Early-life seizures produce lasting alterations in the structure and function of the prefrontal cortex

Abstract

Early-life seizures (ELS) are associated with long-term behavioral disorders including autism and ADHD, suggesting that frontal lobe structures may be permanently affected. We tested whether ELS produce structural alterations in the prefrontal cortex (PFC) and impair PFC-mediated function using an operant task of behavioral flexibility in rats. Adult rats that had been exposed to 75 flurothyl seizures during postnatal days 1–10 showed decreased behavioral flexibility in the task compared to controls over multiple behavioral sessions, measured as a lever preference asymmetry (p<0.001) and a decreased efficiency of attaining food rewards (p<0.05). ELS rats also showed an increased thickness of the PFC (p<0.01), primarily attributed to layer V (p<0.01) with no differences in cell density. These structural changes correlated with lever preference behavioral impairments (p<0.05). This study demonstrates that the consequences of ELS extend to the PFC, which may help explain the high prevalence of comorbid behavioral disorders following ELS.

Autistic characteristics in adults with epilepsy

“…Unsurprisingly, Tuchman & Rapin (2002) highlight how unusual repetitive behaviours, common in children with ASD, can be difficult to distinguish clinically from seizures. However, recent evidence in animals by Kleen and colleagues has indicated a strong relationship between seizures and some RRBs, as it was demonstrated that those with early-life seizures show impaired behavioural flexibility in later adulthood (Kleen et al, 2011). Taken together, this evidence suggests that some components of RRBs may indicate either the presence of active epilepsy, or that early-life seizures have occurred in an individual.…”

“…In addition to the implication of the vmPFC in the formation of somatic markers, recent evidence of lasting alterations resulting from early-life seizures has been found in an animal study (Kleen et al, 2011). The researchers found that repeated early-life seizures resulted in both structural changes in the PFC and abnormal PFC functioning.…”

“…A recent animal study has demonstrated that both abnormal pre-frontal cortex [PFC] functioning and a thicker prelimbic PFC can result from early-life seizures (Kleen et al, 2011). Further, these brain structural abnormalities correlated with measures of impaired behavioural flexibility, which is mediated by the PFC.…”

“…Successful social interaction depends on representations of internal somatic states, emotion-based biasing signals, which play a major role in social cognition. The vmPFC has been implicated in the integration of somatic markers, and recent evidence has demonstrated lasting alterations in the structure and functioning of the PFC resulting from early-life seizures (Kleen et al, 2011). Damage to the ventromedial region of the PFC can result in an inability to experience somatic states (Bechara, Damasio, Tranel, & Damasio, 2005).…”

“…In a recent animal study, Kleen and colleagues demonstrated that animals exposed to the flurothyl model of early-life seizures showed impaired behavioural flexibility in later adulthood compared to controls (Kleen et al, 2011). These early-life seizures increased the thickness of the prefrontal cortex, and this thickness correlated with impaired behavioural flexibility.…”