Disruptions in cortico-subcortical covariance networks associated with anxiety in new-onset childhood epilepsy

Abstract

Anxiety disorders represent a prevalent psychiatric comorbidity in both adults and children with epilepsy for which the etiology remains controversial. Neurobiological contributions have been suggested, but only limited evidence suggests abnormal brain volumes particularly in children with epilepsy and anxiety. Since the brain develops in an organized fashion, covariance analyses between different brain regions can be investigated as a network and analyzed using graph theory methods. We examined 46 healthy children (HC) and youth with recent onset idiopathic epilepsies with (n = 24) and without (n = 62) anxiety disorders. Graph theory (GT) analyses based on the covariance between the volumes of 85 cortical/subcortical regions were investigated. Both groups with epilepsy demonstrated less inter-modular relationships in the synchronization of cortical/subcortical volumes compared to controls, with the epilepsy and anxiety group presenting the strongest modular organization. Frontal and occipital regions in non-anxious epilepsy, and areas throughout the brain in children with epilepsy and anxiety, showed the highest centrality compared to controls. Furthermore, most of the nodes correlating to amygdala volumes were subcortical structures, with the exception of the left insula and the right frontal pole, which presented high betweenness centrality (BC); therefore, their influence in the network is not necessarily local but potentially influencing other more distant regions. In conclusion, children with recent onset epilepsy and anxiety demonstrate large scale disruptions in cortical and subcortical brain regions. Network science may not only provide insight into the possible neurobiological correlates of important comorbidities of epilepsy, but also the ways that cortical and subcortical disruption occurs.

Keywords: Anxiety comorbidity; Graph theory analysis; Pediatric epilepsy; Structural MRI.

Fig. 1

Adjacency matrices. Unthresholded matrices for (A) controls, (B) epilepsy without anxiety, and (C) epilepsy with anxiety. The order of nodes is the same as in the Supplemental document 1. Adjacency matrices. Unthresholded matrices for (A) controls, (B) epilepsy without anxiety, and (C) epilepsy with anxiety. The order of nodes is the same as in the Supplemental document 1.

Fig. 2

Community structure. Community structure in controls (top), children with epilepsy without anxiety (middle), and children with epilepsy with anxiety (bottom). 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. Nodes with a similar color belong to the same module. Calculated at a density of 26%. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

Global measures. Transitivity (left), harmonic mean (middle), and modularity index (right). Participants with epilepsy and anxiety presented significantly higher global segregation and integration compared to both healthy controls and participants with epilepsy without anxiety. *Statistically significant between groups after ANOVA testing (corrected for multiple comparisons). Each group result and at each density level is significant (corrected for multiple comparisons) against zero (null hypothesis).

Fig. 4

Centrality measures. Ranked Z-score distribution for node strength (top), eigenvector centrality (middle), and subgraph centrality (bottom) on children with epilepsy without anxiety disorder (green), and children with epilepsy with anxiety disorder (red) with respect to controls. Bars with different pattern represent nodes with a Z-score value > 2 or lower than − 2. Calculated at a threshold of 26%. *Statistically significant (corrected for multiple comparisons) against zero (null hypothesis); †Statistically significant between the given group and controls (corrected for multiple comparisons). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 5

Amygdala network in anxious epilepsy. Amygdala network in children with epilepsy and anxiety. Red = nodes correlated to bilateral amygdala, blue = nodes correlated to the left amygdala, green = nodes correlated to the right amygdala, gray = nodes correlated to amygdala volumes through intermediate nodes. Bigger circles represent nodes with high BC. Calculated at a threshold of 26%. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)