Disconnection after traumatic brain injury: impairments of cognitive control and their impact on learning.

Lead Research Organisation: Imperial College London
Department Name: Dept of Medicine

Abstract

Head injuries often lead to profound disability. Although patients may recover physically, many find it difficult to return to work or continue their social life. The reasons for this are often difficult to determine using conventional tests. A common and disabling problem is that patients have reduced awareness of their own physical and mental limitations. This lack of self-awareness makes attempts at rehabilitation difficult. How head injuries cause this problem is unknown. Awareness is thought to depend on long distance communication between distinct brain regions. This occurs through connections deep within the brain that are organized into bundles or ‘tracts‘, rather like electrical cabling in a switchboard. These connections are vulnerable in head injury, and new advances in brain imaging have provided tools to study damage in detail. I will investigate whether damage to the connections between brain regions involved in controlling actions produce impairments of self-awareness. As reduced self-awareness leads to difficulty in learning, I predict damage to this control network will be a critical factor in determining patient recovery. This work is important as it will identify a target within the brain for the development of new treatment strategies, which will form the next stage of my research.

Technical Summary

The World Health Organisation has identified traumatic brain injury (TBI) as a major public health problem with a huge unmet need for effective long-term treatment. Despite this, there have been few attempts to use emerging insights from cognitive neuroscience to guide new approaches to effective rehabilitation. Frontal lobe and executive function are particularly vulnerable to the effects of head injury, and as a result patients often develop a lack of self-awareness, which limits attempts at rehabilitation and leads to more severe functional disability. Such impairment is likely to involve dysfunction in brain regions - including thalamic and frontal areas - critical for cognitive control, a network which I have studied previously. My hypothesis is that critical executive impairments after TBI result from reduced connectivity between relatively intact brain regions involved in cognitive control. I will use behavioural methods and multimodal imaging techniques to provide structural, functional, and resting state measures of connectivity. 50 TBI patients with frontal impairments and 25 normal control subjects will be recruited. Patients will be divided into those with high and low self-awareness. I propose an initial cross-sectional study with longitudinal follow up at one year. I will use diffusion tensor imaging (DTI) to investigate structural connectivity. Functional MRI (fMRI) and magnetoencephalography (MEG) will provide complementary functional measures of brain activity at different spatiotemporal scales. I will test whether integrity within specific white matter tracts connecting critical nodes in the cognitive control network correlate with cognitive impairment. A spatial variant of the Stroop task - the Simon task - will be used to probe cognitive control. I will study a subcomponent of self-awareness - the ability of patients to monitor and react to their own errors. I predict that low levels of self-awareness will result from reduced functional connectivity in the cognitive control network, secondary to diffuse axonal injury. I will also investigate whether an ‘executive‘ network identified in resting state data could be used to quantify network function after TBI, as this would have great potential as a clinical tool. Cognitive control is critical for learning and I will test whether changes in brain connectivity after TBI predict the ability of patients to learn and whether this in turn predicts functional outcome. This work will demonstrate why cognitive control breaks down after TBI and will define a target for future therapeutic interventions.

Publications

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Bonnelle V (2012) Salience network integrity predicts default mode network function after traumatic brain injury. in Proceedings of the National Academy of Sciences of the United States of America

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Bonnelle V (2011) Default mode network connectivity predicts sustained attention deficits after traumatic brain injury. in The Journal of neuroscience : the official journal of the Society for Neuroscience

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Braga RM (2013) Echoes of the brain within default mode, association, and heteromodal cortices. in The Journal of neuroscience : the official journal of the Society for Neuroscience

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Carhart-Harris RL (2012) Implications for psychedelic-assisted psychotherapy: functional magnetic resonance imaging study with psilocybin. in The British journal of psychiatry : the journal of mental science

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Deligianni F (2013) A Framework for Inter-Subject Prediction of Functional Connectivity From Structural Networks. in IEEE transactions on medical imaging

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Deligianni F (2011) A probabilistic framework to infer brain functional connectivity from anatomical connections. in Information processing in medical imaging : proceedings of the ... conference

 
Description Consultation on the White Paper; 'Equity and excellence: Liberating the NHS'.
Geographic Reach National 
Policy Influence Type Participation in a national consultation
Impact In my capacity as a board member of The Acquired Brain injury for London I contributed to a response to the government white paper; 'Equity and excellence: Liberating the NHS'. We are currently awaiting the outcome of this consultation process.
 
Description Imperial College Representative for Academic Clinical Fellows Training.
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
Impact I am involved in the training of Academic Clinical Fellows (ACFs) at Imperial College, and am the Imperial College representative for ACF training.
 
Description Lecture at Headfirst conference
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
Impact Education of healthcare practitioners and public in issues surrounding brain injury.
 
Description Track record in training researchers
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
Impact I am a co-organiser of the Cognitive Neuroscience module of the Integrative Neuroscience MSc Course at Imperial College London. I have taught extensively on BSc and MSc courses at Imperial College and The University of Roehampton. I am currently supervising or co-supervising five PhD students, two of whom are due to submit in the near future. In my group I also have a trainee neurosurgeon who is registered for an MD as well as an academic training fellow, who has been awarded a prestigious Wellcome/GSK Clinical Training Fellowship and will start in 2012. I have previously supervised three MSc, one MRes, and four BSc projects.
 
Description Training of specialist registrars in neurology.
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
Impact The education of specialist registrars in neurology in the South East region in the assessment of frontal lobe function.
 
Description Training of specialist registrars in neurology.
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
Impact Training of neurology specialist registrars in the South East in the neurological aspects of managing traumatic brain injury.
 
Description Investigator Initiated Research Funding
Amount £175,000 (GBP)
Organisation Pfizer Ltd 
Sector Private
Country United Kingdom
Start 04/2010 
End 04/2013
 
Description Royal Army Medical Corps - The Blast Injury Outcome Study of Armed Forces Personnel (BIOSAP).
Amount £48,000 (GBP)
Organisation Ministry of Defence (MOD) 
Sector Public
Country United Kingdom
Start 01/2010 
 
Description The Imperial College Charitable Trustee's Project Grant/The Imperial College Charitable Trustee's
Amount £25,000 (GBP)
Organisation Imperial College Healthcare NHS Trust 
Department Imperial College Healthcare NHS Charity
Sector Charity/Non Profit
Country United Kingdom
Start 03/2010 
End 03/2013
 
Description The Imperial College Charitable Trustee's Research Fellowship
Amount £50,000 (GBP)
Organisation Imperial College London 
Department Imperial College Trust
Sector Charity/Non Profit
Country United Kingdom
Start 09/2011 
End 02/2013
 
Description The Imperial College Charitable Trustee's Research Fellowship.
Amount £50,000 (GBP)
Organisation Imperial College London 
Department Imperial College Trust
Sector Charity/Non Profit
Country United Kingdom
Start 03/2011 
End 03/2012
 
Title Award for high performance cluster computing for the Computational, Cognitive and Clinical Neuroimaging Laboratory, Imperial College London. 
Description A high performance computing cluster was established with a grant I received from The Imperial College Charitable Trustee's. 
Type Of Material Improvements to research infrastructure 
Year Produced 2010 
Provided To Others? Yes  
Impact The cluster provides core computing for the newly established Computational, Cognitive and Clinical Neuroimaging Laboratory (C3NL), at Imperial College London. It is used by three other research groups within the C3NL. 
 
Title Development of novel software for cognitive assessment. 
Description We have developed a number of novel tools for cognitive assessment. These are programmed in matlab/psychophysics toolbox and are available to be used by other research groups. 
Type Of Material Improvements to research infrastructure 
Year Produced 2010 
Provided To Others? Yes  
Impact A novel version of the Stop Signal Task was used in our PNAS publication ID 20220100. The paradigm has been shared with other researchers, and is currently being used by the Centre for Addication Medicine at Massachusetts General Hospital. We have been awarded an i4i NIHR grant to commercialise our internet-based assessment tool for cognitive impairment after TBI. 
 
Title Traumatic brain injury research database. 
Description My group at Imperial have collected clinical, neuroimaging, neuropsychological, olfactory and genetic data on a group of appoximately seventy five patients with traumatic brain injury. Normative data for this group has also been collected. 
Type Of Material Biological samples 
Year Produced 2012 
Provided To Others? Yes  
Impact The database is central to our research programme. It has resulted in multiple primary research publications. Three further papers are in submission, and a number of others are in preparation. 
 
Title Traumatic brain injury research database 
Description We have collected a detailed database of neuroimaging, neuropsychological, clinical and endocrinological data about patients who have previously suffered a traumatic brain injury. There is also accompanying control data. 
Type Of Material Database/Collection of data 
Year Produced 2011 
Provided To Others? Yes  
Impact This database has resulted in 24 high impact publications to date. 
 
Description Dopaminergic imaging following traumatic brain injury 
Organisation Imanova
Country United Kingdom 
Sector Private 
PI Contribution We are running a study of dopamine deficiency following TBI, using PHNO PET.
Collaborator Contribution Imanova are providing the PET scanning.
Impact none
Start Year 2012
 
Description Growth hormone and traumatic brain injury: a neuroimaging study. 
Organisation Medical Research Council (MRC)
Department MRC Clinical Sciences Centre (CSC)
Country United Kingdom 
Sector Academic/University 
PI Contribution We are investigating the impact of endocrine disturbance following traumatic brain injury using imaging methods such as diffusion tensor imaging that allow quantification of brain damage and repair following brain injury.
Collaborator Contribution Investigation of the endocrine status of patients following traumatic brain injury. This has lead to the award of £175000 to strengthen my research programme on brain injury.
Impact £175000 investigator lead award from Pfizer Ltd. We have completed a research audit of endocrine abnormalities observed after traumatic brain injury. This is due to be presented at the Sixth Hammersmith Multidisciplinary Endocrine Symposium.
Start Year 2009
 
Description Inflammatory imaging of traumatic brain injury 
Organisation General Electric
Country United States 
Sector Private 
PI Contribution We are running a study of inflammation after TBI using GE180, a PET TSPO ligand.
Collaborator Contribution GE will provide the GE180 ligand free of charge
Impact none
Start Year 2012
 
Description Inflammatory imaging of traumatic brain injury 
Organisation Imanova
Country United Kingdom 
Sector Private 
PI Contribution We are running a study of inflammation after TBI using TSPO PET ligands provided by Imanova.
Collaborator Contribution Imanova are providing the PET scanning expertise.
Impact none
Start Year 2012
 
Description Methodological investigation of brain connectivity after traumatic brain injury. 
Organisation Imperial College London
Department Department of Computing
Country United Kingdom 
Sector Academic/University 
PI Contribution My research team is collaborating with the Imperial College Biomedical Research Analysis Group. Together we are investigating the optimal ways to approach the imaging analysis of data from brain injured patients.
Collaborator Contribution Methodological input into imaging analysis techniques for traumatic brain injury research.
Impact This collaboration has resulted in the publication 21761665.
Start Year 2010
 
Description The investigation of brain network changes following aphasic stroke. 
Organisation Medical Research Council (MRC)
Department MRC Clinical Sciences Centre (CSC)
Country United Kingdom 
Sector Academic/University 
PI Contribution We have been analysing previously acquired data to investigate brain network changes after focal brain injury resulting from Stroke. This links to our work on traumatic brain injury as similar cognitive mechanisms are involved in the recovery from different types of brain injury.
Collaborator Contribution I am collaborating with the Stroke recovery group (now named The Cognitive Neuroimaging Group) to investigate changes in brain network function after brain injury that results in language impairment. This group provides expertise in methodological and theoretical aspects of the research.
Impact This collaboration has resulted in the publications ID 19777554 and 20687116.
Start Year 2008
 
Description The investigation of cognitive impairment after traumatic brain injury. 
Organisation Goldsmiths, University of London
Department Department of Psychology
Country United Kingdom 
Sector Academic/University 
PI Contribution We have been working with the Department of Psychology at Goldsmiths college to develop accurate ways of assessing cognitive impairments after traumatic brain injury.
Collaborator Contribution We have had extensive input into the appropriate way to assess cognitive impairment following traumatic brain injury.
Impact The collaboration has contributed to the following publications: 21940437, 21710619, 21841202, 21193486, 22393019
Start Year 2008
 
Description Oral presentations to Headway groups in London 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Participants in your research and patient groups
Results and Impact I have visited a number of Headway groups to give a talk about our research and take part in a general discussion about brain injury. Headway is the National Charity for Brain Injury and the purpose of the talks were to 1) disseminate information about the research 2) promote greater understanding of brain injury among patients and their carers and 3) obtain feedback about the research programme.

These meeting have in part lead to an application to Hammersmith and Fulham PCT to expand the clinical Head Injury service in West London. This proposal includes an application to fund an expansion of the Headway service provision in the area to allow a day case centre to be set up for patients with brain injury.
Year(s) Of Engagement Activity 2009,2010
 
Description Participation in Imperial Traumatic brain injury patient and carer day. 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact In October 2017, this research team took part for the very first time in the patient and public engagement event "Meet the Scientists" hosted annually by Imperial College London. Members of the public learned about our research and were able to ask questions to the researchers and Clinical Psychologist. We had young people and their families attend this event for the first time which was really positive.
Year(s) Of Engagement Activity 2017
 
Description Presentation at the Headway family information day 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact I gave an oral presentation at the annual Headway carers conference. This day session was aimed at promoting understanding of head injury in patients carers. I gave a talk outlining the neurological impact of traumatic brain injury, and lead a discussion on the topic.

This session in part contributed planning for the PCT application described earlier in this section.
Year(s) Of Engagement Activity 2009
 
Description Presentation to 'Recent advances in brain injury rehabilitation', The Homerton Hospital, London. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Health professionals
Results and Impact I presented work to around 150 health professionals, and discussed the optimum way to manage traumatic brain injury.

I had positive feedback from the course organisers about the educational value of my talk.
Year(s) Of Engagement Activity 2008,2011
 
Description The Aquired Brain Injury for London Forum. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Health professionals
Results and Impact Around 100 health professionals attended a talk that was part of the Acquired Brain Injury for London's educational meeting. This resulted in extensive discussion of the role advanced neuroimaging has to play in the investigation of traumatic brain injury.

I was invited to join the executive board of the Acquired Brain Injury for London, and I subsequently took up the offer.
Year(s) Of Engagement Activity 2010,2011