Development of brain activity and motor control in early human life

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.

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.

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.