Tract-based spatial statistics (TBSS): application to detecting white matter tract variation in mild hypoxic-ischemic neonates

The aim of this study is to employ tract-based spatial statistics (TBSS) to analyze the voxel-wise differences in DTI parameters between normal and mild hypoxic-ischemic (HI) neonatal brains. Forty-one full term neonates (24 normal controls and 17 with mild HI injury) and 31 preterm neonates (20 normal controls and 11 with mild HI injury) underwent T1 weighted imaging, T2 weighted imaging and diffusion tensor imaging (DTI) within 28 days after birth. The voxel differences of fractional anisotropy (FA), lambda1, lambda2, and lambda3 values between mild HI group and control group were analyzed in preterm and full term neonates respectively. The significantly decreased FA with increased lambda2, lambda3 in corticospinal tract, genu of corpus callosum (GCC), external capsule (EC) and splenium of the corpus callosum (SCC) in mild HI neonates suggested deficits or delays in both myelination and premyelination. Such impaired corticospinal tract, in both preterm and term neonates, may directly lead to the subsequent poor motor performance. Impaired EC and SCC, the additional injured sites observed in full term neonates with mild HI injury, may be causally responsible for the dysfunction in coordination and integration. In conclusion, TBSS provides an objective, independent and sensitive method for DTI data analysis of neonatal white matter alterations after mild HI injury.published_or_final_versio

Disrupted brain connectivity in children treated with therapeutic hypothermia for neonatal encephalopathy

Therapeutic hypothermia following neonatal encephalopathy due to birth asphyxia reduces death and cerebral palsy. However, school-age children without cerebral palsy treated with therapeutic hypothermia for neonatal encephalopathy still have reduced performance on cognitive and motor tests, attention difficulties, slower reaction times and reduced visuo-spatial processing abilities compared to typically developing controls. We acquired diffusion-weighted imaging data from school-age children without cerebral palsy treated with therapeutic hypothermia for neonatal encephalopathy at birth, and a matched control group. Voxelwise analysis (33 cases, 36 controls) confirmed reduced fractional anisotropy in widespread areas of white matter in cases, particularly in the fornix, corpus callosum, anterior and posterior limbs of the internal capsule bilaterally and cingulum bilaterally. In structural brain networks constructed using probabilistic tractography (22 cases, 32 controls), graph-theoretic measures of strength, local and global efficiency, clustering coefficient and characteristic path length were found to correlate with IQ in cases but not controls. Network-based statistic analysis implicated brain regions involved in visuo-spatial processing and attention, aligning with previous behavioural findings. These included the precuneus, thalamus, left superior parietal gyrus and left inferior temporal gyrus. Our findings demonstrate that, despite the manifest successes of therapeutic hypothermia, brain development is impaired in these children

Diffusion tensor imaging and resting state functional connectivity as advanced imaging biomarkers of outcome in infants with hypoxic-ischaemic encephalopathy treated with hypothermia

Therapeutic hypothermia confers significant benefit in term neonates with hypoxic-ischaemic encephalopathy (HIE). However, despite the treatment nearly half of the infants develop an unfavourable outcome. Intensive bench-based and early phase clinical research is focused on identifying treatments that augment hypothermic neuroprotection. Qualified biomarkers are required to test these promising therapies efficiently. This thesis aims to assess advanced magnetic resonance imaging (MRI) techniques, including diffusion tensor imaging (DTI) and resting state functional MRI (fMRI) as imaging biomarkers of outcome in infants with HIE who underwent hypothermic neuroprotection. FA values in the white matter (WM), obtained in the neonatal period and assessed by tract-based spatial statistics (TBSS), correlated with subsequent developmental quotient (DQ). However, TBSS is not suitable to study grey matter (GM), which is the primary site of injury following an acute hypoxic-ischaemic event. Therefore, a neonatal atlas-based automated tissue labelling approach was applied to segment central and cortical grey and whole brain WM. Mean diffusivity (MD) in GM structures, obtained in the neonatal period correlated with subsequent DQ. Although the central GM is the primary site of injury on conventional MRI following HIE; FA within WM tissue labels also correlated to neurodevelopmental performance scores. As DTI does not provide information on functional consequences of brain injury functional sequel of HIE was studied with resting state fMRI. Diminished functional connectivity was demonstrated in infants who suffered HIE, which associated with an unfavourable outcome. The results of this thesis suggest that MD in GM tissue labels and FA either determined within WM tissue labels or analysed with TBSS correlate to subsequent neurodevelopmental performance scores in infants who suffered HIE treated with hypothermia and may be applied as imaging biomarkers of outcome in this population. Although functional connectivity was diminished in infants with HIE, resting state fMRI needs further study to assess its utility as an imaging biomarker following a hypoxic-ischaemic brain injury.Open Acces

The neonatal brain in Down Syndrome : white matter alterations and the relationship between brain volumes and childhood cognitive abilities

Down Syndrome (DS) is the most common genetic cause of intellectual disability. This project is the first attempt to (1) determine associations between early structural brain imaging with subsequent neurodevelopmental outcomes in DS; and (2) explore white matter (WM) alterations in neonates with DS. Magnetic resonance imaging (MRI) was performed on neonates with DS and age- and sex-matched controls from 32 to 45 weeks postmenstrual age. WM microstructure alterations were explored with Tract-Based Spatial Statistics (TBSS) and Fixel-based Analysis (FBA) in a subsample of 10 neonates with DS and 39 typical developing (TD) controls. Planned and exploratory correlations were performed to analyse the relationship between neonatal brain volumes and cognitive outcome in infants with DS in an independent sample of 12 individuals with DS, who had neuropsychological assessments performed, between 6 months and 5 years of age. The diffusion data showed that all TBSS metrics (including fractional anisotropy and mean diffusivity) were reduced in the neonates with DS, relative to TD, in anterior WM tracts, corpus callosum and cerebral peduncles. FBA results showed statistically significant differences between DS and TD groups in WM organisation, but image registration was compromised by underlying volumetric difference between the groups and therefore the results were deemed unreliable. Regarding the structural data, there were no significant correlations between any of the brain tissue volumes and the outcome measures, but there were medium to large effect sizes (e.g., correlations between cortical grey matter and Mullen Receptive Language scores). However, there was a significant strong negative correlation between lateral ventricle volumes and Mullen Receptive Language Developmental quotient (DQ) scores (i.e., larger ventricle volumes relate to lower DQ 5 scores, or bigger delay). Overall, the research demonstrated that WM alterations in DS are present from early on in life, consistent with previous findings. However, it is too early to determine whether neonatal brain volumes might help predict measures of cognitive abilities in DS. Further research is needed to support these findings, to investigate whether other brain measures might be better predictors of outcomes (e.g., functional measures), and to understand the developmental mechanisms underlying the DS genotype-phenotype relationship across multiple levels of description

The relationships of inflammation with brain structures in older individuals as revealed by multimodal magnetic resonance imaging techniques

Inflammation plays important roles in ageing and neurodegenerative diseases. Although studies have shown the association of increased inflammatory markers with brain structural and functional degeneration in ageing, the implication for clinical practice is often restricted by the examination of selected inflammatory markers and inconsistent findings across different studies. This Ph.D. thesis aims to examine the impacts of inflammation on ageing brains in community-based older individuals aged 70-90 years, using multimodal MRI data. In order to assess how inflammation associates with ageing brains, I first examined age-related brain structural changes over two years in the study sample. The findings showed widespread atrophy across brain grey (GM) and white matter (WM), which is comparable to previous longitudinal studies in similar age range. Next, all inflammatory markers available to the study sample (n = 11) were examined for their associations with brain structural indices. The results showed that higher macrophage inhibitory cytokine-1 (MIC-1/GDF15) levels were associated with lower GM and WM volumes. The inflammatory markers were then categorised into cytokine, acute phase and vascular factors using principal component analysis. Higher levels of the acute phase factor were associated with heavier WM hyperintensity (WMH) burdens, whereas higher levels of the vascular factor were linked to greater GM and WM atrophy. The relationship of MIC-1/GDF15 levels with brain was then investigated in more details using multimodal MRI data in both cross-sectional and longitudinal settings. The findings indicated that higher MIC-1/GDF15 serum levels were associated with GM and WM deterioration, and decline in WM microstructural integrity. Over two years, individuals with more increase in MIC-1/GDF15 levels had greater atrophy in cortices and subcortical structures. In conclusion, this thesis started with examining the association of eleven inflammatory markers with ageing brains, and then focused on MIC-1/GDF15 in relation to various brain structural measures. It identified an inverse relationship between MIC-1/GDF15 and integrity of the ageing brains. The findings have practical implications for using MIC-1/GDF15 as a diagnostic and therapeutic target for age-related brain degeneration