Improving Outcomes of Deep Brain Stimulation for Essential Tremor with Motion Tracking and Speech Analysis

IETF Grant Proposal: 27 February 2015

Brief Summary

Deep Brain Stimulation (DBS) is a common form of treatment for medically refractory essential tremor (ET). DBS consists of one or two small electrode arrays that are placed in specific brain targets by a trained neurosurgeon. Controlled electrical pulses are then sent to these electrodes by a neurostimulator to modify brain activity and provide therapeutic benefit. The characteristics (duration, amplitude, and frequency) of these pulses must be set to minimize tremor, yet prevent unwanted side- effects such as speech difficulties. Usually, these parameters are set by a neurologist based on their observation of tremor and side-effect. In general, the ventral intermediate nucleus (VIM) of the brain is considered the most appropriate target for stimulation. Recently, however, the posterior subthalamic area (PSA) was also discovered to be an effective stimulation target. Since this discovery, much debate has ensued regarding which is the better target in terms of tremor and side-effect reduction. For each target, the stimulation level must also be considered due to influence on implant battery life. In this study we aim to determine which of the two targets provides the best outcome to the patient using novel methods to quantify tremor and side- effect. The majority of clinical assessments of ET rely on clinical scores based on observation. These are subjective measures influenced by the clinician’s opinion and experience. Unfortunately, the accuracy and sensitivity of such measures can be inadequate. To improve assessment of ET, we have developed our own method of tremor measurement based on electronic motion tracking. This system, with its accompanying software, is able to give us a real-time objective measure of tremor amplitude, velocity, and frequency – with far greater accuracy, sensitivity, and reliability than that of clinical rating scales. Additionally, we will measure side-effect severity using automated speech analysis algorithms. We plan to use novel algorithms to detect side-effects during natural conversations with patients. We believe the inclusion of these objective assessment techniques will help us determine which DBS target gives optimum benefits to each patient.

Publications and conference presentations arising from this research will better inform the research community, neurologists, and neurosurgeons about choosing DBS targets for the treatment of ET. Future research will determine if the results we observe in a short-term clinical setting can be verified during long-term stimulation in ET patients using DBS. The present proposal will therefore provide important data that will enable us to seek government grants in the future.

1 Specific aims The primary objective of this research is to compare the efficacy of deep brain stimulation (DBS) of the ventral intermediate nucleus (VIM) and posterior subthalamic area (PSA) to treat the symptoms of essential tremor (ET) using measures of tremor severity, stimulation-induced side-effect intensity, vocal tremor, stimulation intensity, and patient quality of life indicators. We aim to use both subjective instruments (clinical rating scales) and objective techniques (motion tracking system and speech analysis algorithms) to compare VIM and PSA targets. Based on past experience and the expert opinion of the principal investigator (Dr Richard Peppard, Neurologist), the hypothesis to be tested is that a greater level of tremor suppression can be achieved without side-effect at lower stimulus amplitudes for PSA stimulation compared to VIM stimulation. Furthermore, we believe that simultaneous stimulation of both the VIM and PSA will show greater benefit than stimulation of any single region alone.

2 Rationale and relevance to essential tremor DBS is a surgical technique currently used to treat some patients with movement disorders and certain psychiatric conditions. It involves the implantation of one or two stimulating electrode arrays which are placed in specific brain regions with the intention to modulate local and connected brain activity, which in turn leads to a reduction or cessation of symptoms. The particular brain region that is targeted depends on the neurological condition; for example, electrodes are usually placed in the subthalamic nucleus for a patient with Parkinson’s disease and in the VIM or the PSA for a patient with ET.

The global prevalence of ET ranges from 0.4 – 5% across different populations, and is higher in persons older than 60 years of age (4.6 – 6.3%) [6]. It is estimated that the USA alone has 7 million people living with ET [7]. If not properly treated, ET has detrimental effects on the patient’s quality of life due to social isolation, stress, functional impairment, and embarrassment caused by eating and drinking difficulties among other activities of daily living [9]. ET may also be associated with increased risk of mortality; however, further research is needed to confirm this [11].

DBS is used as a treatment for patients suffering from ET who do not respond to other pharmacological therapies – an estimated 25 - 55% of ET sufferers [8]. The quality-adjusted life year (QALY) is a useful and widely accepted measure of disease burden, including both the duration and the quality of life [12]. Effective DBS, which is contingent upon the optimal selection of stimulation targets, leads to an average QALY gain over 10 years of 2.538 [10] – a significant benefit for the ET population in general.

The conventional DBS target for ET patients is the VIM, where long term stimulation has been shown to achieve either a complete or near-complete resolution of the tremor in nearly 80% of patients [1, 2]. However, there is a well-known tolerance to VIM stimulation which occurs over time, and possible stimulation-induced side-effects such as dysarthria (abnormal speech) and gait disturbance are also observed [3, 4]. The need to increase stimulation over time leads to reduced lifetime of the implantable neurostimulator battery, requiring more frequent surgical replacements – a burden on the patient as well as the healthcare economy. Therefore, the VIM may not be the most suitable DBS target for the optimal treatment of ET. An area of the PSA called the zona incerta is a newer DBS target which has

shown promise as a better alternative to VIM. Currently, however, there is little or no data to guide target selection [5].

An important requirement of the proposed study is an objective Figure 1 measurement of tremor severity. In a typical clinical setting, tremor is assessed by clinical observation and the application of simple tests such as tracing a spiral on a piece of paper (as shown in Figure 1). We have developed a novel technique to more reliably and accurately measure tremor severity using advances in electromagnetic motion tracking technology and customized software. Up to four different parts of the body can be simultaneously tracked using small, light- weight sensors (Figure 2), with accuracy to within 0.4mm. The custom-designed software we have developed at the Bionics Institute (Figure 3) is able to show tremor severity in real-time, and we have shown that in ET patients it is highly correlated (r2 > 0.90, p < 0.001) with clinical ratings. This system was utilized in a recent clinical study to determine the time-course of DBS therapeutic effect for ET. We found that after DBS application, tremor improved within 10 seconds, however when DBS was disabled, we observed an immediate increase in tremor which peaked after 2 minutes and receded to steady-state approximately 6 minutes post DBS. These ‘wash-in’ and ‘wash-out’ periods must be carefully observed during clinical studies.

Our research is clinically significant because at this time no reliable scientific evidence exists to guide neurologists with their decision to target the PSA or VIM since the degree of therapeutic benefit for the patient when stimulating either target is uncertain.

Figure 2 Figure 3

3 Research methods and procedures We aim to recruit 20 adults who are using existing DBS therapy to treat ET. These patients have a unique DBS lead trajectory that allows us to stimulate both PSA and VIM targets simply by changing electrode configurations. This provides us with a unique opportunity to study the effectiveness of PSA and VIM stimulation within the same patient. Existing pre-operative MRI and post-operative CT imaging will be used to determine exact electrode location to verify stimulation targets. Informed written consent will be sought from each participant prior to enrolment and we have obtained ethics approval from the Royal Melbourne Hospital and St. Vincent’s Hospital Human Research Ethics Committee to conduct this study.

We aim to evaluate and compare the effectiveness of the following stimulation conditions in each patient: 1) PSA stimulation only; 2) VIM stimulation only; and 3) simultaneous VIM and PSA stimulation. These conditions will be randomized to prevent causal bias emerging from effects such as fatigue. Adequate rest periods will be allowed between conditions. Control baseline tremor severity will be recorded with DBS turned off. For each of the three conditions, we will systematically increase DBS amplitude in 0.5V steps, starting at levels which begin to decrease tremor severity, until persistent side- effects become evident or the patient reports discomfort. At least 10 seconds will be allowed between consecutive stimulus level changes to allow for ‘wash-in’ (transition from low to high DBS level) based on preliminary results. For each stimulus amplitude we will perform the following assessments:

1. Postural tremor (arms outstretched) 2. Kinetic and intention tremor (finger to nose exercise) 3. Speech (spontaneous speech and prescribed paragraph recordings will be analyzed objectively using computer algorithms to detect vocal tremor and other abnormalities) 4. Traditional spiral drawing (Figure 1) 5. Patient-reported rating of side-effect 6. Drinking from a cup

Electromagnetic motion tracking will be used to asses tremor during exercises (including spiral drawing and drinking from a cup) with accompanying software developed at the Bionics Institute to give real- time measures of tremor severity. Additionally, spiral drawing will also be rated by an independent clinician.

4 Anticipated results The objective measures of therapeutic benefit (reduced tremor and side-effect) will be analyzed for each stimulus paradigm across the patient cohort. The results obtained will allow us to determine whether our hypothesis is supported; i.e., a greater level of tremor suppression can be achieved without side-effects at lower stimulus amplitudes for PSA stimulation compared to VIM stimulation. Additionally, we believe that simultaneous PSA and VIM stimulation is more effective than PSA alone because we are targeting both brain pathways involved in tremor. Simultaneous stimulation has not been explored in the past and this is a novel aspect of the present study. We believe our research will improve patient

quality-of-life by allowing DBS users to carry out fine motor tasks with reduced tremor (handwriting, eating with knife and fork, etc.). Importantly, our research will determine the ideal stimulation target and translate this into clinical practice by enabling neurologists to make better-informed decisions in the future.

Finally, we aim to promote objective measurement technologies in all similar research, and wider adoption would see increased reliability and reproducibility of tremor measures, which would lead to improved therapeutic benefit and ultimately better quality of life for ET patients. We will publish our results in relevant journals (such as Movement Disorders, Brain and Neurology) as well as presentations at international conferences. Future long-term follow up studies will be required to establish an evidence base from which changes to guidelines and clinical practice will be made. Translation to clinical practice should take no more than three years and is simply a matter of modifying surgical lead trajectory for the stimulating electrodes.

5 Detailed budget and justification

Expenditure Item Description Cost (USD) Patient expenses Transportation, catering, accommodation $11,068.73 Trained in DBS programming and care for patients with ET Patient care nurse $3,120.00 $39.00/hr standard rate Collection and analysis of data Research assistant $10,170.00 $33.90/hr standard rate Total: $24,358.73

A total of 20 participants will be recruited into our study from Melbourne and Tasmania, Australia from the medical register of Dr. Peppard. Those patients travelling from the adjacent state of Tasmania require reimbursement of a modest airfare and one night’s accommodation.

ET patients will be assessed off-medication and therefore cannot travel alone. They will be accompanied by a carer, and taxi transport services will be offered.

The participants will be assessed over a 3-4 hour time period, with short rest breaks. It has been our practice to provide patients with lunch at the conclusion of experiments. During this time, medication and DBS stimulation will resume, and we can ensure that each patient returns to their usual clinical state before returning home.

During the assessment period we will be enlisting the assistance of a Patient Care Nurse trained in the use of DBS therapy to adjust stimulation parameters. This ensures our participants are well cared for and DBS is always applied safely by an experienced clinician. We also require an experienced part-time Research Assistant to collect, manage, and analyze experimental data recorded using our novel motion tracking device. We estimate that this work will take 20 weeks to complete at 40% EFT.

Unfortunately, we have not received funding support from Australia’s National Health and Medical Research Council, NIH, or philanthropic organizations. The preliminary results gathered from the proposed study will be used to support future applications for government funding.

References

1. Kringelbach, M. L., Jenkinson, N., Owen, S. L., & Aziz, T. Z. (2007). Translational principles of deep brain stimulation. Nature Reviews Neuroscience, 8(8), 623-635.

2. Zhang, K., Bhatia, S., Oh, M. Y., Cohen, D., Angle, C., & Whiting, D. (2010). Long-term results of thalamic deep brain stimulation for essential tremor: Clinical article. Journal of neurosurgery, 112(6), 1271-1276.

3. Blomstedt, P., Sandvik, U., & Tisch, S. (2010). Deep brain stimulation in the posterior subthalamic area in the treatment of essential tremor. Movement Disorders, 25(10), 1350-1356.

4. Sitburana, O., Almaguer, M., & Ondo, W. G. (2010). A pilot study: Microlesion effects and tremor outcome in the ventrointermediate deep brain stimulation (VIM-DBS). Clinical neurology and neurosurgery, 112(2), 106-109.

5. Chopra, A., Klassen, B. T., & Stead, M. (2013). Current clinical application of deep-brain stimulation for essential tremor. Neuropsychiatric disease and treatment, 9, 1859.

6. Louis, E. D., and Ferreira, J. J. (2010). How common is the most common adult movement disorder? Update on the worldwide prevalence of essential tremor. Movement Disorders, 25(5), 534–541.

7. Flora, E. D., Perera, C. L., Cameron, A. L. and Maddern, G. J. (2010). Deep brain stimulation for essential tremor: A systematic review. Movement Disorders, 25(11), 1550–1559.

8. Diamond, A., & Jankovic, J. (2005). The effect of deep brain stimulation on quality of life in movement disorders. Journal of Neurology, Neurosurgery & Psychiatry, 76(9), 1188-1193.

9. Louis, E. D., & Ottman, R. (2014). How Many People in the USA Have Essential Tremor? Deriving a Population Estimate Based on Epidemiological Data. Tremor and Other Hyperkinetic Movements, 4.

10. Medical Services Advisory Committee. (2008). Deep brain stimulation for dystonia and essential tremor. Canberra, Australia: MSAC.

11. Louis, E. D., Benito-León, J., Ottman, R., & Bermejo-Pareja, F. (2007). A population-based study of mortality in essential tremor. Neurology, 69(21), 1982-1989.

12. National Institute for Clinical Excellence (NICE). (2013). Measuring effectiveness and cost effectiveness: the QALY.

6 Biographical sketches

BIOGRAPHICAL SKETCH: Richard Peppard

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 POSITION TITLE Richard F. Peppard Neurologist 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.) DEGREE INSTITUTION AND LOCATION MM/YY FIELD OF STUDY (if applicable) University of Melbourne, Australia MB, BS 12/1977 Medical Degree Royal Australasian College of Physicians Fellow 1986 University of Melbourne, Australia MD 1993 Neurology St. Vincent’s Hospital, Melbourne, Neurology 1978-86 Neurology registrar

A. Personal Statement Since 1990, participation in functional neurosurgery program with intra-operative neurophysiology, clinical testing, selection and assessment of patients for functional neurosurgery. From 1997, special interest in DBS surgery for movement disorders with 300 patients under current treatment for DBS programming and 40-50 patients per year undergoing DBS surgery with pre-op assessment, intra-op microelectrode recording and trials of stimulation and post-operative programming of pulse generators.

B. Positions and Honors PAST POSITIONTS: 1986 - 1988: Post-doctoral research fellow, Division of Neurology, Department of Medicine, University Hospital, University of British Columbia, Vancouver, BC, Canada.

CURRENT POSITIONS: From 1988 Neurologist - St. Vincent’s Hospital, Fitzroy From Feb 2001 – Neurologist Movement Disorder Clinic, Wantirna Health

SOCIETIES: Australasian Association of Neurologists, 1985 – Present Australian Medical Association, 1978 -1986, 1988-Present Movement Disorder Society

C. Selected Peer-reviewed Publications (Selected from 40 publications) McKay, C. M., McDermott, H. J., Perera, T., Peppard, R., Jones, M., & Vogel, A. P. (2015). The influence of rate of stimulation and pulse duration on efficacy of deep brain stimulation for Essential Tremor. Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation, 8(2), 331.

Perera, T., Yohanandan, S. A., Vogel, A. P., McKay, C. M., Jones, M., Peppard, R., & McDermott, H. J. (2015). Deep brain stimulation wash-in and wash-out times for tremor and speech. Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation, 8(2), 359.

Zhong M, Evans A, Peppard R, Velakoulis D, Validity and Reliability of the PDCB: a tool for the assessment of caregiver burden in Parkinson's disease. International Psychogeriatrics. 2013 PMID 23635603

Silberstein P, Bittar RG, Boyle R, Cook R, Coyne T, O'Sullivan D, Pell M, Peppard R, Rodrigues J, Silburn P, Stell R, Watson P. Australian DBS Referral Guidelines Working Group. Deep brain stimulation for Parkinson's disease referral guidelines. Journal of Clinical Neuroscience 2009;1001-8; PMID 19596113

Lim SY, O'Sullivan SS, Kotschet K, Gallagher DA, Lacey C, Lawrence AD, Lees AJ, O'Sullivan DJ, Peppard RF, Rodrigues JP, Schrag A, Silberstein P, Tisch S, Evans AH. Dopamine dysregulation syndrome, impulse control disorders and punding after deep brain stimulation surgery for Parkinson's disease. Journal of Clinical Neuroscience 2009;1148-52, PMID 19553125

O'Sullivan JD, Maruff P, Tyler P, Peppard RF, McNeill P, Currie J. Unilateral pallidotomy for Parkinson's disease disrupts ocular fixation. Journal of Clinical Neuroscience 2003; 181-5, PMID 12637045

Crowe SF, O'Sullivan JD, Peppard RF, McNeill PM, Bardenhagen F, Bowden S. Left posteroventral pallidotomy results in a deficit in verbal memory. Behavioural Neurology. 1998:11(2):79-84, PMID 11568404

Castiello U, Bonfiglioli C, Peppard RF. Dopaminergic effects on the implicit processing of distractor objects in Parkinson's disease. Exp Brain Res. 2000;135(2)251-8, PMID 11131510

Castiello U, Bennet KM, Bonfiglioli C, Peppard RF. The reach-to-grasp movement in Parkinson's disease before and after dopaminergic medication. Neuropsycholgia 2000;38(1):46- 59, PMID 10617291

Castiello U, Bennet KM, Bonfiglioli C, Peppard RF. The reach-to-grasp movement in Parkinson's disease: response to a simultaneous perturbation of object position and object size. Ex Brain Res. 1999;125(4):453-62. PMID 10323292

Bennett KM, O'Sullivan JD, Peppard RF, McNeill PM, Castiello. The effect of unilateral posteroventral pallidotomy on the kinematics of the reach to grasp movement. Journal of Neurology Neurosurgery Psychiatry 1998;65(4):479-87. PMID: 9771769

Peppard RF. Martin WR. Carr GD. Grochowski E. Schulzer M. Guttman M. McGeer PL.

Phillips AG. Tsui JK. Calne DB. Cerebral glucose metabolism in Parkinson's disease with and without dementia. Archives of Neurology. 1992;49(12):1262-8.

D. Research Support

Ongoing Research Support 2014 Principal Investigator, “Using Objective Measures of Tremor Severity to Identify Optimal Deep Brain Stimulation Targets”, St. Vincent’s Hospital Research Endowment Fund.

BIOGRAPHICAL SKETCH: Hugh McDermott

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 POSITION TITLE Hugh J McDermott Deputy Director, The Bionic Institute of Australia, eRA COMMONS USER NAME (credential, e.g., agency login) and Professorial Fellow, The University of Melbourne, Australia EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable.) DEGREE INSTITUTION AND LOCATION MM/YY FIELD OF STUDY (if applicable) University of Melbourne, Australia BAppSc 12/81 Electronics (Hons)

University of Melbourne, Australia Otolaryngology/Electrical PhD 12/88 Engineering

A. Personal Statement I am a biomedical engineer and Fellow of the Institute of Electrical and Electronics Engineers (IEEE). For over 30 years I have contributed directly to the design, development, and evaluation of neurostimulation devices, particularly cochlear implants and signal processing systems. The outcomes of this research have frequently had direct application to practical improvement of products manufactured by the world’s foremost companies in this field (particularly Cochlear Ltd, Australia and Sonova AG, Switzerland). My research in the 1980s leading to the award of the PhD degree involved the design of a complete receiver-stimulator (implantable electronic component) for an advanced cochlear implant. Since then I have devised and directed the development of hardware and software systems for conducting psychophysical experiments, processing signals, and stimulating neurons electrically. Over the past 5 years this work has been extended into the fields of prosthetic vision and brain stimulation. The latter research aims to treat conditions such as movement disorders and certain neuropsychiatric conditions by means of electric stimulation of selected brain targets. I hold an honorary Professorial Fellow appointment at the University of Melbourne in the Department of Audiology and Speech Pathology, where I lecture for a Master of Clinical Audiology course, and in the Department of Medical Bionics. I have supervised over 20 graduate students to successful completion of their studies, and I presently supervise 5 PhD students. In my current role as Deputy Director of the Bionics Institute of Australia I oversee the research activities of a medium-sized not-for-profit organization that is focused on the improvement and evaluation of cochlear implants, a prototype bionic eye, and several neurobionics devices. I am named as an inventor on over 20 patent families, and have a further 10 patent applications currently being processed. I have authored more than 105 journal articles, 7 book chapters, and over 100 additional publications. On more than 100 occasions I have been invited to present lectures to international conferences, corporate workshops, and research seminars. I was elected Fellow of the Acoustical Society of America in 2002, for “signal processing that improves speech recognition with cochlear implants.” In 2009 I was awarded the first Callier Prize in Communication Disorders, a biennial award from the University of Texas, Dallas, for leadership “that has fostered scientific advances and significant developments in the diagnosis and treatment of communication disorders”.

B. Positions and Honors

Positions and Employment

1982-1984 Graduate Research Assistant (part time), Department of Otolaryngology, University of Melbourne, Australia. 1984-1996 Research Fellow, Department of Otolaryngology, University of Melbourne. 1989-2007 Senior Research Consultant, Bionic Ear Institute, Melbourne, Australia. 1996-2001 Senior Research Fellow, Department of Otolaryngology, University of Melbourne. 2001-2006 Principal Research Fellow (with title of Associate Professor) in the Department of Otolaryngology, The University of Melbourne. 2006-2010 Honorary Fellow, and member of the Scientific Advisory Committee, The Bionic Ear Institute, Melbourne. 2006-2010 Full Professor (inaugural appointment), Chair of Auditory Communication and Signal Processing, Department of Otolaryngology, The University of Melbourne. 2007-2008 Member of Science Advisory Group and Research Project consultant, The Hearing Co-operative Research Centre, Australia. 2006-2008 Consultant to Phonak AG, Stäfa, and visiting researcher at the Laboratory for Experimental Audiology, University Hospital, Zurich, Switzerland. 2010-present Deputy Director, the Bionics Institute of Australia (formerly the Bionic Ear Institute) 2010-2012 Honorary Professorial Fellow in the Department of Otolaryngology, University of Melbourne, Australia. 2012-present Honorary Professorial Fellow in the Department of Audiology and Speech Pathology, and Honorary Professorial Fellow in the Department of Medical Bionics, University of Melbourne, Australia. 2013-present Visiting Researcher in the Computer Vision Group, NICTA.

Professional Memberships and Honors 1997 Elected Member of the Acoustical Society of America 1998 Member of the Institute of Electrical and Electronics Engineers (IEEE) 2000 Elected Senior Member of the IEEE 2002 Elected Fellow of the Acoustical Society of America 2009 Inaugural Callier Prize in Communication Disorders (a biennial award from the University of Texas, Dallas, Callier Center for Communication Disorders) 2012 Elected Fellow of the IEEE (Institute of Electrical and Electronics Engineers)

C. Selected Publications

Most relevant to the current application 1. Perera, T., Yohanandan, S. A. C., McDermott, H., J., “A Simple and Inexpensive Test-Rig for Evaluating the Performance of Motion Sensors used in Movement Disorders Research,” Medical & Biological Engineering & Computing, 2015. [Accepted for publication] 2. Perera, T., Yohanandan, S. A., Vogel, A. P., McKay, C. M., & McDermott, H. J. (2015). Development of precise tremor assessment software to aid deep brain stimulation parameter optimization. Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation, 8(2), 358-359. 3. McKay, C. M., McDermott, H. J., Perera, T., Peppard, R., Jones, M., & Vogel, A. P. (2015). The influence of rate of stimulation and pulse duration on efficacy of deep brain stimulation

for Essential Tremor. Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation, 8(2), 331. 4. Sinclair, N., Perera, T., Thevathasan, W., Bullus, K., Fallon, J., & McDermott, H. (2015). Clinical efficacy of symmetric constant-current biphasic pulses for deep brain stimulation. Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation, 8(2), 361. 5. Perera, T., Yohanandan, S. A., Vogel, A. P., McKay, C. M., Jones, M., Peppard, R., & McDermott, H. J. (2015). Deep brain stimulation wash-in and wash-out times for tremor and speech. Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation, 8(2), 359. 6. McDermott, H., Villalobos, J., Bibari, O., Fallon, J., Perera, T., Sinclair, N., Bulluss, K., Thevathasan, W. (2015). A personalised, closed-loop DBS system based on a cranial neurostimulator for treating Parkinson’s disease and other disorders. Brain Stimulation, 8(2), 365-366. 7. McDermott HJ: “Neurobionics: neural prostheses for the CNS.” in “Neurobionics: The Biomedical Engineering of Neural Prostheses” ed Rob Shepherd. John Wiley & Sons, Inc., Hoboken (in press). 8. Shepherd RK, Fallon JB, McDermott HJ: “Medical Bionics.” Chapter 10.17 in: Comprehensive Biomedical Physics, Anders Brahme, editor-in-chief, vol 10, pp. 327-341, Elsevier, Amsterdam, 2014. 9. McDermott HJ: “Medical Bionics Device Design: Its History and Future.” Presentation and Abstract for the Third International Conference of Medical Bionics: Engineering Solutions for Neural Disorders, Phillip Island, Australia, 17 - 20 November, 2013. 10. Vogel AP, McDermott HJ, Peppard R, McKay C M: “Optimising speech outcomes in deep brain stimulation for essential tremor.” 17th International Congress of Parkinson's Disease and Movement Disorders, Movement Disorders 28:S1-S464. doi: 10.1002/mds.25605, Sydney, Australia, 16-20 June, 2013. 11. Perera T, Yohanandan S, McDermott HJ, McKay CM: “Development of objective tremor- severity measurement software to advise clinicians during deep brain stimulation programming.” Poster presentation for the Aikenhead Centre for Medical Discovery Research Week, 2013. 12. Perera T, McKay CM, Peppard R, McDermott HJ, and Vogel A: “Optimising deep brain stimulation through tremor quantification.” Abstract for NeuroEng 2013: Australian Workshop on Computational Neuroscience, University of Melbourne, Australia, 30 – 31 January 2013. 13. Vogel AP, McDermott HJ, Peppard R, and McKay CM: “Optimising speech outcomes in Deep Brain Stimulation for essential tremor.” Abstract for the 3rd Australasian Cognitive Neuroscience Conference, University of Queensland, Brisbane, 29 Nov 2012 to 2 Dec 2012. http://www.frontiersin.org/10.3389/conf.fnhum.2012.208.00108/event_abstract

Additional recent publications of importance to the application (in chronological order)

Relevant patent applications: 1. McDermott HJ. 2011. Device and circuitry for controlling delivery of stimulation signals, Provisional US 61/512,752 (priority date 28/07/2011). Australian national entry phase (filing date 25/07/2012, AU 2012/286586). WO2013/013265; PCT/AU2012/000879; US 2014/0303691. 2. Seligman P, McDermott HJ. 2011. Device and circuitry for generating nerve stimulation signals, Provisional AU 2012/286590 (priority date 28/07/2011). WO2013/013269; PCT/AU2012/000886; AU 2012/286590 B2 (granted 08/01/2015); US 2014/0277274 (pending)

Ongoing Research Support

2015 Associate Investigator, “Closed-loop deep brain stimulation for treatment of movement disorders” (with Dr K Bulluss, Dr W Thevathasan, N Sinclair, and Dr Thushara Perera), St Vincent’s Hospital Research Endowment Fund. This project aims to improve deep brain stimulation technology by developing an innovative closed-loop system for treatment of movement disorders such as Essential Tremor and Parkinson’s Disease, specifically to provide part funding for a clinical trial. 2014 – 2016 Associate investigator, “Improving a new form of deep brain stimulation to treat gait and balance disturbance in Parkinson’s disease”, National Health and Medical Research Council of Australia Project Grant. This project is developing new technology to assist in objective assessment of movement disorder symptom severity. 2012 – 2015 Chief Investigator “Delivering Neurobionics to the Clinic”, Colonial Foundation. This project aims to develop innovative Deep Brain Stimulation (DBS) systems to treat disorders of the central nervous system for which no other effective therapies are available. Such disorders include movement disorders (e.g., Parkinson’s disease, Essential Tremor); psychiatric conditions (e.g., obsessive-compulsive disorder, severe depression); and other disabling conditions (e.g., chronic pain and epilepsy). 2013 – 2015 Chief Investigator “Monitoring Cortical Excitability using a Probing Stimulus for Epileptic Seizure Anticipation” (with Prof M Cook, A/Prof D Grayden, and Prof D Nesic), National Health and Medical Research Council of Australia Project Grant. This project aims to record and analyze electrical brain activity associated with selected stimuli to enable anticipation and subsequently termination of epileptic seizures. It is an important part of a larger research program that will result in improved diagnosis and therapy for many people with epilepsy. 2014-2017 Associate Investigator, “Early detection of hearing acuity loss using non-invasive, objective measures of neural degeneration” (with Dr Hamish Innes-Brown), NHMRC New Investigator grant.

Completed Research Support

2012 – 2014 Co-investigator “Using novel cochlear implants with focused multipolar stimulation to improve perception” (Chief Investigator: Prof C McKay), Garnett Passe and Rodney Williams Memorial Foundation and Cochlear Ltd. 2014 Associate Investigator “Using objective measures of tremor severity to identify optimal deep brain stimulation targets” (with Dr Richard Peppard and Dr Thushara Perera), St Vincent’s Hospital Research Endowment Fund. 2012 – 2013 Investigator “Deep Brain Stimulation: Optimising Patient Outcomes” (with Prof M Cook and Prof C McKay), St Vincent’s Hospital Research Endowment Fund. 2011 - 2013 Chief Investigator (with Drs. J Fallon, DRF Irvine, RK Shepherd), “The plastic effects of long-term partial deafness and chronic cochlear implant use on the response of primary auditory cortex to combined electro-acoustic stimulation,” National Health and Medical Research Council of Australia Project Grant. 2011 – 2012 Chief Investigator “Optimising brain stimulation parameters for Essential Tremor” (with Prof C McKay), Helen Macpherson Smith Trust. 2010 - 2013 Associate Investigator, “Bionic Vision Australia,” Australian Research Council Special Research Initiative in Bionic Vision Science and Technology (CIs: Burkitt, Lovell, Shepherd, et al).

BIOGRAPHICAL SKETCH: Colette McKay

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 POSITION TITLE McKay, Colette Mary Professor of Translational Hearing Research 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.) DEGREE INSTITUTION AND LOCATION MM/YY FIELD OF STUDY (if applicable) University of Melbourne, Australia BSc(Hons) 12/74 Physics and Math University of Melbourne, Australia PhD 12/79 Physics University of Melbourne, Australia PGDip 12/80 Audiology Audiology Society of Australia CCASA 01/86 Clinical Certification

NOTE: The Biographical Sketch may not exceed four pages. Follow the formats and instructions below.

A. Personal Statement I am an international leader in the field of psychophysics with electrical stimulation. From 1991- 2004, as a Research Fellow, Senior Research Fellow, and Principal Research Fellow at the University of Melbourne, I contributed significantly to the design and signal processing strategies used in the Nucleus family of cochlear implants manufactured by Cochlear Ltd., through my studies in psychophysics, speech perception, speech processing and mathematical modeling. I have 87 peer reviewed publications and 3 patents, the majority of which are in the cochlear implant field.

My aim is to bring the knowledge and experience I gained with Cochlear implantees to those with Deep Brain Stimulation and develop a mathematical model to describe the influence of electrical stimulation on changes in tremor and side-effect.

B. Positions and Honors Positions and Employment 1991-1995 Research Fellow, Department of Otolaryngology, The University of Melbourne, Australia. 1995-2001 Senior Research Fellow, Department of Otolaryngology, The University of Melbourne 2002-2004 Principal Research Fellow, Department of Otolaryngology, The University of Melbourne 2005-2006 Chair in Auditory Sciences, Aston University, School of Life and Health Sciences, Birmingham, UK 2007- Honorary Professorial Fellow, University of Melbourne, Department of Otolaryngology 2007-2010 Director of Research for School of Psychological Sciences, University of Manchester 2007-2011 Research Group Leader for Audiology and Deafness Research Group, University of Manchester

2007-2013 Chair in Applied Hearing Research, University of Manchester, UK 2011- Professor (full time from 2013), The Bionics Institute, Melbourne, Australia 2012- Honorary Professorial Fellow, University of Melbourne, Department of Medical Bionics

Other experience and professional memberships 1981- Member, the Audiological Society of Australia 1986- Clinical certification from Audiological Society of Australia 1997 Visiting Scholar, Wolfson College, Cambridge University 2002- Elected Fellow of the Acoustical Society of America (member since 1995) 2002- Member, Association for Research in Otolaryngology (ARO) 2008- Member, British Society of Audiology 2009-2010 Associate Editor, Journal of the Association for Research in Otolaryngology (JARO).

Honors and Awards 1974 Four physics prizes contributed to my research studies for BSc(Hons): (a) John Tyndall Scholarship; (b) Dixson Research Scholarship; (c) Professor Kernot Research Scholarship; (d) Dunlop Rubber Australia Ltd. Research Scholarship 1998 Garnett Passe and Rodney Williams Memorial Foundation Senior/Principal Research Fellowship. This is a highly-competitive award (only one being considered per year) for Australian researchers in Otolaryngology who show exception potential and track record in research. 2002 Elected Fellow of the Acoustical Society of America for “the measurement and improvement of speech recognition with cochlear implants”. 2003 Principal Research Fellowship by the Australian National Health and Medical Research Council. A fellowship at this level is awarded to only about 5 people per year. 2009 The Thomas Simm Littler Prize, awarded by the British Society of Audiology for contributions to auditory research in 2008 2010 The inaugural Graeme Clark visiting Research Fellowship at the Bionic Ear Institute in Melbourne, Australia, which included a public lecture: “From exclusion to electronics: transforming the communication ability of deaf people” Federation Square Melbourne, March 2011 2013 The veski Innovation Fellowship: awarded by the Victorian Government to assist world leading Australian expat scientists to return to Australia

C. Selected Peer-reviewed Publications (selected from 87) All relevant to the current application (reverse chronological order, most relevant *starred) 1. *McKay CM, Lim HH and Lenarz T (2013). “Temporal processing in the central auditory system: insights from cochlear and midbrain implants” Journal of the Association for Research in Otolaryngology 14(1): 103-124 2. McKay CM (2012) “Forward masking as a method of measuring place specificity of neural excitation in cochlear implants: a review of methods and interpretation,” J. Acoust. Soc. Am. 131:209-225 3. *Fraser M and McKay CM. (2012). “Temporal modulation transfer functions in cochlear implantees using a method that limits overall loudness cues,” Hearing Research 283: 59-69 4. *Azadpour M and McKay CM (2012) “A psychophysical method for measuring spatial resolution in cochlear implants,” Journal of the Association for Research in Otolaryngology 13: 145-157.

5. Carlyon RP, Deeks J, and McKay CM (2010) “The upper limit of temporal pitch: Stimulus duration, conditioner pulses, and the number of electrodes stimulated,” J. Acoust. Soc. Am. 127: 1469-1478. 6. *McKay CM and Henshall KR. (2010) “Amplitude modulation and loudness in cochlear implantees,” Journal of the Association for Research in Otolaryngology. 11(1) 101 – 111. 7. Carlyon RP, Long C, Deeks J, and McKay CM. (2007) “Concurrent Sound Segregation in Electric and Acoustic Hearing,” Journal of the Association for Research in Otolaryngology 8(1):119-33. 8. *McDermott HJ, Sucher CM, and McKay CM. (2005) “Speech perception with a cochlear implant sound processor incorporating loudness models” ARLO 6(1): 7-13. 9. Prado-Guitierrez P, Fewster LM, Heasman JM, McKay CM, Shepherd RK. (2006) “Effect of interphase gap and pulse duration on electrically evoked potentials is correlated with auditory nerve survival” Hearing Research 215: 47-55. 10. McKay CM, Henshall KR, and Hull AE. (2005) “The effect of rate of stimulation on perception of spectral shape by cochlear implantees,” J Acoust Soc Am 118: 386-392. 11. McKay CM and Henshall KR. (2003). “The perceptual effects of interphase gap duration in cochlear implant stimulation,” Hearing Research 181: 94-99. 12. *McDermott HJ, McKay CM, Richardson L, and Henshall KR. (2003). “Application of loudness models to sound processing for cochlear implants,” J Acoust Soc Am 114: 2190- 2197. 13. *McKay CM, Henshall KR, Farrell RJ, and McDermott HJ. (2003) “A practical method of predicting the loudness of complex electrical stimuli,” J Acoust Soc Am 113: 2054-2063. 14. *McKay CM, Remine MD, and McDermott HJ. (2001). "Loudness summation for pulsatile electrical stimulation of the cochlea: effects of rate, electrode separation, level, and mode of stimulation," J Acoust Soc Am 110: 1514-1524. 15. *McKay CM and McDermott HJ (1998) “Loudness perception with pulsatile electrical stimulation: the effect of interpulse intervals,” J Acoust Soc Am 104: 1061-1074.

D. Research Support Current support (selected, relevant) Garnett Passe and Rodney Williams Memorial Foundation project grant 2011-2014 “Using novel cochlear implants with focused multipolar stimulation to improve perception” Investigators: McKay (PI), McDermott, and Marozeau This project includes a collaboration with Cochlear Ltd to investigate the effectiveness of highly focused electrical stimulation for improving the perception of across-frequency temporal cues in cochlear implants.

Veski Innovation Fellowship (2013-2016) “Objective programming of cochlear implants and other devices for electrical stimulation of the brain” Investigator: McKay (PI)

Completed projects (most relevant first) Royal Society Joint Project award ref# JP0872240 2009-2010 “Auditory perception using auditory mid-brain implants” Investigators: McKay (PI), Lenarz (co-PI), Lim (CI)

MRC Project Grant G0701461/85204 2008-2011 “Automatic and individually optimised fitting of cochlear implants” Investigators: McKay (PI), Carlyon, El-Deredy (Collaborator Beynon)

This major grant investigated perceptual an physiological factors that underlie differences in outcomes in cochlear implant users.

RNID Flexi Grant 2010 “Improving outcomes for auditory brainstem implants” Investigator: McKay (PI) This small grant helped to collect pilot data to investigate the transmission of temporal speech features in ABI users. It led to the current industry-funded grant (Cochlear Ltd).

HEAR Trust Research Grant 2008-2110 “Investigating individual differences in outcomes for cochlear implant patients” Investigator: McKay (PI) This charity funded grant expanded the MRC project detailed above.

ESRC CASE award with Advanced Bionics 2008-2011 “Listening in noise: improved speech understanding by cochlear implantees” Investigator: McKay (PI) A project that funded a PhD student to investigate whether focused (tripolar) stimulation would assist with speech perception.

Cochlear Ltd project grant 2011-2012 “Improved fitting of auditory brainstem implants” Investigators: McKay (PI), O’Driscoll, and Azadpour This industry funded project evaluated the benefit of selecting a subset of electrodes that evoke ‘better’ psychophysical properties to improve speech perception in ABI users.

Cochlear Ltd supported PhD studentship 2009-2012 “Automated fitting of cochlear implants” Investigator: McKay (PI) This is an industry funded PhD studentship to develop automated (electrophysiological) methods for fitting a cochlear implant.

HEAR Trust Research Grant 2009 “Investigation of cross-modal plasticity using fMRI in CI candidates” Investigator: McKay (PI) This small grant was used to fund a pilot study to investigate the effectiveness of fMRI as a prognostic tool for CI candidates.

Advanced Bionics Corporation: project grant 2011-20102 “Using frequency compression in bimodal hearing” Investigator: McKay (PI) This industry-funded project investigated whether frequency compression benefits CI users who wear a hearing aid on the other ear.

MRC project grant ref# G0802190 2009-2011 “Development of an objective method for diagnosing dead regions in the cochlea” Investigators: Kluk-de Kort (PI), McKay (CI) This major grant was for the development of an objective method of diagnosing cochlear dead regions using auditory steady-state responses.

BIOGRAPHICAL SKETCH: Adam Vogel

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: Dr Adam Vogel POSITION TITLE Senior Research Fellow eRA COMMONS USER NAME (credential, e.g., agency login)

The University of Queensland, Australia MSc 10/03 Speech Pathology

Behavioural The University of Melbourne, Australia PhD 03.10 Neuroscience

A. Personal Statement The goal of the proposed research is to determine which brain targets for deep brain stimulation work best for the treatment of ET. I have the expertise and motivation necessary to successfully carry out the proposed work. I am responsible for the design of the speech components of the protocol, including acquisition, stimuli and analysis. I am well placed for this role given my clinical and research experience. I hold a prestigious National Health and Medical Research Council of Australia Career Development Fellowship. I also lead the Speech Neuroscience Unit within The University of Melbourne. Relative to opportunity, I have a very strong track record in research, following just four years of active postgraduate research. I have published more than 49 journal articles (38 as first/senior author), two clinical guidelines, and two book chapters. The quality of my work has been recognized with five prizes for research excellence (two international, two national, one state), $3.3M in competitive research funding ($1.6M as PI), and Editorial Board Membership on the journal ‘Speech, Language and Hearing’ and Frontiers. I am also involved (AI) in the new Australian Research Council (ARC) Centre of Excellence: Dynamics of Language (2014-2020; AU$28M) and have demonstrated robust industry collaborations (e.g. 2 Australian Research Council Linkage Projects as PI with Cogstate and Cochlear) and a proven record of research supervision (5 PhD students, 31 completed Honours students).

B. Positions and Honors Positions and Employment 2004-2006 Speech Therapist, National Health Service, London, UK 2004-2006 Research Assistant, Institute of Child Health, University College London, London, UK 2006 -2010 Clinical Scientist, Cogstate 2007-2010 PhD candidate, University of Melbourne 2006-present Consultant Speech Pathologist, Friedreich Ataxia Clinic, Monash Medical Centre, Australia 2010 Post-Doctoral Research Fellow, Institute for Safety, Compensation & Recovery Research, Monash University, Australia

2013-present Consultant Speech Pathologist, Eastern Cognitive Disorders Clinic, Melbourne Australia 2011-2012 Research Fellow, University of Melbourne, Australia 2012-present Senior Research Fellow, University of Melbourne, Australia

Other Experience and Professional Memberships 2012- Editorial board, Speech, Language & Hearing 2014-15 Editor of special issue in Frontiers of Biotechnology and Bioengineering 2014- National Health & Medical Research Council Australia, Postgraduate Scholarships Panel Member 2014-16 International Parkinson and Movement Disorder Society member 2013- Australian Research Council reviewer 2011- Research Grant Council (RGC) Hong Kong International Reviewer 2012- Czech Science Foundation International reviewer 2012- Australian Cognitive Neuroscience Society Member 2007- Australian Speech Science & Technology Association (ASSTA) member

Honours 2014 Alexander von Humboldt Experienced Research Fellow at the Hertie Institute for Clinical Brain Research, University of Tübingen, Germany 2014-15 Visiting Research Fellow, Mathematics Institute, Oxford University, UK 2014 Dyason Fellowship, The Istituto Superiore di Sanità, Rome Italy 2013 Young Tall Poppy Science Award (Victoria) from the Australian Institute of Policy and Science 2013 Bethlehem Griffiths Research Foundation Young Researcher of the Year Award, Australia 2011-15 National Health and Medical Research Council Early Career Research Fellowship 2010 New Researcher Award: Australasian Speech Science and Technology Association (ASSTA) 2009 U21 Mobility Scheme: Postgraduate Overseas Research Experience Scholarship, Sweden 2009 National Health and Medical Research Council Dora Lush (Biomedical) Postgraduate Scholarship 2009 New Investigator Award: The Voice Foundation’s 38th Annual Symposium, Philadelphia USA

C. Selected Peer-reviewed Publications (Selected from 51 peer-reviewed publications) Most relevant to the current application 1. Vogel, A.P., Fletcher, J. Snyder, P.J., Fredrickson, A. & Maruff, P. (2011) Reliability, stability and sensitivity to change and impairment in acoustic measures of timing and frequency. Journal of Voice. 25 (2), 137-49. 2. Vogel AP, Fletcher, J. & Maruff, P. (2010) Acoustic analysis of the effects of sustained wakefulness on speech. Journal of the Acoustical Society of America.128 (6) 3747-3756. 3. Vogel AP, Shirbin C, Churchyard A & Stout J (2012). Speech acoustic markers of early stage and prodromal Huntington's Disease: a marker of disease onset? Neuropsychologia. 50 (14) 3273-3278 4. Vogel AP & Maruff, P. (2008) Comparison of voice acquisition methodologies in speech research. Behavior Research Methods. 40 (4), 982-987.

5. Vogel AP & Maruff P (2014) Monitoring change requires a re-think of assessment practices in voice and speech. Logopedics, Phoniatrics, Vocology. 39(2), 56-61

Additional recent publications of importance to the field (in chronological order) 1. Pearson-Dennett V, Flavel SC, Wilcox RA, Thewlis D, Vogel AP, White JM, Todd G. (2014) Hand Function is Altered in Individuals with a History of Illicit Stimulant Use. PLoS ONE 9(12): e115771. doi:10.1371/journal.pone.0115771 2. Poole ML, Wee J, Folker JE, Corben LA, Delatycki M, & Vogel AP (2015) Nasality in Friedreich ataxia. Clinical Linguistics Phonetics. 29(1), 46-58 3. Vogel AP, Folker J, Poole ML. Treatment for speech disorder in Friedreich ataxia and other hereditary ataxia syndromes. Cochrane Database of Systematic Reviews 2014, Issue 10. Art. No.: CD008953. DOI: 10.1002/14651858.CD008953.pub2. 4. Vogel AP, Fletcher J. & Maruff P. (2014) The impact of task automaticity on speech in noise. Speech Communication. 65, 1-8 5. Vogel AP, Brown SE, Folker JE, Corben LA & Delatycki M. (2014) Dysphagia and swallowing related quality of life in Friedreich ataxia. Journal of Neurology. 261(2), 392-399 6. Gibilisco P & Vogel AP (2013) Friedreich Ataxia. British Medical Journal. 347: f7062 7. Mundt JC, Vogel AP, Feltner DE, & Lenderking WR (2012). Vocal Acoustic Biomarkers of Depression Severity and Treatment Response. Biological Psychiatry. 72 (7) 580-7. 8. Folker JE, Murdoch BE, Cahill LM, Delatycki M, Corben LA & Vogel AP. (2012) Differentiating profiles of speech impairments in Friedreich's ataxia: A perceptual and instrumental approach. International Journal of Language & Communication Disorders. 47:65-76. 9. Folker, J.E., Murdoch, B.E., Cahill, L.M., Delatycki, M.B., Corben, L.A. & Vogel AP. (2010). Dysarthria in Friedreich’s ataxia: a perceptual analysis. Folia Phoniatrica et Logopaedia. 62 (3), 97-103. 10. Vogel AP, & Morgan, A. T. (2010). Assessment of impairment or assessment of change in Friedreich ataxia. Movement Disorders. 25 (11), 1753-1754. 11. Vogel AP, Chenery, H., Dart, C., Doan, B., Tan, M., & Copland, D. (2009) Verbal fluency, semantics, context and symptom complexes in schizophrenia. Journal of Psycholinguistic Research. 38 (5), 459-473 12. Vogel AP & Morgan, A. T. (2009) Factors affecting the quality of sound recording for speech and voice analysis. International Journal of Speech-Language Pathology. 11 (6), 431-437 13. Vogel AP, Ibrahim, S., Reilly, S. & Kilpatrick, N. (2009) A comparative study of two acoustic measures of hypernasality. Journal of Speech, Language & Hearing Research. 52 (6), 1640-1651

D. Research Support Year Investigators Type/Title Amount Australian Research Council (ARC) 2014- Vogel, Dowell Linkage Grant: Tonal language development in AU$416K 2016 Mandarin and Cantonese-speaking children with cochlear implants 2013- Arciulli, Ballard, Discovery Grant: Discovering the developmental AU$185K 2015 Vogel trajectory of lexical stress production

2012- Vogel, Rajaratnam, Linkage Grant: Sleep and speech: objectively AU$159K 2015 Maruff, Andersen monitoring the residual effects of sleep promoting compounds 2011- Collie, Vogel, Linkage Grant: Determining the individual, community AU$481K 2014 Keleher, McClure, and societal impacts of compensable injury in Australia Petersen, Ellis 2008- Reilly, Onslow, Discovery Grant: Stuttering in childhood: Patterns of AU$347K 2011 Packman, Wake, recovery and persistence Prior, Bavin, Eadie, Ukoumunne, Block, Vogel (PI) 2014- Evans, Cutler, ARC Centre of Excellence: Dynamics of Language AU$28M 2020 Wigglesworth, Rumsey, Wiles, Sterelney (Vogel AI) National Health & Medical Research Council (NHMRC) 2015-19 Vogel NHMRC Career Development Fellowship AU$411K 2011-14 Vogel NHMRC Training Fellowship AU$290K

2009 Vogel Dora Lush (Biomedical) Postgraduate Scholarship AU$29K

Philanthropic and Institutional Sources (selected grants) 2014- Kefalianos, Reilly, Murdoch Childrens Research Institute: Piloting an AU$27K 2015 Vogel SMS method for stuttering data collection 2009- Reilly, Morgan, Vogel Telematics Trust: Developing novel methods for AU$32K 2010 collecting speech samples in children 2007- Vogel Special Postgraduate Award: Cogstate AU$67K 2009 International (selected grants) 2015- Vogel, Synofzik, Ataxia Charlevoix-Saguenay Foundation (Canada) CAN$57K 2016 Schöls 2015- Vogel, Synofzik, Deutsches Zentrum für Neurodegenerative €30K 2016 Schöls Erkrankungen, DZNE (Germany) 2014-16 Vogel Alexander von Humboldt Fellowship (Germany) €48K 2008- Mundt (Lead) NIH: Small Business Innovation Research Grant US$528K 2010 Healthcare (Phase II): Development of a convenient, automated, Technology Systems, objective measure of depression (USA) Vogel (Partner Investigator) CogState

BIOGRAPHICAL SKETCH: Thushara Perera

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 POSITION TITLE Thushara Perera Research Engineer (Software/Electronics) 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.) DEGREE INSTITUTION AND LOCATION MM/YY FIELD OF STUDY (if applicable) La Trobe University, Australia BE 12/06 Electronics (hons.) La Trobe University, Australia ME 12/08 Biomedical Engineering La Trobe University, Australia PhD 01/14 Anesthesiology

NOTE: The Biographical Sketch may not exceed four pages. Follow the formats and instructions below.

A. Personal Statement I am an electronics engineer with experience in medical device technology and software design. I developed the software program that interfaces with the electromagnetic motion tracking hardware. The software is responsible for collecting the raw data from the motion tracker and performing analysis to detect tremor, while ignoring purposeful motion. Tremor is then quantified using a series of techniques raging from simple amplitude and frequency to more complex modelling parameters that look at displacement volume. The system was designed to provide a level of accuracy and sensitivity that does not exist in present tremor assessment scales. With this technology, I hope to establish an objective measure of Essential Tremor treatment outcomes.

I have previously worked with the Bionic Eye project (Bionics Institute, Australia), developing software to determine perception of electrically-stimulated vision in blind patients. This software has been used to gather results from three Bionic Eye recipients and is still in use with continuous development to add increasingly novel features.

B. Positions and Honors Positions and Employment 2008-2011 Biomedical Technologist, Department of Biomedical Engineering, The Royal Children’s Hospital, Parkville, Victoria, Australia

2009-2011 Casual Teaching Assistant, Department of Electronic Engineering, La Trobe University, Bundoora, Victoria, Australia

2012-present Research Engineer, Neurobionics Department, Bionics Institute, East Melbourne, Australia

Professional Memberships 2008-present Graduate Member, Institute of Engineers Australia 2014-present Brain Foundation Member

Honors 2004 La Trobe University Wanda Henry Memorial Undergraduate scholarship recipient

2004-2006 Listed on the Dean’s Honours List (awarded to students with an average overall mark of 80% or more during the year)

2007 Best Poster Presentation Prize at Hooper Memorial Research Presentations

2008 Tad Szental Prize in Electronic Engineering (awarded annually to best electronic engineering graduate)

2009 Australian Commonwealth Postgraduate Research Award (PhD Scholarship)

C. Selected Peer-reviewed Publications Perera, T., Yohanandan, S. A. C., McDermott, H., J., “A Simple and Inexpensive Test-Rig for Evaluating the Performance of Motion Sensors used in Movement Disorders Research,” Medical & Biological Engineering & Computing, 2014. [Accepted]

Perera, T., Lewis, P. M., Davidson, A. J., Junor, P., Bottrell, S., “A Pilot study to determine whether visually evoked hemodynamic responses are preserved in children during inhalational anesthesia,” Pediatric Anesthesia, 25(3), 2014.

Ayton, L. N., Blamey, P. J., Guymer, R. H., Luu, C. D., Nayagam, D. A. X., Sinclair, N. C., Shivdasani, M. N., Yeoh, J., McCombe, M. F., Briggs, R. J., Opie, N. L., Villalobos, J., Dimitrov, P. N., Varsamidis, M., Petoe, M. A., McCarthy, C. D, Walker, J. G., Barnes, N., Burkitt, A. N., Williams, C. E., Shepherd, R. K., Allen, P. J., Bionic Vision Australia Research Consortium*, “First-in-Human Trial of a Novel Suprachoroidal Retinal Prosthesis,” PLoS one, 9(12), 2014.

Shivdasani, M. N., Sinclair, N. C., Dimitrov, P. N., Varsamidis, M., Ayton, L. N., Luu, C. D., Perera, T., McDermott, H. J., Blamey, P. J., “Factors affecting perceptual thresholds in a suprachoroidal retinal prosthesis," Investigative Ophthalmology & Visual Science, 55(10), 2014.

Perera, T., Yohanandan, S. A., Vogel, A. P., McKay, C. M., & McDermott, H. J. (2015). Development of precise tremor assessment software to aid deep brain stimulation parameter optimization. Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation, 8(2), 358-359.

McKay, C. M., McDermott, H. J., Perera, T., Peppard, R., Jones, M., & Vogel, A. P. (2015). The influence of rate of stimulation and pulse duration on efficacy of deep brain stimulation for Essential Tremor. Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation, 8(2), 331.

Sinclair, N., Perera, T., Thevathasan, W., Bullus, K., Fallon, J., & McDermott, H. (2015). Clinical efficacy of symmetric constant-current biphasic pulses for deep brain stimulation. Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation, 8(2), 361.

McDermott, H., Villalobos, J., Bibari, O., Fallon, J., Perera, T., Sinclair, N., Bulluss, K., Thevathasan, W. (2015). A personalised, closed-loop DBS system based on a cranial neurostimulator for treating Parkinson’s disease and other disorders. Brain Stimulation, 8(2), 365-366.

Shivdasani, M. N., Sinclair, N. C., Dimitrov, P. N., Varsamidis, M., Ayton, L. N., Luu, C. D., Perera, T., Petoe, M. A., McDermott, H. J., Blamey, P. J., “Influence of Clinical and Stimulus Parameters on Perceptual Thresholds in a Suprachoroidal Retinal Prosthesis,” The 8th Biennial The Eye and The Chip World Research Congress on Artificial Vision, Michigan, US, 2014.

Gillespie, L. N., Sinclair, N. C., Petoe, M. A., Perera, T., Shivdasani, M. N., Diaz, D. P., Dimitrov, P. N., Blamey, P. J., “Characterisation of Phosphenes and Perception using a Suprachoroidal Electrode Array,” The Aikenhead Centre for Medical Discovery Research Week, Melbourne, Australia, 2014.

* Please note that Thushara Perera is an acknowledged member of the Bionic Vision Australia Research Consortium.

D. Research Support Ongoing Research Support 2015 Investigator, “Closed-loop deep brain stimulation for treatment of movement disorders”, St. Vincent’s Research Endowment Fund.

Completed Research Support 2013 Investigator, “Developing mathematical models to analyse postural stability data from Deep Brain Stimulation of the Pedunculopontine nucleus for treatment of Parkinson’s Disease”, Brain Foundation Grant.

2014 Investigator, “Using Objective Measures of Tremor Severity to Identify Optimal Deep Brain Stimulation Targets”, St. Vincent’s Research Endowment Fund.

7 Copies of relevant abstracts

Deep Brain Stimulation Wash-in and Wash-out Times Quantified using Objective Real-Time Tremor Measurements

Thushara Perera1, Shivanthan A. C. Yohanandan1, 2, Mary Jones3, Richard Peppard1, 3, Wesley Thevathasan1, 3, 4, 5, Colette M. McKay1, 6, Hugh J. McDermott1, 6 Submitted to the International Neuromodulation Society’s 12th World Congress, Montreal, Canada, 2015.

1. Bionics Institute, 384-388 Albert St, East Melbourne 3002, Australia ([email protected]) 2. Electrical and Electronic Engineering, The University of Melbourne, Parkville 3010, Australia 3. Department of Neurology, St. Vincent’s Hospital, Fitzroy 3065, Australia 4. Department of Neurology, The Royal Melbourne Hospital, Melbourne, Australia 5. Department of Medicine, The University of Melbourne, Melbourne, Australia 6. Medical Bionics Department, The University of Melbourne, Parkville 3010, Australia

Objective

Deep brain stimulation (DBS) is an accepted therapy for some patients who have severe tremor associated with progressive conditions such as Parkinson’s disease and Essential Tremor [1]. We used a real-time objective tremor measurement system (TREMBAL) developed at the Bionics Institute to determine the DBS ‘wash-in’ and ‘wash-out’ periods to establish guidelines for clinical practice and future research.

Materials and Methods

Nine adults using DBS to treat tremor participated in our study. During the assessment, we systematically varied the DBS amplitude between 100% (therapeutic level) and 0% (DBS off) with 75% and 50% as intermediate steps. Following each adjustment, participants were asked to perform the hands-outstretched and nose-finger-nose exercises. Three trials per DBS condition were conducted with appropriate rest periods. Tremor was objectively measured using TREMBAL which incorporates an electromagnetic motion tracker to measure displacements with sub-millimetre accuracy [2]. The raw data was processed in real-time to determine tremor amplitude, velocity, and frequency at a rate of one measurement per second. One-Way Repeated Measures ANOVA followed by Mann-Whitney U-tests were performed to determine significant differences in medians between tremor datasets.

Results

Overall tremor medians differed (p < 0.01) and in the transition from DBS off to 50% the tremor was ameliorated within 10 seconds (p = 0.03) post DBS activation. When examining wash-out data, tremor severity rose to a peak (p < 0.01) in the first two minutes then decreased to reach stability after 6 minutes (p = 0.04) following DBS cessation.

Discussion

For tremor, the wash-in period is an order of magnitude shorter than the wash-out period. Also, consistent with clinical observation, a tremor overshoot is evident when decreasing DBS amplitude. During clinical DBS parameter optimisation, the patient must be allowed at least 6 minutes rest before tremor assessment. Furthermore, in studies where DBS parameters are randomised during assessments, adequate rest periods must be included to account for DBS wash-out [3]. The rest periods can be shortened if a systematic assessment procedure is applied where each trial progressively increments DBS amplitude.

Conclusion

Using objective tremor measures, we found that DBS wash-in times for tremor (10 seconds) were faster than wash-out times (6 minutes). Adequate rest periods are required during patient assessments in both standard clinical care and scientific studies to account for wash-in and wash-out times when DBS parameters are adjusted.

Acknowledgements

Colonial Foundation, St. Vincent’s Hospital REF, Victorian Government OIS.

References

1. W. Thevathasan and R. Gregory, “Deep brain stimulation for movement disorders,” Pract. Neurol., vol. 10, no. 1, pp. 16–26, Feb. 2010.

2. Ascension Technology Corporation, “3D Guidance trakSTAR Specification Sheet,” 2012. [Online]. Available: http://www.ascension-tech.com/medical/pdf/trakSTAR_SpecSheet.pdf. [Accessed: 15-Jan- 2015].

3. P. E. O’Suilleabhain, W. Frawley, C. Giller, and R. B. Dewey, “Tremor response to polarity, voltage, pulsewidth and frequency of thalamic stimulation,” Neurology, vol. 60, no. 5, pp. 786–790, 2003.

Clinical validation of a precise tremor assessment system to aid deep brain stimulation parameter optimisation

Thushara Perera1, Shivanthan A.C. Yohanandan1, 2, Mary Jones3, Richard Peppard3, Wesley Thevathasan1, 3, 4, 5, Andrew H. Evans4, Joy L. Tan1, 6, Colette M. McKay1, 6, Hugh J. McDermott1, 6 Submitted to the World Congress on Medical Physics & Biomedical Engineering, Toronto, Canda, 2015.

1. The Bionics Institute, Melbourne, Australia ([email protected]) 2. Electrical and Electronic Engineering, The University of Melbourne, Melbourne, Australia 3. Department of Neurology, St Vincent's Hospital, Melbourne, Australia 4. Department of Neurology, The Royal Melbourne Hospital, Melbourne, Australia 5. Department of Medicine, The University of Melbourne, Melbourne, Australia 6. Medical Bionics Department, The University of Melbourne, Melbourne, Australia

Introduction

Deep brain stimulation (DBS) is an established therapy for Parkinson’s disease and Essential Tremor. Yet finding the most efficacious stimulation amplitude, pulse duration and frequency is difficult due to the numerous parameter permutations. The therapeutic outcomes are measured using a variety of clinical assessments including subjective rating scales. These measures lack sufficient sensitivity to inform DBS parameter optimisation, thus justifying our aim to develop a more precise and objective measure.

Methods

The Tremor Biomechanics Analysis Laboratory (TREMBAL) system, developed at the Bionics Institute, provides real-time tremor severity measurements for clinicians using an electromagnetic motion tracker (Ascension, Vermont, US) to acquire absolute displacements and rotations of the tremulous body part. TREMBAL automatically computes tremor amplitude, velocity, peak frequency and peak power spectral density (PSD) for both translational and rotational components of motion.

We placed two sensors on each hand at the proximal phalanges of the middle fingers and approximately 5 cm above the olecranon of the elbows to measure proximal and distal tremors of nine participants with existing DBS therapy. Four trials were performed where DBS level was systematically reduced from 100% (clinically optimal level) to 75%, 50% and finally 0% (DBS off). In each trial, after waiting 12 minutes for adaptation, the participant held their hands outstretched for 10 seconds and performed the finger-nose exercise. These were video recorded and presented to three blinded experts (W.T., A.H.E., J.L.T.) for clinical rating using the Bain Tremor Rating Scale. Linear regression analysis between the average expert tremor ratings and computed tremor metrics were used to validate TREMBAL. Pearson’s correlations were also performed to confirm any associations.

Results

Sixty-four clinical ratings were included in the analysis. One patient was excluded because they presented with dystonia. Results were deemed significant if 푝 < 0.0063 (Bonferroni correction for multiple comparisons). Objective measures of translational amplitude and velocity had the strongest ability to predict clinical ratings (table 1).

푹ퟐ SE 풓 풑

Amplitude 0.81 0.53 0.90 < 0.001 Velocity 0.81 8.34 0.90 < 0.001 Frequency 0.32 0.09 0.56 < 0.001

Translation PSD 0.71 0.22 0.84 < 0.001

Amplitude 0.34 0.27 0.59 < 0.001 Velocity 0.34 5.15 0.58 < 0.001

Frequency 0.20 0.09 0.45 < 0.001 Rotation PSD 0.20 0.01 0.44 < 0.001 Table 1. The coefficient of determination (푅2) and standard error (SE) indicated the goodness-of-fit of the linear regression between clinical ratings and TREMBAL metrics for distal tremor of the worst affected hand. Pearson’s correlations indicated strength (푟) and statistical significance (푝) of the association. PSD = Power Spectral Density.

Discussion

Tremor frequency and PSD in addition to all angular measures showed weaker agreement with clinical ratings. We believe that clinicians rely mostly on displacement and speed to assess tremor severity thus accounting for the high concordance with translational TREMBAL data. Further work will aim to determine the test-retest reliability of the system and the optimal combination of metrics to reduce TREMBAL’s output to a single measure based on machine learning algorithms.

Acknowledgements

Colonial Foundation and the Victorian Government Operational Infrastructure Support Program.

The influence of rate of stimulation and pulse duration on efficacy of deep brain stimulation for Essential Tremor

C.M. McKay, H.J. McDermott, T. Perera, R. Peppard, M. Jones, A.P. Vogel, 1st International Brain Stimulation Conference, Singapore, 2015.

Deep brain stimulation (DBS) is used to alleviate tremor in patients diagnosed with Essential Tremor who do not respond to conventional treatments. To achieve optimal tremor suppression, a large stimulus parameter space needs to be explored. In practice, a default pulse duration and stimulation rate (generally 60 us and 130 Hz) are often chosen and current or voltage varied to determine a clinically effective setting. This study explored the effect of rate of stimulation in 5 patients with bilateral DBS stimulation to the posterior sub-thalamic area (PSA). Additionally the effects of varying charge per pulse by varying pulse duration alone or by varying current/voltage alone were compared.

In experiment 1, rate was varied using the values 20, 70, 100, 130, 150, and 210 Hz, keeping pulse duration (90 us) and current (1patient) or voltage (4 patients) fixed. In experiment 2, rate was fixed at 130 Hz, and charge per phase was varied first by changing pulse duration between 60, 90, and 120 us, and secondly by altering current or voltage by the same ratios. Tremor severity was categorized by two experienced clinicians.

Figure 1 shows the effect of rate for each subject. A repeated-measures ANOVA showed a significant effect of rate (p < 0.001) with the 40 Hz rate producing worse tremor scores than all rates of 100 Hz and above. Two patients showed a U-shaped response with best tremor suppression between 100 and 130 Hz, whereas the remaining patients showed a trend for better tremor suppression as rate increased across the whole range. Paired t-tests showed no significant difference between changing charge per phase via pulse duration or current/voltage, although both these effects were small, leading to poor statistical power.

5 P1 P2 4 P4 P5 P6 3

Tremor Category Tremor 1

40 70 100 130 150 210 Rate of Stimulation

Fig.1 Results of experiment 1.

Funding: Colonial Foundation, Victorian government OIS program, NHMRC.

Optimising Speech Outcomes in Deep Brain Stimulation for Essential Tremor

Vogel , A.P., McDermott, H.J., Peppard, R., McKay, C.M., MDS 17th International Congress of Parkinson's Disease and Movement Disorders, Sydney, Australia, 2013. Oral Presentation.

Objective: We aimed to pilot a speech evaluation procedure that would form the basis of an objective clinical Deep Brain Stimulation (DBS) optimization tool for use in patients with tremor. Background: DBS is rapidly emerging as a safe and effective treatment option for mitigating the effects of tremor. Despite the relative success of DBS for treating tremor, a common and typically unquantified adverse effect of treatment is dysarthria (slurred speech). Current assessment protocols are driven by the qualitative judgements of treating clinicians and lack the sensitivity and objectivity required to make reliable decisions about treatment optimization. Methods: Six patients diagnosed with essential tremor receiving treatment via deep brain stimulation of the posterior sub-thalamic nucleus were recruited. Electrical stimulation parameters (i.e., pulse rate, pulse duration, and current amplitude) were systematically adjusted and speech samples recorded to identify the patient-specific settings required for optimal therapeutic benefit (reduced tremor) with minimal adverse effects (dysarthria). Altered speech production between stimulation parameters was quantified via acoustic analysis. Results: Measures of timing (e.g., speech rate), intonation (e.g., pitch variation) and quality (e.g., noise- to-harmonics ratio) reflected increasing/decreasing levels of dysarthria.

Conclusions: Via this protocol we aim to understand the inter-relationship between the effects of the parameters as well as to develop a real-time objective system for surgeons to optimise these parameters for each patient. A secondary outcome is to increase our understanding of how electrical parameter settings are related to movement and speech, and how the optimal parameters are related to the nature of the individual's pathology.

Objective Measures of Efficacy of Deep Brain Stimulation for Treatment of Tremor

McKay, C. M., Perera, T., Peppard, R., McDermott, H. J., Vogel, A. P., 3rd Australasian Cognitive Neuroscience Conference, Brisbane, Australia, 2012. Poster Presentation.

Patients with intractable tremor not alleviated by pharmaceutical therapies can be successfully treated using Deep Brain Stimulation of subcortical areas such as the Subthalamic Nucleus (STN). Current DBS devices produce constant-current or constant-voltage biphasic pulse trains and offer a range of pulse rate and pulse duration options as well as different current or voltage levels. The clinical method of setting the parameters by observation is non-ideal, firstly because of the number of possible parameter combinations, and a current lack of knowledge of how the parameters interact with each other, and secondly because subjective clinical observation is prone to observer error and bias. In this study, we aimed to develop an objective method of recording the severity of tremor and to use it to explore the effect on tremor of stimulus parameters.

Six patients with Essential Tremor who had been fitted with a DBS device in the Posterior Subthalamic Area (PSA) participated in the study. Tremor was measured by position sensors attached to the arms and wrists while the patient was holding both arms stretched out in front of them and when performing a finger-nose pointing task. Clinical rating of tremor was also performed. Results of the experiments showed that the optimal stimulus parameters were subject specific and the effects of each parameter were non-monotonic, often with a very specific range providing therapeutic benefit (for example, Fig. 1). The objective measures were more sensitive than clinical judgement and show that an objective fitting method could improve benefits in individual patients.

Fig. 1. Effect of stimulus current on tremor 2.0 2.0 Translational tremor amplitude Angular tremor amplitude Frequency of tremor 1.8 1.5

1.6

1.0

1.4

0.5 1.2

Frequency of tremor (Hz - stars) tremor (Hz of Frequency

Normalisedtremor measures(circles) 0.0 1.0 0 1 2 3 4

Current (mA)

Acknowledgments: Supported by the Helen McPherson Smith Trust and the Colonial Foundation. The Bionics Institute acknowledges the support it receives from the Victorian Government through its Operational Infrastructure Support Program.

8 Conflict-of-Interest Declaration