Stimulation Parameters and Non-motor Symptoms in PD Treated With DBS
Phase: NA
Conditions: Parkinson Disease
Sponsor: Darlene Floden

Version Date: August 28, 2020 
IRB # 17-1350 
Title: Stimulation Parameters and Non-motor Symptoms in PD Treated With DBS 
Version Date: 08/28/2020 
 
 

Version Date: August 28, 2020 
Introduction 
Deep brain stimulation of the dorsolateral Subthalamic Nucleus is a highly effective treatment for 
the motor symptoms of moderate to advanced Parkinson’s disease. At the same time, however, 
this therapy is also associated with small but consistent changes in cognitive and affective 
function. The mechanisms underlying these unintended DBS side effects is unknown. The goal 
of this research is to systematically evaluate two aspects of stimulation (location and frequency) 
that may explain the non-motor changes associated with STN DBS.  
Background and Significance 
A number of outcome studies have looked at neuropsychological and psychiatric function both 
before and after STN DBS. The overall picture has indicated small declines on verbal fluency 
tests, executive function, and verbal memory retrieval1. A number of studies have evaluated 
cognitive function with stimulation on or off, and there is clear evidence that stimulation does 
impact cognitive abilities including verbal fluency 2, facial affect recognition 3, timing 4, and 
response inhibition 5. However, the mechanism underlying these changes is unknown. 
One hypothesis is that changes in cognitive and affective function are due to spread of electrical 
stimulation to neighboring non-motor regions of the STN (Jahanshahi, Ardouin et al. 2000; 
Hershey, Revilla et al. 2004; Czernecki, Pillon et al. 2005; Funkiewiez, Ardouin et al. 2006; Halbig, 
Tse et al. 2009). The possibility that variability in on-off effects arises from a difference in 
stimulation location is corroborated by our prior work (____ et al., under review) and others’ 
demonstrating that contact location is relevant to cognitive outcomes from STN DBS 6, 7 
An alternative hypothesis that could explain stimulation effects on cognition concerns the 
frequency of stimulation. The optimal benefit for motor function occurs with high frequency 
stimulation, on the order of 130 Hz, although there is some minor variation across patients. 
Stimulation at this frequency appears to interrupt the pathological beta oscillations that occur in 
the basal ganglia associated with motor impairments. LFP recording in PD patients suggests that 
oscillatory activity is important for cognitive function 8 and high frequency stimulation may interfere 
with cognitive processing. This fits with Wojtecki and colleagues 9 finding that verbal fluency 
performance worsens with high frequency stimulation and improves with low frequency 
stimulation. 
This study will clarify prior observations of cognitive changes in patients with STN DBS27 and 
opens the door to tailoring stimulation parameters to independently influence cognitive or motor 
function. For example, DBS technology could be designed to improve both cognitive and motor 
symptoms by stimulating at one frequency in dorsal STN, and another frequency in ventral STN.  
Aim 1. To evaluate the cognitive effects of high frequency stimulation at dorsal and ventral 
contact locations in PD patients with bilateral subthalamic nucleus DBS electrodes. We 
hypothesize that, relative to OFF stimulation, performance on tasks involving executive functions 
will show greater change at ventral contacts than at dorsal contacts.  
Aim 2. To evaluate the cognitive effects of low frequency stimulation at dorsal and ventral 
contact locations in PD patients with bilateral subthalamic nucleus DBS electrodes. We 
hypothesize that, for tasks where high frequency stimulation produces a deficit relative to OFF 
stimulation (e.g., verbal fluency), low frequency stimulation will eliminate or reverse performance 
changes relative to OFF stimulation.  
Aim 3. To characterize changes in cognitive network activity during alternative stimulation 
of the STN. We will also collect scalp EEG data during task performance when stimulation is OFF 
compared to alternative DBS settings. Patients with Medtronic or Abbott/St. Jude DBS systems 
that have been MRI safety tested will also undergo fMRI on a second day to examine BOLD 

Version Date: August 28, 2020 
responses during task performance while stimulation is OFF compared to alternative DBS 
settings.  
 
Study Design  
This is a prospective cohort study. All data will be collected at the Cleveland Clinic over one or 
more study days. The Figure provides an overview of the study procedures and timing for 
patients. 
Sample 
We will recruit 15 patients diagnosed with Idiopathic Parkinson disease.  
Inclusion Criteria:  
1. Between 40 and 70 years of age, 
2. Ability to provide informed consent, 
3. Clinical diagnosis of idiopathic Parkinson disease (PD) by a movement disorders neurologist, 
4. Disease duration of at least 4 years, 
5. Treated with bilateral STN DBS for at least 3 months prior to study enrollment. 
Exclusion criteria:  
1. History of prior neurosurgical intervention for PD (e.g., DBS, thalamotomy, pallidotomy)  
2. History of other central nervous system disease (excluding migraine),  
3. Presence of active psychiatric symptoms meeting Diagnostic and Statistical Manual of Mental 
Disorders-4th Edition (DSM-IV) criteria for Axis-I disorder on formal psychiatric evaluation, with 
the exception of mild depression (Beck Depression Inventory-2 score below 19), 
4. Cognitive impairment meeting Diagnostic and Statistical Manual of Mental Disorders-4th 
Edition (DSM-IV) criteria for dementia on formal neuropsychological evaluation, 
5. Current alcohol or substance abuse,  
6. Lack of fluency in English which would invalidate cognitive testing,  
7. Hearing or visual impairment precluding cognitive testing. 
 
Exclusion criteria for Imaging procedures: 
8. Inability to safely undergo MRI procedure (i.e., metal objects like prostheses, pacemakers) 
Controls 
We will recruit 20 health controls without Idiopathic Parkinson disease to examine normal 
performance and EEG variability over repeated task administration. 
Inclusion Criteria: 
1. Between 3 and 70 years of age, 
2. Ability to provide informed consent. 
Exclusion Criteria: 
1. History of  central nervous system disease (excluding migraine), 
2. Presence of active psychiatric symptoms meeting the Diagnostic and statistical Manual of 
Mental Disorders – 4th Edition (DSM-IV) criteria for Axis-I disorder on formal psychiatric 
evaluation, with the exception of mild depression (Beck Depression Inventory-2 score below 
19), 
3. Cognitive impairment meeting the Diagnostic and statistical Manual of Mental Disorders – 4th 
Edition (DSM-IV) criteria for dementia on formal neuropsychological evaluation, 
4. Current alcohol or substance abuse, 

Version Date: August 28, 2020 
5. Lack of fluency in English which would invalidate cognitive testing, 
6. Hearing or visual impairment precluding cognitive testing 
Exclusion criteria for Imaging procedures is not applicable. Healthy controls will only complete 
EEG monitoring and cognitive testing.  
 
Research Procedures – Arm 1 (12 patients) 
Study Day 1: Patients will be admitted to the Clinical Research Unit of the Clinical and 
Translational Research Center on Study Day 1 after withholding Parkinson’s medications 
overnight. After admission, they will undergo initial stimulation threshold evaluation (for 
sensorimotor stimulation side effects) with a physician’s assistant trained in DBS programming. 
An EEG technician will apply scalp electrodes and electroencephalogram (EEG) activity will be 
monitored throughout the Study visit using standard electrophysiological equipment under the 
supervision of Dr. ____. Subjects with then complete two test sessions, at different stimulation 
parameters (varying contacts and frequencies designed by Dr. ____ ____ at Case Western 
Reserve University) at the amplitude corresponding to 90% of side effect threshold.  
Test sessions: Each testing session involves performance of several tasks including a phonemic 
fluency, semantic fluency, Simon task, Facial Affect Recognition task (FAR), Time Production 
task, Interval Judgment task, as well as a speeded finger tapping test and a group of visual 
analogue rating scales regarding current mood and well-being (anxiety, motivation, fatigue, 
physical discomfort).  
There will be at least 30 minutes between each session for wash-in/washout of stimulation effects 
and to rest. Patients will be provided with lunch and additional rest breaks, as needed. At the end 

Version Date: August 28, 2020 
of the last session, patients will take their regular 
PD medications and stimulation will be readjusted 
to their clinically-defined settings. Note that STN 
DBS therapy has a ‘wash-in’ period of seconds to 
minutes, while medication therapy typically has a 
‘wash-in’ period of around 15 to 30 minutes. EEG 
electrodes will be removed and they will be 
discharged from the CRU when the patient 
subjectively feels that their stimulation therapy and 
medications have taken effect, and the supervising 
neurologist or movement disorder Physician’s 
Assistant delegate observe that Parkinsonian 
symptoms have improved.  
Patient-specific stimulation settings: Deidentified 
pre- and post-operative imaging will be shared 
with Dr. ____ ____ at Case Western Reserve 
University 
for 
creation 
of 
patient-specific 
stimulation parameters (Data Use Agreement 
attached). Patient specific stimulation models for 
the active cathode/anode that preferentially 
activate dorsal and ventral aspects of the 
Subthalamic Nuclei will be constructed prior to the 
patients’ arrival. All stimulation adjustments will be 
completed by an unblinded Physician Assistant 
trained in DBS programming. Patients will be 
blinded to stimulator settings and all data 
collection will be completed by blinded study 
personnel. We recognize that it is likely not 
possible to complete the research sessions for 
DBS patients in a fully blinded manner: in 
particular, the off-stimulation state and the low 
frequency stimulation states may be obvious to 
both patients and study personnel in the absence 
of medications. At each session, we will assess 
patient blinding (i.e., query patients’ belief 
regarding current stimulator setting) to identify 
those patients who remain blinded for possible 
subgroup analyses. 
Study Day 2: On a second day (scheduled at the 
subjects’ convenience, within 4 weeks of the first 
study day), patients will again be admitted to the 
Clinical Research Unit of the Clinical and 
Translational Research Center after withholding Parkinson’s medications overnight. After 
admission, an EEG technician will apply scalp electrodes and electroencephalogram (EEG) 
activity from the Epilepsy Monitoring Unit, under the supervision of Dr. ____. Subjects will then 
complete the three remaining test sessions at different stimulation parameters (varying contacts 
and frequencies designed by Dr. ____ ____ at the Case Western Reserve University) at the 
amplitude corresponding to 90% of side effect threshold. 
ARM 1
Day 1  Clinical Research Unit
Start Time
Minutes
Procedure
7:00
15
Informed Consent and Admit to CRU
7:15
60
EEG leads applied
8:15
15
Threshold Evaluation
8:30
30
Setting 1 and wash-in 
9:00
30
Test Session 1
9:30
30
10:00
30
Test Session 2
10:30
60
Day 2  Clinical Research Unit
Start Time
Minutes
Procedure
7:00
60
EEG leads applied and admit to CRU
8:00
30
8:30
30
Test Session 3
9:00
30
Setting 4 initiated 
9:30
30
Test Session 4
10:00
30
10:30
30
Test Session 5
11:00
60
Day 3  Research MRI at Mellen Center
Minutes
Procedure
20
Safety checklist and MRI prep
20
Setting 1 initiated and position in MRI
30
MRI scan with tasks
20
30
MRI scan with tasks
20
Clinical settings applied, meds resumed 
Extract from scanner, Setting 2 initiated, position in MRI
Setting 2 and wash-in
Setting 3 and wash-in
Meds resumed, Clinical settings applied, 
EEG leads removed, and discharge
Setting 5 initiated 
Meds resumed, Clinical settings applied, 
EEG leads removed, lunch, and discharge

Version Date: August 28, 2020 
Study Day 3: On a third day (scheduled at the subjects’ 
convenience within 4 to 6 weeks of the first study day), 
only subjects with MRI-safe DBS systems will undergo 
fMRI scanning at the Mellen Center Imaging Center 
after withholding Parkinson’s medications overnight. 
Patients will have their stimulators adjusted (in a 
randomized order) to OFF and to the patient-specific 
stimulation parameters that induced maximal cognitive 
change on Study Day 1. Specific sequences for 
structural and functional MRI will be determined by Drs. 
____ and ____ based on their prior studies 
demonstrating safety of intracranial electrodes and 
DBS equipment in MRI environments 10-12. 
Research Procedures – Arm 2 Harmonics (3 patients) 
Study Session 1. Patients with MRI-compatible DBS 
systems will be admitted to the Clinical Research Unit 
of the Clinical and Translational Research Center for 
Study Session 1. Patients will be tested while ON their 
regular Parkinson’s medications. We will also record 
EEG from a sparse electrode array (Fz, Cz, Pz, Oz, F3, 
F4, C3, C4). At the first session, each patient will have 
bilateral STN DBS electrodes adjusted by a physician-
assistant trained in DBS programming procedures. 
Settings are adjusted in randomized order to deliver 
stimulation bilaterally at six low frequencies – 2, 4, 8, 
11, 17, and 32 Hz. All other clinical personnel and the 
patient will remain blinded to stimulation settings. At 
each setting, patients will remain seated and at rest for 
a 10-15 minute wash-in period while monitored for 
sensorimotor or other neurological side effects. They 
will then perform two of the tasks from the existing 
protocol (Simon task, Verbal fluency task) for 10-15 
minutes. After this 20-30 minute period, stimulation 
settings will again be changed to another setting. After 
all 6 settings are completed, patients’ stimulation will be 
returned to their clinically-determined settings and 
scalp electrodes removed. 
Study Session 2. On the same or different day 
(scheduled at the subjects’ convenience maximum of 6 
weeks of the first study session), subjects with MRI-
safe DBS systems will undergo fMRI scanning at the 
Mellen Center Imaging Center. Patients will be tested 
while ON their regular Parkinson’s medications. 
Patients will have their stimulators adjusted (in a 
randomized order) to each of the six low-frequency 
stimulation parameters from Study Session 1 and 
resting-state fMRI scans lasting completed at each 
setting. Specific sequences for structural and functional MRI will be determined by Drs. ____ and 
ARM 2
Session 1  Clinical Research Unit
Start Time
Minutes
Procedure
7:00
15
Informed Consent and Admit to CRU
7:15
30
EEG leads applied
7:45
15
Threshold Evaluation
8:00
15
Setting 1 and wash-in 
8:15
15
Test Session 1
8:30
15
Setting 2 and wash-in 
8:45
15
Test Session 2
9:00
15
Setting 3 and wash-in 
9:15
15
Test Session 3
9:30
15
Setting 4 and wash-in 
9:45
15
Test Session 4
10:00
15
10:15
15
Test Session 5
10:30
15
10:45
15
Test Session 6
11:00
45
Session2  Research MRI at Mellen Center
Minutes
Procedure
20
Safety checklist and MRI prep
15
Setting 1 initiated and position in MRI
10
MRI scan at rest
15
10
MRI scan at rest
15
10
MRI scan at rest
15
10
MRI scan at rest
15
10
MRI scan at rest
15
10
MRI scan at rest
10
Extract from scanner, Clinical settings applied
Extract from scanner, Setting 3 initiated, position in MRI
Extract from scanner, Setting 4 initiated, position in MRI
Extract from scanner, Setting 6 initiated, position in MRI
Extract from scanner, Setting 5 initiated, position in MRI
Setting 5 and wash-in
Setting 6 and wash-in
Clinical settings applied, EEG leads 
removed, lunch, and discharge
Extract from scanner, Setting 2 initiated, position in MRI

Version Date: August 28, 2020 
____ based on their prior studies demonstrating safety of intracranial electrodes and DBS 
equipment in MRI environments 10-12. 
 
Research Procedures – Healthy Controls (20 patients) 
Study Day 1: Controls will be not be admitted to the Clinical Research Unit of the Clinical and 
Translational Research Center; testing will take place in private laboratory space (T2-303). An 
EEG technician will apply scalp electrodes and electroencephalogram (EEG) activity will be 
monitored throughout the Study visit using standard electrophysiological equipment under the 
supervision of Dr. ____. Controls will then complete the remaining study procedures over one 3-
hour period.   
Test sessions: Controls will complete five 25-minute testing sessions separated by 10-15 minute 
break periods. Each session will involve performance of several tasks that may include phonemic 
fluency, semantic fluency, Simon task, Facial Affect Recognition task (FAR), or Interval Judgment 
task.  
 
Data Analysis  
Behavioral Tasks: With the support of a Biostatistics consultant (____), we propose to evaluate 
the behavioral task data using a combination of methods for General Linear model and categorical 
data methods where appropriate. Selected details are presented with the relevant aims above. 
Statistical corrections will be applied to avoid any increase in family-wise error rate.  
EEG: We will analyze event-related potentials (ERP) to trial events in individual tasks to 
investigate phase-locked activity. Non-phase-locked activity will be investigated by averaging 
power within alpha, beta, and gamma frequency bands with respect to the trial events. The latter 
analysis technique will permit identification of event-related desynchronizations (ERD) and 
synchronizations (ERS)24 associated with non-clinical stimulation parameters. 
BOLD:  Event-related functional MRI data at all stimulation settings will be analyzed for individual 
subjects to evaluate patient-specific changes in activated networks. Group-level analyses will be 
dependent on the degree of similarity across patients in terms of specific cognitive performance 
changes and associated stimulation parameters.  
Confidentiality: CCF study investigators will have sole access to the study data. To protect 
confidentiality, participants’ data will be identified only by coded subject number and stored in a 
secure location in a de-identified manner. All data provided to Dr. ____ for construction of 
stimulation models will be de-identified and encrypted. A password-protected, electronic record 
linking subject numbers with identifying information will be maintained in a password-protected 
folder on a secure server and only CCF-based study investigators will have access to this file. 
Data analysis will be conducted by the study investigators in consultation with biostatistics (____), 
where appropriate. Dissemination of the results will largely involve aggregate data, although 
individual data points may be used where illustrative. All dissemination of the study findings will 
maintain confidentially and include only de-identified data, except in the situation where express 
written permission has been obtained from the patient in advance. 
Adverse Events and Safety 
For Study sessions involving stimulation and EEG recording, the patients are admitted to the 
CRU with continuous monitoring by nursing staff. Given the minimal risk of the computerized 
tasks and EEG recordings, the likelihood of adverse events due to the behavioral task or scalp 
electrodes is very low. Non-clinical or no DBS delivery is expected to worsen some Parkinson's 

Version Date: August 28, 2020 
symptoms temporarily. The Physician Assistant completing the stimulation adjustment and 
threshold testing will also monitor for patient safety and well-being during parameter changes.  
In addition, patients will complete ratings scales of their well-being and discomfort at each 
stimulator setting change, as an additional check on subject safety. For fMRI procedures, Drs. 
____ and ___ will closely monitor data integrity and patient safety. They are experts in the 
safety of MRI scanning in patients with implanted DBS systems.  
A Data Monitoring Committee is not planned for this study. The Principal and Co-Investigators, 
as well as other protections in place (i.e., CRU clinical staff), will continuously monitor subject 
safety and data integrity. Adverse events and Unanticipated Problems will be reviewed by the 
Principle and Co-Investigators. If an Adverse Event occurs, it will be recorded on the Adverse 
Event Summary Sheet, and this will be submitted along with the Adverse Event Report in 
accordance with the stated time limitations. No clinical electrophysiological report will be 
generated as the recordings performed do not constitute diagnostic studies. However, if an 
unexpected finding is observed during the electrophysiological analysis (e.g., seizure activity), 
consult to the Epilepsy Center will be ordered. Likewise, if an unexpected finding is observed 
during the MRI procedure (e.g., mass), Dr. ____ will consult with the patient.  
Consent  
The informed consent process for controls will be completed on the study day prior to EEG 
electrode application by Dr. ____ or the research coordinator. The informed consent process for 
patients will be completed by Dr. ____ or the research coordinator/technician in a 2-step process.  
Step 1:  
For patients approached during a regularly scheduled clinical visit to CCF Main campus: The full 
procedures, risks, benefits, and alternatives to participation will be reviewed with patients in a 
private setting (i.e., exam room). Potential participants will be given a copy of the full written 
consent document (either with or without Study Day 3, depending on the type of DBS system 
implanted) and are given the opportunity to review the document and ask questions or 
clarifications of the person conducting the consent interview. The patient is also permitted to 
discuss the matter with their spouse/caregiver privately before consenting to participate. Patients 
who wish to proceed will provide limited written consent to access their neuroimaging data 
obtained as part of routine clinical care for pre-surgical planning and post-operative electrode 
placement confirmation, de-identify those scans, and deliver them in encrypted format to Dr. ___ 
for creation of patient-specific stimulation parameters.  
For patients not seen in clinic: A letter will be mailed to potential subjects (see Recruitment letter), 
which includes the screening consent and the main study consent. Study personnel will conduct 
a follow up phone call (See Screening Telephone Script) to ensure that patients received the letter 
and to review the main study and the initial screening consent. If the patient agrees to participate, 
he/she will be asked to sign the screening consent and return it via the self-addressed and 
stamped envelope provided in the mailing. Upon receipt of the signed screening consent, de-
identified scans will be transmitted to Dr. ____ at CWRU. The appropriate confirmation letter (see 
Confirmation letters – ScreenIn or ScreenFail) will be sent to patient to inform them of whether 
personalized stimulation models could or could not be constructed.  For those patients who screen 
in, there will be a follow up phone call to serve as the main study consent discussion (See Consent 
Telephone Script) and to schedule an appointment at the CRU, if the patient provides verbal 
consent to participate).  
Step 2: 
Patients will be consented with the full informed consent process when they arrive at the CRU for 
the first Study Day. The consent process will take place in a private CRU inpatient room.  

Version Date: August 28, 2020 
When patients return for additional study sessions, they will be reminded, before study 
procedures commence, that they may withdraw consent at any time without consequences.  
 
References 
1. 
Parsons TD, Rogers SA, Braaten AJ, Woods SP, Troster AI. Cognitive sequelae of subthalamic 
nucleus deep brain stimulation in Parkinson's disease: a meta-analysis. Lancet Neurology 2006;5:578-
588. 
2. 
Ehlen F, Krugel LK, Vonberg I, Schoenecker T, Kuhn AA, Klostermann F. Intact lexicon running 
slowly--prolonged response latencies in patients with subthalamic DBS and verbal fluency deficits. PLoS 
One 2013;8:e79247. 
3. 
Dujardin K, Blairy S, Defebvre L, et al. Subthalamic nucleus stimulation induces deficits in 
decoding emotional facial expressions in Parkinson's disease. Journal of Neurology, Neurosurgery & 
Psychiatry 2004;75:202-208. 
4. 
Wojtecki L, Elben S, Timmermann L, et al. Modulation of human time processing by subthalamic 
deep brain stimulation. PLoS One 2011;6:e24589. 
5. 
Jahanshahi M, Obeso I, Baunez C, Alegre M, Krack P. Parkinson's disease, the subthalamic 
nucleus, inhibition, and impulsivity. Mov Disord 2015;30:128-140. 
6. 
York MK, Wilde EA, Simpson R, et al. Relationship between neuropsychological outcome and 
DBS surgical trajectory and electrode location. Journal of the Neurological Sciences 2009;287:159-171. 
7. 
Witt K, Granert O, Daniels C, et al. Relation of lead trajectory and electrode position to 
neuropsychological outcomes of subthalamic neurostimulation in Parkinson's disease: results from a 
randomized trial. Brain 2013;136:2109-2119. 
8. 
Anzak A, Gaynor L, Beigi M, et al. A gamma band specific role of the subthalamic nucleus in 
switching during verbal fluency tasks in Parkinson’s disease. Experimental Neurology 2011;232:136-142. 
9. 
Wojtecki L, Timmermann L, Jorgens S, et al. Frequency-dependent reciprocal modulation of 
verbal fluency and motor functions in subthalamic deep brain stimulation. Archives of Neurology 
2006;63:1273-1276. 
10. 
Bhattacharyya PK, Mullin J, Lee BS, Gonzalez-Martinez JA, ____ SE. Safety of externally 
stimulated intracranial electrodes during functional MRI at 1.5T. Magn Reson Imaging 2017;38:182-188. 
11. 
Baker KB, Kopell BH, Malone D, et al. Deep brain stimulation for obsessive-compulsive 
disorder: using functional magnetic resonance imaging and electrophysiological techniques: technical 
case report. Neurosurgery 2007;61:E367-368; discussion E368. 
12. 
Phillips MD, Baker KB, ____ MJ, et al. Parkinson disease: pattern of functional MR imaging 
activation during deep brain stimulation of subthalamic nucleus--initial experience. Radiology 
2006;239:209-216.