Biomarkers for Deep Brain Stimulation

Lead Research Organisation: University of Oxford
Department Name: Clinical Neurosciences

Abstract

Parkinson?s disease and dystonia are two of the most common neurological disorders of movement. Recently there has been immense interest in the neurosurgical treatment of these disabling disorders through electrical deep brain stimulation. However, the cost of deep brain stimulation, its partial usefulness and its side-effects mean that there is still a pressing need to improve current therapy. One major problem is that existing brain stimulators only provide continuous and fixed stimulation which increases side effects, while reducing battery life. As a result batteries have to be surgically replaced at periodic intervals. Our growing understanding of how different patterns of brain activity are associated with different symptoms raises the possibility of improving therapy using ?smart? stimulation. Smart stimulators modify their electrical output according to the level of a particularly informative brain signal known as a biomarker. In this way the smart stimulator can determine when and how much stimulation is necessary, thereby improving the clinical result and extending battery life.
In this research program we will study the brain signals that can be recorded from the tip of deep brain electrodes so as to clarify their nature and determine which may provide biomarkers suitable for smart stimulation in Parkinson?s disease and dystonia. In particular, we will establish which biomarkers are causally linked to symptoms. The latter is a crucial step in both understanding disease processes and in identifying the best biomarkers for smart stimulation. In addition, we will define how deep brain stimulation interacts with each patient?s own brain signals. This will help us identify the most effective stimulation pattern in individual patients, rather than use the same pattern for all patients regardless of their particular symptoms. Finally, we will develop and test smart stimulation, comparing it to existing stimulation therapy. The understanding gained in this research program will lay the foundation for improved therapies involving brain stimulation in disorders of movement, and in other neurological disorders which can be resistant to available drug treatments.

Technical Summary

Parkinson?s disease (PD) and dystonia are two of the most common movement disorders. Recently there has been immense interest in the neurosurgical treatment of these debilitating disorders through deep brain stimulation (DBS). However, the cost of DBS, its partial efficacy and side-effects mean that there is still a need to improve current therapy. One major problem is that present neurostimulators only provide continuous and fixed ?open-loop? stimulation which increases side effects and habituation, while reducing battery life. Our growing understanding of how different patterns of activity in the basal ganglia (BG) are associated with different symptoms raises the possibility of improving DBS through closed loop stimulation. In closed-loop mode, stimulation is titrated using a biomarker to determine when and how much stimulation is necessary. Here we will extend our studies of BG local field potential (LFP) activities in patients undergoing neurosurgery in order to clarify the pathophysiology of PD and dystonia and thereby to identify local biomarkers suitable for closed loop stimulation regimes. To this end we will refine our ?noisy signal? model of BG disease, based on the hypothesis that it is the balance between synchronised activities indexed in the LFP, rather than one activity per se, which determines motor state. Our intention is to equate these diverse changes with psychophysical processes, and thereby formulate a model that links various levels of observation, has heuristic value and proffers more sophisticated biomarkers. The reliability and mechanistic importance of these biomarkers will then be assessed through a series of correlational and interventional experiments in patients. Establishing which biomarkers are causally linked to symptoms is critical in both understanding disease processes and in identifying legitimate targets for emerging ?smart? stimulation approaches. In addition, we will define how current DBS works. Specifically we will test the hypothesis that DBS acts as a high frequency dither injection similar to that used to quench low frequency oscillations in nonlinear feedback control loops. Our intention is to model this process in the BG, which will in turn allow the identification of the most effective stimulation regime in individual patients. Finally, we will optimise algorithms for closed-loop stimulation based on LFP features, and prove closed loop stimulation can be effective in a double-blind cross-over trial of closed-loop versus current open-loop DBS in PD. Understanding gained in this research program will lay the foundation for improved DBS therapy for motor and other disorders.

Publications

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Anzak A (2015) Excessive neural synchrony in Machado-Joseph disease responsive to subthalamic nucleus stimulation. in Movement disorders : official journal of the Movement Disorder Society

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Aron AR (2016) Frontosubthalamic Circuits for Control of Action and Cognition. in The Journal of neuroscience : the official journal of the Society for Neuroscience

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Beudel M (2015) Tremor Reduction by Deep Brain Stimulation Is Associated With Gamma Power Suppression in Parkinson's Disease. in Neuromodulation : journal of the International Neuromodulation Society

 
Description Member of Scientific Affairs Council of International Movement Disorders Society
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guideline committee
Impact Contributed to several guideline and clinical reviews
 
Description Parkinsons UK Research Advisory Committe
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
Impact As part of the panel we award research and training grants
 
Description Scientific Affairs Council
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guideline committee
Impact Member of Scientific Affairs Council, International Movement Disorders Society which produces international guidelines for the diagnosis and management of movement disorders.
 
Description l'Institut du Cerveau et de la Moelle Epinière
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
URL http://icm-institute.org/menu/actualites
 
Description Clinical Research training fellowship
Amount £194,000 (GBP)
Funding ID MR/K022172/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 05/2013 
End 04/2016
 
Description Clinical Training fellowship
Amount £173,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2011 
End 03/2013
 
Description EC FP6 funding
Amount £150,000 (GBP)
Organisation Sixth Framework Programme (FP6) 
Sector Public
Country European Union (EU)
Start 01/2006 
End 01/2008
 
Description MRC Clinical training fellowship
Amount £195,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 03/2013 
End 04/2015
 
Description MRC Program grant
Amount £1,700,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 11/2010 
End 12/2015
 
Description Multicentre Collaborative Group Grant
Amount € 400,000 (EUR)
Organisation European Commission 
Department Seventh Framework Programme (FP7)
Sector Public
Country European Union (EU)
Start 01/2014 
End 12/2017
 
Description Oxford BRC
Amount £2,800,000 (GBP)
Organisation Oxford University Hospitals NHS Foundation Trust 
Department NIHR Oxford Biomedical Research Centre
Sector Public
Country United Kingdom
Start 04/2012 
End 03/2017
 
Description Project
Amount £333,000 (GBP)
Organisation Rosetrees Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2012 
End 09/2017
 
Description Project
Amount £35,000 (GBP)
Organisation University of Oxford 
Department John Fell Fund
Sector Academic/University
Country United Kingdom
Start 11/2012 
End 09/2013
 
Description Project
Amount £60,000 (GBP)
Organisation Cure Parkinson's Trust 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Description Project
Amount £20,000 (GBP)
Organisation Rosetrees Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2012 
End 01/2014
 
Description Project
Amount £60,000 (GBP)
Organisation Cure Parkinson's Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2011 
End 03/2012
 
Description Project
Amount £250,000 (GBP)
Organisation Medtronic 
Sector Private
Country United States
Start 02/2013 
End 01/2016
 
Description Project
Amount £126,000 (GBP)
Organisation Parkinson's UK 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2012 
End 09/2014
 
Description Project grant
Amount £126,153 (GBP)
Organisation Parkinson's UK 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2012 
End 11/2014
 
Description Research Training Fellowship
Amount £173,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2011 
End 02/2014
 
Description Rosetrees Trust project grant
Amount £60,000 (GBP)
Organisation Rosetrees Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2015 
End 10/2017
 
Description StopBeta
Amount € 195,455 (EUR)
Organisation European Commission 
Department Horizon 2020
Sector Public
Country European Union (EU)
Start 06/2015 
End 05/2017
 
Title Depth LFPs 
Description Depth recordings in patients with Parkinson's disease 
Type Of Material Biological samples 
Provided To Others? No  
Impact Publications 
 
Title Local field potential recordings from basal ganglia in patients 
Description Pioneered the recording of local field potentials during and immediately after functional neurosurgery 
Type Of Material Physiological assessment or outcome measure 
Provided To Others? No  
Impact Forms the basis of a new form of functional intra-operative localisation 
 
Description Bionics institute 
Organisation Bionics Institute
Country Australia 
Sector Public 
PI Contribution Advice on paradigms and evaluation of data
Collaborator Contribution Device development
Impact National Health and Medical Research Council of Australia: Closed-loop deep brain stimulation: Optimising treatment of Parkinson's disease using adaptive stimulation. $726,000 Co-applicant.
Start Year 2014
 
Description Dr Litvak 
Organisation University College London
Department Institute of Neurology
Country United Kingdom 
Sector Academic/University 
PI Contribution Clinical advice, supervision and interpretation
Collaborator Contribution Scanning and analysis
Impact PMID: 21147836 PMID: 25754518 PMID: 25134978 PMID: 24150222 PMID: 24089489 PMID: 23277109 PMID: 22855804 PMID: 22815506
Start Year 2008
 
Description Marwan Hariz and Ludvic Zrinzo 
Organisation University College London
Department Division of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution recording and analysis and publication preparation
Collaborator Contribution provision of clinical material
Impact Multidisciplinary with over 15 publications
Start Year 2007
 
Description Prof Kuhn 
Organisation Charité - University of Medicine Berlin
Country Germany 
Sector Academic/University 
PI Contribution Experimental design, data collection and manuscript preparation
Collaborator Contribution Provision of research material and data collection. Intellectual input
Impact 16476944 16364953 16623853 16499911 16905134 16930593 17113373 17213215 17336961 17425586 17561827 17686048 17686426 18178569 18312587 18430031 18682201 18550758 18760276 19070616 19139047 19291224 19525877
 
Description Prof T Aziz 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution Experimental design and recording. Analysis and joint manuscript preparation
Collaborator Contribution Provision of research material and intellectual input
Impact 17084697 17686426 18312587 18430031 18682201 19226423
Start Year 2006
 
Description SIBET 
Organisation Chinese Academy of Sciences
Department Department of Medical Electronics
Country China 
Sector Academic/University 
PI Contribution Specified equipment and paradigms. Training and supervision
Collaborator Contribution Equipment, data, personnel
Impact Engineering from Chinese arm Engineering and clinical from UK
Start Year 2014
 
Title TACS control of tremor 
Description Non-invasive stimulation for tremor therapy 
Type Therapeutic Intervention - Medical Devices
Current Stage Of Development Refinement. Clinical
Year Development Stage Completed 2013
Development Status Under active development/distribution
Impact Interest from industry and press 
 
Title adaptive brain stimulation 
Description Funded by MRC 
Type Therapeutic Intervention - Medical Devices
Current Stage Of Development Refinement. Clinical
Year Development Stage Completed 2013
Development Status Under active development/distribution
Impact Interest from Industry, and press. 
 
Description BBC South East News 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Article on our latest research on BBC news South East.

None
Year(s) Of Engagement Activity 2013
 
Description Biomedical Research Centre Open day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Over 500 people (lay persons, patients, carers) attended to see the research that is being done.

None
Year(s) Of Engagement Activity 2014
URL http://oxfordbrc.nihr.ac.uk/
 
Description Brain awareness week workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Approximately 100 visitors per year with questions and interaction

none
Year(s) Of Engagement Activity 2011,2012
 
Description DANA Foundation interview 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Journalist interview

A-level student contact re career in research
Year(s) Of Engagement Activity 2013
URL http://www.dana.org/news/features/detail.aspx?id=43604
 
Description Discussion of the relative uses of clinical and animal research 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact Dissemination of information


Meeting discussions were disseminated widely through branch publications
Year(s) Of Engagement Activity 2015
 
Description Discussion of the relative uses of clinical and animal research 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact Dissemination of information.

Meeting discussions were disseminated widely through branch publications
Year(s) Of Engagement Activity 2015
 
Description Media briefing 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Internet research news site for engineering and lay community

Increased interest from engineers
Year(s) Of Engagement Activity 2013
URL http://www.extremetech.com/extreme/161411-real-time-adaptive-brain-control-combining-a-bci-with-dbs-...
 
Description Presentation to members of Parkinson's UK 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact Discussion

none
Year(s) Of Engagement Activity 2011
 
Description Public lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact 3rd Gretschen Amphlet Memorial Lecture, Fitzwilliam College, Cambridge. Brain rhythms: From Bedside to Bench and Back again.

Positive patient feedback
Year(s) Of Engagement Activity 2012
 
Description School charity visit 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach National
Primary Audience Health professionals
Results and Impact Enthusiastic reception from ~30 A level students

Increased interest in research careers
Year(s) Of Engagement Activity 2013
URL http://www.generatinggenius.org.uk/
 
Description School visit (Brown) 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Schools
Results and Impact Encouraging students in to science, very enthusiastic reception to the subject.



Please see evaluation report and http://www.ndcn.ox.ac.uk/news/international-students-visit-our-department-to-learn-about-neuroscience
Year(s) Of Engagement Activity 2015
URL http://www.ndcn.ox.ac.uk/news/international-students-visit-our-department-to-learn-about-neuroscienc...
 
Description Schools visit (Generating genius) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Schools
Results and Impact about 30 students from different state schools interested in doing sciences at University

Workshop enthusiastically received
Year(s) Of Engagement Activity 2014
URL http://www.generatinggenius.org.uk/