Scalar Closed-Loop STN/GPi DBS Based on Evoked and Spontaneous Potentials (Intraoperative Studies)
Phase: NA
Conditions: Parkinson Disease
Sponsor: Dennis Turner, M.D.

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Scalar Closed-Loop STN / GPi DBS Based on Evoked and Spontaneous 
Potentials (Intraoperative Studies) 
 
 
NCT03270657 
 
Document Date: March 8, 2019 
 
 
 

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Purpose of the Study 
The purpose of this study is to measure neural activity during deep brain stimulation (DBS). There are 
two types of neural activity that we will record from DBS electrodes during this study: DBS local evoked 
potentials (DLEPs) and spontaneous, local field potentials (LFPs). We will measure the effects of varying 
stimulation parameters on both the neural activity and changes in motor symptoms -- bradykinesia and 
tremor -- in subjects with Parkinson's disease (PD). Correlating neural activity characteristics with 
changes in symptoms will improve our understanding of the mechanisms of action of DBS.  This 
intraoperative study will specifically compare our ability to record neural activity using circuitry 
developed at Duke for this purpose [Kent et al, 2015] to a new, implanted pulse generator (IPG; RC+S) 
developed by Medtronic.  These intraoperative studies will specifically test a preliminary version of the 
RC+S (that is not designed for implantation), and will lead to a clinical trial assessing the efficacy of the 
implantable RC+S IPG in PD patients once this device is available and approved for this trial. 
 
Background and Significance 
Deep brain stimulation (DBS) is a surgical intervention that is effective in treating movement disorders, 
particularly Parkinson's disease (PD). A battery-powered IPG, placed in the patient's chest, delivers 
electrical stimulation to a connected brain electrode typically implanted in the subthalamic nucleus 
(STN) or globus pallidus internus (GPi). Despite the clinical effectiveness of DBS, the underlying 
physiological mechanisms of action remain unclear and there is no capability for device self-adjustment 
or responsiveness to patient symptoms, limiting the full optimization of this treatment.  
 
Stimulation parameters (amplitude, frequency, and pulse width) are programmed after surgery and at 
follow-up intervals, and the efficacy of DBS depends on finding parameters that reduce symptoms 
without causing side effects. However, there are over 42,000 available combinations of amplitude, 
frequency, and pulse width in the IPG, and few data describing the relationships between stimulation 
parameters and clinical outcomes. As a result, the selection of stimulation parameters is an ad hoc 
process, with associated difficulties of time, expense, and patient discomfort. Further, the patient is 
often deprived of the optimal benefits of stimulation until this time consuming process leads to efficacy. 
 
Application of each DBS pulse results in activation of a population of neurons around the electrode. This 
evoked neuronal activity creates a signal -- the DBS local evoked field potential (DLEP) -- that can be 
recorded with two of the four contacts on either the clinical DBS electrode or a second electrode. Thus, 
this intraoperative recording approach does not require implantation of any electrical hardware. The 
magnitude and character of the DLEP response will reveal the type and spatial extent of neuronal 
element activation during stimulation, including between brain regions, such as between subthalamic 
nucleus (STN) and globus pallidus externa (GPe). Our previous work exploring the mechanisms of action 
of DBS revealed a very strong correlation between the number and type of activated neurons and 
clinical efficacy during variation in stimulation intensity [Kuncel et al, 2007; Kent et al, 2015]. Therefore, 
we expect a strong correlation between the recorded DLEP and the changes in symptoms during DBS. 
Spontaneous, local field potentials (LFPs) are also recorded using the same methods described above. 
LFPs are signals measured with electrode contacts that are continuously generated by ongoing neural 
activity, whereas DLEPs are short-duration signals evoked immediately following stimulation pulses. 
Together, DLEPs and LFPs are a potential biomarker for disease state and severity in PD, which we will 

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test initially intraoperatively and long-term using the RC+S IPG for scalar closed-loop control of the DBS 
parameters. 
 
The shape and magnitude of DLEPs and LFP activity may also be sensitive to DBS electrode location, and 
this dependence suggests that they may assist with targeting brain structures during DBS implant 
surgery as well as post-operative selection of stimulation contacts and dynamic adjustment of 
stimulation parameters [Kent et al., 2015; Chen et al., 2006].  We therefore expect that DLEP and/or LFP 
characteristics will vary with the placement of DBS electrode relative to the brain regions targeted for 
stimulation. 
 
Study Design and Procedures 
We will measure DBS local evoked potentials (DLEPs) and/or local field potentials (LFPs) together with 
motor symptoms (tremor and/or bradykinesia) in response to deep brain stimulation (DBS). The study 
will be conducted in the operating room at Duke University Medical Center.  Additional operating room 
costs will be covered by institutional resources at Duke. The study will be performed on subjects who 
are undergoing implantation of the DBS system during an awake, stereotactic procedure for PD. 
 
The subject group will only include patients undergoing a DBS implant procedure for PD. The surgical 
procedure will proceed as needed for treatment of Parkinson's disease (PD), including implantation of 
the DBS electrode (one into STN or dual electrodes into STN and GPi/GPe) into the targeted regions of 
the brain. For this research, subjects will receive temporary (~45 min) percutaneous extensions to the 
DBS electrode(s) and DBS lead cannula after implantation. These temporary extensions will connect to 
both our Duke stimulation and recording system or the Medtronic RC+S test recording system, 
alternating as needed, to allow recording and direct comparison of neural DLEP responses and/or LFPs 
using the two different stimulation/recording systems.  Details of the stimulation and recording system 
are provided in the Study Interventions section. After the study is completed, the second DBS electrode 
(if placed) and the temporary percutaneous extensions will be removed. Then, the ordinary clinical 
conduct of the procedure will continue for treatment of the patient’s movement disorder. 
             
We will measure tremor and/or bradykinesia in persons with PD during DBS. Subjects will be familiarized 
with and able to practice the evaluation tasks before preparation for surgery. Further, they will be asked 
to discontinue use of dopaminergic and/or anti-tremor medications overnight prior to the study (as is 
the clinical routine for this procedure), to reduce variability of motor symptoms due to the time course 
of medications. We will conduct evaluations using unilateral stimulation, with the limb contralateral to 
the side of stimulation used for measurement of motor symptoms. Subjects may also be asked to rate 
any side effects that they experience on a 0 - 10 scale. 
             
Contacts on the subject's DBS electrode will be used for stimulation and recording, with a second 
electrode in either STN or GPi/GPe used for recording. The four DBS contacts are designated as 0-1-2-3 
in the ventral-dorsal direction. For monopolar stimulation, a single contact will be used for cathodic 
stimulation (1- or 2-) and a conductive pad will be placed on the subject's skin, outside of the sterile 
field, to serve as the return electrode. The recording contacts will be two other contacts on the DBS 
lead. For bipolar stimulation, DBS pulses will be applied between two electrode contacts, and the 
recording contacts will be the two remaining free contacts. The stimulus waveform will be a charge-
balanced biphasic pulse, with charge restricted to values below the limit set by the manufacturer, 30 
µC/cm2. Another conductive pad will be placed on the subject to serve as the recording reference.  The 

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DBS lead cannula or a surgical retractor normally placed at the cranial incision site may also be used as 
the recording reference or return electrode.            
 
In subjects with tremor-dominant PD, we will record both the tremor and DLEP and/or LFP responses 
from the DBS electrode(s). Several trials will be conducted with different stimulation amplitudes, 
frequencies (≤185 Hz), temporal patterns, and contact configurations. The stimulation amplitude will be 
less than that identified to be uncomfortable to the subject or that generates side effects, as 
determined by a neurologist and/or neurosurgeon during the initial testing phase following 
implantation. The different stimulation parameters will be delivered in randomized order, and the 
subject will be blinded to the parameters. Measurements will be made during 2-minute trials, in which 
stimulation will be off for the first minute of the trial, and on for the remaining minute. At 30 s into both 
the off (baseline) and on phases of the trial, tremor will be measured for 20 s. The neural activity will 
also be measured from the electrode during both the off and on phases. The total amount of time 
necessary for data collection will be about 45 minutes. 
             
Tremor will be measured using an accelerometer taped to the back of the subject's hand, and with the 
wrist extended such that the hand is parallel to the forearm. The elbow may either be supported or 
unsupported, depending on which induces greater tremor (determined prior to any trials in each 
subject). Tremor as measured by an accelerometer correlates well with clinical tremor rating scales 
[Elble et al, 2006]. 
             
In subjects with Parkinson's disease who do not have dominant tremor symptoms, we will record both 
bradykinesia testing responses and DLEP and/or LFP potentials. Several trials will be conducted with 
different stimulation amplitudes, mean frequencies (≤185 Hz), temporal patterns, and contact 
configurations. The maximum amplitude delivered will be determined as described as above. The 
different stimulation parameters will be delivered in randomized order, and the subject will be blinded 
to the parameters. Measurements will be made in 10-minute trials, in which stimulation will be off for 
the first five minutes of the trial, and on for the remaining five minutes. At approximately 90, 210 and 
250 s into both the off (baseline) and on phases of the trial, bradykinesia will be measured for 20 s. The 
neural activity will also be measured from the electrode during both the off and on phases of the trial. 
The total amount of time necessary for data collection will be about 45 minutes. 
             
For bradykinesia measurements, the subject will be instructed to press alternately the right and left 
buttons of a computer mouse with the index and middle finger of their hand as rapidly and regularly as 
possible. Bradykinesia will be measured as the timing of alternating finger presses, a validated test of 
bradykinesia [Taylor-Tavares et al., 2005]. 
 
Before DBS surgery, the subject's baseline pathological motor symptoms may be assessed in the pre-
operative setting, to familiarize the patient with the task ahead of the implant procedure. Tremor or 
bradykinesia will be measured using the previously-described accelerometer measurement or the 
mouse click task, respectively. This task will take about 5 minutes, and will be performed in the DBS-off 
condition. No sedation will be administered until after this has been completed. 
 
Following DBS surgery, the subject’s pre-operative MRI and post-operative high-resolution CT scans may 
be used to determine the location of DBS electrode contacts within the brain.  Placement of the 
electrode during DBS implant surgery will not be altered by the research study. 

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Study Interventions 
The stimulation and recording system applies deep brain stimulation (DBS) and simultaneously 
measures the DBS local evoked potential (DLEP) and/or local field potential (LFP) responses from either 
the same or a second DBS electrode. Stimulation will be delivered through either an optically isolated 
stimulator (bp isolator, FHC Inc.) and pulses controlled by a high-speed digital-to-analog converter via 
MATLAB (Mathworks, Inc.), or the Medtronic RC+S test device. Both of these stimulation/recording 
devices are nonsterile and outside of the sterile field and will be connected to the DBS electrode using 
sterile connecting wires.  The DBS lead cannula or a surgical retractor normally placed at the cranial 
incision site may be used as a return electrode. The locations used for the return electrode and 
recording reference will be recorded on the case report form. 
             
For recording DLEP and/or LFP signals, the Duke system combines commercial amplifiers -- either SR560 
low-noise voltage preamplifiers (Stanford Research Systems) in a custom serial configuration or a single 
g.USBamp amplifier (g.tec Medical Engineering) -- to limit the amplitude of the DBS stimulation artifact 
in the recording.  Differential recordings are made from two DBS contacts, with each recording contact 
serving as an input to the preamplifier. A circuit employing solid-state relays and anti-parallel diodes is 
utilized at the inputs of the amplifiers to limit the size of the artifact signal at high amplification and 
prevent saturation of the recording amplifiers. The DBS lead cannula may be used as a recording 
reference.  The Medtronic RC+S test system includes the full stimulation and recording circuitry 
embedded in the RC+S IPG/PC+S IPG but in a non-implantable form that can be directly connected to 
the DBS electrode through a sterile extension. 
             
Study subjects may undergo standard of care imaging procedures required for their surgery, including 
pre-operative MRI and/or post-operative high-resolution CT scans.  The research protocol will not 
modify these procedures, but the images collected may be used to determine the location of DBS 
electrode contacts in the brain. 
             
The electrical safety of the study apparatus will be tested and certified annually for electrical safety. 
             
Perioperative staff responsible for preparing subjects for surgery will be given a flyer that explains how 
perioperative patient care will be affected by requirements of the research study.  This form will require 
all monitoring equipment (IV line, blood pressure cuff, pulse oximeter, etc.) to be placed contralateral to 
the limb used for measurement of motor symptoms.  Additionally, instructions for sedation and 
intraoperative sterile drape setup will be listed.  Contact information for the study coordinator, 
attending surgeon, and principal investigator will also be provided. 
 
Selection of Subjects 
It is anticipated that a total (maximum) of 32 individuals will be studied over four years. Subjects will be 
recruited from the Movement Disorders Programs at Duke University after having been referred for DBS 
surgery and have agreed to undergo the clinical procedure.  Patients will only be asked about research 
participation after being scheduled for the procedure. They will participate on a volunteer basis with 
informed consent as approved by Duke University. Apart from Parkinson's disease (PD) these individuals 
will be in good health, as determined by their ability to undergo the DBS procedure. Inclusion criteria 
(separate from the criteria to undergo the DBS implant procedure for Parkinson’s disease) are that the 
patient is able to understand the study and consent form, and is interested in proceeding with research 

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during the invasive brain surgery to receive a DBS system for treatment of PD. Exclusion criteria are an 
inability to execute the motor tasks during the study and pregnancy. The age range will be 18 to 
80.  Since all patients will be undergoing an elective surgical procedure for a chronic movement disorder 
then the possibility of pregnancy is determined during standard pre-operative screening, and if the 
patient is determined to be pregnant (using a pregnancy test obtained along with the other needed 
blood tests per standard of care) then the elective procedure will be canceled and delayed until after the 
pregnancy is concluded and the patient has recovered.  This is standard practice for any elective surgical 
procedure since there is a possibility of unintended harm with anesthesia to the pregnancy. 
 
Subject Recruitment and Compensation 
We expect to enroll a total of 32 subjects maximum in this intraoperative study at Duke University. 
Subjects will be recruited and enrolled from individuals who have Parkinson’s disease (PD) and who are 
scheduled to already undergo the planned deep brain electrode placement for treatment of their 
movement disorder. The surgical operation and research study will occur at Duke University Medical 
Center. Initial contact concerning the research study will be made by the patient’s neurosurgeon (Dr. 
Dennis Turner or Dr. Shivanand (Nandan) Lad), who will be performing the stereotactic surgery (either 
frame-based or frameless), during the patient’s pre-operative appointment. Patients receiving either 
type of electrode implantation will be recruited for the study. Duke patients that cannot be contacted in 
the Duke Clinic prior to surgery will be screened by the study staff using a telephone script. Consent will 
then be performed by Dr. Turner, Dr. Lad, or the study staff. 
             
If the subject agrees to be enrolled, the Study Coordinator will contact the PI or his staff to indicate the 
patient’s enrollment in the research during the planned procedure. If the subject does not sign the 
informed consent or does not qualify for the study, any recorded information will be destroyed.  
  
Subject selection will not discriminate on the basis of gender, race, or ethnicity, but the eligible 
population is limited, since only patients already scheduled for DBS procedures for their Parkinson’s 
disease will be candidates. The incidence of Parkinson's disease (PD) is higher in men (~65%) than 
women (~35%), and so we expect to enroll more male PD subjects than female subjects. The incidence 
of patients who undergo deep brain stimulation (DBS) for PD and are minorities is low (~5%), so we 
expect to enroll fewer subjects that are minorities than subjects who are not minorities. The percentage 
of the population undergoing DBS for PD and are children is very small, and so we do not expect to 
enroll any children. The age range will be 18 to 80.  
             
Subjects will be identified by assignment of an identification code consisting of the year the study was 
conducted and the order of subject enrollment.   
 
Subjects will be compensated $50 for their participation in this study.  There will be no costs to the 
subject as a result of participation in the study. 
 
Consent Process 
The consent process will typically be conducted by the Study Coordinator, but may also be conducted 
by the PI and Collaborators included in the Key Personnel. Dr. Grill will not obtain consent due to a 
conflict of interest. 
 

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The consent process will occur at the Duke Clinic, in a preoperative holding consult room, or in the 
personal offices of the study staff.  The consent process will take approximately 10 minutes, but will 
continue until all participant questions are answered. During the consenting process, a member of the 
study staff will meet with the participant to answer any questions. Participants are then given the 
personal contact information of the study's PI, neurologists, and neurosurgeons, as well as the Duke 
University Institutional Review Board. Each subject will be allowed as much time as desired to make 
their decision. 
 
All potential subjects will be informed that participation in the research study is completely optional and 
that declining to participate will not affect their medical care. Study related risks will be conveyed 
through a review of the consent form led by a member of the study staff. 
 
Since the study procedures require communication between the subject and investigators, subjects that 
do not speak English will be excluded from the study. 
 
Subjects will be competent to give consent as they have already consented to undergo the DBS 
procedure.  Competency will be determined by the research team. 
 
Risk / Benefit Analysis 
Subjects who participate in this clinical study will derive no direct benefits to themselves. However, the 
data gathered in this study will be used to understand the mechanisms of action of deep brain 
stimulation (DBS) and provide a means for the rational selection of stimulation parameters based on 
recorded neural activity. 
 
This proposed clinical research study has certain risks, though these are similar to the risks associated 
with DBS electrode implantation surgery or replacement of the implantable pulse generator (IPG) and 
clinical selection of stimulation parameters (routinely performed after DBS implantation).  In some 
patients (and in the eventual clinical trial with the implantable RC+S IPG) we will place dual STN and 
GPi/GPe DBS electrodes.  This is similar to the clinical practice of replacing the DBS electrode clinically 
(up to 5 times in different brain regions) as needed for optimization of the electrode stimulation results 
and the risks are within the ordinary risks of the DBS surgical procedure. 
             
There are risks associated with having subjects refrain from taking their dopaminergic and/or anti-
tremor medication overnight prior to the study, but this is the clinical standard of practice implemented 
for new DBS implants in PD patients. This will create risks associated with the symptoms a subject 
experiences in the unmedicated state, and will be reviewed with the subject at the time of consent. 
             
There is a risk of infection at the incision site where the extension wire is externalized for connection to 
our stimulating and recording system. To minimize the risk of infection, the surgery to place the 
percutaneous extension is done under sterile conditions and the incision site will remain in a sterile field 
through the clinical study. 
             
There is a slight risk of inadvertent electrical shock due to connection to the external stimulating and 
recording equipment required to conduct the study. All electrical equipment will undergo routine and 
periodic biomedical safety checks. Further, all electromechanical equipment used during the clinical 
study will be tested and certified annually for electrical safety. Surgical retractors and cannulae used to 

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deliver electrical stimulation will be protected against corrosion, and will therefore not increase 
electrical safety risks. 
            
There is a risk of subject discomfort as stimulation may cause transient side effects, reduce the benefit 
of DBS, or even transiently worsen symptoms. Subjects may experience slight discomfort due to side 
effects experienced with certain stimulation parameters. Side effects include muscle contractions, 
dysarthria, ocular deviations, tremor, and paresthesias. However, side effects are reversible and will 
cease once the stimulation is turned off. In addition, some stimulation parameters may cause symptoms 
to worsen, but these symptoms will return to pre-stimulation levels soon after stimulation is turned off. 
Subjects will be asked to report any sensations they feel as a result of stimulation, and will be observed 
for any effects of the stimulation on tremor or bradykinesia. 
             
There is a slight risk of tissue damage resulting from the electrode-tissue interaction during stimulation. 
To minimize this risk, we will apply charge-balanced biphasic pulses. This stimulation waveform is similar 
to that used in the clinically implanted stimulator (Medtronic), and charge densities will be below the 
manufacturer's established limit of 30 μC/cm2. Thus, the risk of tissue damage will be similar to the risks 
associated with everyday use of the implanted DBS system. 
             
No general anesthesia will be given to subjects during surgery, and the procedure will be performed 
under local anesthesia to allow subjects to perform the tasks required in this study. Subjects will receive 
monitored anesthesia care (MAC), in which sedation will be administered as needed, such that subjects 
are still responsive and pathological motor symptoms (tremor or bradykinesia) are present. 
             
There are risks associated with undergoing brain imaging procedures (MRI and/or CT) required for 
conduct of DBS surgeries and post-operative follow-up.  The research study does not modify these 
procedures or their associated risks. 
             
If an individual chooses not to participate in the study, he or she will still have surgery to implant the 
DBS electrode. 
 
Data Analysis and Statistical Considerations 
The data set will consist of recordings of neural and/or LFP recordings, and either mouse click timing 
data for measurement of bradykinesia in Parkinson's disease subjects or tremor accelerometry data for 
patients with Parkinson’s disease. The DLEP recordings will be serially averaged with stimulus-triggering 
to remove random noise while preserving the evoked response. The signal-to-noise ratios of DLEP 
recordings will be compared across data sets to determine which combination of stimulation and 
recording sites maximize recording quality. We will quantify performance on the mouse click timing task 
by the delay between key presses and the time each key is held. Tremor will be quantified by calculating 
the total power within a window of the power spectrum of the time series of the tremor. We will 
perform ANOVA and post-hoc statistical analysis, in which the amplitude, frequency, and contact 
configuration used for stimulation will be the independent variables, and with dependent variables 
describing bradykinesia, tremor, and DLEP characteristics. We will also calculate correlation coefficients 
between tremor or bradykinesia and DLEP characteristics. Data and statistical analyses will be 
conducted by the study team, including the study statistician, Donna Niedzwiecki (Associate Professor of 
Biostatistics and Bioinformatics). 
             

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Additionally, clinical study staff may use pre- and post-operative brain imaging to determine the location 
of implanted DBS electrode contacts.  The only data generated from this analysis will be a determination 
of the location of the contacts used to record neural activity (DLEPs and/or LFPs) relative to the brain 
region targeted for stimulation.  Other study staff will analyze DLEP and/or LFP recordings obtained 
during surgery to generate a prediction of recording contact location prior to imaging analysis for each 
subject, and clinical study staff will be blinded to these predictions during imaging analysis.   
             
Subjects will be included in data analysis if DBS is clinically effective at reducing motor symptoms for 
particular stimulation parameters, and DLEP and/or LFP data are observed during at least one trial. 
             
Dr. Dennis Turner and Dr. Shivanand (Nandan) Lad conduct a total of 4-6 new DBS implants for PD per 
month. We have recruited approximately 1 subject per month at Duke over the past 18 months to 
participate in other intraoperative studies. Thus, we expect to recruit a maximum of 32 subjects during 
the course of this study at Duke University. 
 
Data and Safety Monitoring 
Safety concerns in this study include risks of worsening motor symptoms experienced by subjects in the 
non-medicated state, hemorrhage or infection at the incision site where the extension wire is 
externalized, inadvertent electrical shock by the stimulation and recording system, DBS-induced side 
effects or worsening of symptoms, and tissue damage at the electrode-tissue interface.  Research 
subjects will be monitored by their physician during the study and in post-operative follow-up 
appointments. Further, subjects' medical records will be reviewed by study staff to monitor for study-
related complications. The PI will review adverse events as needed to determine if there are any 
unexpected risks or if events are occurring at a higher than expected frequency. Any complication will 
be reported to the Duke University Medical Center Institutional Review Boards as a safety adverse 
event.