Study links brain network interactions to depression risk in pediatric epilepsy - Children's National

A multidisciplinary team at Children's National has identified a potential neurobiological marker for depression risk in children with epilepsy by studying how brain lesions interact with large-scale functional networks. Conducted through the NIH-funded Focal Cortical Dysplasia Research Program, the study brought together experts from the divisions of Neurology, Neurosurgery, Neuropsychology, Neuroradiology, Psychiatry and Behavioral Sciences and Psychology and Behavioral Health.

Using focal cortical dysplasia (FCD), the most common cause of surgically treatable, drug-resistant epilepsy in children, investigators found that greater overlap between lesions and the brain's default mode network (DMN) is associated with increased depressive symptoms, particularly during adolescence.

Dive deeper

FCD disrupts cortical development and functional connectivity, making it a powerful model for understanding how focal brain abnormalities affect distributed neural systems.

In this study, researchers analyzed children with FCD-related epilepsy who completed the Child Behavior Checklist, linking parent-reported psychiatric symptoms with advanced imaging. They mapped FCD lesions from MRI and measured how those lesions overlapped with major functional brain networks, then used statistical models accounting for age and gender to examine how network-level brain organization related to real-world psychiatric symptoms.

The results showed that greater overlap between FCD lesions and the default mode network was associated with higher depressive symptom scores, even after accounting for age and gender. Female sex was also associated with increased depressive symptoms. These associations were stronger in adolescents, suggesting that network maturation amplifies risk during this developmental stage.

"By anchoring depression risk to a specific brain network, we're starting to connect the biology of epilepsy with the lived experience of patients in a much more direct way," said Xiaotong Li, BA, first author of the study and clinical research coordinator with the Focal Cortical Dysplasia Research Program. "This kind of approach helps move the field toward identifying measurable markers that could eventually guide more personalized care."

By contrast, overlap with the limbic network was not associated with depressive symptoms, and no meaningful relationship was found between network overlap and anxiety.

What this means

The findings support a shift from region-based to network-based models of pediatric epilepsy and its comorbidities.

"Rather than thinking of psychiatric symptoms as separate from epilepsy, this work suggests they may arise from the same underlying network disruptions that drive seizures," said Nathan T. Cohen, MD, corresponding author and director of the Focal Cortical Dysplasia Research Program.

The default mode network is involved in self-referential processing and emotional regulation, aligning with broader evidence linking DMN dysfunction to depressive disorders.

The absence of a relationship with anxiety suggests that depression and anxiety in pediatric epilepsy may arise through distinct mechanisms. Overall, the results indicate that lesion-network colocalization contributes to depression vulnerability and that DMN involvement may serve as a neurobiological marker of risk, particularly in adolescence.

Why this matters

By showing that depression risk is tied to how lesions engage functional brain networks, this study provides a more precise framework for understanding psychiatric comorbidity in epilepsy.

The identification of DMN involvement as a potential marker of depressive symptoms opens the door to future work focused on individualized, network-informed diagnostics and therapies.

Together, these findings highlight how Children's National is advancing a more integrated view of pediatric brain disease-one that connects imaging, behavior and clinical care to move toward more personalized treatment strategies.

Additional authors from Children's National include: Ty Charde, Priyanka Illapani, MS, Sonya M. Leikin, BS, Hua Xie, PhD, Chima O. Oluigbo, MD, L. Gilbert Vezina, MD, William D. Gaillard, MD, Hayley J. Loblein, PhD, Perrine Heymann, PhD, Madison M. Berl, PhD, Adelaide S. Robb, MD

Read the full study "Network Colocalization Correlates of Depression and Anxiety in Pediatric Focal Cortical Dysplasia-Related Epilepsy" in the Annals of Neurology here.