This has been challenging, particularly since subtle lesions are by definition similar in appearance to normal cortex, and because FCD lesions are heterogeneous. Pathologically, FCD type IIa is characterized by the presence of large dysmorphic neurons, FCD type IIb is distinguished by the additional presence of balloon cells \citep{Blümcke2011}.
In this work, we contribute to this literature by using normative modeling to explore similarities between normal cortex and FCDs. We use a generic feature set, as opposed to FCD-specific features, and create a normative model using healthy volunteer data from multiple MR contrasts. We found that while FCD lesions do appear anomalous in our representation, so do several "normal" brain regions. In fact, we find that on average, FCDs appear quite similar to some of these outlying regions, particularly paralimbic cortical areas. These similarities may lead to challenges in specificity of post-processing approaches to FCD identification, and may also be a source of error in visual identification of FCDs. We also demonstrate the utility of our FCD-based similarity maps and an automated detection method in aiding with FCD identification, showing a similar performance to other reported methods.
Materials and Methods
Study Participants
From our surgical epilepsy imaging database, we retrospectively identified 15 consecutive patients undergoing presurgical evaluation for drug-resistant focal epilepsy with 1) radiologically apparent (MRI+) or histologically proven (MRI+ or MRI negative, MRI-) FCDs and 2) 3T MRI structural imaging using our standard NIH epilepsy imaging protocol from 2014-2019. Patients were excluded if they had other MR imaging protocols, low image quality on visual inspection. The control group consisted of 30 healthy volunteers (HVs) scanned using the same imaging protocol, with no previous history of neurologic, psychiatric or other significant medical illnesses that may affect the central nervous system. Data were collected at the Clinical Center of the National Institutes of Health (NIH; Bethesda, MD). All participants were enrolled in a research protocol approved by the Institutional Review Board; informed consent was obtained from all participants.
Lesion Labels
For MRI+ patients, lesions were traced in the volume using AFNI by an experienced neurologist using the T1, informed by the T2 and FLAIR images when necessary. For MRI- patients, the postoperative T1 was registered to the preoperative T1 in the same manner as described previously for T2 and FLAIR; the resected region was traced using AFNI. The resulting lesion masks were mapped onto the surface at the gray-white junction using AFNI's 3dVol2Surf function.
MR Acquisition Protocol
All participants were scanned sagittally with a Philips Achieva 3T scanner in the NIH Clinical Center Radiology Department as follows: 1) 3D T1 weighted MPRAGE (T1): TR = 6.8–7.2, TE = 3.2 ms, TI = 900ms, flip angle = 90, voxel size = 0.75 x 0.75 x 0.8, acceleration factor 2 in slice direction, acquisition time = 7:02 min; 2) 3D T2 weighted FSE (T2): TR = 2500, TE = 225–245, voxel size = 1 x 1 x 2 or 1 x 1 x 1, acceleration factor 2 in slice and phase directions, acquisition time = 5:03 min; 3) 3D FLAIR: TR = 4800, TE = 271–415, TI = 1600, voxel size = 0.9 x 0.9 x 1, acceleration factor 2 in slice direction, 2.6 in phase direction, acquisition time = 6:10 min.
Image Preprocessing
For each individual subject, T
2 and FLAIR images were co-registered to the T
1 with an affine transformation and a normalized mutual information cost function and sampled to the T
1 grid using Analysis of Functional NeuroImages software (
AFNI)
\cite{Cox1996a}. Registered images were visually assessed for alignment. Cortical reconstruction was performed using T
1 and T
2 images as input to FreeSurfer's standard processing pipeline with
FreeSurfer v6.0.0 \cite{Dale1999,Fischl1999}. Results were visually inspected and manually corrected if needed. Cortical surfaces were deformed to a standard mesh. Intensity correction was implemented using an in-house procedure (see supplementary materials).