Seizures are named for their unpredictability. This project seeks to understand the conditions that lead to seizure initiation so that we can develop anticonvulsant strategies to ameliorate those conditions. Organotypic hippocampal slice cultures first develop interictal spikes and then spontaneous seizures over 3 - 7 days in vitro (DIV). The question addressed here is: why does a seizure occur instead of another interictal spike? Answering this requires a careful dissection of the conditions just prior to each spike, and each seizure. That is not feasible to do even in vitro, whereas in computer models, pre-ictal conditions can be stored, analyzed, manipulated, and re-run. In the last round, we developed the first neural network model that generates both interictal spikes and seizures. The seizures are self-sustaining reentrant waves of activity that have recently been recorded with high-density electrodes in human epilepsy. The conditions for sustained re-entry are difficult to achieve, which may account for the relative rarity of seizures vs. interictal spikes. In this proposal, we will test three pre-ictal conditions that we have identified in silico. The first condition is the wiring of the network. Neuronal synaptic wiring strategies are largely unknown, but we have developed technologies to determine synaptic wiring in the organotypic slice, including a microcscope within an incubator (?IncuScope?) and deployment of digital micromirror chips to stimulate single neurons using optogenetics (?optical synapses?). We will read out the synaptic targets of the stimulated neurons using sensitive new transgenic calcium fluorophores. We will then test the necessity of that ictal wiring pattern by altering it using excitatory and inhibitory optical synapses. The second pre-ictal condition is the pattern of refractoriness in the network. These patterns shape the wave of activation, and most waves die out without forming stable re- entrant cycles. The third preictal condition is the location of the onset of the wave of activation; reentrant waves of activity can only be initiated from particular regions within a pre-ictal network pattern of refractoriness. We will test the second and third conditions by converting spiking networks to seizing networks, and seizing networks to spiking or quiescent networks, with appropriate stimulation using excitatory optical synapses. These experiments will provide unique new insights into brain connectomics; ictogenesis; and the mechanisms of efficacy and failure of the therapies for medically intractable epilepsy: seizure surgery (changing network wiring;
Aim 1) and brain stimulation (changing the refractory patterns in epileptic networks;
Aim 2).

Public Health Relevance

We have developed a computational model of epileptic networks that generates both interictal spikes and seizures. We record every parameter in the model so that we can plot, rewind, replay, analyze, and modify the conditions that exist in the milliseconds just prior to the onset of a seizure. We will use newly-developed stimulation and recording technologies in an experimental model of chronic epilepsy to test three key conditions that we have found to be necessary for seizure onset in our modeling studies, all three of which have direct bearing on treatments for intractable epilepsy.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Churn, Severn Borden
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Massachusetts General Hospital
United States
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Lillis, K P; Staley, K J (2018) Optogenetic dissection of ictogenesis: in search of a targeted anti-epileptic therapy. J Neural Eng 15:041001
Liu, Jing; Saponjian, Yero; Mahoney, Mark M et al. (2017) Epileptogenesis in organotypic hippocampal cultures has limited dependence on culture medium composition. PLoS One 12:e0172677
Song, Yu; Pimentel, Corrin; Walters, Katherine et al. (2016) Neuroprotective levels of IGF-1 exacerbate epileptogenesis after brain injury. Sci Rep 6:32095
Lillis, Kyle P; Wang, Zemin; Mail, Michelle et al. (2015) Evolution of Network Synchronization during Early Epileptogenesis Parallels Synaptic Circuit Alterations. J Neurosci 35:9920-34
Park, Kyung-Il; Dzhala, Volodymyr; Saponjian, Yero et al. (2015) What Elements of the Inflammatory System Are Necessary for Epileptogenesis In Vitro? eNeuro 2:
Shapiro, Kevin A; McGuone, Declan; Deshpande, Vikram et al. (2015) Failure to detect human papillomavirus in focal cortical dysplasia type IIb. Ann Neurol 78:63-7
Staley, Kevin (2015) Molecular mechanisms of epilepsy. Nat Neurosci 18:367-72
Lillis, Kyle P; Dulla, Chris; Maheshwari, Atul et al. (2015) WONOEP appraisal: molecular and cellular imaging in epilepsy. Epilepsia 56:505-13
Berdichevsky, Yevgeny; Dryer, Alexandra M; Saponjian, Yero et al. (2013) PI3K-Akt signaling activates mTOR-mediated epileptogenesis in organotypic hippocampal culture model of post-traumatic epilepsy. J Neurosci 33:9056-67
Sabolek, Helen R; Swiercz, Waldemar B; Lillis, Kyle P et al. (2012) A candidate mechanism underlying the variance of interictal spike propagation. J Neurosci 32:3009-21

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