Brain phenotyping in Moebius syndrome and other congenital facial weakness disorders by diffusion MRI morphometry

Abstract

In this study, we used a novel imaging technique, DTI (diffusion tensor imaging)-driven tensor-based morphometry, to investigate brain anatomy in subjects diagnosed with Moebius syndrome (n = 21), other congenital facial weakness disorders (n = 9) and healthy controls (n = 15). First, we selected a subgroup of subjects who satisfied the minimum diagnostic criteria for Moebius syndrome with only mild additional neurological findings. Compared to controls, in this cohort, we found a small region of highly significant volumetric reduction in the paramedian pontine reticular formation and the medial longitudinal fasciculus, important structures for the initiation and coordination of conjugate horizontal gaze. Subsequently, we tested if volume measurements from this region could help differentiate individual subjects of the different cohorts that were included in our study. We found that this region allowed discriminating Moebius syndrome subjects from congenital facial weakness disorders and healthy controls with high sensitivity (94%) and specificity (89%). Interestingly, this region was normal in congenital facial weakness subjects with oculomotor deficits of myopathic origin, who would have been classified as Moebius on the basis of purely clinical diagnostic criteria, indicating a potential role for diffusion MRI morphometry for differential diagnosis in this condition. When the entire Moebius syndrome cohort was compared to healthy controls, in addition to this 'landmark' region, other areas of significantly reduced volume in the brainstem emerged, including the location of the nuclei and fibres of cranial nerve VI (abducens nerve), and fibres of cranial nerve VII (facial nerve), and a more rostral portion of the medial longitudinal fasciculus. The high sensitivity and specificity of DTI-driven tensor-based morphometry in reliably detecting very small areas of volumetric abnormality found in this study suggest broader applications of this analysis in personalized medicine to detect hypoplasia or atrophy of small pathways and/or brainstem nuclei in other neurological disorders.

Keywords: brainstem, DTI, DTBM, magnetic resonance imaging, quantitative.

Published by Oxford University Press on behalf of the Guarantors of Brain 2020. This work is written by US Government employees and is in the public domain in the US.

Figures

Graphical Abstract

Figure 1

Demographic information of the study cohort. HC = healthy controls; MBS = Moebius syndrome; CFW = congenital facial weakness. Boxes highlighted by a black outline are subcategories used in group comparison.

Figure 2

Volumetric differences in subjects with MBSt compared to HC. Top: Areas of significant volumetric reduction (indicated by the arrows) in subjects with MBSt compared to HC (FWE corrected P < 0.01) superimposed on the directionally encoded color (DEC) map. Middle: Effect size of lnJ maps. Bottom: Areas in the orange boxes are enlarged. Areas of reduced volume can be clearly seen in the brainstem. In the effect size map, dark areas indicate regions that are smaller in MBSt subjects, whereas bright areas indicate areas that are larger in these subjects. Black corresponds to −4, white to +4, and the grey background is equal to 0.

Figure 3

The average value of the Jacobian (relative volume) for the region of volume reduction detected with high significance in the MBSt versus HC comparison for each subject. The data reported in the left panel (A) is used for training the machine learning algorithm while the data used in the right panel (B) is used in performing individual classification.

Figure 4

Differences in diffusion metrics in subjects with MBS compared to HC. A few voxels (indicated by the arrows) are areas of significant increase in MD (top) and decrease in FA (bottom) in subjects with MBS compared to HC (FWE corrected P < 0.01) superimposed on the MD and FA maps, respectively.

Figure 5

Volumetric differences in subjects with MBS compared to HC. Top: Areas of significant volumetric reduction (indicated by the arrows in the sagittal view) in subjects with MBS compared to HC (FWE corrected P < 0.01) superimposed on the directionally encoded color (DEC) map. Bottom: Effect size of lnJ maps. Dark areas indicate regions that are smaller in MBS subjects, whereas bright areas indicate areas that are larger. In the effect size map black corresponds to −4, white to +4, and the grey background is equal to 0. Areas of reduced volume can be clearly seen in the brainstem.

Figure 6

Top: Directionally encoded color (DEC) map for anatomical reference. Bottom: Effect size of lnJ maps comparing iCFW subjects to HC. Dark areas indicate regions that are smaller in iCFW subjects, whereas bright areas indicate areas that are larger in these subjects. There are no regions of significant volumetric difference between iCFW subjects and HC. In the effect size map, black corresponds to −4, white to +4 and the grey background is equal to 0.