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One of the largest single sources of epilepsy in the world is produced as a neurological sequela in survivors of cerebral malaria. Nevertheless, the pathophysiological mechanisms of such epileptogenesis remain unknown and no adjunctive therapy during cerebral malaria has been shown to reduce the rate of subsequent epilepsy. There is no existing animal model of postmalarial epilepsy. In this technical report we demonstrate the first such animal models. These models were created from multiple mouse and parasite strain combinations, so that the epilepsy observed retained universality with respect to genetic background. We also discovered spontaneous sudden unexpected death in epilepsy (SUDEP) in two of our strain combinations. These models offer a platform to enable new preclinical research into mechanisms and prevention of epilepsy and SUDEP.

Sleep is important for normal brain function, and sleep disruption is comorbid with many neurological diseases. There is a growing mechanistic understanding of the neurological basis for sleep regulation that is beginning to lead to mechanistic mathematically described models. It is our objective to validate the predictive capacity of such models using data assimilation (DA) methods. If such methods are successful, and the models accurately describe enough of the mechanistic functions of the physical system, then they can be used as sophisticated observation systems to reveal both system changes and sources of dysfunction with neurological diseases and identify routes to intervene. Here we report on extensions to our initial efforts [1] at applying unscented Kalman Filter (UKF) to models of sleep regulation on three fronts: tools for multi-parameter fitting; a sophisticated observation model to apply the UKF for observations of behavioral state; and comparison with data recorded from brainstem cell groups thought to regulate sleep.

Sleep-wake regulation is thought to be governed by interactions among several nuclei in midbrain, pons, and hypothalamic regions. Determination of the causal role of these nuclei in state transitions requires simultaneous measurements from the nuclei with sufficient spatial and temporal resolution. We obtained long-term experimental single- and multi-unit measurements simultaneously from multiple nuclei of the putative hypothalamic and brainstem sleep-wake regulatory network in freely behaving rats. Cortical and hippocampal activity, along with head acceleration were also acquired to assess behavioral state. We found that although the average activity of cell groups during states matches the patterns presented previously in brief recordings of individual nuclei in head-fixed animals, the firing rates with respect to cortical and behavioral signs of state transitions differ in critical ways. Our findings pose fundamental questions about the neural mechanisms that maintain specific states and the neural interactions that lead to the emergence of new states.