Development of brain activity and motor control in early human life

Lead Research Organisation: King's College London
Department Name: Imaging & Biomedical Engineering

Abstract

An injury to the brain during the crucial stages of early life in the womb and around the time of birth can lead to life-long difficulties with brain function. Damage to the specific areas of the brain which control how the body moves at this time can result in cerebral palsy, which can consist of permanent limb paralysis or uncontrolled movements. There is no cure for cerebral palsy, perhaps due to a fundamental lack of knowledge about how the brain and its activity actually develops control over how the body moves in the earliest stages of life. Furthermore, current medical tests cannot accurately identify which babies will develop cerebral palsy later in childhood, which means that doctors cannot start early treatment and leaving families with several months of stressful uncertainty.

Right from the earliest stages of pregnancy, babies can be seen and felt to be moving inside the womb. After birth, they continue to move in a seemingly random way until 6 months of age when they begin to make clearer controlled and purposeful movements. Previous studies suggest that even at this early stage, the brain can alter how it controls movement through simple learning. In this early period of life, the human brain is undergoing more dramatic changes in size, shape, and structure than at any other time, and therefore there must also be enormous changes in how its activity evolves to allow these new patterns of movement.

I therefore plan to use specialist techniques to precisely measure how babies move (both inside and outside the womb) and then identify and locate the accompanying brain activity. I will study how this changes as a baby grows during their first 6 months, and explore how the relationship is affected by early brain injury. Finally I will try to understand how brain activity and movements can be altered by stimulation through learning. The results of these studies will provide new and important insights about how the brain matures through and then controls movements in the first year. This fundamental knowledge will help doctors and scientists understand how to try and ensure healthy brain development and movements in early life. It will also help them to diagnose, potentially prevent and treat conditions like cerebral palsy which affect the control of movement in children.

Technical Summary

I will use non-invasive neuroimaging techniques to study the maturation of human brain activity related to early spontaneous motor behaviour. This will be accomplished through inter-institutional (King's College London, Imperial College London, University College London, and Columbia University) and multi-disciplinary collaboration (Neonatal medicine, Imaging Sciences, Bioengineering, Neuroscience, Psychology) with colleagues at the forefront of their respective fields. This unique comprehensive approach will ensure that state-of-the-art techniques are used, supported and supervised by the very best team of researchers possible.

I will use foetal MRI to visualise in-utero spontaneous movements and then precisely localise the associated brain activity with functional MRI (fMRI). This has never been done before, but will be possible using a recently developed acquisition and image processing pipeline. I will then study spontaneous motor behaviour in preterm and term infants (including a group who have suffered focal brain injury) by precisely measuring movements using accelerometers and will identify associated brain activity using simultaneous EEG-fMRI. This complimentary combination will provide entirely novel detailed information about both the temporal (EEG) and spatial (fMRI) features of the brain activity. I have already performed the first-ever simultaneous EEG-fMRI studies in preterm infants and will build on this further by studying a specific and clinically important question. Finally I will study how motor behaviour and its related brain activity can be altered by multimodal stimulation and associative learning. Precisely controlled stimulation will be achieved using technology which I have pioneered with bioengineering colleagues over the several years, and the related neural activity will be measured with simultaneous EEG-fMRI. To ensure robust methodology, I will collaborate with colleagues who have successfully demonstrated learning in neonates.

Planned Impact

The primary beneficiaries of the proposed research will be infants with perinatal brain injury, who will be later affected by disorders of motor control in childhood such as cerebral palsy and developmental coordination disorder. It is hoped that the findings will lead to major advances in clinical management and novel treatments which will markedly improve the quality of life of affected individuals and their families, both through altering the trajectory of their motor difficulties and improving psychosocial outcomes. Whilst the possible benefits of new neuroprotective agents may not be realised for several years, in the short term the families of at-risk infants will benefit from the improved diagnostic and prognostic information the advances in imaging will represent. In the short term, I plan to disseminate the methodology and results to clinical and academic colleagues around the world, and will freely share the acquired data so that it can be analysed by other researchers to benefit their own study populations. The methods and technology will also be translatable to study other subject groups including adults with motor difficulties (such as Parkinson's disease and following stroke) and even animal models of developmental diseases. In the long-term it is also possible that some of the technology will be industrialised (as have previous innovations by Professor Burdet's group) which will ensure wider uptake of the methods in both the clinical and basic science settings.

Understanding the early life causes of long-term conditions of childhood and cerebral palsy has been identified as a key priority by the Chief Medical Officer for the department of health in 2012 (https://www.gov.uk/government/publications/chief-medical-officers-annual-report-2012-our-children-deserve-better-prevention-pays) and following a parliamentary enquiry in 2015 (https://issuu.com/actioncerebralpalsy/docs/acp_report_21st_jan_2015/0). It has become a prominent issue for policy makers and wider society, because the lifetime public health costs of cerebral palsy for a single affected child are extremely significant (estimated at 860,000 euros in 2009) and one of the commonest causes (preterm birth) has estimated societal costs which total a staggering 2.48 billion pounds per year. There are therefore very significant economic benefits for society from gaining a better understanding and subsequently improving the early clinical care of cerebral palsy and/or preterm birth. In combination, the findings of the research will potentially have a large impact on society as a whole through improving health outcomes and thus relieving the associated social and health care burden. These factors are also of clear prominence globally as the prevention of cerebral palsy in developing countries is of vital importance where the prevalence is high and the allocation of scarce resources is a challenging problem for policy makers.

Publications

10 25 50
 
Description Automated Fetal and Neonatal Movement Assessment for Very Early Health Assessment
Amount £625,543 (GBP)
Funding ID EP/S013687/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 01/2019 
End 12/2021
 
Description Ultra-high resolution 7T MRI mapping of basal ganglia connectivity on an individual patient basis for Paediatric Deep Brain Stimulation (DBS)
Amount £116,617 (GBP)
Funding ID MR/T005424/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 10/2019 
End 09/2022
 
Title Preterm brain sensori-motor functional activation maps 
Description Activation maps derived from fMRI data from groups of preterm infants, aligned to age specific template space. Total of 5 maps showing location of functional responses following somatosensory stimulation of the left wrist, right wrist, left ankle, right ankle, and mouth/lips. Methodology and data set has been described in the paper (Dall'Orso et al. Cerebral Cortex 2018). Group activation maps have been made available for download. 
Type Of Material Database/Collection of data 
Year Produced 2018 
Provided To Others? Yes  
Impact As performing these kind of task based fMRI studies is challenging in preterm infants - we have made this data available so it can be used by other researchers to explore functional and structural connectivity in this age group. 
URL https://brain-development.org/somatotopicmap/
 
Title Preterm delta brush functional activation maps 
Description Functional activation maps from a group of preterm infants studied with simultaneous EEG-fMRI. Group maps have been aligned to an age-specific template and have been made available for download. 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
Impact We acknowledge that this is challenging data to collect - we have therefore made it available for download so that other researchers can use the activation maps to explore functional and structural connectivity in this population. 
URL https://brain-development.org/activation-maps-related-to-spontaneous-delta-brush-activity/
 
Description Collaboration Columbia University, New York USA 
Organisation Columbia University
Country United States 
Sector Academic/University 
PI Contribution Ongoing collaboration with Professor William Fifier of Sackler Institute of Developmental Biology at Columbia University. Currently collaborating on study of MR imaging correlates of assoicative learning in newborn infants. Subject recruitment, data collection is all being done by myself/team at King's College London.
Collaborator Contribution Professor Fifer has expertise in infant learning so has been providing essential input into the study design, training of the PhD student and postdoctural researcher involved in the project, and is also involved in the intepretation of the results.
Impact Abstract submitted to the OHBM meeting 2018: Dall'Orso S, Fifer WP. Balsam PD, Vecchiato K, O'Keefe C, Edwards AD, Burdet E, Arichi T. fMRI investigation of associative learning in newborn infants.
Start Year 2017
 
Description Collaboration Imperial College Bioengineering department 
Organisation Imperial College London
Department Department of Bioengineering
Country United Kingdom 
Sector Academic/University 
PI Contribution We have been collaborating together to develop new robotic tools for fMRI experiments. I am involved in the development from the MRI and clinical perspective, and in the data collection/analysis.
Collaborator Contribution My collaborators are responsible for the engineering development of the tools, and the data analysis
Impact Multi-disciplinary - involving both clinicians (myself) and engineering colleagues. Together we have successfully attained 1 grant (Imperial College BRC) and co-authored 6 publications.
Start Year 2008
 
Description Collaboration UCL Developmental Neuroscience 
Organisation University College London
Department Developmental Neurosciences
Country United Kingdom 
Sector Academic/University 
PI Contribution I am provided clinical expertise and experience/knowledge in MRI methods.
Collaborator Contribution Working in collaboration with Professor Maria Fitzgerald and Dr Lorenzo Fabrizi who are experts in neurophysiology and neurobiology of pain.
Impact Fabrizi L, Arichi T, Lee A, Fitzgerald M, Edwards AD. Identification of the spatial origin of delta brush activity in the preterm brain with simultaneous EEG and fMRI. Pediatric Academic Society meeting (PAS), Vancouver, Canada, 2014.
Start Year 2013
 
Description Collaboration with Jessica Dubois, INSERM Neurospin, Paris 
Organisation National Institute of Health and Medical Research (INSERM)
Country France 
Sector Academic/University 
PI Contribution Collaboration initiated with INSERM in Paris (Jessica Dubois) - including shared clinical research fellow who will carry out data collection for our project data. We will developing the methods and collecting the data in London.
Collaborator Contribution Clinical fellow is funded by the group in Paris. Analysis of data will be shared collaboratively between the two centres.
Impact Grants have been applied for - multidisciplinary collaboration between clinical neuroscience (Arichi) and computational neuroscience (Dubois)
Start Year 2019
 
Description Article for popular science website "The Conversation" 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Popular Science article following publication of article in eLIFE about simultaneous EEG-fMRI work. Article was also picked up by the Independent online
Year(s) Of Engagement Activity 2017
URL https://theconversation.com/how-a-babys-brain-prepares-for-the-outside-world-72708
 
Description Article in the Financial Times 
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 Media (as a channel to the public)
Results and Impact Article in the national press: Financial Times entitled "Baby brain maps point ot origins of neurological disorders" describing work carried out in our department. Requested to give quote about our EEG-fMRI work which appears at the end of the article.
Year(s) Of Engagement Activity 2018
URL https://www.ft.com/content/ce8a3d40-b8c3-11e7-bff8-f9946607a6ba
 
Description Comment in the Guardian newspaper 
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 Interviewed to give comments and opinion about a study published in Current Biology using machine learning and connectomic imaging in children with learning disabilities
Year(s) Of Engagement Activity 2020
URL https://www.theguardian.com/science/2020/feb/27/brain-wiring-could-be-behind-learning-difficulties-s...
 
Description Developmental Medicine and Child Neurology Video Podcast 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Developmental Medicine and Child Neurology blog on Youtube - Down sydnrome: new approaches to studying early brain development
Year(s) Of Engagement Activity 2019
 
Description ISMRM annual scienific meeting 2019, abstract and presentation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Exploration of the spatial and temporal characteristics of sensorimotor neural activity in the preterm human brain with simultaneous EEG-fMRI
Tanya Poppe 1, Kimberley Whitehead 2, Sofia Dall'Orso 3, Camilla O'Keefe 1, Jakki Brandon 1, Katy Vecchiato 1, Rui Pedro AG Teixeira 1, Felipe Godinez 1, Anthony N Price 1, A David Edwards 1, Lorenzo Fabrizi 2, Tomoki Arichi 1,3
Abstract and platform presentation at the 2019 ISMRM annual scientific meeting
Year(s) Of Engagement Activity 2019
 
Description Invited presentation at ISMRM Annual Scientific Meeting, Paris 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Invited presentation in symposium at the ISMRM annual scientific meeting in Paris, June 2018 entitled "Imaging Function in Developing Preterm Brain with Simultaneous EEG-fMRI". Symposium attended by approximately 100 people with 20 minute discussion/question time.
Year(s) Of Engagement Activity 2018
URL https://www.ismrm.org/18/program_files/MIS02.htm
 
Description Official Opening of the Wellcome EPSRC Centre for Medical Engineering, Kings College London 
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 Policymakers/politicians
Results and Impact Open day showcasing research done within the Division at King's College London. I was selected with 14 others from the division to host a stand showing my research to dignitaries including Princess Anne, board members from the Wellcome trust and the MRC, media, and charitable donors. Approximately 150 people attended.
Year(s) Of Engagement Activity 2018
 
Description Press release for Brain Products GmbH 
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 Other audiences
Results and Impact Press release for the company manufacturing the EEG-fMRI equipment (Brain Products GmbH) describing our previous studies. Distributed to all customers of the equipment (including users in the adult and animal fields) via email newsletter and on the company website.
Year(s) Of Engagement Activity 2018
URL https://pressrelease.brainproducts.com/tag/tomoki-arichi/