Developmental MRI markers cosegregate juvenile patients with myoclonic epilepsy and their healthy siblings

Abstract

Objective MRI studies of genetic generalized epilepsies have mainly described group-level changes between patients and healthy controls. To determine the endophenotypic potential of structural MRI in juvenile myoclonic epilepsy (JME), we examined MRI-based cortical morphologic markers in patients and their healthy siblings. MethodsIn this prospective, cross-sectional study, we obtained 3T MRI in patients with JME, siblings, and controls. We mapped sulco-gyral complexity and surface area, morphologic markers of brain development, and cortical thickness. Furthermore, we calculated mean geodesic distance, a surrogate marker of cortico-cortical connectivity. ResultsCompared to controls, patients and siblings showed increased folding complexity and surface area in prefrontal and cingulate cortices. In these regions, they also displayed abnormally increased geodesic distance, suggesting network isolation and decreased efficiency, with strongest effects for limbic, fronto-parietal, and dorsal-attention networks. In areas of findings overlap, we observed strong patient-sibling correlations. Conversely, neocortical thinning was present in patients only and related to disease duration. Patients showed subtle impairment in mental flexibility, a frontal lobe function test, as well as deficits in naming and design learning. Siblings' performance fell between patients and controls. ConclusionMRI markers of brain development and connectivity are likely heritable and may thus serve as endophenotypes. The topography of morphologic anomalies and their abnormal structural network integration likely explains cognitive impairments in patients with JME and their siblings. By contrast, cortical atrophy likely represents a marker of disease.Glossary ANOVA = analysis of variance; JME = juvenile myoclonic epilepsy.

Cognitive Function in Genetic Generalized Epilepsies: Insights From Neuropsychology and Neuroimaging

“…The previously detailed surface-based morphometry study, which investigated cortical folding complexity and corticocortical connectivity via a geodesic distance metric, identified concomitant abnormalities within high-order fronto-temporal cortices both in patients with JME and siblings. Similarly, abnormal embedding of the latter areas within large-scale cognitive networks, mostly affecting fronto-parietal, dorsal attention and limbic systems, was detected in both groups (132). Finally, recent work demonstrated co-segregation of abnormalities of hippocampal volume, shape and positioning both in patients with JME and their siblings, and showed their association with reorganization of both hippocampal and lateral frontal recruitment during a memory encoding functional MRI paradigm (108).…”

“…By ILAE definition, patients with GGE present with normal clinical MRI. Advanced post-processing methods such as voxelbased morphometry (122), surface-based MRI analysis (123), diffusion tensor imaging [DTI; (124)], and functional MRI have identified widespread structural and functional abnormalities in GGE, mostly implicating fronto-cortico-thalamic regions and their connections (125)(126)(127)(128)(129)(130)(131)(132)(133).…”

“…Interestingly, further support to the neurodevelopmental hypothesis comes from recent analyses, indicating increased cortical folding complexity and inefficient cortico-cortical connectivity of orbitofrontal, ventrolateral frontal, premotor and temporo-polar areas. The latter regions also displayed abnormal cognitive network embedding, with fronto-parietal, dorsal attention and limbic cognitive systems being most affected (132).…”

Altered dynamic effective connectivity of the default mode network in newly diagnosed drug-naïve juvenile myoclonic epilepsy

“…Patients with JME typically show various cognitive impairments, such as deficits in working memory, attention, and executive functions ( Carvalho et al, 2016 , Pascalicchio et al, 2007 , Wandschneider et al, 2012 ), and these cognitive impairments severely affect patients’ quality of life and to some extent increase social and economic burden. Because of these apparent cognitive comorbidities, continuous efforts have been made to understand the fundamental mechanisms underlying the neuropsychology of JME ( Caciagli et al, 2019 , Jiang et al, 2018 , Wandschneider et al, 2019 ).…”

Network-based atrophy modelling in the common epilepsies: a worldwide ENIGMA study

“…While initial work focused on the mesiotemporal lobe, histopathological and neuroimaging studies increasingly detail morphological, structural, and functional compromise beyond this region Blanc et al, 2011;Bonilha et al, 2015;Concha et al, 2012;Keller and Roberts, 2008;Labate et al, 2010;Labate et al, 2008;McDonald et al, 2008;Rodriguez-Cruces et al, 2018;Sinjab et al, 2013), which becomes progressively more severe in patients with a longer disease duration (Bernhardt et al, 2009b;Caciagli et al, 2017;Coan et al, 2009;Galovic et al, 2019). Conversely, idiopathic generalized epilepsy (IGE), also known as genetic generalized epilepsy (Scheffer et al, 2017), has been increasingly linked to subtle degrees of structural compromise, mainly in subcortico-cortical circuits (Bernhardt et al, 2009a;Caciagli et al, 2019;Nuyts et al, 2017;O'Muircheartaigh et al, 2012;Wandschneider et al, 2019;Wang et al, 2019). Support for a network perspective also comes from both experimental studies in animal models and electro-clinical observations in patients showing bursts of spike and slow-wave discharges occurring simultaneously over subcortical and cortical areas (Avoli and Gloor, 1982;Blumenfeld, 2003;Gotman et al, 2005).…”