Longitudinal measurement of the developing grey matter in preterm subjects using multi-modal MRI.

Preterm birth is a major public health concern, with the severity and occurrence of adverse outcome increasing with earlier delivery. Being born preterm disrupts a time of rapid brain development: in addition to volumetric growth, the cortex folds, myelination is occurring and there are changes on the cellular level. These neurological events have been imaged non-invasively using diffusion-weighted (DW) MRI. In this population, there has been a focus on examining diffusion in the white matter, but the grey matter is also critically important for neurological health. We acquired multi-shell high-resolution diffusion data on 12 infants born at ≤28weeks of gestational age at two time-points: once when stable after birth, and again at term-equivalent age. We used the Neurite Orientation Dispersion and Density Imaging model (NODDI) (Zhang et al., 2012) to analyse the changes in the cerebral cortex and the thalamus, both grey matter regions. We showed region-dependent changes in NODDI parameters over the preterm period, highlighting underlying changes specific to the microstructure. This work is the first time that NODDI parameters have been evaluated in both the cortical and the thalamic grey matter as a function of age in preterm infants, offering a unique insight into neuro-development in this at-risk population

Early brain morphometrics from neonatal MRI predict motor and cognitive outcomes at 2-years corrected age in very preterm infants

Infants born very preterm face a range of neurodevelopmental challenges in cognitive, language, behavioural and/or motor domains. Early accurate identification of those at risk of adverse neurodevelopmental outcomes, through clinical assessment and Magnetic Resonance Imaging (MRI), enables prognostication of outcomes and the initiation of targeted early interventions. This study utilises a prospective cohort of 181 infants born <31 weeks gestation, who had 3T MRIs acquired at 29-35 weeks postmenstrual age and a comprehensive neurodevelopmental evaluation at 2 years corrected age (CA). Cognitive, language and motor outcomes were assessed using the Bayley Scales of Infant and Toddler Development – Third Edition and functional motor outcomes using the Neuro-sensory Motor Developmental Assessment. By leveraging advanced structural MRI pre-processing steps to standardise the data, and the state-of-the-art developing Human Connectome Pipeline, early MRI biomarkers of neurodevelopmental outcomes were identified. Using Least Absolute Shrinkage and Selection Operator (LASSO) regression, significant associations between brain structure on early MRIs with 2-year outcomes were obtained (r = 0.51 and 0.48 for motor and cognitive outcomes respectively) on an independent 25% of the data. Additionally, important brain biomarkers from early MRIs were identified, including cortical grey matter volumes, as well as cortical thickness and sulcal depth across the entire cortex. Adverse outcome on the Bayley-III motor and cognitive composite scores were accurately predicted, with an Area Under the Curve of 0.86 for both scores. These associations between 2-year outcomes and patient prognosis and early neonatal MRI measures demonstrate the utility of imaging prior to term equivalent age for providing earlier commencement of targeted interventions for infants born preterm

Early changes in brain structure correlate with language outcomes in children with neonatal encephalopathy.

Global patterns of brain injury correlate with motor, cognitive, and language outcomes in survivors of neonatal encephalopathy (NE). However, it is still unclear whether local changes in brain structure predict specific deficits. We therefore examined whether differences in brain structure at 6 months of age are associated with neurodevelopmental outcomes in this population. We enrolled 32 children with NE, performed structural brain MR imaging at 6 months, and assessed neurodevelopmental outcomes at 30 months. All subjects underwent T1-weighted imaging at 3 T using a 3D IR-SPGR sequence. Images were normalized in intensity and nonlinearly registered to a template constructed specifically for this population, creating a deformation field map. We then used deformation based morphometry (DBM) to correlate variation in the local volume of gray and white matter with composite scores on the Bayley Scales of Infant and Toddler Development (Bayley-III) at 30 months. Our general linear model included gestational age, sex, birth weight, and treatment with hypothermia as covariates. Regional brain volume was significantly associated with language scores, particularly in perisylvian cortical regions including the left supramarginal gyrus, posterior superior and middle temporal gyri, and right insula, as well as inferior frontoparietal subcortical white matter. We did not find significant correlations between regional brain volume and motor or cognitive scale scores. We conclude that, in children with a history of NE, local changes in the volume of perisylvian gray and white matter at 6 months are correlated with language outcome at 30 months. Quantitative measures of brain volume on early MRI may help identify infants at risk for poor language outcomes

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

Deep and cortical gray matter volumetric of extremely low gestational age and full term newborn children at 9 to 11 years of age

PURPOSE: Extremely low gestation age newborns (ELGANs) are at high risk for developmental brain abnormalities. This study is to determine deep and superficial gray matter volumetric abnormalities of ELGAN children and full term children at 9 to 11 years of age. METHODS: High-resolution magnetic resonance imaging (MRI) scans were obtained from 160 ELGAN children (70 males and 90 females) and 30 full term children (15 males and 15 females) using a dual-echo turbo spin-echo (DE-TSE) pulse sequence at 3.0T (or 1.5T at only one site). The DICOM MR images were processed with quantitative MRI algorithms programmed in Mathcad. The brain deep gray matter (dGM) was manually segmented; dGM and cortical gray matter (cGM) volumes were quantified using semi-automated clustering segmentation algorithms. RESULTS: ELGAN children had smaller deep gray matter volume (41.86 ± 7.42 ml) than full term children (49.24 ± 10.91 ml). Deep gray matter volumes of ELGAN children showed similar distribution range (SD = 7.42 ml) with the full term children (SD = 10.91 ml). About 83% of the ELGAN children had smaller deep gray matter volumes compared to the average volume of full term children at the same ages. Male children had smaller deep gray matter volumes in ELGAN (42.77 ± 7.09 ml) than in full term (51.74 ± 9.76 ml), but female children had similar deep gray matter volumes in ELGAN (41.14 ± 7.62 ml) with full term (44.27 ± 7.56 ml). Additionally, smaller deep gray matter volumes were observed more often in males (90%) than in females (65%). Cortical gray matter volumes of ELGAN children distributed from 345.60 to 1177.50ml. Moreover, female ELGAN children had smaller cortical gray matter volumes (828.14 ± 147.61 ml) than males (883.13 ± 151.34 ml). Correlation analysis revealed a positive correlation between cerebral deep gray matter volumes and total gray matter volumes (total: r = 0.57, p<0.0001; male: r = 0.542, p < 0.0001; female: r = 0.587, p < 0.0001). CONCLUSION: Male ELGAN children had smaller brain deep gray matter volumes than full term children at ages of 9 to 11 years, but not females. Cortical gray matter volumes of female ELGAN were smaller than male ELGAN. Smaller deep gray matter volumes were associated with smaller total gray matter volumes in ELGAN children

Early brain activity : Translations between bedside and laboratory

Neural activity is both a driver of brain development and a readout of developmental processes. Changes in neuronal activity are therefore both the cause and consequence of neurodevelopmental compromises. Here, we review the assessment of neuronal activities in both preclinical models and clinical situations. We focus on issues that require urgent translational research, the challenges and bottlenecks preventing translation of biomedical research into new clinical diagnostics or treatments, and possibilities to overcome these barriers. The key questions are (i) what can be measured in clinical settings versus animal experiments, (ii) how do measurements relate to particular stages of development, and (iii) how can we balance practical and ethical realities with methodological compromises in measurements and treatments.Peer reviewe

Measuring Cot-Side the Effects of Parenteral Nutrition on Preterm Cortical Function

Early nutritional compromise after preterm birth is shown to affect long-term neurodevelopment, however, there has been a lack of early functional measures of nutritional effects. Recent progress in computational electroencephalography (EEG) analysis has provided means to measure the early maturation of cortical activity. Our study aimed to explore whether computational metrics of early sequential EEG recordings could reflect early nutritional care measured by energy and macronutrient intake in the first week of life. A higher energy or macronutrient intake was assumed to associate with improved development of the cortical activity. We analyzed multichannel EEG recorded at 32 weeks (32.4 ± 0.7) and 36 weeks (36.6 ± 0.9) of postmenstrual age in a cohort of 28 preterm infants born before 32 weeks of postmenstrual age (range: 24.3–32 weeks). We computed several quantitative EEG measures from epochs of quiet sleep (QS): (i) spectral power; (ii) continuity; (iii) interhemispheric synchrony, as well as (iv) the recently developed estimate of maturational age. Parenteral nutritional intake from day 1 to day 7 was monitored and clinical factors collected. Lower calories and carbohydrates were found to correlate with a higher reduction of spectral amplitude in the delta band. Lower protein amount associated with higher discontinuity. Both higher proteins and lipids intake correlated with a more developmental increase in interhemispheric synchrony as well as with better progress in the estimate of EEG maturational age (EMA). Our study shows that early nutritional balance after preterm birth may influence subsequent maturation of brain activity in a way that can be observed with several intuitively reasoned and transparent computational EEG metrics. Such measures could become early functional biomarkers that hold promise for benchmarking in the future development of therapeutic interventions.Peer reviewe