Modelling the Development of Complex Brain Networks

Lead Research Organisation: University of Cambridge
Department Name: Psychiatry

Abstract

Networks are everywhere around us. In nature, society, technology and commerce it is often useful to analyze the patterns of connections between individual components. This approach can, for example, be used to identify key players in a social network or to ensure the robustness of a power-grid to both targeted attacks and random failures.

The brain too can be viewed as a large network. Various brain imaging techniques can be used to identify the links between individual brain regions, either in terms of anatomical connection or in terms of the flow of information (For a video illustration, visit: http://www.youtube.com/watch?v=f3P15X_62xQ). Over the last 5 years, scientists have increasingly studied this pattern of connections between brain regions to gain a better understanding of the brain as a whole. For example, they have found that certain properties of these networks are correlated with higher IQ. Another surprising finding was that many different types of networks, from the human brain to the stock exchange have a large number of properties in common. Finally, this new approach has allowed researchers to identify differences in the structure of brain networks between different populations.

For example, brain networks are known to have somewhat different properties in young and older people. Other alterations of brain networks were identified in people with mental health disorders such as schizophrenia. Describing such differences in the organization of brain networks is likely to become important in the diagnosis of mental illness. However, in order to lead to better treatment and prevention, we also need to understand how these differences come about.

Currently, most mathematical methods are designed for the analysis of static networks, 'frozen in time'. This project aims to develop new tools to model the development of brain networks over time and to understand the driving forces behind these changes. These new methods will then be applied to the study of two key periods of human brain development: adolescence and ageing. For this, we will be using cognitive tests as well as high-quality brain imaging data previously collected from participants ranging from 14 to 88 years of age. We will focus, in particular, on the following questions:

1. What network features are most useful in describing the maturational changes in brain organization taking place during development and ageing? In addressing this question, we will be using both novel and pre-existing measures of network structure.

2. What characteristics of brain networks are associated with better cognitive performance in youth, and especially in old age? Are certain features of network organisation at a young age predictive of cognitive capabilities at a later stage?

3. Having quantified how brain networks change over the course of human brain development, we can begin to look for the rules governing these changes. Can we, for example, build simple models to predict the pattern of tissue loss during ageing? This question is of particular importance as more of us are living longer.

This research will be conducted in the Brain Mapping Unit (BMU), at the University of Cambridge. The BMU is headed by Professor Ed Bullmore and combines researchers from a variety of backgrounds such as medicine, physics and mathematics. This unique combination offers world-class expertise in a range of areas crucial to this project and provides the perfect environment to carry out the proposed work.

Technical Summary

Graph theoretical methods are increasingly being used to study biological and medical problems at a systems level. In the brain, understanding the network structure of neurons at the microscopic level, and of brain regions at the macroscopic level is crucial to elucidating the mechanisms underpinning both healthy and impaired brain-function.

While we now possess a sophisticated set of measures to describe the topology of static brain networks, the driving forces that shape the networks into these characteristic topologies remain largely unknown. More generally, the temporal evolution of networks has so far received very little attention both theoretically and in its applications to neuroscience. My proposed research aims to fill these gaps by studying the temporal evolution of brain networks in two developmental epochs of particular clinical interest: (i) the maturation of brain networks during adolescence and (ii) the changes in network structure associated with ageing.

My key hypothesis is that many complex network-level changes in human brain organization can be parsimoniously explained (and therefore modelled) in terms of simple trade-offs between cognitive function, spatial constraints and energetic costs. To test these ideas, I will first characterize developmental changes in brain networks using both novel and existing graph theoretical methods. Second, I will correlate the changes observed in various network features with changing abilities in several cognitive domains. This will allow me to consider the functional role of network properties that may offset energetic cost in a trade-off model of human brain development. Based on these insights, I will then build computational models that predict the pattern of network growth and degeneration in terms of biologically plausible rules and simple physical constraints.

Planned Impact

My proposed research has three facets, which will each impact on a different set of beneficiaries both within and outside academia.

1. Advances in Neuroscience
Perhaps the most direct impact of my work will be a better understanding of brain maturation and senescence. Beyond the advancement of scientific knowledge, this may result in downstream medical and pharmaceutical applications with potentially important impacts on health and wellbeing in society, as well as on the UK's economic competitiveness.

2. Methodological Advances in Network Science
Methodological advances in network analysis will immediately impact on a large number of academic disciplines from epidemiology to economics. As described in Pathways to Impact, I will work to ensure that these advances are propagated further to the companies, policy makers and other organizations that use network analysis in their products and/or decision-making.

3. Communication and Dissemination
As described in the Communication Plan, I am committed to disseminating my research, its motivation and its outcomes to a broad audience, from the general public to Parliament. Through the various activities described in Pathways to Impact I hope to:
(i) Raise awareness of the relevance of science to both everyday life and policy making.
(ii) Work towards a more balanced and better-informed public perception of mental health and healthy ageing.

Publications

10 25 50
 
Title Scarbeus Aerial Theatre group 
Description I consulted in the development of an aerial theatre performance entitled "Depths of my Mind" 
Type Of Art Performance (Music, Dance, Drama, etc) 
Year Produced 2016 
Impact DEPTHS OF MY MIND is an innovative performance that combines aerial skills with visual theatre, to bring to life the latest developments in neuroscience and neuroimaging connected to the teenage brain. The piece is the second in our three-year trilogy of work for all ages, created in consultation with young people aged 12-25. We expect the piece to increase awareness in the general public of both basic and cutting edge concepts in neuroscience and their relevance to mental health. We also expect the production to help young people better understand and handle the mental health challenges associated with adolescence (a particularly sensitive period of brain development marked by a high incidence of mental health issues). 
URL http://www.scarabeus.co.uk/coming-in-autumn-2016-depths-of-my-mind/
 
Title Science and Poetry 
Description Participated in a series of encounters between scientists and authors/poets leading to the publication of a book based on (1) the scientist's explanation of a project they are working on (2) the writings of the author/poet inspired by this work. 
Type Of Art Creative Writing 
Year Produced 2014 
Impact The book will be published in early 2015 and will help promote public understanding of science. The encounters with authors also provided an opportunity to discuss the role of science and convey the importance of the particular research we are engaged in. 
URL http://www.larbredediane.be/collections/frontpage/products/geodesiques
 
Title WhyWolf Animation 
Description We have been approached by a film/animation artist to help develop a short animation film around the findings of our recent PNAS paper regarding brain changes in adolescence. The film is currently in development. It will be presented at a number of science festivals and events focussed on mental health. 
Type Of Art Film/Video/Animation 
Year Produced 2017 
Impact We expect it will raise awareness around the neuroscientific basis for mental health issues and their prevalence in adolescence. It will also increase the general public's understanding of scientific methods for brain research. 
 
Description Funds for travel
Amount £2,000 (GBP)
Organisation Northeastern University - Boston 
Sector Academic/University
Country United States
Start 08/2015 
End 08/2015
 
Description MQ Fellowship
Amount £225,000 (GBP)
Organisation MQ Transforming Mental Health 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2018 
End 03/2021
 
Description Researcher development funding through the Graduate School of Life Sciences
Amount £2,000 (GBP)
Organisation University of Cambridge 
Department Faculty of Biology
Sector Academic/University
Country United Kingdom
Start 09/2014 
End 09/2015
 
Description Researcher development funding through the Graduate School of Life Sciences (£ 2000; 2015)
Amount £2,000 (GBP)
Organisation University of Cambridge 
Sector Academic/University
Country United Kingdom
Start 09/2015 
End 09/2016
 
Description Various Industry partners: - Sponsorship for Cambridge Networks Network events (£ 400; 2015)
Amount £400 (GBP)
Organisation Cambridge University Press 
Sector Private
Country United Kingdom
Start 05/2015 
End 05/2015
 
Title Recordings of Caenorhabditis elegans locomotor behaviour 
Description Recordings of Caenorhabditis elegans locomotor behaviour following targeted ablation of single motorneurons 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
Impact This database was developed to accompany a recent Nature paper applying control theory to the C elegans nervous system (https://www.ncbi.nlm.nih.gov/pubmed/29045391). Here we present a dataset of ~300 video recordings representing the locomotor behaviour of animals carrying single-cell ablations of 5 different motorneurons. Each file includes a raw video of approximately 27,000 frames; each frame has also been segmented to yield the position, contour, and body curvature of the tracked animal. These recordings can be further analysed using publicly-available software to extract features relevant to behavioural phenotypes. This dataset therefore represents a useful resource for probing the neural basis of behaviour in C. elegans, a resource we hope to augment in the future with ablation recordings for additional neurons. 
URL https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5647482/
 
Description Collaboration on Network Control 
Organisation Medical Research Council (MRC)
Department MRC Laboratory of Molecular Biology (LMB)
Country United Kingdom 
Sector Academic/University 
PI Contribution Guided application of recently developed network control methods to neurobiological networks. Facilitated collaboration with MRC Laboratory of Molecular Biology who performed experiments to validate the theoretical predictions. I was also involved in an NIH grant designed to extend the work above. If awarded I will serve as a consultant to that grant.
Collaborator Contribution I was invited to visit the lab in Boston, which broadened my skillset in bioinformatics and allowed me to meet a number of relevant academics. I was also involved in an NIH grant designed to extend the work above. If awarded I will serve as a consultant to that grant.
Impact Our joint work has been published in the journal Nature and we are preparing a number of follow-up articles. It is interdisciplinary work involving phsyicists/control theorists and experimental biologists.
Start Year 2014
 
Description Collaboration on Network Control 
Organisation Northeastern University - Boston
Country United States 
Sector Academic/University 
PI Contribution Guided application of recently developed network control methods to neurobiological networks. Facilitated collaboration with MRC Laboratory of Molecular Biology who performed experiments to validate the theoretical predictions. I was also involved in an NIH grant designed to extend the work above. If awarded I will serve as a consultant to that grant.
Collaborator Contribution I was invited to visit the lab in Boston, which broadened my skillset in bioinformatics and allowed me to meet a number of relevant academics. I was also involved in an NIH grant designed to extend the work above. If awarded I will serve as a consultant to that grant.
Impact Our joint work has been published in the journal Nature and we are preparing a number of follow-up articles. It is interdisciplinary work involving phsyicists/control theorists and experimental biologists.
Start Year 2014
 
Description Collaboration with the NSPN consortium 
Organisation NSPN (NeuroScience in Psychiatry Network)
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution I have collaborated on a project applying my skills in bioinformatics to a large dataset made available by the consortium. Note that I was previously employed by the consortium and had responsibility for a different neuroimaging modality within the same dataset. This work was not related to the current collaboration. In addition to my own work on this project I am now supervising one postdoc and co-supervising one PhD student working within the consortium.
Collaborator Contribution The consortium provided the dataset and other collaborators with more background in psychiatry and more experience in structural mri analysis. This has allowed me to broaden my skillset.
Impact This collaboration has yielded six publications and a few more are in preparation. One of these publications was high profile and has lead to a large number of related outputs including interviews and articles by the media, an award, and some related artistic outreach projects.
Start Year 2015
 
Description NIMA 
Organisation University of Cambridge
Country United Kingdom 
Sector Academic/University 
PI Contribution I am collaborating on a project applying my skills in bioinformatics to large datasets collected as part of the consortium I have also attended regular teleconferences and face to face meetings for the last year to discuss the outcomes of this research and their interpretation
Collaborator Contribution The consortium provided the datasets and other collaborators . This has allowed me to broaden my skillset.
Impact The consortium (of which I am a listed member) has begun generating multiple publications. The work I am most heavily involved in is currently being prepared for publication. The project is multi-disciplinary and involves physicists and statisticians as well as biologists and psychiatrists. It involves both academia and industry (Johnson & Johnson).
Start Year 2017
 
Description Participation in the MRC Immunopsychiatry Consortium 
Organisation Medical Research Council (MRC)
Department MRC Immunopsychiatry Consortium
Country United Kingdom 
Sector Public 
PI Contribution I have collaborated on a project applying my skills in bioinformatics to a large dataset made available by GlaxoSmithKline as part of the consortium I have also attended regular teleconferences and face to face meetings for the last year to discuss the outcomes of this research and their interpretation
Collaborator Contribution The consortium provided the dataset (from GlaxoSmithKline) and other collaborators including from the MRC Biostatistics Unit. This has allowed me to broaden my skillset.
Impact The consortium (of which I am a listed member) has begun generating multiple publications. The work I am most heavily involved in has been presented at the Society for Biological Psychiatry in Atlanta and was published in the journal "Biological Psychiatry". The project is multi-disciplinary and involves physicists and statisticians as well as biologists and psychiatrists. It involves both academia and industry (Johnson & Johnson).
Start Year 2015
 
Title Figshare repo for PNAS paper on myelination 
Description It is a Figshare repository with the data and code required to replicate the results of our recent PNAS paper. Importantly, the code can easily be adapted to apply these new analysis methods to a large variety of datasets. 
Type Of Technology Software 
Year Produced 2016 
Open Source License? Yes  
Impact Over a dozen people have been in touch regarding the use of the code for their own projects. Many more are probably using the code without my knowledge. The figshare page has had 591 views int he last 4 months. 
URL https://figshare.com/projects/NSPN_Adolescent_consolidation_of_human_connectome_hubs/4710
 
Title Github - code for control theory applied to networks 
Description This software implements the control theoretic calculation in our recent Nature paper: https://www.ncbi.nlm.nih.gov/pubmed/29045391. We expect to release this code in the next few weeks 
Type Of Technology Software 
Year Produced 2018 
Open Source License? Yes  
Impact It will be released in the next few weeks 
 
Description A string of interviews and articles following a press release about our PNAS paper on brain changes in adolescence 
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 Media (as a channel to the public)
Results and Impact Our recent PNAS paper on brain changes in adolescence and possible links to schizophrenia attracted wide media attention. I was featured on the 10 o'clock BBC news, on Radio 4's All in the Mind programme and on various other national news outlets. It was also discussed in a number of online articles in the UK and USA.
Year(s) Of Engagement Activity 2016,2017
URL http://www.bbc.co.uk/programmes/b0832fq5
 
Description Allen Institute Data Story 
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 The Allen Institute for Brain Sciences produced two short videos focusing on my research. These were narrated by my co-author who happened to be visiting Seattle at the time of filming. The videos have been viewed over 15000 times int he last 4 months
Year(s) Of Engagement Activity 2016
URL https://www.youtube.com/watch?v=JHFI2QP2Dnc
 
Description CSaP Policy Fellowship meeting - Deputy Director, Data, Horizon Scanning and Project Development, Government Office for Science 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact We had a stimulating discussion during which we both took notes and exchanged book recommendations. We then connected on LinkedIn so that we can get back in touch with each other if/when relevant.

No immediate tangible impact.
Year(s) Of Engagement Activity 2014
URL http://www.csap.cam.ac.uk/network/andrew-greenway/
 
Description Cambridge Networks Network 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I am the founder and organizer of the Cambridge Networks Network (CNN). Our original aim was to bring together faculty, postdocs and research students from a wide range of departments at the University of Cambridge who share an interest in Complex Networks. This includes a large audience who don't normally interact, from over 40 departments and institutes as diverse as Anthropology, Genetics, History, Biochemistry, Music, Politics, Engineering, Mathematics etc. Since its inception in 2011, CNN has grown to over 450 members from around the world (receiving our newsletter) and over 10,000 visitors to our website. Our members are mostly academics but also include audiences from Industry and Business.
Year(s) Of Engagement Activity 2014,2015,2016,2017,2018,2019,2020
URL http://www.cnn.group.cam.ac.uk/
 
Description Engagement with CSaP 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact I have participated in a number of focussed workshops, one-to-one meetings, seminars and other events organized by the Centre for Science and Policy. The aim is to explore the role of networks and network science in policy, to convey the broader relevance of scientific advances in the field and to explore further partnership opportunities.
Year(s) Of Engagement Activity 2014,2015,2016,2017
URL http://www.csap.cam.ac.uk/
 
Description Hosting visitors, supporters and charitable donors 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Supporters
Results and Impact I have repeatedly participated in small groups hosting visitors, supporters and potential charitable donors. I am currently helping with the writing of a popular science book by one potential donor.
Year(s) Of Engagement Activity 2015,2016,2017,2018
 
Description Invitation to present work at the Cambridge Neuroscience Symposium 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Postgraduate students
Results and Impact About 500 researchers and students attended the talk, which sparked questions and discussion afterwards. I was approached by two students wishing to embark on graduate studies in this area.
Year(s) Of Engagement Activity 2017
 
Description Invitation to present work at the Forschunszentrum (Juelich, Germany) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact The aim was to spark potential collaboration between the Forschungzentrum in Juelich, Germany and the University of Cambridge, including access to a valuable dataset based at the Forschungzentrum. Two new collaborations were started and access to the data was verbally agreed.
Year(s) Of Engagement Activity 2017
 
Description Invited Presentation a the Centre du Cerveau et de la Moelle Epiniere in Paris 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact About 50 people attended the talk, which sparked questions and discussions.

I was given a tour of the facilities and we discussed several opportunities for collaboration with my hosting group.
Year(s) Of Engagement Activity 2014
 
Description Invited presentation at the MRC Biostatistics Unit 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact About 40 people attended the talk, which sparked questions, discussions and suggested collaborations.
Year(s) Of Engagement Activity 2015
 
Description Invited presentation at the University of Limerick 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact 20 to 30 people attended the talk which sparked questions and discussions on the kinds of mathematical tools that could be applied to human neuroimaging data.

One PhD student from Limerick expressed interest in collaboration.
Year(s) Of Engagement Activity 2014
 
Description Organised conferences 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I helped organise a number of conferences in my field, including the Complex Networks 2018 conference (an international conference that was hosted in Cambridge that year) and the Network Neuroscience satellite of the Network Science conference (in Paris)
Year(s) Of Engagement Activity 2018
 
Description Organizing the annual Cambridge Networks Day 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation workshop facilitator
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact 150 scientists from disciplines ranging from genetics to anthropology, through social science and land economy gathered to exchange ideas on how they use the tools of network analysis in their respective disciplines. About 20 students gave short oral presentations alongside 7 internationally reknowned speakers.

Sparked many conversations and several new collaborations. Many participants gave us positive feedback about this yearly event.
Year(s) Of Engagement Activity 2012,2013,2014,2015,2017,2019
URL http://www.cnn.group.cam.ac.uk/cambridge-networks-day
 
Description Participated in Workshop on New technologies and better evidence for EU policy making: Brussels, 15 & 16 May 2014 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact The workshop was attended by a large number of policy makers from the UK government and EU commission as well as a large number of scientists. We discussed specific ideas and recommendations for an improved, data-driven use of evidence as a foundation for future EU policy development.

We discussed:
-the changing nature of what constitutes evidence for policy making;
-the processes and tools through which such evidence can be acquired;
-how such evidence can be used for policy-making in the EU.

Each round table (mine was lead by Anne Glover - Chief Scientific Adviser to the President of the European Commission) produced a summary of our discussions and recommendations. In addition, the event provided useful exchange of ideas and perspectives between scientist and policy makers.
Year(s) Of Engagement Activity 2014
URL http://www.csap.cam.ac.uk/events/new-technologies-better-evidence-eu-policy-making/
 
Description Talks for careers in academia 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact I gave a number of presentations in Cambridge and at Queen Mary University fo London intended to inspire younger researchers to pursue a career in academia and/or to give advice related to:
- career choice
- fellowship applications
- work-life balance
- being a woman and a mother in academia
Year(s) Of Engagement Activity 2018,2019
 
Description Teaching at Cambridge Summer School 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Undergraduate students
Results and Impact About 20 people followed this course. 7 of them chose to write an optional essay at the end of the course.

I received positive feedback from several students. One in particular reported that she discovered thanks to this course that she wanted to be a researcher and focus on network science in the future.
Year(s) Of Engagement Activity 2014
URL http://www.ice.cam.ac.uk/courses/summer-schools