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Fixel-based analysis of white matter differences between patients with cerebral palsy and typically developing children
Chih-Chien Tsai1, Chia-Ling Chen2,3, Yao-Liang Chen4, Jur-Shan Cheng5, Sung-han Lin6, and Jiun-Jie Wang1,6,7
1Healthy Aging Research Center, Chang-Gung University, TaoYuan, Taiwan, 2Department of Physical Medicine and Rehabilitation, Chang Gung Memorial Hospital, Linkou, TaoYuan, Taiwan, 3Graduate Institute of Early Intervention, College of Medicine, Chang Gung University, TaoYuan, Taiwan, 4Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital, Keelung Branch, Keelung, Taiwan, 5Clinical Informatics and Medical Statistics Research Center, Chang-Gung University, TaoYuan, Taiwan, 6Department of Medical Imaging and Radiological Sciences, Chang Gung University, TaoYuan, Taiwan, 7Medical Imaging Research Center, Institute for Radiological Research, Chang Gung University/Chang Gung Memorial Hospital, TaoYuan, Taiwan

Synopsis

Disruption to white matter pathways is an important contributor to the pathogenesis of cerebral palsy but fail to delineate white matter tracts with lesions precisely with conventional magnetic resonance imaging. Fixel-based analysis, which has recently emerged as a useful fiber-specific tool for examining white matter structure, was used in this study. Reductions of fixel-based metrics in patients with cerebral palsy are represented in the corpus callosum, superior/posterior thalamic radiation, optic radiation, superior longitudinal fasciculus, and cingulum with corresponding direction of fiber tract. By using fixel-based analysis, this study described the white matter differences during development in patients with cerebral palsy.

INTRODUCTION

Spastic cerebral palsy is the most common motor disease and affects the movement, posture and life quality in children1. The subtype of spastic cerebral palsy, which included unilateral spastic cerebral palsy (hemiplegia) and bilateral spastic cerebral palsy (diplegia and quadriplegia), are observed with white matter lesion in pathological studies2, 3. The most common patterns of white matter lesion were periventricular leukomalacia, which exists irregular outlines of the trigone and body of the lateral ventricle with ventriculomegaly from magnetic resonance imaging4. However, conventional magnetic resonance imaging had limitations and often failed to delineate white matter tracts with lesions precisely 1, 5. Studies also used diffusion tensor imaging to reveal white matter lesions. The measurement of diffusion tensor imaging may be potentially affected by 1) complex of white matter fiber configurations (e.g., crossing)6, 7, and 2) an imprecise representations and projections with inadequate modeling8 and 3) tensor properties from fractional anisotropic and mean diffusivity did not provide additional information about fiber orientation. To circumvent these issues, fixel-based analysis was proposed to investigate white matter changes7. In this cross-sectional study, we used fixel-based analysis to investigate white matter differences between patients with cerebral palsy and typically developing children.

METHODS

The study protocol complied with the tenets of the Declaration of Helsinki and was approved by the Institutional Review Board. All participants gave their written informed consent. A total of 34 children with cerebral palsy (19 boys and 15 girls; mean age: 11.5±3.2 years), and 27 sex-balanced typically developing children (14 boys and 13 girls; mean age: 17.5±3.6 years) were recruited. Children diagnosed with cerebral palsy and aged 3-20 years met the inclusion criteria. MRI was performed with a 3T MR750 scanner using a 12-channel head matrix coil (GE Medical Systems, Milwaukee, WI). Diffusion-weighted images were acquired using a spin-echo echo-planar-imaging sequence with repetition time/echo time/slice thickness = 4000 ms/103.5 ms/ mm, matrix size = 96 × 96, and field of view = 192 × 192 mm2, 40 slices which covered the whole brain down to the cerebellum. Diffusion-weighted gradients were applied along 30 non-collinear directions using b-values of 0, 500, 1000, 1500, 2000, and 2500 s/mm2. FBA was performed by MRtrix3 (https://github.com/MRtrix3/mrtrix3) following the recommended procedures9, including preprocessing, estimation for distribution of fiber orientations, study-specific template establishment, and calculation of fixel-based metric, which included fiber density (FD), fiber bundle cross-section (FC), and combined measure by multiplying FD and FC (FDC). Statistical analyses of the image were performed with the code fixelcfestat in MRtrix3. Using age and sex as covariates, comparisons of metrics between patients with cerebral palsy and typically developing children were performed. A FWE-corrected p < 0.05 with a cluster-extent-based threshold of 10 or more voxels was considered statistically significant10.

RESULTS

The difference of white matter development between children with cerebral palsy and typically developing children was shown in Figure 1. Compared to the typically developing children, patients with cerebral palsy reduced in FC and FDC predominantly in the anterior and posterior part of the corpus callosum, commissural area, posterior limb of internal capsule, superior and posterior thalamic radiation, cingulum fiber, optic radiation, and superior longitudinal fasciculus. In contrast, FD reductions were identified in the posterior part of the corpus callosum, posterior thalamic radiation, fornix, and cingulum fiber. To clearly illustrate the differences between both groups, significant variations along fixels were plotted in axial slices (Fig. 2).
To shed more light on the differences between patients with cerebral palsy and typically developing children, significant reduced FDC were displayed in representative slices with information of tract direction (Fig. 3). The FDC reduced regions were displayed in an axial view (panels a and b) – including the anterior and posterior of the corpus callosum, optic radiation, posterior thalamic radiation, and posterior limb of internal capsule. The FDC changes in a representative coronal slice of the corticospinal tract and commissural area (panel c and d) and in a representative sagittal view of the superior thalamic radiation, superior longitudinal fasciculus, cingulum and corpus callosum (panel e-h) are depicted.

DISCUSSION

The major reductions in white matter were observed in the anterior, posterior corpus callosum, and corticospinal tract, consistent with previous knowledge of the spatial distribution characteristics of white matter lesions by voxel-based analysis or tract-based spatial statistics in patients with cerebral palsy11, 12. Reductions of FC and FDC in the superior, posterior thalamic radiation and cingulum were also represented, indicated the importance of thalamus, cingulate gyrus for relaying information between different subcortical and cerebral cortex13. Besides, reductions of FC and FDC in optic radiation also were consistent with deficiency of visual-motor integration in patients with cerebral palsy14. These observations suggested that white matter development might be related to axonal lesions, which was subsequently followed by fiber bundle atrophy9.

CONCLUSION

This study provided a thorough fixel-based metrics of white matter differences in patients with cerebral palsy and typically developing children with new evidence of FD, FC, and FDC, which helped to clarify the influence of cerebral palsy on the development of specific white matter regions.

Acknowledgements

No acknowledgement found.

References

  1. Bax M, Tydeman C, Flodmark O. Clinical and MRI correlates of cerebral palsy: the European Cerebral Palsy Study. JAMA 2006;296(13):1602-1608.
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  8. Bach M, Laun FB, Leemans A, et al. Methodological considerations on tract-based spatial statistics (TBSS). NeuroImage 2014;100:358-369.
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  11. Arrigoni F, Peruzzo D, Gagliardi C, et al. Whole-Brain DTI Assessment of White Matter Damage in Children with Bilateral Cerebral Palsy: Evidence of Involvement beyond the Primary Target of the Anoxic Insult. AJNR Am J Neuroradiol 2016;37(7):1347-1353.
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Figures

Figure 1. The overall display of significant fixel-based metrics between children with cerebral palsy and typically developing children. Areas of significant differences (family-wise error corrected p < 0.05) in fiber density (FD), fiber-bundle cross-section (FC), and fiber density and cross-section (FDC) displayed stereoscopically in the (a) anterior (b) left anterior and (c) posterior view. Comm, commissural; ACC, anterior corpus callosum; CG, cingulum; SLF, superior longitudinal fasciculus; PCC, posterior corpus callosum.

Figure 2. Significant reduction in fixel-based metrics between children with cerebral palsy and typically developing children

Significant fixels (family-wise error corrected p < 0.05) were displayed in the axial slices. FD, Fiber density; FC, fiber-bundle cross-section; FDC, fiber density and cross-section; PCC, posterior corpus callosum; fx: fornix; PTR, posterior thalamic radiation; CG, cingulum; OR, optic radiation; ACC, anterior corpus callosum; PLIC, posterior limb of internal capsule; SLF, superior longitudinal fasciculus.


Figure. 3. Significant fixels colored by direction

Significant decreased fixels (family-wise error corrected p < 0.05) of FDC between cerebral palsy and typically developing children were displayed in the axial (a, b), coronal (c, g), and sagittal (d, e, f, h) slices. Arrows, hyperdirect pathways. PCC, posterior corpus callosum; fx: fornix; STR, superior thalamic radiation; CG, cingulum; CST, corticospinal tract; Comm, commissural; OR, optic radiation; ACC, anterior corpus callosum; PLIC, posterior limb of internal capsule; SLF, superior longitudinal fasciculus.


Proc. Intl. Soc. Mag. Reson. Med. 28 (2020)
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