Transcript Implications in absence epileptic seizures

Spike-and-wave Oscillations
Salva Sadeghi
December 1st, 2009
OUTLINE
 Definition
of Spike-and-Wave Patterns
 SWD Observations and Characteristics
 Thalamocortical Circuits
 Experimental Paper from the Journal of
Neuroscience

Activity of Ventral Medial Thalamic Neurons during Absence
Seizures and Modulation of Cortical Paroxysms by the
Nigrothalamic Pathway (Paz et al., 2007)
 References
DEFINITION
 Spike-and-wave
discharge (SWD) refers to a
particular EEG pattern
 Absence (petit mal) seizure


Clinical: momentary lapse of consciousness due
to abnormal electrical activity in the brain
Neuroscience: clear oscillation consisting of
generalized and bilaterally synchronous SWDs in
the neocortex due to irregularities in the
thalamocortical network


Typically a frequency of 3 Hz in humans
Can be 5-10 Hz in cats and rats
SWD IN A HUMAN EEG READING
(Destexhe, 1992)
“Spike”
“Wave”
OBSERVATIONS (Pollen, 1964)
 Intracellular



recordings indicate that:
Spike – neuronal firing
Wave – hyperpolarization of neurons
Firing of the spike triggers slow K+ currents which
in turn cause hyperpolarization and result in the
wave
Slow K+
currents
Spike
Hyperpolarization
MECHANISM (McCormick & Pape, 1990)
 Recall: Single cell oscillation in a thalamocortical neuron
Ih is active during hyperpolarized
state: it repolarizes membrane to
IT activation range
IT activation results in a wide
Ca2+ spike
Depolarization occurs and
deactivates Ih and inactivates IT
Membrane is repolarized by slow
K+ currents and hyperpolarization
occurs; cycle continues….
Na+
Spike
Thalamocortical Circuits

Outside-in approach: Spike-and-wave seizures disappear following thalamic lesions or
by inactivating the thalamus (Pellegrini et al., 1979; Avoli and Gloor, 1981; Vergnes and Marescaux,
1992)

Spindle oscillations, which are generated by thalamic circuits, can be gradually
transformed into spike-and-wave discharges and all manipulations that promote or
antagonize spindles have the same effect on spike-and-wave seizures (Kostopoulos et al.,
1981a, 1981b; McLachlan et al., 1984)
(Destexhe, 1998)
Thalamocortical Circuits (cont.)

An important proportion of thalamic neurons are steadily hyperpolarized and
completely silent during cortical seizures with spike-and-wave patterns (Steriade and
Contreras, 1995; Lytton et al., 1997; Pinault et al., 1998

Cortical and thalamic cells fire prolonged discharges in phase with the "spike"
component, while the "wave" is characterized by a silence in all cell types (Pollen, 1964;
Steriade, 1974; Fisher and Prince, 1977b; Avoli et al., 1983; McLachlan et al., 1984; Buzsaki et al., 1988;
Inoue et al., 1993; McCormick and Hashemiyoon, 1998; Seidenbecher et al., 1998; Staak and Pape, 2001)
Synchronization
(Destexhe, 1998)
Thalamocortical Circuits (cont.)
(Destexhe, 1998)
Thalamocortical Circuits during SWD
CORTEX
1) Increased cortical
excitability leads to
SWDs
3) Increased cortical
excitability results in
runaway excitation/
prolonged firing
5) Strong K+ currents
result in wave, firing
results in spike
THALAMUS
2) Strong Inhibitory
Feedback (GABAb)
from activated
cortex results in
IPSPs in thalamic
relay cells
4) Cortical feedback
continues and
IPSPs convert
spindle oscillations
to 3 Hz SWD
providing rebound
bursts to continue
the cycle
How to control absence seizures?
Possible influence from the nigrothalamic pathway
Experiment: Introduction
Substantia
Nigra
GABAergic
projection
Ventral
Medial
Thalamic
Neurons
Strong
feedback
loop
Cortex
SWD leads
to
paroxysms
Hypothesis:
GABAergic projections from the substantia nigra pars reticulata
(SNR) to thalamocortical neurons of the ventral medial thalamic
nucleus provide a potent network for the control of absence
seizures by basal ganglia.
Pharmalogical blockade of excitatory inputs to nigrothalamic
neurons leads to a transient interruption of SWDs by increasing
the firing rate of thalamic cells and converting the SWDs into
arrhythmic firing patterns.
Experiment: Purpose
 Purpose
1: Characterize VM thalamic neuron
activity during SWD in the GAERS (genetic
absence epilepsy rat from Strasbourg).
 Purpose
2: Determine impact of a transient
blockade of SNR excitation on the firing of
VM cells and the result in cortical
excitability.
Experiment: Methods
 EEG
recordings above the orofacial motor
cortex with control placed in the muscle on
the opposite side of the head
 Intracellular recordings to find membrane
input resistance
 Pharmacology to provide AMPA receptor
antagonists
 Morphological identification to identify areas
Experiment: Results
 During
SWDs, VM firing rate is slow at 7 Hz
(accurate for rats which are typically
between 5-10 Hz during seizures)
 At the end of SWDs, VM firing returns to its
natural state of repetitive discharges of APs
Repetitive
discharge of
APs in the VM
cells results in
end of cortical
paroxysms
Experiment: Results (cont.)
 When
an SWD appears in the EEG, the firing
of VM cells switches from single spike activity
to rhythmic firing, accompanied by
membrane potential oscillations temporally
correlated with SWDs
Experiment: Results (cont.)
 During
SWD, VM cell experiences
subthreshold rhythmic membrane
depolarizations during sustained
hyperpolarization (caused by IPSPs)
Subthreshold
depolarizations
Experiment: Results (cont.)
 Pharmacological
Glutamatergic
Antagonist in the
SNR
Increases rate of
firing in VM cells
Irregular tonic firing
correlated with an
interruption of SWDs
blockade:
Experiment: Conclusions
 Early
rhythmic depolarization of VM is
attributed to activation of Ih due to sustained
hyperpolarization
 IT is activated from a deinactivated state and
can generate Calcium-dependent
depolarizations
 Nigrothalamic inhibition is indirectly
responsible for the deinactivation of IT
 Depolarizations act as rebound bursts and
can generate APs that propagate the SWD in
the cortex
Experiment Conclusions (cont.):
Disinhibition can terminate seizures in the GAERS model
Substantia
Nigra
GABAergic
projection
Inhibition of the
GABAergic
projections results
in disinhibition of
VM
Ventral
Medial
Thalamic
Neurons
Strong
feedback
loop
No longer inhibited,
the VM neurons fire
faster
Cortex
SWD leads
to
paroxysms
SWDs are terminated
and cortical
paroxysms end;
cortex returns to
tonic mode
References
Avoli M., & Gloor P. (1982) Role of the thalamus in generalized penicillin epilepsy:
observations on decorticated cats. Exp. Neurol. 77, 386-402.
Destexhe, A. (2007) Spike-and-wave oscillations. Scholarpedia, 2(2), 1402.
Kostopoulos, G., Gloor, P., Pellegrini, A., & Gotman, J. (1981a) A study of the transition
from spindles to spike and wave discharge in feline generalized penicillin epilepsy:
microphysiological features. Exp. Neurol. 73, 55-77.
McCormick, D.A., & Hashemiyoon, R. (1998) Thalamocortical neurons actively participate
in the generation of spike-and-wave seizures in rodents. Soc. Neurosci. Abstracts 24,
129.
McLachlan, R.S., Avoli, M., & Gloor, P. (1984) Transition from spindles to generalized
spike and wave discharges in the cat: simultaneous single-cell recordings in the cortex
and thalamus. Exp. Neurol. 85, 413-425.
Paz, J., Chavez, M., Saillet,S., Deniau, J-M., & Charpier, S. (2007). Activity of Ventral
Medial Thalamic Neurons during Absence Seizures and Modulation of Cortical
Paroxysms by the Nigrothalamic Pathway. Journal of Neuroscience, 27(4), 929-941.
Pellegrini, A., Musgrave, J., & Gloor, P. (1979) Role of afferent input of subcortical origin in
the genesis of bilaterally synchronous epileptic discharges of feline generalized
epilepsy. Exp. Neurol. 64, 155- 173.
Pollen, D.A. (1964) Intracellular studies of cortical neurons during thalamic induced wave
and spike. Electroencephalogr. Clin. Neurophysiol. 17, 398-404.
Vergnes, M., & Marescaux, C. (1992) Cortical and thalamic lesions in rats with genetic
absence epilepsy. J. Neural Transmission 35 (Suppl.), 71-83.