title: Attention deficit associated with early life interictal spikes in a rat model is improved with ACTH.
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.
authors.affiliation: Department 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.
authors.forename: Amanda E
authors.initials: AE
authors.lastname: Hernan
authors.affiliation: Department of Neurology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States of America.
authors.forename: Abigail
authors.initials: A
authors.lastname: Alexander
authors.affiliation: Department of Neurological Sciences, University of Vermont College of Medicine, Burlington, Vermont, United States of America.
authors.forename: Pierre-Pascal
authors.initials: PP
authors.lastname: Lenck-Santini
authors.affiliation: Institute of Child Health, University College London, London, United Kingdom ; Department of Neurological Sciences, University of Vermont College of Medicine, Burlington, Vermont, United States of America.
authors.forename: Rod C
authors.initials: RC
authors.lastname: Scott
authors.affiliation: Department of Neurological Sciences, University of Vermont College of Medicine, Burlington, Vermont, United States of America.
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Holmes
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000704:Analysis of Variance; D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology*; D001640:Bicuculline / Q000031:analogs & derivatives / Q000633:toxicity; D004195:Disease Models, Animal; D004828:Epilepsies, Partial / Q000139:chemically induced / Q000150:complications* / Q000473:pathology*; D058787:GABA-A Receptor Antagonists / Q000633:toxicity; D007279:Injections, Subcutaneous; D008297:Male; D017397:Prefrontal Cortex / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D058787:GABA-A Receptor Antagonists; C017069:bicuculline methiodide; D000324:Adrenocorticotropic Hormone; D001640:Bicuculline