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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
ic p
atie
ntbr
ain
slic
e
“paroxysmal depolarization shift”
+
+
+
+
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
cel
l
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
V
TM (
mV
)
+
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
+
+
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