Behavior problems, as well as impaired cognition, language, and social skills are common comorbidities of pediatric epilepsy, with enduring adverse effects on functioning (see review in Lin et al., 2012a). Population-based epidemiologic investigations have uniformly documented higher rates of attention-deficit hyperactive disorder (ADHD), anxiety disorders, and depression, as well as lower intelligence quotient (IQ) and poor social skills in children with epilepsy compared to children with other medical problems (Davies et al., 2003), healthy controls (Hoie et al., 2006), and siblings without epilepsy (Berg et al., 2007). These behavioral, cognitive, linguistic, and social comorbidities can collectively exert a negative effect on daily activities, such as relationships within the family, peer interactions, school performance, and extracurricular activities (Baca et al., 2011).
There is now substantial evidence indicating that childhood-onset epilepsy is associated with altered brain development (Hutchinson et al., 2010; Pulsipher et al., 2011; Tosun et al., 2011; Lin et al., 2012) and that these structural abnormalities are linked to neurobehavioral comorbidities (Daley et al., 2007; Caplan et al., 2008; Pulsipher et al., 2009; O'Muircheartaigh et al., 2011; Vollmar et al., 2011; Lin et al., 2012). In healthy growing children, cortical gray matter volume and thickness declines with increasing age (Giedd & Rapoport, 2010). In addition to age, the dynamic process of change in cortical thickness is associated with the maturation of intellectual abilities (Shaw et al., 2006). Against this background of expected developmental trajectory, Tosun et al., in a cross-sectional study, showed that pruning of the frontal and temporal regions is altered in children with complex partial seizures (CPS). Specifically, children with CPS with average IQ demonstrated greater cortical thickness than controls, whereas those with below average IQ scores show more thinning with age compared to typically developing children (Tosun et al., 2011). Behavior problems and linguistic deficits are also associated with abnormal cortical development in pediatric epilepsy. Smaller inferior frontal gyrus white matter volumes are related to the presence of a psychiatric diagnosis, mainly ADHD in children with chronic CPS (Daley et al., 2007). Furthermore, frontal lobe volumes are increased in children with new-onset epilepsy and comorbid ADHD relative to both children with epilepsy but without comorbid ADHD and to controls (Hermann et al., 2007). Structural abnormalities involving language-related cortex are associated with impaired language skill in children with epilepsy with average intelligence (Caplan et al., 2009).
Similar to the cortex, subcortical regions undergo age-related developmental changes with increasing volumes in childhood followed by decreasing volumes in adolescence (Sowell et al., 2002; Lenroot et al., 2007; Brain Development Cooperative Group, 2012). Although the link between age and subcortical volumes has not been extensively examined in childhood epilepsy, several lines of evidence suggest that children with epilepsy might have aberrant subcortical developmental trajectory compared to typically developing peers. First, volumetric reductions in the striatum and thalamus have been found in children with localization-related epilepsy (Cormack et al., 2005) and idiopathic generalized epilepsy (Chan et al., 2006; Pulsipher et al., 2009, 2011; Luo et al., 2011) compared to their healthy peers. Second, thalamic and striatal volumetric abnormalities are evident in children with new-onset epilepsy, thus implying a neurodevelopmental impact of childhood epilepsy on subcortical maturation prior to the onset of seizures (Pulsipher et al., 2011; Lin et al., 2012). Third, subcortical development is closely linked to cortical development in healthy children (Lenroot et al., 2007). Given our previous findings of abnormal age-related cortical development in childhood epilepsy (Tosun et al., 2011), we hypothesized that subcortical development might also deviate from normal.
Subcortical structural volumes are related to cognitive performance in pediatric epilepsy. In children with new-onset juvenile myoclonic epilepsy, baseline frontothalamic volume is associated with deficits in executive function (Pulsipher et al., 2009), and striatal enlargement predicts better executive function performances in children with new-onset benign epilepsy with centrotemporal spikes (Lin et al., 2012). These subcortical structures that are vulnerable to childhood-onset epilepsy are also implicated in pediatric psychiatric disorders. Specifically, structural and functional abnormalities in the thalamus and basal ganglia are found in children with ADHD (Xia et al., 2012), depression (Matsuo et al., 2008), internalizing symptoms (Herba et al., 2010), and anxiety disorder (Guyer et al., 2012).
Therefore, in the current study, we focused on subcortical regions in the corticostriatal circuit—including the caudate, putamen, pallidum, and thalamus—that have been implicated in both childhood-onset epilepsy and neuropsychiatric disorders. Among these subcortical regions, we targeted structures that would differentiate children with localization-related epilepsy (LRE) and idiopathic generalized epilepsy (IGE) from healthy controls (HC). Cryptogenic epilepsy with CPS and childhood absence epilepsy (CAE) were chosen as epilepsy syndromes that represent the two respective broad band epilepsy diagnoses, namely LRE and IGE. We predicted that children with CPS and CAE would have significantly smaller volume of the striatum and thalamus compared to the HC group. We also hypothesized that we would identify a different age relationship with striatal and thalamic volumes in the epilepsy and HC groups. We then examined the shared versus unique structural–functional relationships with behavior problems, intelligence, language, peer interaction, and epilepsy variables in these two epilepsy syndromes. In terms of behavioral problems, we focused on attention problems (e.g., daydreaming, difficulties with concentration), social problems (e.g., poor interpersonal skills and/or school performances, few hobbies), and thought problems (e.g., impaired or illogical reasoning, disorganized communication skills) because a recent meta-analysis (N = 2,434) showed that these problems were more common in childhood epilepsy compared to other pediatric chronic diseases (Rodenburg et al., 2005). In addition, several studies have shown that children with epilepsy have impaired social competence and peer interaction (see review in Hamiwka et al., 2011). Our previous study also linked linguistic skills with frontal lobe white matter volumes (Caplan et al., 2009). Given the integral connections among thalamus, basal ganglia, and prefrontal cortex (Draganski et al., 2008), and the evidence for the role of the thalamus in language (see review in Llano, 2013), we hypothesized that subcortical volumes will be related to linguistic skills. Therefore, among the children with epilepsy, we posited that smaller striatal and thalamic volumes will be related to more attention, social, and thought problems; lower IQ; impaired language skill; poor peer interaction; and severity of epilepsy. Together with previously described cortical findings, these predicted findings might provide a neuroimaging signature of the neurobehavioral comorbidities of pediatric epilepsy.