DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY

SYSTEMATIC REVIEW

Fractional anisotropy alterations in individuals born preterm: a diffusion tensor imaging meta-analysis KE LI 1,2

| ZEGUANG SUN 1 | YINGPING HAN 1 | LUOBIN GAO1 | LI YUAN 1 | DONG ZENG 1,2

1 Key Laboratory for NeuroInformation of Ministry of Education, University of Electronic Science and Technology of China, Chengdu; 2 School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China. Correspondence to Ke Li at Key Laboratory for NeuroInformation of Ministry of Education, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 610054, China. E-mail: [email protected] This article is commented on by Conti and Guzzetta on pages 307–308 of this issue.

PUBLICATION DATA

Accepted for publication 28th August 2014. Published online 30th October 2014. ABBREVIATIONS

ALE DTI SMD

Activation likelihood estimate Diffusion tensor imaging Standardized mean difference

AIM This meta-analysis explored cerebral microstructural changes in individuals born preterm using fractional anisotropy from diffusion tensor imaging. METHOD We used the activation likelihood estimate (ALE) method for the meta-analysis to locate anatomical regions with white matter abnormalities in a group of individuals born preterm and in term-born comparison participants. A statistical analysis of fractional anisotropy was conducted to quantitatively explore the extent of fractional anisotropy changes in the three subregions of the corpus callosum in the preterm group. RESULTS ALE analysis identified 11 regions of decreased fractional anisotropy and four regions of increased fractional anisotropy. Analysis of the corpus callosum revealed the largest decrease in fractional anisotropy in the splenium (standardized mean difference [SMD]= 0.75, 95% confidence interval [CI] 0.93 to 0.57), followed by the body (SMD= 0.73, 95% CI 1.13 to 0.32) and the genu (SMD= 0.65, 95% CI 0.97 to 0.33). INTERPRETATION Significant changes in fractional anisotropy in individuals born preterm reflect white matter abnormalities from childhood to young adulthood, and the mechanism of fractional anisotropy alterations in preterm infants may vary during different stages of white matter development. Furthermore, the variability of fractional anisotropy between studies can primarily be attributed to the age of the individuals at scanning and to the field strength of magnetic resonance scanners.

Preterm birth is frequently accompanied by a variety of disabilities, such as cerebral palsy, intellectual disability, deafness, or blindness. The incidence of preterm birth has increased significantly in the past decades, but is associated with higher survival rates1 and a lower incidence of major disabilities than in the past.2 However, there is strong evidence that preterm survivors without brain malformations, congenital infection, or metabolic disease and with normal outcomes or mild abnormalities on structural brain magnetic resonance imaging (MRI) may experience more problems of motor, cognitive, language, and behavioural functioning throughout childhood and young adulthood.3–6 These sequelae have been attributed to perinatal brain injuries,7,8 which frequently involve white matter,9 during normal brain maturation.10 Nevertheless, the location, severity, and mechanism of white matter injuries on neurodevelopment and their impact on future function have not been conclusively determined.11 Additional neuroimaging evidence is necessary to explain the mechanism of white matter injuries and to predict the future influence of these impairments in individuals who are born preterm. Diffusion tensor imaging (DTI), a novel MRI technique, can quantify the fibre orientation and integrity of white 328 DOI: 10.1111/dmcn.12618

matter pathways within neural networks. This technique is superior to conventional MRI methods for the detection of white matter abnormalities because of its ability to assess the microstructural organization of white matter. One important measure of DTI is fractional anisotropy, which describes the degree to which water diffusion is constrained in a certain direction. Fractional anisotropy is sensitive to the alignment of white matter fibres and their structural integrity, including the degree of myelination.12 DTI has been used successfully to evaluate leukoencephalopathies in childhood and to follow brain maturation in abnormal states, such as preterm birth or early brain injury. Fractional anisotropy has been used extensively to characterize the relationship between white matter integrity and cognitive abilities.13 Significant age-related increases in fractional anisotropy probably occur during the normal development process of brain white matter in children born preterm.14,15 Microstructural white matter differences have been detected using DTI in individuals born preterm compared with term-born comparison participants, and these microstructural differences are generally observed as reductions in fractional anisotropy in the central white matter regions of © 2014 Mac Keith Press

term individuals of equivalent age.16 However, DTI studies of preterm infants have reported inconsistent anatomical regions. In addition, many studies concentrated on changes in fractional anisotropy in the corpus callosum in preterm infants. The corpus callosum facilitates communication between the left and right cerebral hemispheres, and this area is probably involved in several motor, perceptual, and cognitive functions.17–19 Deficits in fractional anisotropy have been detected in the corpus callosum in preterm infants, but previous studies reported inconsistent outcomes in subregions of the corpus callosum.11,20 Furthermore, the mechanism of fractional anisotropy variations in the corpus callosum remains unclear. Meta-analysis is essential to review the findings of different studies and can be used to summarize statistical relationships and gather comprehensive between-study characteristics and findings.21 A meta-analysis was conducted to combine the findings of published DTI studies that examined fractional anisotropy changes in individuals born preterm and to provide greater insight into white matter abnormalities and the factors that influence them in individuals born preterm from childhood to adulthood. The meta-analysis included two parts: an analysis that employed the activation likelihood estimate (ALE) method to locate anatomical regions with white mater abnormalities and a statistical analysis of fractional anisotropy values to quantitatively explore the extent of fractional anisotropy changes in the corpus callosum.

METHOD Study selection Articles published between January 1980 and May 2014 were retrieved using a systematic search strategy of the following electronic databases: PubMed, Web of Science, and EMBASE. The adopted search terms included a systematic combination of ‘preterm’, ‘premature’, ‘prematurity’ or ‘low birth weight’, and ‘diffusion tensor imaging’ or ‘DTI’. Searches were supplemented by checking the reference lists of included publications and systematic reviews to identify additional studies not retrieved by electronic searches. The inclusion criteria for the articles were as follows: (1) data were acquired from human infants, adolescents, and adults who were born preterm without brain malformations, congenital infection, or metabolic disease (normal or mild abnormalities on structural brain MRI) in the original studies; (2) studies included samples in which healthy age-matched term-born participants were included as a comparison group; (3) DTI was performed in infancy, childhood, or adolescence; (4) studies reported fractional anisotropy values or coordinates from clusters of significant fractional anisotropy differences between the preterm and comparison groups; and (5) articles were limited to publications in peer-reviewed English-language journals. Data extraction The recorded variables for each article included in the quality assessment consisted of sample size, sex, gestational

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What this paper adds Anatomical regions with a significantly decreased or increased fractional anisotropy are found in preterm cohort groups. The mechanism of fractional anisotropy alterations in preterm infants may vary during different stages of white matter development. Changes in fractional anisotropy correlate with problems that children born preterm encounter. A subgroup analysis indicated that the heterogeneity may be attributed to different ages at scanning and to the field strength of magnetic resonance imaging.

age, birthweight, diagnosis, magnetic field strength, acquisition voxel size, number of diffusion directions, analysis type, coordinate system, fractional anisotropy value, and p-value. The Lancaster transform in the GingerALE application was used to convert coordinates reported in the Montreal Neurological Institute stereotactic space to Talairach coordinates before performing the ALE analysis.

Meta-analysis We performed ALE analyses using GingerALE version 2.1.1 (The BrainMap Project, San Antonio, TX, USA) to create probabilistic maps that described the probability that a voxel in a template MRI would show increased or decreased white matter.22,23 GingerALE is a coordinatebased meta-analysis method that is supported in the BrainMap software (Research Imaging Institute of the University of Texas Health Science Center San Antonio, San Antonio, TX, USA) environment, and it is useful for the identification of consistent regions of activation across a collection of studies. The ALE technique treats the reported foci not as points but as spatial probability distributions centred on the given coordinates. The reported coordinates from existing journal articles were transformed from Montreal Neurological Institute to Talairach space24 using the GingerALE software when necessary.25,26 Ginger-ALE version 2.1.3 supports random effect metaanalyses, and it gives more weight to the spatial conjunction of different foci from different studies than to different foci from a single study.21 The data were thresholded using a false discovery rate correction of q=0.05 and a minimum volume of 40mm3 in increased clusters. No other information regarding gestational age, birthweight, magnetic field strength, or fractional anisotropy value was included in the ALE statistical calculation because none of these factors can be used in our method. GingerALE reports results as coordinates, and therefore, we used multi-image analysis GUI (MANGO http://ric.uthscsa.edu/mango; Research Imaging Institute, University of Texas Health Center, San Antonio, TX, USA) to localize the correct regions for reported coordinates. The resulting maps were registered to the standard anatomical template in Talairach space, and the reported coordinates were calculated to match the standard maps. We report the brain anatomical regions that showed a statistically significant convergence based on published studies (p

Fractional anisotropy alterations in individuals born preterm: a diffusion tensor imaging meta-analysis.

This meta-analysis explored cerebral microstructural changes in individuals born preterm using fractional anisotropy from diffusion tensor imaging...
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