DATA-MINING PROPOSAL (TEMPLATE)

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PO Box 14005 | Lenexa, Kansas 66285-4005 | USA | 888.387.3667 (toll free) | 913.341.3880 (local) | essentialtremor.org

Deep Brain Stimulation of the Posterior Subthalamic Area: A Treatment for Essential Tremor Refractory to Thalamic Stimulation

The Regents of the University of California, San Francisco

Katz Maya

M.D. Assistant Clinical Professor

Neurology

4150 Clement St. #219G, Room 127

San Francisco CA 94143

USA [email protected]

(415) 353-2273 (415) 353-2898

UNIVERSITY OF CALIFORNIA, SAN FRANCISCO

B E R K E L E Y D A V I S I R V I N E L O S A N G E L E S M E R C E D R I V E R S I D E S A N D I E G O S A N F R A N C I S C O S A N T A B A R B A R A S A N T A C R U Z

OFFICE OF SPONSORED RESEARCHRESEARCH MANAGEMENT SERVICES3333 CALIFORNIA STREET, SUITE 109SAN FRANCISCO, CALIFORNIA 94143-0962Office: (415) 502-8763Fax: (415) 502-8775http://officeofresearch.ucsf.edu/rms

February 27, 2014 Proposal No. P0500973

Dear Grant Administrator:

We are presenting for your review a request for support of the following project:

PROJECT TITLE: Deep Brain Stimulation of the Posterior Subthalamic Area:A Treatment for Essential Tremor Refractory to Thalamic Stimulation

PRINCIPAL INVESTIGATOR: Maya Katz, M.D.TYPE OF PROPOSAL: Grant, Clinical TrialINDIRECT COST RATE: 0%

Your favorable consideration will be appreciated. In the event of an award, the Regents of the University of California reserve the right to negotiate the terms of the award. The University of California, San Francisco submits this proposal with the understanding that it is unclassified, fundamental research as defined by the Export Control regulations. As such there should be no limitation on the freedom to publish research results or restrictions on the citizenship or national origin of those performing the research.

In the event of an award, please send checks or wires as follows: Please make checks payable to (please note new address): For wires:

The Regents of the University of California Bank of America NAUCSF Controller’s Office 100 West 33rd Street1855 Folsom Street, MCB 425, Box 0897 New York, NY 10001San Francisco, CA 94143-0897 (94103 for courier services) Account No. BofA #12335-23601

Routing No. 026009593Swift Code BOFAUS3N

Any Award documentation or correspondence should be sent directly to:

Monica HazlewoodContracts and Grant OfficerUCSF – Office of Sponsored ResearchContracts and Grants3333 California Street, Suite 315San Francisco, CA 94143-0962Telephone: (415) 476-2977e-Mail: [email protected]

Please direct question to Roderick Brown at (415) 758-1407 or via e-mail at [email protected].

Sincerely,

Monica Hazlewood Pre-Award Team Manager / Contracts and Grants Officer

Monica HazlewoodDigitally signed by Monica Hazlewood DN: cn=Monica Hazlewood, o=UCSF, ou=RMS, [email protected], c=US Date: 2014.02.28 11:19:16 -08'00'

International Essential Tremor Foundation Research Program Grant Application Authors: Maya Katz, M.D., Jill L. Ostrem, M.D., Philip A. Starr, M.D., Paul Larson, M.D.


Summary of the Proposed Project

The discovery of an effective treatment option for essential tremor patients who have failed all accepted medical and surgical therapies has the potential to profoundly improve function and quality of life for this group of patients. Currently, deep brain stimulation (DBS) of the thalamus significantly improves tremor in many individuals with severe essential tremor, but up to one-third of patients either have no initial benefit from stimulation, lose benefit over several years, or have to limit the strength of stimulation due to side effects. Therefore, there is a need to identify alternative deep brain stimulation targets that will offer more effective and better tolerated tremor control. Several European studies have described excellent reduction in tremor and fewer side effects with stimulation of an alternative brain target called the posterior subthalamic area. We propose an innovative study to investigate the use of posterior subthalamic area DBS in patients who do not have adequate tremor control despite already having DBS of the more traditional thalamic target. To date, only one small study using posterior subthalamic area DBS in 5 patients who already have thalamic DBS has been completed. This prior report used a limited (retrospective) study design, a small number of patients, and did not report on any side effects (whether present or absent). Our study will add to the currently limited knowledge about this treatment for severe essential tremor patients with a rigorous study design using standardized tools to carefully monitor for any side effects and report clinical benefit. The study will include 10 patients who will be followed over a 12-month period of time. Clinical effectiveness, side effects, impact on quality of life, surgical technique and optimal DBS programming strategies will be evaluated during chronic stimulation of the posterior subthalamic area in patients who have disabling tremor despite thalamic stimulation.

International Essential Tremor Foundation Research Program Grant Application Authors: Maya Katz, M.D., Paul Larson, M.D., Jill L. Ostrem, M.D., Philip A. Starr, M.D.,


AIMS: The primary aim is to investigate if deep brain stimulation (DBS) of the posterior subthalamic area (PSA) is an effective treatment for severe essential tremor (ET) refractory to pharmacological treatment and thalamic DBS. Secondary aims include evaluating the safety of PSA DBS, and documenting any adverse effects from chronic PSA stimulation. This study will also describe optimal intraoperative targeting and post-operative programming strategies for PSA DBS. RATIONAL/RELEVANCE OF THE PROPOSAL: ET is the most common cause of tremor1, with a prevalence between 4% to 5.6% in individuals aged 40 years and older, and 6% to 9% among individuals aged 60 years and older2-3. Patients with severe ET suffer from significant impairments in activities of daily living. Current treatments include pharmacologic therapies that provide adequate tremor control in only about 50%-70% of patients4-6. Deep brain stimulation (DBS) of the thalamus (ventral intermediate nucleus -VIM) is an FDA approved surgical treatment for severe ET that is refractory to medications. Many studies have reported on the significant effectiveness of this treatment7-11, with most long-term studies showing a 70-80% reduction in the severity of tremor11-17. Despite these results, there are several limitations to the clinical effectiveness of thalamic DBS, as listed below: 1) About 10% of severe ET patients do not have adequate tremor control with thalamic DBS18, particularly those with proximal tremor7. 2) A loss of efficacy of thalamic stimulation has been reported in 8-19% of patients 3 months to 1 year after surgery7,13, and up to 30% of patients after 6 to 7 years10. This has been traditionally believed to be due to emerging tolerance of the brain of ET patients to prolonged stimulation7,17, but more recent evidence suggests that this loss of efficacy over time may be due to progression of disease19. 3) Adverse effects of chronic stimulation, including dysarthria, ataxia, and persistent paresthesias can limit or complicate programming in 6 to 30% of patients receiving bilateral thalamic DBS11, 16-17, 20-21. Given these complications and limitations of thalamic stimulation, the posterior subthalamic area (PSA), which includes the zona incerta and the prelemniscal radiation, has been explored as an alternative DBS target for severe ET22, with several studies showing superiority of PSA stimulation compared with thalamic stimulation23-24. Currently, 13 studies have been published using PSA DBS for ET, with a total of 201 patients implanted. Most of these studies have shown either no adverse effects25 or a more mild side effect profile compared to thalamic stimulation, including transient paresthesias, dysphagia, and dysequilibrium25-27. Although there are a few reports of PSA DBS causing more significant paresthesias, dysarthria and gait ataxia that compromise programming23,28, these and other PSA DBS studies22 lack the use of standardized assessment tools, and a rigorous evaluation process, and some do not assess adverse effects at all24, 29-30. Therefore, it is difficult to accurately evaluate the preoperative baseline severity and change in severity of symptoms postoperatively without more robust assessment methods, as we plan to use in our study. Patients who have already failed pharmacological treatments and thalamic stimulation are the most vulnerable to a life of severe disability secondary to their tremor disorder. These patients are refractory to every accepted treatment modality, and could therefore stand to benefit the most from the development of a well-characterized, safe and effective alternative treatment modality. Only one study has previously reported on the effect of PSA DBS for patients who failed both pharmacological treatments and thalamic DBS, with improved tremor control found with PSA DBS31. This study was limited by a small sample size (5 patients), a retrospective design, and lack of long-term follow-up. In addition, there was no discussion of adverse effects, whether present or absent, after PSA DBS implantation. We propose to add to this limited literature with a larger study that includes a prospective and rigorous, double-blind design to better understand the role of PSA DBS in the treatment of severe ET patients who have failed every other treatment option.


RESEARCH METHODS AND PROCEDURES: Patient Selection: This prospective, double-blind, phase 4 clinical trial will examine the effectiveness of PSA DBS to treat ET refractory to medications and thalamic (VIM) DBS. Ten subjects will be enrolled at the University of California, San Francisco, Surgical Movement Disorders Center and the San Francisco Veterans Affairs Medical Center Parkinson’s Disease Research Education and Clinical Center. Inclusion Criteria will include: 1. ET refractory to pharmacological therapy and thalamic DBS either due to lack of adequate tremor control or intolerable adverse effects compromising stimulation parameters. Lack of adequate tremor control is defined as at least a 3 out of 4 postural and/or kinetic tremor score in the target limb on the Fahn-Tolosa-Marin Tremor Rating Scale (TRS) with thalamic stimulation turned on. The target limb is defined as the limb that exhibits the most severe tremor symptoms, or is chosen when the patient’s dominant hand presents with significant tremor symptoms. 2. Ability to understand the study process and sign informed consent. 3. Age 18 years or older 4. Stable medical therapy regimen and thalamic DBS settings for ET for at least one month prior to baseline exam 5. Willingness and ability to be available for appropriate follow-up times for the length of the study Exclusion Criteria will include: 1. Improper positioning of thalamic leads, which could potentially cause treatment failure32. 2. Prior intracranial procedure 3. Significant neurological injury or disease other than ET 4. Intracranial abnormalities that would make surgery contraindicated 5. Medical contraindications to surgery or MRI 6. Metallic implants that may interfere with the functioning of the device 7. Active alcohol or drug abuse 8. Female of child bearing age with a positive pregnancy test or not using adequate contraception 9. Dementia, significant cognitive impairment, or significant psychiatric disease 10. Any condition requiring repeated MRI scans or diathermy 11. Chronic anticoagulant use 12. Inability to speak or read English 13. Inability to comply with study requirements Study Design: Study Assessments: Response to PSA DBS will be assessed using a battery of clinical rating scales at three study visits, which includes a baseline pre-DBS visit (visit #1), and visits at 6 months post-DBS (visit #2), and 12 months post-DBS (visit #3). Study subjects will serve as their own controls and will be evaluated while taking their usual oral medications and under optimal programming settings. Motor assessments performed at each study visit will include the Fahn-Tolosa-Marin Tremor Rating Scale (TRS) and the Scale for the Assessment and Rating of Ataxia (SARA). These motor assessments will be done in up to four stimulation paradigms to evaluate the contributions of thalamic and PSA stimulation, both independently and concurrently, to tremor control (Table 1). There will be a one-hour washout period after each paradigm change before assessments are carried out. Both the patient and the evaluator will be blinded to the stimulation paradigm being used. An advanced practice nurse with extensive experience with DBS will place the patients in the different stimulation paradigms in a random order. Patients will also complete several non-motor assessments at each study visit to evaluate neuropsychological function and quality of life during chronic PSA stimulation. These non-motor assessments include measures of cognitive function (Montreal Cognitive Assessment –MoCA), measures of psychiatric function (Beck Depression Inventory – BDI; Beck Anxiety Inventory – BAI), and measures of quality of life and function (Quality of Life in Essential Tremor Questionnaire – QUEST; Short Form (36)- Health Survey - SF-36). In addition, in order to evaluate the effects of PSA stimulation on dysarthria, a detailed speech evaluation will be conducted by a licensed speech-language pathologist (SLP) during visit #1 and visit #3. During this speech evaluation, study participants will make audio recordings during readings of the standard Rainbow Passage in each of stimulation paradigms listed below (Table1). An SLP will use the Dysarthria Rating Scale (DRS) to evaluate overall dysarthria, as well as resonance, respiration, pitch, prosody and loudness in each stimulation paradigm, in a blinded fashion.


Table 1. Stimulation paradigms per study visit Visit #1:

Pre-DBS baseline Visit #2: 6 months post-DBS

Visit #3: 12 months post-DBS

Stimulation paradigms

OFF VIM ON VIM

OFF VIM/OFF PSA DBS ON VIM/OFF PSA DBS OFF VIM/ON PSA DBS ON VIM/ON PSA DBS

OFF VIM/OFF PSA DBS ON VIM/OFF PSA DBS OFF VIM/ON PSA DBS ON VIM/ON PSA DBS

Surgical Procedures: All patients will be implanted with Medtronic FDA approved neurostimulators, quadripolar leads (model 3387), extension wires and accessories. Both bilateral and unilateral surgery will be performed (depending on tremor severity) under monitored local anesthesia. The initial anatomic target will be defined on stereotactic brain magnetic resonance imaging (MRI). Images will be imported into a workstation (Framelink version 4.1, Medtronic) and computationally reformatted parallel to the anterior commissure-posterior commissure (AC-PC) line. The PSA will be targeted by direct visualization of the white matter tract at the level of the largest radius of the red nucleus on axial imaging and the posterior border of the subthalamic nucleus (approximate stereotactic parameters: 11-12mm lateral to the midline, 6-7.5mm behind the mid-commissural point, and 3-4mm below the inter-commissural line22). Following the placement of the 3387 lead, we will observe for an intra-operative effect of lead insertion and will perform intraoperative test stimulation to assess for stimulation-induced thresholds. In the same surgical sessions, a dual-channel implantable pulse generator (IPG) Activa PC will be implanted in the chest wall over the pectoralis fascia and connected to the brain leads by a 40cm lead extender. For most patients, the IPG will be placed on the side opposite to the current IPG (connected to the thalamic leads), but it may also be implanted on the same side as the current IPG, or in the abdomen, based on specific patient preferences and/or medical necessity. The thalamic DBS leads will remain implanted. All patients will undergo postoperative MRI to confirm lead placement, using a transmit-receive headcoil in accordance with the device manufacturer recommendations. DBS Programming: All neurostimulator programming will be performed by a non-blinded advanced practice nurse specializing in movement disorders and DBS. Patients will undergo initial programming at about 7-10 days after DBS implantation, followed by further programming sessions postoperatively, at regular intervals, depending on medical necessity. Outcome measures: The primary outcome will include the mean change in TRS tremor score for the target limb from baseline (ON VIM DBS) to 12 months (OFF VIM/ON PSA DBS). The TRS tremor score includes assessments of tremor severity as well as functional capabilities: [(question 5 (right arm) or question 6 (left arm) + questions 11-13 (writing and pouring)].

Secondary outcomes will include changes in TRS at earlier time points and in all four stimulation paradigms, as well changes in ataxia severity in all four stimulation paradigms during the three study visits, using the SARA. We will also look at changes in quality of life and overall function using the QUEST and the SF-36 forms. Any differences in neuropsychological measures will be assessed using MoCA, BDI, and BAI. Dysarthria will be evaluated by a SLP using the DRS. All device and procedure-related adverse events will be documented intra-operatively, peri-operatively and at the 6-month and 12-month post-operative visits. Lead position, neurosurgical targeting techniques and effective DBS programming strategies will be recorded. Study personnel: The design and conduct of the study will be directed by Dr. Maya Katz (PI). Dr. Paul S. Larson will perform the majority of DBS implantation procedures. Dr. Jill L. Ostrem and Dr. Philip A. Starr will provide additional mentorship. Statistical Analysis: Assuming the same data variability seen in the other previous studies of PSA DBS in ET, and a 50% conservative effect size; with 10 patients, using a two-sided alpha of 0.05, we would have greater than 90% power to detect a statistically significant difference. A paired t-test or non-parametric equivalent (Wilcoxon matched-pairs signed ranks test) will be used to analyze the statistical significance of changes in pre-DBS and post-DBS clinical rating scales. All analyses will be conducted using STATA software. Tests will be significant at p value <0.05. Additionally, descriptive statistics will be used to describe patient characteristics and clinical outcome measures. All patients with available data at the 12-month visit will be included in the analysis.


ANTICIPATED RESULTS: This study will be the largest to date evaluating the PSA as a treatment option for patients with severe ET refractory to both medications and thalamic stimulation. We anticipate that chronic stimulation of the PSA will be an effective treatment for patients who have failed every other accepted treatment modality. Standardized techniques and validated measurement tools will be used to evaluate outcomes and adverse effects. DBS of the PSA has been shown to be better tolerated than thalamic stimulation in several small, retrospective studies, although adverse events and stimulation complications have had limited and inconsistent documentation in prior reports. Our study will systematically and carefully record these findings to better define expected clinical effect, optimal programming and targeting, as well as patient selection for chronic PSA stimulation.

BUDGET AND JUSTIFICATION

PERSONNEL Role Effort Salary Benefits Rate Benefits TOTAL

Maya Katz, M.D. Principal Investigator 8% $11,124 33% $3,671 $14,795 Paul Larson, M.D. Co-Investigator 1% $1,514 33% $500 $2,014 TBN Clinical Study Coordinator 4.583% $3,139 41% $1,287 $4,426 PERSONNEL SUBTOTAL $15,777 $5,458 $21,235 NON-PERSONNEL EXPENES Patient Reimbursement Costs for Travel ($100 per visit, 3 visits, 10 patients) $3,000 Speech-Language Pathology ($50 per hour, 10 hours) $500 Data Network Recharge $67 Computing and Communication Device Support Service Charge $75 General Automobile & Employee Liability (GAEL) $123 NON-PERSONNEL SUBTOTAL $3,765 TOTAL BUDGET REQUEST $25,000

PERSONNEL Maya Katz, MD, Principal Investigator, 8% effort, salary and benefits requested: Dr. Katz takes primary responsibility for study design, implementation and oversight. Dr. Katz is responsible for all patient evaluations. She will also be responsible for analysis of the data and preparation of the manuscript for publication. Paul S. Larson, MD, Co-Investigator, 1% effort, salary and benefits requested: Dr. Larson will perform the majority of the deep brain stimulation implantation surgeries, and will monitor study subjects postoperatively for any surgical complications. He will also provide assistance with study design and manuscript preparation. TBN, Study Coordinator, 4.583% effort, salary and benefits requested: patient scheduling, visit coordination, maintenance of regulatory binders & IRB compliance, maintenance of study database. Additional study coordination at the VA will be carried out by a full-time staff member at the VA PADRECC. Philip A. Starr, MD, Other Significant Contributor, effort as needed, no salary or benefits requested: Dr. Starr will provide guidance for study development and manuscript preparation. Jill Ostrem, MD, Other Significant Contributor, effort as needed, no salary or benefits requested: Dr. Ostrem will provide mentorship on study design, implementation, data analysis and manuscript preparation. OTHER DIRECT EXPENSES Speech-language pathology ($500): The rehabilitation department at UCSF will provide a certified speech language pathologist to perform the baseline and 12 month dysarthria evaluations. Services are $50 per hour; we estimate that this will take a total of 10 hours. Travel Reimbursement for Patients ($3,000): Patients will be reimbursed $100 per visit. This is for 10 patients, with 3 visits for patient to complete the study. Computing and Communication Device Support Services: Computing and communication device support services (CCDSS) provides integral support to campus voice and data technology functions. CCDSS includes software installation/updates, internet security, hardware setup/configuration, and centrally managed patching, storage and backup. The university charges these expenses to all funding sources based on a monthly recharge rate per pro-rated FTE; currently $46 per FTE per month. Data Network Recharge: UCSF data network services recharge provides funding for critical equipment in support of UCSF’s electronic information flow. Almost all electronic communications, ranging from administrative systems to e-mail and connection with the internet, relies on and makes use of UCSF’s data network. Calculations are based on the percent effort to be charged to the project for each person named in the grant. The network recharge rate will be approximately $41 per month per pro-rated FTE effective 7/1/14. UCSF General Automobile & Employee Liability (GAEL): UCSF is responsible for the University's General Automobile & Employee Liability self-insurance program. An assessment of $0.78 per $100 of payroll will be calculated for Fiscal Year 2014-2015. FACILITIES & ADMINISTRATIVE COSTS In adherence to the IETF indirect cost policy, no indirect costs have been calculated for this proposal.


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18. Koller W, Pahwa R, Busenbark K, Hubble J, Wilkinson S, Lang A, Tuite P, Sime E, Lazano A, Hauser R, Malapira T, Smith D, Tarsy D, Miyawaki E, Norregaard T, Kormos T, Olanow CW. High-Frequency Unilateral Thalamic Stimulation in the Treatment of Essential and Parkinsonian Tremor. Ann Neurol. 1997;42:292-9. 19. Favilla CG, Ullman D, Shukla AW, Foote K, Jacobson CE, Okun MS. Worsening essential tremor following deep brain stimulation: disease progression versus tolerance. Brain. 2012:1-8. 20. Obwegeser AA, Uitti RJ, Turk MF, Strongosky AJ, Wharen RE. Thalamic stimulation for the treatment of midline tremor in essential tremor patients. Neurology. 2000;54:2342-4. 21. Pahwa R, Lyons KL, Wilkinson SB, Carpenter MA, Troster A, Searl JP, Overman J, Pickering S, Koller WC. Bilateral thalamic stimulation for the treatment of essential tremor. Neurology. 1999;53(7):1447-50. 22. Xie T, Bernard J, Warnke P. Post subthalamic area deep brain stimulation for tremor: a mini-review. Translational Neurodegeneration. 2012:1-20. 23. Hamel W, Herzog J, Kopper F, Pinsker M, Weinert D, Muller D, Krack P, Deuschl G, Mehdorn HM. Deep brain stimulation in the subthalamic area is more effective than nucleus ventralis intermedius stimulation for bilateral intention tremor. Acta Neurochir (Wien). 2007;149:749-758. 24. Herzog J, Hamel W, Wenzelburger R, Potter M, Pinsker MO, Bartussek J, Morsnowski A, Steigerwald F, Deutschl G, Volkmann J. Kinetic analysis of thalamic versus subthalamic neurostimulation in postural and intention tremor. Brain. 2007;130:1608-25. 25. Plaha P, Patel NK, Gill SS. Stimulation of the subthalamic region for essential tremor. J Neurosurg. 2004;101:48-54. 26. Kitagawa M, Murata J, Kikuchi S, Sawamura Y, Saito H, Sasaki H, Tashiro K. Deep brain stimulation of subthalamic area for severe proximal tremor. Neurology. 2000;55:114-6. 27. Blomstedt P, Sandvik U, Tisch S. Deep brain stimulation in the posterior subthalamic area in the treatment of essential tremor. Mov Disord 2010;25:1350-6. 28. Barbe MT, Liebhart L, Runge M, Deyng J, Florin E, Wojtecki L, Schnitzler A, Allert N, Surm V, Fink GR, Maarouf M, Timmerman L. Deep brain stimulation of the ventral intermediate nucleus in patients with essential tremor: stimulation below intercommissural line is more efficient but equally effective as stimulation above. Exp Neurol 2011;230:131-7. 29. Blomstedt P, Fytagoridis A, Tisch S. Deep brain stimulation of the posterior subthalamic area in the treatment of tremor. Acta Neurochir 2009;151:31-6. 30. Blomstedt P, Sandvik U, Hariz MI, Fytagoridis A, Forsgren L, Hariz GM, Koskinen LD. Influence of age, gender and severity of tremor on outcome after thalamic and subthalamic DBS for essential tremor. Parkinsonism Relat Disord 2011;17:617-20. 31. Blomstedt P, Lindvall P, Linder J, Olivecrona M, Forsgren L, Hariz M. Reoperation after failed deep brain stimulation for essential tremor. World Neursurg. 2012;78(5):554.e1-5. 32. Papavassiliou E, Rau G, Heath S, Abosch A, Barbaro NM, Larson PS, Lamborn K, Starr PA. Thalamic deep brain stimulation for essential tremor: relation of lead location to outcome. Neurosurgery. 2004;54(5):1120-9.

BIOGRAPHICAL SKETCH Provide the following information for the Senior/key personnel and other significant contributors in the order listed on Form Page 2.

Follow this format for each person. DO NOT EXCEED FOUR PAGES.

NAME Maya Katz, M.D.

POSITION TITLE Assistant Professor, Department of Neurology, University of California, San Francisco Staff Neurologist and Associate Director of Research, Parkinson's Disease Research, Education and Clinical Center (PADRECC), San Francisco VA Medical Center (VAMC)

eRA COMMONS USER NAME (credential, e.g., agency login)

EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable.)

INSTITUTION AND LOCATION DEGREE (if applicable) MM/YY FIELD OF STUDY

Cornell University B.A 1999 Anthropology Cornell University, Weill Medical College M.D. 2007 Medicine Mount Sinai Medical Center Internship 2008 Internal Medicine Mount Sinai Medical Center Residency 2011 Neurology UCSF Medical Center, San Francisco VAMC Fellowship 2013 Movement Disorders

A. PERSONAL STATEMENT I am an Assistant Professor at the University of California, San Francisco Surgical Movement Disorders Center. This multidisciplinary group is one of the busiest deep brain stimulation (DBS) centers in the country and is internationally recognized for its comprehensive clinical care and therapeutic innovations. I am also a Staff Neurologist and Associate Director of Research at the Parkinson's Disease Research, Education and Clinical Center (PADRECC) at the San Francisco Veterans Affair Medical Center. The San Francisco PADRECC is one of six national centers of excellence focused on state-of-the-art clinical care, education and research for movement disorders. As a part of my positions at UCSF and the VAMC, I mentor and teach movement disorders fellows, neurology residents and UCSF medical students. My research interests include enhancing our understanding of DBS target selection and outcomes. This includes the discovery of new brain targets as well as new implantation and targeting techniques for deep brain stimulation to enhance treatment options for patients with essential tremor, Parkinson’s disease, and dystonia. In addition, my research focuses on neuroprotection in Parkinson’s disease to help identify disease-modifying therapies.

B. POSITIONS AND HONORS Positions and Employment 2000-2002 Healthcare Advocate, Medicare Rights Center, New York, NY 2002-2003 Director, Social Services and Direct Advocacy Programs, Medicare Rights Center, New York, NY 2003-2007 Co-Founder, Clinical Co-Director, Weill Cornell Community Clinic for the uninsured, New York, NY 2010-2011 Chief Resident, Department of Neurology, Mount Sinai Medical Center, New York, NY 2011-2013 Instructor, Department of Neurology, University of California, San Francisco 2013-present Staff Neurologist and Associate Director of Research, San Francisco VA Medical Center, Parkinson's Disease Research, Education and Clinical Center (PADRECC), San Francisco, CA 2013-present Assistant Professor, Surgical Movement Disorders Center, Department of Neurology University of California, San Francisco, CA

Honors and Awards 1999 Graduated Magna Cum Laude, Cornell University 2004 Weill Cornell Medical College Class of 1981 Scholarship 2004-2007 Joseph Collins Foundation Medical Scholarship 2006 Elaine Asnis Summer Fellowship in Cancer Research 2012-2013 UCSF Apex Fellows’ and Residents’ Advisory Group Professional Memberships 2008-present American Academy of Neurology 2008-present Medical Society of the State of New York 2011-present California Medical Association C. PEER-REVIEWED PUBLICATIONS Original Manuscripts 1. Katz M, Kilbane C, Rosengard J, Alterman R, Tagliati M. Referring patients for deep brain stimulation: an improving practice. Arch Neurol. 2011; 68 (8): 1027-1032. PMID: 21825238. 2. Bryson E, Aloysi A, Katz M, Popeo D, Kellner C. Rocuronium as muscle relaxant for electroconvulsive therapy (ECT) in a patient with adult onset muscular dystrophy. J ECT. 2011. Dec;27(4):e63-4. PMID: 22124227. 3. Dumont M, Kipiani K, Yu F, Willie E, Katz M, Calingasan NY, Gouras GK, Lin MT, Beal MF. Coenzyme Q10 decreases amyloid pathology and improves behavior in a transgenic mouse model of Alzheimer's Disease. J Alzheimers Dis. 2011;27(1):211-23. PMID: 3267988. 4. Cheung T, Nuno M, Hoffman M, Katz M, Kilbane C, Alterman R, Tagliati M. Longitudinal impedance variability in patients with chronically implanted DBS devices. Brain Stimul. 2013:1-6. PMID: 23619246. 5. Katz M, Byl NN, San Luciano M, Ostrem JL. Focal task-specific lower extremity dystonia associated with intense repetitive exercise: a case series. Parkinsonism and Related Disorders. 2013;19(11):1033-8. PMID: 23932354. Selected Abstracts 1. Chan Y, Richardson L, Moskowitz A, Katz M, Chason K, Singhal A, Poojary I, Kramer S, Levine SR. Out-of-Hospital Normobaric Oxygen Therapy in Presumptive Acute Stroke Patients: A Preliminary Study. [Abstract]. Annals of Emergency Medicine. 2009 Sept;54(3):S72. 2. Chan Y-F Y, Richardson LD, Katz M, Moskowitz A, Singhal AB, Chason K, Allison T, Lakoff D, Yang AH, Levine SR: Oxygen use for suspected acute ischemic stroke in pre-hospital and emergency department settings. [Abstract]. Neurology. 2010;74(Suppl 2):A448. 3. Katz M, San Luciano M, Luo P, Carlson K, Marks WJ, Larson PS, Starr PA, Follet K, Weaver F, Stern M, Reda D, Ostrem JL. Responsiveness of Parkinson’s disease motor subtypes to Subthalamic Nucleus (STN) vs. Globus Pallidus Internus (GPi) deep brain stimulation (DBS): an additional analysis of the VA CSP #468 Study. [Abstract]. Neurology. 2013 Feb;80(Meeting Abstracts 1):S23.006. Presented as a platform presentation at the American Academy of Neurology 65th Annual Meeting, March 2013 D. RESEARCH SUPPORT Completed Research Support Singing Field Foundation (Glass-PI) 1/1/2012 – 1/2014 Phase I trial evaluating the bioavailability and safety of oral N-acetylcysteine in Parkinson’s disease.

The goal of this project is to determine the lowest effective and well-tolerated dose of N-acetylcysteine to maintain concentrations in the CSF of Parkinson’s disease (PD) patients that have been shown to be neuroprotective in animal models of PD. Role: Co-Investigator

BIOGRAPHICAL SKETCH Provide the following information for the key personnel and other significant contributors in the order listed on Form Page 2.


NAME Paul S. Larson, MD

POSITION TITLE Associate Clinical Professor, Vice Chairman Department of Neurological Surgery University of California, San Francisco

eRA COMMONS USER NAME PAULLARSON EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, and include postdoctoral training.)

INSTITUTION AND LOCATION DEGREE (if applicable) YEAR(s) FIELD OF STUDY

Arizona State University BS 1990 Zoology The University of Arizona, College of Medicine MD 1995 Medicine University of Louisville Internship 1995–1996 General Surgery University of Louisville Residency 1996–2001 Neurological Surgery

A. Positions and Honors. 2001 – 2009 Assistant Clinical Professor, Department of Neurological Surgery, UCSF 2009 – present Associate Clinical Professor, Department of Neurological Surgery, UCSF 2008 – present Chief, Neurosurgical Service, Veterans Affairs Medical Center, San Francisco, CA 2009 – present Director and Founder, Center for Advanced Neurosurgical Operative Procedures (CanOp),

VAMC, San Francisco, CA 2011 – present Surgical Director, Parkinson’s Disease Research, Education and Clinical Center

(PADRECC), VAMC, San Francisco, CA 2011 – present Co-Director, Residency Program, Department of Neurological Surgery, UCSF 2011 – present Vice Chairman, Department of Neurological Surgery, UCSF Other Experience and Professional Memberships 2004 – present Neurosurgery Task Force, The Movement Disorders Society 2006 – 2010 Executive Council, American Society for Stereotactic and Functional Neurosurgery 2009 – present Joint AANS/CNS Guideline Committee 2009 – present Associate Editor for Psychiatry and Movement Disorders, Neurosurgery 2010 – present Editorial Board, NeuroMapping & Therapeutics 2012 – present Editorial Board, NeuroImage: Clinical Various dates Ad Hoc or Invited Reviewer, Neurotherapeutics, Neuropsychiatric Disease and Treatment,

Parkinsonism and Related Disorders, The International Journal of Neuroscience, Journal of Neuroscience Methods, Surgical Neurology International, PLos ONE, Journal of Neuro-Oncology, Journal of Neurosurgical Anesthesiology

Memberships 2001 – present Congress of Neurological Surgeons 2001 – present AANS-CNS Joint Section on Stereotactic and Functional Neurosurgery 2001 – present American Society for Stereotactic and Functional Neurosurgery 2001 – present World Society of Stereotactic and Functional Neurosurgery 2004 – present The Movement Disorder Society 2008 – present American Association of Neurological Surgeons 2008 – present Intraoperative Imaging Society 2013 – present Society of Neurological Surgeons Honors and Awards 1999 First Place, Biotechnology Research Category, Research!Louisville 1999 2000 Excellence in Clinical Education Award, University of Louisville School of Medicine 2004 Harold Rosegay Teaching Award, Department of Neurological Surgery, UCSF 2007 Diane D. Ralston Teaching Award, Department of Neurological Surgery, UCSF 2013 Harold Rosegay Teaching Award, Department of Neurological Surgery, UCSF

B. Selected peer-reviewed publications or manuscripts in press (in chronological order). Martin AJ, Larson PS, Ostrem JL, Sootsman WK, Talke P, Weber OM, Levesque N, Meyers J, Starr PA: Placement of deep brain stimulator electrodes using real-time high-field interventional magnetic resonance imaging. Magn Reson Med 54(5):1107-14, 2005. Larson PS, Richardson RM, Starr PA, Martin AJ: MR imaging of implanted deep brain stimulators: Experience in a large series . Stereotact Funct Neurosurg 86(2):92-100, 2007. Larson PS: Deep brain stimulation for psychiatric disorders. Neurotherapeutics 5(1):50-58, 2008. Martin AJ, Hall WA, Roark C, Starr PA, Larson PS, Truwit CL: Minimally invasive precision brain access using prospective stereotaxy and a trajectory guide. J Magn Reson Imaging 27(4):737-43, 2008. Marks WJ, Ostrem JL, Verhagen L, Starr PA, Larson PS, Bakay RA, Taylor R, Cahn-Weiner D, Stoessl AJ, Olanow CW, Bartus RT: Safety and tolerability of intraputaminal delivery of CERE-120 (adeno-associated virus serotype 2-neurturin) to patients with idiopathic Parkinson’s disease: an open-label, phase I trial. Lancet Neurol 7(5):400-8, 2008. Papavassiliou E, Rau G, Heath S, Abosch A, Barbaro NM, Larson PS, Lamborn K, Starr PA. Thalamic deep brain stimulation for essential tremor: relation of lead location to outcome. Neurosurgery 62(Suppl 2):884-94, 2008. Eberling JL, Jagust WJ, Christine CW, Starr PA, Larson PS, Bankiewicz KS, Aminoff MJ: Results from a phase I clinical trial of hAADC gene therapy for Parkinson’s disease. Neurology 70(21):1980-3, 2008. Richardson RM, Larson PS, Bankiewicz KS. Gene and cell delivery to the degenerated striatum: status of preclinical efforts in primate models. Neurosurgery 63(4):629-442, 2008. Martin AJ, Larson PS, Ostrem JL, Starr PA. Interventional magnetic resonance guidance of deep brain stimulator implantation for Parkinson disease. Top Magn Reson Imaging 19(4):213-221, 2008. Weaver F, Follett K, Stern M, et al; for the CSP 468 Study Group. Bilateral deep brain stimulation vs best medical therapy for patients with advanced Parkinson disease: a randomized controlled trial. JAMA 301(1):63-73, 2009. Glass GA, Ku S, Ostrem JL, Heath S, Larson PS. Fluoroscopic EMG-guided injection of botulinum toxin into the longus colli for the treatment of anterocollis. Parkinsonism Relat Disord 15(8):610-3, 2009. Christine CW, Starr PA, Larson PS, Eberling JL, Jagust WJ, Hawkins R, VanBrocklin H, Wright JF, Bankiewicz K, Aminoff MJ. Safety and tolerability of putaminal AADC gene therapy for Parkinson’s disease. Neurology 73(20):1662-9, 2009. Shimamoto SA, Larson PS, Ostrem JL, Glass GA, Turner RS, Starr PA. Physiological identification of the human pedunculopontine nucleus. J Neurol Neurosurg Psychiatry 81(1):80-6, 2010. Starr PA, Martin AJ, Ostrem JL, Talke P, Levesque N, Larson PS. Subthalamic nucleus deep brain stimulator placement using high field interventional MRI and a skull-mounted aiming device: technique and application accuracy. J Neurosurg 112(3):479-90, 2010. Follett KA, Weaver FM, Stern M, et al; for the CSP 468 Study Group. Pallidal versus subthalamic deep-brain stimulation for Parkinson’s disease. N Engl J Med 362(22):2077-91, 2010. Cheung SW, Larson PS. Tinnitus modulation by deep brain stimulation in locus of caudate neurons (area LC). Neuroscience 169(4):1768-78, 2010. Valles F, Fiandaca MS, Eberling JL, Starr PA, Larson PS, Christine CW, Forsayeth J, Richardson RM, Su X, Aminoff MJ, Bankiewicz KS. Qualitative imaging of AAV2-hAADC gene therapy in a phase I study for the treatment of Parkinson’s disease. Neurosurgery 67(5):1377-85, 2010. Marks WJ Jr, Bartus RT, Siffert J, Davis CS, Lozano A, Boulis N, Vitek J, Stacy M, Turner D, Verhagen L, Bakay R, Watts R, Guthrie B, Jankovic J, Simpson R, Tagliati M, Alterman R, Stern M, Baltuch G, Starr PA, Larson PS, Ostrem JL, Nutt

J, Kieburtz K, Kordower JH, Olanow CW. Gene delivery of AAV2-neurturin for Parkinson’s disease: a double-blind, randomised, controlled trial. Lancet Neurol 9(12):1164-72, 2010. Fiandaca MS, Salegio EA, Yin D, Richardson RM, Valles FE, Larson PS, Starr PA, Lonser RR, Bankiewicz KS. Human/nonhuman primate AC-PC ratio – considerations for translational brain measurements. J Neurosci Methods 196(1):124-30, 2011. Shahlaie K, Larson PS, Starr PA. Intraoperative CT for DBS surgery: technique and accuracy assessment. Neurosurgery 68(1 Suppl Operative):114-24, 2011. Chang EF, Cheng JS, Richardson RM, Lee C, Starr PA, Larson PS. Incidence and management of venous air embolisms during awake deep brain stimulation surgery in a large clinical series. Stereotact Funct Neurosurg 89(2):76-82, 2011. Richardson RM, Kells AP, Rosenbluth KH, Salegio EA, Fiandaca MS, Larson PS, Starr PA, Martin AJ, Lonser RR, Federoff HJ, Forsayeth JR, Bankiewicz KS. Interventional MRI-guided putaminal delivery of AAV2-GDNF for a planned clinical trial in Parkinson’s disease. Mol Ther 19(6):1048-57, 2011. Englot DJ, Chang EF, Larson PS. Lead cap localization using ultrasound in deep brain stimulation surgery: technical note. Minim Invasive Neurosurg 54(1):48-9, 2011. Richardson RM, Kells AP, Martin AJ, Larson PS, Starr PA, Piferi PG, Bates G, Tansey L, Rosenbluth KH, Bringas JR, Berger MS, Bankiewicz KS. Novel platform for MRI-guided convection-enhanced delivery of therapeutics: preclinical validation in nonhuman primate brain. Stereotact Funct Neurosurg 89(3):141-51, 2011. Larson PS, Starr PA, Bates G, Tansey L, Richardson RM, Martin AJ. An optimized system for interventional MRI guided stereotactic surgery: preliminary evaluation of targeting accuracy. Neurosurgery 2011 Jul 25 (Epub ahead of print). Englot DJ, Glastonbury CM, Larson PS. Abnormal T2-weighted MRI signal surrounding leads in a subset of deep brain stimulation patients. Stereotact Funct Neurosurg 89(5):311-7, 2011. Larson PS, Cheung SW. Deep brain stimulation in area LC controllably triggers auditory phantom percepts. Neurosurgery 2011 Aug 12 (Epub ahead of print). Air EL, Ryapolova-Webb E, DeHemptinne C, Ostrem JL, Galifianakis NB, Larson PS, Chang EF, Starr PA. Actue effects of thalamic deep brain stimulation and thalamotomy of primary sensorimotor cortex local field potentials in essential tremor. Clin Neurophysiol 123(11):2232-8, 2012. Mettermeyer G, Christine C, Rosenbluth K, Baker S, Starr P, Larson P, Kaplan P, Forsayeth J, Aminoff M, Bankiewicz K. Long-term evaluation of a phase I study of AADC gene therapy for Parkinson’s disease. Hum Gene Ther 23(4):377-81, 2012. Potts MB, Larson PS. Securing dual ipsilateral leads through a single burr hole in deep brain stimulation surgery. Stereotact Funct Neurosurg 90(6):361-4, 2012. Ostrem JL, Galifianakis NB, Markun LC, Grace JK, Martin AJ, Starr PA, Larson PS. Clinical outcomes of PD patients having bilateral STN DBS using high-field interventional MR-imaging for lead placement. Clin Neurol Neurosurg 115(6):708-12, 2013. Larson PS, Cheung SW. A stroke of silence: tinnitus suppression following placement of deep brain stimulation electrode with infarction in area LC. J Neurosurg 118(1):192-4, 2013. Ostrem JL, Galifianakis NB, Markun LC, Grace JK, Martin AJ, Starr PA, Larson PS. Clinical outcomes of PD patients having bilateral STN DBS using high-field interventional MR-imaging for lead placement. Clin Neurol Neurosurg 115(6):708-12, 2013.

C. Research Support Ongoing Research Support

Sponsor: NIH/NIDCD U01 (1U01DC013029-01) - 2.4 calendar months 04/2013-03/2018 $3,380,211 total (approximately $480,000 direct/year) Title: “Deep Brain Stimulation for Chronic Tinnitus” Description: This is a pilot clinical trial to investigate the use of DBS in human subjects to treat chronic, medically refractory tinnitus. This is the first clinical trial ever performed to study the use of DBS to treat a phantom percept disorder. Role: PI Sponsor: Michael J. Fox Foundation (A119476) - 0.24 calendar months 04/2012-07/2014 $1,236,647 total direct Title: “A Phase I Bridging Study of Adeno-Associated Virus Encoding Human Aromatic L-Amino Acid Decarboxylase (AAV2-hAADC) Administered by MRI-Guided Real-Time Convective Infusion in the Putamen of Subjects with Parkinson’s Disease" Description: This is a Phase Ib bridging study to study the safety and efficacy of AAV-hAADC gene therapy infusions using interventional MRI to provide real-time convection enhanced delivery. Role: PI Sponsor: MRI Interventions, Inc. – 0.47 calendar months 11/2013-11/2014 $232,839 direct/year Title: “Interventional MRI Deep Brain Stimulator Implantation" Description: This project involves both the development of hardware and software technologies to perform DBS implantation using interventional MRI and a clinical trial studying outcomes in Parkinson’s subjects undergoing this novel procedure. Role: Co-PI Sponsor: California Institute of Regenerative Medicine (RT2-01975) - 0.24 calendar months 04/2011-03/2014 $400,000 direct/year 1, $1,200,000 direct/years 1-3 Title: “Development and Preclinical Testing of New Devices for Transplantation to the Human Brain" Description: This project involves the development and testing of hardware technologies to deliver cell transplants to the human basal ganglia. Role: Co-Investigator

Completed Research Support (selected) Sponsor: Ceregene, Inc./Michael J. Fox Foundation 2010-2013 Title: “A Phase I/II Trial Assessing the Safety and Efficacy of Bilateral Intraputaminal and Intranigral Administration of CERE-120 (Adeno-Associated Virus Serotype 2 [AAV2]-Neurturin [NTN]) in Subjects with Idiopathic Parkinson’s Disease” Goals/aims: Phase II, double blind, sham controlled clinical trial to examine the efficacy of bilateral intraputaminal and intranigral infusion of AAV-Neurturin in subjects with Parkinson’s disease. Role: Co-Investigator Sponsor: NIH/NIBIB (R21) 2009-2013 Title: “MR Guided DBS Implantation for Parkinson’s Disease” Description: This project aims to improve STN visualization and surgical target selection in interventional MRI using using diffusion tensor imaging, high field strength MRI and internal micro-MR coils. Role: Consultant Sponsor: Image Guided Neurologics, Inc./Medtronic, Inc. 2003-2007 Title: “Implantation of Deep Brain Stimulators Using Interventional MRI " Description: This project involved the development of hardware, software and a methodology for DBS implantation using interventional MRI as well as clinical trial studying application accuracy and preliminary outcomes in Parkinson’s subjects undergoing this novel procedure. Role: Co-PI

BIOGRAPHICAL SKETCH Provide the following information for the Senior/key personnel and other significant contributors.


NAME Starr, Philip A.

POSITION TITLE Professor of Neurological Surgery

eRA COMMONS USER NAME (credential, e.g., agency login) starrp EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable.)


Princeton University, Princeton, NJ B.A. 05/83 Chemistry Harvard Medical School, Boston, MA M.D. 05/89 Harvard Medical School, Boston, MA Ph.D. 05/89 Neurobiology Brigham and Women’s Hospital, Boston, MA Internship 1989 - General Surgery Brigham and Women’s Hospital and Children’s Hospital, Boston, MA Centre Hospitalier Universitaire Vaudois (C.H.U.V.), Lausanne, Switzerland Emory University, Atlanta, GA

Residency Clinical Elective Clinical Fellowship

1990 - 1995 1995 1996 - 1997

Neurosurgery Neurosurgery Movement Disorders Surgery

A. Personal Statement I am surgical director of the largest program for the surgical treatment of movement disorders in the Western USA, and have performed deep brain stimulation (DBS) implantation surgery in over 1000 patients. My clinical group has conducted many surgical trials in patients with Parkinson’s disease, dystonia and essential tremor. My research goals are (1) to understand the pathophysiology of movement disorders, and mechanism of deep brain stimulation (DBS), using the combined basal ganglia and cortical recording in humans undergoing surgery; and (2) develop novel stimulation paradigms to improve clinical therapies. I have pioneered the use of electrocorticography in the understanding of cortical dysfunction in movement disorders, and the use of totally implanted brain recording devices for chronic brain recording in humans. B. Positions and Honors Positions and Employment 1997 - 1998 Instructor in Neurosurgery, Emory University 1998 - 2003 Assistant Professor of Neurosurgery, University of California, San Francisco 2003 - 2009 Associate Professor of Neurosurgery, University of California, San Francisco 1998 - 2001 Chief of Neurosurgery, San Francisco Veteran’s Affairs Medical Center 2001 - 2010 Surgical Director, Parkinson’s Disease Research, Education and Care Center (PADRECC) at San Francisco Veteran’s Affairs Medical Center 2006 - present Dolores Cakebread Endowed Chair in Neurological Surgery 2009 - present Professor of Neurosurgery, University of California, San Francisco 2011 - present Director of Functional Neurosurgery, University of California, San Francisco Other Experience and Professional Memberships

Professional Memberships

1997 - American Association of Neurological Surgeons 1998 - Society for Movement Disorders 1999 - Congress of Neurological Surgeons 2000 - American Society for Stereotactic and Functional Neurosurgery 2007 - International Basal Ganglia Society 2007 - American Academy of Neurological Surgeons

2009 - Society for Neuroscience

NIH Study section

2011-2017 NIH study section regular member, Clinical Neurosciences and Neurodegeneration (CNN) Editorial review 2000 - Ad hoc reviewer, Neurosurgery 2002 - Ad hoc reviewer, Neurology 2004 - Ad hoc reviewer, Pain 2005 - Ad hoc reviewer, Neuromodulation 2005 - Ad hoc reviewer, Brain Research 2006 - Ad hoc reviewer, Experimental Neurology 2006 - Ad hoc reviewer, Movement Disorders 2006 - Ad hoc reviewer, Journal of Neurology, Neurosurgery, and Psychiatry 2006 - Ad hoc reviewer, European Journal of Neuroscience 2007 - Ad hoc reviewer, Journal of Neurophysiology 2007 - Ad hoc reviewer, Brain 2008 - Ad hoc reviewer, New England Journal of Medicine 2008- Ad hoc reviewer, Journal of Neuroscience 2008 - Ad hoc reviewer, Annals of Neurology 2010 - Ad hoc reviewer, Cerebral Cortex 2011 - Ad hoc reviewer, Frontiers in Human Neuroscience 2006 - 2010 Editorial review board, Stereotactic and Functional Neurosurgery

Service to Professional Organizations

2004 Scientific program director, Biennial Meeting of the American Society for Stereotactic and Functional Neurosurgery, Cleveland, Ohio

2004 - 2006 Secretary-Treasurer, American Association for Stereotactic and Functional Neurosurgery 2006 - 2008 Vice President, American Association for Stereotactic and Functional Neurosurgery 2008 - 2010 President, American Association for Stereotactic and Functional Neurosurgery 2012 Meeting Chair, Biennial meeting of the American Society for Stereotactic and Functional

Neurosurgery, San Francisco Honors 1983 Phi Beta Kappa Society 2001 and 2010 Rosegay teaching award for excellence in clinical teaching (awarded by UCSF residents) 2004 Dystonia Doctor of Excellence Award from the Dystonia Medical Research Foundation 2013 Named as one of ten finalists for an international competition in neuroprosthetics, the Israeli

B.R.A.I.N prize 2013 Nominee for UCSF academic senate Distinction in Mentoring (DIM) award C. Selected peer-reviewed publications (selected from 85 peer-reviewed publications) Most relevant to the current proposal 1. de Hemptinne C, Ryapolova-Webb ES, Air EL, Garcia PA, Miller KJ, Ojemann JG, Ostrem JL, Galifianakis

NB, Starr PA (2013) Exaggerated phase-amplitude coupling in the primary motor cortex in Parkinson disease. PNAS 110:4780-4785. PMCID: PMC3606991.

2. Shimamoto SA, Ryapolova-Webb ES, Ostrem JL, Galifianakis NB, Miller KJ, Starr PA (2013) Subthalamic nucleus neurons are synchronized to primary motor cortex local field potentials in Parkinson's disease. J Neurosci 33:7220-7233. PMCID: PMC3673303.

3. Crowell AL, Ryapolova-Webb ES, Ostrem JL, Galifianakis NB, Shimamoto S, Lim DA, Starr PA. Oscillations in sensorimotor cortex in movement disorders: an electrocorticography study, Brain,135 (Pt 2):615-30, 2012.

4. Ryapolova-Webb, E., P. Afshar, S. Stanslaski, T. Denison, C.d. Hemptinne, K. Bankiewicz, and Starr PA, Chronic cortical and electromyographic recordings from a fully implantable device: preclinical experience in a nonhuman primate. J Neural Eng, in press. PMCID: PMC3281473.

5. Ostrem JL, Racine CA, Glass GA, Grace JK, Volz MM, Heath SL, Starr PA (2011) Subthalamic nucleus deep brain stimulation in primary cervical dystonia. Neurology 76:870-878. PMID: 21383323.

Additional recent publications of importance to the field 1. Starr PA, Christine CW, Theodosopoulos PV, Lindsey N, Byrd D, Marks WJ, Implantation of deep brain

stimulators into the subthalamic nucleus: Technical approach and MRI-verified electrode locations. Journal of Neurosurgery, 97:370-387, 2002. PMID: 12186466.

2. Starr PA, Rau GM, Davis V, Marks WJ, Ostrem JL, Simmons D, Lindsey N, Turner, R. S. Spontaneous pallidal neuronal activity in human dystonia: comparison with Parkinson's disease and normal macaque. Journal of Neurophysiology, 93:3165-3176, 2005. PMID: 15703229.

3. Starr PA, Turner RS, Rau G, Lindsey N, Heath S, Volz M, Marks WJ. Microelectrode-guided implantation of deep brain stimulators into the globus pallidus internus for dystonia: techniques, electrode locations, and outcomes. Journal of Neurosurgery 104:488-501, 2006. PMID: 16619651.

4. Chang, E.F., R.S. Turner, J.L. Ostrem, V.R. Davis, and Starr PA, Neuronal Responses to Passive Movement in the Globus Pallidus Internus in Primary Dystonia. Journal of Neurophysiology, 98:3696-3707, 2007. PMID: 17942626.

5. Starr PA, Kang GA, Heath S, Shimamoto S, Turner RS, Pallidal neuronal discharge in Huntington’s disease: support for selective loss of striatal cells originating the indirect pathway. Experimental Neurology 211:227-233, 2008. PMCID: PMC3673313.

6. Sillay K, Larson P, Starr PA. Deep brain stimulator hardware infections: incidence and management in a large series. Neurosurgery, 62:360-366, 2008. PMID: 18382313.

7. Sani S, Ostrem JL, Shimamoto S, Levesque N, Starr PA. Single Unit "Pauser" Characteristics of the Globus Pallidus Pars Externa Distinguish Primary Dystonia from Secondary Dystonia and Parkinson's Disease. Experimental Neurology, 216:295-299, 2009. PMCID: PMC2659350.

8. Schrock LE, Ostrem JL, Turner RS, Shimamoto SA, Starr PA. The subthalamic nucleus in primary dystonia: single unit discharge characteristics. Journal of Neurophysiology, (102) p 3740-52, 2009. PMID: 19846625.

9. Follett KA, Weaver FM, Stern M, Hur K, Harris CL, Luo P, Marks WJ, Jr., Rothlind J, Sagher O, Moy C, Pahwa R, Burchiel K, Hogarth P, Lai EC, Duda JE, Holloway K, Samii A, Horn S, Bronstein JM, Stoner G, Starr PA, Simpson R, Baltuch G, De Salles A, Huang GD, Reda DJ. Pallidal versus subthalamic deep-brain stimulation for Parkinson's disease. The New England Journal of Medicine, 362(22):2077-91, 2010. PMID: 20519680.

10. Shahlaie K, Larson PS, Starr PA. Intraoperative computed tomography for deep brain stimulation surgery: technique and accuracy assessment. Neurosurgery, 68(1 Suppl Operative):114-24; 2011. PMID: 21206322.

D. Research Support Ongoing Research Support NINDS R01 NS069779 4/2010-4/2014 Cortical and basal ganglia local field potentials in human movement disorders In this project, we study cortical local field potentials in patients with the three most common movement disorders, Parkinson’s disease, primary dystonia, and essential tremor during DBS implantation, and in patients with medically intractable epilepsy undergoing ECoG monitoring. The goal is to determine how different movement disorders are represented with respect to oscillatory activity in the basal-ganglia thalamocortical network. Role: Principal Investigator

Bachman-Strauss Foundation Research Grant Starr (PI) 1/2013-1/2014 Phase-amplitude coupling in primary motor cortex in dystonia This grant supports postdoctoral fellow Cora DeHemptinne in studies of cortical physiology in patients with primary dystonia Role: Principal investigator MRI Interventions, Inc. Martin (PI) 11/1/2012-10/30/2014 Use of interventional MRI for placement of deep brain stimulators MRI Interventions, Inc., paired with a UC Discovery grant, is providing support to develop new devices for the use of interventional MRI for placement of DBS electrodes. Interventional MRI allows placement of DBS electrodes using real time MR guidance. The intended brain target is visualized directly by MR imaging, and a skull mounted aiming device eliminates the need for a stereotactic frame. The grant supports patient evaluations and MRI time during the procedures, and for the investigators to develop new skull mounted hardware, and associated software, to enhance the procedure. Role: Co-investigator Pending Research Support NINDS R01 NS069779 Starr (PI) 4/2013-4/2017 Competitive renewal of: Cortical and basal ganglia local field potentials in human movement disorders In this ongoing project, we extend our work in analysis of basal ganglia and cortical local field potentials in patients undergoing movement disorders surgery. We introduce the use of high spatial resolution recording grids, a more sophisticated movement task, and assessment of both acute and chronic effects of DBS. The goal is to relate disease related patterns of neuronal synchronization to specific phases of a motor task and to specific motor cortical regions, and to understand how therapeutic DBS alters cortical function. Recently Completed Research Support Michael J Fox Foundation deHemptinne (PI) 9/2011-8/2012 Effect of deep brain stimulation on cortical cross frequency coupling in Parkinson’s disease: an electrocorticography study Role: mentor for PI Dystonia Medical Research Foundation Starr(PI) 2009-2010 STN and M1 local field potentials in patients with dystonia Role: PI Benign Essential Blepharospasm Research Foundation Foundation Ostrem (PI) 2008-2009 Clinical trial of STN-DBS for cervical dystonia Role: co-investigator

BIOGRAPHICAL SKETCH Provide the following information for the Senior/key personnel and other significant contributors.


NAME Ostrem, Jill Louise

POSITION TITLE Professor of Neurology

eRA COMMONS USER NAME (credential, e.g., agency login) ostremj EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable.)


University of Minnesota, Morris, MN B.A. 05/91 Psychology George Washington University School of Medicine, Washington, DC

M.D. 05/98 Medicine

Washington Hospital Center, Washington, DC Internship 06/99 Internal Medicine UCLA Medical Center, Los Angeles, CA Residency 06/02 Neurology Fellowship 06/03 Movement Disorders

A. Personal Statement I am the Medical Director and Division Chief of the UCSF Surgical Movement Disorders Division in the Department of Neurology. Since 2003 I have successfully built, with our tertiary care team, our internationally recognized Center. Under my direction the division has grown substantially to include 6 movement disorders neurologists, 2 full time research coordinators, 3 nurses, and many clinical staff members. My position requires me to juggle and manage a busy multidisciplinary integrated clinical program (with neurosurgery), direct and coordinate our clinical research program (with 20 current ongoing clinical research trials), and mentor/teach our movement disorders fellows, neurology residents, and medical students. I have a special career interest in understanding the factors that may predict patients’ response to deep brain stimulation therapy for Parkinson’s disease, dystonia, and tremor disorders. I also seek to find and advance new treatment options for essential tremor, dystonia and Parkinson’s patients. I have 10 years of clinical experience managing movement disorders patients and in the programming of deep brain stimulators and successfully built one of the busiest movement disorders botulinum toxin injection clinics on the West Coast. B. Positions and Honors Positions and Employment 1991-94 Positron Emission Tomography Coordinator, Clinical Brain Disorders Branch, NIMH, Bethesda, MD 2003- Attending Neurologist, San Francisco VA Medical Center, Parkinson’s Disease Research, Education and Clinical Center (PADRECC), San Francisco, CA 2003-09 Assistant Professor of Neurology, UCSF 2007- Director Surgical Movement Disorders Botulinum Toxin Clinic, UCSF 2009- Medical Director, Surgical Movement Disorders Program, UCSF 2009-13 Associate Professor of Neurology, UCSF 2009- Division Chief, Surgical Movement Disorders, UCSF 2013- Interim Director, PADRECC SFVA Medical Center, San Francisco, CA 2013- Professor of Neurology, UCSF

Honors and Awards 2001 UCLA Neurology Resident Research Poster Day Award 2009- Best Doctors Award 2012 AAMC Mid-Career Women Faculty Professional Development Seminar 2013- Bachmann Strauss Dystonia and Parkinson’s Disease Center of Excellence (PI- Ostrem)

C. Selected Peer-reviewed Publications (Selected from 50+ peer-reviewed publications) 1. Starr PA, Rau GM, Davis V, Marks WJ, Ostrem JL, Simmons D, Lindsey N, Turner RS. Spontaneous

pallidal neuronal activity in human dystonia: Comparison with Parkinson's disease and normal macaque. J Neurophysiol. 2005 Jun; 93(6):3165-76. PMID: 15703229.

2. Davis TL, Brodsky MA, Carter VA, DiFazio M, Frishberg B, Lai EC, McGuire J, Meyer DP, Ostrem JL, Sarwar AI, White K. Consensus statement on the use of botulinum neurotoxin to treat spasticity in adults. Pharmacy and Therapeutics. 31(11):666-682, 2006.

3. Starr PA, Turner RS, Rau G, Lindsey N, Heath S, Volz M, Ostrem JL, Marks WJ Jr. Microelectrode-guided implantation of deep brain stimulators into the globus pallidus internus for dystonia: techniques, electrode loctions, and outcomes. J Neurosurg. 104(4):488-501,2006. PMID: 16619651.

4. Ostrem JL, Marks WJ, Volz M, Heath S, Starr PA. Pallidal deep brain stimulation in patients with cranial-cervical dystonia (Meige Syndrome). Mov Disord. 22(13):1885-1891: 2007. PMID: 17618522.

5. Chang EF, Turner RS, Ostrem JL, Davis VR, Starr PA. Neuronal responses to passive movement in the globus pallidus internus in primary dystonia. J Neurophysiol. 98(6):3696-3707:2007.

6. Berman B, Starr PA, Marks WJ, Ostrem JL. Induction of bradykinesia with pallidal deep brain stimulation in patients with cranial-cervical dystonia. Stereotact Funct Neurosurg. 87(1):37-44: 2009. PMCID: PMC2835378.

7. Glass GA, Ku S, Ostrem JL, Heath S, Larson PS. Fluoroscopic, EMG-guided injection of botulinum toxin into the longus colli for the treatment of anterocollis. Parkinsonism and Related Disorders. 15(8):610-3:2009. PMID: 19250855.

8. Schrock LE, Ostrem JL, Turner RS, Shimamoto SA, Starr PA. The subthalamic nucleus in primary dystonia: single unit discharge characteristics. J Neurophys. 102(6):3740-52: 2009. PMID: 19846625.

9. Timmermann L, Pauls KA, Weiland K, Jech R, Kurlemann G, Sharma N, Gill S, Haenqqeli CA, Hayflick S, Leenders K, Limousin P, Malanga C, Moro E, Ostrem J, et al. Dystonia in neurodegeneration with brain iron accumulation: outcome of bilateral pallidal stimulation. Brain. 133(Pt3):701-12: 2010. PMCID: PMC2842517.

10. Air EL, Ostrem JL, Sanger TD, Starr PA. Deep brain stimulation in children: experience and technical pearls. J Neurosurg.: Pediatrics 8(6):566-574: 2011. PMID: 22132914.

11. Ostrem JL, Racine CA, Glass GA, Grace JK, Volz MM, Heath SL, Starr PA. Subthalamic nucleus deep brain stimulation in primary cervical dystonia. Neurology. 76(10):870-8:2011. PMID: 21383323.

12. Isaias IU, Volkmann J, Kupsch A, Burgunder JM, Ostrem JL, Alterman RL, Mehdorn HM, Schönecker T, Krauss JK, Starr P, Reese R, Kühn AA, Schüpbach WM, Tagliati M. Factors predicting protracted improvement after pallidal DBS for primary dystonia: the role of age and disease duration. J Neurol. 258(8):1469-76:2011. PMID: 21365458.

13. Crowell AL, Ryapolova-Webb ES, Ostrem JL, Galifianakis NB, Shimamoto S, Lim DA, Starr PA. Oscillations in sensorimotor cortex in movement disorders: an electrocorticography study. Brain. 2012 Feb; 135(Pt 2):615-30. PMCID: PMC 3281473.

14. Markun LC, Starr PA, Air EL, Marks WJ, Volz MM, Ostrem JL. Shorter disease duration correlates with improved long-term DBS outcomes in young-onset DYT1 dystonia. Neurosurgery 71(2):325-30:2012. PMID: 22811083.

15. Mills KA, Scherzer R, Starr PA, Ostrem JL. Weight change after globus pallidus internus or subthalamic nucleus deep brain stimulation in Parkinson’s disease and dystonia. Stereotactic and Functional Neurosurgery. 91:243-247: 2013. PMCID: PMC3698968.

16. Witt JL, Starr PA, Ostrem JL. Use of pallidal deep brain stimulation in post-infarct hemidystonia. Stereotact Funct Neurosurg. Accepted for Publication, Oct 2012. PMID: 23549056.

17. Kilbane,C, Ostrem J, Galifianakis, Grace J, Markun L, Glass GA. Mutlichannel electromyographic mapping to optimize Onabotulinum toxin A efficacy in cervical dystonia. Tremor Other Hyperkinet Mov 2012;2: http://tremorjournal.org/article/view/91. PMCID: PMC3569932.

http://www.ncbi.nlm.nih.gov/pubmed/21383323




18. Witt JL, Moro E, Ash RS, Hamani C, Starr PA, Lozano AM, Hodaie M, Poon YY, Markun LC, Ostrem JL. Predictive factors of outcome in primary cervical dystonia following pallidal deep brain stimulation. Mov Disord. 2013 Jun 20. doi: 10.1002/mds.25560. [Epub ahead of print]. PMID: 23787946.

D. Research Support Ongoing Research Support Bachmann Strauss Dystonia and Parkinson’s Disease Foundation (Ostrem-PI) 8/2013-8/2015 UCSF Bachmann Strauss Dystonia and Parkinson’s Disease Foundation Center of Excellence Center grant providing support for the establishment of multi-disciplinary clinical care center, outstanding fellowship training program, and four clinical research projects related to dystonia and PD. Surgivision/UC Discovery Grant (Martin/Starr-PI) 5/2009-9/2013 Use of Interventional MRI for Implantation of Deep Brain Stimulator Electrodes A single-center study designed to develop and better understand the use of interventional MRI implantation of DBS electrodes using real time MR guidance. The intended brain target is visualized directly by MR imaging, and a skull mounted aiming device eliminates the need for a stereotactic frame. Advanced Neuromodulation Systems/St Judes Medical (Ostrem- Site PI) 6/2005-12/13 Clinical Evaluation of the Libra™ Implantable Deep Brain Stimulation System for the Suppression of Tremor in the Upper Extremities of Patients with Essential Tremor A multi-center trial to evaluate the effectiveness of the Libra DBS system in the suppression of tremor in the upper extremities in patients with essential tremor. VA/ NINHS (Ostrem- Site PI) 10/2010-12/2015 CSP#468F: Long-Term Study of Deep Brain Stimulation for Parkinson’s Disease: A longitudinal Follow-up Study of the VA/ NINDS CSP#468 Cohort. A multi-center long-term extension trial to evaluate the long-term effect of DBS on two different brain targets: subthalamic nucleus (STN) or the globus pallidus (GPI). Ceregene (Marks-PI) 5/2008-12/2012 CERE-120-03, An Extended Observation Study to Assess the Safety and Effectiveness of CERE-120 in Subjects with Parkinson’s Disease A long-term extension study to evaluate the safety and efficacy of CERE-120 in PD. Role: Co- investigator Completed Research Support NIH/NINDS (Starr- PI, Ostrem- Co- PI) 4/2009-4/2012 Cortical and Basal Ganglia Local Field Potentials in Human Movement Disorders To investigate cortical and subthalamic nucleus oscillation in movement disorders patients. NIH R21 EB008888 (Martin-PI) 9/2009-9/2011 MRI - guided DBS implantation for Parkinson's disease This project aims to improve STN visualization and target selection for stimulation therapy in PD. It investigates the role of diffusion tensor imaging, higher magnetic field strengths and internal MR coils for improving target selection and correlates clinical outcome with the position achieved with image guidance. Role: Co-Investigator

OTHER SUPPORT KATZ, M. ASSISTANT PROFESSOR NEUROLOGY UCSF MEDICAL CENTER ACTIVE/PENDING NONE

OTHER SUPPORT

LARSON, PAUL A. PROFESSOR OF NEUROLOGY UCSF MEDICAL CENTER ACTIVE: Sponsor: NIH/NIDCD U01 (1U01DC013029-01) - 2.4 calendar months 4/2013-3/2018 $3,380,211 total (approximately $480,000 direct/year) Title: “Deep Brain Stimulation for Chronic Tinnitus” Description: This is a pilot clinical trial to investigate the use of DBS in human subjects to treat chronic, medically refractory tinnitus. This is the first clinical trial ever performed to study the use of DBS to treat a phantom percept disorder. Role: PI No overlap with proposed project. Sponsor: Michael J. Fox Foundation (A119476) - 0.24 calendar months 4/2012-7/2014 $1,236,647 total direct Title: “A Phase I Bridging Study of Adeno-Associated Virus Encoding Human Aromatic L-Amino Acid Decarboxylase (AAV2-hAADC) Administered by MRI-Guided Real-Time Convective Infusion in the Putamen of Subjects with Parkinson’s Disease" Description: This is a Phase Ib bridging study to study the safety and efficacy of AAV-hAADC gene therapy infusions using interventional MRI to provide real-time convection enhanced delivery. Role: PI No overlap with proposed project. Sponsor: MRI Interventions, Inc. – 0.47 calendar months 11/2013-11/2014 $232,839 direct/year Title: “Interventional MRI Deep Brain Stimulator Implantation" Description: This project involves both the development of hardware and software technologies to perform DBS implantation using interventional MRI and a clinical trial studying outcomes in Parkinson’s subjects undergoing this novel procedure. Role: Co-PI No overlap with proposed project. Sponsor: California Institute of Regenerative Medicine (RT2-01975) - 0.24 calendar months4/2011-3/2014 $400,000 direct/year 1, $1,200,000 direct/years 1-3 Title: “Development and Preclinical Testing of New Devices for Transplantation to the Human Brain" Description: This project involves the development and testing of hardware technologies to deliver cell transplants to the human basal ganglia. Role: Co-Investigator No overlap with proposed project.

RECENTLY COMPLETED Sponsor: Ceregene, Inc./Michael J. Fox Foundation 2010-2013 Title: “A Phase I/II Trial Assessing the Safety and Efficacy of Bilateral Intraputaminal and Intranigral Administration of CERE-120 (Adeno-Associated Virus Serotype 2 [AAV2]-Neurturin [NTN]) in Subjects with Idiopathic Parkinson’s Disease” Goals/aims: Phase II, double blind, sham controlled clinical trial to examine the efficacy of bilateral intraputaminal and intranigral infusion of AAV-Neurturin in subjects with Parkinson’s disease. Role: Co-Investigator No overlap with proposed project.

Sponsor: NIH/NIBIB (R21) 2009-2013 Title: “MR Guided DBS Implantation for Parkinson’s Disease” Description: This project aims to improve STN visualization and surgical target selection in interventional MRI using using diffusion tensor imaging, high field strength MRI and internal micro-MR coils. Role: Consultant No overlap with proposed project.

Sponsor: Image Guided Neurologics, Inc./Medtronic, Inc. 2003-2007 Title: “Implantation of Deep Brain Stimulators Using Interventional MRI " Description: This project involved the development of hardware, software and a methodology for DBS implantation using interventional MRI as well as clinical trial studying application accuracy and preliminary outcomes in Parkinson’s subjects undergoing this novel procedure. Role: Co-PI No overlap with proposed project.

OTHER SUPPORT

STARR, PHILIP A. PROFESSOR OF NEUROLOGY UCSF MEDICAL CENTER

ACTIVE Bachman-Strauss Foundation Research Grant Starr (PI) 1/2013-1/2014 Phase-amplitude coupling in primary motor cortex in dystonia $60,000/year This grant supports postdoctoral fellow Cora DeHemptinne in studies of cortical physiology in patients with primary dystonia. Role: Principal investigator, 2% Effort Aims: To evaluate cortical synchronization as a mechanism for production of dystonic movement Overlap: No overlap with proposed project. MRI Interventions, Inc. Martin (PI) 11/1/2012-10/30/2014 Use of interventional MRI for placement of deep brain stimulators $200,000/year MRI Interventions, Inc., paired with a UC Discovery grant, is providing support to develop new devices for the use of interventional MRI for placement of DBS electrodes. Interventional MRI allows placement of DBS electrodes using real time MR guidance. The intended brain target is visualized directly by MR imaging, and a skull mounted aiming device eliminates the need for a stereotactic frame. The grant supports patient evaluations and MRI time during the procedures, and for the investigators to develop new skull mounted hardware, and associated software, to enhance the procedure. Role: Co-investigator, 8% Effort Aims: To evaluate the accuracy of a novel skull mounted aiming system for DBS implantation Overlap: No overlap with proposed project. PENDING NINDS R01 NS069779 Starr (PI) 4/2013-4/2017 Competitive renewal of: Cortical and basal ganglia $250,000/year local field potentials in human movement disorders In this ongoing project, we extend our work in analysis of basal ganglia and cortical local field potentials in patients undergoing movement disorders surgery. We introduce the use of high spatial resolution recording grids, a more sophisticated movement task, and assessment of both acute and chronic effects of DBS. The goal is to relate disease related patterns of neuronal synchronization to specific phases of a motor task and to specific motor cortical regions, and to understand how therapeutic DBS alters cortical function. Role: Principal investigator, 25% Effort Aims: To understand the role of abnormal synchronization in movement disorders, and the effect of deep brain stimulation on cortical function Overlap: No overlap with proposed project, though they are complementary.

RECENTLY COMPLETED

NINDS R01 NS069779 Starr (PI) 4/2010-4/2013 Cortical and basal ganglia local field potentials in human movement disorders $250,000/year In this project, we study cortical local field potentials in patients with the three most common movement disorders, Parkinson’s disease, primary dystonia, and essential tremor during DBS implantation, and in patients with medically intractable epilepsy undergoing ECoG monitoring. The goal was to determine how different movement disorders are represented with respect to oscillatory activity in the basal-ganglia thalamocortical network. Role: Principal investigator, 20% Effort Aims: To understand physiological biomarkers of PD, essential tremor, and dystonia Overlap: No overlap with proposed project.

Michael J Fox Foundation deHemptinne (PI) 9/2011-8/2012 Effect of deep brain stimulation on cortical cross frequency coupling in Parkinson’s disease:$70,000/year an electrocorticography study This was a pilot study to provide preliminary data for NIH funding, on the acute effects of DBS on cortical synchronization in PD. Most % effort was for a postdoctoral fellow. Role: Mentor for PI, 2% Effort Aims: To understand the effect of acute DBS on cortical synchronization in PD

Overlap: No overlap with proposed project.

Dystonia Medical Research Foundation Starr (PI) 2009-2010 STN and M1 local field potentials in patients with dystonia $65,000/year To provide pilot data for NIH funding to compare cortical function in dystonia versus other movement disorders. Role: Principal investigator, 10% Effort Aims: To understand the electrophysiologic signatures of dystonia at the level of the cortex and basal ganglia Overlap: No overlap with proposed project.

Benign Essential Blepharospasm Research Foundation Ostrem (PI) 2008-2009 Clinical trial of STN-DBS for cervical dystonia $65,000/year This was a plot study of STN DBS for cranial and cervical dystonia in 10 patients Role: Co-investigator, 5% Effort Aims: To analyze the clinical efficacy of subthalamic nucleus DBS in 10 patients with primary cranial and cervical dystonia Overlap: No overlap with proposed project.

OTHER SUPPORT

OSTREM, J. L. PROFESSOR OF NEUROLOGY UCSF MEDICAL CENTER

ACTIVE

C-06-13(Ostrem) 05/18/2010-05/17/2015 11%/1.32 cal mos Adv.Neuromodulation Syst. Inc./St. Jude Medical $67,511.90 TDC for Project Period A Long-Term Follow-Up Study of the Patients who Underwent Unilateral or Bilateral Stimulation of the VIM using the Libra Deep Brain Stimulation System for the Suppression of Tremor in the Upper Extremities of Patients with Essential Tremor Follow-up study for patients who underwent DBS surgery and treatment with the St. Jude Medical Libra Deep Brain Stimulation system for the suppression of tremor in the upper extremities of patients with essential tremor.

(Ostrem) 05/13/2013-05/13/2014 16%/1.92 cal mos Merz $15,000 TDC Educational efforts related to dystonia and botulinum toxin at the UCSF Surgical Movement Disorders Center

R01 NS069779 (Starr) 05/01/2010-04/30/2014 8%/0.96 cal mos NIH Natl Inst Neurological Disord &Stroke $214,375 Y3 TDC Cortical and basal ganglia local field potentials in human movement disorders To investigate cortical and subthalamic nucleus oscillation in movement disorders patients.

(Ostrem) 06/23/2005-12/31/2013 4%/0.48 cal mos St. Jude/Advanced Neuromodulation Systems, Inc. $115,892 TDC for Project Period A clinical evaluation of the ANS totally implantable Deep Brain stimulation System for the suppression of tremor in the upper extremities of patients with essential tremor Multi-center trial to evaluate the effectiveness of the Libra DBS system in the suppression of tremor in the upper extremities in patients with essential tremor.

(Martin) 10/01/2012-09/30/2014 16%/1.92 cal mos MRI Interventions, Inc $204,736 TDC for Project Period Optimized Methodology for Implantation of DBS Electrodes The major goal of this project is to establish the technical and clinical outcomes that can be achieved with optimized MR-guided DBS electrode implantation.

(Ostrem) 08/16/2013-07/01/2015 10%/1.2 cal mos Bachmann-Strauss Dystonia & Parkinson Fdn $400,000 TDC for Project Period UCSF and Bachmann-Strauss Dystonia and Parkinson Foundation Center of Excellence Center grant providing support for the establishment of multi-disciplinary clinical care center, outstanding fellowship training program, and four clinical research projects related to dystonia and PD.

CSP LUO 001 (Ostrem-Site PI) 05/13/2010-02/28/2015 Effort as Needed Chicago Assoc for Research & Ed in Science $126,067 Year 3 TDC Long Term Study of Deep Brian Stimulation for Parkinson's Disease: A Longitudinal Study A multi-center long-term extension trial to evaluate the long-term effect of DBS on two different brain targets: subthalamic nucleus (STN) or the globus pallidus (GPI).

PENDING

Renewal R01NS069779 (Starr) 04/01/2013-03/31/2019 15%/1.8 cal mos NIH-NINDS $250,000 TDC Cortical and basal ganglia local field potentials in human movement disorders In this ongoing project, we extend our work in analysis of basal ganglia and cortical local field potentials in patients undergoing movement disorders surgery. We introduce the use of high spatial resolution recording grids, a more sophisticated movement task, and assessment of both acute and chronic effects of DBS. The goal is to relate disease related patterns of neuronal synchronization to specific phases of a motor task and to specific motor cortical regions, and to understand how therapeutic DBS alters cortical function.

OVERLAP: NONE

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DATA-MINING PROPOSAL (TEMPLATE)