Impaired development of intrinsic connectivity networks in children with medically intractable localization-related epilepsy

Abstract

Typical childhood development is characterized by the emergence of intrinsic connectivity networks (ICNs) by way of internetwork segregation and intranetwork integration. The impact of childhood epilepsy on the maturation of ICNs is, however, poorly understood. The developmental trajectory of ICNs in 26 children (8-17 years) with localization-related epilepsy and 28 propensity-score matched controls was evaluated using graph theoretical analysis of whole brain connectomes from resting-state functional magnetic resonance imaging (fMRI) data. Children with epilepsy demonstrated impaired development of regional hubs in nodes of the salience and default mode networks (DMN). Seed-based connectivity and hierarchical clustering analysis revealed significantly decreased intranetwork connections, and greater internetwork connectivity in children with epilepsy compared to controls. Significant interactions were identified between epilepsy duration and the expected developmental trajectory of ICNs, indicating that prolonged epilepsy may cause progressive alternations in large-scale networks throughout childhood. DMN integration was also associated with better working memory, whereas internetwork segregation was associated with higher full-scale intelligence quotient scores. Furthermore, subgroup analyses revealed the thalamus, hippocampus, and caudate were weaker hubs in children with secondarily generalized seizures, relative to other patient subgroups. Our findings underscore that epilepsy interferes with the developmental trajectory of brain networks underlying cognition, providing evidence supporting the early treatment of affected children.

Keywords: functional connectivity; generalized tonic clonic (GTC); graph theoretical analysis; intrinsic connectivity network; resting-state fMRI.

Figure 1

Differences in whole brain connectome hubs in children with epilepsy compared to controls. (A) Group effects show that insulae of children with epilepsy are weaker regional hubs compared to controls. (B) Age effects show that the PCC and frontal lobe demonstrate age‐related interactions in children with epilepsy. The PCC becomes more central as a function of age in controls compared with children with epilepsy, while the centrality of the frontal lobe fails to weaken with age in children with epilepsy. Axes scaled to show variance in data; steepest increases with age identified in the PCC (slope_controls = 1.1 × 10⁻³; slope_epilepsy = 7.0 × 10⁻⁵). [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 2

Seed‐based analysis reveals stronger internetwork connectivity and weaker intranetwork connectivity in children with epilepsy. Using core nodes of the DMN and salience networks as ROI, we determined that children with epilepsy demonstrate significantly stronger internetwork connectivity and weaker intranetwork connectivity compared to controls, suggesting a failure of network integration and segregation during development. Color bars represent z‐scores. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 3

Differing trajectories for functional integration and segregation of DMN and salience networks with age among children with epilepsy and controls. Mean clustering and characteristic pathlength of the DMN increase and decrease with age, respectively. Although children with epilepsy demonstrated less steep slopes, the interaction was not significant. Mean clustering and characteristic pathlength of the salience network were significantly lower and greater in children with epilepsy, respectively. While internetwork correlations decreased with age, children with epilepsy demonstrated greater internetwork correlations than controls among various nodes. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 4

Agglomerative hierarchical clustering reveals more disorganized network architecture in children with epilepsy compared to controls. Less separation of individual networks was observed in children with epilepsy. Children with epilepsy also had a higher frequency of significant internetwork connection and fewer significant intranetwork connections relative to controls (P < 0.01, uncorrected; P = 0.01, corrected). [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 5

Differential intrinsic connectivity in children with secondarily generalized seizures. The connectomes of children with secondarily generalized demonstrated weaker hubs in the anterior thalamus, left hippocampus, and globus pallidus and greater hubs in nodes of the DMN. The DMN hubs also demonstrated pathological connectivity patterns in seed‐based analysis. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 6

Duration of epilepsy is associated with weaker intranetwork integration and internetwork separation. With longer duration of epilepsy, nodes of the DMN express reduced EC and show greater disorganization. Similar patterns were observed when evaluating proportion of life with epilepsy and age of epilepsy onset as independent variables. Color bars represent distribution of subject ages. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 7

Extratemporal epilepsy location associated with weaker centrality in the salience network. Bilateral insular regions were weaker hubs in the connectomes of children with extratemporal epilepsy relative to children with temporal lobe epilepsy. The latter demonstrated greater centrality of the lateral parietal cortex (a component of the DMN). No significant differences were observed with seed‐based connectivity between the two groups. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]