Adaptive Closed Loop Neuromodulation and Neural Signatures of Parkinson's Disease
Phase: NA
Conditions: Parkinson's Disease
Sponsor: Stanford University

 
 
 
 
Adaptive Closed Loop Neuromodulation and Neural Signatures of 
Parkinson's Disease 
Study Protocol, Statistical Analysis Plan, and Informed Consent Form 
NCT02384421 
June 16, 2020 

1. NAME AND ADDRESS OF THE SPONSOR
Helen Bronte-Stewart, MD MSE
John E. Cahill Family Professor  
Director, Stanford Movement Disorders Center  
Director, Stanford Human Motor Control and Balance Laboratory Department of 
Neurology and Neurological Sciences  
300 Pasteur Drive   
 
Stanford, 
CA 
94305 
hbs@stanford.edu  
2. REPORT OF PRIOR INVESTIGATIONS
For prior investigations with Medtronic DMF 2010 – Activa PC+S Neurostimulation
System, please refer to Medtronic Right of Reference Letter located in Appendix B and
 Master File # 
 (PDF Page 58).
Clinical investigations of the standard DBS system
The Bronte-Stewart Lab has performed several clinical investigations using the FDA
approved Medtronic device, the Activa PC Deep Brain Stimulation (DBS) system, since
2005. From here on, this term - the DBS system - will refer to the standard (nonsensing)
implantable pulse generator (IPG), its connectors, leads and the four electrodes that are
implanted in the brain. We were the first to show that the presumed brain biomarker of
Parkinson’s disease (PD), specifically the beta rhythm, was attenuated after short periods of
DBS1. We subsequently showed that the resting beta rhythm was stationary and was similar
across hemispheres in individuals but different among people with PD, and that there was
evidence that this abnormal rhythm in the brain in PD was a property of a widespread
bilateral sensorimotor network2, 3. We demonstrated that there was a gradient in the power
of this rhythm within the main target nucleus for DBS in PD, the subthalamic nucleus
(STN), and that DBS both at this site and dorsal to the nucleus attenuated the beta rhythm
power in a voltage-dependent fashion in PD and showed prolonged attenuation of beta
power after longer periods of DBS2,4,5. We have also reported that such abnormal
electrophysiology is seen in both primary and secondary dystonia in the brain and that DBS
also attenuates beta rhythm power in dystonia in the target nucleus, the globus pallidus
interna (GPi). We are in the pilot stages of our investigations of abnormal electrophysiology
during tremor and movement and the effects of DBS on such. With the technological
development of the sensing IPG, we will be able to move these experiments from the
operating room to the laboratory.
3. INVESTIGATIONAL PLAN (Study 2: Adaptive Closed Loop
Neuromodulation for Parkinson’s Disease)
3.1. Purpose 

Deep brain stimulation (DBS) of the subthalamic nucleus (STN), internal segment of the 
globus pallidus (GPi), and/or thalamus has become the standard of care FDA-approved 
treatment for Parkinson's disease (PD), tremor, and dystonia. DBS consists of the 
implantation of chronic stimulating electrodes (leads) - Medtronic models 3387 or 3389  
- into the nucleus of choice. The DBS leads are connected to an implantable neurostimulator
called Activa PC (already FDA approved). Medtronic has developed a new DBS
implantable system called Activa PC+S. Activa PC+S will have therapy equivalent to
Activa PC.
Activa PC+S’s new sensing capability allows for chronic recording of neural activity in the 
presence of stimulation or when stimulation is turned off. Furthermore, the new device 
permits non-invasive data transfer of recorded neural signals.  
 The Nexus-D system is a newly developed research technology allowing for bidirectional 
communication of information between the Activa® PC+S and a portable computer (PC).  
Currently, cDBS is limited to “open-loop” stimulation without real-time adjustment for the 
patient’s state of activity, fluctuations and types of motor symptoms, medication dosages, or 
neural markers of the disease. The purpose of this proposed study is to determine if an 
adaptive DBS system, responding to patient-specific clinically relevant neural or kinematic 
feedback, is more effective than continuous DBS on the motor Unified Parkinson’s Disease 
Rating Scale (UPDRS III) and specific phenotypic measures in Parkinson's Disease.  
Used in conjunction, the Nexus-D and Activa® PC+S devices will allow us to begin to 
investigate “closing the loop” and will allow for the implementation of adaptive 
neuromodulation (aDBS) which adjusts stimulation parameters in real-time to account for 
patients’ symptoms and actions. The Nexus-E system firmware update, when used in 
conjunction with Nexus-D, allows for neural recording without data compression in order to 
analyze the effect of adaptive DBS on LFP power.  
Currently, there are a myriad of possible algorithms to inform aDBS based on numerous 
potential kinematic and neural options for use as input signals. Preliminary studies have 
shown improvement in items of the motor Unified Parkinson’s Disease Rating Scale  (UPDRS 
III), and predicted decreased energy when using aDBS triggered by resting state beta band 
(13-30 Hz) peak power compared to continual feed-forward DBS and randomized 
stimulation1. However, it is unknown if peak beta power is the optimal  neural classifier for 
tremor, bradykinesia, freezing, and/or when the patient is undergoing their activities of daily 
life. The tools available in the   
Activa® PC+S, Nexus-D and Nexus-E System will allow the opportunity to test such 
algorithms within safe and externally-controlled boundary conditions for the first time in 
human subjects with PD.  
3.2. Protocol 
3.2.1 Background and significance 
The proposed study will mark the first clinical implementation of the Nexus-D/E device to 
create a closed-loop stimulation system. Neuromodulation and changes of stimulation 
parameters will be implemented by computer algorithms using neural and kinematic triggers 

imputed to the PC and communicated to the Activa® PC+S neurostimulator using the 
Nexus-D/E system. 
Concurrent synchronized kinematic signals will be recorded using an analog-to-digital 
converter (CED, Cambridge Electronic Design Limited, Cambridge, England). These will be 
used to determine classifier algorithms for the states of tremor or bradykinesia using angular 
velocity sensors strapped to the hands. Patient-specific kinematic triggers of tremor amplitude 
and movement velocity will be used to trigger aDBS. By optimizing neurostimulation outside 
the clinical setting, aDBS will reduce the number of office visits and travel for many PD 
patients. The ideal aDBS system would also adjust to therapies and motor states over time, 
preventing harmful side effects. Additionally, aDBS may allow for significantly less total 
energy delivered compared to cDBS since neurostimulation is only turned ON when disease-
pertinent classifiers are present. This should prolong battery life and reduce the necessity and 
frequency of neurostimulator replacement surgeries which reduces overall surgical risk. 
Adaptive or “intelligent” deep brain stimulation will allow for the continuous optimization of 
therapy on an individual basis, maximizing motor improvement and minimizing adverse 
effects.  
We believe that the field of neurostimulation is about to undergo a significant paradigm 
shift, similar to the revolution in cardiac pacing when demand-based pacemakers were 
realized that could pace the heart in response to abnormal heart rhythms. This research will 
allow us to identify the abnormal brain signals or brain “arrhythmias” responsible for 
abnormal motor behavior in PD and will ultimately allow the design of demand or feedback 
brain pacemakers.  
3.2.2 Specific Aims  
SA1: Determine the efficiency and effectiveness on PD signs of aDBS, triggered by patient-
specific resting or movement state neural activity, compared to cDBS, using the UPDRS III 
and validated high-resolution kinematic metrics of tremor, bradykinesia and freezing of gait 
(FOG). 
Primary Hypothesis: Resting state aDBS will reduce energy consumption compared to 
cDBS as well as improve overall motor outcome, but may have differing effects on the 
individual PD motor signs. 
SA1a. Determine the neural classifier of the resting or movement state to use as a 
trigger for aDBS. Hypothesis: Patient-specific beta band synchrony is a classifier of 
the off therapy resting or movement state in PD and can be used as a trigger for 
aDBS1,2. Using individualized algorithms, resting or movement state neural activity 
will be tested as the stimulation trigger, activating aDBS when beta power is above a 
specific threshold. SA1b. Compare the efficiency and effectiveness on PD symptoms 
of aDBS (using the patient specific resting state neural classifier) compared to cDBS 
at the same neurostimulation parameters. 
SA2: Determine whether aDBS using a kinematic classifier pertinent to the patientspecific 
phenotype is more efficient and/or effective on PD symptoms than aDBS using the using 
the patient’s specific resting or movement state neural classifier and/or cDBS. 

Secondary Hypothesis: Different PD motor phenotypes may respond better to aDBS 
triggered by the kinematic classifier respective to that state than to aDBS triggered by the 
resting or movement state neural classifier or to cDBS. 
SA2a. Determine the kinematic classifiers for the states of tremor and bradykinesia, 
and develop the control policy algorithms of optimal DBS settings that improve each 
motor abnormality. SA2b. Compare the efficiency and effectiveness on PD 
symptoms of tremor or bradykinesia kinematic aDBS versus resting or movement 
state neural aDBS and cDBS.  
SA3: Determine whether aDBS is more efficient and effective than cDBS in the optimized 
on medication state after six months of cDBS.   
Tertiary Hypothesis: Neural and/or kinematic classifiers and control policy algorithms will 
need to be adapted to different medication states, making aDBS more or less useful. After 
six months of cDBS plus medication, SA1 and SA2 will be repeated in the optimized on 
medication state. The control policy algorithms will be adjusted as necessary to adapt to this 
state. 
3.2.3 Study Design, Setting/Location 
This is an open-label pilot study of up to 30 people with Parkinson’s disease. All 
experiments will be performed in the Stanford Human Motor Control and Balance 
Laboratory in the department of Neurology and Neurological Sciences at Stanford  
University Medical Center. A unique aspect of the Stanford Movement Disorders Center is 
the Stanford Human Motor Control and Balance Laboratory, in which we have developed 
several quantitative measures of motor control and a parallel line of research in human 
motor control in movement disorders. These measures have been validated with the clinical 
scale most widely used in PD research, the UPDRS III, as stated above.  
Study Population 
The study will be carried out in up to 30 people with moderate to advanced PD who will 
have been evaluated and approved to have subthalamic deep brain stimulation to treat their 
motor signs. Subjects who have been implanted with Activa PC+S and are participating or 
have completed Study 1 will be asked to complete Study 2. In order to account for study 
attrition additional subjects (up to 30) will be recruited into study 2.   
Battery life on the Activa PC + S (research device) and the Activa PC (FDA-approved clinical 
device) is estimated to last approximately 3-5 years. A limited number of subjects will be 
invited to be replaced with an Activa PC+S, should they chose to remain in the study. 
Invitations to receive a replacement Activa PC+S will depend on the focus of future 
experiments, quality of signal, and device availability. If the patient would prefer not to 
continue in the study, or if they are not invited to continue, they may proceed with the 
standard implantation of the non-research device.   
3.2.4 Eligibility Criteria 
The eligibility criteria are the same as those used for Study 1 
Inclusion criteria: 

1. A diagnosis of idiopathic Parkinson’s disease with bilateral symptoms at Hoehn and Yahr Stage ≥ II.
2. Documented improvement in motor signs on versus off dopaminergic medication, with a change in the
Unified Parkinson’s Disease Rating Scale motor (UPDRS III) score of ≥ 30% off to on medication.
3. The presence of complications of medication such as wearing off signs, fluctuating responses and/or
dyskinesias, and/or medication refractory tremor, and/or impairment in the quality of life on or off
medication due to these factors.
4. Subjects should be on stable doses of medications, which should remain unchanged until the DBS
system is activated. After the DBS system is optimized (during which time the overall medication
dose may be reduced to avoid discomfort and complications such as dyskinesias), the medication
dose should remain unchanged, if possible, for the duration of the study.
5. Treatment with carbidopa/levodopa and with a dopamine agonist at the maximal tolerated doses as
determined by a movement disorders neurologist.
6. Ability and willingness to return for study visits at the initial programming and after three, six, and
twelve months of DBS.
7. Age > 18
Exclusion criteria: 
1. Subjects with significant cognitive impairment and/or dementia as determined by a standardized
neuropsychological battery.
2. Subjects with clinically active depression, defined according to the Diagnostic and Statistical manual of
Mental Disorders, Fourth Edition (DSM-IV) criteria and as scored on a validated depression assessment
scale.
3. Subjects with very advanced Parkinson’s disease (Hoehn and Yahr stage 5 on medication (non-
ambulatory)).
4. Age > 80.
5. Subjects with an implanted electronic device such as a neurostimulator, cardiac pacemaker/defibrillator,
or medication pump.
6. Subjects who are pregnant, are capable of becoming pregnant, or who are breast feeding.
7. Subjects with an MRI showing focal brain lesions that could indicate a non-idiopathic movement
disorder.
8. Subjects having a major comorbidity increasing the risk of surgery (prior stroke, severe hypertension,
severe diabetes, or need for chronic anticoagulation other than aspirin).
9. Subjects having any prior intracranial surgery.
10. Subjects with a history of seizures.
11. Subjects who are immunocompromised.
12. Subjects with an active infection.
13. Subjects who require diathermy, electroconvulsive therapy (ECT), or transcranial magnetic stimulation
(TMS) to treat a chronic condition.
14. Subjects who have an inability to comply with study follow-up visits.
15. Subjects who are unable to understand or sign the informed consent
Subgroups: We will attempt to recruit an equal number of tremor-dominant and tremor 
absent people as well as an equal number of people with documented freezing episodes and 
those without. Some with tremor may or may not freeze and vice versa. We will also 
attempt to recruit women and minorities, although the incidence of PD is higher in men and 
highest in Caucasians, so with only 30 subjects in this pilot trial, there may be more men 
than women and more Causasians than other ethnic groups in our cohort.  
3.2.5 Study outcomes 

Beta power, UPDRS III, and quantitative measures of tremor (rest tremor recording for 1 
minute), bradykinesia (WFE task), speech and FOG (using a Stepping in Place (SIP) 
task4/Gait Analysis), and time DBS ON over the time on aDBS.  
3.2.6 Recruitment 
Subjects with Parkinson’s disease who have been accepted for DBS implantation will be 
asked if they wish to participate in this study. All subjects will have undergone challenged 
on medication and practically defined off medication evaluations by a fellowship-trained 
movement disorders neurologist and detailed neuropsychological testing by a 
neuropsychologist prior to being presented at the movement disorders surgical review 
board. The movement disorders surgical review board consists of the neurosurgeons, 
movement disorders neurologists, psychiatrist, neuropsychologist, and nurse specialists, 
who evaluate each candidate’s suitability for surgery and reach a consensus decision about 
each person. If s/he is accepted for DBS, s/he is scheduled to meet the neurosurgeon. At this 
visit they will be met in person by the research coordinator, who will with permission sit 
down in person with them and any family present to explain the study and review the 
informed consent. Feasibility of and time for recruitment: on average the Stanford 
Movement Disorders Surgical Review board accepts 6 – 10 patients for DBS per month. If 
it is assumed conservatively that 50% of patients asked will consent, then the recruitment of 
15 subjects will take a maximum of five months. We recruit subjects currently for intra-
operative investigations, which we think would be harder to recruit for than the current 
study and our acceptance rate is higher than 80%.  
We will also recruit subjects who are participating in or have completed Study 1 to consent 
to and complete Study 2. In order to account for study attrition additional subjects (up to 10 
additional) will be recruited into study 2.  
Sample Size/Power Analysis: Our preliminary data: change ON versus OFF DBS (mean +/- 
std dev): beta band power = 57 +/- 62, UPDRS = 58 +/- 22%5, Vrms 45% +/- 63%3. Power 
analysis (paired t-test, p=0.8, alpha =0.001, to allow for multiple comparisons) on the above 
data gave the largest sample size required for significant outcomes = 27 (STNs), which is 
similar to the sample size (21) needed to detect difference between aDBS and cDBS 
reported in previously published results1.   
3.2.7 Study procedures 
Medical Adhesive Use: During Activa PC+S implantation surgery, a small amount of 
medical adhesive (Medtronic Part #080118, Dow Corning Medical Adhesive) is placed on 
the Activa PC+S Implantable Neurostimulator (INS) (Model 37604) header setscrew 
grommets and the header bore where the lead extensions are inserted and secured. For 
further information regarding use of medical adhesive during Activa PC+S implantation and 
replacement please see Appendix K (PDF Page 179), Appendix L (PDF Page 181) and 
Appendix M (PDF Page 190).  
Nexus E Firmware Update: Subjects enrolled in study 2 will sign an updated informed 
consent, please see Appendix N (PDF Page 197) and undergo a Nexus E Firmware update 
at their next study visits. Subjects who have not yet been implanted with Activa PC+S will 
undergo Nexus E Firmware update at their initial programming visit. The Nexus E firmware 
update will take approximately 30 minutes to perform. During the firmware update the 

subject will not receive any therapeutic stimulation. For further information regarding 
Nexus E please see Appendix E (PDF Page 120) and Appendix F (PDF Page 150.)  
SA1: Determine the efficiency and effectiveness on PD signs of aDBS, triggered by patient-
specific resting state or movement neural activity, compared to cDBS, using the UPDRS III 
and validated, high-resolution kinematic metrics of tremor, bradykinesia and freezing of gait 
(FOG). 
SA2: Determine whether aDBS using a kinematic classifier pertinent to the patient specific 
phenotype is more efficient and/or effective on PD symptoms than aDBS using the using 
the patient’s specific resting or movement state neural classifier and/or cDBS. 
Aim 1 and 2 will be done at the time of initial programming of the DBS system and at the first 
follow-up visit for subjects who consent before DBS implantation. For subjects who already have 
the Activa PC+S implanted, Aims 1 and 2 will be performed after they have completed Study 1:  
1.
Patients will arrive in the off medication, OFF DBS state. Medication will be stopped
72 hours (extended release forms of dopamine agonists), 24 hours (regular form of
dopamine agonists, controlled release forms of carbidopa/levodopa (CD/LD)) and/or 12
hours (regular CD/LD, entacapone, rasagiline, selegiline, amantadine) before testing.
The DBS system will not have been activated after implantation or will be turned off as
per the protocol in Study 1.
2.
An interval history, examination, and UPDRS III will be performed. LFPs will be
recorded from the DBS leads at rest during the repetitive wrist flexion-extension task
and during stepping in place.
3.
Real-time STN LFP beta band power will be calculated both OFF DBS and during
“therapeutic” DBS. DBS will be applied through the electrode (1 or 2) that lies in
between the electrode pair (0-2 or 1-3) with the greatest beta power. Therapeutic DBS:
140 Hz, 60 microsec at 3 volts OR the highest voltage <3V, that does not cause adverse
effects.
4.
We will determine if the therapeutic DBS will attenuate rest beta power by >= 40%4.
5.
Patients will be seated at rest, or while performing self-paced repetitive wrist flexion-
extension (WFE) for periods of 10 seconds after a “Go” signal with angular velocity
sensors attached to the hand.
6.
SA1a and SA2a (Initial Programming or Initial visit): Determination of classifier
thresholds: 1. Resting or movement state neural: ON and OFF triggers when the beta
band power is greater than or less than different thresholds of the resting or movement
state beta power differential (beta power OFF – ON therapeutic DBS). 2. Kinematic
(tremor/bradykinesia): ON and OFF triggers when rectified tremor amplitude/root mean
square angular velocity (Vrms) of WFE is greater than or less than different thresholds
of tremor/Vrms differential (OFF – ON therapeutic DBS) respectively. SA1b and SA2b
(First Followup Visit): Outcomes will be measured after 30 minutes of aDBS or cDBS.
For neural and tremor aDBS, the Activa® PC+S will be updated in real time (see
delays). For bradykinesia aDBS, the Activa® PC+S will be updated with the Vrms from
10 second epochs of WFE that the PD subject will perform every 2 minutes during the
30 minute trial (rwFE, angular velocity sensors, Motus Motion analysis system, and
EMG). SA3: Determine whether aDBS is more efficient and effective than cDBS in the
optimized on medication state after six months of cDBS.
Aim 3 will be completed after 6 months of continuous DBS and optimized therapeutic 
medication.  

7.
Patient arrives in on medication/on stimulation state. Patient is instructed to bring
appropriate doses of medication to take throughout the day at pre-set intervals.
8.
An interval history, examination, and UPDRS III will be performed. LFPs will be
recorded from the DBS leads during some of the clinical assessments such as the
repetitive wrist flexion-extension task and during stepping in place.
9.
Real-time STN LFP beta band power will be calculated both on medication/OFF
DBS, and during “therapeutic” DBS. DBS will be applied through the electrode (1 or
2) that lies in between the electrode pair (0-2 or 1-3) with the greatest beta power.
Therapeutic DBS: 140 Hz, 60 microsec at 3 volts OR the highest voltage <3V that
does not cause adverse effects.
10. We will confirm that the therapeutic DBS will attenuate rest beta power by >= 40%4.
11. Patients will be seated at rest, or while performing self-paced repetitive wrist flexion-
extension (WFE) for periods of 10 seconds, after a “Go” signal with angular velocity
sensors attached to the hand.
12. SA3: Determination of classifier thresholds: 1. Resting or movement state neural: ON
and OFF triggers when the LFP band power or variability is greater than or less than
different thresholds of the resting or movement state LFP power differential (LFP
power OFF – ON therapeutic DBS). 2. Kinematic (tremor/bradykinesia): ON and OFF
triggers when rectified tremor amplitude/root mean square angular velocity (Vrms) of
WFE is greater than or less than different thresholds of tremor/Vrms differential (OFF –
ON therapeutic DBS) respectively.
13. Outcomes will be measured during trials up to 8 hours of aDBS or cDBS. For neural
and tremor aDBS, the Activa® PC+S will be updated in real time (see delays). For
bradykinesia aDBS, the Activa® PC+S will be updated with the Vrms from 10-60
second epochs of WFE that the PD subject will perform throughout during the trial
(rwFE, angular velocity sensors, Motus Motion analysis system, and EMG).
Blinding: The PD subject, investigators (certified) performing the UPDRS III, and 
investigator analyzing data will be blinded to the type of DBS used for a particular 
experiment. All experiments will be videotaped and two additional independent certified 
raters will rate the UPDRS III. 
Randomization: The order of aDBS, cDBS, and all motor tasks will be randomized for each 
subject and enough time will be given in between for patient rest and for return to baseline 
of beta power, tremor, and bradykinesia. 
3.2.8 Clinical Assessments 
Clinical Assessments  
Pre- 
surgery  
Baseline 
Initial 
programming  
1 mo. 
Post IP  
6 mo. 
post IP 
Off Meds  
Off Meds  
Off Meds  On Meds 
Repetitive Wrist Flexion- 
Extension Movement  
x 
x 
x 
x 
Tremorography 
x 
x 
x 
x 
Stepping in Place (SIP)  
x 
x 
x 
x 

Gait Analysis  
x 
x 
x 
UPDRS III / H&Y  
x 
x 
x 
x 
Medical History 
x 
x 
x 
x 
Physical Exam 
x 
MOCA 
x 
Columbia Suicide Severity 
Scale  
x 
x 
x 
x 
Electromyography (EMG)  
x  
x 
x  
Local Field Potentials  
x  
x 
x  
Adaptive DBS Testing  
( Kinematic and Neural triggers) 
x  
x 
Note: The subjects will be given practice trials for all of the quantitative tasks listed below 
to ensure that the goal and the instructions of the task are understood before each 
assessment is performed. At the baseline visit, the baseline version of the Columbia 
Suicide Severity scale (CSSS) will be used. At every subsequent visit, the “Since last 
visit” version of the CSSS will be used. 
1. Repetitive wrist flexion-extension movement – rwFE: Using solid-state gyroscopic
sensors (Motus Motion analysis system) that fit like a glove on the patient's hands and
surface EMG sensors (Delsys Bagnoli 2 EMG System) placed on the wrist flexor and
extensor muscles, the wrist movement and the muscle activation patterns will be quantified.
Specifically, we will directly measure angular velocity and muscle activations. The
patient’s arm will be kept at 90 degrees in elbow flexion with the forearm in a neutral
position. The patient will perform a wrist flexion-extension movement continuously from
the “go” to the “stop” command. This test will assess the subject’s bradykinesia state.
2. Tremorography: If the subject shows visible tremor of the hands using the above
mentioned angular velocity sensors, his/her resting or postural tremor behavior will be
measured. Surface EMG sensors will be placed on forearm muscles to capture the muscles’
activation pattern.
3. Repetitive alternating finger tapping (RAFT) keyboard task: RAFT is a computerized
objective measure of movement velocity, speed of movement, and timing using an
engineered keyboard (Quantitative DigitoGraphy) with two adjacent keys. The subject will
alternatively finger tap (trill) on the keyboard. The test will be performed twice for each
hand. The patient will be seated at a table on which the keyboard is placed with the hand
that does not perform the task placed in his/her lap. The subject will be instructed to tap as
fast as s/he can while maintaining the alternating movement. This test will quantify a set of
movement abnormalities seen in Parkinson’s disease patients such as bradykinesia, freezing
of movement, tremor, or fatigue.

4. Stepping in place (SIP) task: The subject will be asked to step in place repetitively on two
adjacent force plates (Smart EquiTest, Neurocom Inc) with each foot on each forceplate.
The subject will step at a speed similar to his/her normal walking. A baseline quiet stance
will be acquired at the beginning and the end of the test. The
subject will wear a harness to protect him/her from falling. This test will quantify measures
such as gait asymmetry, gait rhythmicity, and left-right step coordination. These metrics
may provide clues to underlying mechanisms involved in freezing of movement in PD. Our
lab showed that the SIP metric has a high sensitivity (93%) and specificity (87%) for
identifying freezers from non-freezers5.
5. Unified Parkinson's Disease Rating Scale part III – Motor Examination (UPDRS
III): The clinical motor assessment of the subject will be performed using the UPDRS III
scale.
6. Gait Analysis: Subjects will wear sensors on their hands, arms, chest, trunk, feet and legs
(Opal sensors, APDM, Inc). These tasks will quantify measures such as gait asymmetry,
gait rhythmicity and left-right step coordination during subjects normal walking. Subjects
may be asked to do regular forward walking as well as walking around obstacles (such as
chairs, or small room dividers) or turning in place. These obstacles and turning in place will
be used in order to elicit freezing, which often occurs in constrained spaces. This type of
freezing is frequently encountered in subjects' daily lives. Subjects will be monitored
carefully by research team in order to ensure their safety and comfort.
7. Cognitive Testing: Subjects will be administered the Montreal Cognitive Assessment at
visits after the pre-surgery baseline visit. In both the resting and movement state, subjects
will perform cognitive tasks that include but are not limited to reciting the months of the
year backwards and serial 7s.
8. Speech Assessment: While wearing a voice-recording headset, subjects will be performing
speech tasks that include reading sentences and phonation.
9. Vibrotactile Stimulation: Subjects may be asked to perform the above gait tasks with
sensory cueing using the VibroGait system. Intermittent vibrotactile stimulation may be
applied to the wrists, or another body part with intact sensation, in a manner that is either
coordinated with or unrelated to the subject’s gait cycle in real time. Subjects will be
allowed to practice with the VibroGait on before completing the tasks.
In addition to Nexus testing, subjects attending clinical programming follow-up visits will come in off
medication and on stimulation and will be asked to repeat quantitative assessment of motor function and
simultaneous LFP recording. Subjects come in for programming visits every 3-6 months for 1-3 years
post device implantation. Patients who receive replacement Activa PC+S devices will continue to
complete the same assessments listed above in order to further the aims of both Study 1and 2. These
experiments will allow us to collect data related to longer term disease tracking. Disease tracking
includes monitoring the patients' beta band over time, in accordance with SA3 from study 1 (SA3:
Determine the long-term effects of STN DBS on neural signatures and motor behavior; ascertaining
whether long-term DBS changes the underlying neural signatures and dose response characteristics of
PD behavioral states).
Testing for disease tracking will include quantitative digitography (QDG), quantitative range of
motion analysis (Motus, LG G Watch, APDM System), tremorography, surface
electromyography (EMG), and computerized dynamic posturography, SIP, gait analysis,
cognitive testing and UPDRS III. Testing for replacement device patients will also include
aDBS experiments, with the same protocol as detailed above. The subjects will perform these

assessments in the on clinical stimulation state and will repeat all or a subset of these tests in 
the off stimulation state. 
3.2.9 Adverse Event Reporting 
We will report any unanticipated adverse device effects to Medtronic and IRB as soon as 
possible after the event occurs (within 10 working days after first learning about event). 
Evaluations of unanticipated adverse device effects will be reported to the FDA, IRB, and 
Medtronic within 10 days after receiving notice of effect and in accordance with guidance 
812.150. We do not expect any adverse events related with the functionality of the 
implanted device. 
3.2.10 Data Analysis 
Experimental outcomes: Beta power, UPDRS III and quantitative measures of tremor (rest 
tremor recording for 1 minute), bradykinesia (WFE task) and FOG (using a Stepping in Place 
(SIP) task and gait analysis), and time DBS ON over the 30 minutes on aDBS.  
Number of arms: (One) Patients will be used as their own controls.  
All quantitative data will be post-processed using custom MATLAB software (The 
MathWorks, USA).  
1. Repetitive wrist flexion-extension movement – rwFE: The Motus motion analysis
system will be used to obtain an objective quantitative assessment of bradykinesia by
measuring hand angular velocity during a quantitative repetitive wrist flexion-extension
task (rwFE). The system consists of sensors in which vibrating quartz crystals act like
solid-state gyroscopes and produce an analog signal whose voltage is proportional to the
angular velocity when rotated about its measurement axis. These sensors are unlike
conventional accelerometers in that they are indifferent to their orientation with respect to
gravity. Each sensor weighs about 60 g, has a maximum range of 1,900 degrees per
second, a low noise level of 1 degree per second RMS, and a flat response to 30 Hz. The
angular velocity data will be digitized at a rate of 100 samples per second per sensor. The
root mean square velocity of angular movement (Vrms) will be used as an indication of
the average speed at which the flexion-extension task is performed. The frequency
spectrum of the angular velocity will be analyzed using a fast Fourier transform (FFT)
analysis in each trial to ensure that patients’ movements are not dominated by a fast-
action tremor (7–12 Hz).
2. Tremorography; Using the above mentioned angular velocity sensors, the angular
velocity data during rest and/or postural poses will be digitized at a rate of 100 samples
per second per sensor and the frequency spectrum will be will be analyzed using an FFT
analysis to detect and quantify the type of tremor (rest 4-6 Hz or action/postural 712 Hz)
that is present.
3. Muscle activation patterns: The Delsys Surface EMG System will be used to collect
electromyography signals from the wrist flexor and extensor muscles. The signals will be
filtered using a fourth-order band pass Butterworth (20-300 Hz) applied in the forward
and reverse directions to prevent phase distortions. The linear envelope of the rectified
signals will be calculated by finding the absolute value of the signal and then calculating
the RMS value at every 50 ms. The signals will be normalized by the average of the three
greatest peak values of each muscle for comparing amplitude of muscle activity within
tasks for each patient and also across patients.
4. Repetitive alternating finger tapping (RAFT) keyboard task: The engineered
keyboard outputs a calibrated analog signal that corresponding to the displacement of the
keys. The downstrike velocity, interval between strikes, and duration of keystrikes will
be extracted from the recorded signal.

5. Stepping in place (SIP) task; During the SIP task, ground reaction forces will be
captured at 100 Hz with two force plates (Advance Mechanical Technology Inc,
Watertown, MA, USA). A freezing episode (FE) will be defined when the patient is
unable to completely lift a foot from the force plates (i.e. when the vertical forces did not
reach 100% (foot in stance) and 0% (lifting phase)). FEs will be identified only if
detected visually and with the computerized algorithm. The experimenter will document
the occurrence of FEs to compare with the offline force plate data analysis. A
computerized algorithm to automatically detect freezes will be performed in MATLAB.
Signals from the force plates will first be low-pass filtered at 12 Hz with a second order
Butterworth filter. Peaks reaching values below 15% and above 85% and separated by
more than 400ms
will be detected. If fewer than 20 peaks are detected on one of the force plates, the
entire trial will be considered a FE and the analysis will be terminated. For each
signal, abnormally long intervals will be defined as intervals between two maxima or
two minima whose duration is longer than either 1.2 times the average duration of the
intervals between the corresponding extrema in the three previous cycles, or longer
than twice the average interval duration in the whole trial. A FE will be defined as an
episode of abnormally long intervals detected concurrently on the two force plates.
Finally, using the same criterion as for visual detection, when fewer than four
minima and fewer than four maxima on each force plate (fewer than three strides)
separated two FEs, these will be combined into a long FE. The stepping cycle
symmetry and rhythmicity of SIP will be calculated for the first 25 s of each SIP trial
and will be averaged over the three trials. According to previous studies, asymmetry
and rhythmicity were defined as: SIP cycle asymmetry = 100 x [ln(SSWT/LSWT)],
where SSWT and LSWT correspond to the leg with the shortest and longest mean
swing time over the trials, respectively and rhythmicity = the mean stride time
coefficient of variation (CV) of both legs. A large stride time CV would be indicative
of a less rhythmic gait.
6. Gait Analysis: Standard quantitative gait metrics including but not limited to freezing
episode duration, gait speed, gait asymmetry, gait rhythmicity, swing phase and left-right
step coordination.
7. Speech Analysis: Audio recordings of the speech tasks will be analyzed to obtain
metrics that include but are not limited to diadochokinesis rate, speaking rate,
intelligibility rate, and communication efficiency ratio.
3.3. Risk Analysis 
The tools used for kinematic analysis are non-invasive (do not enter your body). Physical 
sensors are applied to the surface of your body. The tests are not physically painful (other 
than in the removal of adhesive tape holding the sensors on the skin). 
The VibroGait is non-invasive and provides mild sensory feedback in the form of vibration, 
set to a frequency and intensity similar to a cell phone on vibrate mode. The vibration 
should not be painful, but if subjects do experience discomfort or pain they will be able to 
stop using the VibroGait at any time. 
The Nexus-D/E System does not allow the clinician to change the stimulation configuration 
beyond what a patient programmer (model 37642) is capable of changing; therefore, a 
research system utilizing the Nexus-D/E system can effectively act only as an automated 
patient programmer when updating stimulation parameters.  

Just like the existing patient programmer, the Nexus-D/E system provides the host computer 
with the capability of changing stimulation only within physician-configured 
neurostimulator limits programmed with the model 8840 Clinician Programmer (e.g. – 
incrementing or decrementing stimulation amplitude). Since the only stimulation updates 
allowed are those that stay within the physician limits, all risk mitigations implemented by 
the model 8840 Clinician Programmer are in full effect with no new stimulation-related 
risks introduced by the use of the Nexus-D/E System. Furthermore, the Nexus-D/E system 
is used under the direct supervision of the clinician and is not used outside of the acute 
clinical setting (i.e. – not taken home by the patient).  
The Nexus D/E system does not make any stimulation update decisions. The system acts 
only as a conduit for data and commands between a host computer and the implanted 
neurostimulator. All decisions are made by the clinician who implements the host 
application. The Nexus E system is used in conjunction with Nexus D for improved fidelity 
of neural recordings. The Nexus E system firmware update takes approximately 30 minutes 
to perform. During the firmware update the subject will not receive any therapeutic 
stimulation.  
Prior to all experiments performed using Nexus D and/or Nexus E system, the clinician 
will manually test the transition rise and fall times (“ramp rates”) used during closedloop 
functionality. These manual tests will confirm patient comfort during adaptive DBS 
research protocols. Following all in-clinic experiments including closed loop experiments 
with Nexus-D or Nexus-E, patients will always be set back to their clinical stimulation 
settings before leaving the laboratory and will not be sent home with any aDBS settings. 
The application of medical adhesive prevents observation of cardiac artifact in Activa PC+S 
brain recordings. Neither application of medical adhesive nor observation of cardiac artifact 
in Activa PC+S brain signal recordings impacts standard Deep Brain Stimulation (DBS) 
patient therapy or patient safety. Please see 
 Master File # 
 and 
Appendix L (PDF page 181) for further details.  
There may be risks associated with the other unapproved Activa PC+S and Nexus-D 
components. Please reference Appendix G and H risk assessment for Nexus-D, Nexus E 
and Activa PC+S and 
 Master File # 
  
3.4. Description of Device 
Please see Appendix C (PDF Page 60) for description of Activa PC+S Neurostimulator 
System and Appendix D (PDF page 69) for description of Nexus-D System. Please see 
Appendix E - F (PDF page 120 and 150) for information regarding Nexus-E system. Please 
see Appendix K-M (PDF Page 179, 181 and 190) for information regarding medical 
adhesive.  
Wireless Nexus-D System Infrared Interface Update  
The Nexus-D consists of a reprogrammed Medtronic sensing programmer telemetry module 
(SPTM) to create a communication channel to the implanted Activa neurostimulator. A host 
application on a desktop computer can access this communication channel through a 
commercially available USB to IrDA (infrared data association) bridge (an Actisys 
IR224UN). The Nexus-D system is comprised of this combination of the reprogrammed 
SPTM and the commercially available USB to IrDA bridge. It is important to note that the 
bridge is purely a translator between the USB interface from the PC and the infrared 
communication interface. No command generation, interpretation or parsing of data is 

performed in the bridge of any kind. It simply passes any data communicated over USB 
directly to the Nexus SPTM and viceversa.  
Figure 1 Nexus-D Block Diagram  
Due to the fact that this bridge is a commercially available device that is unneeded for the overall 
functionality that the Nexus-D system provides, we have decided that it would be advantageous to 
remove it from the system. Our collaborators at University of Washington-Biorobotics lab (UW-
BRL) have built a system that instead communicates directly to the Nexus SPTM over the infrared 
interface.  
Figure 2 UW BRL Nexus Modification 
In this system all of the safety mechanisms and functionality of the Nexus-D is maintained. 
However, this system give us the advantage of building battery-powered embedded systems 
that will allow for studies in ambulatory patients without the need to be tethered to a PC for 
the duration of the experiments.  
3.5. Monitoring Plan 
Same Monitoring Plan as Study 1 
The project will be monitored to ensure the rights and well-being of the patients who 
consent to it; to ensure that the technical aspects of the study are carried out in a safe, 
accurate, and consistent manner; and to ensure that the data is collected and stored in a 
secure manner and is accurate, complete and verifiable.  
Prior to the initiation of the experiments, monitors will review the protocol, inspect the 
laboratory and the equipment to be used, ensure that the data will be collected and stored in 
a secure and reliable manner, and that the investigators are trained in the protocol. Monitors 
will participate in “dry runs” of the experiments with the investigators to document the 
above readiness before the study will commence.  
The monitors will verify that the investigators have adequate qualifications and resources 
which remain adequate throughout the trial period; and that facilities, including laboratories, 
equipment, and staff, are adequate to safely and properly conduct the trial and remain 
adequate throughout the trial period. The monitors will have formal meetings with the 
protocol director, Dr. Bronte-Stewart, and the investigative team every two months to review 
the number of patients recruited; to document that the data is being collected and stored 
correctly; and to document any adverse events, equipment issues and or data concerns. 
Monitors will formalize these with a report which will be provided to the IRB annually. 
Monitors will agree to meet on an ad hoc basis if there are any concerns that need to be 
Nexus-D
Nexus
SPTM
Activa
PC/PC+S
Coil 
Host Application 
Infrared 
USB-IR 
Bridge
Modified 
Nexus-D
Nexus-D Extension 
Nexus
SPTM
Infrared 
Embedded 
Host 
Application 
Activa
PC/PC+S
Coil 

addressed immediately. They will have the authority to recommend that the study be 
terminated if they believe that this is in the best interest of the subjects enrolled.  
Monitor Names & Addresses 
Matthew Petrucci, MS, PhD 
Stanford University Medical 
Center 300 Pasteur Drive,  
 Stanford, CA 94305  
Dr. Petrucci has a MS in mechanical engineering and PhD in neuroscience.  He has 
expertise in biomechanics, neurophysiology, mechatronics, engineering controls, and signal 
analysis in MATLAB, Simulink, C++.  He has previous experience with closed-loop DBS 
protocols and PC+S recordings. His role as an engineer is to help oversee the technological 
and data aspects of the study.  
Brent Bluett, DO  
Stanford University School of Medicine,  
213 Quarry Rd 
 Stanford, CA 94305 
Dr. Bluett is a Fellowship trained Movement Disorders neurologist and a Clinical  
Assistant Professor in the Department of Neurology and Neurological Sciences at Stanford 
University School of Medicine. Dr. Bluett has special expertise in the management of 
patients with implanted DBS devices as well as research experience with Parkinson’s 
disease. Dr. Bluett will monitor all the clinical aspects of the protocol and experiments.   
Robert Fisher, MD  
Stanford University Medical Center 300 Pasteur Drive, 
 Stanford, CA 
94305  
Dr. Robert Fisher is the Maslah Saul Professor in the Department of Neurology and 
Professor, by courtesy, of Neurosurgery at the Stanford University Medical Center. He has 
extensive experience in conducting clinical trials including a stage III trial for DBS therapy 
treatment of epilepsy.  
3.6. References 
1. Little, S., Pogosyan, A., Neal, S., Zavala, B., Zrinzo, L., Hariz, M., Foltynie, T., Limousin, P.,
Ashkan, K., FitzGerald, J., Green, A. L., Aziz, T. Z. and Brown, P., Adaptive deep brain
stimulation in advanced Parkinson disease. Ann Neurol., 2013.
74: 449–457.
2. Bronte-Stewart, H., Barberini, C., Miller Koop, M., Hill, B.C., Henderson, J.M., Wingeier, B.,
The STN beta-band profile in Parkinson’s disease is stationary and shows prolonged
attenuation after deep brain stimulation. Experimental Neurology, 2009. 215:20-28.
3. Wingeier, B., Tcheng, T., Miller Koop, M., Hill, B.C., Heit, G., Bronte-Stewart, H., Intra-
operative STN DBS attenuates the prominent beta rhythm in the STN in Parkinson’s disease.
Experimental Neurology, 2006. 197:244-251.
4. Miller-Koop, M., Andrzejewski, A., Hill, B.C., Heit, G., Bronte-Stewart, H.,

Improvement in a quantitative measure of bradykinesia after microelectrode recording in 
patients with Parkinson’s disease during deep brain stimulation surgery. Movement Disorders, 
2006. 21(5):673-678. 
5. Nantel, J., de Solages, C., Bronte-Stewart, H., Repetitive stepping in place identifies and
measures freezing episodes in subjects with Parkinson’s disease. Gait & Posture, 2011. 34(3):
329-333.
6. Bronte-Stewart, H., Louie, S., Batya, S., Henderson, J.M., Clinical motor outcome of bilateral
subthalamic nucleus deep-brain stimulation for Parkinson’s disease using image-guided
frameless stereotaxy. Neurosurgery, 2010. 67(4): 1088-93.
5.
MANUFACTURING INFORMATION
Please reference 
 Master File # 
. 
6.
INVESTIGATOR AGREEMENT
Please see Appendix I. 
7.
IRB INFORMATION
Research Compliance Office, Stanford University 
3000 El Camino Real  
Five Palo Alto Square, 4th Floor  
Palo Alto, CA 94306  
Please see Appendix J for roster. 
. 
8.
ENVIRONMENTAL ASSESSMENT
This study releases no toxic substances into the environment, nor does it generate any
radioactive material. Extracranial electrical fields produced by stimulation are negligible.
The sponsor requests categorical exclusion for this study protocol under 21 CFR 25.34 (g).
9.
LABELING
Upon receipt of the Activa PC+S, Nexus-D and Nexus-E devices, each individual box will 
be labeled “INVESTIGATIONAL USE ONLY” and will be kept in locked storage 
accessible to only the investigator and/or coordinator.  
Other device labeling can be found in the 
 Master File # 
. 
10.
INFORMED CONSENT
Study 2  
Please see Appendix N for informed consent forms. There are two versions of the 
consent form.  
1. Informed Consent for those already implanted with Activa PC+S in or completed
study 1 and/or study 2.

2. Informed Consent for those who have not been implanted with the Activa PC+S.

Adaptive Closed Loop Neuromodulation and Neural Signatures of Parkinson’s 
Disease -Nexus E Update 
Are you participating in any other research studies?  _____ Yes   _____No 
You are invited to participate in a study of your movements for the treatment of your 
movement disorder (such as Parkinson’s disease, Parkinsonism, Essential Tremor, 
Dystonia, or other). You have been asked to participate because you are being evaluated 
for Deep Brain Stimulation (DBS) surgery to treat your movement disorder. This research 
is separate from the DBS, but you can only be in the study if you receive DBS. Up to 15 
people who qualify for DBS surgery and up to 15 people who have already had the Activa 
PC+S implanted will be enrolled into this study (up to 30 Participants total). 
Kinematic analysis (computerized movement measurements) will be done in addition to 
standard clinical examinations. The information gathered from these measurements will be 
used for the clinical evaluation. Some of it may also be used for clinical outcomes and 
research projects.  
Neural activity will be recorded using the implantable Activa PC+S Neurostimulator 
System, (Medtronic INC). Data will be retrieved after and during each kinematic testing 
using a Clinician Sensing Programmer and the Nexus-E System (Medtronic INC). 
PURPOSE 
The purpose of this study is to provide objective measurements of abnormal movements 
of the body in correlation with neural activity of the brain and track how these change 
over time. The secondary purpose is to use brain and movement signals to automatically 
regulate therapeutic deep brain stimulation within clinically safe limits. This may allow for 
the development of a DBS System that uses signals from your brain and movements to 
provide customized demand-based therapy in the future. 
This study is being conducted to understand more about brain signals that are involved in 
movement and not to test the non-FDA approved components of the device. 
Your participation in this study is entirely voluntary and your decision not to participate will 
not have any negative effect on you or your medical care. You can decide to participate 
now, but withdraw your consent later and stop being in the study without any loss of 
benefits or medical care to which you are entitled. If you decide to terminate your 
participation in this study, you should notify Dr. Bronte-Stewart by writing to the following 
address: Dr Helen Bronte Stewart, 300 Pasteur Drive, 
, Stanford, CA 94305. 
This research study is looking for up to 30 participants with movement disorder (such as 
Parkinson’s disease, Parkinsonism, Essential Tremor, Dystonia, or other). 

DURATION OF STUDY INVOLVEMENT 
Research in this study will occur at each of your already scheduled clinic visits. 
PROCEDURES DURING RESEARCH TESTING 
You will have been implanted with the Activa PC+S Neurostimulator System. The device 
you have received is an investigational device, which is similar to the FDA approved 
commercial device but has some new components associated with sending information 
from the stimulator to an external computer. The study will begin after the device has 
been implanted. 
Kinematic analysis during your clinical evaluation:  Your doctor will ask for your 
medical history, and you will have a full physical and neurological examination. This will 
also reevaluate whether it is appropriate for you to continue participation in this study 
once enrolled. The clinical examination will include an assessment of your movement 
disorder (such as the Unified Parkinson’s Disease Rating Scale or other clinical rating 
scale). If you are currently taking medications for symptomatic relief of your movement 
disorder, you may be evaluated OFF your medications and again ON your medications. As 
most patients are taking little or no medication once on DBS, this does not usually cause 
difficulty in your mobility.  
You will undergo computerized assessment of your motor function in the Stanford Human 
Motor Control and Balance Laboratory. Depending on your condition, this could include 
repetitive alternating finger tapping (RAFT), repetitive wrist flexion-extension (rWFE) 
with simultaneous monitoring of muscle activity (EMGs), tremorography, and a 
stepping in place (SIP) task. The tests that you undergo will depend on your symptoms, 
for instance if you do not have tremor, we shall not do the tremorography test. The length 
of time for each test (range 10-160 seconds) will depend on the assessment point in the 
study. 
RAFT is a computerized objective measure of fine motor control using an engineered 
quantitative digitography (QDG) keyboard. This test will involve you performing alternating 
finger tapping movements (trill) on adjacent keys on the keyboard for each hand for either 
10, 30, or 80 seconds depending on the test condition. During this test, you will wear a 
pair of headphones playing white noise at an adjustable, tolerable volume.  
RWFE is an objective measure of the speed at which you can move your hand in a repetitive 
backwards and forwards motion. Motus motion analysis sensors that fit like a glove will be placed 
on your hands. 
EMGs (sensors that record the electrical activity of your muscles) may be placed on the 
skin above the wrist flexor and extensor muscles that move the hand. Measurements will 
be taken using the Delsys Surface EMG System while you move your hand from side to 

side while holding the rest of your arm stationary for 10, 30, or 80 seconds for each hand 
depending on the test condition.  
Tremorography may be performed using the same glove-like sensors and surface EMG 
sensors. Using these sensors on your hands/arms and feet/legs, we can record the 
presence of tremor. During the task, your hands and feet should be in a relaxed position 
and your hands and feet are extended out in front of your body. This test will last for 10, 
30, or 70 seconds for both the hands and the feet depending on the test condition.  
Gait Analysis: You will wear sensors on your hands, arms, chest, trunk, feet and legs 
(APDM System). These tasks will quantify measures such as gait asymmetry, gait 
rhythmicity and left-right step coordination during your normal walking. You may be asked 
to do regular forward walking, step in place, turn in place, and/or walk around obstacles 
such as small room dividers. These obstacles will be used in order to elicit freezing, which 
can often occur in constrained spaces. You will be monitored carefully by the research 
team in order to ensure your safety and comfort. All quantitative tests are non-invasive. 
The stepping in place (SIP) task is an objective measure of your ability to walk. While 
wearing a harness and the APDM sensors on your body, you will be asked to step in place 
repetitively on two adjacent force platforms (Bertec Balance Advantage – Dynamic CDP by 
Bertec Corporation, Columbus OH) with one foot on each force platform. You will be asked 
to perform this stepping motion at your normal walking speed for 60, 100, or 160 seconds 
depending on the test condition.  
Vibrotactile Stimulation: You may be asked to perform some or all of the gait tasks 
above while wearing the VibroGait device on your wrists or other extremities. The 
VibroGait was developed by our collaborators at Oregon Health & Sciences University, 
who may also be present during testing with this device. The VibroGait produces an 
intermittent vibrotactile (i.e., vibration) stimulation. The vibration feels similar to a cell 
phone on vibration mode. 
During or before the above tasks, you may also be asked to wear google glasses and 
watch a series of videos of an individual walking to a predetermined cadence. Videos are 
developed by Moving Through Glass, a project created by the Mark Morris Dance 
Company. There are videos that address typical Parkinson's disease symptoms such as 
balance, smooth movement, walking, and freezing of gait. You will be watched carefully to 
be sure you can handle the walking while wearing the glasses. 
Cognitive Testing 
A certified administrator will administer the Montreal Cognitive Assessment (MoCA) to assess 
overall cognitive function. During kinematic tasks, subjects may be asked to perform cognitive 
tasks that include but are not limited to reciting the months of the year backwards and serial 7s. 

Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS questionnaire is used for suicide assessment developed by multiple university 
institutions. The purpose of this risk assessment is to help establish a person’s immediate risk of 
suicide. At your initial research visit, the baseline version of the C-SSRS will be administered; at 
every subsequent visit, the “Since last visit” version will be used. 
Speech Assessment 
While wearing a voice-recording headset, subject will perform speech tasks that include 
reading sentences and phonation. 
At your study visits an investigational research tool (Nexus D and E Systems) will be used. 
The Nexus D/E systems establish a connection between your implanted neurostimulator 
(Activa PC+S) and an external computer or your sensing device (implanted in your chest). 
This will allow for recording of your brain activity in real time and adjustment of 
stimulation within clinically safe limits using a program that responds to real time 
recordings of your movement and brain. 
Nexus E Firmware Update: You will undergo a Nexus E Firmware update at one of your 
study visits. The Nexus E Firmware update allows the researchers to record signals from 
your brain in real time with better resolution when using the Nexus D research tool. The 
Nexus E firmware update will take approximately 30 minutes to perform. During the 
firmware update you will not receive any stimulation therapy. Once the firmware update is 
complete your clinician can turn your clinical stimulation settings back on. 
Video recording 
All the kinematic testing will be video recorded. The video content will be used at a later 
time only by the research staff to review what happened during the experiment. The video 
content will be stored on encrypted hard drives in a locked office room. 
Participant Responsibilities  
As a participant, your responsibilities include: 
•
Follow the instructions of the Protocol Director and study staff.
•
Keep your study appointments. If it is necessary to miss an appointment, please contact
the Protocol Director or research study staff to reschedule as soon as you know you will
miss the appointment.
•
Tell the Protocol Director or research study staff about any side effects, doctor visits, or
hospitalizations that you may have.
•
Ask questions as they come to mind.
•
Tell the Protocol Director or research staff if you change your mind about participating in
the study.

WITHDRAWAL FROM STUDY 
If you first agree to participate and then you change your mind, you are free to withdraw 
your consent and discontinue your participation at any time. Your decision will not affect 
your ability to receive medical care for your disease and you will not lose any benefits to 
which you would otherwise be entitled.  
If you decide to withdraw your consent to participate in this study, you should notify Dr. 
Bronte-Stewart in writing (Dr. Helen Bronte-Stewart 300 Pasteur Drive, 
, 
Stanford, CA 94305.) You can also reach Dr. Bronte-Stewart by calling (650) 723-2116. 
The Protocol Director may also withdraw you from the study without your consent for one 
or more of the following reasons:   
o
Failure to follow the instructions of the Protocol Director and/or study staff.
o
The Protocol Director decides that continuing your participation could be
harmful to you.
o
You need treatment not permitted in the study.
o
The study is cancelled.
o
Other administrative reasons.
o
Unanticipated circumstances.
Battery life of the Activa PC+S (research device) and the Activa PC (non-research device, 
used in standard DBS surgeries) is estimated to last approximately 3-5 years. Once the 
battery of your Activa PC+S runs out, you will need to get a replacement device, and at 
that point, Dr. Bronte-Stewart will reevaluate whether you are a good candidate for future 
experiments. If you are a good candidate for future experiments, you may be given the 
option of receiving a replacement Activa PC+S device and continuing in the study. If you 
are not a good candidate for future experiments, you will be treated with the standard 
implantation of the non-research device.  
POSSIBLE RISKS, DISCOMFORTS, AND INCONVENIENCES 
The tools used for kinematic analysis are non-invasive (do not enter your body). Physical 
sensors will be applied to the surface of your body. Besides potential removal of adhesive tape 
holding the sensors on the skin, the tests are at all not physically painful. The risk of 
participating in the study is that the DBS device (Activa PC+S) implanted in study participants is 
not yet FDA approved. This device is the same as the currently FDA approved PC 
neurostimulator but contains additional sensing components. Potential changes that could occur 
with the new sensing components may include sensing malfunction or premature battery 
drainage. Risks associated with vibrotactile stimulation are discomfort or pain. Preliminary 
testing by the researchers has not indicated any discomfort or worsening of symptoms, but you 
will be able to stop using stimulation if you notice any of these events occurring. Risks 

associated with using Google Glasses during forward walking tasks are minimal but may include 
losing balance while watching videos on display.  
The Nexus-D and Nexus E investigational research tools have not received FDA approval, 
are not commercially available, and can only be used in studies such as this one. For your 
safety the Nexus D and Nexus E System will only be used during study visits. Before 
testing, your clinician will set safety limits for the amount of stimulation you can 
comfortably tolerate. Your clinician and the Nexus-D and Nexus-E systems will only be 
able to make changes to your stimulation within these preset safety constraints. Potential 
issues that could occur while using the Nexus-D/Nexus-E system may include device 
malfunction or premature battery drainage of your DBS device. Closed-loop experiments 
using the Nexus-D/Nexus-E system may require over multiple hours of continuous 
streaming. For the Activa PC+S device, for every 1 hour of sensing, there is approximately 
a 12-hour loss in battery longevity. For example, an 8-hour session of streaming will result 
in a 2-day loss in battery longevity. 
General Risks of Deep Brain Stimulation 
The potential complications associated with deep brain stimulation include tingling, numbness, 
muscle contractions, double vision, eye deviation, cognitive problems, speech difficulties, mania, 
depression, suicidal ideation or others that we might not anticipate, as well as the risk of infection 
or device malfunction which could necessitate removal of the system.  
These potential complications will be monitored throughout the study by evaluation with 
your physician and completion of questionnaires. Suicidal ideation over the course of the 
study will be monitored by the C-SSRS questionnaire. 
If you notice any of the above symptoms between visits please call the Stanford 
Movement Disorders Center at (650) 736-0514. If you are having a suicidal thoughts or a 
psychiatric emergency please call the National Suicide Hotline 1-800-273-8255.  
Medication Withdrawal Risk 
If you are taking medications for Parkinson’s disease you will be asked to stop these up to 
72 hours before testing. There is a chance your symptoms of slowness, stiffness, and 
walking difficulty will temporarily worsen OFF of these medications. You can restart your 
medications as soon as the testing is complete.  
While participating in this study, you should not take part in any other research project 
without approval from all of the investigators. This is to protect you from possible injury 
arising from such things as extra blood drawing and x-rays, interaction of research drugs, 
or similar hazards. 

BENEFITS 
We cannot and do not guarantee or promise that you will receive any benefits from this 
study.  
ALTERNATIVES 
The alternative is to get the standard DBS device implanted and not participate in the 
study. 
PARTICIPANT’S RIGHTS 
You should not feel obligated to agree to participate. Your questions should be answered 
clearly and to your satisfaction.  
If you decide not to participate, tell the Protocol Director. You will still receive care for 
your disease and will not lose any benefits to which you would otherwise be entitled.  
You will be told of any important new information that is learned during the course of this 
research study, which may affect your condition or your willingness to continue 
participation in this study. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov , as 
required by U.S. law. This website will not include any information that can identify you. 
At most, the website will include a summary of the results. You can search this website at 
any time. 
CONFIDENTIALITYThe results of this research study may be presented at scientific or 
medical meetings or published in scientific journals. Your identity and/or your personal 
health information will not be disclosed except as authorized by you or as required by law. 
However, there is always some risk that even de-identified information might be re-
identified. 
Some deidentified data related to vibrotactile stimulation may be shared with collaborators 
at the Oregon Health and Sciences University. 
Patient information may be provided to Federal and other regulatory agencies as required. 
The Food and Drug Administration (FDA), for example, may inspect research records and 
learn your identity if this study falls within its jurisdiction. 
CERTIFICATE OF CONFIDENTIALITY 
This research is covered by a Certificate of Confidentiality from the National Institutes of 
Health. The researchers with this Certificate may not disclose or use information, 
documents, or biospecimens that may identify you in any federal, state, or local civil, 
criminal, administrative, legislative, or other action, suit, or proceeding, or be used as 
evidence, for example, if there is a court subpoena, unless you have consented for this 

use. Information, documents, or biospecimens protected by this Certificate cannot be 
disclosed to anyone else who is not connected with the research except, if there is a 
federal, state, or local law that requires disclosure (such as to report child abuse or 
communicable diseases but not for federal, state, or local civil, criminal, administrative, 
legislative, or other proceedings, see below); if you have consented to the disclosure, 
including for your medical treatment; or if it is used for other scientific research, as 
allowed by federal regulations protecting research subjects. 
The Certificate cannot be used to refuse a request for information from personnel of the 
United States federal or state government agency sponsoring the project that is needed 
for auditing or program evaluation by NIH which is funding this project or for information 
that must be disclosed in order to meet the requirements of the federal Food and Drug 
Administration (FDA). You should understand that a Certificate of Confidentiality does not 
prevent you from voluntarily releasing information about yourself or your involvement in 
this research. If you want your research information released to an insurer, medical care 
provider, or any other person not connected with the research, you must provide consent 
to allow the researchers to release it 
The Certificate of Confidentiality will not be used to prevent disclosure as required by 
federal, state, or local law of child abuse, neglect, or harm to self or others. It will also not 
be used to prevent disclosure for any purpose you have consented to in this informed 
consent document such as the inclusion of research related data to your medical record. 

USE AND DISCLOSURE OF YOUR MEDICAL INFORMATION 
Authorization To Use 
Your Health Information For Research Purposes  
Because information about you and your health is personal and private, it 
generally cannot be used in this research study without your written 
authorization. If you sign this form, it will provide that authorization. The 
form is intended to inform you about how your health information will be 
used or disclosed in the study. Your information will only be used in 
accordance with this authorization form and the informed consent form and 
as required or allowed by law. Please read it carefully before signing it.  
What is the purpose of this research study and how will my health 
information be utilized in the study? 
The purpose of this research is to provide objective measurements of 
abnormal movements of the body and abnormal neural activity in the brain 
and to track changes in both over time. This may allow for the development 
of objective measures of abnormal movements and abnormal nerve cell 
activity and may lead to new types of deep brain stimulators which can sense 
abnormal nerve cell activity that is related to abnormal movement. 
Any data that may be published in scientific journals will not reveal your 
identity. Patient information may be provided to federal and regulatory 
agencies as required. The Food and Drug Administration, for example, may 
inspect research records and learn your identity if this study falls within its 
jurisdiction. In addition, the records of this study may be inspected by your 
doctor and hospital. 
Do I have to sign this authorization form? 
You do not have to sign this authorization form. But if you do not, you will 
not be able to participate in this research study. Signing the form is not a 
condition for receiving any medical care outside the study. 
If I sign, can I revoke it or withdraw from the research later? 
If you decide to participate, you are free to withdraw your authorization 
regarding the use and disclosure of your health information (and to 

discontinue any other participation in the study) at any time. After any 
revocation, your health information will no longer be used or disclosed in the 
study, except to the extent that the law allows us to continue using your 
information (e.g., necessary to maintain integrity of research). If you wish to 
revoke your authorization for the research use or disclosure of your health 
information in this study, you must write to Dr. Bronte-Stewart at the 
following address: 300 Pasteur Drive, Room H3160, Stanford, CA 94305.  
What Personal Information Will Be Used or Disclosed? 
Your health information related to this study, may be used or disclosed in 
connection with this research study, including, but not limited to, name, date 
of birth, phone number, address, email, medical records, physical and 
neurological examinations, neuropsychological test results, MRI scans, x-rays, 
data acquired during the DBS surgical procedure, neural data acquired by the 
implanted stimulator, kinematic analysis data, DBS programming data, 
videotaped evaluations, clinical rating scales (such as the UPDRS), and 
current or past medications may be used or disclosed in connection with this 
research study. 
Who May Use or Disclose the Information? 
The following parties are authorized to use and/or disclose your health 
information in connection with this research study: 
Protocol Director: Dr. Helen Bronte-Stewart
The Study Nurse, Coordinator, and other lab personnel
The Stanford University Administrative Panel on Human Subjects in
Medical Research and any other unit of Stanford University as
necessary.
Who May Receive / Use the Information? 
The parties listed in the preceding paragraph may disclose your health 
information to the following persons and organizations for their use in 
connection with this research study: 
The Office for Human Research Protections in the U.S. Department of
Health and Human Services
The Stanford Movement Disorders Center

All de-identified data (your identity will not be disclosed) will be
shared with Medtronic, Inc.
All de-identified data (your identity will not be disclosed) will be
shared with the Michael J. Fox Foundation for Parkinson's Research and
the NIH (the study funders) This data may be kept for storage at a
central repository either hosted by the Michael J Fox Foundation, its
collaborators, or consultants and will be kept indefinitely. In order to
advance scientific discoveries, your de-identified data will be made
publically available (with no personal identifying information) for the
intended use of research in Parkinson's disease as well as other
biomedical research studies that may not be related to Parkinson's
disease.
FDA (Food and Drug Administration) and other regulatory agencies as
required by Law.
Your information may be re-disclosed if the recipients described above are 
not required by law to protect the privacy of the information. 
When will my authorization expire? 
Your authorization for the use and/or disclosure of your health information 
will expire on January 1, 2055 or when the research project ends, whichever 
is earlier. 
________________________________ 
 ______________ 
Signature of Adult Participant      
 Date 
________________________________ 
Print Name of Adult Participant      

FINANCIAL CONSIDERATIONS 
PAYMENT 
You will not be paid to participate in this research study. 
COSTS 
If you participate in this study, there may be additional costs to you. These include the personal 
time it will take to come to all of the study visits.  
The study will pay for those services, supplies, procedures, and care associated with this study 
that are not a part of your routine medical care. The Michael J. Fox foundation and the National 
Institute of Health (NIH) is providing funding but no materials to Stanford Medical Center for this 
study. Medtronic is providing materials but no financial support to Stanford Medical Center for this 
study.  
You and/or your health insurance must pay for services, supplies, procedures, and care that are 
required during this study for routine medical care. You will also be responsible for any co-
payments and/or deductibles as required by your insurance. Participation in this study is 
not a substitute for health insurance.  
STUDY FUNDING 
This Study is funded by the National Institute of Health (NIH) and the Parkinson’s Disease 
Foundation. 
Consultative or Financial Relationships  
Dr. Bronte-Stewart is a paid advisor to Medtronic, the company sponsoring this study. 
CONTACT INFORMATION 
•
Appointment Contact: If you need to change your appointment, please contact our
research assistant at 
.
•
Questions, Concerns, or Complaints: If you have any questions, concerns or
complaints about this research study, its procedures, risks and benefits, or
alternative courses of treatment, you should ask the Protocol Director. You may
contact her now or later at Dr. Bronte-Stewart: 
. You should also
contact her at any time if you feel you have been hurt by being a part of this study.
•
Alternate Contact: If you cannot reach the Protocol Director, please contact 
, the study coordinator, at 
.
Independent Contact: If you are not satisfied with how this study is being conducted,
or if you have any concerns, complaints, or general questions about the research or
your rights as a participant, please contact the Stanford Institutional Review Board
(IRB) to speak to someone independent of the research team at (650) 723-5244 or

toll free at 1-866-680-2906. You can also write to the Stanford IRB, Stanford 
University, 1705 El Camino Real, Palo Alto, CA 94306. 
COMPENSATION 
All forms of medical diagnosis and treatment -- whether routine or experimental -- involve 
some risk of injury. In spite of all precautions, you might develop medical complications 
from participating in this study. If such complications arise, the Protocol Director and the 
research study staff will assist you in obtaining appropriate medical treatment. In the 
event that you have an injury or illness that is directly caused by your participation in this 
study, reimbursement for all related costs of care first will be sought from your insurer, 
managed care plan, or other benefits program. You will be responsible for any 
associated co-payments or deductibles as required by your insurance.  
If costs of care related to such an injury are not covered by your insurer, managed care 
plan or other benefits program, you may be responsible for these costs. If you are unable 
to pay for such costs, the Protocol Director will assist you in applying for supplemental 
benefits and explain how to apply for patient financial assistance from the hospital.   
You do not waive any liability rights for personal injury by signing this form.  
EXPERIMENTAL SUBJECT’S BILL OF RIGHTS 
As a human subject you have the following rights. These rights include but are not limited 
to the subject's right to: 
•
be informed of the nature and purpose of the experiment;
•
be given an explanation of the procedures to be followed in the medical
experiment, and any drug or device to be utilized;
•
be given a description of any attendant discomforts and risks reasonably to be
expected;
•
be given an explanation of any benefits to the subject reasonably to be expected, if
applicable;
•
be given a disclosure of any appropriate alternatives, drugs or devices that might
be advantageous to the subject, their relative risks and benefits;
•
be informed of the avenues of medical treatment, if any available to the subject
after the experiment if complications should arise;
•
be given an opportunity to ask questions concerning the experiment or the
procedures involved;
•
be instructed that consent to participate in the medical experiment may be
withdrawn at any time and the subject may discontinue participation without
prejudice;
•
be given a copy of the signed and dated consent form;
•
and be given the opportunity to decide to consent or not to consent to a medical
experiment without the intervention of any element of force, fraud, deceit, duress,
coercion or undue influence on the subject's decision.

VIDEO RECORDING  CONSENT 
I give consent to be videotaped during this study: 
Please initial:  
___Yes 
___No 
I give consent for tapes resulting from this study to be used by researcher to review the 
experiment session when data will be analyzed: 
Please initial:  
___Yes 
___No 
Signing your name means you agree to be in this study and that you were given a copy of 
this signed and dated consent form.  
______________________________ 
________________ 
Signature of Adult Participant  
 Date 
______________________________ 
Name of Adult Participant 
_____________________________________ 
________________ 
Signature of Person Obtaining Consent  
Date 
_____________________________________ 
Name of Person Obtaining Consent