Longitudinal analysis of cortical dysplasia microstructure through diffusion-MRI and histology

2138 

Abstract Submission 

Paulina Villaseñor¹, Hiram Luna-Munguía², Alonso Ramírez-Manzanares³, Ricardo Coronado-Leija⁴, Luis Concha⁵

¹Universidad Nacional Autónoma de México, Queretaro, Mexico, ²Universidad Nacional Autónoma de México, Querétaro, Mexico, ³Centro de Investigación en Matemáticas, Guanajuato, Mexico, ⁴Bernard and Irene Schwartz Center for Biomedical Imaging, Dept of Radiology, New York University, New York, NY, ⁵Universidad Nacional Autonoma de Mexico, Queretaro, Please select an option below

Paulina Villaseñor, MSc  
Universidad Nacional Autónoma de México
Queretaro, Mexico

Hiram Luna-Munguía  
Universidad Nacional Autónoma de México
Querétaro, Mexico

Alonso Ramírez-Manzanares  
Centro de Investigación en Matemáticas
Guanajuato, Mexico

Ricardo Coronado-Leija  
Bernard and Irene Schwartz Center for Biomedical Imaging, Dept of Radiology, New York University
New York, NY

Luis Concha  
Universidad Nacional Autonoma de Mexico
Queretaro, Please select an option below

Focal cortical dysplasias (FCD) are malformations of cortical development characterized by cortical layer disruption and neuronal abnormalities associated with refractory focal epilepsy (Blümcke et al. 2011). Surgical resection is available when lesions are visible through magnetic resonance imaging (MRI). Unfortunately, many of these lesions are subtle and difficult to detect by conventional MRI. Several methods to analyze MRI have been proposed aiming to unmask subtle cortical lesions (Kabat et al., 2012). However, most image-processing methods are targeted to detect the macroscopic characteristics of FCD, which do not always correspond to microstructural disarrangement. Novel quantitative diffusion-MRI (dMRI) methods provide valuable microstructural characteristics of complex tissue, including gray matter (Leuze et al. 2012). Through spatial analysis of dMRI metrics using a novel multi-tensor, we demonstrate abnormalities in an animal model of cortical dysplasia that reflect cyto- and myelo-architecture disarrangement as seen by histology.

Pregnant rats were injected with either carmustine (BCNU; 20 mg/kg) (n=3) or saline solution (n=3) at E15 (Benardete et al., 2002). Resulting pups (BCNU: n=16; Control: n=16) were scanned in vivo at 30 and 150 postnatal days using a preclinical 7T scanner. We acquired T2w images (spatial resolution 0.117×0.117×1 mm3) and dMRI (spatial resolution 0.175×0.175×1 mm3) with b values of 670, 1270 and 2010 s/mm2, each with 90 diffusion-sensitizing directions. Additionally, 14 b=0 s/mm2 volumes were obtained. After dMRI data preprocessing, we fitted the diffusion tensor (DTI) (Basser et al., 1994), and the multi-resolution discrete-search method (MRDS) (Coronado-Leija et al., 2017) that can fit up to three independent diffusion tensor profiles. To have a common anatomical descriptor of the cortex, we create a 2D grid-line system of coordinates with fifty curved lines, each one with ten vertices spanning the entire depth of the cortex. Since MRDS fits one or more tensors per voxel, resulting bundle-wise tensors were labeled as parallel or perpendicular to the grid-lines. For our statistical analysis, we conducted a longitudinal vertex-wise Linear Mixed Effect Model. Finally, to validate our diffusion metrics, we performed histological assessments using the primary antibodies myelin basic protein (MBP), and neuronal nuclear (NeuN). Myelin fiber orientations were examined through a structure tensor analysis

T2w images showed normal morphological features in both groups at P30, followed by enlarged ventricles and hippocampal atrophy at P150 in BCNU rats. Metrics derived from DTI failed to reveal differences between groups at any time point. In contrast, multi-tensor metrics at P30 showed significant changes between groups in FApar, FAperp, and MDpar (p<0.05) pointing to the deep cortical layers of the motor and somatosensory cortex. Histological assessment with NeuN revealed radial-columnar disorganization and disrupted transition between layers III-IV and V-VI. Also, MBP stainings highlighted a loss of the myelination process and disarrangement of intracortical fibers at the early stages of development (P30), while P150 displayed subtle changes in the cortex in BCNU rats. This fiber disarrangement was reflected in a loss of coherence from the structure tensor maps, being more noticeable at P30.

Our findings indicate that during the early stages of development (P30), macrostructural alterations in FCD are exceedingly subtle and remain undetectable through conventional MRI. However, our use of dMRI proved to be a valuable tool for identifying microstructural abnormalities. While DTI proved its limitations, our MRDS successfully pinpointed cortical regions with abnormal microstructure related to disorganized radial-tangential fibers and columnar-layer architecture, as confirmed by histology. These findings put forward the potential application of advanced dMRI for the detection of human FCD.

Neurodevelopmental/ Early Life (eg. ADHD, autism)

Diffusion MRI Modeling and Analysis ²

Cortical Cyto- and Myeloarchitecture ¹

Diffusion MRI

Cortex

Cortical Columns

Cortical Layers

Development

Epilepsy

MRI

Other - gray matter; diffusion-MRI