Cerebral Energy Metabolism in Injured and Uninjured Brain

Lead Research Organisation: University of Cambridge
Department Name: Neurosurgery

Abstract

Head Injury is the largest single cause of death in those aged under 45 years in the developed world. After the initial trauma, a number of processes can cause further damage to the brain. One of these factors is the inability of nerve cells (neurones) to make enough energy. This study investigates how neurones use different fuels after head injury, and how this differs from normal brain and other tissues such as muscle. By using a technique called microdialysis we can deliver different brain fuels (glucose, pyruvate, succinate) and track how the brain uses them by tagging each fuel with a form of heavy carbon (C13). We can also use a specialised form of MRI scan called phosphorus MR spectrocopy to measure how much energy is stored in the cells as a molecule called ATP. A better understanding of how the brain makes energy when it is injured can allow us to develop treatments for a variety of conditions including head injury.

Technical Summary

This study aims to investigate derangements in cerebral energy metabolism following traumatic brain injury. While the concept of energy failure is well recognised as a mechanism of neuronal injury and ultimately poor clinical outcome, the specific abnormalities compared with normal metabolism remain unclear. We propose delivering specific 13C labelled substrates to the human brain following trauma using microdialysis, to sequentially interrogate the glycolytic pathway (glucose supplementation), the tricarboxcylic acid cycle (pyruvate supplementation) and oxidative phosphorylation (succinate supplementation). We will monitor the metabolic consequences using a combination of (1) microdialysis parameters (including the lactate/pyruvate ratio to determine the redox state of the cell), (2) high-resolution Nuclear Magnetic Resonance spectroscopy of the microdialysates to analyse the downstream metabolites and determine the positions of 13C-labelling within these molecules (to ascertain which biochemical pathways are functioning), and (3) in vivo 31P Magnetic Resonance Spectroscopy to assess energy status (phosphocreatine/inorganic phosphate ratio and phosphocreatine/adenosine triphosphate ratio) at a cellular level. In order to differentiate the consequences of injury from normal metabolism, we will carry out parallel microdialysis studies in uninjured human brain and muscle. Together, these studies will increase our understanding of metabolic impairment in the injured brain and determine whether supplementation of specific substrates can improve energy generation as a potential therapeutic avenue. This may ultimately lead to novel strategies to improve clinical outcome.

Publications

10 25 50
 
Description 2014 Cambridge International Microdialysis Forum, St Catharine's College
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guidance committee
Impact Update consensus statement for the application of clinical microdialysis
 
Description Consensus conference of intracranial pressure monitoring in traumatic brain injury
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guidance committee
Impact The consensus meeting output is expected to consolidate the place of ICP monitoring in the management of brain-injured patients
URL http://link.springer.com/article/10.1007/s00701-014-2127-4
 
Description Multidisciplinary consensus conference on Multimodality Monitoring in Neurocritical Care
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guidance committee
Impact Consensus statement is expected to act as a catalyst for improving management of brain-injured patients.
URL http://link.springer.com/article/10.1007/s12028-014-0041-5
 
Description Neurosurgical Representative on the current NICE Committee revising the NICE guidelines for the early management of head injury in adults and children (due to be published published in 2013/4)
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
Impact Head injury guidelines
 
Description 2013 EU collaborative grant CENTER-TBI [Prospective longitudinal data collection and Comparative Effectiveness Research (CER) for traumatic brain injury (TBI)] Start 1st October 2013. 78 months Total Euro 29,998,903 University of Cambridge Euro 2,840,158
Amount € 29,000,000 (EUR)
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 11/2014 
End 10/2019
 
Description 2013 NIHR HTC Grant- Brain Injury. Start 1st January 2013 4 years £800,000 (co-applicant)
Amount £800,000 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 01/2014 
End 12/2018
 
Description 2014 NIHR Research Professorship. Start 1st January 2014 5 years £1,237,656
Amount £1,237,656 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 01/2014 
End 12/2018
 
Description 2016 Addenbrooke's Charitable Trust Grant for Seahorse analyser to measure energy metabolism at a cellular level £25k
Amount £25,000 (GBP)
Organisation Addenbrooke's Charitable Trust (ACT) 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2017 
 
Description 2016 NIHR EME 14/205 Mechanisms of Isolated Traumatic Brain Injury- Mechanism of action of Tranexamic Acid in isolated traumatic brain injury start February 1st 2016 for 24 months £404,850.39 (co-applicant)
Amount £404,850 (GBP)
Funding ID EME/14/205/01 
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 02/2016 
End 01/2018
 
Description 2016 NIHR i4i Development of microdialysis online sensor technology for use in critical care of acute brain trauma patients £536,627 start 1st October 2016 for 3 years (PI)
Amount £536,627 (GBP)
Funding ID II-C5-0715-20005 
Organisation National Institute for Health Research 
Department NIHR i4i Invention for Innovation (i4i) Programme
Sector Public
Country United Kingdom
Start 10/2016 
End 09/2019
 
Description 2017 ERA NET International Collaboration On Neuroinflammation in Traumatic Brain Injury (ICON-TBI) Euro 968031 (co-investigator)
Amount € 968,031 (EUR)
Organisation ERA-NET ANIHWA 
Sector Charity/Non Profit
Country European Union (EU)
Start 04/2017 
 
Description 2017 NIHR HTC Grant for Gadolinium microdialysis Multimodality Monitoring £5k start March 2017 (lead applicant and chief investigator)
Amount £5,000 (GBP)
Organisation National Institute for Health Research 
Department NIHR Brain Injury Healthcare Technology Co-operative
Sector Public
Country United Kingdom
Start 04/2017 
End 03/2019
 
Description Cambridge BRC - Clinical Neurosciences Component (PI Head Injury Research)
Amount £1,260,000 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 01/2011 
End 12/2015
 
Description Evidence based planning solution for TBI
Amount € 4,200,000 (EUR)
Funding ID 270259 
Organisation European Commission 
Department Seventh Framework Programme (FP7)
Sector Public
Country European Union (EU)
Start 02/2011 
End 12/2014
 
Description MRC Collaborative Grant for Acute Brain Injury
Amount £1,300,000 (GBP)
Funding ID G0600986 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 02/2007 
End 07/2012
 
Description MRC Confidence in Concepts
Amount £48,375 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2015 
End 09/2016
 
Description NIHR BRC
Amount £1,892,000 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 04/2017 
 
Description NIHR Brain Injury MedTech Co-operative
Amount £1,250,000 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 01/2018 
End 12/2022
 
Description NIHR Global Health
Amount £1,800,000 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 08/2017 
End 07/2020
 
Description NIHR HTC
Amount £5,200 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 08/2017 
 
Description NIHR Health Technology Assessment Grant- Risk adjustment in Neurocritical care (RAIN)
Amount £617,000 (GBP)
Funding ID HTA/07/37/29 
Organisation National Institute for Health Research 
Department Health Technology Assessment Programme (HTA)
Sector Public
Country United Kingdom
Start 01/2009 
End 01/2012
 
Description NIHR RCF
Amount £11,000 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 04/2017 
End 03/2018
 
Description Welcome PhD Fellowship
Amount £310,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2016 
End 12/2019
 
Title Application of PCA to monitoring technology 
Description Cytokine data analysis. Defining the downstream concentration of cytokines following traumatic brain injury 
Type Of Material Model of mechanisms or symptoms - human 
Year Produced 2016 
Provided To Others? Yes  
Impact Improvements in results analysis. 
 
Title Neurosurgical Research Laboratories 
Description Brain tumour, brain imaging and cell culture lab plus neurochemistry lab 
Type Of Material Improvements to research infrastructure 
Year Produced 2016 
Provided To Others? Yes  
Impact Multidisciplinary research output 
 
Title Principle Component Analysis 
Description Application of PCA to micro dialysis 
Type Of Material Physiological assessment or outcome measure 
Provided To Others? No  
Impact Improved understanding of the neuro-inflammatory response to head injury 
 
Title Contribution to TARN 
Description Outcome from traumatic brain injury in the UK. 
Type Of Material Database/Collection of data 
Year Produced 2016 
Provided To Others? Yes  
Impact Availability of head injury outcome data in the open access literature. 
 
Description 13C-labelled microdialysis 
Organisation University of Calgary
Department Section of Neurosurgery
Country Canada 
Sector Academic/University 
PI Contribution 13C labelling studies of brain metabolism using microdialysis in traumatic brain injury patients.
Collaborator Contribution Our collaborator has visited us in Cambridge on a Visiting Fellowship (awarded by the Canadian Institute of Health Research). The collaboration is ongoing and our collaborator is a Co-investigator on a current MRC Research Grant (PI: Peter Hutchinson, G1002277 ID 98489).
Impact Publication: Gallagher CN, Carpenter KL, Grice P, Howe DJ, Mason A, Timofeev I, Menon DK, Kirkpatrick PJ, Pickard JD, Sutherland GR, Hutchinson PJ. The human brain utilizes lactate via the tricarboxylic acid cycle: a 13C-labelled microdialysis and high-resolution nuclear magnetic resonance study. Brain. 2009 Oct;132(Pt 10):2839-2849. PubMed PMID: 19700417.
Start Year 2006
 
Description British Neurosurgical Trainee Research Collaborative 
Organisation Society of British Neurological Surgeons
Country United Kingdom 
Sector Learned Society 
PI Contribution AK and PH led the efforts to establish the British Neurosurgical Trainee Research Collaborative. The BNTRC is a research network for trainees which will aim to develop, run and support neurosurgical trials.
Collaborator Contribution The SBNS has very generously supported this initiative since its inception.
Impact PMID: 22583319
Start Year 2012
 
Description British Neurotrauma Group 
Organisation Society of British Neurological Surgeons
Country United Kingdom 
Sector Learned Society 
PI Contribution Initiative to set up a special-interest group within the Society of British Neurological Surgeons
Collaborator Contribution Increasing understanding of the issues surrounding decompressive craniectomy in head injury
Impact The first academic meeting of the group took place in 2010 (October). The meeting was attended by neurosurgeons, neurorehabilitation consultants, endocrinologists, neurologists and specialist nurses.
Start Year 2008
 
Description Engineering - finite element analysis of decompressive craniectomy 
Organisation University of Cambridge
Department Department of Engineering
Country United Kingdom 
Sector Academic/University 
PI Contribution Increasing the understanding of the clinical consequences of brain deformation after craniectomy
Collaborator Contribution Finite element analysis of decompressive craniectomy
Impact Publications
Start Year 2010
 
Description International Multicentre Randomised Trial 
Organisation European Brain Injury Consortium (EBIC)
Country European Union (EU) 
Sector Charity/Non Profit 
PI Contribution Study set-up, patient recruitment and data collection
Collaborator Contribution Patient recruitment
Impact Recruitment of 280 patients from 43 centres in 17 countries
 
Description International Multicentre Randomised Trial 
Organisation International Neurotrauma Society (INTS)
Country Hungary 
Sector Charity/Non Profit 
PI Contribution Study set-up, patient recruitment and data collection
Collaborator Contribution Patient recruitment
Impact Recruitment of 280 patients from 43 centres in 17 countries
 
Description International Multicentre Randomised Trial 
Organisation Society of British Neurological Surgeons
Country United Kingdom 
Sector Learned Society 
PI Contribution Study set-up, patient recruitment and data collection
Collaborator Contribution Patient recruitment
Impact Recruitment of 280 patients from 43 centres in 17 countries
 
Description NIHR Global Neurotrauma Research Group 
Organisation National Institute for Health Research
Department Global Health Research Unit on Global Surgery
PI Contribution We lead this NIHR Group.
Collaborator Contribution Please see website http://neurotrauma.world.
Impact Please see http://neurotrauma.world
Start Year 2017
 
Description Post traumatic pituitary function working group 
Organisation Society of British Neurological Surgeons
Country United Kingdom 
Sector Learned Society 
PI Contribution Led group.
Collaborator Contribution Production of guidance.
Impact In submission
Start Year 2015
 
Title Cranial access device 
Description MRI compatible device to transmit monitoring probes into the brain. 
IP Reference GB2330080 
Protection Patent granted
Year Protection Granted
Licensed Yes
Impact Use in clinical practice
 
Title IL-1ra 
Description IL1ra for the treatment of traumatic brain injury 
Type Therapeutic Intervention - Drug
Current Stage Of Development Refinement. Clinical
Year Development Stage Completed 2014
Development Status Under active development/distribution
Clinical Trial? Yes
UKCRN/ISCTN Identifier 0
Impact On-going 
 
Title New Chemistry Sensor 
Description Brain chemistry sensor 
Type Diagnostic Tool - Non-Imaging
Current Stage Of Development Initial development
Year Development Stage Completed 2016
Development Status Under active development/distribution
Impact On-going 
 
Title Succinate for the treatment fo traumatic brain injury 
Description Application of succinate to treat mitochondrial dysfunction following traumatic brain injury 
Type Therapeutic Intervention - Drug
Current Stage Of Development Initial development
Year Development Stage Completed 2016
Development Status Under active development/distribution
Impact Non yet. 
 
Title ICMplus 
Description ICU monitoring software. Developed by Marek Czosnyka and Peter Smielewski. 
Type Of Technology Software 
Impact Take up internationally 
 
Company Name ICMplus - Cambridge Enterprise. Led by Marek Czosnyka and Peter Smielewski. 
Description Medical software, 
Impact Improvement of monitoring and data capture in Intensive Care.
 
Description British Science Festival, 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Talk given at the British Science Festival, Newcastle, September 2013.

This activity generated interest in our studies on head-injured patients.
Year(s) Of Engagement Activity 2006,2013
 
Description Cambridge Science Festival Talk on Sports Concussion 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other audiences
Results and Impact Science Festival Talk
Year(s) Of Engagement Activity 2017
 
Description Interview and Video for BBC 
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 Our group has been using computer aided design and 3D printing in medical quality titanium to manufacture cranial plates for human use. I was approached to carry out an interview and filming in the operating theatre and with a patient. This was distributed on BBC digital (http://www.bbc.co.uk/news/av/entertainment-arts-41325582/brain-surgery-revolution), and broadcast three times on the regional BBC network (Look East) reaching an audience of approximately 2.6 million people. I was also interviewed in person on the live evening broadcast.
Year(s) Of Engagement Activity 2017
URL http://www.bbc.co.uk/news/av/entertainment-arts-41325582/brain-surgery-revolution
 
Description Media RESCUEicp results 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Dissemination of the RESCUEicp results published in the BMJ
Year(s) Of Engagement Activity 2016
 
Description Publication of patient's journey after a head injury with patient as the first author 
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 This paper which described the journey after a head injury from the patient's perspective will allow healthcare professionals to understand the challenges brain-injured patients face.

The paper has been tweeted a few times on Twitter
Year(s) Of Engagement Activity 2014
URL http://europepmc.org/abstract/MED/24737905
 
Description Science Festival Presentation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Cambridge Science Festival
Year(s) Of Engagement Activity 2015,2016,2017