Basic Mechanisms of Seizure Generation

1. Basic Mechanisms of Seizure Generation John G.R. Jefferys Marom Bikson Premysl Jiruska John Fox Martin Vreugdenhil Jackie Deans Wei-Chih Chang Joseph Csicsvari Xiaoli Li Petr Marusic Martin Tomasek MRC (UK) Wellcome Trust Epilepsy Research UK

2. Focal Epilepsy interictal seizure scalp EEG  epileptic patient + depth EEG  + + field + brain slice intra- cellular “paroxysmal depolarization shift”

3. Interictal EEG “spikes” • Last hundreds of ms to a few s, • primarily due to recurrent synaptic excitation between pyramidal neurons • Associated with intracellular paroxysmal depolarizing shift

4. Brain Slices and Basic Mechanisms CA1 Entorhinal cortex CA3 Dentate gyrus

5. Interictal EEG spikes • Hippocampal CA3 • mutual excitation of pyramidal cells • strong synapses (~1mV) • intrinsic bursts • ~1000 pyramidal cells needed for interictal spikes simulation 25 mV 40 ms real cell CA3 pyramidal neuron Network simulation Traub & Wong 1982, Science

6. 50 ms Interictal EEG spikes 4 mV 25 | 20 mV 50 | 60 ms Traub & Wong 1982, Science

7. What makes chronic epileptic foci epileptic? neuronal loss

8. ↑Ca, ↑Nap, ↓K channels (channelopathies) intrinsic properties M Vreugdenhil W Wadman What makes chronic epileptic foci epileptic? neuronal loss

9. ↑Ca, ↑Nap, ↓K channels (channelopathies) intrinsic properties What makes chronic epileptic foci epileptic? neuronal loss

10. ↑Ca, ↑Nap, ↓K channels (channelopathies) intrinsic properties synaptic efficacy ↑ EPSPs; ↓IPSPs; presynaptic modulation; dormancy. What makes chronic epileptic foci epileptic? neuronal loss

11. ↑Ca, ↑Nap, ↓K channels (channelopathies) intrinsic properties synaptic efficacy ↑ EPSPs; ↓IPSPs; presynaptic modulation; dormancy. “Sprouting” synaptic connectivity What makes chronic epileptic foci epileptic? neuronal loss Plus: glia; gap junctions; ion transporters; transmitter transporters…

12. Seizure mechanisms What prolongs the hypersynchronous discharge beyond the 1st second? • Interictal discharges normally stopped by IPSPs / AHPs / synaptic vesicle depletion / presynaptic modulation… • Slow excitatory processes, such as increased extracellular potassium ion concentrations which also cause negative DC shifts found in animal models and in appropriate clinical recordings.

13. Extracellular Ions and Seizures K+ K+ Potassium concentration in extracellular space increases during seizures and depolarizes and excites neurons, promoting and prolonging the seizure Barbarosie & Avoli 2002 Epilepsia

14. DC Shifts in Human Epilepsy Vanhatalo et al 2003 Neurology

15. Low Ca epileptic bursts Bikson et al 2003 J Neurophys

16. Seizure mechanisms • Interictal discharges normally stopped by IPSPs / AHPs / synaptic vesicle depletion / presynaptic modulation… • Slow excitatory processes, such as increased extracellular potassium ion concentrations which also cause negative DC shifts found in animal models and in appropriate clinical recordings. • Seizure morphology – synaptic and non-synaptic mechanisms for tonic and phasic components • Dynamic interactions between separate cortical structures: re-entrant loops versus couple oscillators.

17. Focal seizures in vivo 4s before motor seizure (15-30Hz) Stage III: 12-20Hz irregular Stage IV: bilaterally synchronous 16Hz Delays between regions ≈ synaptic Gerald Finnerty  Premek Jiruska

18. Seizure mechanisms Dynamic interactions between cortical structures Seizures spread further as well as last longer than interictal events • re-entrant loops versus coupled oscillators.

19. Seizures due to Reverberatory Loops?

20. Reverberatory Loops? No. DG-CA3 CA3-CA1 Lack of phase lags suggests re-entrant loops not essential Maybe have coupled oscillators? Bragin et al, 1997

21. R CA1 R CA3 L CA3 L CA1 Reverberation / Distributed Focus R CA3 L CA3 1s Finnerty & Jefferys 2002

22. Longer Range Connections In Seizure Generator L R From Bertram

23. HFA during interictal EEG “spikes” • High frequency interictal activity characteristic of epileptic foci

24. Interictal HFA Staba et al 2004, Ann Neurol

25. Synchronizing mechanisms Extracellular potassium Neuron-glia interactions Chemical synapse Electrotonic interactions Field effects 1 1 0.1 10 100 10 [s] [ms]

26. HFA: ripples and IPSPs Interneuron firing Reversal ≈ IPSP Pyramidal cell Ylinen et al 1995 J Neurosci

27. HFA: ripples and field effects D VTM (mV) +  Bikson et al 2002 J Neurophys; 2004 J Physiol

28. High Frequency Activity • Low-amplitude high frequency activity preceding seizures

29. 0.2 mV 0.2 mV 10 s 10 s Fast Oscillations Preceding Seizures in Man raw data raw data ripples (80-250 Hz) 50 µV 10 s Wavelet spectrogram 150 [Hz] 0 10 s Allen et al. (1992) Fisher et al. (1992) Traub et al. (2001) Worrel et al. (2004) Ochi et al. (2007) Petr Marusic, Martin Tomasek

30. 9 8 7 6 5 4 3 2 1 2 mV 5 s 0.4 mV 5 s Wavelet spectrogram 500 [Hz] 0 Jefferys & Jiruska in press High frequency activity before seizures Raw data (10-250 Hz) Global synchronization index Clusters

31. High frequency activity before seizures Tetrode recording Cellular firing probability Multiple cell activity during HFA Averaged oscillation 50 µV 0.02 prob. 0 0 -7 [ms] 7 pyramidal cells (n=46) Interneurons (n=22) Premek Jiruska

32. + +   High frequency activity before seizures Extracellular potassium Neuron-glia interactions Chemical synapse Electrotonic interactions Field effects 1 1 0.1 10 100 10 [s] [ms]

33. Basic Mechanisms of Seizure Generation • Synaptic and nonsynaptic mechanisms involved • Interictal spikes ~few 100ms: recurrent excitation terminated by inhibitory processes • Seizures continue much longer and spread further • Coupled generators • Sustained excitation • (Slow synapses (mGluR)) • Extracellular chemical changes (K+) • High frequency activity: marker for epileptic tissue and transition to seizure • ripples, fast ripples • Fast synaptic inhibition • Field effects

34. Martin Vreugdenhil John Fox Premysl Jiruska Department of Neurophysiology, University of Birmingham, UK John Jefferys Wei-Chih Chang School of Computer Science, University of Birmingham, UK MRC Anatomical Neuropharmacology Unit, University of Oxford, UK Epilepsy Surgery Center, Charles University, Czech Republic Petr Marusic Martin Tomasek Jozsef Csicsvari Xiaoli Li