The Human Brain as a Complex System: Investigating the Relationship between Structural and Functional Networks in the Thalamocortical System

Lead Research Organisation: University of Birmingham
Department Name: School of Psychology

Abstract

The majority of brain functions are performed not be single regions but by the combined, coordinated activity of networks distributed throughout the brain. Several neurological and psychiatric disorders may be caused by a breakdown of the ability of these regions to communicate effectively. While several different methods have been developed to understand how the component regions, or nodes, of a network interact, there is no comprehensive framework for combining the information from different techniques to give an overall picture of network function. Without such a framework, advances in neuroimaging techniques which allow the characterisation of anatomical and functional connections cannot be fully exploited. The purpose of this project is to develop such a framework, making use of intrinsic brain activity which can define well characterised model networks, thereby providing a natural validation of the results.
The nodes of brain networks can be identified using three different definitions of connectivity between regions. Structural connectivity (SC) describes the anatomical connections between regions, functional connectivity (FC) identifies whether the activity of two regions increases and decreases coherently, while effective connectivity (EC) attempts to describe the brain not in terms of EEG or MRI signals, but the underlying neuronal populations which produce them. Each of these measures can be estimated using multiple different data acquisition and analysis techniques. For example, SC can be determined from diffusion tensor imaging (DTI) MRI scans, which are sensitive to the diffusion of water in white matter tracts, or from measurements of cortical thickness. Similarly, FC can be calculated from electroencephalography (EEG) or functional MRI (fMRI) measurements. Understanding how these different measures of connectivity are related, and how measurements of human brain function and structure can be combined to produce a unified picture, is not straightforward. Few studies have acquired the high quality data with multiple techniques that is required for such an undertaking. A further complication is that of defining model networks which are of sufficient complexity to provide a realistic test of any methodological developments, while being sufficiently well-characterised to allow developments to be validated. We will overcome this issue in a novel way by building on decades of invasive neurophysiological experiments which have characterised the networks responsible for the generation of thalamocortical oscillations (TCO), electrophysiological events that are generated by interactions between cortical and thalamic network nodes. TCO can be hallmarks of normal brain function (alpha rhythm, sleep spindles and K-complexes), or pathophysiology, of which the most obvious are generalised spike-wave discharges, characteristic of generalised epilepsy.
This project will use the networks defined by TCO to investigate the relationships between different measures of brain connectivity, developing and optimising new methods to combine and fully exploit all of the information that can be extracted from non-invasive brain imaging data. Modelling and analysis of these networks will be based on graph theoretical approaches. By using these restricted and well-characterised model networks, we will be able to validate our work against previous neurophysiological data, and provide general tools for the neuroimaging community. In addition, we will shed light on the generation of normal and pathological brain activity and how this arises from network connectivity patterns.

Planned Impact

In the short term the primary beneficiaries of this research will be academic, since the project will lead to better tools for using neuroimaging methods to characterise the brain. In addition, it will feed back to the field of communications and computer networks engineering, to provide new information regarding the way in which the human brain solves issues of structural and functional connectivity. Such information can inspire the creation of new engineering approaches on routing and network connectivity in distributed networking solutions. However, once these tools have been developed, the scope of their potential application will be considerable and relate to any number of questions in sensory, cognitive or clinical neuroscience. To take an example from an area with which the applicants are familiar, focal epilepsy has traditionally been considered as resulting from a discrete, localised, generally cortical abnormality. However, recent work has suggested that even a focal epilepsy is a result of network dysfunction, and that the brain regions responsible for an ostensibly cortical focal epilepsy can in fact be much more widely distributed, both cortically and subcortically, than previously believed. Such hypotheses are supported by the observation that even in patients who have undergone successful epilepsy surgery there can be a recurrence of seizures after an absence of several years, a phenomenon attributed to continued epileptic activity in the remaining network nodes. Other brain disorders such as those of sleep, autism and schizophrenia have also been proposed to originate from disrupted networks. What is needed to confirm these hypotheses about brain function are the methods which can characterise distributed networks at the whole brain level, synthesising the information available from structural and functional imaging into a coherent whole. These are the goals of the current project. As such, future beneficiaries of this project will be patients with brain disorders, and the clinicians treating them.

Publications

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Goldstone A (2016) Gender Specific Re-organization of Resting-State Networks in Older Age. in Frontiers in aging neuroscience

 
Description This award has lead to a number of outputs that have helped to shed light on a range of issues related to brain function in wakefulness, sleep and in people with epilepsy. In our initial methodological publications, we investigated the robustness of analysis techniques from communications engineering when applied to brain imaging data, the relationship between brain structure and function, introduced and validated a technique to investigate how brain regions interact dynamically, and examined methods to identify sub-regions of a brain structure that is crucial for sleep regulation and waking information processing, the thalamus. We were able to show that by examining brain connectivity dynamically information could be extracted about brain network interactions in the descent into sleep. We expanded upon this issue and used these techniques to explicitly look at the effect of sleep on the thalamus, and how it is internally and externally connected. We were able to demonstrates the complexity and state-specific nature of functional thalamic relationships over the sleep-wake cycle, and highlight the importance of a thalamocortical focus in the study of sleep mechanisms. We have applied similar methods to the study of epilepsy, specifically examining how the thalamus is affected by sleep in people with generalised epilepsy compared to control subjects, as well as looking more widely at brain connectivity in sleep. We have applied similar techniques to examine brain function in relation to habitual sleep patterns, allowing the impact of long term sleep patterns to be investigated. We were able to demonstrate that the amount of sleep a participant had accumulated over the past two weeks was predictive of their brain connectivity, with the effects specific to the frontal regions of the brain. This is important as complex cognitive processes that require the frontal lobe are the most affected by sleep deprivation, and our observations start to provide a mechanistic explanation of this behavioural observation. We have also demonstrated similar impacts of sleep timing, comparing people who have a preference for early vs late sleep. By characterising these differences in brain function during wakefulness between early and late sleepers we have a way of investigating the biological underpinnings of differences in behaviour, particularly the increased risk of mental health problems in late sleepers. In a review article we outlined theoretical and practical issues related to the use of human brain imaging data to understand alterations to consciousness that arise as a result of the descent into sleep, and epileptic seizures. This project has allowed us to develop strong collaborations with the University of Nottingham, which lead to an EPSRC application that will develop improved techniques for investigating the thalamus. It has also generated a collaboration with UNICAMP in Brazil, working on the use of analytic techniques to understand the brain changes that occur in generalised epilepsy. Both of these collaborations have resulted in successful internal funding applications.
Exploitation Route Results and the conceptual framework have been presented at a number of conferences and workshops attended by researchers and clinicians, as well as the workshop that we organised. A particularly important aspect is the potential for applying the techniques we are working on in clinical practice, and to facilitate this we are highlighting our work to clinical colleagues at every opportunity. The workshop we organised had a combined focus on methodological issues and applications, with a range of speakers who talked about diverse topics ranging from network models to epilepsy and schizophrenia. It was well attended, feedback was positive and there was a good dialogue between basic scientists and clinicians. One aspect that became clear as we developed our work was the need for better methods to characterise the thalamus, a crucial brain structure in health and a wide variety of brain disorders. While we have published our approach based on patterns of functional connectivity, and applied it the investigation of sleep and epilepsy, more work is needed. This has lead to an expansion of our collaborations with the University of Nottingham and UNICAMP, and we are working on an application to develop new tools for segmenting the thalamus, working closely with neurosurgeons at the Queen Elizabeth Hospital Birmingham and Queens Medical Centre Nottingham where deep brain stimulation is undertaken. These interactions and the findings of the current project allow us to move forward in developing better clinical tools and applying our approaches clinically.
Sectors Digital/Communication/Information Technologies (including Software),Healthcare

 
Description Our publications and conference presentations have been well received, as have public engagement events that we have contributed to. We have presented to mixed clinical and engineering audiences, in addition to those focussed on brain imaging, meaning that our approach can gain visibility in the most relevant areas for application. We have participated in public lectures, organised events as part of Brain Awareness Week and the British Science Festival, a TEDx session organised at the Univerity of Birmingham, the Flatpack Film Festival, and an event at the Library of Birmingham. In all of these cases we aimed to describe the advantages and disadvantages of brain imaging for understanding sleep and its effects on the brain to a general audience, building specifcally on the work that was undertaken in this project.
First Year Of Impact 2014
Sector Healthcare
Impact Types Cultural,Societal

 
Description Birmingham-Nottingham Strategic Collaboration Fund
Amount £40,000 (GBP)
Organisation São Paulo Research Foundation (FAPESP) 
Sector Public
Country Brazil
Start 05/2013 
End 05/2015
 
Description Child Development Fund
Amount £56,000 (GBP)
Organisation The Waterloo Foundation 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2018 
End 09/2021
 
Description FAPESP-UoN -UoB Pump-Priming Fund
Amount £60,000 (GBP)
Funding ID FAPESP #: 2012/50894-5 
Organisation São Paulo Research Foundation (FAPESP) 
Sector Public
Country Brazil
Start 09/2013 
End 09/2015
 
Description Collaboration with Professor Fernando Cendes 
Organisation State University of Campinas
Country Brazil 
Sector Academic/University 
PI Contribution Data acquisition and analysis expertise
Collaborator Contribution Access to data, data analysis and clinical expertise
Impact This is a multidisciplinary collaboration with epileptologists lead by Professor Cendes at UNICAMP, and incorporating researchers from the Sir Peter Mansfield Magnetic Resonance Centre at the University of Nottingham. It has lead to a collaborative award from the Universities of Birmingham and Nottingham and FAPESP.
Start Year 2014
 
Description Collaboration with Sir Peter Mansfield Centre 
Organisation University of Nottingham
Country United Kingdom 
Sector Academic/University 
PI Contribution Research application, data analysis expertise
Collaborator Contribution MR physics and MEG expertise, data analysis and acquisition
Impact Award from the Birmingham-Nottingham Strategic Collaboration Fund. A multidisciplinary collaboration between physicists and neurosientists.
Start Year 2013
 
Description Library of Birmingham 
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 We contributed to an outreach event at the Library of Birmingham entitled 'Nice kids can spit', which was designed to engage the public in discussion of various topics related to children's learning. I specifically focussed on the importance of sleep for optimal brain function, building on the work undertaken in this grant.
Year(s) Of Engagement Activity 2016
 
Description Poster Presentation at Sleep 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation poster presentation
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Four posters were presented at Sleep 2014 by Rebecca Wilson (PhD student), Sakh Khalsa (PhD student), David Rollings (PhD student) and Aimee Goldstone (PhD student) on work stimulated by this award.

Increased visibility of research
Year(s) Of Engagement Activity 2014
 
Description Poster presentation (x2) at Human Brain Mapping 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation poster presentation
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Two posters were presented at Human Brain Mapping 2013 in Seattle by Joanne Hale (Postdoctoral fellow) and Rebecca Wilson (PhD student).

Increased visibility of research
Year(s) Of Engagement Activity 2013
 
Description Poster presentation (x2) at first International Conference on Basic and Clinical multimodal Imaging (BaCI) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation poster presentation
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Two posters were presented by Joanne Hale and Rebecca Wilson.

Increased visibility of research
Year(s) Of Engagement Activity 2013
 
Description Poster presentation at Human Brain Mapping 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation poster presentation
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Two posters were presented at Human Brain Mapping 2014 in Hamburg by Joanne Hale (Postdoctoral fellow) and Rebecca Wilson (PhD student).

Increased visibility of research
Year(s) Of Engagement Activity 2014
 
Description Poster presentation at Human Brain Mapping 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Poster accepted for presentation at the OHBM meeting in Geneva, June 2016, entitled 'Thalamic Functional Connectivity During Light Sleep in Idiopathic Generalised Epilepsy'
Year(s) Of Engagement Activity 2016
 
Description Presentation at Biodynamics 2013 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation keynote/invited speaker
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Oral presentation at Biodynamics 2013, a workshop linking computational modellers, basic and clinical scientists, and clinicians.

Increased visibility of research
Year(s) Of Engagement Activity 2013
 
Description Presentation at TEDx session 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact University of Birmingham organised a TEDx session for the general public at which I gave a talk on the importance of sleep. This lead to considerable discussion following the session and by email.
Year(s) Of Engagement Activity 2015
URL https://www.youtube.com/watch?v=YTjtRivj6Qs
 
Description Presentation at UK Epilepsy Research Network Meeting 2nd June 2013 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation keynote/invited speaker
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I gave an oral presentation of work conducted on this grant so far to a mixed audience of basic and clinical researchers and clinicians.

Increased visibility of research
Year(s) Of Engagement Activity 2013
 
Description Presentation at first International Conference on Basic and Clinical multimodal Imaging (BaCI) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation keynote/invited speaker
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Oral presentation in a symposium on EEG-fMRI at which I presented current progress on this grant to a mixed audience of basic and clinical researchers and clinicians.

Increased visibility of research
Year(s) Of Engagement Activity 2013
 
Description Presentation at first International Conference on Basic and Clinical multimodal Imaging (BaCI) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation keynote/invited speaker
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Oral presentation in a symposium on EEG-fMRI at which Dr Jo Hale (Postdoctoral fellow) presented current progress on this grant to a mixed audience of basic and clinical researchers and clinicians.

Increased visibility of research
Year(s) Of Engagement Activity 2013
 
Description Public lecture on Sleep, University of Birmingham Open Day 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Prospective students and their families attend open days at which I talk about sleep, which leads to considerable interest with questions and discussion
Year(s) Of Engagement Activity 2017,2018
 
Description Talk at the British Science Festival 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Around 100 members of the public attended an open lecture on Sleep as part of a session we organised on 'How does the brain cope with modern life?', which lead to a discussion session and questions at the end.

A lively discussion on the impact of society on the brain.
Year(s) Of Engagement Activity 2014