Circuit-driven neuromodulation in the cognitive domain
Lead Research Organisation:
University of Oxford
Department Name: UNLISTED
Abstract
Deep brain stimulation (DBS) is a therapy for brain disorders where electrodes, placed deep in the brain, are used to continuously deliver electrical pulses that interrupt brain activity that causes abnormal movement. DBS has also been used to treat cognitive symptoms of brain disorders, but the results have been inconsistent. Imaging studies suggest cognitive symptoms occur because parts of the brain become too strongly or weakly connected. Delivering continuous electrical pulses, as in current DBS, may not be the best way of returning the strength of these connections to a healthy state. In the healthy brain, connections between groups of brain cells become stronger when they are activated together. We propose to use this principle to find better ways to change the strength of connections between brain areas. To develop these techniques, we will carry out “closed-loop” experiments in rodents, where recordings of brain activity in one area are used to control the timing of stimulation to a connected area. We will test the effectiveness of these approaches by seeing whether they lead to changes in the performance of cognitive tasks. We will carry out our experiments using electronics that allow fast translation of successful approaches to human medical devices
Technical Summary
Neuromodulation using deep brain stimulation (DBS) is a highly successful treatment for the motor symptoms of movement disorders. In comparison, DBS treatment for the cognitive symptoms of brain disorders is in its infancy and has been only partially successful. This suggests the current targets for treating cognitive symptoms are viable, but that current stimulation paradigms are suboptimal. Our goal is to establish novel approaches to neuromodulation of current DBS targets that will improve cognitive symptoms in neurological and psychiatric disorders. These approaches will be designed to modulate specific processes in cortico-basal ganglia-thalamocortical circuits that mediate behaviours relevant to several brain disorders. Specifically, we propose that utilising the temporal dynamics of these neural circuits has the potential to have more direct and powerful effects on cognitive symptoms than current methods. Using experiments in rodents, we will use optogenetic and electrical stimulation to manipulate the timing of activity in connected cortical and subcortical areas, utilising their underlying temporal dynamics to strengthen or weaken their connectivity. This “closed-loop” approach will utilise recordings of neuronal signals, including the phase of ongoing local field potential oscillations and spiking activity, in one area of cortico-basal ganglia-thalamic circuits to control the timing of stimulation delivered to one of its target areas. Our approaches will combine expertise in the cell-type specific composition of cortico-basal ganglia microcircuits and the development of novel methods of brain stimulation. We will target behaviours relevant to several neurological and psychiatric diseases, with the rationale that the crucial first step for novel neuromodulation is to uncover approaches that modulate disease-relevant circuits in a way that leads to reproducible behavioural change. To this end, we will quantify the neurophysiological changes elicited by closed-loop stimulation that occur concurrently with alterations in cognitive task performance. Importantly, we will perform closed-loop manipulations using algorithms that run on self-contained programmable chips. This approach will facilitate the translation of closed-loop algorithms to equivalent platforms in the next generation of human stimulation devices and we will explore collaborations with the medical devices industry to facilitate this. In addition to our translational goals, these studies will provide fundamental insights into how the strength of connectivity between different nodes of cortico-basal ganglia-thalamic loops contribute to the performance of specific behaviours.
Organisations
- University of Oxford (Lead Research Organisation)
- Charité - University of Medicine Berlin (Collaboration)
- University College London (Collaboration)
- University of Manchester (Collaboration)
- University of Twente (Collaboration)
- Wellcome Trust (Collaboration)
- Newcastle University (Collaboration)
- Charite Campus Virchow-Klinikum (Collaboration)
- University Medical Center Hamburg-Eppendorf (Collaboration)
- German Centre for Neurodegenerative Diseases (Collaboration)
- IMPERIAL COLLEGE LONDON (Collaboration)
- UNIVERSITY OF OXFORD (Collaboration)
- Hebrew University of Jerusalem (Collaboration)
- Icahn School of Medicine at Mount Sinai (Collaboration)
- Medical Research Council (MRC) (Collaboration)
People |
ORCID iD |
Andrew Sharott (Principal Investigator) |
Publications
Baaske MK
(2020)
Parkinson's disease uncovers an underlying sensitivity of subthalamic nucleus neurons to beta-frequency cortical input in vivo.
in Neurobiology of disease
Clarke-Williams C
(2024)
Coordinating brain-distributed network activities in memory resistant to extinction
in Cell
Gulberti A
(2023)
Subthalamic and nigral neurons are differentially modulated during parkinsonian gait.
in Brain : a journal of neurology
Kavoosi A
(2022)
Computationally efficient neural network classifiers for next generation closed loop neuromodulation therapy - a case study in epilepsy.
in Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference
McNamara C
(2020)
Phase-dependent closed-loop modulation of neural oscillations in vivo
Related Projects
Project Reference | Relationship | Related To | Start | End | Award Value |
---|---|---|---|---|---|
MC_UU_00003/1 | 31/03/2020 | 30/03/2025 | £1,280,000 | ||
MC_UU_00003/2 | Transfer | MC_UU_00003/1 | 31/03/2020 | 30/03/2025 | £2,361,000 |
MC_UU_00003/3 | Transfer | MC_UU_00003/2 | 31/03/2020 | 30/03/2025 | £1,126,000 |
MC_UU_00003/4 | Transfer | MC_UU_00003/3 | 31/03/2020 | 30/03/2025 | £2,269,000 |
MC_UU_00003/5 | Transfer | MC_UU_00003/4 | 31/03/2020 | 30/03/2025 | £2,274,000 |
MC_UU_00003/6 | Transfer | MC_UU_00003/5 | 31/03/2020 | 30/03/2025 | £2,177,000 |
Description | Participated in Aligning Science Across Parkinson's (ASAP) Grant Peer Review Commiteee |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Participation in a guidance/advisory committee |
URL | https://parkinsonsroadmap.org/ |
Title | Matlab toolbox for plotting and analysis of diurnal patterns in data. |
Description | The Circa Diem toolbox is designed to generate diurnal visualisations and analyses of data points with associated MATLAB 'datetime' values. The basic input data format for the toolbox can be either: a regularly spaced series of time points as a vector of MATLAB 'datetimes' that correspond to events or measurement times, and a series of values or weights corresponding to these measurement times or events. Here the focus is on whether the measured variable has diurnal properties. A series of event times. Here, the focus is on whether the event times are differently distributed across the times of day. Circa Diem also allows for some statistical tests of the extent of non-uniformity of diurnal patterns. For this, the toolbox is indebted to the circstat_matlab toolbox by Philipp Berens (some of the statistical functions are essentially wrapper functions around circstat functions). |
Type Of Material | Physiological assessment or outcome measure |
Year Produced | 2021 |
Provided To Others? | Yes |
Impact | This toolbox was used for the data analysis in: Van Rheede at el, Diurnal modulation of subthalamic beta oscillatory power in Parkinson's disease patients during deep brain stimulation (10.1101/2022.02.09.22270606) |
URL | https://github.com/joramvanrheede/circa_diem |
Title | OscillTrack |
Description | OscillTrack tracks oscillatory activity of a defined frequency in real-time. It provides a complex estimate of the signal within a frequency band of interest and from this the instantaneous phase and amplitude. It can be used to trigger electrical, optogenetic or other stimulation. |
Type Of Material | Physiological assessment or outcome measure |
Year Produced | 2022 |
Provided To Others? | Yes |
Impact | Downloaded by other investigators |
URL | https://ora.ox.ac.uk/objects/uuid:f526084e-6c26-48ef-b211-fb2933aeaaf1 |
Title | Electrocorticogram with closed-loop stimulation of basal ganglia nuclei aligned to beta oscillation phase |
Description | This is the electrocortigram data and stimulation times described in McNamara et al, 2022 (https://doi.org/10.1016/j.celrep.2022.111616) |
Type Of Material | Database/Collection of data |
Year Produced | 2022 |
Provided To Others? | Yes |
Impact | Many investigators have already requested to use the data |
URL | https://data.mrc.ox.ac.uk/ecog-closed-loop |
Title | Wideband recordings from silicon probes in the subthalamic nucleus of 6-OHDA hemi-lesioned rats during anaesthesia |
Description | MATLAB (.mat) formatted electrophysiological wideband recordings from silicon probes in the subthalamic nucleus of 6-OHDA hemi-lesioned rats during anaesthesia. Details of the data recording can be found in SmrData.WvTits for every file. All files include ECoG recordings (channel 1 +2, ipsi and contralateral of the lesioned hemisphere) and 32 raw wideband channels (Probe 1-32). These probe channels are recorded along the lead trajectory as described in the Wiest et al, 2023 (https://elifesciences.org/articles/82467). |
Type Of Material | Database/Collection of data |
Year Produced | 2022 |
Provided To Others? | Yes |
Impact | No output so far |
URL | https://data.mrc.ox.ac.uk/data-set/wideband-recordings-silicon-probes-subthalamic-nucleus-6-ohda-hem... |
Description | Berlin University Alliance collaboration with Prof. Zoltan Molnar |
Organisation | Charité - University of Medicine Berlin |
Country | Germany |
Sector | Academic/University |
PI Contribution | Collaborator on Einstein Visiting Fellowship to Prof. Zoltan Molnar (https://www.dpag.ox.ac.uk/news/einstein-visiting-fellowship-awarded-to-zoltan-molnar). We will contribute to experiments in trans-synaptic tracing as part of the larger consortium. |
Collaborator Contribution | The project will establish a core in developmental and circuit neuroscience with leading groups in Oxford and Berlin. This will provide us with further opportuninties to collaborate with other teams in Oxford and Charite that can contribute technical and conceptual expertise to this programme and the wider BNDU. |
Impact | None so far |
Start Year | 2020 |
Description | Brain computer interfaces to control NREM sleep oscillations |
Organisation | University of Oxford |
Department | Department of Physiology, Anatomy and Genetics |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We are designing a brain computer interface to modulate oscillations in non-rapid eye movement sleep. This will be a valuable tool for basic research and could have clinical benefits for a variety of brain disorders. |
Collaborator Contribution | Our partners have contributed electrophysiological recordings from the cortex of sleeping mice to use for the development of the brain computer interface. |
Impact | No outcomes so far |
Start Year | 2021 |
Description | Circadian Modulation of Beta oscillations in Parkinson's Disease |
Organisation | Charite Campus Virchow-Klinikum |
Country | Germany |
Sector | Academic/University |
PI Contribution | Our partners made recordings of the amplitude of beta oscillations from the subthalamic nucleus of people with Parkinson's Disease with implanted deep brain stimulation devices (Medtronic Percept) over many weeks. We developed an analytical tool box to analyse circadian/diurnal variation in this data (https://github.com/joramvanrheede/circa_diem) and applied it to this data. This demonstrated that the amplitude that beta oscillations vary with the diurnal cycle. In collaboration with our partners, we also charecterised the contribution of movement artifacts to these diurnal patterns. |
Collaborator Contribution | Our partners made recordings of the amplitude of beta oscillations from the subthalamic nucleus of people with Parkinson's Disease with implanted deep brain stimulation devices (Medtronic Percept) over many weeks. |
Impact | doi: https://doi.org/10.1101/2022.02.09.22270606 |
Start Year | 2021 |
Description | Closed-loop Neural Interface Technologies (Close-NIT) Network Plus awarded by EPSRC |
Organisation | Imperial College London |
Department | Division of Brain Sciences |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Successful funding application for an MRC Network Plus award. |
Collaborator Contribution | Successful funding application for an MRC Network Plus award. |
Impact | Have conducted our first funding round - awarding 5 grants for feasibility studies to investigators across the UK. |
Start Year | 2022 |
Description | Closed-loop Neural Interface Technologies (Close-NIT) Network Plus awarded by EPSRC |
Organisation | Medical Research Council (MRC) |
Department | MRC Cognition and Brain Sciences Unit |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Successful funding application for an MRC Network Plus award. |
Collaborator Contribution | Successful funding application for an MRC Network Plus award. |
Impact | Have conducted our first funding round - awarding 5 grants for feasibility studies to investigators across the UK. |
Start Year | 2022 |
Description | Closed-loop Neural Interface Technologies (Close-NIT) Network Plus awarded by EPSRC |
Organisation | Newcastle University |
Department | Newcastle University Medical School |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Successful funding application for an MRC Network Plus award. |
Collaborator Contribution | Successful funding application for an MRC Network Plus award. |
Impact | Have conducted our first funding round - awarding 5 grants for feasibility studies to investigators across the UK. |
Start Year | 2022 |
Description | Closed-loop Neural Interface Technologies (Close-NIT) Network Plus awarded by EPSRC |
Organisation | University of Manchester |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Successful funding application for an MRC Network Plus award. |
Collaborator Contribution | Successful funding application for an MRC Network Plus award. |
Impact | Have conducted our first funding round - awarding 5 grants for feasibility studies to investigators across the UK. |
Start Year | 2022 |
Description | Consolidation of motor memories and myelin plasticity: implications for rehabilitation |
Organisation | Wellcome Trust |
Department | Wellcome Trust Cente for Neuroimaging |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Sharott is a collaborator on the Principle Research Fellowship of Prof. Hiedi Johansson-Berg. Sharott and Johansson-Berg are co-supervising a PhD student (Yingshi Feng) based at the Welcome Centre for Intergrative Neuroimaging. Our group is assisting our partners in developing electrophysiology and closed-loop brain stimulation in freely-moving mice. |
Collaborator Contribution | Our partners will contribute staff time, equipment and consumables to our collaborative project. They also bring expertise in behavioral training and neuroimaging. |
Impact | Shared PhD student (Yingshi Feng) |
Start Year | 2022 |
Description | Deep Brain Stimulation for Sleep with Prof. Hagai Bergman |
Organisation | Hebrew University of Jerusalem |
Department | Faculty of Medicine |
Country | Israel |
Sector | Academic/University |
PI Contribution | Our team is applying our expertise in closed-loop stimulation to design a system of manipulating sleep oscillations in parkinsonian non-human primates. |
Collaborator Contribution | Our partners have given us electrophysiological data from sleeping primates to aid the development of closed-loop systems. We are applying for seed funding from the Oxford-Huji SPINE scheme to assist in developing these systems. |
Impact | No outcomes yet. |
Start Year | 2021 |
Description | Defining the role neural oscillations in motor plasticity and learning |
Organisation | University College London |
Department | Institute of Neurology |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Preliminary data on the role of neural oscillations in motor learning during reaching in mice |
Collaborator Contribution | Preliminary data on motion tracking in humans |
Impact | Funding application to MRC Responsive Mode |
Start Year | 2022 |
Description | Dr Christian Moll/Prof Andreas Engel |
Organisation | University Medical Center Hamburg-Eppendorf |
Country | Germany |
Sector | Hospitals |
PI Contribution | Introduction of new experimental stimulation protocols |
Collaborator Contribution | Complementary data to our Parkinson's Disease animal models from Parkinson's patients |
Impact | Translational pilot data for phase dependent stimulation |
Start Year | 2015 |
Description | Electrophysiological markers of sleep timing and quality in the subcallosal cingulate cortex |
Organisation | Icahn School of Medicine at Mount Sinai |
Country | United States |
Sector | Academic/University |
PI Contribution | We have developed novel analytical tools/conceptual approaches to analyse chronically recorded data from the subcullosal cingulate in patients with Major Depressive Disorder |
Collaborator Contribution | Our partners have provided data and developed the project conceptually with us. |
Impact | No outputs so far |
Start Year | 2022 |
Description | Mechanisms of Motivation: How Cortical-Basal Ganglia-Dopamine Circuits Orchestrate Adaptive Reward Pursuit |
Organisation | University of Oxford |
Department | Department of Experimental Psychology |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Electrophysiological recordings from rats performing complex behavioral task to measure cost-benefit decision making |
Collaborator Contribution | Expertise in design and implementation of rodent behavioral tasks. |
Impact | Funding application to MRC Neuroscience and Mental Health Board. |
Start Year | 2022 |
Description | Multi-modal network modulation in Parkinson's disease |
Organisation | University of Twente |
Country | Netherlands |
Sector | Academic/University |
PI Contribution | The aim of this project is twofold: to test common assumptions on the basics of transcranial alternating current stimulation (tACS) in order to get a thorough understanding of this technique, and to then apply the obtained knowledge on the functional connection between motor cortex and basal ganglia by combining tACS and deep brain stimulation (DBS). The interplay between systems and clinical neuroscience is crucial to this project. It takes advantage of both state-of-the-art technical setups and advanced data analysis. |
Collaborator Contribution | Our partners have been awarded a fellowship from the German Reseach Council (DFG) and will perform experiments in deep brain stimulation patients at the University Medical Centre Hamburg. |
Impact | No outputs so far |
Start Year | 2021 |
Description | Towards a hippocampal network prosthesis for the treatment of Alzheimer's disease |
Organisation | German Centre for Neurodegenerative Diseases |
Country | Germany |
Sector | Public |
PI Contribution | Preliminary data on effects of closed-loop stimulation on hippocampal oscillations |
Collaborator Contribution | Preliminary data on hippocampal oscillations in mouse models of Alzheimer Disease. |
Impact | Funding application to the COEN scheme (https://www.coen.org/) |
Start Year | 2022 |
Title | APPARATUS AND METHOD FOR PHASE TRACKING AN OSCILLATORY SIGNAL |
Description | Apparatus and methods for phase tracking an oscillatory signal are provided. In one arrangement, an input signal is received. First and second reference oscillatory signals are received at the frequency of a target frequency component of the input signal. The first and second reference oscillatory signals are phase shifted relative to each other. Weights of a weighted sum of the first and second reference oscillatory signals are iteratively varied to match the weighted sum to the input signal. The weights of the matched weighted sum are used to provide real time estimates of the phase of the target frequency component of the input signal. |
IP Reference | WO2020183152 |
Protection | Patent application published |
Year Protection Granted | 2020 |
Licensed | No |
Impact | There have been no impacts so far. |
Description | Host for In2Science student placement |
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 | Schools |
Results and Impact | My research team hosted a 6th form student on the In2Science scheme. Over a week they were supervised in a series of activities relating to work going on in the group aswell as activities run by In2Science |
Year(s) Of Engagement Activity | 2022 |
URL | https://in2scienceuk.org/ |
Description | IBM 24 Hours of Science |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | I participated on a panel in IBMs 24hrs of Science event, whereby they have have 24hrs of talks and presentations on scientific topics relevant to the company. >3000 employees have access to the talks online and recorded. My role was to talk about the challenges of big data in neuroscience. |
Year(s) Of Engagement Activity | 2022 |
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. Naomi Berry from Sharott group took part in an online mentor for local school children. |
Year(s) Of Engagement Activity | 2020 |
URL | https://in2scienceuk.org/ |
Description | School Visit (Swan School, Oxford) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Myself and two colleagues visited a local school and engaged a group for around 30 students in various activities related to different aspects of neuroscience. |
Year(s) Of Engagement Activity | 2022 |