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Epileptiform ictal discharges are prevented by periodic interictal spiking in the olfactory cortex.

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Epileptiform Ictal Discharges Are Prevented
by Periodic Interictal Spiking in the
Olfactory Cortex
Laura Librizzi, PhD, and Marco de Curtis, MD
Interictal potentials are commonly observed between seizures in human epilepsies and in animal models of epilepsy. It
is uncertain whether interictal spiking in partial epilepsies is causally related with the onset of an ictal discharge. To
analyze the reciprocal correlation between interictal and ictal epileptiform events, we performed extracellular recordings
in the limbic system of the in vitro isolated guinea pig brain preparation. Arterial perfusion of bicuculline (50␮M) in
vitro consistently induced a focal ictal discharge in the hippocampal-entorhinal region that in one third of the experiments was associated with periodic interictal spikes in the piriform cortex. In the absence of active interictal spiking, the
piriform cortex was secondarily invaded by the ictal discharge initiated in the hippocampal-entorhinal region, whereas no
secondary ictal entrainment was observed in the presence of periodic piriform cortex spikes at circa 0.1 to 0.2Hz.
Similarly, ictal events never occurred when arterial perfusion of bicuculline was preceded by a local injection of the same
drug in the piriform cortex, a procedure that induces a sustained interictal spiking. A reduced responsiveness to incoming
paroxysmal discharges generated in the hippocampus was observed during the interval between two interictal spikes in
the piriform cortex.
Ann Neurol 2003;53:382–389
This study demonstrates that interictal spiking (IS) interferes with the generation of ictal discharges in the
piriform cortex and suggests that the interictal state
may represent a condition that delays or prevents seizure onset.
Paroxysmal activity in partial limbic epilepsies is expressed by different neuronal discharge patterns defined as interictal and ictal. Interictal events are characterized by isolated or periodically recurring large and
highly synchronous potentials.1,2 Depending on the
cortical region affected, ictal events show variable features, most commonly characterized by a localized
tonic discharge of small amplitude rhythmic activity
that progressively increases in amplitude, recruits
neighboring areas, and resolves with large amplitude,
rhythmic potentials (after-discharges).3–5 The causal
correlation between IS and the generation of ictal discharges has been scarcely investigated in human epilepsy. Scalp electroencephalogram and depth recordings in human focal epilepsies (largely from temporal
lobe epilepsies) demonstrated that the frequency and
the amplitude of ISs do not change in the few minutes
that precede a partial seizure.6 –9 More recently, a re-
port on nonlinear analysis of scalp and depth electroencephalogram recordings in epileptic patients with
temporal lobe epilepsy suggested that preictal changes
associated with the anticipation of seizure activity do
not correlate with modifications of the IS pattern.10 In
line with these clinical observations, several experimental findings suggest a possible protective role of IS
against the precipitation of ictal phenomena11–18 (for
review, see de Curtis and Avanzini2).
The studies by Lebovitz first demonstrated the existence of a prolonged period of inhibition after a single
IS.19 Such a finding has been confirmed recently in the
acute focal epilepsy model utilized in this study.2,16 It
has been suggested that the period of post-IS inhibition
is proportional to the amplitude of the IS itself, that is,
to the number of neurons and the intensity of their
discharge during the IS.16,20 On the basis of these experimental and clinical observations, it could be hypothesized that the IS state represents an extreme attempt of the brain tissue to prevent the occurrence of
an ictal discharge.2 This hypothesis is here verified by
studying the correlation between interictal and ictal
discharges induced by the GABAa receptor antagonist,
From the Department Experimental Neurophysiology, Istituto Nazionale Neurologico, Milan, Italy.
Address correspondence to Marco de Curtis, Department Experimental Neurophysiology, Istituto Nazionale Neurologico Carlo
Besta, via Celoria 11, 20133 Milan, Italy.
Received Apr 17, 2002, and in revised form Sep 10 and Nov 8.
Accepted for publication Nov 9, 2002.
© 2003 Wiley-Liss, Inc.
bicuculline, in the olfactory and limbic cortices of the
isolated guinea pig brain preparation.21–23
Materials and Methods
Brains of young adult guinea pigs (weight, 150 –250gr) were
isolated and transferred to a perfusion chamber, according to
the standard technique.24 –27 A complex saline solution composed of NaCl 126mM, KCl 3mM, KH2PO4 1.2mM,
MgSO4 1.3mM, CaCl2 2.4mM, NaHCO3 26mM, glucose
15mM, and 3% dextran molecular weight 70,000, oxygenated with a 95% O2–5% CO2 gas mixture (pH 7.3) was
arterially perfused in vitro at 5.5ml/min. Experiments were
performed at 32°C. The experimental protocol was reviewed
and approved by the Committee on Animal Care and Use
and by the Ethics Committee of the Istituto Nazionale Neurologico, in accordance with the international policy on care
and use of laboratory animals.
Simultaneous extracellular recordings were performed in
the anterior piriform cortex (PC), in the entorhinal cortex
(ERC) and in the hippocampus (area CA1 and dentate gyrus) with single glass pipettes filled with 1M NaCl (input
resistance of 3–5MOhm). A twisted silver wire was positioned on the lateral olfactory tract (LOT) for stimulation to
evaluate evoked responses in the olfactory-limbic cortices.
The insertion of the electrodes in the ventral hippocampus
was guided by the waveform features of the evoked responses.28 The position of the recording electrodes in the PC
and ERC was visually controlled with a stereoscopic microscope. Signals were amplified via a differential extracellular
amplifier (Biomedical Engineering, Thornwood, NY) and
were stored on digital tape (Biologic Instruments, Claix,
France). Data were digitized with an ATMIO-64E3 National
board (National Instruments, Milan, Italy) for on-line and
off-line analysis with a custom developed computer software.
Extracellular potassium measurements were performed with
potassium-selective electrodes according to the standard technique.20
The GABAa receptor antagonist, bicuculline, was applied
either locally via a single 10-second injection in the PC
(1mM) or by arterial perfusion for 3 minutes (50␮M). The
effect of a single bicuculline application was followed until
the excitability of the preparation, as measured by evaluating
the amplitude of the PC and ERC responses to LOT stimulation, returned to pre-bicuculline control conditions.
The study was performed on 27 isolated guinea pig
brains. The viability of the preparation was verified by
evaluating the responses evoked by LOT stimulation in
the PC, in the ERC and in the ventral hippocampus
(Fig 1B). Brief arterial perfusions of the GABAareceptor antagonist, bicuculline (50␮M for 3 minutes),
induced ictal events in the ERC-hippocampal region
(Figs 1A and 2) in all but two experiments (n ⫽ 16).
Seizure activity was initiated by isolated complex ISs in
the hippocampus (see Fig 1Ca) that increased in amplitude and progressively entrained a sequence of fast
rhythmic activity at 20.1 ⫾ 0.8Hz (mean ⫾ standard
error; n ⫽ 17). Such fast recruiting activity was fol-
lowed by large amplitude after-discharges (see Fig
1Cc). The ictal discharge propagated to the ERC and,
in the absence of independent and periodic ISs in the
PC, secondarily invaded the PC (n ⫽ 7; see Fig 1A).
Within 30 seconds from the ictal onset, hippocampal
after-discharges were followed with a variable delay
(ranging between 40 and 100 milliseconds) by large
amplitude potentials in the ERC and in the PC (see
Fig 1Cc) that gradually increased in amplitude and determined prolonged ictal-like discharges characterized
by rhythmic sequences at circa 10Hz independent from
the activity in the hippocampus (see Fig 1Ce).
In 7 of 16 bicuculline tests, the ictal discharge in the
hippocampal-entorhinal region was preceded by the activation of spontaneous ISs in the PC (see Fig 2B). Just
before the onset of the hippocampal ictal event, and in
coincidence with the activation of independent and
asynchronous ISs in the hippocampus-ERC, ISs in the
PC ceased for several seconds or decreased in frequency. In all the experiments in which periodic ISs
were elicited, no ictal discharges were recorded in the
PC (see Fig 2B). At the end of the ictal hippocampusERC event, periodic IS reestablished in the PC. The
described sequence of epileptiform events suggest that
ictal-like activity in the PC can be recorded exclusively
in the absence of an active IS condition.
As previously reported16,21,22 and as illustrated in
Figure 2C, a brief (10 seconds) local injection of bicuculline (1mM) in the PC does not induce ictal activity,
but determines the appearance of periodic ISs that recur with a 5 to 10 –second period (8.9 ⫾ 0.8 seconds;
n ⫽ 10) for several tens of minutes. To confirm the
protective role of the ISs against the precipitation of an
ictal discharge in the PC, we performed arterial perfusion of 50␮M bicuculline just after the setting of periodic ISs by a previous local ejection of bicuculline in
the PC (n ⫽ 13). The presence of periodic and sustained ISs determined by the local bicuculline injection
hindered the occurrence of secondarily ictal-like discharges in the PC after the hippocampal-entorhinal ictal event induced by arterial bicuculline application. As
illustrated in Figure 3A and B, the pattern of activation
observed in the hippocampus-ERC was similar to that
described in Figure 1, but the PC was not invaded by
the ictal discharge.
We recently demonstrated that a single IS is followed by a period of reduced excitability during which
the threshold for the generation of an additional IS is
enhanced for several seconds.16 We evaluated whether
such inter-IS disfacilitation (1) occurred in the PC in
our experimental conditions and (2) was able to filter
the incoming excitatory input determined by the hippocampal ictal discharge. As already mentioned, at the
onset of an ictal discharge in the hippocampus, the ISs
in the PC were either abolished or transiently decreased
in frequency (Figs 3A and 4A). Such a modification in
Librizzi and de Curtis: Focal Interictal Spiking
Fig 1. Ictal discharges generated in the hippocampus secondarily invade the PC when no interictal spiking occurs in the PC. (A)
Epileptiform discharges simultaneously recorded in PC, ERC, and ventral hippocampus after arterial application of bicuculline for 3
minutes (50␮M). The duration of the perfusion is marked by the horizontal bar. (B) Field potentials recorded at each recording
site in the PC, ERC, and hippocampus in response to lateral olfactory tract (LOT) stimulation. The progressive increase of the response delay demonstrates the sequential propagation of the olfactory input from the PC to the hippocampus. (C) Details of the recordings illustrated with an expanded time scale at the time points marked by the vertical dotted lines in A. The dotted lines facilitate the visual correlation of the events between recording sites. See text for details. PC ⫽ piriform cortex; ERC ⫽ entorhinal
cortex; Hipp ⫽ hippocampus.
IS frequency correlated with the appearance of small
amplitude potentials in the PC that repeated with a
2.7 ⫾ 0.3 second interval (asterisks in Fig 4A and B).
During the late phase of the hippocampal ictal event,
an unequivocal correlation between a single hippocampal after-discharge and either an IS or a small amplitude potential in the PC was observed (see Fig 4B and
lower couple of traces in Fig 4A; see also Fig 3Cd). In
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this phase of the experiment, all the ISs were entrained
by the incoming input carried by a preceding afterdischarge in the hippocampus, but not all the afterdischarges were followed by an IS. Measurements of
PC inter-ISs interval in this phase was 5.8 ⫾ 0.2 seconds, whereas the interval between hippocampal afterdischarges was 3.6 ⫾ 0.1 seconds. To verify the existence of a refractory period during the interval between
vals between IS and small amplitude potentials and
higher intervals between two ISs.
In another set of experiments, extracellular potassium measurements were simultaneously performed in
PC and ERC with potassium-selective electrodes. Before and during an hippocampal ictal discharge each IS
in the PC was associated with a small change in [K]o
(0.28 ⫾ 0.2mM; n ⫽ 3), whereas larger and longerlasting [K]o increases were observed in the ERC during
the ictal discharge (5.3 ⫾ 0.9mM; n ⫽ 6). These results confirmed that PC IS does not represent an extension of the hippocampal-ERC ictal discharge.
Fig 2. The two most common pattern of epileptiform activation induced by arterial perfusion of bicuculline (50␮M). (A)
As shown in Figure 1, the entorhinal ictal event induces an
ictal discharge in the PC. (B) The presence of a periodic interictal spiking in the PC prevents the propagation in this
cortical region of the ictal discharge generated in the ERC.
(C) Local intracerebral application of 1mM bicuculline in the
PC induces periodic interictal spiking. The arrow marks the
10-second pressure ejection of bicuculline. The asterisk and the
dot mark the lateral olfactory tract–evoked response and a
typical ISs, respectively, illustrated in the bottom panel at
higher time resolution. PC ⫽ piriform cortex; ERC ⫽ entorhinal cortex.
two after-discharge–induced ISs, we calculated the delays between a small amplitude event and a preceding
IS (time 0) and the delays between two ISs (approximated for 250-millisecond intervals) in six experiments
and plotted them as illustrated in Figure 4C. The averaged data show a bimodal distribution of the afterdischarge–associated events, characterized by low inter-
This study demonstrates that (1) arterial perfusion with
bicuculline induces seizure-like activity in the hippocampus-ERC; (2) the absence of IS in the PC is
consistently associated with secondary invasion of the
piriform region by the ictal event that originates in the
hippocampus-ERC; (3) the secondary entrainment of
the PC can be prevented by periodic IS; and (4) the
interval between two ISs in the PC is characterized by
an inhibitory phase that filters out the synaptic excitation carried by the propagation of the hippocampal
In the model utilized in this study, arterial perfusion
of the GABAa-receptor antagonist induced two different focal epileptiform patterns, characterized by a
seizure-like discharge in the hippocampus-ERC with
and without the expression of IS in the PC. The amplitude and morphology of the LOT-evoked field responses before bicuculline application demonstrated
that the excitability of the piriform region and the limbic cortex was similar in experiments that showed either one of the two epileptiform activation pattern.
Spatial-temporal variability of discharge patterns that
probably represents different functional organizations
within the epileptogenic region is not uncommon in
partial epilepsies.29 –32
The activity generated in the hippocampus-ERC
propagated to the PC in the absence of an active IS.
Preliminary findings obtained by performing laminar
field profiles in the PC with 16-channel silicon probes
during the propagated ictal discharge demonstrate that
such activity is, indeed, generated within the PC and is
not volume conducted from other limbic sites (M. de
Curtis, L. Librizzi, and L. Uva, unpublished observations). The dependence of the PC ictal discharge on
the hippocampal-ERC activity is confirmed by the
time correlation between hippocampal discharges and
piriform cortex ISs. The propagation of epileptiform
discharges to the PC is probably attained via a synaptic
pathway that involves either associative ERC-to-PC
projections.33–37 or subcortical pathways mediated
through the amygdala, the midline thalamic nuclei, or
the basal forebrain.38 – 40
Librizzi and de Curtis: Focal Interictal Spiking
Fig 3. Reinforcement of interictal spiking activity induced by local application of bicuculline (1mM) prevents the invasion of the
PC by the ictal discharge that originates in the hippocampus. The horizontal bar marks the arterial perfusion of bicuculline
(50␮M) performed after periodic interictal spiking was induced by local PC application of bicuculline. A and C illustrate the epileptiform events simultaneously recorded in PC, ERC, and hippocampus at low and high time resolution. B shows the LOT-evoked
responses in the same experiment. PC ⫽ piriform cortex; ERC ⫽ entorhinal cortex; Hipp ⫽ hippocampus; LOT ⫽ lateral olfactory
The novel finding in this study is the observation
that secondary invasion of the PC by an ictal event
generated in the hippocampus is hindered by the induction of a periodic IS condition. This report represents to our knowledge the first demonstration that
Annals of Neurology
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spontaneously occurring IS activity has the ability to
interfere with the generation of ictal discharges. The
hypothesis that IS could be associated with a reduced
seizure occurrence has been formulated for the kindling
model by Engel and Ackerman14 and was supported
Fig 4. (A) Simultaneous extracellular recordings in the PC and the hippocampus during PC interictal spiking induced by local
intra-PC application of bicuculline (1mM; top traces), before the ictal onset (second couple of traces from top), during the onset of
the ictal event characterized by fast activity in the hippocampus (third couple of traces), and during the late ictal event characterized by after-discharges in the hippocampus (bottom traces) induced by arterial bicuculline perfusion (50␮M). (B) PC and hippocampal recording during the after-discharge phase of an hippocampal ictal event illustrated with an expanded time scale. The
after-discharges are followed by either IS or small amplitude potentials (asterisks) in the PC. The delays between two ISs (filled
rectangle) and between an IS and a small amplitude potential (striped rectangle) were calculated. (C) Distribution of the delays
of the small amplitude potentials (striped bars) and the ISs (filled bars) from a precedent IS calculated as illustrated in B. The
plot summarizes the results of five experiments. PC ⫽ piriform cortex; Hipp ⫽ hippocampus.
further by the demonstration that lesions that interrupt
the PC-ERC associative fibers facilitate instead of reduce amygdala kindling in rats.41,42 As further evidence, it has been reported that ictal discharges in the
hippocampus are not blocked during pharmacological
manipulations that abolish IS in an in vitro model of
focal epilepsy induced by tissue perfusion with a highpotassium solution.43 Finally, stimulation of the hippocampal region at variable frequencies and with diverse patterns of stimulation that mimic interictal
events have been shown to occlude or reduce the probability of ictal discharges in experimental studies in
vitro,12,15,44 – 47 in vivo,48 and in human temporal lobe
The putative mechanisms that mediate the protective
role of IS against seizure onset are still unclear. We
recently showed that the threshold to synaptic excitation of the PC is enhanced during the interval between
two ISs that recur periodically.16 This study confirmed
that the period between two ISs that recur at 0.1/
0.2Hz is associated with a decrease in PC excitability.
The ability to induce an additional IS by the synchronous incoming input mediated by the propagation to
the PC of an hippocampal after-discharge was impaired
Librizzi and de Curtis: Focal Interictal Spiking
for several seconds after an IS. Just after an IS, indeed,
hippocampal after-discharges are not effective in generating a subsequent IS but induce small amplitude potentials subthreshold for the generation of an IS; preliminary laminar analysis demonstrated that such
subthreshold potentials are generated by a local response in PC superficial layers (not shown). In addition to IS-induced synaptic inhibitory after-potentials,
the post-spike inhibition has been shown to correlate
with an activity-dependent extracellular alkalinization
that was proposed to control neuronal excitability, possibly through a pH-dependent uncoupling of neurons.20 The possibility that activity-dependent extracellular changes in ionic composition during periodic
spiking may play a protective role against seizure onset
will be further investigated in this model.
This study was partially funded by the Italian Health Ministry
(2002-1, M.D.).
We thank G. Avanzini for careful revision of the manuscript.
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