigator/coordinator will provide the informed consent form ahead of time to potential 
candidates.  Candidates will be asked to review and mark the document with questions.  Study 
investigators will be available for questions in person or over the phone or teleconference.  The 
coordinator will then arrange for a consent meeting with the sponsor to: (a) review the informed 
consent form; (b) clearly explain all study procedures, risks, potential benefits, alternative 
therapies (if available); and (c) answer any questions the participant may have regarding the 
study.  The sponsor will be present for the entire informed consent meeting.  A consent for 
release of medical records will be obtained during the consent meeting to acquire additional 
information and medical records related to study eligibility.  The participant will be reminded 
that study eligibility will not be finalized until all screening and pre-operative tests and 
procedures have been completed. 
After the study has been fully explained to the potential subject and all questions have been 
addressed, written informed consent will be obtained prior to the performance of any study-
specific procedures.  The method of obtaining and documenting the informed consent and the 
contents of the consent will comply with ICH-GCP and all applicable regulatory requirements, 
including local IRB requirements.  
6.3. 
Randomization to Multiple Baseline Condition and Treatment 
Withdrawal 
Following study enrollment, participants will be randomly assigned to 1 of 3 baseline conditions 
lasting 30, 44, or 58 days.  Two participants will be assigned per condition.  The staggered 
baseline schedule will enable assessment of CT-DBS effects within individual subjects and 
across subject pairs.  Each participant will also be randomly assigned to a treatment withdrawal 
or continuation condition.  Neither the investigator nor the participant will have knowledge or be 
apprised as to whether DBS is on or off during this period.  For participants assigned to the 
treatment withdrawal condition, DBS will be switched off for 21 days (on days 170, 184, and 
198 for cohorts 1-3, respectively) immediately after completing the 90-day unblinded treatment 
phase.  Participants randomized to the continuation condition will continue to receive stimulation 
12 hours per day over the same 21-day period.  Upon conclusion of the 21-day treatment 
withdrawal phase, participants will undergo a final re- assessment on the multi-dimensional 
outcome assessment battery and on the electrophysiologic measures (on day 191, 205, or 219, 
depending on cohort).  Currently there are no known safety issues related to withdrawing 
stimulation.  The purpose of this follow-up visit is to determine if there is evidence of loss of 
effect in those assigned to the treatment withdrawal condition, and to evaluate the influence of 

CT-DBS Clinical Protocol, Ver 7 
 
 
CONFIDENTIAL 
 
Page 17 of 39 
intervening factors on the effectiveness of DBS.  The trial will be considered complete at the end 
of the treatment withdrawal phase. 
6.4. 
Screening Imaging 
Following study enrollment but before the screening visit, participants will undergo volumetric 
MRI imaging including diffusion tensor imaging for surgical planning and to assess the degree of 
structural damage, which could preclude successful targeting of the DBS leads.  Feasibility of 
successful targeting of the CT will be determined by the investigative team.  If targeting is 
determined to be infeasible the subject will be withdrawn from the study. 
6.5. 
Screening and Preoperative Baseline Evaluation 
One to two months before DBS implant surgery (with 1 month defined as 30 days ± 3 days), 
participants will complete physical and neurological screening examinations and complete 
laboratory studies to ensure study eligibility and suitability for surgery.  A screen failure is 
defined as a potential participant who has been consented for screening but is not enrolled for 
randomization and implantation.  A screen failure does not meet all inclusion criteria and/or has 
answered or tested affirmatively to any exclusion criteria.  A potential participant may also fail 
screening if they are deemed unsuitable for participation based on the clinical judgment of the 
sponsor investigator.  We estimate the screen failure rate to be 3:1, which is based on efficiently 
pre-screening interested participants, and extensive team review of each case prior to screening. 
Participants will also undergo pre-operative multi- dimensional baseline assessment using a 
battery of cognitive (e.g., attention, memory, information processing speed, executive functions), 
psychological health (e.g., depression, anxiety) functional status (e.g., employment level) and 
quality of life (e.g., satisfaction with life) measures (see Description of Outcome Asssessments 
below).  A structured interview will also be conducted to obtain additional background 
information and determine pre-injury levels of academic, vocational and social function.  These 
evaluations can be done either on a single day or on multiple days. 
6.6. 
Inpatient Hospital Stay 
Following completion of the preoperative baseline evaluation, participants will be admitted for 
surgical implantation of the DBS system.  All patients will receive one DBS lead in each side 
of the diencephalon.  Both leads will be connected to a single pulse generator that may be 
implanted on the right or left side of the chest.  The procedures m a y  be performed on the 
same day or staged.  The surgical procedures are discussed in more detail below. 
6.6.1. 
Stage I:  Bilateral DBS Lead Implantation 
Patients will undergo implantation in a fashion similar to that routinely performed by the 
investigators for movement disorders (Bronte-Stewart, Louie, Batya, & Henderson, 2010 [3]; 
Machado et al., 2006 [15]).  We anticipate that targeting will be simpler in the present study than 
in our prior experience (Schiff et al., 2007 [22]) because patients in the present population are 
expected to have less post- traumatic gross anatomical deformities of the cerebrum and 
diencephalon (see Figure 3).  Surgical planning will be performed prior to surgery based on 
preoperative volumetric MR images acquired with and without contrast, unless there is a clinical 
contraindication to the use of contrast (Figure 4 below).  

CT-DBS Clinical Protocol, Ver 7 
 
 
CONFIDENTIAL 
 
Page 18 of 39 
Figure 3: 
Bilateral DBS, targeting the central thalamic region.  In this example, the DBS lead 
has 1.5 mm height contacts, separated by 1.5 mm gaps.  The ventral-most contact 
was targeted at the central lateral nucleus of the thalamus. 
  
 
Figure 4: 
Thalamic nuclei visualized at 7T (left), with corresponding segmentations (right) 
based on the Morel thalamic atlas (Tourdias, Saranathan, Levesque, Su, & Rutt, 
2013 [32])).  The central lateral nucleus is highlighted in orange. 
 
One or more days prior to surgery, five stainless steel fiducial markers will be implanted in the 
skull through small stab incisions under local anesthesia in the neurosurgery outpatient clinic 

CT-DBS Clinical Protocol, Ver 7 
 
 
CONFIDENTIAL 
 
Page 19 of 39 
(Holloway et al. 2005 [12]).  A high-resolution volumetric CT scan will be obtained and these 
images will be imported into the surgical planning station and fused with the previously 
obtained MRI images, and the final target location determined.  On the day of surgery, the 
patient will be positioned in a custom head cradle.  The patient’s anatomy will be registered to 
the neuronavigational system by touching each fiducial marker with a passive planar 
registration probe equipped with reflective spheres, which can be tracked by the cameras of the 
surgical navigation unit.  Entry points will be marked on the scalp and the patient will be 
prepared and draped in a sterile fashion.  After burr-hole placement, high-impact plastic towers 
will be attached to the skull bilaterally with 3 titanium bone screws.  A sterile reference arc will 
be fastened to the base of the platform to allow real-time tracking for maximum accuracy.  Each 
fiducial marker will be touched through the drape to perform registration again.  Alignment of 
the trajectory will be accomplished by adjusting the frameless device platform to orient the 
trajectory to the planned target, using the guidance view of the target provided by the planning 
software. 
Implantation will be guided either by intraoperative imaging (O-arm or MRI) or by 
microelectrode recording and intraoperative macrostimulation via the DBS leads.  Image-guided 
procedures will be performed under general anesthesia. Microelectrode-guided procedures will 
be performed under conscious sedation, titrated according to the judgement of the anesthesiology 
team. In either case, routine procedures for DBS placement will be used. In a recent meta-
analysis, no significant difference was found between the two techniques with regard to targeting 
accuracy and symptom reduction (Ho et al. Mov Disord 2017). Based on the results from the first 
5 patients in this study, there does not appear to be a unique neurophysiological signal associated 
with the CL nucleus. In addition, intraoperative stimulation has not caused side effects that 
proved informative with relation to the eventual postoperative lead location. Therefore, the final 
patient in the study will be implanted using image guidance, which we believe will result in 
equivalent or improved accuracy. 
Once the final location for the DBS lead is selected, it will be anchored to the skull in the routine 
fashion and the surgical sites closed under sedation.  The procedure will then be repeated on the 
opposite side.  Following surgery, the patient will be admitted for observation under routine 
neurosurgical care for intracranial surgery.  The investigators will attempt to implant both sides 
in the same surgical procedure.  However, if the patient is tired or, if in the opinion of the 
investigators there is added risk to completing the implantation of the second side in the same 
day, the investigator can make the decision to stop the surgery and implant the second side in a 
separate date, no more than 60 days after implantation of the first side.  Because this is routinely 
done in surgery for movement disorders we will not consider staging of the DBS lead implants to 
be a deviation of the protocol.  At least one CT scan will be done postoperatively during the 
hospital admission to verify lead location and rule out intracranial hemorrhage. 
6.6.2. 
Stage II 
Implantable pulse generator (IPG) implantation and connection to the DBS leads.  This is a 
routine procedure that will be performed under general anesthesia on the same day, following 
bilateral DBS lead implant.  The pulse generator (Model 37601 PC, Medtronic, Inc., 
Minneapolis, MN) will be implanted on the right or left chest and connected to the DBS leads.  
Under general anesthesia and with standard surgical technique for DBS, the skin over the distal 
tip of the leads (protected by a temporary connector) will be opened and the connector 
externalized and discarded.  An approximately 7-10 cm incision will be made in the 

CT-DBS Clinical Protocol, Ver 7 
 
 
CONFIDENTIAL 
 
Page 20 of 39 
infraclavicular region and a pocket fashioned for the pulse generator.  A tunneling tool will be 
used to create a subcutaneous tunnel connecting the infraclavicular subcutaneous pocket to the 
scalp incision where the lead is externalized.  The extension wires will be passed with the 
tunneling tool.  The extension wires will then be connected to the DBS leads and to the pulse 
generator.  Medical adhesive may be used to insure a tight seal and improve signal quality. The 
incisions will then be approximated with standard surgical technique. 
6.7. 
Post-Surgical Washout Phase 
Participants will enter the washout phase following hospital discharge.  The length of the 
baseline will be staggered for each participant pair.  The purpose of this phase is twofold: (1) to 
provide a 30-day surgical washout for resolution of any transient physiological or behavioral 
effects of surgery and (2) to detect the temporal onset of the stimulation effects for each subject, 
should these occur at the time of stimulation titration onset.  At the end of the surgical washout 
period, the multidimensional outcome assessment battery that was administered during the pre-
surgical baseline phase will be repeated to assess for any changes in function before CT-DBS is 
switched on (see Description of Outcome Assessments below).  A CT scan will be performed on 
day 65 to assess the final lead location, after any post-surgical changes have been allowed to 
resolve.  
6.8. 
DBS Stimulation Titration/Optimization 
On completion of the postsurgical washout phase (beginning day 66, 80, or 94, depending on 
cohort), DBS will be turned on for the first time to initiate the stimulation titration phase.  During 
this phase, which will last 14 days for all participants, an array of stimulation parameters will be 
assessed to optimize the settings that will be used during the treatment phase.  See Appendix 1 to 
this protocol for the device programming SOP.  
6.9. 
Unblinded Treatment Phase 
After DBS titration/optimization is complete, participants will enter the unblinded 90-day 
treatment phase during which DBS will remain on for 12 hours per day.  At the end of the 90-day 
treatment phase, participants will undergo re-assessment on the multi-dimensional outcome 
assessment battery.  Electrophysiologic measures will also be sampled on day 139 (± 3 days), 
153 (± 3 days), or 167 (± 3 days), respectively, to compare performance before and after 
treatment. 
6.10. 
DBS Stimulation Long-term Continuation  
If ongoing benefits for the subject are determined by the patient and the team, the patient will 
continue long-term DBS.  Decisions about the presence of benefit are expected to be guided by 
evidence of causal influence of DBS on changes in neuropsychological functions that covary 
with clinically meaningful outcomes on performance measures or quality of life indices.  After 
the initial battery expires, a rechargeable replacement will be available for individuals who will 
continue with stimulation.  
6.11. 
Six Month Open Label Follow-Up Period 
There will be a 6-month follow-up period at the end of the unblinded treatment phase.  There 
will be two visits during this period with the visits occurring at months three and six.  The month 
three follow up visit will be to assess general health, quality of life and to monitor battery supply 

CT-DBS Clinical Protocol, Ver 7 
 
 
CONFIDENTIAL 
 
Page 21 of 39 
of the device.  The six month follow up visit will be to assess general health, quality of life, 
neuropsychological status and to monitor battery supply of the device. 
6.12. 
Unscheduled Visits: 
Participants may have visits in between their regularly scheduled study visits if the sponsor-
investigator deems necessary.    
7. 
DESCRIPTION OF OUTCOME ASSESSMENTS 
7.1. 
Measures of Cognition 
• Trail Making Test (Primary Outcome Measure) {Army Individual Test Battery, 
1944, Manual of directions and scoring}.  The TMT is a measure of attention, speed, 
and mental flexibility.  It also tests spatial organization, visual pursuits, recall, and 
recognition.  Part A requires the individual to draw lines to connect 25 encircled 
numbers distributed on a page.  Part A tests visual scanning, numeric sequencing, and 
visuomotor speed.  Part B is similar except the person must alternate between 
numbers and letters and is believed to be more difficult and takes longer to complete.  
Part B tests cognitive demands including visual motor and visual spatial abilities and 
mental flexibility.  Both sections are timed and the score represents the amount of 
time required to complete the task. 
• Ruff 2 & 7 (Ruff, 1992, The Ruff 2 and 7 Selective Attention Test:  a 
neuropsychological application).  The Ruff 2 & 7 Test was developed to measure 
two aspects of visual attention: sustained attention (ability to maintain consistent 
performance level over time) and selective attention (ability to select relevant stimuli 
while ignoring distractors).  The test consists of a series of 20 trials of a visual search 
and cancellation task.  The respondent detects and marks through all occurrences of 
the two target digits: “2″ and “7.”  In the 10 Automatic Detection trials, the target 
digits are embedded among alphabetical letters that serve as distractors.  In the 10 
Controlled Search trials, the target digits are embedded among other numbers that 
serve as distractors.  Correct hits and errors are counted for each trial and serve as the 
basis for scoring the test.  Speed scores reflect the total number of correctly identified 
targets (hits).  Accuracy scores evaluate the number of targets identified in relation to 
the number of possible targets. 
7.2. 
Physical Symptoms (self-report) 
 
• Rivermead Post-Concussion Symptom Questionnaire (RPQ) {King, 1995, The 
Rivermead Post Concussion Symptoms Questionnaire: a measure of symptoms 
commonly experienced after head injury and its reliability}.  The Rivermead PCS 
Questionnaire (RPQ) was originally developed as a measure of severity of symptoms 
following mild TBI.  It consists of 16 post-concussion symptoms including 
headaches, dizziness, nausea/vomiting, noise sensitivity, sleep disturbance, fatigue, 
irritability, feeling depressed/tearful, feeling frustrated/ impatient, forgetfulness, poor 
concentration, taking longer to think, blurred vision, light sensitivity, double vision 
and restlessness.  In the original version of the RPQ, participants are asked to rate the 

CT-DBS Clinical Protocol, Ver 7 
 
 
CONFIDENTIAL 
 
Page 22 of 39 
degree (on a scale of 0 to 4) to which a particular symptom has been absent or a mild, 
moderate or severe problem over the previous 24 hours compared with premorbid 
levels. 
7.3. 
Psychological Health (self-report) 
 
• Patient Health Questionnaire-9 (PHQ-9) {Kroenke, 2001, The PHQ-9}.  The 
Participant Health Questionnaire 9 is a standardized assessment instrument designed 
to screen, diagnose, monitor, and measure the severity of depression. 
• Columbia Suicide Severity Rating Scale (C-SSRS) {Posner, 2011, The Columbia-
Suicide Severity Rating Scale: initial validity and internal consistency findings 
from three multisite studies with adolescents and adults}.  The C-SSRS is a 
standardized assessment instrument designed to assess the presence and severity of 
suicidal ideation and behavior, identify those at risk, and track response to treatment.  
It has three main sections that evaluate suicidal ideation, the intensity of ideation and 
suicidal behavior.  The first section, suicidal ideation, assesses risk ranging from a 
death wish or unspecific suicidal thoughts to active ideation with specific plans.  In 
the second section the severity of ideation is evaluated and takes into account the 
frequency, duration and controllability of suicidal thoughts as well as environmental 
and cultural deterrents and reasons for suicidal ideation.  The third section evaluates 
actual suicidal behavior and asks if there was an actual attempt, interrupted attempt, 
aborted attempt or preparatory acts of behavior.  It also asks whether there was active 
suicidal behavior at the time of assessment and, finally, if suicide was completed.  A 
fourth section is only answered in case there was / were suicidal attempts and 
measures the lethality and potential lethality of each suicidal attempt and respective 
dates.  The CCSRS is a widely-used instrument and is currently being utilized in 
other first-in-man DBS clinical trials. The C-SSRS will be administered during the 
pre-surgery baseline assessment and then at any follow-up visit only if the 
participant screens positive for suicidal ideation/behavior on the PHQ-9 (i.e. 
score ≥ 1 on question 9). 
7.4. 
Quality of Life (self-report) 
• Traumatic Brain Injury Quality of Life (TBI-QOL) {Tulsky, 2015, TBI-QOL: 
Development and Calibration of Item Banks to Measure Patient Reported 
Outcomes Following Traumatic Brain Injury}.  The TBI-QOL was developed as a 
comprehensive patient-reported outcomes (PRO) measurement system specifically 
for individuals with TBI.  It consists of 20 independent calibrated item banks and 2 
uncalibrated scales that measure physical, emotional, cognitive, and social aspects of 
health-related quality of life.  We will administer the short form (6-10 questions each) 
of the TBI-QOL Fatigue, Attention/Concentration, and Executive Function subscales. 
7.5. 
Global Functional Outcome Measure 
• Glasgow Outcome Scale – Extended (GOSE) {Wilson, 1998, Structured 
interviews for the Glasgow Outcome Scale and the extended Glasgow Outcome 
Scale: guidelines for their use}.  The Glasgow Outcome Scale Extended (GOSE) is 
a measure of disability and handicap intended for use following head injury.  The 

CT-DBS Clinical Protocol, Ver 7 
 
 
CONFIDENTIAL 
 
Page 23 of 39 
GOSE subdivides the upper three categories of the original Glasgow Outcome Scale 
(GOS), severe disability, moderate disability and good recovery, into an eight-
category scale: dead, vegetative state, lower severe disability, upper severe disability, 
lower moderate disability, upper moderate disability, lower good recovery, and upper 
good recovery to provide more detailed assessment of the functional effects of the 
injury.  A structured interview has been developed to standardize assignment of an 
outcome category (Wilson et al. 1998). 
7.6. 
Participant Interview 
• A structured interview will be administered to obtain information about preinjury 
medical and social history, and level of social, educational and vocational function. 
7.7. 
Exploratory Measures 
7.7.1. 
Electrophysiological 
Each enrolled participant will have electroencephalogram (EEG) studies obtained several times 
during the course of the study following DBS implantation.  The initial EEG recording will be 
made on the day of admission for surgery.  EEG recordings will be obtained using an EGI 
system (129 scalp sites using the Geodesic EEG Net Station (EGI, Eugene, OR) with the 129-
channel Geodesic Sensor Net (Tucker 1993 [33]).  For each recording session 5 minutes of 
resting baseline will be obtained at the beginning and end of the session.  In addition, subjects 
will perform the Attention Network Test paradigm, a standard measure for assessment of 
attention that has been normed in the study population (Fan et al. 2002 [8]).  The ANT will be 
presented using Eprime (Psychology Software Tools) on a standard flat screen monitor and the 
total duration of each ANT experimental session will be approximately 25 min. Local thalamic 
recordings will be recorded using the Percept PC system during the performance of the Attention 
Network Task.   
To measure local population dynamics within the central thalamus during stimulation conditions 
in clinic we will record a differential signal on pairs of open channels adjacent to the channel 
used for stimulation using the Percept PC system. We will record up to 6 channels during OFF 
stimulation periods and 2 channels during stimulation. We will use a sampling rate of 250Hz (to 
optimize recording against known noise characteristics of the device) and filtered (4Hz to 
100Hz) in compressed format. To characterize the EEG activation profiles we will use 
monopolar and bipolar stimulation through each contact individually and pairs of contacts in 
ON/OFF blocks of 5-10 second stimulation periods interleaved to obtain a minimum of 100 
seconds of recording per condition with matched adjacent resting periods.  
A similar approach will be used to collect behavioral, EEG and local thalamic recording data 
during performance of the Attention Network Task (Fan et al. 2002). EEG and local thalamic 
recordings will be synchronized using brief 1-2 second 20Hz pulses at the start and end of 
recording sessions.  We will compare behavioral and EEG effects during interleaved blocks of 
10 minutes of continuous ANT performance.  Monopolar review for side effects will be 
completed prior to behavioral testing with the ANT.  
We will use the sensing recording capabilities of the Percept PC to obtain longitudinal samples 
of brain activity during sleep-wake cycles in between outpatient office visits. Recordings with 
the device will occur as described above and as follows. Uniformly sampled and bandpassed 

CT-DBS Clinical Protocol, Ver 7 
 
 
CONFIDENTIAL 
 
Page 24 of 39 
power will be obtained from one channel per electrode every ten minutes over 2 months. These 
data are stored on the device and will be downloaded at patient visits during the trial.  We will 
evaluate the time domain recordings with spectral analysis. 
8. 
EARLY WITHDRAWAL OR TERMINATION  
Subjects will be informed that they may withdraw or be discontinued (early termination) from 
this study at any time.  Further, they will be informed that the Investigator may withdraw them if 
they fail to comply with the study requirements or if the investigator feels it is in the best interest 
of the subject to discontinue their participation.  The reason(s) for withdrawal or early 
termination will be documented on the appropriate page of the CRF.  No further study 
assessments will be performed after the subject has withdrawn. 
Subjects who consent to participate but do not receive the DBS device will not count towards the 
6 patients limit for this study and new patients will be screened.  No attempt will be made to 
replace subjects who are withdrawn or prematurely discontinue their study participation after the 
device has been implanted. 
9. 
ADVERSE EVENTS 
9.1. 
Adverse Event Identification and Assessment 
An adverse event is any undesirable clinical occurrence in a participant during the clinical 
investigation, having been absent at baseline (or, if present at baseline, appears to worsen), 
whether or not it is considered to be related to the device or to stimulation.  The investigator will 
not be required to record transient stimulation-induced neurological effects (e.g., paresthesias) or 
findings within normal expected postoperative outcomes.  For example, postoperative pain that is 
not outside expected levels will not be recorded as an adverse event.  Postoperative events that 
involve a clinically significant severity of symptoms, duration of symptoms, or that require 
deviation from usual postoperative clinical interventions (e.g., pain lasting longer than expected 
and requiring long-term opioid use) will be recorded as adverse events.  The testing of DBS in 
MCS subjects did not identify any adverse events that are specific to brain injured subjects.    
9.2. 
 
Adverse Device Effect 
An adverse device effect is a device related adverse event.  During this clinical investigation an 
event should be considered related to the device when it is the result of: 
• The implanted components (lead, extension, neurostimulator) 
• The implant procedure 
• Programming 
• Stimulation 
A non-related event is one that results from: 
• A patient related condition 
• Concomitant medication 

CT-DBS Clinical Protocol, Ver 7 
 
 
CONFIDENTIAL 
 
Page 25 of 39 
• Other (specify) 
The relationship or association of the AE to the study product will be characterized by the 
Investigator as one of the following in Table 2.  
Table 2: 
AE Relationship to Device 
Relationship 
Definition 
Not related 
There is no temporal relationship between the study product/treatment and the 
event, which makes a causal relationship clearly and incontrovertibly due to 
extraneous causes, i.e. not related to the study product. 
Unlikely 
Other factors, such as concurrent illness, progression or expression of a disease, 
or a reaction to a concomitant medication are more likely the cause of the event.  
It is improbable that the study product/treatment caused the AE. 
Possibly 
The AE cannot be fully explained by other causes, and it is possible that the 
study product/treatment caused the event. 
Probably 
A reasonable temporal association exists between the AE and the study 
product/treatment, and, based upon the investigator's clinical experience, the 
association of the AE with the study product/treatment seems probable. 
Definitely 
A definite or certain temporal association exists between the AE and the study 
product/treatment, and, based upon the investigator's clinical experience, the 
association of the AE with the study product/treatment seems definite or certain. 
9.3. 
 
 
Serious Adverse Events (SAEs) 
A serious adverse event is one that meets any of the following criteria (ICH Good Clinical 
Practice Guideline, April 1996, Section 1.50): 
• Results in death 
• Is life threatening 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
Events that do not meet these criteria are considered non-serious 
A planned hospitalization for pre-existing condition, or a procedure required by the Clinical 
Investigation Plan, without a serious deterioration in health, is not considered to be a serious 
adverse event.  
9.4. 
Anticipated & Unanticipated (UADEs) Adverse Device Effects  
9.4.1. 
Anticipated Adverse Events  
Those known adverse events and surgical interventions related to the device or procedure are 
extrapolated from a population of 299 patients who underwent DBS for movement disorders 
(Medtronic® DBS™ Therapy for Parkinson’s Disease and Essential Tremor CLINICAL 
SUMMARY, 2013):

CT-DBS Clinical Protocol, Ver 7 
 
 
CONFIDENTIAL 
 
Page 26 of 39 
• 
Abnormal behavior 
• 
Abnormal dreams 
• 
Activities of daily living 
impaired 
• 
Adverse drug reaction 
• 
 Agitation  
• 
Akinesia  
• 
Anemia  
• 
Anxiety  
• 
Aortic stenosis 
• 
Appendicitis perforated  
• 
Arteriosclerosis 
• 
Arthralgia  
• 
Arthritis 
• 
Asthenia  
• 
Asthma 
• 
Back pain  
• 
Balance disorder 
• 
Benign prostatic 
hyperplasia 
• 
Biopsy bone 
• 
Bladder catheter removal  
• 
Blood pressure increased 
• 
Bone Fractures 
• 
Bone graft 
• 
Bradykinesia  
• 
Breast cancer 
• 
Bronchitis  
• 
Burns third degree 
• 
Cardiac pacemaker 
insertion 
• 
Cartilage injury 
• 
Cellulitis 
• 
Cerebral haematoma 
• 
Cerebral haemorrhage 
• 
Cerebrovascular accident  
• 
Chest discomfort  
• 
Chest pain  
• 
Cholelithiasis  
• 
Clostridium difficile 
colitis  
• 
Clostridium difficile 
sepsis  
• 
Cognitive disorder 
• 
Complication of device 
removal 
• 
Confusional  state 
• 
Constipation  
• 
Convulsion  
• 
 Cough  
• 
Debridement 
• 
Decubitis ulcer 
• 
Deep vein thrombosis 
• 
Deep vein thrombosis 
postoperative 
• 
Dehydration 
• 
Delirium 
• 
Delusion 
• 
Delusional disorder, 
persecutory type 
• 
Depression  
• 
Depression suicidal  
• 
Device electrical finding  
• 
Device failure  
• 
Device migration  
• 
Diabetic ketoacidosis  
• 
Diverticulitis  
• 
Dizziness  
• 
Drooling  
• 
Drug hypersensitivity  
• 
Drug toxicity  
• 
Dysgraphia  
• 
Dyskinesia  
• 
Dysphagia  
• 
Dyspnoea  
• 
Dystonia  
• 
Dysuria  
• 
Erectile dysfunction 
• 
Fall  
• 
Fatigue  
• 
Freezing phenomenon 
• 
Gait disturbance 
• 
Gastric polyps  
• 
Gastroduodenitis  
• 
Gastrointestinal disorder  
• 
Gastrooesophageal 
reflux disease 
• 
Glioma  
• 
Grand mal convulsion  
• 
Haematoma  
• 
Haemoglobin decreased  
• 
Haemorrhage 
intracranial  
• 
Hallucination  
• 
Head injury 
• 
Headache  
• 
Hiatus hernia 
• 
Hip arthroplasty 
• 
Homelessness 
• 
Hyperhidrosis  
• 
Hyperkalaemia 
• 
Hypertension  
• 
Hypoaesthesia  
• 
Hypotension  
• 
Hypovolaemia 
• 
Hypoxia 
• 
Implant site erosion 
• 
Implant site infection 
• 
Implant site reaction 
• 
Incision site 
complication 
• 
Incision site pain 
• 
Inguinal hernia 
• 
Insomnia  
• 
Intestinal obstruction 
• 
Intestinal perforation 
• 
 Intraventricular 
haemorrhage 
• 
Labile blood pressure 
• 
Labile hypertension 
• 
 Lethargy 
• 
Localized infection  
• 
Lumbar spinal stenosis 
• 
Lung neoplasm 
malignant  
• 
Major depression  
• 
Malnutrition 
• 
Mechanical complication 
of implant 
• 
Mediastinal 
haemorrhage   
• 
Medical device 
complication 
• 
Medical device 
discomfort 
• 
Medical observation 
• 
Memory impairment 
• 
Meniscus lesion 
• 
Mental status changes 

CT-DBS Clinical Protocol, Ver 7 
 
 
CONFIDENTIAL 
 
Page 27 of 39 
• 
Mental status changes 
postoperative 
• 
Metabolic 
encephalopathy 
• 
Mobility decreased 
• 
Motor dysfunction 
• 
Muscle rigidity  
• 
Muscle spasms  
• 
Musculo-skeletal pain 
• 
Musculo-skeletal 
stiffness 
• 
Musculoskeletal chest 
pain 
• 
Nausea  
• 
Neck pain  
• 
Neuropathy peripheral  
• 
Oedema peripheral 
• 
Oesophageal spasm 
• 
Oesophagitis 
• 
Orchitis  
• 
Orthostatic hypotension 
• 
Osteoarthritis   
• 
Pain  
• 
Pain in extremity 
• 
Paraesthesia  
• 
Parkinson’s disease  
• 
Perseveration 
• 
Pleuritic pain 
• 
Pneumocephalus 
• 
Pneumonia   
• 
Pneumonia aspiration 
• 
Pollakiuria  
• 
Poor quality sleep 
• 
Post-traumatic stress 
disorder 
• 
Procedural complication 
• 
Procedural pain  
• 
Prostate cancer 
• 
Prostate cancer 
metastatic   
• 
Psychotic disorder 
• 
Pyelonephritis  
• 
Pyrexia  
• 
Rapid eye movements 
sleep abnormal 
• 
Rash  
• 
Rectal haemorrhage  
• 
Rectocele  
• 
Restless legs syndrome 
• 
Retinal detachment  
• 
Reversible ischaemic 
neurological deficit 
• 
Road traffic accident  
• 
Rotator cuff repair 
• 
Rotator cuff syndrome  
• 
Scar pain  
• 
Self-medication   
• 
Sepsis  
• 
Sexual dysfunction 
• 
Sialoadenitis  
• 
Small intestinal 
obstruction 
• 
Somnolence  
• 
Speech disorder 
• 
Subdural haematoma  
• 
Suicidal ideation  
• 
Suicide attempt  
• 
Syncope  
• 
Syncope vasovagal  
• 
Tooth abscess  
• 
Transient ischaemic 
attack  
• 
Treatment 
noncompliance 
• 
Tremor  
• 
Upper respiratory tract 
infection 
• 
Urethral injury  
• 
Urethral stenosis  
• 
Urinary incontinence 
• 
Urinary tract infection 
• 
Urosepsis 
• 
Viral infection 
• 
Visual disturbance 
• 
Vomiting 
• 
Weight decreased 
• 
Weight increased 
• 
Wound dehiscence 
 
The known or expected adverse effects that are attributable to stimulation are the following:
• Paresthesia 
• Diplopia 
• Dysarthria 
• Dysequilibrium 
• Paresis 
• Dystonia 
• Gait disorder 
• Electrical shocking or jolting 
• Headaches 
• Pain, discomfort or local stress 
• Attention deficit 
• Dysphasia 
• Insufficient therapeutic effect 
• Ataxia 
• Dyskinesia 
• Sensory deficits 
• Suicidal ideation 
• Mania or hypomania 
• Facial weakness 
• Fatigue 
• Loss of energy 
• Numbness 
• Other speech deficits 
• Rebound symptom worsening with 
discontinuation of stimulation 
• Transient heaviness in arm 

CT-DBS Clinical Protocol, Ver 7 
 
 
CONFIDENTIAL 
 
Page 28 of 39 
• Changes in blood pressure or heart 
rate 
• Nausea or vomiting 
• Rapid or shallow breathing 
• Anxiety 
• Apathy 
• Agitation 
• Aggression 
• Asthenia 
• Balance disorder 
• Akinesia 
• Bradykinesia 
• Chest discomfort 
• Seizures 
• Weight gain or weight loss 
• Somnolence 
• Tremor 
• Undesired change in libido 
 
9.4.2. 
Unanticipated adverse device effects (UADEs)  
An unanticipated adverse device effect is “any serious adverse effect on health or safety or any 
life-threatening problem or death caused by, or associated with, a device, if that effect, problem, 
or death was not previously identified in nature, severity, or degree of incidence in the 
investigational plan or application (including a supplementary plan or application), or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, or 
welfare of subjects” [21 CFR 812.3(s)]. Unanticipated means the event is not listed in the 
labeling, or the frequency or severity is greater than that reported in the labeling. 
9.5. 
Adverse Event Reporting 
Since we do not know in advance what, if any, adverse effects deep brain stimulation may have 
in this patient population, we will record and code any adverse clinical event on the Adverse 
Event form, whether it is mild or severe, and regardless of whether it is likely to be stimulation 
related or not.  The AE forms will subsequently be analyzed to empirically determine which AEs 
are likely to be due to or exacerbated by the stimulation.  We have developed specific procedures 
for coding AEs and have developed guidelines for breaking the blind should this be viewed as 
necessary by the treating physician.  These procedures and guidelines are described below:  
Two types of AE’s be recorded: 
• A new onset AE refers to the onset of an abnormality in a patient previously 
determined to have normal function in that area.  This would include such things as 
the onset of spasticity in a patient who had normal tone previously, or the 
development of a tremor in someone who had active movement without a tremor 
before.    
• A worsening AE involves either an increase in severity of some symptom or some 
deterioration of function or ability.  This would include such things as worsening 
hypertonia in someone who already had hypertonia.  This category should be used 
once an adverse event has already been recorded, to indicate subsequent worsening of 
that adverse event. 
Note that many AEs are, by their nature, chronic events with waxing and waning courses (e.g., 
behavioral dyscontrol) while others are discrete single events (e.g., development of a DVT).  
Chronic patterns will be reported as AEs only if their pattern of occurrence changes (i.e., the 
episodes become more frequent or severe), and will be considered resolved when the pattern 
returns to the pre-treatment baseline.  New onset AEs which may become chronic patterns (i.e., a 
first episode of aggression) will be identified as starting at the time of the first event.  AEs which 

CT-DBS Clinical Protocol, Ver 7 
 
 
CONFIDENTIAL 
 
Page 29 of 39 
have no clear date of resolution but require long-term treatment will be considered ongoing until 
that treatment is completed (e.g., DVT with anticoagulant prophylaxis, osteomyelitis with 
prolonged antibiotic treatment). 
In addition to recording descriptive information about the AE on the form, AEs will be 
characterized as anticipated or unanticipated (based on the previously-established side effect 
profile), a severity rating (reflecting seriousness and impact on clinical status) will be assigned, 
and the probability that the AE was related to the study treatment will be estimated (based on the 
plausibility to the known clinical effects of neurostimulation, and knowledge of other clinical 
risk factors for the AE).  We will also indicate whether treatment of the AE was required, 
whether the study treatment was changed as the result of the AE, the date the AE resolved and 
the outcome of the AE. 
9.5.1. 
Reporting Serious Adverse Events 
The Sponsor-Investigator will direct all study personnel to inform him as soon as possible 
(within 24 hours) of any serious adverse event.  If necessary, study personnel may communicate 
by telephone or e-mail, and follow-up later with completed case report forms.  The Sponsor-
Investigator will conduct an evaluation of the event and if it is determined to be a UADE, it will 
be reported as described in the following section. 
9.5.2. 
Reporting UADEs 
If an event is determined by the Sponsor-Investigator to be a UADE, he will report the event to 
the FDA and the IRB within the required timeframe of 5 business days if death or life 
threatening, and 10 business days if other serious criteria are met. 
9.5.3. 
Stopping Rules 
If two of the six study participants experience either a serious UADE or an adverse device effect 
that the Sponsor-Investigator determines would present an unreasonable risk to other participants 
enrolled in the trial, the Sponsor-Investigator must terminate the clinical trial 5 days after making 
that determination and not later than 15 days after the Sponsor-Investigator first receive notice of 
the effect. 
9.5.4. 
Reporting Deaths and Suicides 
For any death that occurs during the course of the study, the sponsor will notify the IRB within 
an expedited timeframe according to the following guidelines: 
• Report the event within 24 hours when the death is unforeseen (unexpected) and 
indicates participants or others are at increased risk of harm. 
• Report the event within 72 hours, for all other deaths, regardless of whether the death 
is related to study participation. 
The sponsor will notify the FDA within 5 business days as noted above. 
10. 
CLINICAL OVERSIGHT COMMITTEE 
It is the responsibility of the Sponsor-Investigator to oversee the safety of the study participants.  
This includes careful assessment and appropriate reporting of adverse events as noted above.  

CT-DBS Clinical Protocol, Ver 7 
 
 
CONFIDENTIAL 
 
Page 30 of 39 
In addition, a Clinical Oversight Committee (COC) has been appointed to conduct ongoing 
reviews of the safety of the Study and make recommendations regarding changes to the 
risk/benefit of the Study, including recommendations to discontinue new patient enrollments or 
discontinue the Study.  The COC will review all SAEs as they occur and will conduct routine 
reviews at least quarterly throughout the study. 
10.1. 
Medical Monitor 
An Independent Medical Monitor has been designated for this study to regularly assess reports of 
unanticipated study-related events.  Once per quarter the Medical Monitor will review reports of 
any study-related unanticipated adverse events.  The Clinical Oversight Committee will convene 
an ad hoc meeting to review any report of an unanticipated adverse event that is both study-
related and serious. 
11. 
STATISTICAL PLAN  
This is a feasibility study to inform the safety and efficacy of central thalamic-deep brain 
stimulation (CT-DBS) in the treatment of chronic cognitive impairment and residual disability 
caused by traumatic brain injury (TBI).  The primary outcome measure used will be the Trail 
Making test and secondary outcome measures include measures of cognition (Ruff 2 & 7), 
physical symptoms (Rivermead Post-Concussion Symptom Questionnaire (RPQ)), psychological 
health (Patient Health Questionnaire-9 and Columbia Suicide Severity Rating Scale (C-SSRS), 
quality of life (Traumatic Brain Injury Quality of Life (TBI-QoL subscales)), and measure of 
global function (Glasgow Outcome Scale-Extended (GOSE)).  For the present study all baseline, 
procedural, and safety and effectiveness follow-up data will be summarized with appropriate 
descriptive statistics.  For continuous variables we will summarize data by the mean, median, 
standard deviation, minimum and maximum.  For non-continuous variables we will summarize 
by percentages and frequency distributions.  We will tabulate data for all enrolled patients.  Our 
statistical analysis will be limited due to the small sample size.  
Exploratory statistical analyses of primary and secondary endpoints will be performed to identify 
potential relationships between the treatment and the outcome variables.  
Adverse event data will also be reported and tabulated. 
12. 
RISK ASSESSMENT AND MITIGATION 
12.1. 
Known and Anticipated Surgical Risks 
The Sponsor-Investigator (who will also be the implanting surgeon in this study) is an 
experienced functional neurosurgeon with nearly 20 years’ experience with deep brain 
stimulation.  He was one of the original investigators in the first trial of DBS for movement 
disorders in the US (“Clinical Investigation of Deep Brain Stimulation for Treatment of Tremor 
Using the Medtronic Model 3382 DBS,” 1996-1999).    He will perform the surgical procedures 
in this study using his standard technique, developed in over 600 successful implants. 

CT-DBS Clinical Protocol, Ver 7 
 
 
CONFIDENTIAL 
 
Page 31 of 39 
12.2. 
Device-Related and Therapy-Related Risks 
Co-Investigators Nicholas Schiff, Joseph Giacino, and Andre Machado were all involved in the 
original trial of CT-DBS for the treatment of the minimally conscious state (MCS).  Drs. Giacino 
and Schiff are world experts in traumatic brain injury.  They will direct parameter selection for 
DBS programming and will consult on targeting of the CT along with Drs. Machado and Butson, 
both of whom have extensive experience in targeting this region. 
The inclusion/exclusion criteria have been developed to exclude participants with concurrent 
illnesses that could increase the risk of DBS placement, as well as major developmental, 
neurologic, psychiatric or substance use disorders that may confound interpretation of results.  
Participants for whom DBS implants are contraindicated are excluded from study participation 
(e.g., a medical condition requiring MRI, and/or exposure to diathermy). 
Participants will be counseled that they are not to undergo an MRI examination or shortwave 
diathermy as long as the DBS system is implanted.  
12.3. 
Protocol for Managing Suicidal Ideation and Intent 
All study personnel will be provided with the following protocol for managing suicidal ideation 
and intent.  Participants will be closely monitored for any suicidal thoughts or plans during all 
study interactions, including telephone calls and in-person visits. 
If the participant endorses an item suggesting suicidal ideation on any self-report questionnaire, 
or reports suicidal ideation at any time during participation in the study, immediately administer 
questions 1 and 2 from the Columbia Suicide Severity Rating Scale (CSSRS).  Proceed with 
administering items as needed according to the instructions for that scale.  Based on the 
participant’s responses, follow one of the following procedures.  
1. Scenario 1: Participant responds “no” to question 2 on C-SSRS (“Have you actually 
had any thoughts of killing yourself?”) 
Empathize with how hard things have been for them and let them know that it is not 
unusual for people to have these thoughts when they have experienced TBI.  Encourage 
them to talk to a family member or friend when they feel this way.  Also provide them 
with a crisis line number and encourage them to phone if they ever start thinking about 
actually killing themselves.  Proceed with the study protocol.  
2. Scenario 2: Participant responds “yes” to question 2 on C-SSRS (“Have you 
actually had any thoughts of killing yourself?”) AND answers “no” to question 3 
(“Have you been thinking about how you might kill yourself?”)  
Empathize with how hard things have been for them and let them know that it is not 
unusual for people to have these thoughts when they have experienced TBI.  Encourage 
them to talk to a family member or friend when they feel this way.  Also provide them 
with a crisis line number and encourage them to phone if they ever start thinking about 
actually killing themselves.  Proceed with the study protocol.  
3. Scenario 3: Participant responds “yes” to question 3 on C-SSRS (“Have you been 
thinking about how you might kill yourself?”) AND answers “no” to question 4 
(“Have you had these thoughts and had some intention of acting on them?”).  
Discuss a safety plan with the participant.  If you are meeting with the participant in 
person, have them complete the safety plan themselves, providing guidance as necessary.  

CT-DBS Clinical Protocol, Ver 7 
 
 
CONFIDENTIAL 
 
Page 32 of 39 
Then have the participant sign it and ask the study physician or a licensed psychologist 
on the team to review the plan with them.  Provide them with the crisis line information 
by writing it on the safety plan.  If you are talking with the person by phone, go over the 
safety plan, asking them to generate responses to the items, while providing guidance as 
necessary.  Record their responses and then ask the study physician or a licensed 
psychologist on the team to review the plan with them.  Send them a copy by mail, 
provide the contact information for the crisis line verbally over the phone and write it on 
the safety plan before mailing.  
4. Scenario 4: Participant responds “yes” to question 3 on C-SSRS (“Have you been 
thinking about how you might kill yourself?”) AND either answers “yes” to question 
4 (“Have you had these thoughts and had some intention of acting on them?”) or is 
equivocal regarding whether they intend to act on their thoughts.  
Ensure that they are safe at the moment.  This means that they are not in imminent danger 
of harming themselves and do not have guns, knives or other weapons available to use.  If 
you cannot deem that they are safe, ask their permission to speak with a family member 
who is with them.  Tell the family member that they should stay with the patient and 
should make sure that they are safe, provide them with the crisis line number, advise 
them to take the person to an emergency room if possible, and advise them to call 911 if 
they fear that they cannot stop the person from hurting themselves and cannot talk them 
into going to the emergency room.  If there is no family member present, or they refuse to 
have you speak with one, and you cannot deem that they are safe, maintain them on the 
line and ask the study physician, another research team member or an administrative 
assistant to call 911 and ask that the police visit the participant at their current location.  
Meanwhile, ask the participants’ permission to connect them to a crisis line so that they 
can talk with someone who is trained to help them through the crisis.  If they agree, 
connect them to the crisis line.  
NOTE: Occasionally, someone may withhold permission for you to transfer them to a crisis line.  
If this refusal appears to be due to fear, uncertainty, or embarrassment, then talk them through 
the reasons for the crisis line and ask their permission again.  If they still refuse, or if they appear 
to simply want to stay on the line talking with you, tell them that for their own safety, you need 
to connect them to the crisis line.  Ask them to stay on hold while you dial the crisis line.  Make 
sure that they have your telephone number so that they can call you back in case you are 
disconnected.  You may call them back if you are disconnected.  If you are unable to reach them, 
and you deem that they are in imminent danger of harming themselves, then call 911 and ask the 
police to visit the person at their current location.  
NOTE:  The same protocol can be applied to a person who endorses suicidal ideation and intent 
during an on-site assessment.  Simply have them call the crisis line from a nearby office.  
REMEMBER TO DOCUMENT EACH STEP THAT YOU PERFORM, HAVE THE 
SPONSOR-INVESTIGATOR OR HIS DESIGNEE (EG, STUDY PHYSICIAN, 
PSYCHOLOGIST) REVIEW THE SAFETY PLAN AND PLACE IT IN THE 
PARTICIPANTS’ RESEARCH FILE.  
The process for connecting on-line telephone participant to crisis line: 
While on the phone with the participant, ask them to hold while you connect them to the 
crisis line (or use the conference-calling feature, if available): 

CT-DBS Clinical Protocol, Ver 7 
 
 
CONFIDENTIAL 
 
Page 33 of 39 
Crisis Line #:  
1-800-273-TALK (8255) National Suicide Prevention Lifeline 
 
 
 
 
 
1-888-628-9454 (Spanish) 
Be sure that they have been connected to a crisis counselor before hanging up. 
13. 
Administrative Requirements, including Investigator Responsibilities 
13.1. 
 Good Clinical Practice (GCP) 
The study will be conducted in accordance with, but not limited to, 21CFR parts 812, 11, 50, 54, 
56 and ICH - GCP.  The Investigator will be thoroughly familiar with the appropriate use of the 
study product as described in the protocol and Directions for Use.  Essential study documents 
will be maintained to demonstrate the validity of the study and the integrity of the data collected.  
Trial Master Files will be established at the beginning of the study, maintained for the duration 
of the study and retained according to the appropriate regulations and SOPs.  
13.2. 
Ethical Considerations  
The study will be conducted in accordance with ethical principles founded in the Declaration of 
Helsinki.  IRBs will be provided all relevant study documents in order to safeguard the rights, 
safety, and well-being of the subjects per their mandate.  This study will be implemented only at 
sites where IRB approval has been obtained.  The protocol, Product Literature, informed consent, 
written information given to the subjects, safety updates, and any revisions to these documents 
will be provided to the IRB by the Investigator.  
13.3. 
Subject Information and Informed Consent  
After the study has been fully explained to the potential subject, written informed consent will be 
obtained prior to the performance of any study-related procedures.  The method of obtaining and 
documenting the informed consent and the contents of the consent will comply with ICH-GCP 
and all applicable regulatory requirements, including local IRB requirements.  
It is understood that Informed Consent is a process and not an event.  The Investigator is 
responsible for maintaining an ongoing, open dialog with the subject in regards to their 
continued participation in the study. 
13.4. 
 Subject Confidentiality  
In order to maintain subject privacy, CRFs, study product accountability records, study reports 
and communications will identify the subject by initials and the assigned subject number only.  
The Investigator will grant monitor(s) and/or auditor(s) from regulatory authorities’ access to the 
subject’s original medical records for verification of data recorded in the CRFs and to audit the 
data collection process.  The subject’s confidentiality will be maintained and no Protected Health 
Information will be disclosed, other than that which is described in the Informed Consent Form.  
13.5. 
Protocol Compliance  
Strict adherence to the protocol is expected.  However, there are times when this is not possible.  
Any failure to follow the protocol (i.e. a deviation) must be identified and recorded.  Deviations 
from the protocol which:  (1) increase subject risk or (2) impact on study endpoints, will be 

CT-DBS Clinical Protocol, Ver 7 
 
 
CONFIDENTIAL 
 
Page 34 of 39 
considered protocol violations.  Protocol deviations and violations will be tabularized in the data 
listings.   
Substantive changes to the protocol will require written FDA and IRB approval prior to 
implementation, except when such departures are necessary to eliminate an immediate hazard(s) 
to subjects.  The IRB may provide expedited review and approval for minor change(s) in 
ongoing studies that have the approval of the IRB.   
13.6. 
Maintenance of Study Records 
The Investigator is responsible for maintaining adequate and accurate study records.  These may 
include, but are not limited to:  Screening, Consent and Enrollment Logs, staff training records, 
licenses & certifications, correspondence between Investigator and Sponsor and/or IRB, financial 
disclosures, investigator agreement, Product Accountability Logs, Protocol Signature Pages, 
authorization forms and other study related documents. 
13.7. 
Study Monitoring  
The Sponsor/Investigator will oversee and monitor the progress of the Clinical Study to assure 
that it is conducted, recorded, and reported in accordance with the Clinical Protocol, written 
procedures, agreements, and applicable regulations.  This will be accomplished by: 
• Ensuring proper informed consent and the protection of the rights and well-being of 
study subjects 
• Assessing data integrity 
• Identifying and addressing non-compliance issues 
• Identifying research misconduct or fraud 
• Reviewing essential documents and approvals 
• Assessing overall site capabilities 
• Ensuring device accountability is maintained 
13.8. 
On-Site Audits  
Regulatory authorities or the IRB, may request access to all source documents, eCRFs, and other 
study documentation for on-site audit or inspection.  Direct access to these documents must be 
guaranteed by the Investigator, who must provide support at all times for these activities.  
13.9. 
Case Report Form Completion  
Case Report Forms will be completed for each subject enrolled in the study.  It is the 
Investigator’s responsibility to ensure the accuracy, completeness, and timeliness of the data 
reported in the subject’s CRF.  Source documentation supporting the eCRF data must indicate 
the subject’s participation in the study and document the dates and details of study assessments, 
inter-current procedures, and adverse events.  
The Investigator will be provided a copy of all completed CRF pages.  

CT-DBS Clinical Protocol, Ver 7 
 
 
CONFIDENTIAL 
 
Page 35 of 39 
13.10. 
Study Product Accountability  
Accountability for the study product and other clinical study supplies at each site participating in 
this study is the responsibility of the Investigator and appropriate records of receipt of product 
will be maintained.  The Investigator will ensure that the study product is used only in 
accordance with this protocol and is maintained under appropriate IDE (21CFR 812) conditions.  
14. 
REFERENCES  
1. Baker, JL, Ryou, JW, Wei, X, Butson, C, Schiff, ND, and Purpura, KP (2011) 
Modulation of global beta oscillations within the frontal-striatal-central thalamic network 
during sustained attention. Society for Neuroscience Abstract 197.26. 
2. Baker, JL, Ryou, JW, Wei, X, Butson, C, Schiff, ND, and Purpura, KP (2012) Behavioral 
modulation with central thalamic deep brain stimulation in non-human primates. Society 
for Neuroscience Abstract 597.14. 
3. Bronte-Stewart H, Louie S, Batya S, Henderson JM. (2010) Clinical motor outcome of 
bilateral subthalamic nucleus deep-brain stimulation for Parkinson's disease using image-
guided frameless stereotaxy. Neurosurgery 67:1088–93; discussion 1093. 
4. Corrigan JD, Selassie AW, Orman JA. (2010) The epidemiology of traumatic brain 
injury. J Head Trauma Rehabil. Mar-Apr;25(2):72-80. 
5. Corrigan JD, Cuthbert JP, Harrison-Felix C, Whiteneck GG, Bell JM, Miller AC, et al. 
(2014) US Population Estimates of Health and Social Outcomes 5 Years After 
Rehabilitation for Traumatic Brain Injury. J Head Trauma Rehabil.29(6):E1-9. 
6. Dikmen SS, Machamer JE, Powell JM, Temkin NR. (2003) Outcome 3 to 5 years after 
moderate to severe traumatic brain injury. Arch Phys Med Rehabil. Oct;84(10):1449-57. 
7. Duncan J, Owen AM. (2000) Common regions of the human frontal lobe recruited by 
diverse cognitive demands.Trends Neurosci. Oct;23(10):475-83. 
8. Fan J, McCandliss BD, Sommer T, Raz A, Posner M. Testing the efficacy and 
independence of attentional networks. (2002)  J Cogn Neurosci 2002 14(3): 340-347. 
9. Fridman, EA, Beattie BJ, Broft A, Laureys S, Schiff ND. (2014) Regional cerebral 
metabolic patterns demonstrate the role of anterior forebrain mesocircuit dysfunction in 
the severely injured brain. Proc Natl Acad Sci  Apr 29; 111 (17): 6473-8. 
10. Giacino J, Fins JJ, Machado A, Schiff ND. (2012) Central thalamic deep brain 
stimulation to promote recovery from chronic posttraumatic minimally conscious state: 
challenges and opportunities. Neuromodulation. 15(4):339-49. doi: 10.1111/j.1525-
1403.2012.00458.x. Epub 2012 May 24. 
11. Heaton R, Miller SW, Taylor MJ and Grant I. (2004) Revised Comprehensive norms for 
an Expanded Halstead-Reitan Battery: Demographically-Adjusted Neuropsychological 
Norms for African American and Caucasian Adults. Lutz, FL: Psychological Assessment 
Resources, Inc.  
12. Holloway KL, Gaede SE, Starr PA, Rosenow JM, Ramakrishnan V, Henderson JM. 
(2005) Frameless stereotaxy using bone fiducial markers for deep brain stimulation. 
Journal of Neurosurgery 103:404–413.  

CT-DBS Clinical Protocol, Ver 7 
 
 
CONFIDENTIAL 
 
Page 36 of 39 
13. Jeanmonod D1, Magnin M, Morel A. (1996) Low-threshold calcium spike bursts in the 
human thalamus. Common physiopathology for sensory, motor and limbic positive 
symptoms. Brain. Apr;119 ( Pt 2):363-75. 
14. Levin HS, Li X, McCauley SR, Hanten G, Wilde EA, Swank P.Neuropsychological 
outcome of mTBI: a principal component analysis approach. J Neurotrauma. 2013 Apr 
15;30(8):625-32. doi: 10.1089/neu.2012.2627. Epub 2013 Mar 4. 
15. Machado a, Rezai AR, Kopell BH, Gross RE, Sharan AD, Benabid AL.  Deep brain 
stimulation for Parkinson’s disease: surgical technique and perioperative management. 
Mov Disord 2006; 21 Suppl 14:S247-58. PMID: 16810722 
16. Mair RG, Onos KD, Hembrook JR. (2011) Cognitive activation by central thalamic 
stimulation: the yerkes-dodson law revisited. Dose Response. 9(3):313-31. doi: 
10.2203/dose- response.10-017. 
17. Maxwell, W.L., MacKinnon, M.A., Smith, D.H., McIntosh, T.K. & Graham, D.I. (2006) 
Thalamic nuclei after human blunt head injury. J Neuropathol Exp Neurol, 65, 478-488. 
18. McCormick DA, Shu Y, Hasenstaub A, Sanchez-Vives M, Badoual M, Bal T. (2003) 
Persistent cortical activity: mechanisms of generation and effects on neuronal excitability. 
Cereb Cortex. 2003 Nov;13(11):1219-31. 
19. Murray CJ, Lopez AD. (1997) Alternative projections of mortality and disability by cause 
1990-2020: Global Burden of Disease Study. Lancet. May 24;349(9064):1498-504. 
20. Purpura, K. and Schiff, N.D. (1997) The thalamic intralaminar nuclei: a role in visual 
awareness. The Neuroscientist 3:8-15. 
21. Schiff, N.D. and Plum, F. (2000) The role of arousal and ‘gating’ systems in the 
neurology of impaired consciousness. Journal of Clinical Neurophysiology 17(5): 438-
452. 
22. Schiff , ND Giacino, J.T., Kalmar, K., Victor, JD, Baker, K, Gerber, M, Fritz, B, 
Eisenberg, B, Biondi, T, O’Connor, J, Kobylarz , EJ, Farris, S, Machado, A, McCagg , C, 
Plum, F, Fins, JJ, and Rezai, AR. (2007) Behavioral improvements with thalamic 
stimulation after severe traumatic brain injury. Nature 448:600-603. 
23. Schiff, ND (2008) Central thalamic contributions to arousal regulation and neurological 
disorders of consciousness. Annals of New York Academy of Sciences 1129: 105-118. 
24. Schiff, N.D. (2009) Central thalamic deep brain stimulation: mechanisms and rationale 
for treatment of non-progressive brain injury. Annals of New York Academy of Sciences 
1129:105-118. 
25. Schiff, ND. (2010) Recovery of consciousness after brain injury: a mesocircuit 
hypothesis. Trends in Neuroscience 33(1):1-9. 
26. Schiff ND. (2012) Moving toward a generalizable application of central thalamic deep 
brain stimulation for support of forebrain arousal regulation in the severely injured brain. 
Ann N Y Acad Sci. 1265:56-68. doi: 10.1111/j.1749-6632.2012.06712.x. Epub 2012 Jul 
26. 

CT-DBS Clinical Protocol, Ver 7 
 
 
CONFIDENTIAL 
 
Page 37 of 39 
27. Selassie AW, Zaloshnja E, Langlois JA, Miller T, Jones P, Steiner C. (2003) Incidence of 
long- term disability following traumatic brain injury hospitalization, United States, 2003. 
J Head Trauma Rehabil. 2008 Mar-Apr;23(2):123-31. 
28. Shirvalkar, P., Seth, M. Schiff, N.D., Herrera, D.G. (2006) Cognitive enhancement with 
central thalamic electrical stimulation. Proceedings of the National Academy of Sciences 
103(45): 17007-17012. 
29. Smith, AC, Shah, S, Hudson, AE, Purpura, KP, Victor, JD, Brown, EN, Schiff, ND. 
(2009) State-space and parametric models for characterizing behavioral facilitation 
associated with deep brain stimulation. J Neurosci Methods. 183(2):267-76. 
30. Stuss DT, Knight, RT, eds. Principles of Frontal Lobe Function. New York: Oxford 
University Press, 2013.  
31. TBI Model Systems National Data and Statistical Center. Traumatic brain injury model 
systems national database. http://www.tbindsc.org 
32. Tourdias T, Saranathan M, Levesque IR, Su J, Rutt BK. (2013) Visualization of intra-
thalamic nuclei with optimized white-matter-nulled MPRAGE at 7T. Neuroimage, 1–39 
33. Tucker, DM. (1993) Spatial sampling of head electrical fields: the geodesic sensor net. 
Electroencephal Clin Neurophys 87:154-163. 

CT-DBS Clinical Protocol, Ver 7 
 
 
CONFIDENTIAL 
 
Page 38 of 39 
APPENDIX 1. DEVICE PROGRAMMING SOP 
Programming of the device will utilize standard DBS techniques for assessing effects and side 
effects during a cathode survey of the DBS leads.  Programming will be conducted under the 
direct supervision of Dr. Henderson or under the direct supervision of personnel trained by Dr. 
Henderson.  Dr. Henderson will review and sign all forms summarizing adverse events observed 
during stimulation programming.  
The primary purpose of DBS programming is to select the optimal chronic stimulation 
parameters to use during stimulation titration and chronic stimulation.  Dr. Henderson may 
consult with other investigators to select the best stimulation parameters but will be responsible 
for the final decision based on effects and adverse effects.  Given the nature of this study, the 
selection of initial stimulation parameters for testing will be partially based on available animal 
data from Dr. Schiff’s laboratory as well as the group’s prior experience in deep brain 
stimulation in patients with traumatic brain injury.  Based on this combined experience, it is 
expected that stimulation frequency will be set in the range of 130-185 Hz. Final selection of 
chronic frequency, active contacts, pulse widths and amplitudes will be based on the titration 
testing using a systematic cathode survey as outlined below.  
A cathodal survey will be performed by activating, in a systematic fashion, each of the four 
contacts in each DBS lead as the cathode.  All patients will have bilateral deep brain stimulation 
and the investigators will first test the effects of stimulation on the left side lead and then test the 
right side separately.  Bilateral stimulation will only be attempted after each side has been tested 
individually.  All stimulation testing will be conducted below the safe change density limit of 30 
μC/cm2/phase.  
Each contact on each lead will be tested as the cathode (with the IPG set as the anode).  
Amplitude will be tested with stepwise increments in amplitude from 0 to a maximum of 10 V. 
Amplitudes will be increased until acute effects are noted or reported by the patient or the charge 
density limit is reached.  Pulse widths will be initially set at 60 microseconds and will not exceed 
120 microseconds.  The investigators will look for and ask about the following acute effects but 
will also ask the patient to report any subjective changes: 
• Paresthesias or pain 
• Motor changes such as twitches, dystonia, changes in posture 
• Verbal Fluency 
• Speech changes 
• Mood and anxiety 
• Alertness or energy level 
• Occulomotor changes or diplopia 
• Behavioral changes 
While mild or transient sensory changes such as mild paresthesias may allow stimulation 
titration to continue, unpleasant effects such as pain, motor effects or occulomotor effects will 
prompt the investigators to no longer increase stimulation amplitude, at which time it will be 
recorded that the Threshold for side effect was identified with that given electrical contact as the 
cathode.  Likewise, positive effects such as improvements in energy or alertness will be recorded 

CT-DBS Clinical Protocol, Ver 7 
 
 
CONFIDENTIAL 
 
Page 39 of 39 
and the lowest amplitude that produces desirable effects will be recorded as the Threshold for 
positive effects.  Once the cathode survey is completed, the investigators will select the electrical 
contacts that produce the most robust positive effects at the lowest amplitudes and negative 
effects at the highest amplitudes (i.e. therapeutic index) for chronic stimulation.  It is relevant to 
notice that the initial cathode survey will only provide the initial guidance for stimulation 
adjustment.  Because the cathode survey is typically conducted over a session of 2-3 hours, it 
does not account for temporal summation of effects.  If adverse effects are reported over days or 
hours, further programming will be needed in order to identify the parameters that produce the 
intended benefits with limited adverse effects.