Imaging of White Matter and Myelination in Normal and Autistic NeuroDevelopment

Lead Research Organisation: King's College London
Department Name: Medicine School Office

Abstract

Broadly, brain tissue may be classified into either white or grey matter. White matter is comprised of fibers which carry information to and from specific grey matter areas where that information is processed. Surrounding these fibers is myelin, a fat layer which increases the speed information is transfered and is critical for correct and efficient brain function. Myelination, or the formation of the myelin layer, is a crucial element of brain development and the loss of myelin can significantly impair function. Another disorder in which differences in myelin may occur is autism, a brain disorder in which patients have trouble communicating, lack imagination, and show restricted or repetitive behaviour. However, when and where differences in myelination exist in the autistic brain remain open questions. This project aims to answer these key questions by investigating myelination during brain development using a non-invasive brain imaging technique. This research is important for two reasons: First, it will enable us to determine which brain regions or systems underly autistic symptoms, and secondly, by understanding the evolution of these differences during brain maturation we can make more informed choices about the timing of therapeutic interventions.

Technical Summary

Background: Autism is a pervasive developmental disorder characterized by impairments in social, communicative and behavioural functioning. Although post-mortem and structural imaging studies have identified volume differences in specific brain regions between autistic patients and healthy controls, the neural basis of these differences remains poorly understood. One proposed candidate is aberrant white matter maturation, specifically myelination, in the autistic brain. Myelination is a key element of brain development and is essential for normal function and cognition. Despite this critical role, the time-course of myelination in autism is not well known, and the affect of atypical maturation remains a key question.



Aims: This work proposes to assess, quantitatively, myelin content and myelination throughout healthy and autistic neurodevelopment. Using a recently developed non-invasive quantitative myelin imaging technique (multi-component driven equilibrium single pulse observation of T1 and T2 - mcDESPOT) we will perform the first longitudinal investigation of normal and autistic neurodevelopment from early childhood to adolescence, exploring the hypothesis that aberrant (ie. rate and/or extent of) myelination is a neurobiological trait of the disorder.



Methods/Design: To test our hypothesis, a combined cross-sectional / longitudinal study design will be used with 192 autistic patients and healthy controls recruited from three narrowly defined age-groups: toddlers (2-4 years of age), children (6-9 years) and adolescents (12-16 years). Each participant will be scanned at least once per year (depending on age) for 3 years using mcDESPOT method as well as a conventional volumetric structural acquisition. Within each, and across all, age-group cohorts, we will investigate and compare myelination and brain volume trajectories to determine if enlarged brain regions are associated with myelination differences. Further, we will examine correlations between affected brain areas with psychological testing measures to determine which changes most accurately predict autistic symptoms.



Scientific & Medical Relevance: Despite the widespread assertion that autism is a developmental disorder, to date no longitudinal study of neurodevelopment in this condition has been performed. Results of this study will help elucidate both regional differences in autism, as well as the time-course over which such differences manifest. Such information may allow earlier and/or more specific diagnosis, and provide a means of monitoring and evaluating therapeutic interventions.

Publications

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Balardin JB (2015) Relationship Between Surface-Based Brain Morphometric Measures and Intelligence in Autism Spectrum Disorders: Influence of History of Language Delay. in Autism research : official journal of the International Society for Autism Research

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Deoni SC (2011) Mapping infant brain myelination with magnetic resonance imaging. in The Journal of neuroscience : the official journal of the Society for Neuroscience

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Deoni SC (2008) Gleaning multicomponent T1 and T2 information from steady-state imaging data. in Magnetic resonance in medicine

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Deoni SC (2011) Magnetic resonance relaxation and quantitative measurement in the brain. in Methods in molecular biology (Clifton, N.J.)

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Deoni SC (2010) Quantitative relaxometry of the brain. in Topics in magnetic resonance imaging : TMRI

 
Description Alzheimer's Association New Scientist Award
Amount £40,000 (GBP)
Organisation Alzheimer's Association 
Sector Charity/Non Profit
Country United States
Start 02/2010 
End 02/2012
 
Description Effects of Placental Transfusion on Early Brain Development
Amount $2,080,000 (USD)
Funding ID 5R01HD076589-05 
Organisation National Institute of Child Health (NICH) 
Sector Hospitals
Country Pakistan
Start 09/2012 
End 09/2017
 
Description Effects of Placental Transfusion on Early Brain Development
Amount $100,000 (USD)
Organisation Bill and Melinda Gates Foundation 
Sector Charity/Non Profit
Country United States
Start 07/2012 
End 07/2013
 
Description NIMH BRAINS
Amount £1,400,000 (GBP)
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start 09/2009 
End 09/2014
 
Title mcDESPOT 
Description This technique, allows for the first time, non-invasive quantitative estimation of myelin content throughout the brain using MRI. Though the MRC funded project aims to use this technique specifically in investigating autism, it has wide application to neurological and psychiatric disorder research. 
Type Of Material Data analysis technique 
Year Produced 2009 
Provided To Others? Yes  
Impact To date, mcDESPOT has been applied in several areas of MS, schizophrenia and neurodevelopmental research. Within neurodevelopment, we have produced the first non-invasive visualization of white matter and myelin development in healthy infants (2-12 months of age). 
 
Description Clinically Feasible Quantitative Relaxation Time Measurement 
Organisation Bayer
Department Bayer HealthCare
Country Germany 
Sector Private 
PI Contribution We are developing a suite of techniques for performing whole-brain quantitative imaging.
Impact No output as yet.
Start Year 2011
 
Description How does the Deaf Brain Develop? 
Organisation Brown University
Department Department of Pediatrics
Country United States 
Sector Academic/University 
PI Contribution Contribution of imaging expertise and image analysis techniques.
Collaborator Contribution Participant recruitment and clinical expertise
Impact Grant proposal submitted to the Hewlett-Packard Foundation
Start Year 2012
 
Description Imaging Early Brain Development in Infants Born to Mothers with Major Depressive Disorder 
Organisation Brown University
Department Department of Psychiatry and Human Behaviour
Country United States 
Sector Academic/University 
PI Contribution Contribution of imaging expertise and analysis to imaging infants under the age of 1 year.
Collaborator Contribution Selection of research subjects from current on-going studies
Impact Grant proposal in submission
Start Year 2011
 
Description Imaging In Pediatric Epilepsy 
Organisation King's College London
Department Department of Neuroimaging
Country United Kingdom 
Sector Academic/University 
PI Contribution Imaging expertise
Collaborator Contribution Post-doctoral Fellow and clinical expertise
Impact Grant submission to the National Institutes of Health (USA)
Start Year 2012
 
Description Myelin Imaging in Alzheimer's Disease 
Organisation Butler Hospital
Country United States 
Sector Hospitals 
PI Contribution This collaboration aims to investigate the utility of a novel white matter and myelin imaging technique (developed by S Deoni) in the diagnosis and early differentiation of Alzheimer's Dementia.
Collaborator Contribution This collaboration has opened the door to numerous potential applications of the white matter / myelin imaging technique in healthy ageing, vascular and other forms of dementia.
Impact Following initial discussions, this collaboration has so far led to the submission and successful funding for a New Scientist Award to S Deoni by the Alzheimer's Association, entitled: Investigation of Myelin Loss Associated with Alzheimer's Dementia. (approximate value: $80k USD over 2 years)
Start Year 2008
 
Title A rapid method for correcting transmit flip angle errors in MR images 
Description Quantitative imaging techniques, such as mcDESPOT, rely on accurate knowledge of the transmitted flip angle, which varies from it's nominal (or prescribed) value due to intrinsic tissue dieletric effects. We have developed, verified, published and patented a rapid technique for correcting for these flip angle induced errors. 
IP Reference WO2008037994 
Protection Patent granted
Year Protection Granted 2008
Licensed No
Impact This discovery allows the use of the mcDESPOT technique on newer high field systems.
 
Description IRB 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact Presentation of in-going research at local schools specialising in special education. A working collaboration between our group and the schools has resulted, with a number of teachers volunteering within our research lab.

Our group has been invited back to give several talks, furthering the working relationship between the school and our group.
Year(s) Of Engagement Activity 2010