Investigating the thermoregulatory role of neurovascular coupling and the anti-epileptogenic and neuroprotective effects of focal cerebral cooling
Lead Research Organisation:
University of Sheffield
Department Name: Psychology
Abstract
Acute focal epilepsy is a disease that has proved incredible difficult to treat and often results in very poor outcomes for the patients suffering from the condition. Epilepsy is a disease in which certain parts of the brain become over active this can lead to acute seizures and permanent brain damage; many of the drugs that have been developed don't work over a long time scale. There have been very few therapies that have been shown to work for epilepsy after the primary brain injury has occurred.
A promising new treatment for epilepsy is called focal cooling (FC). FC is a method in which the effected region of the brain is cooled down below body temperature. It is thought that FC works by stopping neuronal activation in the brain. The most appropriate beneficial effects shown by cooling down the brain have been seen in people who have fallen through the ice and have been recovered after tens of minutes or even hours, these patients have been known to make a complete recovery with very careful re-warming procedures, it is thought brain damage is prevented as the cold water puts the brain into a hibernation state which uses very little oxygen. FC applies the same cooling strategy but focused on the area of brain damage. In the case of epilepsy it is to stop the over active region of the brain and bring it down to normal levels therefore preventing any seizures.
Although FC is an incredibly promising method to treat epilepsy with clinical trials already being planned, there has been little research into developing an optimised method for FC treatment in terms of the duration and magnitude of temperature drop in the brain or even in understanding the actual mechanisms by which FC works. For this application we have developed a method for FC treatment in an anaesthetised animal model in which we can measure brain function in an extremely detailed way. The pilot data produced as part of this application shows that FC works as expected by reducing baseline neuronal activation in the brain but also that FC makes oxygen more freely available in the brain to keep it healthy for longer, this second effect has never been shown before. Our pilot experiments also show that focal cortical epilepsy dramatically increases the temperature within the brain by over 2oC and causes a dramatic reduction in the amount of available oxygen. These could be the main reasons for long term brain damage seen in epilepsy patients and explain why FC provides a therapeutic benefit. Using our animal model we will perform experiments to assess the best conditions for FC treatment in the normal animal and then apply these results to acute animal models of epilepsy in our laboratory.
This project will also assess the role of blood flow in keeping the brain at a constant temperature during normal function. Alterations in blood flow in certain diseases or old age, may actually cause increases in brain temperature with the potential to cause brain damage (such as those seen in epilepsy) again this has never been systematically investigated before.
A promising new treatment for epilepsy is called focal cooling (FC). FC is a method in which the effected region of the brain is cooled down below body temperature. It is thought that FC works by stopping neuronal activation in the brain. The most appropriate beneficial effects shown by cooling down the brain have been seen in people who have fallen through the ice and have been recovered after tens of minutes or even hours, these patients have been known to make a complete recovery with very careful re-warming procedures, it is thought brain damage is prevented as the cold water puts the brain into a hibernation state which uses very little oxygen. FC applies the same cooling strategy but focused on the area of brain damage. In the case of epilepsy it is to stop the over active region of the brain and bring it down to normal levels therefore preventing any seizures.
Although FC is an incredibly promising method to treat epilepsy with clinical trials already being planned, there has been little research into developing an optimised method for FC treatment in terms of the duration and magnitude of temperature drop in the brain or even in understanding the actual mechanisms by which FC works. For this application we have developed a method for FC treatment in an anaesthetised animal model in which we can measure brain function in an extremely detailed way. The pilot data produced as part of this application shows that FC works as expected by reducing baseline neuronal activation in the brain but also that FC makes oxygen more freely available in the brain to keep it healthy for longer, this second effect has never been shown before. Our pilot experiments also show that focal cortical epilepsy dramatically increases the temperature within the brain by over 2oC and causes a dramatic reduction in the amount of available oxygen. These could be the main reasons for long term brain damage seen in epilepsy patients and explain why FC provides a therapeutic benefit. Using our animal model we will perform experiments to assess the best conditions for FC treatment in the normal animal and then apply these results to acute animal models of epilepsy in our laboratory.
This project will also assess the role of blood flow in keeping the brain at a constant temperature during normal function. Alterations in blood flow in certain diseases or old age, may actually cause increases in brain temperature with the potential to cause brain damage (such as those seen in epilepsy) again this has never been systematically investigated before.
Technical Summary
This grant application will develop new and existing technology to assess exactly how one of the most promising treatments for focal cortical epilepsy works. The proposed treatment is called focal cooling (FC); essentially it means cooling down the part of the brain affected by epilepsy to stop or reduce seizures. FC offers the opportunity to develop a successful treatment after the initial cerebral event has occurred and therefore is extremely relevant to human patients.
To investigate how FC works we will employ an acutely anaesthetised rodent model to achieve the following research objectives:
(i) Measure the amount of temperature reduction needed and maximal duration the cerebral cortex and withstand with no side effects and to understand the role played by thermoregulation in neurovascular coupling. We will employ an array of sophisticated imaging and electrophysiological techniques for this research often simultaneously to reduce animal numbers. These include :
2-dimensional optical imaging spectroscopy - To measure hemoglobin changes from the surface of the cortex
Laser Doppler Flowmetry to measure blood flow
Tissue Oxygen measurements
Direct measurement of cerebral cortical temperature changes
Multi-channel electrophysiology to measure neural activity as a function of cortical depth.
Functional magnetic resonance imaging (fMRI) to measure effects of FC from deep brain regions
Thermal imaging to measure the spatial spread of temperature changes produced by physiological stimulation and focal cortical epilepsy
Post mortem histology will be performed after each experiment to asses any tissue damage caused by the FC treatment.
(ii) Apply the optimised FC method to an acute model of focal cortical epilepsy at time points relative to the clinic. The 4-AP model of focal cortical epilepsy has already been developed in Sheffield and a senior post doc is named on the application.
To investigate how FC works we will employ an acutely anaesthetised rodent model to achieve the following research objectives:
(i) Measure the amount of temperature reduction needed and maximal duration the cerebral cortex and withstand with no side effects and to understand the role played by thermoregulation in neurovascular coupling. We will employ an array of sophisticated imaging and electrophysiological techniques for this research often simultaneously to reduce animal numbers. These include :
2-dimensional optical imaging spectroscopy - To measure hemoglobin changes from the surface of the cortex
Laser Doppler Flowmetry to measure blood flow
Tissue Oxygen measurements
Direct measurement of cerebral cortical temperature changes
Multi-channel electrophysiology to measure neural activity as a function of cortical depth.
Functional magnetic resonance imaging (fMRI) to measure effects of FC from deep brain regions
Thermal imaging to measure the spatial spread of temperature changes produced by physiological stimulation and focal cortical epilepsy
Post mortem histology will be performed after each experiment to asses any tissue damage caused by the FC treatment.
(ii) Apply the optimised FC method to an acute model of focal cortical epilepsy at time points relative to the clinic. The 4-AP model of focal cortical epilepsy has already been developed in Sheffield and a senior post doc is named on the application.
Planned Impact
The projects main aim is to understand how focal cooling (FC) works and to optimise its use for the treatment of focal cortical epilepsy. This is a basic science application that has a strong translational component and that is to underpin and refine FC strategies that are currently being proposed for clinical trials with little or no pre-clinical optimisation. The medical, economic, ethical and social impacts of this work will be as follows.
Medical Impact
This research will have two medical impacts the first is that it will assess how useful FC treatment can be using clinically relevant timings for intervention for epilepsy. In this way we will set up criteria that clinical applications will need to meet to translate FC treatment to humans with the best chance of success. The second aspect of research is that the FC may resolve the role played by temperature changes in cerebral pathology. This may extend to many brain disorders in which temperature changes are known to occur such as stroke and traumatic brain injury and lead to new potential treatments. Professor Theodore Schwartz, a named collaborator on this application and a world leading epilepsy neurosurgeon will provide guidance ensure all relevant translational findings of this research are disseminated to the medical community.
Economic Impact
Although this research has no direct commercial component at present the results may lead to new treatment strategies being developed to alleviate the chronic effects of acute epilepsy all of which have significant economic drains on society in terms of caring for these patients. If we can establish a treatment that alleviates all or some of these effects patients will be able to lead productive lives more quickly after the disease has been treated.
Ethical Impact
This research will closely adhere to the principals of the 3R's (reduction, refinement and replacement) for all experimental procedures performed as part of the project. By using multi-modal procedures for the acute animal experiments we will be able to collect a large amount of data from each subject; previously these experiments were carried out in isolation greatly increasing animal numbers used. All ethical permissions for this research are in place.
Social Impact
The research team in Sheffield has a program of outreach to explain the research that we perform and how important it is to society. This project is to develop and refine one of the most promising (and few) treatments for epilepsy that can be performed after the initial brain injury. Many people in society will know the devastating social effects of acute epilepsy not only to the patient but their immediate family and friends. This will be an opportunity to explain to the public the research we do and why it is important. Over the past 12 months researchers in Dr Berwick's team have been actively involved in European researcher's night, to present our findings to the local community in an interactive and fun way. We have also requested £500 per year to further fund these activities including the purchase of interactive 'brain games' and to fund travel costs to local schools.
Medical Impact
This research will have two medical impacts the first is that it will assess how useful FC treatment can be using clinically relevant timings for intervention for epilepsy. In this way we will set up criteria that clinical applications will need to meet to translate FC treatment to humans with the best chance of success. The second aspect of research is that the FC may resolve the role played by temperature changes in cerebral pathology. This may extend to many brain disorders in which temperature changes are known to occur such as stroke and traumatic brain injury and lead to new potential treatments. Professor Theodore Schwartz, a named collaborator on this application and a world leading epilepsy neurosurgeon will provide guidance ensure all relevant translational findings of this research are disseminated to the medical community.
Economic Impact
Although this research has no direct commercial component at present the results may lead to new treatment strategies being developed to alleviate the chronic effects of acute epilepsy all of which have significant economic drains on society in terms of caring for these patients. If we can establish a treatment that alleviates all or some of these effects patients will be able to lead productive lives more quickly after the disease has been treated.
Ethical Impact
This research will closely adhere to the principals of the 3R's (reduction, refinement and replacement) for all experimental procedures performed as part of the project. By using multi-modal procedures for the acute animal experiments we will be able to collect a large amount of data from each subject; previously these experiments were carried out in isolation greatly increasing animal numbers used. All ethical permissions for this research are in place.
Social Impact
The research team in Sheffield has a program of outreach to explain the research that we perform and how important it is to society. This project is to develop and refine one of the most promising (and few) treatments for epilepsy that can be performed after the initial brain injury. Many people in society will know the devastating social effects of acute epilepsy not only to the patient but their immediate family and friends. This will be an opportunity to explain to the public the research we do and why it is important. Over the past 12 months researchers in Dr Berwick's team have been actively involved in European researcher's night, to present our findings to the local community in an interactive and fun way. We have also requested £500 per year to further fund these activities including the purchase of interactive 'brain games' and to fund travel costs to local schools.
Publications
Slack R
(2016)
A novel method for classifying cortical state to identify the accompanying changes in cerebral hemodynamics.
in Journal of neuroscience methods
Sharp P
(2019)
Neurovascular coupling preserved in a chronic mouse model of Alzheimer's disease: Methodology is critical
in Journal of Cerebral Blood Flow & Metabolism
Shabir O
(2018)
Neurovascular dysfunction in vascular dementia, Alzheimer's and atherosclerosis.
in BMC neuroscience
Shabir O
(2020)
Enhanced Cerebral Blood Volume under Normobaric Hyperoxia in the J20-hAPP Mouse Model of Alzheimer's Disease.
in Scientific reports
Lee L
(2020)
Key Aspects of Neurovascular Control Mediated by Specific Populations of Inhibitory Cortical Interneurons.
in Cerebral cortex (New York, N.Y. : 1991)
Huber LR
(2021)
Validating layer-specific VASO across species.
in NeuroImage
Horsburgh K
(2018)
Small vessels, dementia and chronic diseases - molecular mechanisms and pathophysiology.
in Clinical science (London, England : 1979)
Harris SS
(2018)
Physiological and Pathological Brain Activation in the Anesthetized Rat Produces Hemodynamic-Dependent Cortical Temperature Increases That Can Confound the BOLD fMRI Signal.
in Frontiers in neuroscience
David T
(2023)
The Reversal Characteristics of GABAergic Neurons: A Neurovascular Model.
in Journal of biomechanical engineering
Bruyns-Haylett M
(2017)
The neurogenesis of P1 and N1: A concurrent EEG/LFP study
in NeuroImage
Brezzo G
(2020)
Acute effects of systemic inflammation upon the neuro-glial-vascular unit and cerebrovascular function.
in Brain, behavior, & immunity - health
Boorman LW
(2023)
Bidirectional alterations in brain temperature profoundly modulate spatiotemporal neurovascular responses in-vivo.
in Communications biology
Description | Batelle PhD Studentship |
Amount | £136,000 (GBP) |
Organisation | University of Sheffield |
Sector | Academic/University |
Country | United Kingdom |
Start | 08/2019 |
End | 03/2023 |
Description | Epilepsy Research UK Project grant |
Amount | £147,000 (GBP) |
Organisation | Epilepsy Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 08/2015 |
End | 08/2017 |
Description | FRIENZ study group tour of New Zealand |
Amount | € 8,000 (EUR) |
Organisation | European Commission |
Sector | Public |
Country | European Union (EU) |
Start | 09/2015 |
End | 10/2015 |
Description | MRC-KHIDI UK-Korea partnering award |
Amount | £20,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2015 |
End | 04/2016 |
Description | Massaging brain vessels with vasomotion: Targeting the vasculature to alter disease progression in mouse models of dementia. |
Amount | £1,265,952 (GBP) |
Funding ID | MR/X003418/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 02/2023 |
End | 01/2026 |
Title | Multi-modal investigation of neurovascular function |
Description | We have successfully developed an anaaesthetised rat model to simulutaneously measure Oxygen, temperature, neural, blood flow and hemodynamics in the brain to both sensory stimulation and in focal cortical epilepsy. |
Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
Provided To Others? | No |
Impact | It will allow us to use fewer animals as we are getting far more detailed and robust data sets from each animal. Better science with less animals |
Title | Source data for - Bidirectional alterations in brain temperature profoundly modulate spatiotemporal neurovascular responses in-vivo: Implications for theragnostics |
Description | Neurovascular coupling (NVC) is a mechanism that, amongst other known and latent critical functions, ensures activated brain regions are adequately supplied with oxygen and glucose. This biological phenomenon underpins non-invasive perfusion-related neuroimaging techniques, and recent reports have implicated NVC impairment in several neurodegenerative disorders. Yet, much remains unknown regarding NVC in health and disease, and only recently has there been burgeoning recognition of a close interplay with brain thermodynamics. Accordingly, we developed a novel multi-modal approach to systematically modulate cortical temperature and interrogate the spatiotemporal dynamics of sensory-evoked NVC. We show that changes in cortical temperature profoundly and intricately modulate NVC, with low temperatures associated with diminished oxygen delivery, and high temperatures inducing a distinct vascular oscillation. These observations provide novel insights into the relationship between NVC and brain thermodynamics, with important implications for brain-temperature-related therapies, functional biomarkers of elevated brain temperature, and in-vivo methods to study neurovascular coupling. |
Type Of Material | Database/Collection of data |
Year Produced | 2022 |
Provided To Others? | Yes |
URL | http://datadryad.org/stash/dataset/doi:10.5061/dryad.n2z34tmzq |
Description | New Zealand Collaboration with Canterbury University |
Organisation | University of Canterbury |
Department | School of Medicine and Health Sciences |
Country | New Zealand |
Sector | Academic/University |
PI Contribution | We are providing in vivo data for the team in New Zealand to analyse using sophisticated mathematical modelling techniques |
Collaborator Contribution | They are providing mathematical expertise to allow better interpretation of out data. |
Impact | On the basis of my contact with Tim David I was awarded a travel grant to New Zealand on an EU funded study tour. This solidified the collaboration and resulted in this grant award |
Start Year | 2015 |
Description | Article in University of Sheffield Discover Magazine |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Our neurovascular imaging research group were part of a focused Neuroscince edition of the Universities Discover magazine. Our Epilepsy funding is an important aspect of this work and the ERUK grant is mentioned in the article. |
Year(s) Of Engagement Activity | 2016 |
URL | https://www.sheffield.ac.uk/research/impact/stories/neurological-imaging-brain-diseases-1.573959 |
Description | Cheque collection and talk on behalf of ERUK at the Young Farmers meeting in Feb 2017 |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Industry/Business |
Results and Impact | Dr Sam Harris gave a brief talk about the research and collected a cheque on behalf of ERUK from the Young Farmers association. |
Year(s) Of Engagement Activity | 2017 |
Description | Harvest Festival Talk for Young Farmers Association |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Supporters |
Results and Impact | Dr Sam Harris gave a talk about the ERUK funded project and how it relates to understanding seizure spread in focal cortical epilepsy |
Year(s) Of Engagement Activity | 2016 |
Description | Interview for Local newspaper - The Yorkshire post |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | As part of media coverage for Alzheimer's Research UK's National conference I took park in a media interview that was published in the Yorkshire Post and publicised by ARUK's media team. |
Year(s) Of Engagement Activity | 2019 |
URL | https://www.alzheimersresearchuk.org/harrogate-hosts-global-experts-at-leading-dementia-conference/ |
Description | The great Yorkshire Bike Ride 2015 presentation evening |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | I Attending the annual award giving ceremony on behalf of Epielpsy Research UK to collect a check for money raised during the Great Yorkshire Bike Ride. I gave a short speech describing exactly what this money means to the charity and the funded research I do. |
Year(s) Of Engagement Activity | 2015 |