Improving function in Huntington's disease through neurofeedback: using real-time fMRI to enhance cortical plasticity in early stages of the disease

Lead Research Organisation: University College London
Department Name: Institute of Neurology

Abstract

Huntington's disease (HD) is a rare, inherited, neurological condition where progressive brain damage leads to severe difficulties with movement, emotion and thought. The most characteristic sign of HD is uncontrolled movement of the limbs but subtle movement, emotion and thinking difficulties can start many years before this. There is no known cure for HD; a few drug treatments can help with some of the symptoms but have many deleterious side effects.

HD is characterized by slow, progressive atrophy of the brain, which theoretically allows the brain the opportunity to re-organize and compensate for the disease-related structural and functional changes. In this proposal, we will develop state-of-the-art technologies using functional magnetic resonance imaging (fMRI) and biofeedback to enhance such compensation and potentially alleviate symptoms. fMRI is a well-known technique that allows activity in the brain to be recorded non-invasively while people perform a task. Normally the analyses of these data are carried out off-line over a period of several weeks. However, recent developments allow real-time analysis of brain images and enable us to feed back the level of activity in selected brain areas to an individual while they lie in the brain scanner. Such real-time feedback can be used to train people to control their own brain activity through repeated sessions where they learn to enhance the activity that is fed back. This has been successfully used to allow people to control activity in many different regions of the brain and has also been applied to clinical conditions such as Parkinson's disease, depression and pain management with encouraging initial results for symptom management.

In this proposal we will use such advanced neurofeedback fMRI techniques to train individuals with symptomatic HD to control the level of activity in motor cortex, or the coupling of motor cortex with areas deep in the brain that are affected early in HD. Our underlying hypothesis is that if individuals with HD can learn to regulate the activity of brain regions that underpin their disease and contribute to the manifestation of certain symptoms, then the symptoms should improve.

Apart from the urgent need for new therapies, one advantage of studying HD is that genetic testing can establish with 100% accuracy whether an individual carries the mutant gene and will therefore develop HD at some point in their life. This enables us to not only monitor disease progression many years before an individual manifests the disease (pre-symptomatic stage), but also to develop interventions that can be applied at very early stages of the disease, when the brain damage is still limited and function is still well preserved. We know that structural and functional brain changes precede the manifestation of overt clinical signs by many years. This means that there is a mechanism of compensation at work, enabling gene-carriers to maintain a normal level of function despite degeneration. As the disease progresses and brain atrophy increases, this mechanism starts to break down and clinical signs start to become more evident. This is another gradual process and pre-symptomatic HD gene-carriers gradually move to a peri-symptomatic phase (with soft motor signs and mild cognitive impairment) and then eventually express unequivocal signs of the disease.

Our aim is to determine through a proof of concept study that the training protocol can be tolerated and followed by HD patients, and show that the intervention can improve symptoms in early stage HD. If the results are positive we will then proceed to develop this intervention more generally for both early and pre-symptomatic stages of the disease. Because neurofeedback training is a non-invasive intervention with no side effects, it is an ideal candidate for both pre-symptomatic treatment and in combination with other treatments at later stages of the disease.

Technical Summary

Huntington's disease (HD) is a genetic, neurodegenerative condition that leads to extensive brain atrophy, starting from the striatum and gradually spreading throughout the brain. Clinically it is characterized by progressive motor impairment, e.g. chorea, cognitive decline and neuropsychiatric symptoms. There is currently no known cure for HD and treatments prescribed for symptom management have significant side-effects. This project will deliver "proof of concept" testing of a novel, non-invasive intervention: neurofeedback training using real-time functional MRI (rt-fMRI), which will induce neuroplasticity and could help patients better manage the disease symptoms. Patients will be scanned using fMRI and will be trained to regulate the activity of specific brain regions through receiving in-scanner real-time feedback about the activity of these regions. We hypothesise that training patients to regulate the activation of brain regions whose activity has been disrupted by the disease (e.g. premotor cortex and striatum), will lead to improvements in behaviour and slowed disease progression. Such rt-fMRI has already been used for the treatment of other clinical conditions (e.g. Parkinson's disease, chronic pain, depression) with positive results on behaviour and symptom management without any side-effects. The proposed study will be the first "proof of concept" for HD and will provide preliminary evidence on the feasibility and efficacy of the intervention in early stage HD. If the results are positive, then these data will support further development with a large scale, randomized controlled trial in both early stage and premanifest HD. HD is an excellent model of neurodegenerative diseases as there is a precise genetic test, which allows prospective study of disease progression particularly in the premanifest phase. Our results may therefore have broad applicability and be extrapolated to other more common neurodegenerative diseases such as Alzheimer's disease.

Planned Impact

The proposed project is the collaborative effort between different research groups working on MRI physics, HD and cognitive neuroscience. As such the results from the project are relevant to not only the HD research and patient community, but also to research in neuroplasticity, brain functional reserve and neuroimaging methods for the study of neuroplasticity. At present neurofeedback training is being tested as treatment for and has already partly demonstrated efficacy in Parkinson's disease (Subramanian et al., 2011), depression (Linden et al., 2012) and chronic pain management (deCharms et al., 2005). Therefore our systematic approach to training and technical improvements will be highly beneficial for these applications and for the further development of neurofeedback training using rt-fMRI in the clinical setting more generally.

If our results are positive, we expect to actively involve supportive MRI manufacturers (see letter of support by Siemens), who will be able to deploy this technology in the clinical setting through integration into MRI scanner software. Dr Weiskopf has a long-standing collaboration with Siemens and is PI on a joint academia-industry project with Siemens on implementation of novel scanning methods for clinical use.

Developments in the technology of rt-fMRI, such as increase in signal to noise and contrast to noise ratio and prospective head motion correction, will also be relevant for other applications of rt-fMRI, other than neurofeedback training. One such application is the communication with locked-in patients to establish whether a patient is in a vegetative or locked-in state. Improvements in rt-fMRI technology will provide a better tool for communication with these patients.

In HD, we have predictive genetic testing that can establish with absolute certainty whether a person will develop the disease later in life, therefore HD is a good model for research in the development of a preventative treatment. Neurofeedback training is a safe preventative treatment that could be also used for other neurodegenerative conditions, where there are identifiable risk factors, but no clear diagnosis prior to symptom onset, such as Alzheimer's disease. Therefore the outcomes of the research will be of interest in the development of low-risk preventative treatments for other neurodegenerative diseases as well.

Publications

10 25 50
 
Description All Party Parliamentary Group (APPG) in Huntington's Disease
Geographic Reach National 
Policy Influence Type Membership of a guidance committee
 
Description HD Human Biology Project
Amount $68,707 (USD)
Organisation Huntington's Disease Society of America 
Sector Charity/Non Profit
Country United States
Start 03/2018 
End 03/2019
 
Description Research Training Fellowship. Basal ganglia network degeneration and cortical network compensation in Huntington's disease.
Amount £151,903 (GBP)
Funding ID 103437/Z/13/Z 
Organisation Wellcome Trust 
Department Wellcome Trust Research Training Fellowship
Sector Charity/Non Profit
Country United Kingdom
Start 08/2014 
End 07/2017
 
Description Targeting the innate immune system in Huntington's disease
Amount £1,342,343 (GBP)
Funding ID MR/L02053X/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 08/2014 
End 08/2018
 
Description Professor Doug Langbehn 
Organisation University of Iowa
Country United States 
Sector Academic/University 
PI Contribution Provided experimental dataset
Collaborator Contribution Provided Statistical support/advise
Impact We were successful in being awarded the MRC DPFS grant Ref: MR/L012936/1.
Start Year 2014
 
Description Professor Ralf Reilmann 
Organisation University of Münster
Country Germany 
Sector Academic/University 
PI Contribution Provided experimental dataset
Collaborator Contribution Provided support with motor assessments and equipment
Impact We were awarded the MRC DPFS grant Ref: MR/L012936/1
Start Year 2014
 
Description 1st Congress of the EAN, Berlin 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Talk on HD research presented to students, scientists and healthcare practitioners.
Year(s) Of Engagement Activity 2015
 
Description Article/interview in the Telegraph regarding compensation paper 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Interview and article in the Telegraph re HD compensation paper. Served to expose research to wider audience.

Klöppel S1, Gregory S2, Scheller E3, Minkova L3, Razi A4, Durr A5, Roos RA6, Leavitt BR7, Papoutsi M8, Landwehrmeyer GB9, Reilmann R10, Borowsky B11, Johnson H12, Mills JA13, Owen G8, Stout J14, Scahill RI8, Long JD15, Rees G16, Tabrizi SJ8; Track-On investigators. Compensation in Preclinical Huntington's Disease: Evidence From the Track-On HD Study. EBioMedicine. 2015 Aug 4;2(10):1420-9. doi: 10.1016/j.ebiom.2015.08.002. eCollection 2015.
Year(s) Of Engagement Activity 2015
URL http://hdresearch.ucl.ac.uk/wp-content/uploads/Telegraph-Article.jpg
 
Description Attended NIH sponsored workshop on neurofeedback training at the NIH, USA 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Attended focus group on neurofeedback training in disorders sponsored by the NIH
Year(s) Of Engagement Activity 2019
 
Description Gave invited talk at European Huntington's Disease Network 2018 Conference, Vienna 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Presented talk entitled 'Brain Training in Huntington's Disease'. Generated questions from audience
Year(s) Of Engagement Activity 2018
 
Description Interview/profile in Lancet Neurology 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Professor Sarah Tabrizi completed a profile interview in the Lancet Neurology. Helps raise the profile of her research and the UCL HD Centre.
Year(s) Of Engagement Activity 2017
URL http://www.thelancet.com/journals/laneur/article/PIIS1474-4422(17)30303-4/abstract
 
Description Poster presentation at OHBM 2014 Annual Meeting (Hamburg, Germany). 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Presented poster. Generated questions from attendees:

Papoutsi M., Weiskopf N., Langbehn D., Reilmann R., Rees G., Tabrizi S.J. (2014):
Neural re-organisation in Huntington's disease using real-time fMRI neurofeedback training.
OHBM 2014 Annual Meeting (Hamburg, Germany).
Year(s) Of Engagement Activity 2015
 
Description Poster presented at the Cognitive Neuroscience Society annual meeting in San Francisco, USA 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Poster title: Can we train brain function in Huntington's disease patients using real-time fMRI neurofeedback training and what is the best NFT protocol?
Marina Papoutsi, Nikolaus Weiskopf, Douglas Langbehn, Geraint Rees, Sarah J Tabrizi
Year(s) Of Engagement Activity 2019
 
Description Presentation at BNA 2015 Festival of Neuroscience 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other audiences
Results and Impact Presented talk at BNA workshop. Generated questions from attendees:

Papoutsi M., Weiskopf N., Rees G., Tabrizi S.,: Brain Training in Huntington's
disease: Enhancing neural plasticity using real-time fMRI neurofeedback
training. Workshop called "Closing the Loop: Brain Computer Interfaces and
Neurofeedback".
Year(s) Of Engagement Activity 2015
 
Description Presentation at WTCN workshop on realtime fMRI Neurofeedback at UCL 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Other audiences
Results and Impact Presnted talk at workshop.Generated questions from attendees:


Papoutsi M., Weiskopf N., Rees G., Tabrizi S.,: Brain Training in Huntington's
disease: Enhancing neural plasticity using real-time fMRI neurofeedback
training.
Year(s) Of Engagement Activity 2015
 
Description Presented poster at BNA 2015 conference 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other audiences
Results and Impact Presented poster at BNA 2015 Conference. Generated questions from attendees:

04/2015 Papoutsi M., Weiskopf N., Rees G., Tabrizi S.,: Neurofeedback training in Huntington's disease:
enhancing neural plasticity using real-time fMRI neurofeedback training .
Year(s) Of Engagement Activity 2015
 
Description Presented poster at EHDN Plenary meeting 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Presented poster at EHDN plenary meeting. Generated questions for attendees

Papoutsi M., Weiskopf N., Langbehn D., Reilmann R., Rees G., Tabrizi S.J. (2014): Brain
Training in HD: Enhancing neural plasticity using real-time fMRI neurofeedback training. 8Th
EHDN Plenary meeting (Barcelona, Spain). Journal of Neurology, Neurosurgery &
Psychiatry, 85(S1), A65-A66
Year(s) Of Engagement Activity 2015
 
Description Presented poster at European Huntington's Disease Network 2016 Conference, The Hague 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Presented poster titled 'HD Brain-Train: neuroplasticity as a target to improve function in in Huntington's Disease Papoutsi M., Weiskopf N., Langbehn D., Reilmann R., Rees G., Tabrizi S.J.'

Generated questions from Audience
Year(s) Of Engagement Activity 2016
 
Description Presented poster at European Huntington's Disease Network 2016 Conference , The Hague 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Presented poster titled: 'Compensation in preclinical huntington's disease: evidence from the track-on HD study. Gregory S., Klöppel S., Scheller E., Minkova L., Razi A., Durr A., Roos R., Leavitt BR., Papoutsi M., Landwehrmeyer B., Reilmann R., Borowsky B., Johnson H., Mills JA., Owen G., Stout J., Scahill RI., Long JD., Rees G., Tabrizi SJ' . Generated questions from staff members
Year(s) Of Engagement Activity 2016
 
Description Presented poster at European Huntington's Disease Network 2016 Conference, The Hague 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Presented poster titled 'Operationalising compensation over time in Neurodegenerative Disease. Gregory S., Long JD., Klöppel S., Razi A., Scheller E., Minkova L., Papoutsi M., Mills J., Durr A., Leavitt BR, Roos RAC, Stout J., Scahill RI, Langbehn DR, Tabrizi SJ, Rees'

Generated questions from audience
Year(s) Of Engagement Activity 2016
 
Description Presented poster at European Huntington's Disease Network 2018 Conference, Vienna 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Presented poster titled:
J12 HD brain-train: enhancing neural plasticity using real-time FMRI neurofeedback training
Marina Papoutsi, Joerg Magerkurth, Oliver Josephs, Sophia Pepes, Temi Ibitoye, Ralf Reilmann, Nikolaus Weiskopf, Douglas Langbehn, Geraint Rees, Sarah J Tabrizi
Year(s) Of Engagement Activity 2018
URL https://jnnp.bmj.com/content/89/Suppl_1/A102?ct=ct&utm_source=trendmd&utm_medium=cpc&utm_campaign=al...
 
Description Presented poster at the Symposium on Neurofeedback and other neurotechnologies in Psychiatry, Maastricht, Holland 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Presented poster titled:
HD Brain-Train: Enhancing Neural Plasticity Using Real- Time fMRI Neurofeedback Training

Marina Papoutsi, Joerg Magerkurth, Oliver Josephs, Sophia Pepes, Temi Ibitoye, Ralf Reilmann, Nikolaus Weiskopf, Douglas Langbehn, Geraint Rees, Sarah J Tabrizi
Year(s) Of Engagement Activity 2018
 
Description Presented talk at European Huntington's Disease Network 2016 Conference, The Hague 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Presented talk entitled 'HD Brain-Train: neuroplasticity as a target to improve function in in Huntington's Disease'. Generated questions from audience
Year(s) Of Engagement Activity 2016
 
Description Presented talk at King's College London Neuroscience Society's Conference 2017 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact Presented talk entitled: "HD Brain-Train: neuroplasticity as a target to improve function in in Huntington's disease."
Year(s) Of Engagement Activity 2012,2017
 
Description Presented talk at Kings College London Neuroscience Society 'Wiring Together: Neuroplasticity in the brain' conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact Presented talk titled 'HD Brain-Train: neuroplasticity as a target to improve function in in Huntington's Disease'. Generated questions from attendees
Year(s) Of Engagement Activity 2017
 
Description Research open day held at the UCLH 
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 The Tabrizi stall attracted a good number of visitors.

The day was briefly mentioned in the Guardian on-line
Year(s) Of Engagement Activity 2014