Basic Mechanisms of Seizure Generation

John G.R. Jefferys

Marom Bikson Premysl JiruskaJohn Fox Martin VreugdenhilJackie Deans Wei-Chih ChangJoseph Csicsvari Xiaoli LiPetr Marusic Martin Tomasek

MRC (UK) Wellcome TrustEpilepsy Research UK

Focal EpilepsyscalpEEG

depthEEG

field

intra-cellular

interictal seizureep

ilept

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atie

ntbr

ain

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“paroxysmal depolarization shift”

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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

CA3

CA1

Brain Slices and Basic Mechanisms

Dentategyrus

Entorhinalcortex

Interictal EEG spikes

40 ms

25 mV

CA3 pyramidal neuron

sim

ulat

ion

real

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Network simulation

Hippocampal CA3• mutual excitation of pyramidal cells• strong synapses (~1mV)• intrinsic bursts• ~1000 pyramidal cells needed for interictal spikes

Traub & Wong 1982, Science

Interictal EEG spikes

Traub & Wong 1982, Science

50 | 60 ms

4 mV25 | 20 mV

50 ms

What makes chronic epileptic foci epileptic?

neuronalloss

intrinsicproperties

↑Ca, ↑Nap, ↓K channels (channelopathies)

neuronalloss

M VreugdenhilW Wadman

What makes chronic epileptic foci epileptic?

intrinsicproperties

↑Ca, ↑Nap, ↓K channels (channelopathies)

neuronalloss

What makes chronic epileptic foci epileptic?

intrinsicproperties

↑Ca, ↑Nap, ↓K channels (channelopathies)

synapticefficacy

↑ EPSPs; ↓IPSPs; presynaptic modulation; dormancy.

neuronalloss

What makes chronic epileptic foci epileptic?

Plus: glia; gap junctions; ion transporters; transmitter transporters…

intrinsicproperties

↑Ca, ↑Nap, ↓K channels (channelopathies)

“Sprouting”synapticconnectivity

synapticefficacy

↑ EPSPs; ↓IPSPs; presynaptic modulation; dormancy.

neuronalloss

What makes chronic epileptic foci epileptic?

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.

What prolongs the hypersynchronous discharge beyond the 1st second?

Extracellular Ions and Seizures

K+

Potassium concentration in extracellular space increases during seizures and depolarizes and excites neurons, promoting and prolonging the seizure

Barbarosie & Avoli 2002 Epilepsia

K+

DC Shifts in Human Epilepsy

Vanhatalo et al 2003 Neurology

Low Ca epileptic bursts

Bikson et al 2003 J Neurophys

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.

Focal seizures in vivo

4s before motor seizure

Stage IV: bilaterally synchronous 16Hz

(15-30Hz)

Stage III: 12-20Hz irregular

Gerald Finnerty Premek Jiruska

Delays between regions ≈ synaptic

Seizure mechanisms Dynamic interactions between cortical structures

re-entrant loops versus coupled oscillators.

Seizures spread further as well as last longer than interictal events

Seizures due to Reverberatory Loops?

Reverberatory Loops? No.

Lack of phase lags suggests re-entrant loops not essentialMaybe have coupled oscillators? Bragin et al, 1997

DG-CA3 CA3-CA1

R CA1

R CA3

L CA3

L CA1

Reverberation / Distributed Focus

R CA3

L CA3

1s

Finnerty & Jefferys 2002

Longer Range Connections In Seizure Generator

From Bertram

L

R

HFA during interictal EEG “spikes”

High frequency interictal activity characteristic of epileptic foci

Interictal HFA

Staba et al 2004, Ann Neurol

Synchronizing mechanisms

Neuron-glia interactions

Chemical synapse

Electrotonic interactions

Field effects

0.1 1 10 100 1 10[ms] [s]

Extracellular potassium

HFA: ripples and IPSPs

Ylinen et al 1995 J Neurosci

Interneuron firing Reversal ≈ IPSP

Pyramidal cell

HFA: ripples and field effects

Bikson et al 2002 J Neurophys; 2004 J Physiol

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TM (

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High Frequency Activity

Low-amplitude high frequency activity preceding seizures

Fast Oscillations Preceding Seizures in ManFast Oscillations Preceding Seizures in Man

0

150[H

z]

Wavelet spectrogram

10 s

10 s0.2 mV

50 µV

raw data

10 s0.2 mV

raw data

ripples (80-250 Hz)

10 sAllen et al. (1992)Fisher et al. (1992)Traub et al. (2001)Worrel et al. (2004)Ochi et al. (2007) Petr Marusic, Martin Tomasek

High frequency activity before seizures

Clusters

987654

32

1

2 mV5 s

0.4 mV

5 sWavelet spectrogram

500

0

[Hz]

Jefferys & Jiruska in press

Raw data (10-250 Hz)

Global synchronization index

High frequency activity before seizures

0 7-7

0.02

50 µV

0

pro

b.

Averaged oscillation

[ms]

Interneurons (n=22)pyramidal cells (n=46)

Tetroderecording

Multiple cell activity during HFA

Cellular firing probability

Premek Jiruska

High frequency activity before seizures

Neuron-glia interactions

Chemical synapse

Electrotonic interactions

Field effects

0.1 1 10 100 1 10[ms] [s]

Extracellular potassium

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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

Epilepsy Surgery Center,Charles University,

Czech Republic

PremyslJiruska

JohnFox

JohnJefferys

MartinVreugdenhil

Department of Neurophysiology, University of Birmingham, UK

MRC Anatomical Neuropharmacology Unit, University of Oxford, UK

JozsefCsicsvari

Petr Marusic

MartinTomasek

School of Computer Science, University of

Birmingham, UK

XiaoliLi

Wei-ChihChang