Abstracts

Rationale: Healthy brain activity is organized into functionally connected large-scale networks of coordinated activity that co-vary spatially with genetic expression. Malformations of cortical development (MCD) are a group of neurological developmental disorders resulting in abnormally organized cortex and are an important cause of medically refractory epilepsy. In addition to microscopic neuronal disorganization, organization of large scale functional connectivity is disturbed in epilepsy due to MCD. Genetically, MCD is associated with mutations in genes involved in the mammalian target of rapamycin (mTOR) pathway, which regulate the balance between neuronal cell growth and differentiation. However, the genetic support for the functional disorganization is currently undefined. Methods: In resting-state magnetoencephalography (MEG), we investigated differences in functional connectivity (using the corrected Amplitude Envelope Correlation; AEC-C) and brain network organization (Minimum Spanning Tree-based betweenness centrality; MST-BC) between 20 medically refractory epilepsy patients with pathologically confirmed MCD and a control group of 20 healthy subjects in three frequency bands (5-8 Hz, 8-16 Hz and 16-32Hz). In addition, we assessed anatomical overlap between connectivity and network differences in MCD patients and regional expression of genes of the mTOR pathway (MTOR, DEPDC5, NPRL2, NPRL3, PIK3CA, and TSC1/TSC2) extracted from the Allen Human Brain Atlas (AHBA, left hemisphere, interpolated to both hemispheres for correlation with MEG data). Results: Patients showed a statistically significant lower functional connectivity compared to controls in the 16-32 Hz frequency band in 23 out of 90 brain areas of the automated anatomical labeling (AAL) atlas after correction for multiple comparison (p < .013), located mainly in posterior brain regions (Figure 1A). The MST-BC was significantly higher in four AAL regions in patients (16-32 Hz range) in the left hemisphere, anterior part (p < .003) (Figure 1B).Relative regional mTOR gene expression was high in 24 AAL regions (Table 1). Of these regions, 15 also showed lower functional connectivity in patients compared to controls (Figure 1, large green spheres) with the proportion of anatomical overlap between gene expression areas and areas with lower functional connectivity in patients significantly above chance level (binomial test, p < .001). Of the four regions with high MST-BC in patients (Figure 1B, large yellow spheres), none had relatively high mTOR gene expression (binomial test, p = .58). Conclusions: Functional brain connectivity is lower in patients with refractory epilepsy and MCD compared to controls, especially in posterior brain regions. These regions overlap significantly with the regions that show a relatively high expression of genes associated with MCD. These data support the idea that organization of brain activity in MCD patients is disturbed in a non-random fashion, potentially originated from an incorrect genetic predisposition. Funding: No funding