Brain Pathways in LIS1-Associated Lissencephaly Revealed by Diffusion MRI Tractography

Abstract

Lissencephaly (LIS) is a rare neurodevelopmental disorder with severe symptoms caused by abnormal neuronal migration during cortical development. It is caused by both genetic and non-genetic factors. Despite frequent studies about the cortex, comprehensive elucidation of structural abnormalities and their effects on the white matter is limited. The main objective of this study is to analyze abnormal neuronal migration pathways and white matter fiber organization in LIS1-associated LIS using diffusion MRI (dMRI) tractography. For this purpose, slabs of brain specimens with LIS (n = 3) and age and sex-matched controls (n = 4) were scanned with 3T dMRI. Our high-resolution ex vivo dMRI successfully identified common abnormalities across the samples. The results revealed an abnormal increase in radially oriented subcortical fibers likely associated with radial migration pathways and u-fibers and a decrease in association fibers in all LIS specimens.

Keywords: DTI; LIS1; MRI; lissencephaly; tractography.

Figure 1

Showing all the sections from LIS, #683, 8 years and 10 months old female. The color-coding of tractography pathways was based on a standard red-green-blue (RGB) code that was applied to the vector in each brain area to show the spatial locations of every segment of each pathway (red for right-left, blue for superior-inferior, and green for anterior-posterior). Composite colors e.g., orange, yellow, purple, and violet indicate combined RGB orientations.

Figure 2

Showing all the sections from LIS, #4524, 13 years and 11 months old male. The color coding of tractography pathways is the same as in Figure 1.

Figure 3

Showing all the sections from LIS, #641, 1 years and 5 months old female. The color coding of tractography pathways is the same as in Figure 1.

Figure 4

Long tractography pathways (>20 mm) from a section through the hippocampus. (A): LIS, (B): Control subjects, arrows indicate the projection and the stars and white arrows indicate the long cortico-cortical pathways. (Left: LIS #4524, Right: control #4341). The color coding of tractography: blue indicates the superior-inferior and red indicates the right-left.

Figure 5

Cortical layer-like abnormalities seen in the comparative qualitative analysis. The color coding of tractography pathways is the same as in Figure 1. (A–C) show coronal sections through different levels at the optic chiasm, tegmentum of the midbrain, and the isthmus of corpus callosum, respectively. Arrows and squares indicate the typical and corresponding abnormal fibers.

Figure 6

Enlarged sections from the cortical layer-like abnormalities in LIS patients and the corresponding view in healthy controls. (Left: control #4555, Right: LIS #641). The magnified regions show the typical (left) and abnormal (right) formation of short-range association fibers (upper panels) and fiber organization (lower panels), respectively.

Figure 7

Coronal section through the hippocampal level in infant and pediatric subjects showing severely abnormally developed structures neighboring the ventricles. (Upper row: Left: LIS #683, Right: control #877; Lower row: Left: LIS #641, Right: control #4455). The color coding of tractography pathways is the same as in Figure 1.

Figure 8

Enlarged sections from the cortical layer-like and white matter projection abnormalities in LIS patients and the corresponding view in healthy controls. (Left: control #877, Right: LIS #683) (a) Enlarged view of the cortex in the healthy control, (b) corresponding view of the (a) in LIS patient, (c) projection fibers passing through the internal capsule in the healthy control, (d) corresponding view of the (c) in LIS patient. Note that all white matter fibers merge as one single bundle in LIS patients due to agenesis of the structures. This patient was also reported to have agenesis of the corpus callosum. Whole coronal sections and regionally enlarged views (a–d, see panels pointed with arrows) of the cortical layer-like and white matter projection abnormalities in a LIS patient and a healthy control (Left: control #877, Right: LIS #683). The color coding of tractography pathways is the same as in Figure 1.

Figure 9

Showing the age-sex matched sections from the lateral surface through the mid-sagittal of the cerebellum. Upper row: LIS patient #4524, 13 years and 11 months old male, reported to have hypoplastic degenerating cerebellum. Lower row: Control, #4341, 13 years and 11 months old male. The color-coding of tractography pathways for the cerebellum is red for superior-inferior, blue for anterior-posterior, and green for left-right. Composite colors e.g., orange, yellow, purple, and violet indicate combined RGB orientations.

Figure 10

Long tractography pathways (>10 mm) from sections through row (A) mid-sagittal and row (B) middle cerebellar peduncle. Row (A): Arrows show the fibers passing through the superior cerebellar peduncle. (Left: control #4341, Right: LIS #4524) Row (B): Fibers passing through the middle cerebellar peduncle merge as one single bundle in LIS. (Left: control #4341, Right: LIS #4524). The color coding of tractography pathways is the same as used in Figure 9.