Focal epileptiform activity in the prefrontal cortex is associated with long-term attention and sociability deficits

Abstract

There is a well-described association between childhood epilepsy and pervasive cognitive and behavioral deficits. Often these children not only have ictal EEG events, but also frequent interictal abnormalities. The precise role of these interictal discharges in cognition remains unclear. In order to understand the relationship between frequent epileptiform discharges during neurodevelopment and cognition later in life, we developed a model of frequent focal interictal spikes (IIS). Postnatal day (p) 21 rats received injections of bicuculline methiodine into the prefrontal cortex (PFC). Injections were repeated in order to achieve 5 consecutive days of transient inhibitory/excitatory imbalance resulting in IIS. Short-term plasticity (STP) and behavioral outcomes were studied in adulthood. IIS is associated with a significant increase in STP bilaterally in the PFC. IIS rats did not show working memory deficits, but rather showed marked inattentiveness without significant alterations in motivation, anxiety or hyperactivity. Rats also demonstrated significant deficits in social behavior. We conclude that GABAergic blockade during early-life and resultant focal IIS in the PFC disrupt neural networks and are associated with long-term consequences for behavior at a time when IIS are no longer present, and thus may have important implications for ADHD and autism spectrum disorder associated with childhood epilepsy.

Interictal epileptiform activity and autism

“…In other terms, the deleterious effect of IEDs causes a virtual or physiological "injury" to the networks, preventing them from performing their normal function. Recent animal studies lend support to this hypothesis [26]. This also raises the elusive question regarding the role of sleep in cognitive function and its development.…”

Effect of Seizures on the Developing Brain and Cognition

“…Adult rabbits with similarly induced IIS have a normal distribution of receptive field types, highlighting the vulnerability of critical developmental periods to cumulative IIS effects over time. Likewise, focally-induced IIS by stereotaxic injections of bicuculline in the prefrontal cortex (PFC) in rat pups for several days result in long-standing increases in short term plasticity in the PFC and marked inattentiveness during a spatial memory task, when the rats are tested as 79 .…”

Pathogenesis and new candidate treatments for infantile spasms and early life epileptic encephalopathies: A view from preclinical studies

“…Rats with early life flurothyl-induced spikes showed impaired reference memory and long-term potentiation. Repetitive bicuculline infusions in the prefrontal cortex of PN21-25 rats impaired attentiveness and social behavior in adulthood but had no effect on working memory, motivation, anxiety, or activity level (Hernan et al 2014a). To test whether ACTH, which is currently used in the treatment of children with LKS or CSWS, improves outcomes, ACTH (Acthar gel, 150IU/m 2 ) was given once daily 1 hour prior to the first daily bicuculline infusion between PN21-25 (Hernan et al 2014b).…”