Abstracts

Rationale:
Even when structural atrophy is not apparent on routine MRIs it now evident that cortical thickness, cortical and subcortical volumes, and white matter connectivity can be disrupted in Juvenile Myoclonic Epilepsy (JME) compared to healthy controls. Such brain differences may arise from microstructural changes in order to be evident at the macrostructural level. Recent advances in diffusion-weighted imaging facilitate new techniques to interrogate neural microstructure, potentially offering further evidence regarding neuroplasticity discrepancies in JME. In this study, we used multi-shell DWI and the neurite orientation dispersion and density imaging (NODDI) model to investigate cortical microstructural alterations in JME. Specifically, we applied gray matter-based spatial statistics (GBSS), which allows one to extract statistics of the cortical microstructure specific to the gray matter (GM).

Methods:
A total of 49 JME and 25 healthy controls consisting of unaffected siblings (n=13) and unrelated controls (n=12) from the Juvenile Myoclonic Epilepsy Connectome Project (JMECP) were included in this study. Inclusion criteria were: 1) clinical description or directly observed early morning myoclonic jerks, 2) clinical description or directly observed generalized tonic-clonic seizures, 3) EEG with bursts of 3.5-5Hz generalized spike-wave and/or polyspike wave discharges, 4) age between 12-20 years, 5) English speaking, and 6) Verbal and Performance IQ>80. All participants underwent neuropsychological assessment and one 60-minute scan session on GE MR 750 3T clinical scanners with a Nova 32-channel neuroimaging phased array receive head coil and whole-body RF transmission to derive high resolution neuroimages.

Results:
Using GBSS, we found the neurite density index (NDI) to be significantly lower in parietal and temporal regions in JME, but significantly higher throughout frontal and cingulate regions as well as insular and temporal areas compared to controls (Figure 1 left). Regarding the orientation dispersion index (ODI), JME patients were significantly lower in left frontal areas and right insula, but significantly higher than controls in bilateral frontal areas, posterior cingulate and left temporal regions (Figure 1 right). These findings suggest that JME is associated with microstructural deviations compared to controls throughout diverse brain regions.

Conclusions:
These preliminary results from the JMECP demonstrate significant differences in NDI and ODI in patients with JME. The general pattern demonstrates increased NDI and to a lesser extent increased ODI within the broader frontal regions. These results suggest a less organized and hyperconnected neural architecture within the frontal GM—the region at least in part related to seizure generation in JME. Further investigation is needed to determine how these changes relate to seizure types (myoclonus, GTCs, absence), interictal spike frequency, psychosocial and cognitive outcomes, and the influence of genetic background—all to determine the heterogeneity of GBSS changes within JME as a means to improve phenotyping of patients along the spectrum of idiopathic generalized epilepsies.

Funding: NIH-NINDS 5R01NS111022 (JMECP).