1. Modulating seizure-permissive states with weak electric fields Marom Bikson Davide Reato, Thomas Radman, Lucas Parra Neural Engineering Laboratory - Department of Biomedical Engineering The City College of New York of CUNY

2. Rational Epilepsy Electrotherapy Specific Objective: Characterize the modulation of gamma-band network activity by weak electric fields. Epilepsy Control Rationale: Changes in gamma activity may be indicative of a pre-seizure. Early detection and stimulation may control seizures. General Approach: Can the mechanisms of electrical modulation be accurately described to then facilitate rational control strategies. Methods: Stimulation of gamma oscillations in brain slices to characterize acute effects. “Physiological” computational neuronal modeling to describe modulation.

3. Network Gamma and Stimulation Methods Brain Slice 450 μM acute rat hippocampal slice 20 μM carbachol CA3 extra/intracellular electrophysiology Uniform “weak” electric field stimulation (DC, AC, acute, open loop) ‘Izhikevich’ single compartment CA3 neurons 800 pyramidal and 200 inhibitory neurons All-to-all synaptic coupling, weighted strengths Electric Field polarizes pyramidals as: “Physiological” Computational Model I ElectricField = Electric Field * G coupling

4. Electric Field Cell polarization Slope → G coupling

5. I ElectricField = Electric Field * G coupling Electric Field Cell polarization Slope → G coupling DC Uniform DC Uniform Field

6. I ElectricField = Electric Field * G coupling Electric Field Cell polarization Slope → G coupling Hyper-polarized cell compartments Depolarized cell compartments DC Uniform Field

7. I ElectricField = Electric Field * G coupling Electric Field Cell polarization Slope → G coupling Hyper-polarized cell compartments DC Uniform Field Depolarized cell compartments G coupling = 0

8. ? G coupling Electric Field Cell polarization Slope → G coupling Bikson, Jefferys 2004CA1 ~ 0.1 Deans, Jefferys 2007 CA3 ~ 0.2 Radman, Bikson 2009 Cortical Neuron <0.5 I ElectricField = Electric Field * G coupling

9. “Physiological” Computational Model Brain Slice G coupling (field freq) ← t =RC 450 μM acute hippocampal slice 20 μM carbachol CA3 extra/intracellular electrophysiology Uniform “weak” electric field stimulation (DC, AC, acute, open loop) ‘Izhikevich’ single compartment CA3 neurons 800 pyramidal and 200 inhibitory neurons All-to-all synaptic coupling, weighted strengths Electric Field polarizes pyramidals as: Network Gamma and Stimulation Methods

10. “Tonic” gamma “Physiological” Computational Model Brain Slice Network Gamma and Stimulation Methods

11. DC fields -6 mV / mm 6 mV / mm Adaptation?

12. AC fields 2 Hz (4 mV / mm) 28 Hz (6 mV / mm) Sub-harmonics? Modulation? Deans et al. 2008

13. Monophasic ‘AC’ Fields 2 Hz AC (6 mV / mm) + DC 6 mV/mm 2 Hz AC (6 mV / mm) - DC 6 mV/mm

14. Computational Results Qualitative / Quantitative reproduction of brain slice data set (AC, DC, AC+DC) Physiological variables and parameters Simulation effects only pyramidal neurons (soma) Adaptation, sub-harmonics, modulation Extracellular, intracellular Slice

15. In Py In Py carbachol In Py In Py carbachol Mechanism

16. In Py In Py carbachol In Py In Py Electric field carbachol Mechanism DC 28 Hz AC

17. General Approach Gamma Epileptic In vitro model + electric fields → Computational models

18. Conclusions “Weak” electric fields can modulate active gamma oscillations Interactions between the cellular and network level determine responses Response is system/state specific (physiology, pathophysiology) Reduced (e.g. single compartment) but “physiological” and parameterized (G coupling, field) computer models may guide rational epilepsy electrotherapy