Basic Mechanisms of Seizure Generation

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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
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Focal Epilepsy
interictal
seizure
scalp EEG
?
epileptic patient

depth EEG
?


field

brain slice
intra- cellular
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

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Brain Slices and Basic Mechanisms
CA1
Entorhinal cortex
CA3
Dentate gyrus
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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
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Interictal EEG spikes
4 mV 25 20 mV
50 60 ms
Traub Wong 1982, Science
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What makes chronic epileptic foci epileptic?
neuronal loss
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What makes chronic epileptic foci epileptic?
neuronal loss
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What makes chronic epileptic foci epileptic?
neuronal loss
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What makes chronic epileptic foci epileptic?
neuronal loss
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What makes chronic epileptic foci epileptic?
neuronal loss
Plus glia gap junctions ion transporters
transmitter transporters
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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.

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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
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DC Shifts in Human Epilepsy
Vanhatalo et al 2003 Neurology
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Low Ca epileptic bursts
Bikson et al 2003 J Neurophys
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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.

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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
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Seizure mechanisms Dynamic interactions between
cortical structures
Seizures spread further as well as last longer
than interictal events

• re-entrant loops versus coupled oscillators.

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Seizures due to Reverberatory Loops?
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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
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Reverberation / Distributed Focus
R CA3
L CA3
1s
Finnerty Jefferys 2002
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Longer Range Connections In Seizure Generator
L
R
From Bertram
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HFA during interictal EEG spikes

• High frequency interictal activity characteristic
  of epileptic foci

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Interictal HFA
Staba et al 2004, Ann Neurol
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Synchronizing mechanisms
Extracellular potassium
Neuron-glia interactions Chemical synapse
Electrotonic interactions
Field effects
0.1
1
10
100
1
10
s
ms
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HFA ripples and IPSPs
Interneuron firing
Reversal IPSP
Pyramidal cell
Ylinen et al 1995 J Neurosci
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HFA ripples and field effects
D VTM (mV)

?
Bikson et al 2002 J Neurophys 2004 J Physiol
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High Frequency Activity

• Low-amplitude high frequency activity preceding
  seizures

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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
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High frequency activity before seizures
Raw data (10-250 Hz)
Global synchronization index
Clusters
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High frequency activity before seizures
Tetrode recording
Multiple cell activity during HFA
Cellular firing probability
Averaged oscillation
50 µV
0.02
prob.
0
0
-7
ms
7
pyramidal cells (n46)
Interneurons (n22)
Premek Jiruska
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High frequency activity before seizures
Extracellular potassium
Neuron-glia interactions Chemical synapse
Electrotonic interactions
Field effects
0.1
1
10
100
1
10
s
ms
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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

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