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Imaging brain connectivity in children with diverse reading ability Christian Beaulieu,a,* Christopher Plewes,a Lori Anne Paulson,a Dawne Roy,b Lindsay Snook,a Luis Concha,a and Linda Phillipsb a

Department of Biomedical Engineering, Faculty of Medicine and Dentistry, University of Alberta, 1098 Research Transition Facility, Edmonton, Alberta, Canada T6G 2V2 b Elementary Education, University of Alberta, Edmonton, Alberta, Canada T6G 2V2 Received 19 October 2004; revised 19 October 2004; accepted 17 December 2004

Reading is a complex cognitive skill that requires the coordination of multiple brain regions. Although functional neuroimaging studies highlight the cortical brain regions associated with a specific cognitive task like reading, they do not directly address the underlying neural connections necessary for efficient performance of this task. Adults with reading disability have demonstrated lower regional white matter connectivity, but it is not known whether this relationship between neuronal wiring and reading performance also holds in younger readers. Using diffusion tensor magnetic resonance imaging (DTI) that highlights the structural integrity of the brain wiring, we show that regional brain connectivity in the left temporo-parietal white matter correlates with a wide range of reading ability in children as young as 8–12 years old. Diffusion tensor tractography suggests that the posterior limb of the internal capsule is consistent with the location of the largest cluster of correlation between reading ability (Word Identification subtest) and fractional anisotropy. The maturation of the white matter may play a key role in the development of cognitive processes such as reading. D 2005 Elsevier Inc. All rights reserved. Keywords: Dyslexia; Magnetic resonance imaging; MRI; Reading; Diffusion tensor imaging; DTI; Brain

Introduction Despite the fact that most people learn to read quite readily, a significant number (5–17%) have great difficulty in acquiring efficient reading skills despite adequate training, intelligence, and sociocultural opportunity (Demonet et al., 2004). A biological origin for developmental dyslexia is implicated by its genetic association in certain individuals (Fisher and DeFries, 2002). Functional neuroimaging studies with positron emission tomography (PET), functional magnetic resonance imaging (fMRI), or magnetoencephalography (MEG) of precursor skills for reading in

* Corresponding author. Fax: +1 780 492 8259. E-mail address: [email protected] (C. Beaulieu). Available online on ScienceDirect (www.sciencedirect.com). 1053-8119/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.neuroimage.2004.12.053

dyslexic and non-impaired adults have implicated a complex brain network that appears to be dominant in the left hemisphere around the perisylvian region (Demonet et al., 2004). This left temporal network yields less activation in dyslexics presented with a demanding phonological task (Rumsey et al., 1997; Salmelin et al., 1996; Shaywitz et al., 1998), regardless of language and culture (Paulesu et al., 2001). A bdisconnection syndromeQ in which the functional connectivity of the relevant cortical networks in the left hemisphere is disrupted has been proposed as a potential basis for reading difficulties (Horwitz et al., 1998; Paulesu et al., 1996; Pugh et al., 2000). A more direct measure of brain connectivity, namely diffusion tensor magnetic resonance imaging (DTI), has demonstrated a correlation between the micro-structural integrity of the left temporo-parietal white matter and reading ability in dyslexic and control adults (Klingberg et al., 2000). While studying adults has been extremely informative, the imaging findings in dyslexic adults could result from of a lifetime of reduced reading or adaptive compensation mechanisms. The lingering question is whether these neural differences were present at an earlier age during neurodevelopment. Furthermore, the early years of schooling are the critical time period for intervention (Eden and Moats, 2002). Non-invasive functional MRI has made it possible to study children and, in the last 5 years, functional activation studies have demonstrated a reduction of left temporo-parietal activation in children with dyslexia which suggests that this brain abnormality may in fact be fundamentally related to the early development of reading disorders (Backes et al., 2002; Georgiewa et al., 1999; Shaywitz et al., 2002; Simos et al., 2002b; Temple et al., 2001; Turkeltaub et al., 2003). Brain activation patterns in the left superior temporal gyrus are altered with intense therapy focused on improving reading skills (Aylward et al., 2003; Shaywitz et al., 2004; Simos et al., 2002a; Temple et al., 2003). Although the fMRI studies in children are converging towards a few cortical regions relevant for reading, an investigation of brain connectivity (via the underlying white matter) and reading performance in children has yet to be reported. In order to address the potential relationship between brain connectivity and reading performance

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in children, we performed diffusion tensor MRI of the entire brain on 32 healthy 8- to 12-year-old children with a wide range of reading ability.

Materials and methods Volunteers Written informed consent (parents) and assent (children) was obtained from all 32 volunteers (14 male, 18 female). The age range was 8.3–12.9 years with a mean of 11.1 F 1.3 years and 30/32 children were right handed. Volunteers had no history of neurological or psychiatric disorders. Reading abilities were assessed by the Word Identification subtest (Word ID) of the Woodcock Reading Mastery Test-Revised (WRMT-R, American Guidance Service). Measures of non-verbal intelligence and receptive vocabulary were assessed using the Test of Non-verbal Intelligence (TONI-3, PRO-ED Inc) and the Peabody Picture Vocabulary Test (PPVT-3, American Guidance Service), respectively. Results of the Word Identification task revealed a wide range of reading abilities as the standard scores ranged from poor (72) to superior (129) performance with a mean agenormalized score of 105 F 14. Our population mainly consisted of average (Word ID 90–109; N = 16) and above average (Word ID z 110; N = 12) readers with few below average readers (Word ID V 89; N = 4). Performance on Word ID was not correlated to the age of the child (R = 0.20, P = 0.27). Mean scores for non-verbal intelligence and receptive vocabulary measures fell within the above average range, namely 111 F 12 (range of 91–133) for the TONI-3 and 115 F 15 (range of 90–142) for the PPVT-3.

template is that of an adult brain, there is fMRI evidence that spatial normalization to an adult-derived template is feasible in children greater than age 7 (Kang et al., 2003). The spatial normalization procedure reformats the images to 68 slices with isotropic 2  2  2 mm3 resolution. There was no global scaling, smoothing, or masking of the absolute quantitative FA maps. However, a voxel threshold of FA V 0.2 was used to eliminate from the analysis any voxels that had cortical gray matter or cerebrospinal fluid in some subjects. A simple linear regression correlation (P b 0.05) between Word ID and fractional anisotropy was performed and only clusters larger than 7 contiguous voxels were considered for our results. It is important to note that no significant clusters of correlation (P b 0.05, 7 contiguous voxels) were observed between Word ID and either T2-weighted signal intensity on the b = 0 s/mm2 images, the trace apparent diffusion coefficient, or the T1-weighted MPRAGE signal intensity. The latter analysis was limited to those voxels that demonstrated a correlation between Word ID and FA.

MRI data acquisition and analysis MRI protocols were approved by the Human Research Ethics Board of the University of Alberta. Diffusion tensor imaging (DTI) was performed on a 1.5-T Siemens Sonata MRI scanner using single-shot, diffusion-weighted, twice-refocused spin-echo echo planar imaging with a repetition time of 6400 ms, an echo time of 88 ms, and 8 averages. Forty 3-mm-thick contiguous axial slices with a matrix of 96  128 zero-filled to 256  256 and a 22-cm field-of-view were acquired in 6:06 min and yielded an effective in-plane resolution of 0.85  0.85 mm after zero filling. The diffusion tensor was acquired for each slice with six sets involving diffusion gradients placed along non-collinear directions (diffusion sensitivity, b = 1000 s/mm2) and an individual set without diffusion weighting (b = 0 s/mm2). Images were post-processed offline (MRVision, Winchester, MA) to yield maps of water diffusion parameters such as fractional anisotropy, that is, FA (Basser, 1995). Isotropic 3D 1  1  1 mm3 resolution anatomical MP-RAGE (magnetization prepared rapid acquisition with gradient echo) scans were also obtained of the entire brain. Statistical Parametric Mapping software (SPM99) (Friston et al., 1995) was used for voxel-based correlative analysis of the group of 32 children. The non-diffusion-weighted images (i.e. b = 0 s/mm2) were spatially normalized to a common stereotactic space using the Montreal Neurological Institute (MNI) EPI template and the resultant spatial transformation parameters were then applied to the FA maps. Although the MNI

Fig. 1. Regional white matter correlation of fractional anisotropy and Word ID. (a) All voxels of the five significant clusters, four on the left and one on the right, in the white matter are highlighted on six axial fractional anisotropy maps. The largest cluster consists of 42 contiguous 2  2  2 mm3 voxels in the left temporo-parietal white matter with the most significant voxel located at MNI coordinates x, y, z = 28, 14, 24 mm (Z = 3.17, p uncorrected = 0.001). (b) The diffusion tensor derived color maps, which depict the directionality of the fiber tracts on a voxel basis, suggest that the largest cluster (shown in white) is comprised primarily of tracts with an inferior–superior orientation.

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Fiber-tracking of the white matter bundles in the unnormalized DTI data was performed with DTIStudio software (S. Mori and H. Jiang, Johns Hopkins University) using the FACT algorithm (Mori et al., 1999) and an FA minimum of 0.25 and an angle threshold of 708.

Results An index of white matter integrity, fractional anisotropy that ranges from 0 to 1, was correlated on a voxel-by-voxel basis with reading ability measured by the Word Identification (Word ID) subtest of the Woodcock Reading Mastery Test. A significant correlation between anisotropy and Word ID was observed in five clusters (four on the left and one on the right). The largest cluster, consisting of 42 2  2  2 mm3 voxels, was located in the left temporo-parietal white matter with the peak (i.e. maximally correlated) voxel located at Montreal Neurological Institute coordinates x, y, z = 28 mm, 14 mm, 24 mm (Z = 3.17, p uncorrected = 0.001) (Fig. 1). The other four clusters were smaller at 7 voxels each {(x, y, z, Z, p uncorrected) = (26, 14, 24, 3.06,

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0.001), ( 24, 24, 18, 2.78, 0.003), ( 22, 18, 36, 2.39, 0.008), ( 18, 8, 34, 2.12, 0.017)}. The diffusion imaging derived color maps, which illustrate the primary white matter tract direction, suggest an inferior–superior orientation of the tracts (denoted by blue color) within the largest cluster since it is primarily comprised of blue voxels (~89% in all the children) (Fig. 1b). A correlation between regional fractional anisotropy and Word ID was observed (R = 0.54, P = 0.002) in children with diverse reading ability, namely Word ID scores from 72 to 129, where a score of 100 represents the agenormalized mean value (Fig. 2). Furthermore, with a focus on the largest cluster, the fractional anisotropy in the peak voxel did not correlate with either age (R = 0.06, P = 0.74) or non-verbal intelligence (R = 0.25, P = 0.18).

Discussion Most MRI studies of reading have focused on group comparisons, that is, normal readers versus dyslexics. It is important to note that most of our children were average (N =

Fig. 2. White matter structure versus reading ability in the most correlated voxel. The fractional anisotropy of the white matter at the indicated voxel within the largest cluster demonstrated a significant positive correlation (R = 0.54, P = 0.002) with the age-standardized Word ID score that reflects reading ability in the children. The fractional anisotropy in this voxel did not correlate with age (R = 0.06, P = 0.74) or non-verbal intelligence (R = 0.25, P = 0.18). It is interesting to note that the maximum fractional anisotropy in the main cluster, regardless of its voxel location within the cluster in an individual, also correlates with Word ID (R = 0.56, P = 0.0008).

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16) to above average (N = 12) readers with only a few poor readers (N = 4). Our findings suggest that there are regional brain structural correlations over a wide range of reading ability even within a so-called normal population. Our finding in children agrees with an adult study in which fractional anisotropy and reading ability (also given by Word ID) were correlated within either control or dyslexic groups when they were analyzed separately (Klingberg et al., 2000). Interestingly, there is excellent agreement between the location of our maximally correlated voxel (x = 28, y = 14, z = 24) in 8- to 12-year-old children with that found in adults by Klingberg et al. (2000) (x = 28, y = 20, z = 28). Diffusion tensor tractography is a novel imaging method which permits in vivo virtual dissection of white matter tracts and investigation of brain connectivity (Mori et al., 1999). Tractography takes advantage of the fact that water diffuses preferentially along the length of axons, whereas it is hindered perpendicular to the tracts by axonal membranes and myelin (Beaulieu, 2002). White matter fibers that pass through the five significant clusters were observed with tractography and separated on the basis of their primary orientation in the brain, that is, anterior–posterior, left–right, superior–inferior (Fig. 3). The three smaller clusters on the left side either had anterior–posterior tracts consistent with the superior fronto-occipital fasciculus and anterior limb of the internal capsule or left–right tracts consistent with the corpus callosum. The largest cluster (on the left side) and the only rightsided cluster yielded superior–inferior tracts consistent with the posterior limb of the internal capsule (PLIC). This latter result was surprising since we had initially theorized that this cluster

would likely be part of the superior longitudinal fasciculus (SLF) that is thought to connect the important cortical language regions of Wernicke and Broca. A closer investigation of the largest cluster revealed that it is bordered by the superior fronto-occipital fiber on the medial side and the superior longitudinal fasciculus on the lateral side (Fig. 4). Although fibers from the PLIC pass right through the cluster, it is conceivable that other relevant white matter fibers crossing at this level, such as the adjacent SLF, could be responsible for the correlation with reading ability. However, standard six-direction diffusion tensor imaging is not able to extract the complex fiber crossings that are rampant in this portion of the brain. The location of the primary cluster in the left temporoparietal white matter places it among the network of cortical regions implicated by prior functional imaging studies and it could be the link for the bdisconnectionQ or altered flow of neural processing responsible for not reading well. Could the degree of connectivity be a bbiological limitQ on the achievable level of reading performance on standardized tests? Functional MRI studies of remediation show significant improvements (with concurrent greater brain activation) but the reading performance is still usually below normal (Aylward et al., 2003; Shaywitz et al., 2004; Simos et al., 2002a; Temple et al., 2003). Although phonological deficits alone have been shown to be sufficient to cause a reading impairment, sensory and motor symptoms often coexist, but not always, in some dyslexic individuals (Ramus et al., 2003). Although the assignment of a specific fiber tract as the cause of reduced fractional anisotropy in the temporoparietal white matter cluster is inconclusive, the posterior limb

Fig. 3. DTI-derived fiber tracts passing through the clusters. (a) The five fractional anisotropy-Word ID clusters (shown in purple; 4 left, 1 right) were used as selection regions for depicting only those fibers passing through the clusters. White matter tracts were separated based on their primary orientation, namely (b) anterior–posterior, (c) left–right, and (d) superior–inferior. The left anterior cluster has anterior–posterior oriented fibers of the superior fronto-occipital fasciculus (light yellow) and the anterior limb of the internal capsule (bright yellow) passing through it. Left–right callosal fibers intersect the left anterior cluster as well as the two small left superior clusters. Superior–inferior fibers consistent with the posterior limb of the internal capsule pass through the largest left cluster as well as the sole right cluster.

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Fig. 4. Spatial relationship of anatomically defined fibers to the main cluster of reading correlation. (a) The superior longitudinal fasciculus, SLF, (shown in green) is thought to connect the important cortical regions of Wernicke and Broca but this fiber tract passes just lateral to the primary 42 voxel FA-Word ID cluster as seen from a front view. The superior fronto-occipital fasciculus (shown in yellow) also bypasses the cluster but to the medial side. (b) Seen from the back, the main cluster is buried consistently within the posterior limb of the internal capsule, PLIC (shown in blue). However, this cluster is within a region of complex fiber crossings and it cannot be discounted that diffusion tensor imaging could be missing portions of the SLF that may be passing through the cluster; in fact, the shape of the cluster is suggestive of an anterior–posterior fiber possibly crossing the PLIC at the level of the SLF.

of the internal capsule is consistent with the cluster location (Fig. 4) and it contains motor pathways, somatosensory relays, as well as connections associated with saccadic eye movements (Gaymard et al., 2003). A structural abnormality in the centrum semiovale, a complex network relevant to numerous brain functions, could potentially rationalize the concurrent behavioral and physical traits that are often associated with reading impairment. One can hypothesize that the larger fractional anisotropy of water diffusion in better readers is related to physically-relevant connectivity measures such as increased myelination and axonal density, although the relationship between water diffusion and the tissue microstructure it samples is not straightforward (Beaulieu, 2002). Magnetic resonance spectroscopy has demonstrated a decrease of the metabolite choline, a marker of overall cell density and total membrane content, in the left temporo-parietal lobe of dyslexic individuals (Rae et al., 1998). Faster learning of novel speech sounds was associated with greater parietal white matter structure, especially in the left hemisphere, in normal individuals (Golestani et al., 2002). The authors argued that more efficient neural processing, say by more myelination, could be critical in the ability to learn. In agreement with the location of our largest cluster of correlation, the posterior limb of the internal capsule and the left arcuate fasciculus have demonstrated the most significant age-related changes in white matter bdensityQ in healthy children aged 4–18 years (Paus et al., 1999). We did not observe correlations of fractional anisotropy with age in the primary cluster although our 8- to 12-year-old age range was far narrower. These aforementioned studies are all supportive of an enhanced connectivity hypothesis to explain our observed reading-anisotropy correlations. However, it cannot be discounted that the heterogeneity of the fractional anisotropy maps in the centrum semiovale (Fig. 1a) makes this type of brain map more sensitive to subtle morphological shifts than typical MRI scans such as T1weighted 3D MRI scans (Fig. 2) in which the white matter appears very homogeneous in this part of the brain. However, the voxels with the maximum fractional anisotropy within the main

cluster of each of the children were within 6.6 F 4.4 mm of each other. In summary, diffusion tensor imaging of the brain suggests the importance of regional connectivity in left temporo-parietal white matter for enhanced reading performance in healthy children. Although imaging studies, such as ours, are correlative in nature, one could speculate a potential causal association since our experimental observation is in young school-aged readers and over a wide range of ability. It remains to be seen if this macroscopic connectivity is a pre-requisite for achieving adequate reading skills or whether the functional connectivity strengthens with improved reading performance. Acknowledgments This work was supported by the Networks of Centres of Excellence, namely the Canadian Language and Literacy Research Network (CLLRNet). Salary funding from the Alberta Heritage Foundation for Medical Research (AHFMR) and Canadian Institutes for Health Research (CIHR) is appreciated. The MRI facility infrastructure was provided by AHFMR, Alberta Science and Research Authority, University of Alberta Hospital Foundation, and Canada Foundation for Innovation. The authors thank Simon McCrea and Yusuf Bhagat for their assistance in the early phases of the project as well as H. Jiang and S. Mori for their DTIStudio tractography software. References Aylward, E.H., Richards, T.L., Berninger, V.W., Nagy, W.E., Field, K.M., Grimme, A.C., Richards, A.L., Thomson, J.B., Cramer, S.C., 2003. Instructional treatment associated with changes in brain activation in children with dyslexia. Neurology 61, 212 – 219. Backes, W., Vuurman, E., Wennekes, R., Spronk, P., Wuisman, M., van Engelshoven, J., Jolles, J., 2002. Atypical brain activation of reading processes in children with developmental dyslexia. J. Child Neurol. 17, 867 – 871.

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