B r a i n De v e l o p m e n t i n P ret e r m Infants Assessed Using Advanced M RI Te c hn i q u es Nora Tusor, MDa, Tomoki Arichi, MBChB, MRCPCH, PhDa,b, Serena J. Counsell, PhDa, A. David Edwards, MBBS, FRCP, FRCPCH, FMedScia,b,* KEYWORDS  MRI  Diffusion-MRI  Functional MRI  Preterm  Brain KEY POINTS  Diffusion MRI (d-MRI) metrics change with maturation. These changes reflect, in white matter, alterations in water content, axonal caliber, oligodendrocyte proliferation, and myelination. In cortical gray matter changes in d-MRI measures represent increasing cellular density and maturing dendritic cytoarchitecture.  White matter structure, as assessed by fractional anisotropy (FA), correlates with performance in specific neural systems. In addition, FA measures are negatively correlated with immaturity at birth and are reduced in comorbidities associated with preterm birth including acute and chronic respiratory disease and sepsis.  Functional MRI (fMRI) allows the noninvasive assessment of functional brain activity and can study intrinsic neural activity (resting state fMRI) or the response to external stimulation (task-based fMRI) by sampling temporal changes in the blood oxygen level–dependent signal. Resting state networks demonstrate a network-specific rate of development, exhibiting different rates of coherent interhemispheric activity with advancing postmenstrual age, with the auditory system seemingly maturing before others.

INTRODUCTION

The incidence of preterm birth (delivery before 37 weeks’ gestation) continues to increase, with an estimated 14.9 million infants (representing 11.1% of all births) delivered worldwide each year.1 The importance of the preterm period (equivalent to the third trimester of gestation) for brain development is emphasized by a striking increase

The authors have no conflicts to disclose. a Centre for the Developing Brain, Department of Perinatal Imaging, St Thomas’ Hospital, King’s College London, Westminster Bridge Road, London SE1 7EH, UK; b Department of Bioengineering, Imperial College London, South Kensington Campus, London SW7 2AZ, UK * Corresponding author. Centre for the Developing Brain, King’s College London, St Thomas’ Hospital, Westminster Bridge Road, London SE1 7EH, UK. E-mail address: [email protected] Clin Perinatol 41 (2014) 25–45 http://dx.doi.org/10.1016/j.clp.2013.10.001 perinatology.theclinics.com 0095-5108/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.

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in the incidence of adverse neurodevelopmental outcome, with the spectrum of life-long dysfunction covering the motor, cognitive, and psychiatric domains.2,3 In response, there has been an increase in the development of imaging techniques that can be used by both scientists and clinicians to characterize early brain development, to assess the response to perinatal brain injury, and as biomarkers for testing and monitoring the effects of potential interventional strategies.4 Magnetic resonance imaging (MRI) during the neonatal period has become widely used to provide detailed images of the developing brain and define malformations, establish detailed patterns of brain injury, and provide prognostic information.5–10 However, a significant proportion of preterm infants continue to suffer from cognitive impairment despite an apparently normal appearance to their MRI brain scan, suggesting that a more subtle but global insult underlies these difficulties.11 In addition to providing a highly detailed qualitative assessment of brain development, a major advantage of MRI lies in the quantifiable nature of the acquired signal and inherent flexibility of the technique, which can allow accurate measurement of diverse aspects of macroscopic brain tissue structure, integrity, composition, and even function. This review describes the principles underlying these advanced MRI techniques and the findings of studies that highlight their potential to understand early brain development, and in particular, characterize the pathophysiology of preterm brain injury. Due to spatial constraints, the review concentrates predominately on 2 exemplars that underline the ability of MRI to provide diverse yet detailed information about both brain tissue microstructure (diffusion weighted imaging [d-MRI]), and functional activity (blood oxygen level–dependent [BOLD] functional MRI [fMRI]). NEONATAL BRAIN TEMPLATES AND ATLASES

To perform systematic MRI studies across populations of subjects, it is often necessary to normalize the data spatially by accurately aligning or “registering” each of the individual subject brain images to a common space (template).12 Such templates can also allow alignment to standard brain “atlases”, with which regions of the brain can be labeled by tissue type or anatomic location. Although in adult subjects this is relatively easily done using widely available standard space templates, this process is considerably more difficult when studying neonatal subjects because of the marked heterogeneity inherent to the developing brain, as its macroscopic structure proceeds along a dramatic, but highly structured sequence of maturation in the perinatal period and early infancy. To avoid significant bias, data should therefore be registered to an age-appropriate atlas, which accurately represents the dynamic changes occurring during early brain development (Fig. 1).13,14 An important additional benefit of this process is that it is then possible to detect and quantify local tissue abnormalities by exact measurement of the variations in anatomy between an atlas and individual subjects.15 Such atlases should be publically available resources, to allow for consistency and data sharing across the neonatal MRI community (www.brain-development.org). D-MRI

Contrast in d-MRI is based on the random thermal motion of water molecules.16 The travel of water molecules can be represented by a diffusion coefficient, which depends on several factors, including the temperature, molecular mass, viscosity, and microstructural features of the environment. The high sensitivity of the diffusion coefficient to the local microstructure in particular enables its use as a probe of the physical properties of biologic tissues. In the presence of a spatially varying magnetic field, the random motion of protons in diffusing water molecules results in dephasing of the

Advanced MRI Techniques Review

Fig. 1. A 4D atlas of the developing neonatal brain as visualized by T2-weighted MR images. Axial (top row) and coronal (bottom row) slices, with the postmenstrual age (in weeks) listed across the bottom of the figure. Such atlases are vital so that individual subject MRI data can be spatially normalized and allow population-wide studies. (From Serag A, Aljabar P, Ball G, et al. Construction of a consistent high-definition spatio-temporal atlas of the developing brain using adaptive kernel regression. Neuroimage 2012;59(3):2260; with permission.)

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magnetic resonance signal, producing a reduction in its amplitude. Because spatially varying magnetic fields are used for slice selection and spatial encoding in all MRIs, water molecular diffusion leads to a reduction in signal intensity in all images, although the effect is normally quite small. However, by deliberately applying large magnetic field gradients in particular directions, diffusion can be made the dominant image contrast mechanism, and variations in diffusion properties can be visualized, including their directional dependence.17 In d-MRI, the diffusion coefficient is not measured directly; rather, it is inferred from observations of the molecular displacement over a given time. As the extent of diffusion in a given tissue depends on both the local microstructural environment and the choice of diffusion weighting, the diffusion coefficient estimated in a specific tissue is termed the apparent diffusion coefficient (ADC). To quantify diffusion, a minimum of 2 signal measurements are needed: one with diffusion weighting and one without diffusion weighting. The b value reflects the degree of diffusion weighting applied and in clinical settings its value ranges between 750 and 1500 s/mm2. The random motion of water molecules in a homogenous medium such as cerebrospinal fluid is equal in all directions (isotropic). If diffusing water molecules encounter any hindrance, the displacement per unit time will be lower than that observed in free water, and hence, the diffusion of water molecules in a tissue with ordered microstructure, such as white matter (WM), is directionally dependent (anisotropic).18 Anisotropy is influenced by barriers to diffusion, which are both nonaxonal (such as the myelin sheath and neurofibrils) and axonal. Of particular salience to the unmyelinated WM found in the preterm brain, studies in both animals and human infants have shown the axonal membranes themselves are sufficient barriers to hinder water diffusion perpendicular to WM fibers (relative to diffusion along the fibers).19–25 Moreover, genetically modified animal models of dysmyelination have shown that while myelin also modulates anisotropy, the effect is to a smaller degree than the axonal membranes.26–30 DIFFUSION TENSOR IMAGING

A mathematical tensor model (a “diffusion tensor”) is commonly used to characterize diffusion in brain tissue, where water molecule displacement per unit time is unlikely to be equal in all directions. To examine diffusivity in a tissue with ordered microstructure, a minimum of 6 noncollinear directions of diffusion sensitization is required, in addition to one with no diffusion weighting. However, to construct the diffusion tensor accurately, frequently more than 30 directions are acquired. The diffusion tensor can be conceptualized as an ellipsoid, in which the long axis represents the direction with the highest diffusivity (termed axial diffusivity). Its magnitude is given by the major eigenvalue (l1) and its direction is given by the major eigenvector. Perpendicular to the major eigenvector are 2 short axes, with their respective eigenvalues (l2, l3), which are often averaged to produce a measure of radial diffusivity (Fig. 2).17,31 Averaged mean diffusivity can be calculated as one-third of the trace of the diffusion tensor that provides the overall magnitude of water diffusion. The most commonly used measure of diffusion is fractional anisotropy (FA), which is the fraction of the magnitude of diffusion that can be attributed to anisotropic diffusion. FA values range between 0 (diffusion that is equal in all directions) and 1 (Fig. 3). D-MRI DATA ANALYSIS

The most frequently used and simplest technique for analyzing neonatal d-MRI data is to manually delineate regions of interest within which diffusion metrics are then

Advanced MRI Techniques Review

Fig. 2. The diffusion ellipsoid. (A) In an isotropic medium the diffusion is equal in all directions. (B) In an anisotropic medium the diffusion along one direction, termed the principal eigenvalue (l1), is greater than the other 2 eigenvalues (l2, l3).

calculated. This form of analysis is particularly suited for studies that require quantitative assessment of tensor metrics in a clinically relevant timeframe for a single subject or assessment of a particular brain region.32 However, it is time-consuming (especially when a large number of regions and/or subjects are assessed) and is prone to operator-dependent bias.33 Tract-based spatial statistics (TBSS) is a voxel-based whole brain technique for assessing FA in major WM tracts in an automated and operator-independent way.34 The technique consists of 2 steps: first the individual subject FA images are registered into a common space; they are then projected onto a representation of the major WM tracts (the “mean FA skeleton”) from which statistical inferences can then be made. Given maturational differences in brain structure and WM, the TBSS protocol is specifically optimized for use with neonatal data.35 As TBBS can markedly improve the sensitivity, objectivity, and interpretability of analysis in multisubject diffusion imaging studies, it is particularly suitable for longitudinal studies of neonatal subjects, which require assessment of the whole brain WM and/or a large number of subjects.36 D-MRI OF BRAIN DEVELOPMENT

The neonatal brain contains more water than the brain of older children and adults, with a rapid reduction seen toward full term and during early infancy.37 As a result, ADC values in both gray and WM are higher in the neonatal brain compared with adults and are higher in the WM than in gray matter.25 Toward term, ADC values in the gray

Fig. 3. Diffusion MR scalar maps: (A) mean diffusivity, (B) fractional anisotropy, and (C) color-coded fractional anisotropy maps of the brain in a healthy infant.

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matter and hemispheric WM decrease and then continue to decrease further over the first 6 months post term.23,24,38,39 These rapid changes in ADC represent not only changes in water content, but also differences in the localized restriction of water diffusion due to increasing numbers of oligodendrocytes and a gradual thickening of the water-impermeable myelin sheath. ADC values reach mature adult levels by about 2 years of age, although small decreases may still be found until early adulthood.23,39 FA increases with WM maturation and decreases with cortical maturation. This increase takes place in 2 stages: the first occurring before myelin is evident histologically and is attributed to changes in WM structure, which accompany the premyelinating state, including an increase in axonal membrane maturation, microtubule-associated proteins, a change in axon caliber, and an increase in oligodendrocyte number.24,25,40 At this stage, the highest FA values are seen in the unmyelinated but highly organized commissural fibers in the splenium and genu of the corpus callosum. The second stage is associated with the histologic appearance of myelin and subsequent maturation, with the earliest signs observed in the projection fibers of the posterior limb of the internal capsule around term.41 D-MRI OF THE PRETERM BRAIN

Diffusion characteristics of WM in the developing preterm brain have been well described.24,42–47 FA values in the WM of preterm infants at term-equivalent age are significantly lower in comparison to term-born controls in several regions, suggesting widespread microstructural abnormalities, even in absence of major focal lesions.46,48,49 This decreased FA may reflect underlying reductions in myelination or decreased fiber coherence. Preterm birth–associated comorbidities, including acute and chronic lung disease (Fig. 4), punctate lesions, sepsis, and infants who are small for gestational age, have all been found to be associated with altered WM microstructure, including increased radial diffusivity and reduced FA.35,47,50–52 d-MRI techniques are also particularly useful for visualizing ischemic WM lesions, which demonstrate restricted diffusion and a corresponding low ADC during the acute phase, thought to be related to cytotoxic edema.53,54 Of importance, these changes can be seen on d-MRI before they are evident on conventional MRI.53 In infants with cystic periventricular leukomalacia, altered WM microstructure is seen in areas distant from the focal cystic lesions48 at term-equivalent age and in more diffuse WM injury, ADC values are elevated in both the periventricular and the subcortical WM.48,55 d-MRI measures correlate with subsequent neurodevelopmental performance. Increased ADC values in the WM at term-equivalent age are predictive of adverse neurodevelopmental outcome,56 and FA, assessed using TBSS, correlates with neurodevelopmental outcome at 2 years (Fig. 5).57,58 d-MRI can be used to assess specific neural systems, for example, FA in the optic radiation delineated with probabilistic tractography, correlate with visual performance at term-equivalent age.45,59 In a longitudinal study of preterm infants, visual performance correlated with FA in the optic radiation at term-equivalent age but not during the preterm period, suggesting that WM injury occurs between birth and term and that there may be a window of opportunity for therapeutic intervention aimed at reducing preterm WM injury.60 CHARACTERIZING CORTICAL MATURITY AND THALAMOCORTICAL CONNECTIVITY WITH D-MRI

In addition to studying WM, cortical maturation can be studied with d-MRI. Less than 32 weeks’ gestation, the cortex is dominated by perpendicular radial glia and apical

Advanced MRI Techniques Review

Fig. 4. Respiratory morbidity is associated with altered WM microstructure in preterm neonates. Using TBSS, chronic lung disease was found to be associated with significantly increased radial diffusivity (A) and decreased FA (B) but not axial diffusivity independent of both gestational age at birth and postmenstrual age at scan (FWE-corrected, P

Brain development in preterm infants assessed using advanced MRI techniques.

Infants who are born preterm have a high incidence of neurocognitive and neurobehavioral abnormalities, which may be associated with impaired brain de...
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