Development of a cot-side optical biomarker of brain tissue health following neonatal hypoxic-ischaemic brain injury.
Lead Research Organisation:
University College London
Department Name: Medical Physics and Biomedical Eng
Abstract
Problems during birth leading to a lack of oxygen (birth asphyxia) and subsequent brain injury (neonatal encephalopathy or NE) occur in 1-2 per 1000 full term births in the UK. An infant's health is in great danger when there is a prolonged lack of oxygen delivery to meet the metabolic demand of the brain. Perinatal brain injury remains a significant cause of neonatal mortality and is associated with long-term neurological disabilities including cognitive impairment, mental retardation and accounts for 15 to 28% of children with cerebral palsy. Monitoring the tight balance of brain blood flow, oxygen delivery and brain tissue metabolic rate is a major aim in patient diagnosis and care. Clinicians currently cannot monitor the biochemical status of theinjured brain continuously and non-invasively at the infant's cot-side. There is an urgent clinical need to detect as early as possible those neonates at most risk and who may benefit from adjunct therapies and/or redirection of clinical care for effective rehabilitation. Early detection and assessment of brain neurological status and outcome requires sensitive, robust and easy to measure biomarkers.
We are proposing to take a new and creative approach to the way in which the neonatal brain is monitored and useful information is delivered to doctors. We will first develop an entirely novel portable, non-invasive brain monitoring instrument, which will allow birth asphyxiated infants to be monitored at the cot-side in the intensive care unit. This will open up new possibilities for how we guide the management of babies with brain injury. This new instrument will be based on integrating two technologies that use light to monitor the brain. The first technique is broadband near-infrared spectroscopy (or broadband NIRS) and uses low light levels of near-infrared light to measure the distribution of oxygen and blood in the brain, and how oxygen is being utilised by mitochondria the power factory of cells. The second technique is called diffuse correlation spectroscopy and uses a single wavelength (colour) of near-infrared laser light to measure the movement of the red blood cells and hence quantify brain blood flow. In particular this instrument will be able to monitor non-invasively brain blood flow, brain oxygen levels and the metabolic status of the brain tissue by measuring the electrochemical status of cytochrome-c-oxidase, an enzyme in the mitochondria. We will evaluate this instrument and measurement in the lab using a large animal model of the human neonate; after which we will move on to clinical evaluation studies in the neonatal intensive care unit. The system/instrument will be specifically designed to help doctors to quantify the injury severity and optimise the type and duration of therapies, minimise the risk of further injury to the brain, and thus improve the likelihood of the infant's recovery. In addition to building this new neuromonitoring instrument, we will also develop computer programmes which are essential to extract the relevant information from the measured signals from the brain. This will involve developing routines for delivering measurements in real time, and incorporating a computer model of the brain to help us understand the meaning and relationships of our measured signals.
We have a long and successful track record of this type of translational research, i.e. the combined approach of hardware and software engineering of novel brain imaging technologies targeted at specific applications in healthcare, and introduction into clinical use. We have assembled a multidisciplinary team to meet the challenges of this ambitious project including engineers, clinicians and physicists, and we have attracted the interest of an industrial project partner for potential commercial exploitation of our developed systems.
We are proposing to take a new and creative approach to the way in which the neonatal brain is monitored and useful information is delivered to doctors. We will first develop an entirely novel portable, non-invasive brain monitoring instrument, which will allow birth asphyxiated infants to be monitored at the cot-side in the intensive care unit. This will open up new possibilities for how we guide the management of babies with brain injury. This new instrument will be based on integrating two technologies that use light to monitor the brain. The first technique is broadband near-infrared spectroscopy (or broadband NIRS) and uses low light levels of near-infrared light to measure the distribution of oxygen and blood in the brain, and how oxygen is being utilised by mitochondria the power factory of cells. The second technique is called diffuse correlation spectroscopy and uses a single wavelength (colour) of near-infrared laser light to measure the movement of the red blood cells and hence quantify brain blood flow. In particular this instrument will be able to monitor non-invasively brain blood flow, brain oxygen levels and the metabolic status of the brain tissue by measuring the electrochemical status of cytochrome-c-oxidase, an enzyme in the mitochondria. We will evaluate this instrument and measurement in the lab using a large animal model of the human neonate; after which we will move on to clinical evaluation studies in the neonatal intensive care unit. The system/instrument will be specifically designed to help doctors to quantify the injury severity and optimise the type and duration of therapies, minimise the risk of further injury to the brain, and thus improve the likelihood of the infant's recovery. In addition to building this new neuromonitoring instrument, we will also develop computer programmes which are essential to extract the relevant information from the measured signals from the brain. This will involve developing routines for delivering measurements in real time, and incorporating a computer model of the brain to help us understand the meaning and relationships of our measured signals.
We have a long and successful track record of this type of translational research, i.e. the combined approach of hardware and software engineering of novel brain imaging technologies targeted at specific applications in healthcare, and introduction into clinical use. We have assembled a multidisciplinary team to meet the challenges of this ambitious project including engineers, clinicians and physicists, and we have attracted the interest of an industrial project partner for potential commercial exploitation of our developed systems.
Technical Summary
Intrapartum-related events are the 4th leading cause of childhood mortality worldwide. Infants exposed to a perinatal insult typically present with neonatal encephalopathy (NE) that is treated with hypothermia, which prevents adverse outcome in only ~50% of infants. There is an urgent clinical need to detect those neonates at most risk and who may benefit from adjunct therapies. We aim to address this by developing a novel optical instrumentation that will allow non-invasive, in-vivo, at the cot-site measurements of brain oxygenation, blood flow, metabolic rate of oxygen and mitochondrial function. This instrument will use: (1) broadband near-infrared spectroscopy or Broadband NIRS that has the capacity to measure brain vascular oxygenation and mitochondrial function. By measuring the light attenuation at many different near-infrared (NIR) wavelengths, one can estimate the vascular haemoglobin oxygenation and the redox state of mitochondrial respiratory chain enzyme, cytochrome-c-oxidase (CCO). (2) diffuse correlation spectroscopy or DCS has the capacity to measure cerebral blood flow (CBF). DCS uses a single wavelength of NIR light that measures brain blood flow by quantifying temporal fluctuations of light fields emerging from the tissue surface.
Measurements of brain tissue CCO with Broadband NIRS and of CBF with DCS have been successfully but independently applied to monitor NE. For the first time we will combine them into a single instrument. The measurements will then be integrated using our computational model of brain tissue physiology. We will assess the instrument through a series of hypoxic-ischaemic studies in the neonatal preclinical model and validate its predictive capacity to quantify the level of brain injury using a series of multimodal measurements (MRS, EEG, Histology). Finally we will move beyond of proof-of-principle to a clinical observational study in NE infants both during the acute (Days 1-3) and post-acute phases (Days 4-7).
Measurements of brain tissue CCO with Broadband NIRS and of CBF with DCS have been successfully but independently applied to monitor NE. For the first time we will combine them into a single instrument. The measurements will then be integrated using our computational model of brain tissue physiology. We will assess the instrument through a series of hypoxic-ischaemic studies in the neonatal preclinical model and validate its predictive capacity to quantify the level of brain injury using a series of multimodal measurements (MRS, EEG, Histology). Finally we will move beyond of proof-of-principle to a clinical observational study in NE infants both during the acute (Days 1-3) and post-acute phases (Days 4-7).
Planned Impact
Healthcare: Millions of babies around the world suffer brain injuries due to events around the time of birth. Neonatal encephalopathy (NE), the clinical manifestation of disordered brain function in newborns occurs in 1-3 per 1000 live term births in the UK, with 5-10 times higher rates in resource poor settings. NE is the 4th leading cause of death in children and accounts for 50 million disability life adjusted years. Many surviving infants have long-term health and social care needs with substantial resource implications for the NHS.
The primary focus of the management of NE is to reduce on-going brain injury, which is essentially hypoxic-ischaemic in nature, and thereby improve outcome. To achieve this is important to monitor a range of variables related to cerebral haemodynamics, oxygenation and metabolism, and which can be used to identify important physiological events. Our proposed instrument will be able to deliver such measurements and help in the management of NE with the aim of identifying the most severe affected babies that can be helped with adjunct therapies. This research has the potential to revolutionise the pathophysiological assessment of NE. We believe that this work will also transform the trajectory of neurotherapeutic developments, allowing early individualised assessment and a shift towards individually tailored therapies.
Understanding the physiological mechanisms controlling cerebral substrate/oxygen delivery and utilization, and their derangement, is crucial to understanding the pathophysiology of brain injury and its response to treatment. Tools which enable these mechanisms to be characterised from measured neuromonitoring signals can be used to inform optimised and individualised patient management strategies in a broad range of clinical scenarios. In particular it is important to deconstruct the mechanisms and components of haemodynamic, oxygenation and metabolic regulation. This information can then be used to guide individualised treatment strategies and develop novel therapies.
In this proposal we will focus on delivering a solution for the management of NE patients in the neonatal neurocritical care, but our non-invasive brain monitoring, is readily transferrable to other clinical areas and scenarios such as stroke units and the perioperative period. In particular we already have established collaborations with neuro-surgeons and neuro-anaesthetists investigating traumatic brain injury and stroke.
Medical technology: The healthcare decision support market is already a major growth area in health informatics, with a market value of approximately $201.7 million at the end of 2012; it has been forecast to grow to $239 billion by 2019.
Medical technology industries would benefit from a clinically effective tool for the non-invasive assessment of brain injury pathophysiology. A successful outcome to our project would be to explore a commercial market for a combination of a non-invasive neuromonitoring array and model-based data interpretation, and ensure that the UK takes a lead in development of the emerging industry. Development of this impact would require further industrial or translational resourcing, but would have the potential to have significant healthcare and economic benefits in the medium term (3-5 years after the completion of the project).
The primary focus of the management of NE is to reduce on-going brain injury, which is essentially hypoxic-ischaemic in nature, and thereby improve outcome. To achieve this is important to monitor a range of variables related to cerebral haemodynamics, oxygenation and metabolism, and which can be used to identify important physiological events. Our proposed instrument will be able to deliver such measurements and help in the management of NE with the aim of identifying the most severe affected babies that can be helped with adjunct therapies. This research has the potential to revolutionise the pathophysiological assessment of NE. We believe that this work will also transform the trajectory of neurotherapeutic developments, allowing early individualised assessment and a shift towards individually tailored therapies.
Understanding the physiological mechanisms controlling cerebral substrate/oxygen delivery and utilization, and their derangement, is crucial to understanding the pathophysiology of brain injury and its response to treatment. Tools which enable these mechanisms to be characterised from measured neuromonitoring signals can be used to inform optimised and individualised patient management strategies in a broad range of clinical scenarios. In particular it is important to deconstruct the mechanisms and components of haemodynamic, oxygenation and metabolic regulation. This information can then be used to guide individualised treatment strategies and develop novel therapies.
In this proposal we will focus on delivering a solution for the management of NE patients in the neonatal neurocritical care, but our non-invasive brain monitoring, is readily transferrable to other clinical areas and scenarios such as stroke units and the perioperative period. In particular we already have established collaborations with neuro-surgeons and neuro-anaesthetists investigating traumatic brain injury and stroke.
Medical technology: The healthcare decision support market is already a major growth area in health informatics, with a market value of approximately $201.7 million at the end of 2012; it has been forecast to grow to $239 billion by 2019.
Medical technology industries would benefit from a clinically effective tool for the non-invasive assessment of brain injury pathophysiology. A successful outcome to our project would be to explore a commercial market for a combination of a non-invasive neuromonitoring array and model-based data interpretation, and ensure that the UK takes a lead in development of the emerging industry. Development of this impact would require further industrial or translational resourcing, but would have the potential to have significant healthcare and economic benefits in the medium term (3-5 years after the completion of the project).
Publications
Bale G
(2020)
Metabolic brain measurements in the newborn: Advances in optical technologies.
in Physiological reports
Bale G
(2021)
Multimodal Measurements of Brain Tissue Metabolism and Perfusion in a Neonatal Model of Hypoxic-Ischaemic Injury.
in Advances in experimental medicine and biology
Burgess PW
(2022)
Prefrontal cortical activation associated with prospective memory while walking around a real-world street environment.
in NeuroImage
Giannoni L
(2021)
A hyperspectral imaging system for mapping haemoglobin and cytochrome-c-oxidase concentration changes in the exposed cerebral cortex.
in IEEE journal of selected topics in quantum electronics : a publication of the IEEE Lasers and Electro-optics Society
Hakim U
(2022)
Investigation of functional near-infrared spectroscopy signal quality and development of the hemodynamic phase correlation signal.
in Neurophotonics
Harvey-Jones K
(2021)
Role of Optical Neuromonitoring in Neonatal Encephalopathy-Current State and Recent Advances.
in Frontiers in pediatrics
Harvey-Jones K
(2023)
Early assessment of injury with optical markers in a piglet model of neonatal encephalopathy.
in Pediatric research
Description | Development of a cot-side optical biomarker of brain tissue health following neonatal hypoxic-ischaemic brain injury. |
Amount | £822,690 (GBP) |
Funding ID | MR/S003134/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 11/2018 |
End | 10/2022 |
Description | Development of a cot-side optical biomarker of brain tissue health following neonatal hypoxic-ischaemic brain injury. |
Amount | £822,691 (GBP) |
Funding ID | MR/S003134/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 11/2018 |
End | 10/2022 |
Description | Monitoring brain temperature during neonatal seizures following neonatal encephalopathy. |
Amount | £14,200 (GBP) |
Funding ID | F224 |
Organisation | University College Hospital |
Sector | Hospitals |
Country | United Kingdom |
Start | 09/2021 |
End | 09/2022 |
Title | Hybrid broadband NIRS and DCS device |
Description | bNIRS: The system consists of a tungsten halogen lamp light source (HL-2000-FHSA, Ocean Optics, USA) with a 700nm longpass filter, two identical multimode fibre bundles (30µm fibres, 0.57 NA, bundle diameter 2.4mm, Loptek, Germany) one to emit light to the tissue and the other to collect reflected light from the tissue to a micro spectrometer (644-917nm, 1024 pixels, Wasatch Photonics, USA). DCS: The DCS system consists of a 785nm long coherence (>8m) diode laser (iBeam Smart WS, Toptica, Germany), with a clean-up filter at 785nm mounted inside, a multimode fibre (200 µm, 0.22NA, Thorlabs, Germany) to carry light to the tissue; a single mode fibre (5µm, 0.13 NA, Thorlabs, Germany) to detect light from the tissue, and an APD (excelitas SPCM-AQ4C) with correlator (Flex05, 8 channels, correlator.com). bNIRS-DCS: . To test the ability of the optical systems to run near-synchronously, the crosstalk between the systems was tested on solid and liquid neonatal head phantoms (described in next section); and the forearm of a healthy volunteer. In all experimental settings it was found that there was no influence of the bNIRS source on the recovered DCS parameters if the bNIRS source is more than 20mm from the DCS detector. The DCS laser is detected on the bNIRS spectrometer at distances up to 55mm, so it was decided to cycle the laser on and off to obtain a near-synchronous (sequential) measurement. |
Type Of Material | Improvements to research infrastructure |
Year Produced | 2019 |
Provided To Others? | No |
Impact | Used within pre-clinical piglet model of HIE studies |
Title | miniCYRIL - miniature broadband NIRS device |
Description | Miniature broadband NIRS device with software GUI |
Type Of Material | Improvements to research infrastructure |
Year Produced | 2016 |
Provided To Others? | Yes |
Impact | Based 4 collaborations on this device |
Title | FLORENCE neonatal dataset |
Description | The FLORENCE system was used in the NICU to acquire data on brain optical properties, tissue saturation, changes in oxCCO HHb and HbO2, and BFi of 10 newborn babies. Update 2022: We have now scanned 38 babies. Update 2023: We have now scanned 95 babies. |
Type Of Material | Database/Collection of data |
Year Produced | 2021 |
Provided To Others? | No |
Impact | This acquisition of this first dataset demonstrates the capability of our system to be used in a clinical environment and we are currently using it to explore several data processing scheme and extract features from our data that could be clinically relevant. |
Title | Machine Learning Pipeline to Assess the Degree of Brain Injury Severity in Newborns |
Description | This algorithm uses unsupervised machine learning to assess the degree of brain injury severity, examining the shifts of brain injury classification throughout the first four days of life, using bNIRS and DCS data, as well as the full instrumentation data captured on the cot-side of newborns in the NICU. |
Type Of Material | Computer model/algorithm |
Year Produced | 2022 |
Provided To Others? | Yes |
Impact | This work facilitated machine learning applications within the team as it converted the UCLn pre-processing algorithm into Python, as well as examined the potential of using clustering to assess brain injury severity from the first hours to the first days of life. |
URL | https://github.com/multimodalspectroscopy/DiDo |
Description | UCL - Australia |
Organisation | Sydney Children's Hospital |
Country | Australia |
Sector | Hospitals |
PI Contribution | · Co-investigator on a $66 848 (AUD) grant entitled 'Changes in cerebral mitochondrial oxygenation during paediatric and adult cardiac surgery.' |
Collaborator Contribution | We led the optical engineering side of the proposal and developed a device to be used in cardiac surgery |
Impact | Still ongoing Multidiscplinary between us (biomedical optics) and clinical anathestics and surgery |
Start Year | 2018 |
Description | UCL - Columbia |
Organisation | Columbia University |
Country | United States |
Sector | Academic/University |
PI Contribution | · Received funding (£28 300) to develop an optical device for Department of Psychiatry as part of a collaboration. |
Collaborator Contribution | Developed an optical device for Department of Psychiatry and trained them |
Impact | Still ongoing Multidisciplinary between us (biomedical engineering) and clincal psychiatry |
Start Year | 2019 |
Description | UCL - Germany |
Organisation | University of Lubeck |
Country | Germany |
Sector | Academic/University |
PI Contribution | Lending a miniature device for Parkinson's research |
Collaborator Contribution | Developed and trained on device |
Impact | Ongoing Multi-disciplinary - biomedical engineering and neuroscience |
Start Year | 2019 |
Description | UCL - Zurich |
Organisation | ETH Zurich |
Country | Switzerland |
Sector | Academic/University |
PI Contribution | · Received funding (£50 043.55) to develop two optical devices for psychiatric research as part of a collaboration |
Collaborator Contribution | Developed two devices and trained them |
Impact | Still onging Multi-disciplinary between us (biomedical engineering) and clinical psychiatry |
Start Year | 2019 |
Title | Neolight data processing software |
Description | The software enables to (1) import the raw optical data of the FLORENCE system together with the raw systemic data, (2) apply data processing method to extract raw optical properties, tissue saturation, HHb, HbO2 and oxCCO concentration changes and BFi, (3) time synchronise the data and (4) output all the synchronise processed data in a single matrix. UPDATE 2022: The software now also generate information about CMRO2, OEF and cerebral blood volume. UPDATE 2023: The software now also synchronises optical and systemic data with aEEG. |
Type Of Technology | Systems, Materials & Instrumental Engineering |
Year Produced | 2021 |
Impact | This software has been used to analyse the data collected on neonates in the NICU. |
Description | Course Development for The Brilliant Club Scholar Programme |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Schools |
Results and Impact | A course of 6 tutorials was developed for The Brilliant Club who trained 32 postgraduate students to teach it to 388 school children around the country |
Year(s) Of Engagement Activity | 2018 |
URL | https://thebrilliantclub.org/ |
Description | Institute of Physics Lectures |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Invited to give lecture on our research for the South East branch, London branch and Hertfordshire branch of the IOP |
Year(s) Of Engagement Activity | 2018,2019 |
Description | Isambard Kingdom Brunel Award Lecture at the British Science Festival |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Lecture to 60 people at the British Science Festival |
Year(s) Of Engagement Activity | 2018 |
URL | https://www.britishscienceassociation.org/blogs/bsa-blog/british-science-festival-detecting-and-prev... |
Description | Principle Lecture at the London International Youth Science Forum |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Schools |
Results and Impact | Principle talk in a programme for international students of science |
Year(s) Of Engagement Activity | 2019 |
URL | https://www.liysf.org.uk/uncategorized/science-at-the-interface-our-plenary-lectures |
Description | Resource development with Royal Academy of Engineering |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Schools |
Results and Impact | We created a resource for primary school children and their teachers about medical physics. This was delivered through the RAEng Teacher Coordinator scheme. |
Year(s) Of Engagement Activity | 2019 |
Description | Women in engineering day on BBC Newsround |
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 | Schools |
Results and Impact | Gemma Bale interviewed and gave demo of medical physics on Newsround |
Year(s) Of Engagement Activity | 2019 |