White matter abnormalities across different epilepsy syndromes in adults: an ENIGMA Epilepsy study

Abstract

word count: 399 Body word count: 6127 (limit 6000) AbstractThe epilepsies are commonly accompanied by widespread abnormalities in cerebral white matter. ENIGMA-Epilepsy is a large quantitative brain imaging consortium, aggregating data to investigate patterns of neuroimaging abnormalities in common epilepsy syndromes, including temporal lobe epilepsy, extratemporal epilepsy, and genetic generalized epilepsy.Our goal was to rank the most robust white matter microstructural differences across and within syndromes in a multicentre sample of adult epilepsy patients. Diffusion-weighted MRI data were analyzed from 1,069 non-epileptic controls and 1,249 patients: temporal lobe epilepsy with hippocampal sclerosis (N=599), temporal lobe epilepsy with normal MRI (N=275), genetic generalized epilepsy (N=182) and nonlesional extratemporal epilepsy (N=193). A harmonized protocol using tract-based spatial statistics was used to derive skeletonized maps of fractional anisotropy and mean diffusivity for each participant, and fiber tracts were segmented using a diffusion MRI atlas. Data were harmonized to correct for scanner-specific variations in diffusion measures using a batch-effect correction tool (ComBat). Analyses of covariance, adjusting for age and sex, examined differences between each epilepsy syndrome and controls for each white matter tract (Bonferroni corrected at p<0.001). Across "all epilepsies" lower fractional anisotropy was observed in most fiber tracts with small to medium effect sizes, especially in the corpus callosum, cingulum and external capsule. Less robust effects were seen with mean diffusivity. Syndrome-specific fractional anisotropy and mean diffusivity differences were most pronounced in patients with hippocampal sclerosis in the ipsilateral parahippocampal cingulum and external capsule, with smaller effects across most other tracts. Those with temporal lobe epilepsy and normal MRI showed a similar pattern of greater ipsilateral than contralateral abnormalities, but less marked than those in patients with hippocampal sclerosis. Patients with generalized and extratemporal epilepsies had pronounced differences in fractional anisotropy in the corpus callosum, corona radiata and external capsule, and in mean diffusivity of the anterior corona radiata. Earlier age of seizure onset and longer disease duration were associated with a greater extent of microstructural abnormalities in patients with hippocampal sclerosis. We demonstrate microstructural abnormalities across major association, commissural, and projection fibers in a large multicentre study of epilepsy.Overall, epilepsy patients showed white matter abnormalities in the corpus callosum, cingulum and external capsule, with differing severity across epilepsy syndromes. These data further define the spectrum of white matter abnormalities in common epilepsy syndromes, yielding new insights into pathological substrates that may be used to guide future therapeutic and genetic studies.

Multivariate white matter alterations are associated with epilepsy duration

“…Similar associations were shown previously, with a whole brain TBSS analysis by (Tsuda et al., 2018) also showing significant associations between epilepsy duration and FA of the fornix in adult TLE patients after multiple comparisons correction. However contrary to our findings, analyses by (Concha et al., 2009; Kemmotsu et al., 2011; Liu et al., 2012; Chiang et al., 2016; Hatton et al., 2020) found no significant associations between epilepsy duration and FA of the fornix.…”

Temporal Lobe Epilepsy Surgical Outcomes Can Be Inferred Based on Structural Connectome Hubs: A Machine Learning Study

“…To control for the potential effect of scanner type, T1‐ and DTI‐derived individual values (ie, ROI volumes and connectivity strengths) were homogenized by applying ComBat, a well‐established approach originally designed to adjust batch effects in microarray expression data, 28 but more recently validated specifically for DTI, 29 including particularly in multisite cohorts of patients with epilepsy 30 . More specifically, ComBat removes unwanted variation introduced by site while preserving biological variability using a Bayesian framework that estimates an empirical statistical distribution for each parameter by assuming that all voxels share the same common distribution.…”

Mega-Analysis Methods in ENIGMA: The Experience of the Generalized Anxiety Disorder Working Group

“…In brain imaging, the approach has been an effective method to harmonize diffusion tensor imaging data (Fortin et al, 2017), cortical thickness measures (Fortin et al, 2018), rest and task-based functional MRI (Nielson et al, 2018), and functional connectivity (Yu et al, 2018). ComBat has been used in ENIGMA studies (Hatton et al, 2019;Villalón-Reina et al, 2019), although it has been argued that it leads to similar results as random effects linear regression (Zavaliangos-Petropulu et al, 2019). Which statistical harmonization model is optimal remains an active discussion at the time of this writing.…”