Safety and Feasibility of Using Low Frequency Deep Brain Stimulation of the Subthalamic Nucleus to Improve Cognitive Performance in Patients With Parkinson's Disease
Phase: NA
Conditions: Parkinson Disease, Cognitive Impairment
Sponsor: University of California, Davis

PROTOCOL TITLE: Safety and feasibility of using low frequency deep brain 
stimulation of the subthalamic nucleus to improve cognitive performance in 
patients with Parkinson's disease 
Page 1 of 26 
Revised: October 7, 2014 
 
 
 
 
 
1) 
Protocol Title 
 
a)  Safety and feasibility of using low frequency deep brain stimulation of the 
subthalamic nucleus to improve cognitive performance in patients with Parkinson’s 
disease 
 
b)  Version: December, 14, 2015 
 
2) 
Author of Protocol 
 
 
X 
UC Davis Researcher: 
Kiarash Shahlaie MD, PhD (principal investigator) 
Katherine Scangos MD, PhD 
 
 
Researcher from other institution 
Private Sponsor 
Cooperative Group 
Other:   
 
 
 
 
3) 
IRB Review History 
 
NA 
 
4) 
Objectives 
 
 
Our objective is to examine the safety and feasibility of using low frequency deep 
brain stimulation (DBS) to improve cognition in patients with Parkinson’s Disease (PD). 
Although DBS of the subthalamic nucleus (STN) is a FDA-approved operation that is 
routinely performed in our patients with advanced PD, there is no clear standard for the 
stimulation frequency one should use to maximize benefits.  There are few previously 
published studies that use low frequency stimulation (LFS) in PD, and furthermore, there 
are few studies that have examined the effect of DBS on cognition.  Therefore, we propose 
a feasibility study that will provide safety and initial-efficacy data of low frequency DBS on 
cognition. 
To do so, we plan to vary stimulation frequency in patients who are receiving DBS as 
part of their standard care.  With regards to safety, we do not expect adverse outcomes of 
LFS.  A previous group has utilized LFS for cognition in patients with PD and 
reported no adverse events (Wojtecki et al 2006).  However, we will monitor potential 
safety issues through psychological, cognitive, and motor testing in cohorts of four patients.  
In that way, any unexpected safety issues or negative effects on performance will be 
detected prior to testing additional patients. 
We propose to test the executive task performance of 20 patients with PD at baseline 
and following bilateral STN deep brain stimulator placement under no frequency, high 
frequency, and low frequency conditions.  We further propose to 

PROTOCOL TITLE: Safety and feasibility of using low frequency deep brain 
stimulation of the subthalamic nucleus to improve cognitive performance in 
patients with Parkinson's disease 
Page 2 of 26 
Revised: October 7, 2014 
 
 
 
examine cognitive function under a variable duration of LFS.  We hypothesize that there 
will be a trend towards improvement in task performance under the LFS setting, measured 
through reaction time and error rates, and that this improvement will be stable or enhanced 
with sustained LFS.  We hope to utilize these results to inform the design of a larger phase 2 
efficacy study.  Our specific aims are as follows: 
 
1)  To monitor the safety of LFS in the STN of patients with PD by examining the 
psychological, cognitive, and motor consequences of LFS 
. 
2)  To determine the feasibility of utilizing low frequency DBS to improve cognition in 
patients with PD by examining if there is a trend toward improved executive function with 
LFS over high frequency stimulation (HFS) and no stimulation settings. 
 
3)  To further examine feasibility by determining if the differential effects of LFS 
versus HFS of the STN are long lasting in a small patient group. 
 
At present, DBS stimulators are set at varying stimulation frequencies based on the 
acute effects of DBS on motor performance, with limited understanding of cognitive 
consequences.  Understanding the effects of different stimulation frequencies on non- motor 
tasks will help elucidate the mechanism behind cognitive impairment in PD.  If our 
hypotheses are correct it could lead to the development of new treatment plans that involve 
alternating between low and high frequency stimulator settings to optimize both motor and 
cognitive domains.  Ultimately, focused treatment for cognition may slow the progression 
from mild cognitive impairment to dementia, improving real world functioning and quality 
of life. 
 
 
 
5) 
Background 
 
PD affects over 4 million adults over the age of 50 with some estimates predicting 
this rate will double over the next 2 decades (Dorsey et al 2007).  It is a disease 
characterized by the death of dopamine neurons in part of the basal ganglia (BGn) called the 
substantia nigra (SN).  Because the BGn projects heavily to the motor cortical regions of the 
brain, the hallmark symptoms of the disease are predominantly motor.  More recently, the 
resting BGn has been shown to have tight connections with many other 
areas of the brain, leading to the recognition of non-motor symptoms (NMS) as a major part 
of PD (Zgaljardic et al 2003).  Cognitive impairment is one NMS that leads to increased 
disability, reduced quality of life, and may be the predominant source of disability at long 
term follow-up (Goldman & Litvan 2011).  Some studies report that 
80% of patients have Parkinson’s disease with dementia (PDD) at later stages of the disease 
(Hely et al 2008).  The cognitive impairments most often observed in PD are deficits in 
executive functioning, which rely on circuitry that connects the BGn with prefrontal areas 
of the brain.  Patients have difficulty with mental planning, attention, and both establishing 
and adjusting task rules.  They also show difficulties in visuospatial abilities and at later 
stages of the disease, exhibit explicit memory impairments (Owen 
2004). 

PROTOCOL TITLE: Safety and feasibility of using low frequency deep brain 
stimulation of the subthalamic nucleus to improve cognitive performance in 
patients with Parkinson's disease 
Page 3 of 26 
Revised: October 7, 2014 
 
 
 
Treatment for cognitive impairment remains limited.  Only rivastigmine has 
received approval from the FDA for PDD but is only modestly effective (Emre et al 
2004).  The conventional Dopa Replacement Therapy (DRT) improves motor symptoms but 
shows mixed effects on cognitive symptoms, improving some, and worsening others, 
largely due to nonspecific increases in dopamine (Poletti & Bonuccelli 2013).  Deep Brain 
Stimulation (DBS) allows for targeted treatment to specific areas of the BGn. Currently, 
high frequency stimulation (HFS) is performed in the STN or globus pallidus interna (GPi) 
and has proved very effective in reducing motor symptoms when DRT has lost efficacy 
(Volkmann 2004), but like its oral counterpart, does not show substantial improvements in 
cognitive functioning (Halpern et al 2009).  Some studies even show worsening function in 
verbal fluency and some executive function domains (Heo et al 
2008).  Unlike oral therapy, our understanding of how DBS works to improve BGn 
functioning remains in its infancy.  There are great potentials for adjusting contact locations, 
stimulation frequency, and other stimulator settings in increasingly complex ways to 
optimize both motor and non-motor symptoms of PD.  For example, the dorsal STN is 
thought to be more motor related and some propose that spread of current to non- motor 
regions of the STN may be responsible for cognitive impairments associated with STN 
DBS.  In fact, controlling spread by computational modeling techniques to minimize ventral 
stimulation prevented some of the cognitive deficits observed with STN stimulation 
(Frankemolle et al 2010). 
Clinical trials using DBS to improve cognition are underway with exciting 
preliminary reports.  HFS of part of the hypothalamus improved cognition in 6 patients with 
mild Alzheimer’s disease, increased activity in downstream circuitry involved in memory, 
and slowed cognitive decline (Laxton et al 2013, Laxton et al 2010). 
While HFS has traditionally been used, there is new evidence suggesting low 
frequency stimulation (LFS) may be particularly important for cognitive functioning 
(Lisman 2005, McNaughton et al 2006).  Research now suggests that neurons code 
information not only in their firing rate, but also in their firing frequency.  The synchrony of 
neuronal firing within a brain area and the coherence of oscillations across brain areas 
within a network may be crucial for influencing and generating behavior across space and 
time (Engel et al 2001, Mann & Paulsen 2005, Niebur et al 2002).  Low frequency 
oscillation in the theta range has been shown throughout many brain areas, including the 
hippocampus, temporal cortex, entorhinal, olfactory, somatosensory cortex, cingulate 
cortex, thalamus, across species (Lisman 2005).  Animal studies have shown the importance 
of this rhythm for spatial navigation, learning and memory (Colgin 2013, Nyhus & Curran 
2010).  The theta rhythm is thought to be involved in learning by enhancing encoding of 
relevant incoming stimuli and thereby facilitating long term potentiation.  Thus, too much or 
too little synchronization through disease processes that affect neurons and their networks 
would be expected to disrupt function.  This has been demonstrated directly in traumatic 
brain injury (TBI) studies in rats by Dr. Shahlaie and 
co-workers.  TBI rats exhibit impaired learning in water maze tasks.  DBS in the theta range 
improves their performance, presumably returning the oscillatory frequency required for 
working memory and spatial learning (Lee et al 2013). 
There are many exciting potentials for expanding this animal research into human 
populations to directly improve health and disease.  One group of researchers 

PROTOCOL TITLE: Safety and feasibility of using low frequency deep brain 
stimulation of the subthalamic nucleus to improve cognitive performance in 
patients with Parkinson's disease 
Page 4 of 26 
Revised: October 7, 2014 
 
 
 
investigated the effects of LFS on cognitive impairments of PDD in humans (Freund et al 
2009).   They performed bilateral nucleus basalis of Maynert (NBM) DBS and bilateral 
STN DBS on one patient with PD. Using HFS in the STN and LFS in the NBM they 
showed improvement across a wide battery of neuropsychological tests measuring 
executive functioning, visuospatial skills, attention, concentration, language and memory. 
As described above, the cognitive deficits in PD are thought to be due to network 
disruption in fronto-striatal circuits.  Thus, targeting the executive dysfunction in PD may 
require stimulation of the BGn itself.   Wojtechi and collegues demonstrated that low 
frequency STN stimulation improved verbal fluency when compared to HFS in 12 PD 
patients (Wojtecki et al 2006). 
DBS of the STN is a FDA-approved operation that is routinely performed in our 
patients with advanced PD, and is considered to have a favorable safety and efficacy 
profile.  However, stimulation of this brain region at standard stimulation frequencies has 
been linked to affective side effects in some patients receiving HFS (Smeding et al 2006, 
Strutt et al 2012). These effects are hypothesized to be due to ventral stimulation contacts as 
the ventral STN has connections with limbic regions of the brain, in combination with the 
reduction of DRT that can normally be achieved following DBS placement (Strutt et al 
2012).  The ventral region is also thought to be most likely to affect cognition.  The safety 
of LFS in the STN is unknown but presumed to be minimal.  Wojtechi et al reported that 
LFS in the ventral STN region did not cause any adverse events (Wojtechi 
et al 2006).  Furthermore, lower frequencies are anticipated to have a reduced effect on the 
neural circuitry than high frequencies, and thus be safer than the standard high frequency 
stimulation. 
Our goal is to build on this early work to further examine the safety and efficacy of 
theta frequency stimulation on cognition in PD.  We propose that low frequency theta range 
stimulation in the STN is safe and may improve executive function in patients with PD.  
The trial we propose is not a surgical implant study as the patients are scheduled to undergo 
implantation of the deep brain stimulator as part of their routine clinical care, 
and will receive this surgery irrespective of our study.  The implant is FDA approved for 
implantation into the STN of the brain in PD and patients are typically treated at a range of 
frequencies.  The focus of our study is to determine whether theta frequency stimulation is 
safe and shows a trend toward improving cognitive performance, which could inform a 
larger efficacy study.  Understanding the effects of different stimulation frequencies will 
help elucidate the mechanism behind cognitive impairment in PD and help develop 
advanced treatment programs. 
 
 
6) 
Inclusion and Exclusion Criteria 
 
Inclusion Criteria: 
 
(1) Adult men and woman with a diagnosis of PD. 
(2) Patients who are candidates for bilateral STN DBS placement surgery and who will 
receive this treatment as part of their routine care. 
(3) Willingness to undergo temporary changes in STN DBS generator settings. 

PROTOCOL TITLE: Safety and feasibility of using low frequency deep brain 
stimulation of the subthalamic nucleus to improve cognitive performance in 
patients with Parkinson's disease 
Page 5 of 26 
Revised: October 7, 2014 
 
 
 
(4) Patients who have a caregiver who is willing to answer psychological screening 
questions on behalf of the patient. 
 
Exclusion criteria: 
 
(1) Patients less than 18 years of age. 
(2) Patients who are not candidates for bilateral STN DBS placement surgery. 
(3) Adults unable to consent 
(4) Pregnant woman 
(5) Prisoners 
(6) Patients who score over 20 on the BDI indicating moderate depression 
 
7)    Number of Subjects 
 
The target sample size is 22 subjects.  The study design is a phase 1 safety and feasibility 
study.  While results may show a trend towards efficacy, we will not be able to power the 
study toward efficacy.  Two of these subjects will be used to evaluate the ease of use of 
the computerized cognitive test, but will not participate in any other study procedures and 
data will not become part of the study record.  All subjects are to be enrolled locally at 
UC Davis medical center. 
 
 
 
8)    Recruitment Methods 
 
a)  Study-Wide: 
 
NA 
 
b)  Local: 
As part of our routine clinical practice at UC Davis, all patients that undergo STN DBS 
surgery are discussed in detail at the multidisciplinary Deep Brain Stimulation Case 
Conference, which includes representatives from Neurology, Psychiatry, Speech/Cognitive 
Therapy, and Neurosurgery.  If patients are a candidate for the operation and score less than 
20 on the baseline routine BDI, they are candidates for this study. Therefore, at the pre-
operative visit with the patient they will be informed that, independent of their eligibility for 
DBS surgery, they may be eligible for a study investigating DBS frequency on cognitive 
performance in Parkinson’s disease.  If patients are interested in participating, they will be 
offered the opportunity to meet with a member of the study personnel that can provide them 
additional, detailed information regarding the study. The study personnel will be different 
from the treating neurosurgeon so that potential participants do not feel pressured to 
participate in the study. Consent forms will be provided with written information about the 
study goals, risks, and benefits. 
 
Patients that plan to undergo STN DBS surgery at Sutter Medical Center and Kaiser 
Permanente in Sacramento may also be able to participate in this study. ‘Dear Doctor’ 
letters will be distributed to the Sutter and Kaiser DBS groups. Patients will be provided 
with a contact number to call if they are interested in learning more about the study. The  
 

PROTOCOL TITLE: Safety and feasibility of using low frequency deep brain 
stimulation of the subthalamic nucleus to improve cognitive performance in 
patients with Parkinson's disease 
Page 6 of 26 
Revised: October 7, 2014 
 
 
 
study will briefly be described on the phone. Patients interested in participating will be 
invited to UC Davis to meet with study personnel to review the study goals, risks and 
benefits in more detail. Consent forms will be provided at this visit and baseline cognitive 
testing will be performed if the patient decides to participate.  
 
 
The dates of contact and written consent or refusal will be recorded.  Participants will be 
advised that they have the right to say “Refuse to answer” to any questions that they find 
uncomfortable.  They will be assured that participation is on a voluntary basis and they 
reserve the right to withdraw participation in the study at any point of time, and that 
declining to participate in the study will not have any effect on their medical care. 
Participants will be notified that with their consent, the research team will share any data 
collected from the screening and the study with their doctors at the end of their participation 
in the study. 
 
An advertisement will be posted in the newspaper to recruit patients for the study. This 
advertisement will give a brief description of the study and instruct interested individuals to 
contact study personnel at the number provided to learn more about the study.  
 
c)  HIPAA: 
As described in Question 8b above, the main eligibility criterion for this study is eligibility 
for STN DBS surgery.  Therefore, the DBS Case Conference team will review individuals’ 
medical records during evaluation for DBS surgery, per routine clinical practice at our 
institution. If the patient is a candidate for STN DBS and scores less than 20 on the BDI on 
routine screening tests, then a review of medical records may be performed to determine 
eligibility based on the inclusion/exclusion criteria above.  Since medical records will be 
accessed prior to signing the consent form or HIPAA authorization, we request a waiver of 
HIPAA for recruitment purposes only.  The use or disclosure of the PHI involves no more 
than a minimal risk to the privacy of individuals. All identifiers will be password-protected 
and access to data files will be given only to IRB- approved research personnel as listed in 
the research personnel list. Identifiers will be destroyed at the earliest opportunity consistent 
with the conduct of the research, unless there is a health or research justification for 
retaining the identifiers or such retention is otherwise required by law. 
 
The protected health information will not be reused or disclosed to any other person or 
entity, expect as required by law, for authorized oversight of the research study, or for other 
research for which the use of disclosure of PHI for which an authorization or opportunity to 
agree or object is not required by 45 CFR 164.512.  The research could not be practicably 
conducted without the waiver, and without access and use of the PHI for recruitment. 
 
9) 
Compensation to the Subjects 
 
Subjects will be compensated $10 per session.  If the patient decides not to participate in 
further sessions, they will still receive the compensation for the completed sessions.  Travel 
expenses up to $30 per patient will be provided if needed.  The compensation will be in the 
form of a gift card and will be given at the time of the visit. 
 
 

PROTOCOL TITLE: Safety and feasibility of using low frequency deep brain 
stimulation of the subthalamic nucleus to improve cognitive performance in 
patients with Parkinson's disease 
Page 7 of 26 
Revised: October 7, 2014 
 
 
 
10)  Study Timelines 
The duration of the study from subject enrollment of the first patient to final data analysis 
will be approximately two years.  Each individual subject will participate in the study for a 
maximum of 2 months for a total of 3 on-site experimental sessions and one telephone call.  
The first on-site visit will occur within the month prior to their planned DBS placement 
surgery, following the pre-operative visit.  The second and third on-site visits will occur 
within the fourth week after the DBS electrode placement surgery, 3-4 days apart.  A 
telephone call will be made 24 hours prior to the third on-site session to obtain additional 
safety information (Figure 1). Each participant will remain in the study for approximately 2 
months from the time of consent. Participation is on a voluntary basis and subjects will 
reserve the right to withdraw participation in the study at any point of time. 
We expect the duration to enroll all study subjects will be approximately 2 years based on 
the number of patients who meet the inclusion and exclusion criteria. 
 
We expect to complete the study by July 2017.  The data will be analyzed as individual 
patients complete the study with further analyses after data collection is complete. 
 
11)  Study Endpoints 
 
 
1.  Safety:  Safety endpoints will be measured by neuropsychiatric, motor, and cognitive 
testing: 
 
a) Neuropsychiatric tests.  We will perform the BDI and NPI at baseline, at the first 
experimental session, once by telephone call after 24 hours of LFS, and a fourth time at the 
final experimental session.  The score of the BDI will be compared across sessions and a 
score that rises above 20 will be considered positive for the development of moderate 
depression.  The NPI assesses frequency, change in severity, and caregiver distress over 12 
neuropsychiatric domains and we will look for caregiver reports of significant change 
across these domains. 
 
b) Motor tests.  The Unified Parkinson’s Disease Rating Scale (UPDRS) will be 
performed prior to patient’s surgery as part of the patient’s routine care.  We will repeat the 
scale at the final experimental session to assess changes in motor symptoms after sustained 
LFS. 
c) Changes in cognitive function will also be assessed as described below.
 
2.  Feasibility.  Improvement in cognitive function will be measured by three cognitive 
tests: the Stroop test, the N-Back test, and the verbal fluency test.  We will measure reaction 
time and error rates and look for significant changes across stimulator frequencies.  The 
results from 20 patients will help us determine if a large-scale study of effectiveness is 
warranted and feasible. 
 
 
Describe any primary or secondary safety endpoints. 
 
See above. 
 
 
 
 

PROTOCOL TITLE: Safety and feasibility of using low frequency deep brain 
stimulation of the subthalamic nucleus to improve cognitive performance in 
patients with Parkinson's disease 
Page 8 of 26 
Revised: October 7, 2014 
 
 
 
12)  Procedures Involved 
 
a)  Describe and explain the study design. 
 
The study design is a safety and feasibility study.  We aim to identify 20 PD patients who 
will receive bilateral STN DBS as part of their standard care.  We plan to measure the 
safety of LFS in the STN as measured through psychological, cognitive, and motor 
scales, and compare cognitive performance with low and high frequency STN DBS.  We 
propose that LFS in the theta range will not negatively affect psychiatric symptoms or alter 
motor symptoms, and will improve performance on tests of executive functioning. 
 
This study will not affect whether PD patients receive a stimulator as all subjects are 
scheduled to undergo stimulation placement as part of their routine care. It also will not 
disrupt the standard procedure for implantation or initiation of treatment.  The study will be 
conducted only in the brief period prior to the time when the stimulator is typically turned 
on.  FDA approval for PD treatment in not limited to a specific stimulation frequency, and 
stimulator parameters are typically adjusted as symptoms evolve over time. The effect of 
participating in this study will therefore be minimal. 
 
Patient’s stimulators are typically turned on 4 weeks following electrode placement surgery 
at UC Davis. We plan to perform frequency manipulation and cognitive testing 3 weeks 
following electrode placement surgery, and 2 weeks following the surgery for the 
Implantable Pulse Generator (IPG). The study will therefore be completed prior to the 
standard time for the initiation of treatment stimulation.  Patients’ treatment stimulation will 
not be delayed by participating in the study.  Patients’ medications will not be adjusted 
during the study.  The study timeline is shown in Figure 1.  Times are based on when 
surgery can be expected based on the decisions of the patient’s surgeon and neurologist. 

PROTOCOL TITLE: Safety and feasibility of using low frequency deep brain 
stimulation of the subthalamic nucleus to improve cognitive performance in 
patients with Parkinson's disease 
Page 9 of 26 
Revised: October 7, 2014 
 
 
 
 
 
Figure 1: Week 0 (W0): Pre-op visit, Baseline experimental cognitive testing (E-BL Cog) (may occur 1-2 
wks prior to lead placement surgery), Week 1 (W1): Surgery 1: DBS lead placement surgery (S1 Lead) as 
scheduled by patients’ doctors, Week 2 (W2): Surgery 2: IPG surgery (S2 Battery) as scheduled by 
patients’ doctors, Week 3 (W3): Recovery, Week 4 (W4): Experimental testing sessions 1 (E1 Cog) and 2 
(E2 Cog) with frequency modulation, check mark indicates telephone contact, Week 5 (W5): Treatment 
Stimulation typically turned on as part of routine care. 
 
Upon informed consent and enrollment, information regarding participants’ age, gender, 
medications, medical history, surgical history, disease duration and imaging (magnetic 
resonance imaging, computed tomography) will be collected.  As part of the standard 
assessment prior to DBS electrode placement, all patients undergo evaluation with the 
Unified Parkinson’s Disease Rating Scale (UPDRS), Beck depression inventory (BDI) 
(Beck et al 1961), IQ testing, and a battery of neurocognitive tests.  These tests are routinely 
repeated about 6 months to 1 year after DBS placement as part of patients’ routine care.  
These tests will not be a direct part of the study but may be utilized as part of the patient’s 
history. 
 
As part of our experimental design, we will include a baseline experimental session prior to 
the patient’s planned surgery that will consist of approximately 30 minutes of 
cognitive testing and baseline screening for neuropsychiatric symptoms using the BDI 
and NPI (Cummings et al 1994).  Cognitive testing will consist of computerized and non- 
computerized tests.  The NPI requires that a caregiver answer questions about the mental 
state and behaviors of the patient.  The caregiver will be informed of the study at the pre- op 
visit if the patient consents and will be asked if they are willing to participate in the study 
procedure. 
 
After patients’ treatment team has performed their DBS surgeries, there will be two on- site 
experimental testing sessions with frequency manipulation and a telephone psychological 
screening session.  The first will occur 22-24 days following the DBS lead placement 
surgery.  During the session, each patient will repeat baseline cognitive testing 

PROTOCOL TITLE: Safety and feasibility of using low frequency deep brain 
stimulation of the subthalamic nucleus to improve cognitive performance in 
patients with Parkinson's disease 
Page 10 of 26 
Revised: October 7, 2014 
 
 
 
without stimulation and will complete the BDI.  Informers will complete the NPI. 
Subsequently, the stimulators will be turned on, and each patient will repeat cognitive 
testing under gamma frequency (~130 Hz) and theta frequency stimulation (~5 Hz).  The 
order of stimulation will be randomized.  Stimulation will occur for 5 minutes prior to 
and continuously throughout each task.  Amplitude and pulse width will be set to 3 V and 
120 microseconds accordingly (Laxton & Lozano 2013) or as tolerated by the patient, and 
will remain constant across sessions.  We will wait 20 minutes between testing conditions to 
elicit about 75% of DBS effects (Temperli et al 2003).  At the end of the experimental 
testing session, the stimulator will be turned off or set to LFS in preparation for the second 
experimental session. 
 
The second on-site experimental testing session will assess the effects of continuous theta 
stimulation on cognitive function.  Patients will repeat cognitive testing after 48 hours of 
continuous theta stimulation.  This second on-site testing session will occur 3-5 days 
following the first experimental session.  Two days prior to the testing session, patients’ 
stimulators will be turned on to the theta frequency stimulation setting and patients will 
return home and engage in normal activities.  After 48 hours they will return to the clinic 
and repeat cognitive testing with continuous theta frequency stimulation.  The UPDRS, 
NPI, and BDI will also be performed at this time.  At the end of the session, their 
stimulators will be turned off. 
 
We will screen for psychological changes by telephone once during the 2 day stimulation 
period.  The patient will complete the BDI and a relative or caregiver will complete the NPI 
over the phone. 
 
The structure of the experimental sessions is shown in Figure 2 and Figure 3. 
 
 
 
Figure 2: Stimulation schedule. The first experimental session (E1) will include 30 minutes of baseline 
cognitive testing. Stimulation will then be turned on (Stim) for 5 minutes prior to cognitive testing under 
the first frequency condition (either HFS or LFS depending on randomization) (Cog C1). Stimulation will 
then be turned off and the patient will have a 15 minute rest period. Stimulation at the second testing 
frequency condition will then be turned on for 5 minutes and the cognitive testing will be repeated (Cog 
C2). At the completion of this session, LFS will be turned on for 48 hours. When the patient returns to 
clinic for the second experimental session (E2) they will repeat cognitive testing after sustained LFS (Cog 
S-Stim). The stimulation will be turned off and the patients will return home to continue standard care. 
Shaded boxes represent periods of stimulation. 

PROTOCOL TITLE: Safety and feasibility of using low frequency deep brain 
stimulation of the subthalamic nucleus to improve cognitive performance in 
patients with Parkinson's disease 
Page 11 of 26 
Revised: October 7, 2014 
 
 
 
 
Figure 3: Safety Measures. Motor, psychological and cognitive tests present for each patient contact are 
indicated. *This motor test performed by neurologist as part of routine care and occurs at a clinic visit 
prior to the patient’s anticipated surgery. 
 
We will also identify and enroll two subjects that have PD in order to test the ease of use of 
the computerized cognitive test, prior to the enrollment of additional subjects.  These 
subjects will perform the computerized cognitive test once and will not participate in any 
other study procedures.  We will use this information to decide on optimal parameters 
within the computerized cognitive test such as stimulus presentation time and response time 
allowed. 
 
Cognitive testing will include three cognitive tests.  The first is the single-trial computerized 
version of the Stroop color-naming task.  This task is an executive function task that 
measures attention and inhibition (MacLeod 1991).  Performance on this task 
has been shown to be impaired in patients with PD.  Patients make more errors, have a 
slower response times, and show increased Stroop interference relative to controls (Brown 
& Marsden 1988).  Furthermore, performance may worsen following STN DBS placement, 
with further increases in error rates (Jahanshahi et al 2000, Witt et al 2004). Stimuli consist 
of three color words printed in one of the three colors such that there are congruent trials 
where the written color word and ink color match, and incongruent trials where the written 
color word and ink color do not match.  Participants are instructed to ignore the written 
word, and perform one of three key presses corresponding to the color 
of the written word.  They will first be trained to accuracy on the key presses using 100% 
congruent trials.  Patients will be instructed to be both fast and accurate. 
 
The second cognitive test is a computerized version of the N-back test, which has been 
shown to target working memory.  Performance on this task has also been shown to be 
impaired in patients with PD (Beato et al 2008).  Patients will perform 2 blocks of trials 
corresponding to 1-back, and 2-back.  In this task, patients will be asked to make a key 
press when they see a matching spatial configuration one or two stimuli before the current 
stimuli. 
 
The final test is the FAS phonemic fluency test.  Patients will be asked to verbally name as 
many words as they can that start with the letters F, A, or S within a 1 minute time period.  
Patients will perform the verbal fluency test with each of the three letters once in random 
order after Stroop and N-back computer tasks have been completed.  People with PD have 
been shown to have difficulty specifically with phonemic verbal fluency, which is thought  

PROTOCOL TITLE: Safety and feasibility of using low frequency deep brain 
stimulation of the subthalamic nucleus to improve cognitive performance in 
patients with Parkinson's disease 
Page 12 of 26 
Revised: October 7, 2014 
 
 
 
to rely on connections between the basal ganglia and the prefrontal cortex (Dadgar et al 
2013, Jaywant et al 2014).  Furthermore, DBS has been shown in some studies to impair 
phonemic verbal fluency, which may or may not recover over time (Ehlen et al 2014, 
Wojtecki et al 2006, Wu et al 2014). These specific letters were chosen based on the 
frequency of English language words that that begin with the letters (Borkowski et al 1967.)  
 
Total testing time will be approximately 30 minutes per stimulation condition with 20 
minutes between conditions, resulting in a total time of approximately 30 minutes for the 
baseline cognitive testing, 2 hours for the first experimental session and 30 minutes for the 
second experimental session.  Additional time will be needed for setup and explanation of 
the task directions.  Finally, 20 minutes of psychological screening will be performed at the 
baseline session, over the phone between experimental sessions 1 and 2, and following 
cognitive testing during experimental session 2. 
 
Baseline Testing: 30 min cognitive testing, 20 minute psychological screening (Total 
Time: approximately 50 min) 
Experimental Session 1: 20 minutes psychological screening, 2 hours cognitive testing 
(Total Time: approximately 2h 20 min) 
Phone call between experimental session 1 and 2: 20 minutes psychological screening 
Experimental Session 2: 30 min cognitive testing, 20 minute psychological screening, 20 
min motor screening (Total Time: approximately 70 minutes) 
 
b)  Humanitarian Use Device (HUD) 
 
NA 
 
13)  Data and Specimen Banking 
 
No data or specimens will be retained longer than required by law or hospital policy. 
 
14)  Data Management and Confidentiality 
 
The target sample size is 22 subjects. The study design is a safety and feasibility phase1 
study.  While results may show a trend towards efficacy, we will not be able to power the 
study toward efficacy. 
 
Safety Data Analysis: 
To examine possible effects on motor symptoms, we will screen for changes in the motor 
section of the UPDRS score after sustained LFS.  After each patient is tested, we will 
calculate individual changes in UPDRS scoring.  After the entire patient population is 
tested, we will use T-tests to determine if there is a significant change in the overall 
rating scale. 
 
We will also examine changes in psychological symptoms.  For each individual patient, we 
will measure the BDI and NPI at baseline, at the first experimental session, by phone call 
after 24 h LFS, and at the final experimental session. For the BDI, we will consider any 
score greater or equal to 20 as evidence of moderate depression and will terminate the study 
for any individual that shows evidence of depression.  At the group level, we will calculate  

PROTOCOL TITLE: Safety and feasibility of using low frequency deep brain 
stimulation of the subthalamic nucleus to improve cognitive performance in 
patients with Parkinson's disease 
Page 13 of 26 
Revised: October 7, 2014 
 
 
 
the percentage of people that develop depression.  For the NPI, we will calculate the total 
score.  At the individual level we will look for the development of new symptoms in the 12 
subsections.  At the group level we will perform an ANOVA to look for significant changes 
across the 3 time points. 
 
Cognitive Data Analysis: 
The cognitive data analysis will examine the effect of theta frequency stimulation on 
cognitive task performance. Analyses for the Stroop task will include the examination of 
response time and error rates across stimulator settings.  Two (trial type: congruent vs 
incongruent) by three (Setting: low, high, no stimulation) ANOVAs will be performed for 
both reaction time and accuracy.  Post conflict and post error reaction time adjustments will 
also be examined across stimulator settings.   For the N-back test, ANOVAs will also be 
performed to assess the effects of complexity (1,2-back) and stimulation frequency (none, 
high, low) on error rates.  For the verbal fluency test, the average number of words 
generated across stimulation conditions and the change in word number on low and high 
frequency stimulation settings will be compared.  Analyses will be performed using 
MATLAB and STATA. 
 
 
Describe any procedures that will be used for quality control of collected data. 
 a.) Study-Wide: 
NA 
 
b.) Local 
 
Describe the local procedures for maintenance of confidentiality. 
 
This research is partly funded by a donation from the Chevo Foundation.  The Chevo 
Foundation will not have access to any of the study documents including the data.  
 
Data files to be stored include group assignment, background information, any head scans if 
performed, and results from neurocognitive and motor tests. 
 
Data files will be stored on secured server through the assistance of the UC Davis Clinical 
and Translational Science Center, which will be password-protected and access to data files 
will be given only to IRB-approved research personnel as listed in the research personnel 
list. For data analysis, each subject will be assigned a unique 
identification number and there will be no reference to his/her name or any other personal 
identifier in any subsequent publication.  All personal identifiers will be destroyed upon 
completion of the research and the required storage period. Protected Health Information 
(PHI) will not be reused or disclosed to any other persons or entity except if subject to an 
authorized oversight of the research project. Otherwise, the PHI will be protected to the 
fullest extent possible.  Subjects will be given access to their results at the closure of the 
study.  Data will be stored locally for no more than 5 years. 

PROTOCOL TITLE: Safety and feasibility of using low frequency deep brain 
stimulation of the subthalamic nucleus to improve cognitive performance in 
patients with Parkinson's disease 
Page 14 of 26 
Revised: October 7, 2014 
 
 
 
15)  Provisions to Monitor the Data to Ensure the Safety of Subjects 
 
Data from the first two subjects will be used only to determine the ease of use of the 
computerized cognitive test and will not be collected as part of the study.  These 
participants will perform the cognitive test only and will not participate in any other study 
procedures.  Data from the remaining subjects will be analyzed and evaluated in cohorts of 
4 patients through the first 12 patients to determine whether subjects remain safe.  This 
means we will evaluate the safety data from the first 4 patients before proceeding with 
subsequent subjects.  We will evaluate data again after a total of 8 patients, 12 patients, and 
20 patients.  Data will be reviewed by a safety committee.  The committee will include the 
PI, Dr. Kiarash Shahlaie in addition to Dr. Lin Zhang, Dr. Sarah Farias, and Dr. Katherine 
Scangos. Dr. Lin Zhang is a neurologist, co-director of the DBS group, and has participated 
in multiple clinical trials involving the Parkinson’s disease population.  Dr. Farias is an 
expert in neurocognitive assessment in Parkinson’s disease and has experience in 
identifying study related neurocognitive effects in clinical trials in dementia. 
 
Safety data will include performance on psychological screening tests, cognitive tests, and 
motor tests.  Efficacy data will include performance on cognitive tests. All data will be 
reviewed by a safety committee as described above.  If any patient develops motor effects 
that are uncomfortable, the study will be halted for that particular subject. Furthermore, if 
the patient develops worsening psychological effects as measured through psychological 
screening tools, the study will be halted and the patient will be referred for appropriate care 
through the departments of Psychiatry and Neurology at UC Davis. 
 
Safety information will be collected at study visits and with a telephone call.  It will be 
saved in the database established for this study. 
 
Safety data for motor effects will be collected prior to the patient’s surgery and at the final 
study visit.  Psychological data will be collected prior to DBS placement, at the first study 
visit, by phone call during the sustained frequency stimulation period, and at the final clinic 
visit. 
 
The principal investigator and study members will review the data after each clinic visit and 
telephone contact with the patient.  A safety committee will review the data after the first 4 
patients, 8 patients, 12 patients, and 20 patients.  The committee will include the PI, Dr. 
Kiarash Shahlaie in addition to Dr. Lin Zhang, Dr. Sarah Farias, and Dr. Katherine Scangos.  
Dr. Lin Zhang is a neurologist, co-director of the DBS group, and has participated in 
multiple clinical trials involving the Parkinson’s disease population.  Dr. Farias is an expert 
in neurocognitive assessment 
in Parkinson’s disease and has experience in identifying study related neurocognitive effects 
in clinical trials in dementia. 
 
Data will be analyzed and evaluated in cohorts of 4 patients through the first 12 patients to 
determine whether subjects remain safe.  This means we will evaluate the safety data from 
the first 4 patients before proceeding with subsequent subjects.  We will evaluate data again 
after a total of 8 patients, 12 patients, and 20 patients. 

PROTOCOL TITLE: Safety and feasibility of using low frequency deep brain 
stimulation of the subthalamic nucleus to improve cognitive performance in 
patients with Parkinson's disease 
Page 15 of 26 
Revised: October 7, 2014 
 
 
 
Safety Data Analysis:  To examine possible effects on motor symptoms, we will screen for 
significant changes in the motor section of the UPDRS score after sustained LFS.  After 
each patient is tested, we will calculate individual changes in UPDRS scoring.  After the 
entire patient population is tested, we will use a T-test to determine if there is a significant 
change the motor section. 
 
We will also examine changes in psychological symptoms using the BDI and NPI.  We will 
examine percentage of people who convert to moderate depression as indicated by a BDI 
score 20 or higher.  We will also look for significant changes in the BDI and NPI across 
time using ANOVAs. 
 
Changes in cognition will also be analyzed by looking at reaction time and error rates on 
different cognitive tests as described previously. 
 
• 
Any conditions that trigger an immediate suspension of the research. 
 
None. 
 
16)  Withdrawal of Subjects 
 
Describe anticipated circumstances under which subjects will be withdrawn from the 
research without their consent. 
 
Patients unable to perform cognitive tests due to effort or altered mental status. 
 
Patients who experience any change in psychological symptoms that is concerning to the 
patient, caregiver, or test administrator as assessed through psychological screening tools. 
 
Describe any procedures for orderly termination. 
 
The patient is not undergoing any additional procedures, except for stimulation and 
cognitive testing. 
 
Describe procedures that will be followed when subjects withdraw from the research, 
including partial withdrawal from procedures with continued data collection. 
 
Patients’ data will be recorded, unless specifically asked to be withdrawn 
 
Patients will continue to be followed for medical management 
 
17)  Risks to Subjects 
 
Physical Risk: 
 
- 
There is minimal to no physical risk. Once the patient’s stimulation is turned off, the 
patient’s pre-stimulation symptoms will likely return (Temperli et al 2003). 
 
- 
There is a small chance that changes in affective symptoms including dysphoria, 
depression, mania, or psychosis may occur (Smeding et al 
2006, Strutt et al 2012). Patients will be carefully screened using standardized assessment 
tools. 
 
- 
All cognitive and memory tests are designed to be minimally difficult and pose minimal  

PROTOCOL TITLE: Safety and feasibility of using low frequency deep brain 
stimulation of the subthalamic nucleus to improve cognitive performance in 
patients with Parkinson's disease 
Page 16 of 26 
Revised: October 7, 2014 
 
 
 
 
risk to the subject. Patients may experience boredom or uncertainty by the cognitive testing. 
 
Neurological Risk: 
 
- 
There are no risks associated with activating the DBS system on post- operative day 22-24 
for participating in this study.  There is significant variability in timing of DBS therapy 
across institutions, with some groups activating the DBS on post-operative day 1 and other 
groups activating the device on/after post-operative day 30.  There are no documented risks 
associated with the delay between DBS implantation and initiation of therapy. 
 
- 
Although we expect LFS in the STN to improve cognition based on previous literature, we 
cannot rule out the possibility that prolonged ventral STN stimulation may temporarily 
worsen cognition in some patients. 
 
Confidentiality Risk: There is also minimal risk of breach of confidentiality. 
 
 
 
18)  Potential Benefits to Subjects 
 
There is no direct long lasting benefit to individual subjects.  Patients may potentially 
experience sustained cognitive improvement over a period of time with low frequency 
stimulation but the duration is currently unknown.  Patients may benefit from contributing 
to our understanding of the neural mechanism underlying cognitive impairment in PD. The 
information gained in the study will be used to direct treatment plans to improve cognitive 
impairment in PD and slow the progression of mild cognitive impairment to dementia. 
 
 
 
19)  Vulnerable Populations 
 
If the research involves individuals who are vulnerable to coercion or undue influence, 
describe additional safeguards included to protect their rights and welfare. 
 
NA 
 
20)  Multi-Site Research 
 
If this is a multi-site study where you are the lead investigator, describe the processes to 
ensure communication among sites, such as: 
 
NA 
 
21)  Community-Based Participatory Research 
 
NA 
 
22)  Sharing of Results with Subjects 
 
Describe whether results (study results or individual subject results, such as results of 
investigational diagnostic tests, genetic tests, or incidental findings) will be shared with 
subjects or others (e.g., the subject’s primary care physicians) and if so, describe how it 
will be shared. 

PROTOCOL TITLE: Safety and feasibility of using low frequency deep brain 
stimulation of the subthalamic nucleus to improve cognitive performance in 
patients with Parkinson's disease 
Page 17 of 26 
Revised: October 7, 2014 
 
 
 
Subjects will be given access to their results at the closure of the study.  If patients desire, 
the results of the study will be shared verbally with their treatment team at the Parkinson’s 
clinic.  The information will not be shared with any other health care providers. 
 
23)  Setting 
 
Describe the sites or locations where your research team will conduct the research. 
 
 
• Identify where your research team will identify and recruit potential subjects. 
 
Specific locations for recruitment will be in the UC Davis Department of Neurosurgery, 
Department of Neurology and the Ellison Ambulatory Care Center. We will be seeking 
patients who plan to obtain subthalamic nucleus depth electrodes for Parkinson’s disease. 
We will also recruit patients from Sutter Medical Center and Kaiser Permanente in 
Sacramento that plan to undergo STN DBS surgery. A newspaper advertisement will allow 
for recruitment outside of the UC Davis Health network as well.  
 
• 
Identify where research procedures will be performed. 
 
All research procedures and all study visits will take place at UC Davis. For this pilot study, 
we require the DBS generator adjustment equipment and a quiet exam room for 
administration of cognitive and motor tests (i.e. ACC clinic exam room or testing room in 
UC Davis imaging center). The personnel required to consent the subject, administer the 
tests and analyze the data are sufficient and involve members of the Department of 
Neurosurgery, Department of Neurology, Department of Psychiatry, UC Davis Imaging 
Center, UC Davis Clinical and Translational Science 
Center and the Center for Mind and Brain 
 
 
• Describe the composition and involvement of any community advisory board. 
 
NA 
 
 
• For research conducted outside of the organization and its affiliates describe: 
 
NA 
 
24)  Resources Available 
 
Describe your staff and their roles. Describe the qualifications (e.g., training, experience, 
oversight) required to perform each role. When applicable describe their knowledge of the 
local study sites, culture, and 

PROTOCOL TITLE: Safety and feasibility of using low frequency deep brain 
stimulation of the subthalamic nucleus to improve cognitive performance in 
patients with Parkinson's disease 
Page 18 of 26 
Revised: October 7, 2014 
 
 
 
society. Provide enough information to convince the IRB that you have qualified staff for 
the proposed research. 
 
If you specify a person by name, a change to that person will require prior approval by the 
IRB. If you specify people by role (e.g., coordinator, research assistant, co-investigator, or 
pharmacist), a change to that 
person will not require prior approval by the IRB, provided that person meets the 
qualifications described above to fulfill their roles. 
 
- 
Principal Investigator: review of past literature, administration of cognitive tasks, 
reprogramming DBS generator, analysis of data, recruitment of patients, undergo IRB 
course(s) for clinical research 
 
- 
Co-Investigator: administration of cognitive tasks, analysis of data, recruitment of patients, 
undergo IRB course(s) for clinical research 
 
- 
Research assistants: administration of cognitive tasks, analysis of data, undergo IRB 
course(s) for clinical research 
 
Describe other resources available to conduct the research: For example, as appropriate: 
 
• Justify the feasibility of recruiting the required number of suitable subjects within the 
agreed recruitment period. For example, how many potential subjects do you have access 
to? What percentage of those potential subjects do you need to recruit? 
 
We have access to all patients referred to neurosurgery for implantation of electrodes for 
intracranial depth electrode seizure monitoring. 
 
• Describe the time that you will devote to conducting and completing the research. 
 
3 years 
 
• 
Describe your facilities. 
 
We require the ACC clinic exam rooms or cognitive testing rooms in the UC Davis imaging 
center for cognitive testing and electrical stimulation. 
 
• 
Describe the availability of medical or psychological resources 
that subjects might need as a result of an anticipated consequences of the human research. 

PROTOCOL TITLE: Safety and feasibility of using low frequency deep brain 
stimulation of the subthalamic nucleus to improve cognitive performance in 
patients with Parkinson's disease 
Page 19 of 26 
Revised: October 7, 2014 
 
 
 
Patients will be provided the opportunity to discuss untoward events with the clinical team 
and any additional consultations medically indicated. 
 
• Describe your process to ensure that all persons assisting with the research are adequately 
informed about the protocol, the research procedures, and their duties and functions. 
 
Each member of the research team will undergo IRB course(s) for clinical research.  Each 
member will be required to read the protocol. 
 
25)  Prior Approvals 
 
Describe any approvals that will be obtained prior to commencing the research. (E.g., 
school, external site. funding agency, laboratory, radiation safety, or biosafety approval.) 
 
NA 
 
26)  Provisions to Protect the Privacy Interests of Subjects 
 
Describe the steps that will be taken to protect subjects’ privacy interests. “Privacy 
interest” refers to a person’s desire to place limits on whom they interact or whom they 
provide personal information. 
 
Each member of the team will introduce himself/ herself to the patient and identify his/her 
involvement in the study. 
 
Describe what steps you will take to make the subjects feel at ease with the research 
situation in terms of the questions being asked and the 
procedures being performed. “At ease” does not refer to physical discomfort, but the sense 
of intrusiveness a subject might experience in response to questions, examinations, and 
procedures. 
 
The patient will be told that he/she can refuse to participate at any point during the study. 
 
Indicate how the research team is permitted to access any sources of information about the 
subjects. 
 
The research team will have access to the secured database via password protection. 
 
27)  Compensation for Research-Related Injury 
 
The subject should promptly tell the person in charge of the research if they believe that 
they have been injured because of taking part in this study. If a subject is injured as a result 
of being in this study, the University of California will provide necessary medical treatment. 
Depending on the circumstances, the costs of the treatment may be covered by University or 
the study sponsor or may be billed to your 

PROTOCOL TITLE: Safety and feasibility of using low frequency deep brain 
stimulation of the subthalamic nucleus to improve cognitive performance in 
patients with Parkinson's disease 
Page 20 of 26 
Revised: October 7, 2014 
 
 
 
insurance company just like other medical costs. The University and the study sponsor do 
not normally provide any other form of compensation for injury. 
 
28)  Economic Burden to Subjects 
 
Describe any costs that subjects may be responsible for because of participation in the 
research. 
 
NA 
 
29)  Consent Process 
 
Indicate whether you will you be obtaining consent, and if so describe: 
 
• 
Where will the consent process take place: 
 
Consent will be obtained in the preoperative clinic for UC Davis participants. For Sutter or 
Kaiser patients, consent will take place at their initial visit to UC Davis.  
 
 
• Any waiting period available between informing the prospective subject and obtaining the 
consent. 
 
No 
 
• 
Any process to ensure ongoing consent. 
 
Each experimental session will be described to the patient prior to its start, and the patient 
will be asked permission to proceed with the study. 
 
 
• 
Whether you will be following “SOP: Informed Consent Process for 
Research (HRP-090) (attach SOP with submission).” 
 
We will be following HRP-090, Informed Consent Process for 
Research. 
 
HIPAA Authorization for Research 
 
If the research procedures include accessing personal health information, via the medical 
records, it is required that subjects sign a HIPAA Authorization for Research form at the 
time of consent, unless a waiver of informed consent has been granted by the IRB. 
 
For more information on HIPAA Authorization for Research visit the Compliance Program 
website. 

PROTOCOL TITLE: Safety and feasibility of using low frequency deep brain 
stimulation of the subthalamic nucleus to improve cognitive performance in 
patients with Parkinson's disease 
Page 21 of 26 
Revised: October 7, 2014 
 
 
 
We will obtain HIPAA authorization.  Data files to be stored include group assignment, 
background information, any head scans if performed, and results from neurocognitive and 
motor tests.  Data files will be stored on secured server through the assistance of the UC 
Davis Clinical and Translational Science Center, which will be password-protected and 
access to data files will be given only to IRB-approved research personnel as listed in the 
research personnel list. For data analysis, each subject will be assigned a unique 
identification number and there will be no reference to his/her name or any other personal 
identifier in any subsequent publication.  All personal identifiers will be destroyed upon 
completion of the research and the required storage period. Protected Health Information 
(PHI) will not be reused or disclosed to any other persons or entity except if subject to an 
authorized oversight of the research project. Otherwise, the PHI will be protected to the 
fullest extent possible.  Subjects will be given access to their results at the closure of the 
study.  The data and/or specimens will be labeled with a code that the research team can 
link to personal identifying information when acquired. The code sheet will be secured and 
kept separate from the dataset. 
 
 
 
Non-English Speaking Subjects: 
 
The Consent Short Form will be used for non-English speaking subjects and all UC Davis IRB 
procedures and policies will be followed. 
 
Waiver or Alteration of the Consent Process (consent will not be obtained, required 
information will not be disclosed, or the research involves deception) 
 
NA 
 
 
 
Subjects who are not yet adults (infants, children, teenagers): 
 
NA 
 
Cognitively Impaired Adults: 
 
NA 
 
Adults Unable to Consent: 
 
NA 
 
Adults Unable to Consent: 
 
NA 

PROTOCOL TITLE: Safety and feasibility of using low frequency deep brain 
stimulation of the subthalamic nucleus to improve cognitive performance in 
patients with Parkinson's disease 
Page 22 of 26 
Revised: October 7, 2014 
 
 
 
30)  Process to Document Consent in Writing 
 
We will be following the “SOP: Written Documentation of Consent (HRP- 
091)” and have attached the form with submission. We have used the “TEMPLATE 
CONSENT DOCUMENT (HRP-502)”to create the consent document.  We have created 
written consent forms for both patients and their caregivers. 
 
31)  Drugs or Devices: N/A 
 
The deep brain stimulation device is a FDA-approved surgical implant that is normally 
stored in the Implant Storage Room in the Pavilion Main OR. This storage room is locked.  
Operating room staff that normally retrieve this device for DBS surgery have keycard 
access to this room, as do many of the administrative managers in the Pavilion Main OR.  
The person in charge of ordering and stocking this device for surgical implantation is Peter 
Tham, CNIII. 
 
 
References 
Beato R, Levy R, Pillon B, Vidal C, du Montcel ST, et al. 2008. Working memory 
in Parkinson's disease patients: clinical features and response to 
levodopa. Arquivos de neuro-psiquiatria 66: 147-51 
 
Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J. 1961. An inventory for 
measuring depression. Archives of general psychiatry 4: 561-71 
 
Brown RG, Marsden CD. 1988. Internal versus external cues and the control of 
attention in Parkinson's disease. Brain : a journal of neurology 111 ( Pt 
2): 323-45 
 
Colgin LL. 2013. Mechanisms and functions of theta rhythms. Annual review of 
neuroscience 36: 295-312 
 
Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. 
1994. The Neuropsychiatric Inventory: comprehensive assessment of 
psychopathology in dementia. Neurology 44: 2308-14 
 
Dadgar H, Khatoonabadi AR, Bakhtiyari J. 2013. Verbal Fluency Performance in 
Patients with Non-demented Parkinson's Disease. Iranian journal of 
psychiatry 8: 55-8 
 
Dorsey ER, Constantinescu R, Thompson JP, Biglan KM, Holloway RG, et al. 
2007. Projected number of people with Parkinson disease in the most 
populous nations, 2005 through 2030. Neurology 68: 384-6 
 
Ehlen F, Schoenecker T, Kuhn AA, Klostermann F. 2014. Differential effects of 
deep brain stimulation on verbal fluency. Brain and language 134: 23-33 
 
Emre M, Aarsland D, Albanese A, Byrne EJ, Deuschl G, et al. 2004. Rivastigmine 
for dementia associated with Parkinson's disease. The New England 
journal of medicine 351: 2509-18 

PROTOCOL TITLE: Safety and feasibility of using low frequency deep brain 
stimulation of the subthalamic nucleus to improve cognitive performance in 
patients with Parkinson's disease 
Page 23 of 26 
Revised: October 7, 2014 
 
 
 
Engel AK, Fries P, Singer W. 2001. Dynamic predictions: oscillations and 
synchrony in top-down processing. Nature reviews. Neuroscience 2: 704- 
16 
 
Frankemolle AM, Wu J, Noecker AM, Voelcker-Rehage C, Ho JC, et al. 2010. 
Reversing cognitive-motor impairments in Parkinson's disease patients 
using a computational modelling approach to deep brain stimulation 
programming. Brain : a journal of neurology 133: 746-61 
 
Freund HJ, Kuhn J, Lenartz D, Mai JK, Schnell T, et al. 2009. Cognitive 
functions in a patient with Parkinson-dementia syndrome undergoing deep 
brain stimulation. Archives of neurology 66: 781-5 
 
Funkiewiez A, Ardouin C, Krack P, Fraix V, Van Blercom N, et al. 2003. Acute 
psychotropic effects of bilateral subthalamic nucleus stimulation and 
levodopa in Parkinson's disease. Movement disorders : official journal of 
the Movement Disorder Society 18: 524-30 
 
Goldman JG, Litvan I. 2011. Mild cognitive impairment in Parkinson's disease. 
Minerva medica 102: 441-59 
 
Halpern CH, Rick JH, Danish SF, Grossman M, Baltuch GH. 2009. Cognition 
following bilateral deep brain stimulation surgery of the subthalamic 
nucleus for Parkinson's disease. International journal of geriatric 
psychiatry 24: 443-51 
 
Hely MA, Reid WG, Adena MA, Halliday GM, Morris JG. 2008. The Sydney 
multicenter study of Parkinson's disease: the inevitability of dementia at 
20 years. Movement disorders : official journal of the Movement Disorder 
Society 23: 837-44 
 
Heo JH, Lee KM, Paek SH, Kim MJ, Lee JY, et al. 2008. The effects of bilateral 
subthalamic nucleus deep brain stimulation (STN DBS) on cognition in 
Parkinson disease. Journal of the neurological sciences 273: 19-24 
 
Jahanshahi M, Ardouin CM, Brown RG, Rothwell JC, Obeso J, et al. 2000. The 
impact of deep brain stimulation on executive function in Parkinson's 
disease. Brain : a journal of neurology 123 ( Pt 6): 1142-54 
 
Jaywant A, Musto G, Neargarder S, Stavitsky Gilbert K, Cronin-Golomb A. 2014. 
The effect of Parkinson's disease subgroups on verbal and nonverbal 
fluency. Journal of clinical and experimental neuropsychology 36: 278-89 
 
Laxton AW, Lipsman N, Lozano AM. 2013. Deep brain stimulation for cognitive 
disorders. Handbook of clinical neurology 116: 307-11 
 
Laxton AW, Lozano AM. 2013. Deep brain stimulation for the treatment of 
Alzheimer disease and dementias. World neurosurgery 80: S28 e1-8 
 
Laxton AW, Tang-Wai DF, McAndrews MP, Zumsteg D, Wennberg R, et al. 2010. 
A phase I trial of deep brain stimulation of memory circuits in Alzheimer's 
disease. Annals of neurology 68: 521-34 

PROTOCOL TITLE: Safety and feasibility of using low frequency deep brain 
stimulation of the subthalamic nucleus to improve cognitive performance in 
patients with Parkinson's disease 
Page 24 of 26 
Revised: October 7, 2014 
 
 
 
Lee DJ, Gurkoff GG, Izadi A, Berman RF, Ekstrom AD, et al. 2013. Medial septal 
nucleus theta frequency deep brain stimulation improves spatial working 
memory after traumatic brain injury. Journal of neurotrauma 30: 131-9 
 
Lisman J. 2005. The theta/gamma discrete phase code occuring during the 
hippocampal phase precession may be a more general brain coding 
scheme. Hippocampus 15: 913-22 
 
MacLeod CM. 1991. Half a century of research on the Stroop effect: an 
integrative review. Psychological bulletin 109: 163-203 
 
Mann EO, Paulsen O. 2005. Mechanisms underlying gamma ('40 Hz') network 
oscillations in the hippocampus--a mini-review. Progress in biophysics 
and molecular biology 87: 67-76 
 
McNaughton N, Ruan M, Woodnorth MA. 2006. Restoring theta-like rhythmicity 
in rats restores initial learning in the Morris water maze. Hippocampus 
16: 1102-10 
 
Niebur E, Hsiao SS, Johnson KO. 2002. Synchrony: a neuronal mechanism for 
attentional selection? Current opinion in neurobiology 12: 190-4 
 
Nyhus E, Curran T. 2010. Functional role of gamma and theta oscillations in 
episodic memory. Neuroscience and biobehavioral reviews 34: 1023-35 
 
Owen AM. 2004. Cognitive dysfunction in Parkinson's disease: the role of 
frontostriatal circuitry. The Neuroscientist : a review journal bringing 
neurobiology, neurology and psychiatry 10: 525-37 
 
Poletti M, Bonuccelli U. 2013. Acute and chronic cognitive effects of levodopa 
and dopamine agonists on patients with Parkinson's disease: a review. 
Therapeutic advances in psychopharmacology 3: 101-13 
 
Smeding HM, Speelman JD, Koning-Haanstra M, Schuurman PR, Nijssen P, et 
al. 2006. Neuropsychological effects of bilateral STN stimulation in 
Parkinson disease: a controlled study. Neurology 66: 1830-6 
 
Strutt AM, Simpson R, Jankovic J, York MK. 2012. Changes in cognitive- 
emotional and physiological symptoms of depression following STN-DBS 
for the treatment of Parkinson's disease. European journal of neurology : 
the official journal of the European Federation of Neurological Societies 
19: 121-7 
 
Temperli P, Ghika J, Villemure JG, Burkhard PR, Bogousslavsky J, Vingerhoets 
FJ. 2003. How do parkinsonian signs return after discontinuation of 
subthalamic DBS? Neurology 60: 78-81 
 
Volkmann J. 2004. Deep brain stimulation for the treatment of Parkinson's 
disease. Journal of clinical neurophysiology : official publication of the 
American Electroencephalographic Society 21: 6-17 

PROTOCOL TITLE: Safety and feasibility of using low frequency deep brain 
stimulation of the subthalamic nucleus to improve cognitive performance in 
patients with Parkinson's disease 
Page 25 of 26 
Revised: October 7, 2014 
 
 
 
Witt K, Pulkowski U, Herzog J, Lorenz D, Hamel W, et al. 2004. Deep brain 
stimulation of the subthalamic nucleus improves cognitive flexibility but 
impairs response inhibition in Parkinson disease. Archives of neurology 
61: 697-700 
 
Wojtecki L, Timmermann L, Jorgens S, Sudmeyer M, Maarouf M, et al. 2006. 
Frequency-dependent reciprocal modulation of verbal fluency and motor 
functions in subthalamic deep brain stimulation. Archives of neurology 
63: 1273-6 
 
Wu B, Han L, Sun BM, Hu XW, Wang XP. 2014. Influence of deep brain 
stimulation of the subthalamic nucleus on cognitive function in patients 
with Parkinson's disease. Neuroscience bulletin 30: 153-61 
 
Zgaljardic DJ, Borod JC, Foldi NS, Mattis P. 2003. A review of the cognitive and 
behavioral sequelae of Parkinson's disease: relationship to frontostriatal 
circuitry. Cognitive and behavioral neurology : official journal of the 
Society for Behavioral and Cognitive Neurology 16: 193-210