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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS079533-06
Application #
9523438
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Whittemore, Vicky R
Project Start
2012-07-01
Project End
2023-04-30
Budget Start
2018-06-01
Budget End
2019-04-30
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Brown University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
Pesaran, Bijan; Vinck, Martin; Einevoll, Gaute T et al. (2018) Investigating large-scale brain dynamics using field potential recordings: analysis and interpretation. Nat Neurosci 21:903-919
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
Martinet, L-E; Fiddyment, G; Madsen, J R et al. (2017) Human seizures couple across spatial scales through travelling wave dynamics. Nat Commun 8:14896
Gerhard, Felipe; Deger, Moritz; Truccolo, Wilson (2017) On the stability and dynamics of stochastic spiking neuron models: Nonlinear Hawkes process and point process GLMs. PLoS Comput Biol 13:e1005390
Heitmann, Stewart; Rule, Michael; Truccolo, Wilson et al. (2017) Optogenetic Stimulation Shifts the Excitability of Cerebral Cortex from Type I to Type II: Oscillation Onset and Wave Propagation. PLoS Comput Biol 13:e1005349
Sarma, Anish A; Crocker, Britni; Cash, Sydney S et al. (2016) A modular, closed-loop platform for intracranial stimulation in people with neurological disorders. Conf Proc IEEE Eng Med Biol Soc 2016:3139-3142
Truccolo, Wilson (2016) From point process observations to collective neural dynamics: Nonlinear Hawkes process GLMs, low-dimensional dynamics and coarse graining. J Physiol Paris 110:336-347
Aghagolzadeh, Mehdi; Hochberg, Leigh R; Cash, Sydney S et al. (2016) Predicting seizures from local field potentials recorded via intracortical microelectrode arrays. Conf Proc IEEE Eng Med Biol Soc 2016:6353-6356
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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