Role of the advanced MRI sequences in predicting the outcome of preterm neonates

AIM The aim of the project is to evaluate the role of advanced MRI sequences (susceptibility weight imaging (SWI), diffusion tensor imaging (DTI), and arterial spin labeling (ASL) perfusion) in detecting early changes that affect preterm neonatal brain, especially in those patients without lesions at conventional MRI or with small brain injuries (i.e. low grade germinal matrix-intraventricular hemorrhage (GMHIVH)), and to correlate these subtle brain abnormalities with neurodevelopmental outcome at 24 months. METHODS Since November 2015 until June 2017, 287 preterm neonates and 108 term neonates underwent a 3T or 1.5T MRI study at term corrected age (40\ub11 weeks). SWI, DTI and ASL sequences were performed in all neonates. SWI sequences were evaluated using both a qualitative (SWI venography) and quantitative (Quantitative Susceptibility Map analysis (SWI-QSM)) approach. DTI data were analyzed using a Tract-Based Spatial Statistics analysis (TBSS). ASL studies were processed to estimate Cerebral Blood Flow (CBF) maps. Perinatal clinical data were collected for all neonates. Neurodevelopmental data were evaluated at 24 months in 175 neonates using 0-2 Griffiths Developmental Scales. RESULTS The analysis performed on SWI-venography revealed differences in subependymal veins morphology between preterm and term neonates with normal brain MRI, with a higher variability from the typical anatomical pattern in preterm neonates. The same analysis performed in preterm neonates with GMH-IVH revealed that the anatomical features of subependymal veins may play a potential role as predisposing factor for GMH-IVH. Moreover, the SWI-QSM analysis revealed a greater paramagnetic susceptibility in several periventricular white matter (WM) regions in preterm neonates with GMH-IVH than in healthy controls. This finding is likely related to the accumulation of hemosiderin/ferritin following the diffusion of large amounts of intraventricular blood products into the WM, and it is also supposed to trigger the cascade of lipid peroxidation and free radical formation that promote oxidative and inflammatory injury of the WM in neonatal brain after GMH-IVH. The TBSS analysis confirmed that microstructural WM injury can occur in preterm neonates with low grade GMH-IVH even in the absence of overt signal changes on conventional MRI, with different patterns of WM involvement depending on gestational age. Moreover, the distribution of these WM microstructural alterations after GMH-IVH correlates with specific neurodevelopmental impairments at 24 months of age. Finally, the analysis of brain perfusion at term-corrected age revealed lower CBF in preterms with sub-optimal neuromotor development, reinforcing the hypothesis that impaired autoregulation of CBF may contribute to the development of brain damage in preterm neonates. CONCLUSION Advanced MRI sequences can assist the standard perinatal brain imaging in the early diagnosis of preterm neonatal brain lesions and can provide new insights for predicting the neurodevelopmental trajectory. However, detailed and serial imaging of carefully chosen cohorts of neonates coupled with longer clinical follow-up are essential to ensure the clinical significance of these novel findings

Mapping White Matter Microstructure in the One Month Human Brain

White matter microstructure, essential for efficient and coordinated transmission of neural communications, undergoes pronounced development during the first years of life, while deviations to this neurodevelopmental trajectory likely result in alterations of brain connectivity relevant to behavior. Hence, systematic evaluation of white matter microstructure in the normative brain is critical for a neuroscientific approach to both typical and atypical early behavioral development. However, few studies have examined the infant brain in detail, particularly in infants under 3 months of age. Here, we utilize quantitative techniques of diffusion tensor imaging and neurite orientation dispersion and density imaging to investigate neonatal white matter microstructure in 104 infants. An optimized multiple b-value diffusion protocol was developed to allow for successful acquisition during non-sedated sleep. Associations between white matter microstructure measures and gestation corrected age, regional asymmetries, infant sex, as well as newborn growth measures were assessed. Results highlight changes of white matter microstructure during the earliest periods of development and demonstrate differential timing of developing regions and regional asymmetries. Our results contribute to a growing body of research investigating the neurobiological changes associated with neurodevelopment and suggest that characteristics of white matter microstructure are already underway in the weeks immediately following birth

White matter injury predicts disrupted functional connectivity and microstructure in very preterm born neonates

© 2018 The Authors Objective: To determine whether the spatial extent and location of early-identified punctate white matter injury (WMI) is associated with regionally-specific disruptions in thalamocortical-connectivity in very-preterm born neonates. Methods: 37 very-preterm born neonates (median gestational age: 28.1 weeks; interquartile range [IQR]: 27–30) underwent early MRI (median age 32.9 weeks; IQR: 32–35), and WMI was identified in 13 (35%) neonates. Structural T1-weighted, resting-state functional Magnetic Resonance Imaging (rs-fMRI, n = 34) and Diffusion Tensor Imaging (DTI, n = 31) sequences were acquired using 3 T-MRI. A probabilistic map of WMI was developed for the 13 neonates demonstrating brain injury. A neonatal atlas was applied to the WMI maps, rs-fMRI and DTI analyses to extract volumetric, functional and microstructural data from regionally-specific brain areas. Associations of thalamocortical-network strength and alterations in fractional anisotropy (FA, a measure of white-matter microstructure) with WMI volume were assessed in general linear models, adjusting for age at scan and cerebral volumes. Results: WMI volume in the superior (β = −0.007; p =.02) and posterior corona radiata (β = −0.01; p =.01), posterior thalamic radiations (β = −0.01; p =.005) and superior longitudinal fasciculus (β = −0.02; p =.001) was associated with reduced connectivity strength between thalamus and parietal resting-state networks. WMI volume in the left (β = −0.02; p =.02) and right superior corona radiata (β = −0.03; p =.008), left posterior corona radiata (β = −0.03; p =.01), corpus callosum (β = −0.11; p \u3c.0001) and right superior longitudinal fasciculus (β = −0.02; p =.02) was associated with functional connectivity strength between thalamic and sensorimotor networks. Increased WMI volume was also associated with decreased FA values in the corpus callosum (β = −0.004, p =.015). Conclusions: Regionally-specific alterations in early functional and structural network complexity resulting from WMI may underlie impaired outcomes

A structural MRI study of human brain development from birth to two years

pre-printBrain development in the first 2 years after birth is extremely dynamic and likely plays an important role in neurodevelopmental disorders, including autism and schizophrenia. Knowledge regarding this period is currently quite limited. We studied structural brain development in healthy subjects from birth to 2. Ninety-eight children received structural MRI scans on a Siemens head-only 3T scanner with magnetization prepared rapid gradient echo T1-weighted, and turbo spin echo, dual-echo (proton density and T2 weighted) sequences: 84 children at 2- 4 weeks, 35 at 1 year and 26 at 2 years of age. Tissue segmentation was accomplished using a novel automated approach. Lateral ventricle, caudate, and hippocampal volumes were also determined. Total brain volume increased 101% in the first year, with a 15% increase in the second. The majority of hemispheric growth was accounted for by gray matter, which increased 149% in the first year; hemispheric white matter volume increased by only 11%. Cerebellum volume increased 240% in the first year. Lateral ventricle volume increased 280% in the first year, with a small decrease in the second. The caudate increased 19% and the hippocampus 13% from age 1 to age 2. There was robust growth of the human brain in the first two years of life, driven mainly by gray matter growth. In contrast, white matter growth was much slower. Cerebellum volume also increased substantially in the first year of life. These results suggest the structural underpinnings of cognitive and motor development in early childhood, as well as the potential pathogenesis of neurodevelopmental disorders

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 Brains of Babies: A Surface Based Approach To Study Cortical Development in Term and Preterm Human Infants

Half a million infants are born before term gestation each year in the United States. Although advances in newborn medicine have increased survival rates of very preterm infants to almost 90%, surviving preterm infants are at increased risk for developing lasting neurologic impairments. In order to develop a plausible neuroprotective strategy it is imperative that we improve our understanding of normal cortical development and develop tools to evaluate injury. Using a surface based approach we have characterized normal cortical development in healthy term infants and analyzed abnormalities associated with preterm birth. Accurate cortical surface reconstructions for each hemisphere of 12 healthy term gestation infants and 12 low-risk preterm infants at term equivalent postmenstrual age were generated from structural magnetic resonance imaging data using a novel segmentation algorithm. Data from the 12 term infants were used to establish the first population average surface based atlas of human cerebral cortex at term gestation. Comparing this atlas to a previously established atlas of adult cortex revealed that cortical structure in term infants is similar to the adult in many respects, including the pattern of individual variability and the presence of statistically significant structural asymmetries in lateral temporal cortex, suggesting that that several features of cortical shape are minimally reliant on the postnatal environment. Surprisingly, the pattern of postnatal expansion in surface area is strikingly non-uniform; regions of lateral temporal, parietal, and frontal cortex expand nearly twice as much as other regions in insular and medial occipital cortex. Differential expansion may point to differential sensitivity of cortical circuits to normal or aberrant childhood experiences. The pattern of human postnatal expansion parallels the pattern of evolutionary cortical expansion revealed by comparison between the human and the macaque monkey. Finally, in comparing term and preterm infants, region-specific alterations in cortical folding in the preterm population were found. The most striking shape differences were present in the orbitofrontal and inferior occipital regions with reductions in folding in the insular, lateral temporal, lateral parietal, and lateral frontal cortex. Overall these findings improve our understanding of normal cortical development and help elucidate the potential pathways for cortical injury in preterm infants

Diffusion Weighted Imaging of the Neonatal Brain

Although in the last decades advances in fetal and neonatal medicine have reduced mortality in neonatal intensive care units in the Western world, the morbidity due to brain injury remains high. Patterns of neonatal brain injury can be roughly divided in (1) term and (2) preterm patterns. Table 1 shows the number of infants admitted to the NICU in the Sophia Children’s Hospital between March 2008 and March 2010 with a typical ‘neurological’ diagnosis. The table highlights differences in diagnoses between preterm and term infants in relation to gender. In preterm infants the most common diagnoses are: persistent flaring (hypersignal intensity seen in periventricluar white matter using cranial ultrasound), intraventricular haemorrhage and venous infarction. In term infants perinatal asphyxia and perinatal stroke are most often reported

Functional properties of resting state networks in healthy full-term newborns.

Objective, early, and non-invasive assessment of brain function in high-risk newborns is critical to initiate timely interventions and to minimize long-term neurodevelopmental disabilities. A prerequisite to identifying deviations from normal, however, is the availability of baseline measures of brain function derived from healthy, full-term newborns. Recent advances in functional MRI combined with graph theoretic techniques may provide important, currently unavailable, quantitative markers of normal neurodevelopment. In the current study, we describe important properties of resting state networks in 60 healthy, full-term, unsedated newborns. The neonate brain exhibited an efficient and economical small world topology: densely connected nearby regions, sparse, but well integrated, distant connections, a small world index greater than 1, and global/local efficiency greater than network cost. These networks showed a heavy-tailed degree distribution, suggesting the presence of regions that are more richly connected to others (\u27hubs\u27). These hubs, identified using degree and betweenness centrality measures, show a more mature hub organization than previously reported. Targeted attacks on hubs show that neonate networks are more resilient than simulated scale-free networks. Networks fragmented faster and global efficiency decreased faster when betweenness, as opposed to degree, hubs were attacked suggesting a more influential role of betweenness hub in the neonate network

Characterisation of the Haemodynamic Response Function (HRF) in the neonatal brain using functional MRI

Background: Preterm birth is associated with a marked increase in the risk of later neurodevelopmental impairment. With the incidence rising, novel tools are needed to provide an improved understanding of the underlying pathology and better prognostic information. Functional Magnetic Resonance Imaging (fMRI) with Blood Oxygen Level Dependent (BOLD) contrast has the potential to add greatly to the knowledge gained through traditional MRI techniques. However, it has been rarely used with neonatal subjects due to difficulties in application and inconsistent results. Central to this is uncertainity regarding the effects of early brain development on the Haemodynamic Response Function (HRF), knowledge of which is fundamental to fMRI methodology and analysis. Hypotheses: (1) Well localised and positive BOLD functional responses can be identified in the neonatal brain. (2) The morphology of the neonatal HRF differs significantly during early human development. (3) The application of an age-appropriate HRF will improve the identification of functional responses in neonatal fMRI studies. Methods: To test these hypotheses, a systematic fMRI study of neonatal subjects was carried out using a custom made somatosensory stimulus, and an adapted study design and analysis pipeline. The neonatal HRF was then characterised using an event related study design. The potential future application of the findings was then tested in a series of small experiments. Results: Well localised and positive BOLD functional responses were identified in neonatal subjects, with a maturational tendency towards an increasingly complex pattern of activation. A positive amplitude HRF was identified in neonatal subjects, with a maturational trend of a decreasing time-to-peak and increasing positive peak amplitude. Application of the empirical HRF significantly improved the precision of analysis in further fMRI studies. Conclusions: fMRI can be used to study functional activity in the neonatal brain, and may provide vital new information about both development and pathology