Dr Jason Berwick PhD, Bsc(Hons)
Reader in Neurophysiology
Department of Psychology
The University of Sheffield
Tel: (+44) 0114 22 26597
Fax: (+44) 0114 27 66515
Research Group: Neurovascular and Neuroimaging Research Group
Bsc (Hons) Anatomy and Cell Biology, University of Sheffield.
PhD Neuroscience, University of Sheffield
Understanding neurovascular coupling in health and disease
During the past two decades, blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) has become the scientific technique of choice for investigating human brain function. It exploits the local alterations in blood flow produced by changes in neural activity, termed neurovascular coupling. However, BOLD fMRI does not measure neural activity directly and hence a fundamental problem exists: how to interpret BOLD signal changes and make inferences about the neural activity that generates them. This is far from straightforward because the mechanisms linking events that produce neural changes to BOLD signaling are highly complex. For example, increased BOLD activity in a vast range of tasks and experimental conditions is interpreted as indicating areas of increased neural activity. However, many neural circuits in the brain are inhibitory and little is known about what corresponding fMRI signals are generated. Would an inhibitory neural signal be expected to generated negative BOLD for example? Consequently, multi-modal experiments that directly compare different indicators of hemodynamic activity and electrophysiological measures of neural signals are necessary if BOLD contrast is to be correctly interpreted. My research group employs state of the art imaging and electrophysiological techniques to measure and under stand neurovascular coupling in normal function and in pathophysiological states.
Understanding the negative BOLD signal
Despite the uncertainties above scientists are starting to use FMRI to infer decreases in brain activity and if this inference is correct their studies suggest that the majority of psychiatric (e.g. schizophrenia, major depressive disorder), neuro-developmental (e.g. Autism) neurological (e.g. Alzheimer’s) brain diseases are characterised an inability to ‘turn-off’ rather ‘turn-on’ specific brain regions during mental tasks. By directly measuring reductions brain activity, neuroimaging signals and blood oxygen content at the same time we hope to understand the relationships between them and allow this vital aspect of neuroimaging to further our understanding of brain function and its malfunction in disease states.
Neurovascular coupling and epilepsy
Epilepsy is the most common neurological condition in the UK, affecting 1 – 2 % of the population. Epilepsies often involve only a small area of the brain - the epileptic focus – and the abnormal activity can propagate out from there. Although surgery is often curative in epilepsy, effective intervention relies on the correct identification of the location of the epileptic focus. Current pre-operative techniques are of limited use in this regard, but the new generation of imaging techniques based on changes in blood perfusion of active areas offer great promise. However, we currently have very little understanding of how epilepsy affects the relationship of neurovascular coupling. Our research will use state of the art techniques to characterise, define and measure the relationship between activity and perfusion in the epileptic state. We will also assess whether any long term changes in this relationship persist after epileptic activity, and whether antiepileptic medication can return the relationship to normal. The research we propose will develop the use of imaging techniques as a tool for pre-surgical localization of epileptic foci in epilepsy and ultimately improve outcomes for surgical interventions on human epilepsy patients.
The use of focal cooling as a treatment for epilepsy and to understand whether neurovascular coupling has a role in thermoregulation.
Suppression of epileptic activity through focal cooling of the brain promises to be a valuable adjunct in the treatment of pharmacoresistant epilepsy, both as a technique to reduce intra-operative seizures and as a therapeutic alternative where resective surgery is not viable. However, very little is known about the most optimal parameters for induction, its mechanisms of action, or its direct and subsequent effects on cortical neurovascular function. In this pre-clinical project, we intend to address these unresolved questions and provide insights that are essential to maximizing the potential and success of future epilepsy treatment strategies in the clinical setting.
We have developed a novel multimodal rodent model specifically for this proposal, which enables simultaneous measurement of cortical blood flow, haemoglobin concentration, temperature, tissue oxygenation and laminar neural activity during task-related conditions, acute epileptiform activity and manipulations of brain temperature. Our pilot data demonstrates for the first time that recurrent acute neocortical seizures produces a substantial increase in cortical temperature (>2oC) and a decrease in brain tissue oxygenation (~60%). Our data also shows that focal cerebral cooling effectively subdues seizures in our model and causes a dramatic increase in blood oxygenation in the cortex. Taken together with recent literature, we hypothesize there to be a close coupling between neurovascular and thermoregulatory function which underpins the therapeutic benefit of focal cerebral cooling in epilepsy.
This project will also systematically examine the thermoregulatory role of neurovascular coupling and establish the methodology and mechanistic basis for focal cerebral cooling in the suppression of recurrent acute neocortical seizures. The results of this research will provide insights into neurovascular coupling under normal and epileptic conditions, inform the development and use of focal cerebral cooling as an anti-epileptogenic treatment, and be relevant to other brain disorders where chronic changes in brain temperature occur and/or where brain cooling may offer neuroprotective benefits.
Neurovascular breakdown in Alzheimers disease
AD has generally been assumed to be a neuronal disorder of the brain and treatment strategies have been designed to inhibit neurotoxic events. However, there is increasing evidence that a breakdown of cerebrovascular mechanisms may accelerate and even initiate the disease process. Evidence for the ‘neurovascular breakdown’ hypothesis has been growing over the last three years but more research from a functional perspective is required. The focus of our research will be to measure neurovascular function in transgenic AD mice using sophisticated multi-modal imaging and neural recording strategies. We will combine this with detailed post-mortem analysis to investigate pathological markers in cells of the neurovascular unit (e.g. neurons, astrocytes, pericytes, endothelial cells) and disruption to the blood-brain-barrier. Importantly this data will be directly comparable to similar data collected from human AD post mortem tissue. The specific aims are to define neurovascular markers of AD that can be translated to human neuroimaging strategies such as functional magnetic resonance imaging. In conjunction with studies that assess stimulus-induced changes in cerebral blood flow and metabolism, we will also investigate spontaneous activity. There is mounting evidence that an oscillation in blood flow, termed vasomotion, may be a valuable biomarker of cerebral pathology and will form an important part of these investigations. The outcome of this research will allow new insights into the pathophysiological abnormalities that significantly precede overt clinical symptoms. This may open up new therapeutic targets associated with the vascular system, whilst providing a non-invasive physiological biomarker that can be longitudinally tracked and allow for pre-clinical therapeutic intervention.
2016 MRC-KHIDI UK-KOREA PARTNERING AWARDS Title: Integrating multimodal imaging technologies to investigate neurovascular dysfunction in neurological disorders Sheffield University Team: Dr Jason Berwick (PI), Dr Luke Boorman, Dr Sam Harris, Dr Paul Sharp Sungkyunkwan University Team: Professor Minah Suh (PI). Dr Eunha Baeg, Dr Chaejeong Heo, Dr Sohee Lee. Total value: £20K
2016-2018. Brain Research New Zealand. Dysfunctional Neurovascular Coupling: A precursor to Alzheimer’s? David T (PI), Berwick J (CO-I). $180K NZ Dollar.
2015-2017 Epilepsy Research UK project grant. How activation of sensory regions can promote propogation of adjacent focal neocortical seizures. Berwick J (PI), Haris S, Schwartz T, Overton PG, Kennerley A, Zheng Y. £147K
2015-2018 Medical Research Council. Investigating the thermoregulatory role of neurovascular coupling and the anti-epileptogenic and neuroprotective effects of focal cerebral cooling. Berwick J (PI), Harris S, Martin C, Redgrave P, Boorman L, Kennerley A. ~£558K Full Fec
2014-2016 Interdisciplinary Research Grant Alzheimers Research UK. Neurovascular dysfunction in Alzheimer’s disease : the search for early biomarkers. Berwick J (PI), Wharton S, Heath P. ~£507K full fec
2015-2019 Wellcome Trust Health Innovation Challenge Fund – Round 8. GOLD imaging in acute stroke: further technology development incorporating a perfluorocarbon oxygen carrier. Muir K (PI), Santosh C (PI), Macrae IM, Deuchar G, Berwick J (CO-I), Kennerley AJ. £1.79M full fec (£120K to Sheffield)
2013-2016 BBSRC. Understanding neural excitation and inhibition: implications for the interpretation of extracellular field potentials and neurovascular coupling - Zheng Y (PI), Berwick Jm Jones M, Billings S, Coca D, Milne E, Redgrave P ~£850K
2011-2014 MRC & BBSRC. The neurophysiological basis of negative BOLD signals – Berwick J (PI), Jones M, Kennerley A, Boorman L, Martin C, Redgrave P, Zheng Y. £655K
2011-2014 Wellcome Trust. Understanding Epilepsy in the active brain - Berwick J (PI), Overton PG, Schwartz T, Kennerley A, Ma H, Zhao M. ~£523K
2009- 2012 EPSRC. "Engineering virus-like nanoparticles for targeting the central nervous system". G Battaglia (PI), S P. Armes, M. Azzouz, O. Bandmann, J. Berwick, P.G. Ince , A.J. Kennerley, M. Jones, R. Golestanian, R. Hose, R. Mead, K. Ning, A.J. Ryan, P. Shaw, R. Smallwood, D. Walker & Y. Zheng. £ 2,060,808.
2007 – 2010 MRC New Investigator Award.‘Neurovascular Coupling under the microscope’ – Principal Investigator £415K
2008 New Investigator travel award to the Gordon Research conference of Cerebral blood flow and metabolism, Proctor academy, New Hampshire £1000.
Post-doctoral research associates
Dr Sam Harris (Epilepsy Research UK)
Dr Luke Boorman (MRC)
Dr Paul Sharp (Alzheimers Research UK)
Dr Kamar Ameen-Ali (Alzheimers Research UK)
Rebecca Slack (TUOS Demonstratorship, 2012-2016, Principle Supervisor)
Priya Patel (TUOS Demonstratorship, 2012-2016, Co-Supervisor)
Kira Shaw (A*Star, 2012-2016, Principle Supervisor)
Michael Bruyns-Haylett (TUOS Studentship, 2009-2012)
Activities and distinctions
• The French National Research Agency
• Swiss National Science foundation
• Astar – Agency for Science Technology and Research, Singapore
• Neurological Foundation of New Zealand
• Brain Research
• Journal of Neuroscience
• Journal of Cerebral Blood Flow and Metabolism
• European Journal of Neuroscience
• Journal of Neurophysiology
• Human Brain Mapping Conference
• Applied Optics
• Frontiers in Neuroenergetics
• Journal of Neuroscience Methods
• Magnetic Resonance in Medicine
• Cold Spring Harbour Protocols
• Journal of biomedical optics
Invited talks and lectures
Why should we care about what the fMRI BOLD signal is measuring? (February 2016) – Glasgow
Neurovascular coupling in health and disease (October 2015) – Frienz study tour of New Zealand.
Does the BOLD signal always reflect changes in neuronal activity? (October 2014). Imperial College London
Neurovascular function in health and disease (Aug 2013). Singapore bioimaging consortium, Singapore.
Neurovascular function in pathology, does the BOLD signal always reflect changes in neuronal activity? (February 2013), Open University, Milton Keynes
Neurovascular function in disease, is the BOLD signal the most appropriate biomarker to use? (October 2012) . Summer workshop, ‘Des photons et des neurons’, Institute of Neurosciences, Marseille
Neurovascular relationships in pathology, implications for the use of the BOLD signal as a bio-marker of disease progression (June 2012) Institute of Psychiatry, Kings College London
Does the BOLD signal always reflect changes in neuronal activity? (February 2012): Glasgow Experimental MRI Centre, University of Glasgow
Understanding the Neural and hemodynamic drivers of the negative BOLD signal (January 2012) Centre for advanced biomedical imaging, UCL
Is the BOLD signal an appropriate Bio-marker of Disease progression? (January 2012) Experimental Magnetic Resonance Symposium, Cardiff University
Understanding the negative BOLD signal: Application of simultaneous fMRI and optical imaging spectroscopy. (Oct 2011).Keynote invited talk Bruker user group meeting, Ettlingen, Germany
Why perform simultaneous NIRS and fMRI? (October 2010) Functional Near Infrared Spectroscopy Workshop, Center for Brain Sciences, Harvard University, Boston, USA
What are the underlying neural and hemodynamic signal sources of the negative BOLD signal? (July 2010): Cardiff University Brain Research Imaging Centre (CUBRIC) School of Psychology. Cardiff University
Investigating the neural and hemodynamic signal sources of the negative BOLD signal (May 2010) Laboratoire de Neurobiologie ESPCI PARSITECH, Paris
The use of multimodal techniques to advance the understanding of neurovascular coupling. (Jan 2010). UK-Japan workshop on Multimodal Methods for Monitoring Brain Function, British Embassy, Tokyo.
The use of multimodal techniques to advance the understanding of neurovascular coupling (October 2009). Inter-Institue workshop on optical diagnostic and biophotonic methods from bench to bedside. National Institues of Health, Bethesda, USA
Neurovascular Coupling (Sept 2009). ESMRMB Lectures on MR, Tuebingen, Germany
Negative BOLD in rat somatosensory cortex. (October 2008). Institut de Neurosciences Cognitives de la Méditerranée, Marseille, France
Neurovascular coupling investigated with 2-dimensional optical imaging spectroscopy in rat barrel cortex. (June 2007). UCL Centre for Neuroimaging Techniques.
Spatio-temporal analysis of the hemodynamic response reveals fine detail of neurovascular coupling. (April 2006) National Institute of Health, Washington DC, USA
Linearities and nonlinearities of neuro-hemodynamic coupling (August 2006) - Gordon Research Conference, Cerebral Blood Flow and Metabolism, Magdalen College, Oxford University.
A list of key publications can be found below. For a full list of publications please click here