Epilepsy is one of the most common neurological disorders affecting ~65 million people worldwide. Of those, 25-35% are not responsive to pharmacological treatment, despite the development of new antiepileptic drugs in the previous decades. One of the main barriers hindering the development of better therapies for epileptic seizures, such as closed-loop neuromodulation for seizure prevention and abatement, is the lack of understanding of how seizures initiate, spread and terminate over cortical and subcortical regions. Progress thus far has been hampered by the challenge of measuring in humans neural activity at the multiple scales of ensembles of single neurons and large-scale brain networks. In addition, most previous studies have focused on biophysical mechanisms for seizure initiation at seizure onset zones. An overlooked aspect of focal seizures is the formation/maintenance of local and large-scale pathological neuronal networks and the time-varying susceptibility of brain dynamics to seizure initiation and spread (generalization). We hypothesize that these pathological multiscale networks are maintained via the recurring activation of epileptiform spatiotemporal patterns not only during seizures but also during interictal and preictal periods. We will address these problems in patients with pharmacologically intractable focal epilepsy by recording ensemble of single-neurons via intracortical 96-microelectrode arrays (96-MEA, 4 mm X 4 mm) and large-scale brain networks via intracranial EEGs (Truccolo et al., 2011, 2014; Wagner et al., 2015). Neural activity at these multiple levels will be recorded continuously 24hr/day, over a period of ~1-2 weeks. Furthermore, we will determine the association between recurrent pathological patterns and changes in the brain's susceptibility to spread of excitation and seizures by actively probing neural dynamics with a recently developed real-time closed-loop intracranial electrical stimulation platform (Sarma et al., 2016).
Three specific AIMs will: (1) Test the hypothesis that multiscale ictal patterns recur not only during seizures but also during interictal periods, becoming part of the resting state networks' repertoire; (2) Test the hypothesis that precursor biomarkers of seizure initiation include the reactivation of multiscale ictal network patterns; (3) Test the hypothesis that ictal pattern reactivation during interictal periods is accompanied by increases in the brain's susceptibility to both local and large-scale spread of excitation: probing neural dynamics with closed-loop electrical stimulation.

Public Health Relevance

Epilepsy affects about 65 million people worldwide, 3 million in the US alone. Current pharmacological and surgical approaches to treatment are inadequate and risky for a substantial number of patients. This project will use groundbreaking recording technologies, as well as ways of actively probing brain activity, that will provide an unprecedented level of detail into the microphysiology and mechanisms underlying pharmacologically intractable epilepsy. The long-term goals of this research are to provide a basis for new therapies and approaches to seizure prevention, in the hopes of restoring the quality of life of people suffering from pharmacologically intractable epilepsy.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Acute Neural Injury and Epilepsy Study Section (ANIE)
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Whittemore, Vicky R
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Brown University
Schools of Medicine
United States
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Proix, Timothée; Jirsa, Viktor K; Bartolomei, Fabrice et al. (2018) Predicting the spatiotemporal diversity of seizure propagation and termination in human focal epilepsy. Nat Commun 9:1088
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Y Ho, E C; Truccolo, Wilson (2016) Interaction between synaptic inhibition and glial-potassium dynamics leads to diverse seizure transition modes in biophysical models of human focal seizures. J Comput Neurosci 41:225-44
Lu, Yao; Truccolo, Wilson; Wagner, Fabien B et al. (2015) Optogenetically induced spatiotemporal gamma oscillations and neuronal spiking activity in primate motor cortex. J Neurophysiol 113:3574-87

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