Progressive dissociation of cortical and subcortical network development in children with new-onset juvenile myoclonic epilepsy

Abstract

Objective: Structural and functional magnetic resonance imaging (MRI) studies have consistently documented cortical and subcortical abnormalities in patients with juvenile myoclonic epilepsy (JME). However, little is known about how these structural abnormalities emerge from the time of epilepsy onset and how network interactions between and within cortical and subcortical regions may diverge in youth with JME compared to typically developing children.

Methods: We examined prospective covariations of volumetric differences derived from high-resolution structural MRI during the first 2 years of epilepsy diagnosis in a group of youth with JME (n = 21) compared to healthy controls (n = 22). We indexed developmental brain changes using graph theory by computing network metrics based on the correlation of the cortical and subcortical structural covariance near the time of epilepsy and 2 years later.

Results: Over 2 years, normally developing children showed modular cortical development and network integration between cortical and subcortical regions. In contrast, children with JME developed a highly correlated and less modular cortical network, which was atypically dissociated from subcortical structures. Furthermore, the JME group also presented higher clustering and lower modularity indices than controls, indicating weaker modules or communities. The local efficiency in JME was higher than controls across the majority of cortical nodes. Regarding network hubs, controls presented a higher number than youth with JME that were spread across the brain with ample representation from the different modules. In contrast, children with JME showed a lower number of hubs that were mainly from one module and comprised mostly subcortical structures.

Significance: Youth with JME prospectively developed a network of highly correlated cortical regions dissociated from subcortical structures during the first 2 years after epilepsy onset. The cortical-subcortical network dissociation provides converging insights into the disparate literature of cortical and subcortical abnormalities found in previous studies.

Keywords: MRI; brain volumes; development; graph theory; juvenile myoclonic epilepsy.

Figure 1:

Adjacency matrices of percentage change correlations in controls (left) and JME (right). The ordering of nodes is the same as in Table 1S.

Figure 2:

Modularity in controls (left) and JME (right). Node abbreviations are the same as in Table 1S. Same color nodes belong to the same module. Bigger nodes represent the hubs of the network as calculated using BC. The spatial distribution of nodes was calculated using the force-atlas graph algorithm, where nodes that demonstrated stronger connections are located closer in space, while nodes with fewer connections tend to be farther in space. Calculated at a hybrid threshold of 35%.

Figure 3:

Transitivity (left), global efficiency (middle), and modularity index (right) in controls (blue), and JME (red). Error bars represent the standard deviation. Groups were statistically significant after Student’s t-test between themselves and against zero; corrected for multiple comparisons (Bonferroni correction).

Figure 4:

Local efficiency in controls (blue) and JME (red). Filled markers represent statistical significance against random. *Statistically significant between groups after Student’s t-test; corrected for multiple comparisons (Bonferroni correction). Calculated at a hybrid threshold of 35%.

Figure 5:

Nodes with high betweenness centrality (BC) in controls (top) and JME (bottom) at their approximate anatomical location. Nodes with the same color represent the same module. Labels are the node abbreviations from Table 1S. Calculated at a hybrid threshold of 35%.