iPROBE: in-vivo Platform for the Real-time Observation of Brain Extracellular activity

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

Abstract

Understanding how the trillions of action potentials of the brain's billions of neurons produce our thoughts, perceptions, and actions is one of the greatest challenges of 21st century science. Similarly, understanding how this activity is disrupted by neurological and psychiatric diseases is one of the greatest challenges of 21st century medicine. Due to the massively parallel nature of the brain's computations, answering these questions experimentally relies on being able to monitor very large numbers of neurons simultaneously. Advances in electrode microfabrication and high-throughput data analysis have allowed scientists to record from hundreds of neurons in a small local area of brain. However, as both healthy and unhealthy neural operation arises from interaction of multiple, widely-distributed brain circuits, its understanding requires a technological step-change that allows monitoring of much larger numbers of neurons over many brain areas. The research of this proposal will for the first time make this possible. This will not only provide a previously unimaginable opportunity for understanding how the healthy brain functions, but also allow us and others to develop empirically-based treatments for diseases such as Parkinson's, epilepsy, schizophrenia, and Alzheimer's.

Large-scale neuronal recording relies on the use of microfabricated multielectrode arrays (MEAs). Arrays capable of recording from hundreds of local neurons are now commercially available. In principle, these arrays provide the ability to record from thousands of neurons across multiple brain structures, simply by using a large number of probes simultaneously. However, accessing the data produced by these electrodes cannot be achieved with current technologies, as it is simply impossible to pass a sufficient number of very low amplitude analogue signals, as in current passive connection systems. We will solve this problem by using an approach common in computing: a daisy-chain digital serial interface. By allowing simple, robust, and low-noise connection of several multi-electrode arrays, this will allow us to monitor thousands of neurons from multiple structures using a single interface. The system will exploit cheap, commercially available microelectrode arrays (eg. NeuroNexus), connected to a custom CMOS Integrated Circuit (IC) via high-density flexible ribbon cables. CMOS ICs are low cost, produce high yield and area efficient active electronics suitable for amplifying, filtering, analog-to-digital conversion and encoding of each electrode array's spiking neuron data. Each daisy chain (i.e. group of serially-connected probes) will terminate into a standard USB interface. The new USB-3.0 protocol (marketed using the SuperSpeed term) can allow for serial data speeds of 5Gbps. For data sampled at 25kS/sec at 12-bit resolution, this could provide a bandwidth capable of supporting over 10,000 electrodes: two orders of magnitude beyond current technology.

The recording systems we develop will produce vast quantities of data. A second, and essential, part of the platform is thus to develop the algorithms and software that are essential for the timely conversion of this information to concise conclusions about brain function. We will do this by leveraging our previous work, now the de facto worldwide standard for processing of multi-neuron recordings.

Our aim is to produce a system that is widely adopted by the UK and worldwide neuroscientific communities, thereby maximizing its impact on the understanding and treatment of a very wide range of disorders. To ensure that the system meets the need of both basic and clinical brain research, our team includes the world's leading expert on neuronal population recording, as well as the UK's leading manufacturer of neural recording systems. We thus have the expertise needed not only to develop the system, but also enable its rapid commercialization and distribution to scientists worldwide.

Planned Impact

This project will create a new interdisciplinary partnership bridging two of the UK's key academic and commercial strengths: microelectronic design and the biomedical sciences. The technology developed in this project will produce a step-change in the study of neuronal circuit function, exceeding previous recording capability by an order of magnitude. We have strong links with the national and international neuroscience community and will actively support the use of this technology to establish the UK as the world's leading location for the study of neural circuit function. As neural interfaces move from the research lab to the clinic, an expertise base in this critical skill will be of vital importance to the UK's future competitive position in medical technologies.

Understanding how the brain's circuits process information is essential to developing rational treatments for neurological and psychiatric disorders such as Alzheimer's, Parkinson's, schizophrenia, epilepsy, depression, and autism. The technologies we will develop in this project will allow us and others to study the large-scale coordination of activity in both the healthy brain, and in animal models of these devastating diseases, allowing the rational development and testing of both drug and device-based treatments for them. The system we design here is aimed in the first instance at animal models. However, similar designs can be used for interfacing to the human brain. Neural devices now constitute a $2 billion/year industry that is predicted to grow twice as fast as the cardiac implant market. EPSRC has recognised the importance of this area in its initiative 'Developing a Common Vision for UK Research in Microelectronic Design' which describes the interface of electronics to biology and in particular the brain as a Grand Challenge for UK microelectronics. Although the UK has several excellent groups researching non-invasive (EEG-based) BMIs and peripheral interfaces (nerve and muscle FES), it currently lags behind in the invasive BMI field while other countries are investing heavily. For example, the Japanese Strategic Research Program for Brain Sciences (SRPBS) recently chose BMI research as one of two priority areas in its first year with a budget of £14 million. To compete internationally and generate viable commercial spinouts, a portfolio of technology and expertise is essential. The proposed collaboration brings together complementary strengths and IP in medical devices and neural signal analysis. Together these resources make this partnership ideally suited to the challenge of translating basic research and technology development into devices with real clinical and commercial application.

Our partnership with Axona Ltd., the UK's (and Europe's) leading manufacturer of multichannel neural recording systems, will ensure that our technologies can be rapidly commercialized, allowing their widespread application to research on a large number of neurological disorders, as well as benefiting the UK economy. The neural probe market is currently estimated to be worth US$20M, and is growing rapidly. The iPROBE signal acquisition technology is ideally placed to become a value-added component that could be integrated with any of a wide range of probe devices. The simple design of the technology allows it to be manufactured without requiring highly expense custom microfabrication equipment; in addition, iPROBE chips in quantity could be produced cheaply enough that they would fall into the highly desirable "consumables" category. This would generate an income stream and consequently employment in the UK from a guaranteed export market, since no comparable technology exists worldwide. With a solid foothold in the research market, the iPROBE technology would be ideally placed to realise the large returns which will inevitably follow as large-scale neural interfaces transition to from research to clinical use.

Publications

10 25 50

publication icon
Harris KD (2015) The neocortical circuit: themes and variations. in Nature neuroscience

publication icon
Harris KD (2015) Cortical computation in mammals and birds. in Proceedings of the National Academy of Sciences of the United States of America

publication icon
Harris KD (2013) Top-down control of cortical state. in Neuron

publication icon
Harris KD (2014) Sleep replay meets brain-machine interface. in Nature neuroscience

publication icon
Harris KD (2013) Cortical connectivity and sensory coding. in Nature

publication icon
Le Mouel C (2014) Supervised learning with decision margins in pools of spiking neurons. in Journal of computational neuroscience

publication icon
Luczak A (2015) Packet-based communication in the cortex. in Nature reviews. Neuroscience

 
Description Our results have enabled the generation of new systems for recording from large numbers of neurons in the brain.

The working of the brain is a matter of great importance to society; furthermore by gaining this understanding we will open new avenues to the treatment of neurological and psychiatric disorders.
Exploitation Route The tools we have produced are already in use by hundreds of scientists worldwide on a daily basis.
Sectors Education,Electronics,Healthcare

URL http://klusta-team.github.io/
 
Description Our results have enabled the generation of new systems for recording from large numbers of neurons in the brain. The working of the brain is a matter of great importance to society; furthermore by gaining this understanding we will open new avenues to the treatment of neurological and psychiatric disorders.
First Year Of Impact 2014
Sector Education,Electronics,Healthcare,Pharmaceuticals and Medical Biotechnology
 
Description GE/Kavli foundation Brain Trust
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in advisory committee
Impact This committee, convened and funded by General Electric Corporation and the Kavli foundation, seeks to maximize the impact of neuroscience research on patient outcomes through provision of next-generation e-health technology, and by closely integrating brain research with clinical practice.
 
Description Technologies for Understanding the Brain
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a national consultation
 
Description Functional Neuromics of the Cerebral Cortex
Amount £4,189,482 (GBP)
Funding ID 108726/Z/15/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2016 
End 12/2020
 
Description Industrial CASE award
Amount £101,327 (GBP)
Funding ID MR/L015404/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 10/2014 
End 09/2018
 
Description Integration of Internal and External Signals in the Cortex
Amount £1,300,000 (GBP)
Funding ID 095668/Z/11/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2012 
End 10/2017
 
Description Simons Collaboration on the Global Brain
Amount £333,333 (GBP)
Funding ID 325512 
Organisation Simons Foundation 
Sector Charity/Non Profit
Country United States
Start 07/2014 
End 06/2017
 
Description Collaboration with Prof John O'Keefe, UCL 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution In collaboration with Prof. John O'Keefe and Dr. Julija Krupic (a postdoc in the O'Keefe lab), we are investigating the retroaxonal hypothesis experimentally using two-photon microscopy in the hippocampus of behaving mice
Collaborator Contribution We have devised and tested a strategy for silencing the outputs of a small numbers of hippocampal pyramidal neurons, and supplied reagents to make this possible in the O'Keefe lab.
Impact The first results of these experiments are expected in a few months.
Start Year 2014
 
Description Neuronal network disruption in Alzheimer's disease 
Organisation Eli Lilly & Company Ltd
Department Neuroscience Eli Lilly
Country United States 
Sector Private 
PI Contribution We analyze data recorded from the brains of Alzheimer's disease model mice
Collaborator Contribution They record from the brains of Alzheimer's disease model mice
Impact Computing Mathematics Neuroscience
Start Year 2014
 
Description Neuropixels project 
Organisation Howard Hughes Medical Institute
Country United States 
Sector Charity/Non Profit 
PI Contribution We are testing a new generation of high-count active microelectrodes that are set to revolutionize neuronal recordings. The first recordings have been made in visual cortex, with excellent results.
Collaborator Contribution I listed the in-kind contribution as £2,000,000 which represents the amount of money other funders have contributed to the project. But in reality, their contribution is priceless. There is no other way we could have obtained these probes; no-one else in the world has access to them.
Impact The first generation of probes have been fabricated. Disciplines: microfabrication; microelectronics; computer science; neuroscience.
Start Year 2013
 
Title KlustaViewa 
Description Software for graphical analysis of spike sorting data 
Type Of Technology Software 
Year Produced 2013 
Open Source License? Yes  
Impact Used so far by over 200 scientists in over 30 leading research labs worldwide 
URL https://github.com/klusta-team/klustaviewa
 
Title MaskedKlustaKwik 
Description Software for automatic cluster analysis 
Type Of Technology Software 
Year Produced 2013 
Open Source License? Yes  
Impact Used by over 200 scientists in over 30 research labs worldwide. Also finding increasing use outside of neuroscience, including in systems biology 
URL https://github.com/klusta-team/klustakwik
 
Title Neurodata Without Borders Format 
Description A universal file format for neurophysiology data 
Type Of Technology Systems, Materials & Instrumental Engineering 
Year Produced 2015 
Impact Will allow easy sharing of data between investigators in the field 
URL https://crcns.org/NWB
 
Title SpikeDetekt 
Description Software for detection of action potentials in high-count neural probes 
Type Of Technology Software 
Year Produced 2013 
Open Source License? Yes  
Impact Used by over 200 scientists in over 30 leading research labs worldwide 
URL https://github.com/klusta-team/spikedetekt2
 
Title phy 
Description Next-generation software for analysis of electrophysiogy with several hundred channels 
Type Of Technology Software 
Year Produced 2015 
Open Source License? Yes  
Impact First product to allow data digestion from next-generation silicon probes 
URL https://github.com/kwikteam/phy
 
Description Artificial Intelligence and the Brain 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact A panel discussion open to the public, on the question of how what we learn from the brain can inform building of intelligent machines
Year(s) Of Engagement Activity 2016
 
Description Nature Podcost 
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 Raised awareness of our research to an international audience, via an interview for Nature.com's podcast, a very highly respected and widely downloaded podcast for popular science
Year(s) Of Engagement Activity 2013