Networks of neural dynamics: Knowledge-discovery for experimental neuroscience

Lead Research Organisation: University of Manchester
Department Name: School of Biological Sciences

Abstract

What is happening in your brain when you think and act? Cells are firing tiny electrical pulses, little spikes of activity, all across the brain. Some groups of cells emit these spikes at the same time, all of them responding to sudden noise, or to the swinging of your arm. In other groups, the spikes occur in a fixed sequence across the cells, remembering the path you just took from the front door to the bus-stop. Fundamentally, the brain works by co-ordinating activity between its cells.

So when cells stop being precisely co-ordinated, the brain stops working properly. In an epileptic fit, the cells across the cortex all become synchronised and waves of activity drown out the fine control of the muscles. In dementia, the loss of synchronisation between cells prevents reliable recall of past events.

The goal of my research is to enable us to find and analyse the co-ordinated activity of brain cells. Neuroscientists are now able to record the spikes from hundreds of separate cells, for hours at a time, from all across the brain. Yet the resulting data mountain is growing without the ability to analyse those recordings. We have many methods for comparing the activity of two cells, but few for comparing the activity of hundreds. We have even fewer methods for finding when in each recording the co-ordination happens, or for finding which cells are taking part, or for finding if the co-ordination is made up of simultaneous spikes, a sequence of spikes, or something more complex. Without these methods, these recordings cannot reveal what co-ordinated activity of individual cells tells us about how the brain functions and dysfunctions.

I will develop analysis methods that are able to take the recordings and automatically solve all these problems: finding when the cells are active together, which groups they belong to, and what form that co-ordinated activity takes. I will apply these methods to three areas of neuroscience research that seek to study the brain in health and disease by recording many cells at the same time. First, with Dr Constance Hammond's lab in Marseille, we will analyse their recordings of the developing rat striatum, a large forebrain system that is central to both the control and learning of actions. We will use my methods to understand how the co-ordinated activity in the healthy striatum develops over pregnancy and infancy, and then understand how genetic and environmental factors disrupt this correct development, leading to disorders of the striatum that appear in youth, like Tourette's syndrome.

Second, with Dr Sid Wiener's lab in Paris, we will analyse their recordings from the forebrains of rats learning to solve spatial navigation tasks in mazes. We will use my methods to understand how co-ordinated activity across the forebrain develops during learning. Particularly we will analyse how the sudden onset of widespread co-ordination that precedes correct decisions on the task depends on dopamine, and how replays of co-ordinated activity during sleep lead to improved performance. From the first we can gain a better understanding of how abnormal dopamine in the forebrain, as in schizophrenics, disrupts working memory and decision-making; from the second we can gain a better understanding of how poor quality sleep can affect learning.

Third, with Dr Rasmus Petersen's lab in Manchester, we will analyse their recordings from cells in the centre of the rat's brain that fire in response to movements of their whiskers. Dr Petersen's lab study these cells to understand the basic "neural code", the information that is carried by each spike. They have already found that some cells emit spikes in response to single features of movement, such as the whisker's position or velocity, whereas other cells emit spikes only to a complex mix of these features. We will use my methods to understand how these single cell codes combine when co-ordinated, forming the "population code" for sensory information.

Technical Summary

The delicate balance of co-ordinated neuron activity within and between brain regions is essential for normal brain function. Disrupting this co-ordination leads to dysfunction, like the excessive synchrony underlying epileptic seizures, or the loss of synchrony underlying loss of recall in dementia. Consequently, our best understanding of both neural function and dysfunction will be achieved when we can record, control, and analyse system-wide neural activity resolved to the level of co-ordination between each neuron.

Large-scale recording technology and system-wide control via optogenetics are becoming routine - but we lack system-wide analyses. I will develop data-mining methods that are able to solve the problems of finding when cells are co-active, which groups they belong to, and what form that co-ordinated activity takes, whether it be simultaneous, in sequences, or something more complex. I will develop a methodological framework based on network theory, modelling the interactions between neurons as links in a network. We will create network-dividing algorithms that automatically determine the size and number of groups of interacting neurons. These algorithms will be capable of data-mining the direction and type of interaction through analysing their delay, sign, and causality. Establishing this systems approach to neurophysiology will enable knowledge-discovery of novel hypotheses for neural coding, neural computation, and their disruption.

These algorithms will be used for collaborative analysis of large-scale neural activity data, to discover: the key factors in the healthy development of the striatum (with C. Hammond, INMED, Marseille); how dynamic re-organisation of neuron populations across the prefrontal cortex-hippocampal system underpins learning and decision-making (with S. Wiener, College de France, Paris); and how sensory information is coded by neuron populations in the whisker-related thalamus (with R. Petersen, University of Manchester)

Planned Impact

Our work aims to bring systems biology to neurophysiology, by establishing the data-mining tools necessary to enable knowledge discovery of how neurons co-ordinate their activity from large-scale data-sets of recordings. A critical pathway to the public health and economic impact of this work will be through the intermediate step of maximising take-up of the developed methodology across experimental neuroscience. We anticipate that this impact will be on a relatively short time-scale, realisable within the course of the Fellowship.

The potential beneficiaries are all groups that use large-scale recording to understand neural dynamics in both the normal function and dysfunction of neural systems. This encompasses groups using tetrodes, silicon probes, calcium-imaging, and voltage dyes to study, amongst many possible examples, neural coding in the retina and somatosensory systems; motor commands from motor cortex; dynamical systems in the hippocampal formation; behavioural sequencing and learning in the basal ganglia; and working memory in prefrontal cortex. Such groups would directly benefit from our development of a well-grounded methodological approach to data-mining hypotheses for neural computation and coding from their data, and an easily usable software package to pursue that data-mining.

Collaborations within the project will seek to demonstrate how the take-up of our methodology will, in practice, advance knowledge of the dynamics of neural systems. Moreover, we will seek to demonstrate the potential for impact on translational neuroscience through engaging clinical neurologists. In order to maximise our impact, we will focus on our collaboration with the lab of C. Hammond (Marseille) on the development of the striatum and midbrain dopaminergic systems, as this has currently the clearest pathway to potential impact on public health. This work will elucidate the physical and functional maturation of the striatal and dopaminergic systems from embryonic stages to adulthood, and the factors on which healthy maturation depends - in particular, the influence of dopamine over the maturation of the striatum. Clinical neurologists could benefit from our new models for neurodevelopmental disorders of the striatum and midbrain dopaminergic systems, which link developmental insults to abnormal functional development and suggest new targets for intervention and prevention.

We believe the work has two potential impacts on the UK economy. First, in their joint report "Systems Biology: a vision for engineering and medicine" the Academy of Medical Sciences and The Royal Academy of Engineering recommended that establishing systems biology capacity in the UK was critical to its competitiveness at the forefront of science, public health initiatives, and economic potential. A major benefit of this project is thus that it will establish UK capacity in systems biology within neurophysiology, offering a unique opportunity to establish a world-leading research group in a nascent field on the verge of explosion. Within the lifetime of the project, the immediate beneficiaries will be the research staff employed on the project, who will receive extensive cross-disciplinary experience, and the potential to establish their own groups in this area.

Second, we will develop GPU-enabled versions of our data-mining algorithms, which will allow both real-time and exhaustive, high-throughput analyses of neural activity data. As the development and optimisation of GPU-enabled versions is specialised, technically-demanding work, this has the potential for wealth creation via a spin-out company, which will handle the programming, distribution and support of a commercial software package. This package would benefit any experimentalist wishing to achieve either or both of high-throughput and real-time analyses of their data.

Publications

10 25 50
 
Description MRC Project Grant
Amount £255,368 (GBP)
Funding ID MR/P005659/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 01/2017 
End 12/2019
 
Description Project Grant (BBSRC)
Amount £453,638 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 06/2014 
End 05/2017
 
Description Project Grant (MRC)
Amount £550,787 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 05/2014 
End 04/2017
 
Description Workshop Grant
Amount £3,000 (GBP)
Organisation Company of Biologists 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2014 
End 08/2015
 
Title Spike-train community detection 
Description We recently extended community detection algorithms from network theory to create the state-of-the-art neural activity clustering algorithm, capable of identifying simultaneously the number and composition of neural groups. Applicable to large-scale, cellular-level recordings from any neural circuit, in any model animal, using any large-scale recording technique 
Type Of Material Data analysis technique 
Year Produced 2011 
Provided To Others? Yes  
Impact Applications in our groups to: (1) Characterising the development of rat striatum (2) Identifying changes in the motor cortex of Parkisonian mice (3) Understanding the locomotion-control circuit of Aplysia In other groups: (1) Decoding of ensembles controlling arm movement (2) Development of extended community-detection techniques (3) Application of community-detection techniques to cortical activity in vitro 
URL http://www.systemsneurophysiologylab.ls.manchester.ac.uk/code/analysis/
 
Description Adrien Peyrache - MNI 
Organisation University of Montreal
Department Montreal Neurological Institute
Country Canada 
Sector Hospitals 
PI Contribution We have proposed theoretical frameworks for neural computation testable with Dr Peyrache's data. We have analysed the data to test hypotheses arising from these frameworks. We have written manuscripts based on these results.
Collaborator Contribution Dr Peyrache has contributed extensive experimental data. He has discussed results throughout; and contributed to manuscript preparation.
Impact Multi-disciplinary: electrophysiology; computational statistics; theoretical neuroscience; machine learning Conference presentations: Society for Neuroscience 2016, 2016. Manuscript on the bioRxiv pre-print server. DOI: 10.1101/027102
Start Year 2015
 
Description Chicago - Aplysia 
Organisation Rosalin Franklin University
Department School of Medicine Rosalin Franklin
Country United States 
Sector Academic/University 
PI Contribution Development and application of analysis tools for (i) neural population activity encoding locomotion and (ii) physical organisation of neural circuit. Automated methods for identifying separable classes of neurons based on patterns of output.
Collaborator Contribution Development of semi-intact sea slug (Aplysia) preparation with simultaneous voltage-sensitive dye imaging. Recording of neural population activity during fictive locomotion
Impact Challenges of decomposing the contribution of 100+ simultaneously recorded neurons to the locomotion motor program has driven rapid development of powerful analyses tools applicable to any large-scale neural recording project (cf USA BRAIN initiative and the EU Human Brain Project). Paper on correspondence between functional and physical organisation of locomotion circuit, published 2015. PMID: 25819612 Paper on low-dimensional attractors in neural circuits posted to bioRxiv pre-print server, 2017: DOI: 10.1101/104562 Multi-disciplinary collaboration: electrophysiological recording (Chicago); network theory (us); time-series analysis (us)
Start Year 2011
 
Description Christian Beste - HD and others 
Organisation Ruhr University Bochum
Country Germany 
Sector Academic/University 
PI Contribution Models of basal ganglia's role in decision-making. Models of how neurological disorders (Huntington's disease, Parkinson's disease) can both impair and enhance performance on cognitive tasks
Collaborator Contribution Design and testing of decision-making tasks on control and patient groups. Analysis of behavioural and EEG data from those groups.
Impact Conference paper (ICANN2012) Paper in submission on implications for neural function of Huntington's Disease patients' enhanced performance on simple reaction time tasks
Start Year 2009
 
Description Constance's Ca2+ data 
Organisation Aix-Marseille University
Department Mediterranean Institute of Neurobiology
Country France 
Sector Academic/University 
PI Contribution Mathematical analysis of the activity of simultaneously recorded populations of neurons in: (i) the developing brain (striatum and dopaminergic system); and (ii) the parkinsonian brain (motor cortex of parkinsonian mice)
Collaborator Contribution Development of rodent models and slice preparations. Recordings of population activity at single neuron level using calcium imaging.
Impact Work on developing rat striatum published in 2011, PMID: 22125512. Paper on comparing motor cortex activity in wild-type and parkinsonian mouse published in 2014: PMID: 24904316 Multi-disciplinary collaboration: electrophysiological recording (INMED); network theory (us); time-series analysis (us)
Start Year 2010
 
Description Kevin & Pete - UoS 
Organisation University of Sheffield
Department Department of Psychology
Country United Kingdom 
Sector Academic/University 
PI Contribution Theory and models of basal ganglia function. Hypotheses for disruption of that function by neurological disorders. Theories and models on the role of dopamine in learning and performance
Collaborator Contribution Theory and models of basal ganglia function. Hypotheses for disruption of that function by neurological disorders. Theories and models on the role of dopamine in learning and performance
Impact Collaboration continued since postdoctoral work at Sheffield. Papers since then include: Anatomical network of the striatum PMID 21124867 Landmark analytic and synthetic review paper on the ventral basal ganglia's structure and function . PMID 19941931. [Selected for the Faculty of 1000] Comprehensive model of how cortico-striatal plasticity links actions to outcome, published 2015. PMID: 25562526
 
Description Matt Jones 
Organisation University of Bristol
Country United Kingdom 
Sector Academic/University 
PI Contribution Analysis of neural population recordings from multiple regions of cortex in rats learning a maze
Collaborator Contribution Providing data from neural recordings, positions, and choice behaviour
Impact Named collaborator on Matt Jones' successful Wellcome Trust Senior Fellowship application. Our group obtained internal grant funding to support bilateral travel to Bristol (awarded Jan 2018). Multi-disciplinary: experimental neuroscience (Bristol); data science (us)
Start Year 2017
 
Description Mehdi - ISIR 
Organisation Pierre and Marie Curie University - Paris 6
Country France 
Sector Academic/University 
PI Contribution Models of basal ganglia function and their modulation by dopamine. Theories of the role of the basal ganglia in decision-making tasks. Formalisation of theories of reinforcement-driven navigation.
Collaborator Contribution Models of basal ganglia function and their modulation by dopamine. Theories of the role of the basal ganglia in decision-making tasks. Formalisation of theories of reinforcement-driven navigation.
Impact Paper on dopamine's role in decision-making: PMID 22347155 Paper on formalising strategies for navigation and their neural substrates: PMID 23205006
Start Year 2007
 
Description Sid & Karim - Hippocampus-PFC 
Organisation College of France
Country France 
Sector Academic/University 
PI Contribution Development of models of communication between hippocampus and prefrontal cortex during navigation. Testing hypotheses for role of selectively enhanced communication at choice points in mazes
Collaborator Contribution Recordings of neural activity and behaviour from rodents performing maze tasks. Analyses of that data.
Impact Grant from ANR (France) (2010-2014): "NEUROBOT: Coding of information on different time scales for spatial decisions" [€0.87 million]
Start Year 2007
 
Description Tom Gilbertson 
Organisation University of Dundee
Department Dundee Epidemiology and Biostatistics Unit
Country United Kingdom 
Sector Academic/University 
PI Contribution We provide models of the basal ganglia and reinforcement learning; collaborate in methods for fitting those models to data; co-write papers
Collaborator Contribution The partners collect behavioural data from dystonia patients, and matched control groups; alongside fMRI. They fit models to the data. Lead write papers.
Impact Gilbertson, Humphries & Steele "Maladaptive striatal plasticity explains abnormal reward-learning in cervical dystonia" Preprint submitted to bioRxiv
Start Year 2016
 
Title "Spike-train communities" software toolbox 
Description A set of MATLAB functions and scripts for executing the "community detection" approach to detecting ensembles of neurons. Widely applicable to simultaneous single-neuron recordings from any neural circuit in any model system. 
Type Of Technology Software 
Year Produced 2014 
Open Source License? Yes  
Impact In my group, applications to recordings from: Developing rat striatum Motor cortex of parkinsonian mice Locomotion circuit of Aplysia Prefrontal cortex of rats navigating a maze Applications by other groups include: Decoding of motor cortical control of arm movement 
URL http://www.systemsneurophysiologylab.ls.manchester.ac.uk/code/analysis/
 
Title Neural Ensemble Analysis 
Description MATLAB toolbox for analysing neural ensembles So you've found some ensembles of neurons (or ``cell assemblies") in your population recording data - now what? This toolbox tackles this problem by laying out a set of tools for analysing neural ensembles. It contains a collection of scripts and functions for analysing ensembles assuming: (1) you've got a clustering of your spike-train data into ensembles (as might be obtained by: https://github.com/mdhumphries/SpikeTrainCommunitiesToolBox) (2) you've got your spike-trains in some time-series format (i.e. either binned or "spike-density" - convolved each spike with a window function) (as might be obtained by: https://github.com/mdhumphries/SpikeTrainCommunitiesToolBox) The focus is on classifying ensembles: this allows us to then go back to each recording and start to decompose the dynamical systems captured within 
Type Of Technology Software 
Year Produced 2015 
Open Source License? Yes  
Impact Basis for our paper Bruno et al (2015, Neuron) on deconstructing the locomotion circuit of the sea-slug Aplysia 
URL https://github.com/mdhumphries/NeuralEnsembleAnalysis
 
Title Small-world-ness toolbox 
Description A set of code (MATLAB) for computing our widely-used "small-world-ness" metric for networks 
Type Of Technology Software 
Year Produced 2017 
Open Source License? Yes  
Impact GitHub does not track downloads of repositories 
 
Title Spectral rejection for networks 
Description MATLAB toolbox for finding and rejecting noise in networks Accompanies the paper "Spectral rejection for testing hypotheses of structure in networks" arXIv 1901.04747 
Type Of Technology Software 
Year Produced 2019 
Open Source License? Yes  
Impact None yet 
 
Title Spike-train communities toolbox, version 2 
Description MATLAB toolbox for spike-train community detection A set of functions for analysing large-scale recordings of cellular-level neural activity, based on community detection ideas from network theory. 
Type Of Technology Software 
Year Produced 2015 
Open Source License? Yes  
Impact Basis for our paper Bruno et al (2015, Neuron) on mapping the locomotion system of the sea slug Aplysia 
URL https://github.com/mdhumphries/SpikeTrainCommunitiesToolBox
 
Description Brain-Inspired podcast 
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 Other audiences
Results and Impact A podcast interview about our research and career for Paul Middlebrooks' Brain-Inspired podcast series
Year(s) Of Engagement Activity 2018
URL https://braininspired.co/podcast/bi-004-mark-humphries-learning-to-remember/
 
Description Cafe Scientifique (Manchester) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact General public talk on "What on earth is brain modelling?"; 30 minutes talk + 1 hour of questions
Year(s) Of Engagement Activity 2016
 
Description JNNP Podcast interview 
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 Professional Practitioners
Results and Impact Podcast interview to accompany JNNP paper on what computational models of the basal ganglia have taught us about Parkinson's disease. Interview was aimed at introducing computational models, and their uses, to clinicians
Year(s) Of Engagement Activity 2018
URL https://soundcloud.com/bmjpodcasts/can-computational-models-help-us-understand-complex-movement-diso...
 
Description Open Council Meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Presentation of my research at the annual MRC Open Council Meeting, at the Baltic Centre, Gateshead. Gave a 10 minute talk on the high-level aims of my research, on my international collaborations, and on the MRC's impact on my research. Audience was a mixture of MRC Council members, panel members, academics and health professionals from across Tyneside, and the general public.

none so far
Year(s) Of Engagement Activity 2014
 
Description Pint of Science talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact 20 minute talk at the Pint of Science Festival in May 2017, in Manchester
Year(s) Of Engagement Activity 2017
 
Description Popular (systems) neuroscience blog: The Spike 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact I started a popular blog to bring systems neuroscience - the study of neural circuits and their functions - to a wider audience. Posts are fortnightly.

At the time of writing (19/2/2018), the blog has around 33000 followers.
It has averaged ~600 visitors per day over the last 3 months.
Around 27500 views per month
Year(s) Of Engagement Activity 2016,2017,2018,2019
URL https://medium.com/the-spike
 
Description Press release for Aplysia paper in Neuron 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact A press release accompanied our 2015 paper (Bruno, Frost & Humphries, Neuron), on unravelling the motor system of sea slugs. This was picked up by a wide range of media outlets, including the Mail Online: http://www.dailymail.co.uk/sciencetech/article-3013360/Simple-sea-slug-Maps-mollusc-neurons-suggest-brains-not-complex-thought-including-own.html
Year(s) Of Engagement Activity 2015
URL http://www.dailymail.co.uk/sciencetech/article-3013360/Simple-sea-slug-Maps-mollusc-neurons-suggest-...
 
Description Psychology Today 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Invited blogger at PsychologyToday.com. Blog name: Neural Processing
Year(s) Of Engagement Activity 2017,2018
URL http://PsychologyToday.com
 
Description Public talk (Manchester, Humanist Association) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact A 1.5 hour talk to the Manchester Humanist Association; a 30 minute talk and a 60 minute Q&A session.
Year(s) Of Engagement Activity 2016
 
Description Theories of Mind 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact A 5 part series "Theories of Mind" on current theories in neuroscience, commissioned by Medium.com
Year(s) Of Engagement Activity 2017
URL https://medium.com/s/theories-of-mind