Imaging Genetics Study On Structural Brain Development In Rolandic Epilepsy

Rolandic epilepsy(RE)is the most common epilepsy syndrome in childhood.Brain development has become the focus of clinical and family concerns.The factors affecting brain development are endogenous(genetic factors)and exogenous(epileptic activity and antiepileptic drugs).The understanding of the internal regularity of brain development and its external influence is the key to comprehensively and objectively evaluate the development process of epilepsy.This study thus intends to observe the overall developmental trajectory of children and its effects of endogenous genetic factors and exogenous drugs,so as to explain the causal mechanism of brain development abnormalities derived from RE.Objectives:1.To observe the cortical developmental trajectory and the causal promoting relationships in children with RE.2.To investigate the possible regulatory effects of development-related gene on brain development in RE.3.To investigate the effect of anti-epileptic medication on morphological changes of cortex in RE,and their causal relationships with seizure control.Methods:1.Morphometric MRI data of drug-naive RE children(n=70)and age matched children(n=83)were included.ROI-based correlation analysis was applied to depict the different development trajectory of children in each group.The Granger causal network of structural covariance was applied to explore the causal effect of Rolandic region on extra cortical alterations in RE patients.2.RE children(n=75)and healthy children(n=75)were enrolled in the study.The susceptible genes related to brain development in RE were detected.ELP4 and PAX6 genes were included using multi-locus score.The gene × disease two-way analysis of variance was performed separately.The gray matter volume of gene × disease interaction effect was compared,and the whole brain functional connection was performed based on region of interest.Then the gene × disease interaction effect of brain functional connectivity was observed.3.A total of 118 children with RE(including antiepileptic drug group and drug-naive group)and 70 healthy children were enrolled.Cortical morphological parameters were quantitatively measured by applying surface-based morphometry analysis in each group.The imaging parameters among the three groups were compared one another to investigate the cortical morphological changes under seizures and drugs.The causal relationships among anti-epileptic medication,seizure controls and cortical morphometric changes were investigated using causal mediator analysis.Results:1.Compared with typically normal children,RE patients showed increased GMV in Rolandic region and other brain regions(GRF correction,p<0.01).Different developmental curve was showed in RE patients.Causal analysis revealed that the Rolandic region was the primary hub node exerting causal effects on the prefrontal cortex and anterior cingulate cortex.2.The disease × gene interaction effect was showed in the bilateral Rolandic region(GRF correction,p<0.01).The post-hoc analysis indicated the increased gray matter volume of the middle risk group compared with the lower risk group in RE.In the whole brain function connection based on right Rolandic region,the disease × gene interaction was located in the left frontal middle gyrus(GRF correction,p<0.01).Post-hoc analysis suggests that the functional connection of the middle risk group in RE was reduced.3.Compared with the healthy controls,the naive patients showed increased cortical thickness in the Rolandic regions(GRF correction,p<0.01).Compared with the naive group,the cortical thickness decreased in the patients with medication(GRF correction,p<0.01),and further showed negative correlation with duration of medication(r=0.441,p<0.001).Morphological alteration of the Rolandic cortices acted as a mediator in the causal path of anti-epileptic medication on seizure control.Conclusions:1.RE patients showed aberrant cortical structures in Rolandic and extra regions.Abnormal cortical developmental trajectories were found with the progression of disease in RE patients.Causal promoting relationship was presented in Rolandic and other brain regions and Rolandic region is the hub node.2.ELP4 and PAX6 gene effects and disease factors co-regulate the structural development abnormalities and functional connectivity changes of epileptogenic region.ELP4 and PAX6 genes show no significant additive effects,and there may be an inhibitory effect between genes.3.RE showed abnormal increases of cortical thickness in the Rolandic regions.Anti-epileptic medication could restore the cortical morphological alteration in the Rolandic regions,which might partially mediate the effect of anti-epileptic medication on seizure control.