Surgical alleviation of akinesia

Lead Research Organisation: University of Oxford
Department Name: Unlisted

Abstract

Our observations have been and will be presented to learned meetings and in scientific, peer reviewed publications.

Technical Summary

I will continue to study the role of the pedunculopontine region in akinesia. We have so far shown that GABA antagonists when injected into this region will reverse experimental parkinsonism in monkeys. This observation although valuable is not yet clinically practical. We will carry on with studies comparing GABA antagonists with neurostimulation of the PPN in the MPTP parkinsonian primate. We will also initiate pilot clinical neuropharmacological and neurostimulation studies in non-parkinsonian akinetic disorders such as progressive supra-nucler palsy and multi-system atrophy to establish the validity of our findings.

Publications

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Aravamuthan BR (2009) Cortical and subcortical connections within the pedunculopontine nucleus of the primate Macaca mulatta determined using probabilistic diffusion tractography. in Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia

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Jenkinson N (2009) Anatomy, physiology, and pathophysiology of the pedunculopontine nucleus. in Movement disorders : official journal of the Movement Disorder Society

 
Guideline Title International Task Force on Deep Brain Stimulation for Dystonia
Description International Task Force on Deep Brain Stimulation for Dystonia
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical guidelines
Impact An international consultation and recommendations for the most effective management of dystonic patients with deep brain stimulation.
 
Description NICE guidelines for DBS in Parkinson's disease, Tremor and Dystonia
Geographic Reach UK 
Policy Influence Type Participation in a national consultation
Impact I have made many such representaions nationally and internationally over the years. Today DBS is aproved by NICE for PD, tremor and dytonia. I am pressing for approval for neuropathic pain. Recording field potentials, EMGs, EEGs, functional imaging have led to numerous publications from my group and many more internationally.; I did the primate work establishing the STN as a target for surgical alleviation of Parkinson's disease and subsequently the role of the pedunculopontine nucleus as a target to alleviate drug resistant akinesia.
 
Description EPSRC funding (Monitoring for Heath)
Amount £1,000,000 (GBP)
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 10/2009 
End 10/2013
 
Description Local field potentials in Movement disorders 
Organisation University of Oxford
Department Nuffield Department of Clinical Neurosciences
Country United Kingdom 
Sector Academic/University 
PI Contribution This is a collaboration of some years. we have both been recording field potentials from the implanted electrodes I surgically implant for alleviation of movement disorders and pain. This has led to very seminal studies.
Collaborator Contribution Professor Peter Brown has joined the University of Oxford from University College london lasy year. We were able to secure an MRC grant to study the role of local field potentials in movement disorders.
Impact Thevathasan, W., Silburn, P.A., Brooker, H., Coyne, T.J., Khan, S., Gill, S.S., Aziz, T.Z., Brown, P. The impact of low-frequency stimulation of the pedunculopontine nucleus region on reaction time in parkinsonism. (2010) Journal of neurology, neurosurgery, and psychiatry, 81 (10), pp. 1099-1104. Document Type: Article Source: Scopus Sauleau, P., Eusebio, A., Thevathasan, W., Yarrow, K., Pogosyan, A., Zrinzo, L., Ashkan, K., Aziz, T., Vandenberghe, W., Nuttin, B., Brown, P. Involvement of the subthalamic nucleus in engagement with behaviourally relevant stimuli (2009) European Journal of Neuroscience, 29 (5), pp. 931-942. Document Type: Article Source: Scopus Kühn, A.A., Tsui, A., Aziz, T., Ray, N., Brücke, C., Kupsch, A., Schneider, G.-H., Brown, P. Pathological synchronisation in the subthalamic nucleus of patients with Parkinson's disease relates to both bradykinesia and rigidity (2009) Experimental Neurology, 215 (2), pp. 380-387. Cited 19 times. Document Type: Article Source: Scopus Kühn, A.A., Brücke, C., Hübl, J., Schneider, G.-H., Kupsch, A., Eusebio, A., Ashkan, K., Holland, P., Aziz, T., Vandenberghe, W., Nuttin, B., Brown, P. Motivation modulates motor-related feedback activity in the human basal ganglia (2008) Current Biology, 18 (15), pp. R648-R650. Cited 5 times. Document Type: Letter Source: Scopus Brücke, C., Kempf, F., Kupsch, A., Schneider, G.-H., Krauss, J.K., Aziz, T., Yarrow, K., Pogosyan, A., Brown, P., Kühn, A.A. Movement-related synchronization of gamma activity is lateralized in patients with dystonia (2008) European Journal of Neuroscience, 27 (9), pp. 2322-2329. Cited 3 times. Document Type: Article Source: Scopus Androulidakis, A.G., Brücke, C., Kempf, F., Kupsch, A., Aziz, T., Ashkan, K., Kühn, A.A., Brown, P. Amplitude modulation of oscillatory activity in the subthalamic nucleus during movement (2008) European Journal of Neuroscience, 27 (5), pp. 1277-1284. Cited 4 times. Document Type: Article Source: Scopus Kempf, F., Brücke, C., Kühn, A.A., Schneider, G.-H., Kupsch, A., Chen, C.C., Androulidakis, A.G., Wang, S., Vandenberghe, W., Nuttin, B., Aziz, T., Brown, P. Modulation by dopamine of human basal ganglia involvement in feedback control of movement (2007) Current Biology, 17 (15), pp. R587-R589. Cited 3 times. Document Type: Letter Source: Scopus Brown, P., Chen, C.C., Wang, S., Kühn, A.A., Doyle, L., Yarrow, K., Nuttin, B., Stein, J., Aziz, T. Involvement of Human Basal Ganglia In Offline Feedback Control of Voluntary Movement (2006) Current Biology, 16 (21), pp. 2129-2134. Cited 13 times. Document Type: Article Source: Scopus Silberstein, P., Kühn, A.A., Kupsch, A., Trottenberg, T., Krauss, J.K., Wöhrle, J.C., Mazzone, P., Insola, A., Di Lazzaro, V., Oliviero, A., Aziz, T., Brown, P. Patterning of globus pallidus local field potentials differs between Parkinson's disease and dystonia (2003) Brain, 126 (12), pp. 2597-2608. Cited 90 times. Document Type: Article Source: Scopus Brown, P., Williams, D., Aziz, T., Mazzone, P., Oliviero, A., Insola, A., Tonali, P., Di Lazzaro, V. Pallidal activity recorded in patients with implanted electrodes predictively correlates with eventual performance in a timing task (2002) Neuroscience Letters, 330 (2), pp. 188-192. Cited 13 times. Document Type: Article Source: Scopus
 
Description Oxford Functional Neurosurgery 
Organisation Medtronic
Country United States 
Sector Private 
PI Contribution With use of supplied equipment we have studied the brains of patients undegoing DBS surgery for several different conditions.
Collaborator Contribution They supply Deep Brain Stimulators and manufacture and supply bespoke accessories (e.g. cabling and connectors) to help recording from DBS electrodes in human patients. In the past Medtronic also supplied custom deep brain electrodes for primate studies.supply of Deep Brain Stimulators and manufacturing and supply f bespoke accessories (e.g. cabing and connectors) to help recording from DBS electrodes in human patients.
Impact Recordings local field potentials from the brains of patients has allowed us to examine both the pathological changes that take place in the brain due to neurological disease, and the effect of DBS on patients behaviour. 19540864 19366355 19019684 18619592
 
Description Oxford Functional Neurosurgery 
Organisation St Jude Children's Hospital
Department Department of Advanced Neurological Systems
Country United States 
Sector Academic/University 
PI Contribution With use of supplied equipment we have studied the brains of patients undegoing DBS surgery for several different conditions.
Collaborator Contribution They supply Deep Brain Stimulators and manufacture and supply bespoke accessories (e.g. cabling and connectors) to help recording from DBS electrodes in human patients. In the past Medtronic also supplied custom deep brain electrodes for primate studies.supply of Deep Brain Stimulators and manufacturing and supply f bespoke accessories (e.g. cabing and connectors) to help recording from DBS electrodes in human patients.
Impact Recordings local field potentials from the brains of patients has allowed us to examine both the pathological changes that take place in the brain due to neurological disease, and the effect of DBS on patients behaviour. 19540864 19366355 19019684 18619592
 
Title deep brain stimulation of the pedunculopontine nucleus 
Description We have shown that low frequency stimulation of the ppn alleviates parkinsonian gait freezing and falls. 
Type Therapeutic Intervention - Surgery
Current Stage Of Development Refinement. Clinical
Year Development Stage Completed 2006
Development Status Under active development/distribution
Impact Now parkinsonian patients that cannot initiate gait with severe imbalance can now be effectively treated. 
 
Description 2nd Pro-Test March in Oxford 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact I led the second march through Oxford to acknowledge successful completion of the Oxford animal research facilities

Widespread public acknowledgement of the need for animal research as evidenced by polls taken at the time.
Year(s) Of Engagement Activity 2008
 
Description AASFN, San Francisco 2012 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Health professionals
Results and Impact International interest in deep brain stimulation for neuropathic pain.

Adoption of the surgery by centres internationally.
Year(s) Of Engagement Activity 2012
 
Description Cheltenham Science Festival 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact Public lecture on the need for primate research by myself and a patient who benefited from my work.

This led to public debate in the media .
Year(s) Of Engagement Activity 2007
 
Description Debate on animal research, BBC 2008 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Debate on Newsnight againct the BUAV chairwoman about the need for animal research

Widespread support for animal research
Year(s) Of Engagement Activity 2008
 
Description ESSFN, Lisbon 2012 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Health professionals
Results and Impact Increased adoption of PPN stimulation for parkinsonian gait freezing and falls

International study into the efficacy was initiated.
Year(s) Of Engagement Activity 2012
 
Description March in support of animal research 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact As a founding member of the Pro-Test committee I was one of the leaders of a march through Oxford in support of animal research and the opening of the Oxford laboratories. About 1000 people matched with us and the event recieved major international coverage.

The Oxford facilities are about to open, the current government has publicly committed itself to the need for such research to continue, security for scientists speaking out has vastly improved.
Year(s) Of Engagement Activity 2006,2008
 
Description Monkeys Rats and Me 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact This was a BBC documentary following the thread of the research I pursued in primates to find a target for surgical alleviation of parkinsonian akinesia. It also incorporated details of a patient that benefited from such surgery.

After this was broadcast nationally and internationally there has been a massive awareness in the minds of the public of the need for continued animal research.
Year(s) Of Engagement Activity 2007
 
Description Monkeys Rats and Me, BBC documentary 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Documentary of my primate research and clinical work. Awarded the RTS best science documentary of the year by the BBG.

The documentary is used by schools in Oxfordshire as part of general studies.
Year(s) Of Engagement Activity 2007
 
Description News Night November 24th 2008 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Media (as a channel to the public)
Results and Impact Interview with Jeremy Paxman Debating need for animal research against Michelle Thew of BUAV.

I was thanked by members of the public on streets in Oxford, London and also internationally via e mail for informing them why animal research is neccessary.
Year(s) Of Engagement Activity 2008
 
Description Pro-Test March In Oxford 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact As member of Pro-Test I was one of the leaders of a march through Oxford in support of the need for animal research

The campaign led to a government commitment to complete the animal research facilities in Oxford. Tony Blair also openly ststed governmental support for animal research
Year(s) Of Engagement Activity 2006
 
Description Use of Primates in medical research 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Primary Audience Policymakers/politicians
Results and Impact I served on a parliamentary select committee advising the need to use primates in medical research. http://www.publications.parliament.uk/pa/cm199900/cmhansrd/vo000629/debtext/00629-12.htm

The early day motion to ban the use of primates was quoshed
Year(s) Of Engagement Activity 2006,2007,2008,2009
 
Description WCN, 2011 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Presentation of deep brain stimulation of the PPN for Parkinson's disease

Adoption of a new operation.
Year(s) Of Engagement Activity 2011
 
Description WFNS, Recife 2010 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Health professionals
Results and Impact International meeting of neurosurgeons about my results of deep brain stimulation for neuropathic pain

Increased awareness of surgery for intractable pan
Year(s) Of Engagement Activity 2010
 
Description World congree of neurology Miami 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Health professionals
Results and Impact International meeting of neurologists, I was invited to present my work on deep brain stimulation for Dystonia

Widespread acceptance of surgery for dystonia.
Year(s) Of Engagement Activity 2009