Interfacing with the brain for therapy

Lead Research Organisation: University of Oxford

Abstract

The treatment of diseases of the brain remains a major challenge. This is partly because drugs ignore the moment-to-moment interactions between nerve cells that determine brain function and dysfunction. Electrical stimulation therapies, however, can intervene fast enough to modify these interactions. Our central hypothesis is that we can improve therapies based on electrical stimulation by titrating stimulation according to the state of neural circuits at any given instance. In this research programme we will focus on patients with two exemplar conditions, Parkinson’s disease and Essential Tremor, and develop feedback controlled forms of deep brain stimulation, and of non-invasive stimulation techniques where stimulation is delivered by electrodes on the skin to the surface of the brain or to nerves in the limbs. Using these approaches we seek to develop treatment approaches that serve to increase efficacy and lessen side-effects.

Technical Summary

The failure rate for new drugs targeting important central nervous system diseases remains high and investment in drug discovery in this field continues to diminish. A key problem is that current therapeutic approaches tacitly assume a static equilibrium in brain state. In contrast, we seek to identify and correct those circuit interactions that, through their moment-to-moment dynamics, underpin disease symptoms related to aberrant movement. To this end, we will focus on proof-of-principle studies in patients with two exemplar conditions, Parkinson’s disease and Essential Tremor, and leverage electrical stimulation in its different forms. Common to the therapeutic interventions that we plan to develop, whether invasive or non-invasive, is that they increase selectivity by limiting stimulation according to feedback. Increased selectivity should translate in to improved efficacy and reduced side-effects, and these will be our ultimate measures of success. The feedback used to control stimulation may be neural, as in the case of the amplitude or phase of oscillations recorded in the EEG or in depth recordings, or peripheral, as in the case of the amplitude or phase of tremor oscillations recorded by accelerometers. Non-invasive stimulation, like transcranial alternating current or peripheral nerve stimulation, or invasive stimulation delivered through deep brain electrodes, is then controlled according to the amplitude or phase of the feedback. However, the most appropriate choice of feedback signal and control policy can vary according to changing context, such as sleep or gait, and we will therefore develop flexible closed-loop control procedures that change between key contexts. In parallel, we will investigate the functional role of oscillatory activities in the cortical-basal ganglia network so as to inform our targeted therapy development for brain diseases.

Publications

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Debarros J (2020) Artefact-free recording of local field potentials with simultaneous stimulation for closed-loop Deep-Brain Stimulation. in Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference

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Fischer P (2020) Entraining Stepping Movements of Parkinson's Patients to Alternating Subthalamic Nucleus Deep Brain Stimulation. in The Journal of neuroscience : the official journal of the Society for Neuroscience

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Hasegawa H (2020) The Effect of Unilateral Subthalamic Nucleus Deep Brain Stimulation on Contralateral Subthalamic Nucleus Local Field Potentials. in Neuromodulation : journal of the International Neuromodulation Society

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He S (2020) Closed-loop DBS triggered by real-time movement and tremor decoding based on thalamic LFPs for essential tremor. in Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference

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He S (2020) Neurofeedback-Linked Suppression of Cortical ß Bursts Speeds Up Movement Initiation in Healthy Motor Control: A Double-Blind Sham-Controlled Study. in The Journal of neuroscience : the official journal of the Society for Neuroscience

 
Description Advancing adaptive deep brain stimulation for gait disturbances and freezing of gait in Parkinson's disease
Amount £464,000 (GBP)
Funding ID MR/V00655X/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 02/2021 
End 01/2023
 
Description Capital funding for refurbishment of MRC Brain Network Dynamics Unit
Amount £988,500 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 04/2020 
End 03/2027
 
Description Univ of Oxford Medical and Life Sciences Translational Fund
Amount £65,896 (GBP)
Organisation University of Oxford 
Sector Academic/University
Country United Kingdom
Start 10/2020 
End 09/2021
 
Description Univ of Oxford: University Challenge Seed Fund
Amount £63,800 (GBP)
Funding ID Award UCSF 459 
Organisation University of Oxford 
Sector Academic/University
Country United Kingdom
Start 09/2020 
End 09/2021
 
Title EEGs from healthy motor control during neurofeedback training 
Description The EEG data were recorded from 20 human volunteers (10 females) while they were performing a sequential neurofeedback-behaviour task, with the neurofeedback reflecting the occurrence of beta bursts over sensorimotor cortex (C3 or C4) quantified in real time. 
Type Of Material Database/Collection of data 
Year Produced 2020 
Provided To Others? Yes  
Impact In this study, we show that healthy participants can be trained to self-suppress a special pattern of brain activity called 'beta bursts'. We found that this training was accompanied by quicker reactions when prompted to move. The more beta bursts were suppressed, the less time needed to move. Our results suggest such training could be used to speed up movements when needed. 
URL https://data.mrc.ox.ac.uk/data-set/eegs-healthy-motor-control-during-neurofeedback-training
 
Description Collaboration with the Control Team in Dept of Engineering Science in University of oxford 
Organisation University of Oxford
Department Department of Engineering Science
Country United Kingdom 
Sector Academic/University 
PI Contribution I approached Prof Mark Cannon in the Control group of Dept. of Engineering Science at University of Oxford. Through the collaboration, we aim to exploit the benefits of advanced control algorithms including Model Predictive Control (MPC) in closed-loop Deep Brain Stimulation (DBS) for improving the treatment of Parkinson's disease (PD). My group has experience in developing state-dependent adaptive DBS for Parkinson's disease and Essential Tremor, and in developing new Brain Computer Interfaces based on subcortical local field potentials. We will bring their expertise in real-time signal processing, real-time system implementation, dynamic modelling and machine-learning methods.
Collaborator Contribution Prof Mark Cannon has world-wide reputation in model-predictive control, which has revolutionized other areas of biomedical engineering such as drug delivery. His research is concerned with the design of controllers for uncertain systems with the aim of optimising performance subject to constraints. Cannon will bring essential expertise in designing controllers for non-linear stochastic dynamic systems with the aim to optimise performance subject to clinical and technical constraints.
Impact This is a multi-disciplinary collaboration, bringing together expertise and disciplines in clinical neuroscience and modern control theories. We have drafted research proposals on designing and testing a hierarchical, i.e. multi-layer, closed-loop control structure combining the benefits of both classical linear feedback controllers and Model Predictive Control (MPC) for improving the efficacy and reducing side effect of Deep Brain Stimulation for Parkinson's disease.
Start Year 2020
 
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 Oswal A, Gratwicke J, Akram H, Jahanshahi M, Zaborszkye L, Brown P, Hariz M, Zrinzo L, Foltynie T, Litvak V. Intersection of structural and functional connectivity of the nucleus basalis of Meynert in Parkinson's disease dementia and Lewy body dementia. Brain, In Press.
Start Year 2008
 
Description Institut du Cerveau et de la Moelle épinière - ICM 
Organisation ICM (Brain & Spine Institute)
Country France 
Sector Hospitals 
PI Contribution We bring our expertise in recording electrophysiological as well as behavioural data from patients with Parkinson's disease, and our experience in gait research and novel DBS algorithms for the collaboration.
Collaborator Contribution The Institut du Cerveau et de la Moelle épinière - ICM (Brain & Spine Institute) - is an international brain and spinal cord research center where patients, doctors and researchers are brought together with the aim of rapidly developing treatments for disorders of the nervous system, to enable patients to benefit from them as quickly as possible.
Impact We have submitted a joint application and successfully obtained funding for the Network of Centres of Excellence in Neurodegeneration (CoEN) 2019 call. In this proposal, we aim to better understand the neural basis of freezing of gait in Parkinsn's disease with the aim to predict the likely occurrence of these transient FoG episodes, and to evaluate the effectiveness a novel biomimetic pattern of STN stimulation as a treatment promoting resistance to FoG. This would pave the way for early detection of episodic gait disturbances that could be used to control switching between DBS stimulation patterns that are most appropriate for minimizing risk of falling at a given moment in time.
Start Year 2019
 
Description Kareem Zaghloul NIH 
Organisation National Institutes of Health (NIH)
Country United States 
Sector Public 
PI Contribution My research team brings expertise in signal processing and experimental design for studying cognitive and motor function in Parkinson's Disease.
Collaborator Contribution The lab of Dr Kareem Zaghloul exploits the unique investigative opportunities provided by intracranial electrical recordings during neurosurgical procedures. Using recordings captured from epilepsy patients implanted with subdural and depth electrodes, we investigate the activation of cortical networks during memory encoding and recall.And using the recordings captured during the implantation of deep brain stimulators, we investigate the role of the basal ganglia in learning and decision making.
Impact We are collaborating on co-supervising a PhD student funded by the NIH Oxford-Cambridge Scholars Program.
Start Year 2019
 
Description Mainz collaboration 
Organisation Johannes Gutenberg University of Mainz
Country Germany 
Sector Academic/University 
PI Contribution Protocol development and help with ethics application Analysis and Interpretation
Collaborator Contribution Ethics application Muthuraman M, Bange M, Koirala N, Ciolac D, Pintea B, Glaser M, Tinkhauser G, Brown P, Deusch G, Groppa S. (2020) Cross-frequency coupling between gamma oscillations and deep brain stimulation frequency in cortico-subcortical networks in Parkinson's disease patients. Brain, 143:3393-3407. Wiest C, Tinkhauser G, Pogosyan A, Bange M, Muthuraman M, Groppa S, Baig F, Mostofi A, Pereira E, Tan H, Brown P, Torrecillos F. (2020) Local field potential activity dynamics in response to deep brain stimulation of the subthalamic nucleus in Parkinson's disease. Neurobiology of Disease, 143; 105019. Tinkhauser G, Torrecillos F, Pogosyan A, Mostofi A, Bange M, Fischer P, Tan H, Harutomo H, Glaser M, Muthuraman M, Groppa S, Keyoumars A, Pereira E, Brown P. (2020) The cumulative effect of transient synchrony states on motor performance in Parkinson's disease. Journal of Neuroscience, 40; 1571-1580.
Impact None yet
Start Year 2017
 
Description New Collaboration with Sergiu Groppa, JGU University Mainz, Germany 
Organisation Johannes Gutenberg University of Mainz
Country Germany 
Sector Academic/University 
PI Contribution The contribution of my group in this collaboration is to provide mature experimental paradigm to study fine-tuned movements and sensorimotor adaptation with simultaneous LFP/EEG recordings, strong skills and expertise in signal processing and modelling, experiences and equipment for closed-loop neuromodulation.
Collaborator Contribution Sergiu Groppa is Professor of Neurology and Head of Movement Disorders, Neurostimulation and Imaing at the Department of Neurology, Johannes Gutenberg-University of Mainz. The main focus of his scientific work is the investigation of brain reorganization and adaptation in neurological disorders and brain networks modulation through invasive and non-invasive neurostimulation methods. So the two groups have common interest and overlapping skills. But Gergiu's group also bring in skills and expertise in imaging, brain specimens acervation, blood and CSF phenotyping, as well as clinical profiling.
Impact A pre-proposal has been submitted to a call for 'Collaborative Research Network: Circuitry and Brain-body Interactions', a program of the Aligning Science Across Parkinson's (ASAP) initiative being implemented through The Michael J. Fox Foundation. The pre-proposal has been selected for a full submission.
Start Year 2020
 
Description Ruijin Hospital, Shanghai Tiao Tong University 
Organisation Ruijin Hospital
Country China 
Sector Hospitals 
PI Contribution We bring our expertise in experimental design and signal processing in the collaboration.
Collaborator Contribution The functional neurosurgery team in Ruijing Hospital, Shanghai Jiao Tong University is known for piloting clinical trials on new targets for Deep Brain Stimulation for the treatment of psychiatric disorders. This allowed us to record signals from deep brain structures related to emotional processing in patients with Psychiatric disorders.
Impact This collaboration is multi-disciplinary combining disciplines in neuroscience and clinical practice. This collaboration allowed us to complete a study investigating the neural oscillation in the habenula during emotional processing in patients with psychiatric disorders. A manuscript has been uploaded to BioRxiv and under review with eLife.
Start Year 2019
 
Description St George's Hospital London 
Organisation St Georges Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution We have established collaboration with the functional neurosurgery team in St George's Hospital London for recruitment of patients.
Collaborator Contribution The Functional Neurosurgery Group at St George's Hospital London form a very busy clinical centre with over 30 PD patients to be operated for DBS over the course of next year, with the service still expanding. The Group is led by a young, highly motivated team with particular interest in research.
Impact We have recruited more than 30 patients for our studies in St George's hospital London, and have co-authored publications. We have also trained their team in research, including setting up equipment for recording, experimental design and signal processing.
Start Year 2018
 
Description St Georges hospital 
Organisation St George's Hospital
Department Department of Neurosurgery
Country United Kingdom 
Sector Hospitals 
PI Contribution Protocol developed. Ethics obtained Publication Analysis and Interpretation
Collaborator Contribution Protocol developed with me. Ethics obtained Publication Analysis and Interpretation
Impact Mostofi A, Morgante F, Edwards MJ, Brown P, Pereira EAC. Pain in Parkinson's disease and the role of subthalamic nucleus deep brain stimulation. Brain, In Press. He S, Mostofi A, Syed E, Torrecillos F, Tinkhauser G, Fischer P, Pogsyan A, Hasegawa H, Li Y, Ashkan K, Pereira E, Brown P, Tan H. Subthalamic beta targeted neurofeedback training speeds up movement initiation in Parkinsonian. eLife, 2020. eLife, 9:e60979. Tinkhauser G, Torrecillos F, Pogosyan A, Mostofi A, Bange M, Fischer P, Tan H, Harutomo H, Glaser M, Muthuraman M, Groppa S, Keyoumars A, Pereira E, Brown P. (2020) The cumulative effect of transient synchrony states on motor performance in Parkinson's disease. Journal of Neuroscience, 40; 1571-1580.
Start Year 2017
 
Description Subthalamic nucleus studies 
Organisation Chang Gung Memorial Hospital (CGMH)
Country Taiwan, Province of China 
Sector Hospitals 
PI Contribution Supervision and mentorship of visiting research fellow
Collaborator Contribution Visiting fellow funded from Taiwan. Data analysed was collected in Taiwan
Impact di Biase, L., Brittain, J.S., Shah, S.A., Pedrosa, D.J., Cagnan, H., Mathy, A., Chen, C.C., Martín-Rodríguez, J.F., Mir, P., Timmerman, L., Schwingenschuh, P., Bhatia, K., Di Lazzaro, V. & Brown, P. Tremor Stability Index: a new tool for differential diagnosis in tremor syndromes. Brain 140, 1977-1986 (2017). Fischer, P., Chen, C.C., Chang, Y.J., Yeh, C.H., Pogosyan, A., Herz, D.M., Cheeran, B., Green, A.L., Aziz, T.Z., Hyam, J., Little, S., Foltynie, T., Limousin, P., Zrinzo, L., Hasegawa, H., Samuel, M., Ashkan, K., Brown, P. & Tan, H. Modulation of subthalamic nucleus beta oscillations during stepping in place is enhanced in the presence of auditory cues. J Neurosci 38, 5111-5121 (2018). Shah, S.A., Tinkhauser, G., Chen, C.C., Little, S. & Brown. P. Parkinsonian Tremor Detection from Subthalamic Nucleus Local Field Potentials for Closed-Loop Deep Brain Stimulation. IEEE Eng Med Biol Soc (EMBC18), 2320-2324 (2118). Chen CC, Yeh C-H, Chan H-L, Chang YJ, Tu PH, Yeh CH, Lu CS, Fischer P, Tinkhauser G, Tan H, Brown P. (2019) Subthalamic nucleus oscillations correlate with vulnerability to freezing in patients with Parkinson's Disease. Neurobiology of Disease, 132; 104605.
Start Year 2015
 
Title Investigating the possibility and benefit of closed-loop deep brain stimulation by detecting the voluntary movement and postural tremor on patients with tremor 
Description Lots of patients suffer from tremor which predominantly occurs during voluntary movement and/or while maintaining a certain posture. For example, Essential tremor (ET), a progressive neurological disorder that causes involuntary and rhythmic shaking, is one of the most common movement disorders. Dystonia tremor is another condition in which tremor is typically intermittent (stops and starts). Continuous deep brain stimulation (DBS) is an approved and effective therapy for both ET or Dystonia tremor. However, due to disease progression or the brain becoming used to stimulation, many patients lose the benefit of DBS over time. In these circumstances, an increased stimulation intensity is usually required in order to maintain the beneficial effect. Increased stimulation intensity can be associated with side effects including unpleasant sensations, slurred speech and unsteadiness walking. A promising innovative DBS treatment, known as closed-loop or adaptive DBS, aims to only deliver stimulation when necessary, and so, reduce these side effects, save on battery power, and prolong the time for which DBS provides benefit to patients. In this study, the researchers will evaluate if the closed-loop DBS system is effective in reducing tremor, saves energy in comparison to traditional continuous DBS, and could be used to predict the onset of tremors so DBS can be switched on in advance for improved patient outcomes. 
Type Management of Diseases and Conditions
Current Stage Of Development Initial development
Year Development Stage Completed 2020
Development Status Under active development/distribution
Clinical Trial? Yes
Impact A manuscript has been accepted by Movement Disorders based on the first 8 patients recruited for this trial. 
URL http://www.isrctn.com/ISRCTN56186994
 
Description I'm a Scientist, Stay at home Medical Research - April to July 2020 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact In April to July 2020, Petra Fischer and Shenghong He from Brown/Tan group took part in the Virtual I'm a Scientist, Stay at home Medical Research. This is a yearly event organised by the MRC is an online, STEM engagement activity for school students who can take part in live text-based CHATs, ASK questions and VOTE for their favourite researcher/technician.

The children's curiosity and the diversity of scientists participating in the scheme were excellent. The chats were fast-paced and fun - a very effective way to engage with school children.
Year(s) Of Engagement Activity 2020
 
Description IF Oxford Science - Neurotales (27 October 2020) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Beatriz Silveira de Arruda from Prof Peter Brown's group will be taking part in the IF Oxford Science on 27th October 2020. She will be talking about developing noninvasive means of treating tremor in essential tremor and Parkinson's disease.
Year(s) Of Engagement Activity 2020
URL https://if-oxford.com/event/neurotales-2/
 
Description In2science 'virtual placement programme' 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact In July/August 2020, MRC BNDU continues to participate in the previously partnered with the charity In2science to host Year 12 school pupils enrolled on their STEM work-experience programme. Each summer, for the past 4 years, we have delivered personalised mentoring and rich STEM experiences for pupils from disadvantaged backgrounds. Beatriz Silveira de Arruda and Shenghong He from Brown/Tan group together with some members of the Dupret and Magill group took part in a research-based module "Interacting with the brain" that was jointly designed and delivered in support of In2scienceUK's Virtual Placement Programme. They organised webinars and research tasks (with real data!) for the students who took part.
Year(s) Of Engagement Activity 2020
URL https://in2scienceuk.org/
 
Description Lecture by Paul Bolam (4 Nov 2020) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Professor Paul Bolam (Emeritus Professor of BNDU) attended the Cherwell School for the third time on 4th November 2020. He talked to year 12 and 13 Psychology and Biology students on how the brain works and what goes wrong in disease (Parkinson's disease). The following topics were covered:

• How one can study the brain.
• Concepts of neurons synapses and circuits.
• Parkinson's disease and what goes wrong in the disease.
• How we can treat Parkinson's disease and what are the prospects for the future.
• What we do to study Parkinson's disease in animals.
Year(s) Of Engagement Activity 2020
 
Description Presentation at NeuroTales event 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact PhD student Beatriz Silveira de Arruda delivered a talk in the NeuroTales event organised by IF Oxford, which is run by The Oxfordshire Science Festival (charity #1151361) Together with other public engagement ambassadors from the Nuffield Department of Clinical Neurosciences at University of Oxford, Beatriz spoke in the event, during which they shared their personal trajectories that led us to pursue careers in research.
Year(s) Of Engagement Activity 2020
URL https://staging1.if-oxford.com/event/neurotales-2/
 
Description Q&A about PD research through Oxford Sparks 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact PhD student Beatriz Silveira de Arruda delivered a live Q&A about Parkinson's disease research through Oxford Sparks on 26/5/2020. Oxford Sparks is another media/portal for general public to explore and discover science research from the University of Oxford. It is the place to find out about fascinating science and technology from the University of Oxford. The event Beatriz took part in was held through YouTube. Beatriz talked briefly about her research project and answered questions from the public.
Year(s) Of Engagement Activity 2020
URL https://www.youtube.com/watch?v=xPd-mOnNsCk
 
Description School visit 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Together with a few other colleagues from the MRC Brain Network Dynamics Unit, we visited a local girls' school to demonstrated different research tools and did activities with students. Ninety students between 11-16 years old attended the event. This sparked questions and discussion afterwards, and the school reported increased interest in related subject areas.
Year(s) Of Engagement Activity 2020
 
Description Talk on Applied Neurosciences (27-28 Nov 2020) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Undergraduate students
Results and Impact 27-28 November 2020, Dr Petra Fischer in Prof Brown and Dr Tan's group gave a talk on "Applied Neurosciences" at the Institute of Cognitive Science, Osnabrück in Germany via Zoom to Cognitive Science and Psychology students, including BSc, MSc and PhD students attended both days and actively participated in brief practical assignments. Petra gave a detailed overview of research in the BNDU including neuroimaging, deep brain stimulation and neurofeedback. Her colleague discussed applications of neuroscientific tools in business consulting.

The sessions included: Techniques for recording and manipulating brain activity, statistical methods, ethics in neuroscience, project planning, and a career Q&A.

To obtain a grade, 92 participants submitted a project, in which they actively engaged with some of the methods introduced, for example reviewing brain stimulation methods in a video, infographic or written report or designing and programming a behavioural experiment.
Year(s) Of Engagement Activity 2020