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Attention deficit associated with early life interictal spikes in a rat model is improved with ACTH
Amanda E Hernan1, Abigail Alexander2, Pierre-Pascal Lenck-Santini3
1Department of Neurology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States of America ; Department of Neurological Sciences, University of Vermont College of Medicine, Burlington, Vermont, United States of America.
Insights
Frequent early-life brain activity, similar to interictal spikes in epilepsy, can cause lasting attention deficits in young rats. Treatment with ACTH showed a modest improvement in attention, suggesting potential therapeutic avenues for cognitive issues in children with epilepsy.
Area of Science:
- Neuroscience
- Developmental Neuroscience
- Epilepsy Research
Background:
- Children with epilepsy often experience cognitive and behavioral issues like ADHD and autism.
- Frequent focal epileptiform activity, even without seizures, may harm cognitive development.
- An appropriate animal model was needed to study these effects.
Purpose of the Study:
- To develop and utilize a rat model to investigate the impact of frequent focal epileptiform activity on neurodevelopment.
- To assess the long-term cognitive and behavioral consequences of early-life interictal spikes.
- To evaluate the efficacy of ACTH treatment in ameliorating these outcomes.
Main Methods:
- A rat model was created using bicuculline methiodine microinjections to induce frequent focal epileptiform activity in the prefrontal cortex from postnatal day 21 to 25.
- Long-term attention and sociability deficits were assessed in adulthood.
- ACTH was administered daily during the period of induced interictal spike activity.
Main Results:
- Rat pups exposed to frequent focal epileptiform activity exhibited significant, persistent deficits in attention and sociability into adulthood.
- ACTH treatment resulted in a modest amelioration of attention deficits.
- ACTH did not alter the frequency of the induced interictal spike activity.
Conclusions:
- Frequent early-life focal epileptiform activity can lead to long-term cognitive and behavioral deficits.
- Pharmacological interventions, such as ACTH, may offer benefits for cognitive outcomes even if not directly targeting epileptiform activity.
- Further research into non-targeted pharmacological interventions is warranted for preventing or improving adverse cognitive outcomes in conditions with early-life epileptiform activity.
Abstract:
Children with epilepsy often present with pervasive cognitive and behavioral comorbidities including working memory impairments, attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder. These non-seizure characteristics are severely detrimental to overall quality of life. Some of these children, particularly those with epilepsies classified as Landau-Kleffner Syndrome or continuous spike and wave during sleep, have infrequent seizure activity but frequent focal epileptiform activity. This frequent epileptiform activity is thought to be detrimental to cognitive development; however, it is also possible that these IIS events initiate pathophysiological pathways in the developing brain that may be independently associated with cognitive deficits. These hypotheses are difficult to address due to the previous lack of an appropriate animal model. To this end, we have recently developed a rat model to test the role of frequent focal epileptiform activity in the prefrontal cortex. Using microinjections of a GABA(A) antagonist (bicuculline methiodine) delivered multiple times per day from postnatal day (p) 21 to p25, we showed that rat pups experiencing frequent, focal, recurrent epileptiform activity in the form of interictal spikes during neurodevelopment have significant long-term deficits in attention and sociability that persist into adulthood. To determine if treatment with ACTH, a drug widely used to treat early-life seizures, altered outcome we administered ACTH once per day subcutaneously during the time of the induced interictal spike activity. We show a modest amelioration of the attention deficit seen in animals with a history of early life interictal spikes with ACTH, in the absence of alteration of interictal spike activity. These results suggest that pharmacological intervention that is not targeted to the interictal spike activity is worthy of future study as it may be beneficial for preventing or ameliorating adverse cognitive outcomes.
