Abstracts

Rationale:
Epilepsy is increasingly conceptualized as a network disorder. In this mega-analysis, we integrated neuroimaging and connectome analysis to identify network associations with atrophy patterns in 1,021 adults with epilepsy compared to 1,564 healthy controls from 19 international sites.1
Method:
Participants. We included two patient cohorts with site-matched healthy controls: temporal lobe epilepsy with neuroradiological evidence of hippocampal sclerosis (TLE; nHC/TLE=1,418/732, 341 right-sided focus) and idiopathic generalized epilepsy (IGE; nHC/IGE=1,075/289).  Atrophy in the common epilepsies. Cortical thickness was measured across 68 brain regions and volumetric measures were obtained from 12 subcortical regions and bilateral hippocampi. Data were harmonized across sites and corrected for age, sex, and intracranial volume using ComBat. Linear models compared atrophy in patients relative to controls.  Nodal stress models. To evaluate whether atrophy patterns were related to normative network organization, we obtained functional (resting-state fMRI) and structural (diffusion MRI) connectivity data from 207 unrelated healthy adults from the HCP dataset.2 Nodal stress models then tested whether syndrome-specific atrophy patterns were spatially correlated with hub regions (i.e., regions with many connections).  Disease epicenter mapping. We investigated whether these morphological abnormalities were anchored to the connectivity profile of specific brain regions. To identify these epicenters, we compared every region’s functional and structural connectivity profiles to atrophy patterns in TLE and IGE. Regions were ranked in descending order based on their correlation coefficients, with highly ranked regions characterized as epicenters (F2A). Disease progression. We used linear models to examine the effects of age on atrophy in each syndrome, as well as their associations to nodal stress and epicenter models.
Results:
Patients with TLE showed profound bilateral temporo-parietal and ipsilateral hippocampal and thalamic atrophy (pFDR < 3✕10–14), whereas patients with IGE showed atrophy in bilateral precentral gyri and the thalamus (pFDR < 3✕10–6, F1A). In TLE, cortical atrophy co-localized with functional cortico-cortical hubs (pspin < 0.0005). Conversely, in IGE, a stronger relationship was observed between subcortical atrophy and structural subcortico-cortical hubs (pshuf < 0.01, F1B). These morphological abnormalities were anchored to the connectivity profiles of distinct epicenters, pointing to temporo-limbic cortices in TLE and fronto-central cortices in IGE (pspin < 0.05, F2B). Notably, epicenters in both syndromes were connected to hub regions (pspin < 0.05), suggesting differential mechanisms through which atrophy may spread to hub regions in TLE and IGE. Negative effects of age on atrophy further revealed a strong influence of connectome architecture in TLE only (pspin < 0.05, F2C).
Conclusion:
Through worldwide collaboration in ENIGMA-Epilepsy, we provided novel insights into the macroscale features that shape the pathophysiology of the common epilepsies. 1Whelan et al., 2018, Brain, 141:391-408. 2Van Essen et al., 2012, Neuroimage, 62:2222-2231.
Funding:
:FRQS, CIHR, NIH