The generation of interictal epileptiform discharges (IEDs) in partial epilepsies is commonly ascribed to enhanced excitatory interactions within glutamatergic neuronal networks. Recent evidence, however, supports the view that inhibitory networks do play a central role. Human and experimental EEG data indicate that IEDs (i) often present with superimposed high frequency activity; (ii) are followed by inhibition/depression of background activity; (iii) can generate delayed excitatory components; and (iv) can be sustained by either glutamatergic or GABAergic signalling. Pre-surgical intracranial EEG recordings performed in patients have confirmed that interictal spikes in the epileptogenic zone may be followed by either enhanced or depressed inhibition. In addition, recordings of neurons from post-surgical in vitro brain slices obtained from temporal lobe epilepsy patients have demonstrated that IEDs are abolished by GABA_A receptor antagonists. Further evidence has emerged from studies of human brain slices with focal cortical dysplasia and several in vitro animal models of epileptiform synchronization showing GABAergic pre-ictal events occuring in neocortical and limbic structures. Together, these data indicate that diverse ligand-gated mechanisms activate IEDs and lead to network hyperexcitability in epileptic patients and in animal models of epilepsy.

Different IED Patterns in Epileptic Patients: Spikes, Spike Bursts, Sharp Waves

As mentioned above, interictal patterns are diverse and variable in partial epilepsies. Fast events defined as interictal spikes are characterized by a large-amplitude rapid component lasting 50–100 ms that is usually followed by a slow wave, 200–500 ms in duration ¹⁴;¹⁵ (Figure 1A). Highly reproducible interictal spikes are typical of cryptogenic and benign forms of epilepsy, such as epileptic disorders with Rolandic or occipital paroxysms ¹⁶;¹⁷. In these clinical conditions, interictal spikes show selective and specific regional distribution. In contrast, partial epilepsies secondary to brain lesions show more irregular interictal spikes, often associated with IED patterns that include sharp waves (characterized by a rapid component that lasts between 100 and 300 ms), bursts of spikes, fast oscillations, and repetitive, paroxysmal slow waves (Figure 1B–E; but see ¹⁸).

IEDs in partial pharmacoresistant epilepsies have been well characterized. In humans, simultaneous unit recordings and laminar field potential profiles obtained with intracortical multielectrodes during acute (surgical) corticography ¹⁹ or chronic pre-surgical monitoring ²⁰;²¹, have revealed that interictal spikes are initiated by large postsynaptic depolarizations, consistent with a paroxysmal depolarization shift similar to those recorded experimentally ^22–25. Moreover, the cortical layers where these depolarizations occur differed according to whether the spike was locally generated or remotely propagated from a distant area ¹⁹;²¹. Finally, characterization of unit firing during interictal spikes has demonstrated heterogeneity inside and outside the seizure onset zone, suggesting that IED’s are not a simple paroxysm of hypersynchronous excitatory activity, but rather represent the interplay of multiple distinct neuronal types within extended neuronal networks ²⁶.

Certain forms of human ‘lesional’ partial epilepsies and cortical dysplasias show distinctive patterns that have specific diagnostic value ^27–29. One such condition is the Taylor-type II focal cortical dysplasia that features IEDs characterized by high frequency spikes and polyspikes, defined as brushes ^30–32 These brushes last 100–200 ms, recur with a periodicity of 1–2 s, and are enhanced during slow-wave sleep. Electrical stimulation has demonstrated that brushes in Taylor-type II focal dysplasias are followed by a desynchronization/depression of activity that lasts 0.5–1 s and are associated with a higher threshold for the generation of further IEDs. ³³ IEDs in temporal lobe epilepsy (TLE) with hippocampal sclerosis are less frequent than in focal dysplasias, and consist of either spikes or sharp waves that are often undetectable on the scalp EEG ³⁴;³⁵. In patients with severe hippocampal atrophy, large amplitude spikes shorter than 100 ms with small post-spike slow activity have been reported. These IEDs increased in frequency and became rhythmic before and after ictal events ³⁶.

Interictal Spikes in Acute and Chronic Animal Models In Vivo

The temporal correlation between IEDs and ictal discharges has been analyzed in vivo in animal models mimicking both acute seizures and chronic epilepsy. Pioneering intracellular recordings obtained from neurons located in the “epileptic focus” induced by application of convulsants (e.g., penicillin) have demonstrated that interictal spikes correlate with paroxysmal depolarizing shifts of the membrane potential leading to sustained action potential firing and at times followed by a robust hyperpolarization ²²;²³;³⁷. These studies have also shown that the transition to seizure is characterized by IED acceleration along with a decrease or disappearance of the post-burst hyperpolarizing potential, a phenomenon that was proposed to result from the progressive accumulation of extracellular potassium ³⁸;³⁹.

This transition pattern, however, has not been reproduced in chronic models of TLE. Thus in both kindling and drug-induced status epilepticus (SE) models, the IED frequency either did not change or it decreased before the onset of an ictal event ^40–43 (for review see ²). Interictal spiking has also been analyzed in animals injected with kainic acid in one hippocampus; this represents a widely used chronic model that faithfully reproduces TLE. As in TLE patients, unilateral IEDs were reproducibly observed in this model in rats ⁴⁴;⁴⁵, mice ⁴⁶ and guinea pigs (Carriero, Arcieri and de Curtis, unpublished observations). More recently, EEG-video monitoring of the epileptic activity recorded during the latent and chronic periods in rats undergoing pilocarpine-induced SE has revealed that following the appearance of seizures, IEDs diminish in duration in the CA3 region and occur at higher rates in the amygdala ⁴⁷. Therefore, these findings suggest that IEDs undergo structure-specific changes following the appearance spontaneous seizure activity. Little information about IEDs is available for other chronic models of partial epilepsy, such as post-traumatic models or models of cortical dysplasia studied in vivo.

IEDs in Acute Animal Models In Vitro

IEDs can be studied in brain slices that are maintained in vitro following experimental procedures that favor epileptiform synchronization. Several reports have shown that IEDs are initiated by gradual enhancement and progressive recruitment of synaptic excitation that reaches the threshold for regenerative calcium currents ^48–50. This process further sustains recurrent excitation and promotes the synchronous firing of a large number of neurons that contribute to the buildup of a population event recognizable as a population spike/sharp wave. Excitatory postsynaptic potentials associated with these IEDs ²⁵;⁵¹;⁵² are mediated by glutamate receptors of the AMPA and NMDA subtypes ^53–57 . Similar mechanisms of IED generation have also been identified in slices of the neocortex ^58–60, piriform cortex ⁵⁰;⁶¹, and entorhinal cortex ⁶² following a variety of pharmacological manipulations. Regenerative potentials sustained by high-voltage calcium spikes ⁶¹;^63–66 and by a persistent fraction of the voltage-gated sodium current ^67–69 also contribute to paroxysmal depolarizing shifts. Finally, interictal synchronization is further facilitated by non-synaptic interactions which can be mediated by extracellular electric fields (ephaptic interactions) or by intercellular gap junctions⁷⁰;⁷¹ that exist between either principal neurons or interneurons. ^72–74

IEDs and the associated glutamatergic paroxysmal shifts are typically observed during prolonged application of (i) drugs that interfere with GABAergic inhibition such as bicuculline, penicillin and picrotoxin (Figure 2A and B), (ii) agonists of glutamatergic transmission such as kainic acid, or (iii) solutions with a ionic composition that enhances neuronal excitability. However, epileptiform discharges can also be induced by drugs that boost both glutamatergic and GABAergic synaptic transmission such as the potassium blocked 4-aminopiridine (4AP). Early studies have shown that 4AP induces two types of IEDs within the hippocampal formation.. The first type is characterized by fast IEDs that are driven by the CA3 network, and are abolished by AMPA receptor antagonists. The second type consists of slow IEDs that were spared by glutamatergic receptor blockers but abolished by GABAergic antagonists ⁷⁵. It was subsequently shown that these slow IEDs can be recorded from any limbic cortical area as well as from the neocortex in brain slices obtained from rats or mice (as well as in the human neocortex, see below). This evidence has recently been confirmed in several areas of the in vitro isolated guinea pig brain (Figure 2C). ⁷⁶

Figure 2

IEDs analysed in in vitro models of epileptiform synchronization. A: Glutamatergic interictal spikes induced in hippocampal slices (left panel) by application of 20 μM bicuculline. Field potentials recorded in the entorhinal cortex (EC), in the (more...)

Intracellular recordings in brain slices have demonstrated that the slow IEDs induced by 4AP are coupled to a complex intracellular potential consisting of hyperpolarizing and depolarizing components. Recently, similar GABAergic IEDs - which correlated in entorhinal cortex (EC) neurons with inhibitory postsynaptic potentials - have been reported in the isolated guinea pig brain maintained in vitro during glutamatergic receptor blockade ⁷⁶;⁷⁷; under these pharmacological conditions, the slow IEDs continued to propagate within the hippocampal-entorhinal region and from one EC to the EC of the contralateral hemisphere (Figure 2) . These slow IEDs are abolished by GABA_A receptor antagonists as well as by a mu-receptor agonist both in the brain slice and in the isolated guinea pig in vitro preparation, thus confirming that they reflect the synchronous activity of local GABAergic networks. It is unclear how the slow IEDs propagate during glutamatergic receptor blockade, but data obtained in brain slices suggest the involvement of non-synaptic mechanisms such as transient increases in extracellular potassium and subsequent redistribution of this ion (see below). However, the involvement of long-range GABAergic pathways or syncytia-like connections among interneurons cannot be ruled out⁷⁸;⁷⁹.

Experiments performed in the in vitro isolated guinea pig brain, in which inhibition was reduced circa 50% by short-lasting bicuculline systemic perfusions, have demonstrated the existence of IEDs sustained by bursting of inhibitory interneurons that precede (by about 1 minute) the generation of a seizure-like discharge ⁸⁰. These IEDs were associated with inhibitory postsynaptic potentials in EC principal neurons of both superficial and deep layers. In addition, glutamatergic IEDs and GABAergic IEDs could be simultaneously induced by this short-lasting bicuculline application in the piriform cortex and in the EC, respectively. Hence, this evidence suggests that an epileptic brain can generate interictal activity that is sustained by both glutamatergic and GABAergic networks, and is in line with the occurrence of GABA-dependent IEDs as reported in human cortical slices obtained from post-surgical specimens ^81–83. IEDs that correlate with synchronous inhibitory postsynaptic potentials in large groups of neurons are often associated with seizure onset ⁸⁰;⁸⁴. It is therefore tempting to speculate that GABA-mediated interictal events may contribute to enhance synchronization of local epileptic networks through a mechanisms of post-inhibition resetting of neuronal firing ⁸⁵;⁸⁶.

IEDs have recently been analyzed by coupling electrophysiological recordings with imaging of activity-depended intracellular changes of calcium concentration (for review see ⁸⁷). Increases in calcium signals have been identified during IEDs and ictal discharges in neurons, presumably as a correlate of neuronal firing ^88–90 In one of these studies, both IEDs and seizures appeared to be associated with calcium increases in astrocytes and these increases were independent of neuronal activation, thus suggesting that ictogenesis could be sustained exclusively by astrocyte activation and by the associated release of glutamate ⁹⁰. However, even though the contribution of glutamatergic glio-transmission to ictogenesis has been confirmed by other authors, the unique role of astrocyte activity in seizure initiation has not been replicated ⁹¹. One recent report analyzed this issue in different experimental models of seizures and IEDs; these experiments found that astrocyte calcium signalling contributes to sustained ictal activity, but is not involved in the generation of IEDs ⁹².

High Frequency Oscillations as Interictal Events

High-frequency oscillations (HFOs) at >100 Hz have been recorded from cortical structures in humans and other animals, both under physiological conditions and in partial epilepsies (for review see ⁹³). Cortical HFOs at 100–200 Hz occur under physiological conditions, during the interictal state in patients presenting with partial epilepsy, and in animal models ^93–95. Intracranial EEG recordings obtained from pharmacoresistant patients suffering from mesial TLE have shown that HFOs are observed in coincidence with an interictal spike and in isolation. Further studies have confirmed these observations in TLE patients ⁹⁷;⁹⁸ and also in the epileptogenic region of patients with neocortical partial epilepsy ^99–101. Physiological HFOs (also termed ripples) are implicated in the process of memory consolidation ¹⁰², and represent population inhibitory postsynaptic potentials generated by principal neurons entrained by synchronously active interneuron networks ¹⁰³;¹⁰⁴. Juxta-cellular recordings obtained with microelectrodes in the human hippocampus during physiological ripples have demonstrated that pyramidal cells fired preferentially at the highest amplitude of the ripple, while interneurons discharged earlier than pyramidal cells ¹⁰⁵. Pathological fast ripples that express very high-rate oscillations (250–600 Hz) were recorded exclusively from epileptic tissue from epileptic patients and in animal models of TLE ⁹⁶;¹⁰⁶;¹⁰⁷. Fast ripples can be observed in the interictal state, while components in the beta-gamma frequency range are usually associated with ictal discharges ¹⁰⁸. Moreover, pathological fast ripples recorded in vivo, unlike ripples, are supported by synchronous burst firing of abnormally active principal neurons and are assumed to be independent of inhibitory neurotransmission ⁹³.

More recently, a different pattern of very low amplitude HFOs with high intrinsic rhythmicity (>250 Hz) has been identified in the seizure onset region in mesial TLE patients during the pre-ictal period ⁹⁸;¹⁰⁹;¹¹⁰. This activity - which is concealed in the intracranial recordings and can only be extracted by amplifying the appropriately filtered signal - occurs in coincidence with IEDs and sharp waves but also in the absence of any detectable IED ⁹⁸;¹¹¹. In summary, HFOs may be interpreted as typical IEDs in partial epilepsies, and their association with other types of IEDs is not the rule.

The cellular and network mechanisms responsible for interictal HFOs have been analyzed in detail in in vitro brain slices exposed to pro-epileptic drugs. Physiological fast oscillations, either pharmacologically induced ⁸⁵;^112–114 or occurring spontaneously during up-down states ¹¹⁵;¹¹⁶, were proposed to be supported by synchronization of inhibitory GABAergic networks via gap junctions with or without the contribution of glutamatergic networks. Faster oscillations, such as ripples, were also found to be supported by both excitatory and inhibitory transmission and gap junctions ¹¹⁷;¹¹⁸. It is not clear whether the HFOs seen during interictal discharges in epileptic tissue are the same as physiological fast activities. Dzhala and Staley proposed that epileptic HFOs are initiated and synchronized by excitatory interactions between pyramidal cells in the hippocampus ¹⁰⁶;¹¹⁹. More recent reports proposed that HFOs generated at the onset of an ictal hippocampal discharge ¹²⁰;¹²¹ correlate with transient GABAergic input ¹²², indicating GABAergic mechanisms as the source of epileptic HFO at least in this case.

The Slow Component After the Interictal Discharges

IEDs recorded from the epileptogenic zone are assumed to be generated by synchronous neuronal firing. In line with experimental evidence ²³;²⁴;¹²³, presurgical intracranial studies in patients with partial epilepsy have demonstrated that the sharp component of a neocortical IED is followed by a depression of neuronal excitability. This phenomenon has been reported in mesial TLE patients analyzed with unit activity recordings ^124–126 as well as by using the paired pulse stimulation paradigm. Thus, these studies provide evidence for the existence of inhibitory phenomena during the post-spike slow wave ¹²⁷. Moreover, in Taylor type II focal dysplasia a refractory period of 0.5–1 sec has been identified after the interictal spike ³³. In this study, enhanced threshold for spike generation was seen in brain regions that surround the epileptogenic zone during single-shock stimulations at 1 Hz that was performed to identify eloquent and symptomatogenic areas. Interestingly, no refractory period was observed after IEDs that were generated within the seizure-onset zone.

Early experimental studies ¹²³, and more recent reports ¹²⁸, have shown that glutamatergic IEDs are followed by a period of depression in excitability that may result from several mechanisms. Cortical surface IEDs are usually larger then 1 mV and they are associated with the simultaneous activation of large ensembles of neurons and possibly astrocytes. This synchronous activation generates massive neuronal firing that boosts recurrent synaptic activation and non-synaptic field and direct interactions. Since GABAergic inhibitory interneurons are presumably preserved in the area of IED generation ^129–131, the activation of recurrent inhibitory networks during IED may be responsible for dampening neuronal excitability. Recurrent inhibition mediated by GABA_A receptors lasts 100 ms and could be reinforced and prolonged up to circa 1 s by the activation of “slow” GABA_B receptors. Since post-IED depression lasts longer than 1 s ¹²³, other mechanisms should be implicated in its generation. In line with this view, it has been shown in the piriform cortex that intra/extracellular pH changes associated with IEDs contribute to this depression by decoupling gap junctions ¹³²;¹³³.

Intracranial studies in TLE patients have demonstrated that background activity and HFO are reduced in amplitude during the slow wave that follows an IED, suggesting post-IED depression ¹⁰⁰. Preliminary findings obtained at the Claudio Munari Epilepsy Surgery Center in Milano suggest that fast activity is reduced after an IED generated in the “irritative zone” surrounding the area of seizure onset ¹³⁴, whereas it is preserved and even enhanced after IEDs generated within the seizure-onset zone (Figure 3). Thus, IEDs characterized by spikes or sharp waves generate a long-lasting period of inhibition/depression that dampens the fast and transient increase in excitability that occurs during the spike/sharp wave. Post-spike depression is typical of the tissue that borders the seizure-onset zone; hence, these findings may support that idea that some IEDs control brain hyperexcitability within the epileptic network and protect the region against seizure entrainment.

Figure 3

Intracranial recordings performed in a patient with cryptogenic partial epilepsy during pre-surgical evaluation of the epileptogenic region. The area of seizure onset is shaded in light grey in the central panels that illustrates 10 seconds of continuous (more...)

In Vitro Recordings of IEDs from Post-surgical Brain Tissue

The fundamental mechanisms of IEDs have also been analyzed in post-surgical cortical slices of human brain tissue incubated in vitro for electrophysiological analysis. Human cortical slices in vitro do not generate spontaneous ictal discharges in standard saline bath solutions unless excitability is enhanced with various experimental procedures ¹³⁵. Yet, spontaneous IEDs can be recorded in post-surgical slices (that included the subiculum and the CA2 region) obtained from hippocampi of patients suffering from mesial TLE with Ammon horn sclerosis ⁸²;¹³⁶ as well as neocortical partial epilepsies ⁸¹. As detailed in the Chapter by Jefferys et al in this book, interictal spikes in these studies were blocked by antagonists of either glutamate or GABA_A synaptic transmission ⁸²;⁸³. Hence, spontaneous IEDs in human cortical tissue in vitro are generated by both GABA_Aergic and glutamatergic synaptic conductances.

HFOs characterized by very fast frequencies at 80–400 Hz have been reported to occur in post-surgical neocortical slices obtained from patients with drug-resistant TLE ¹³⁷. In this study, HFOs associated with interictal spikes did not require synaptic transmission as they continued to occur in the presence of glutamatergic and GABAergic receptor antagonists; they were however abolished by application of drugs that are known to decouple gap junctions, such as carbanoxolone. The effects induced by gap junction decouplers have also been documented in human neocortical slices obtained from patients with FCD as well as from TLE patients ¹³⁸. It was shown in this study that spontaneous IEDs recorded in the presence of normal medium from FCD tissue were reduced, and even more importantly, were no longer synchronized during carbenoxolone application (Figure 4B); moreover, similar effects were seen when IEDs were elicited by 4AP in neocortical slices that had no obvious structural abnormality (Figure 4D). These IEDs, when recorded in the presence of glutamatergic receptor antagonists, correspond intracellularly to a complex sequence of potentials that are dominated by a long lasting depolarization (Figure 4E) and are accompanied by transient increases in extracellular potassium ¹³⁹.

Figure 4

Effects of gap-junction decouplers on the synchronous activity generated by human neocortical slices in vitro. A: Schematic drawing of the location of the two recording extracellular microelectrodes used in the experiments shown in B–D; inter-electrode (more...)

Electrophysiological analysis of slices of human FCD tissue has shown that during 4AP application, IEDs that are mainly dependent on GABA receptor-mediated conductances may be instrumental in eliciting NMDA receptor-mediated ictal discharges ^140–142. As illustrated in Figure 5B, ictal discharges recorded from FCD slices were preceded by negative-going events resembling those seen in isolation during the interictal period; however, the field potentials leading to ictal discharge onset were always of larger amplitude and were followed by a secondary, slow negative field event from which ictal oscillations emerged. The ability of IEDs in initiating ictal synchronization in the human FCD tissue relies on the presence of a GABA_A receptor mediated mechanism that leads to sizeable increases in extracellular potassium. As illustrated in Figure 5C, the transient elevations in extracellular potassium associated with the IEDs that shortly preceded the ictal discharge onset were characterized by rises in extracellular potassium larger than those seen in association with similar field potentials occurring during the interictal period. A similar association of large elevations in extracellular potassium and ictal discharge onset have been observed in the deep layers of the entorhinal cortex ¹⁴³ as well as in isolated hippocampal slices obtained from young rats ¹⁴⁴;¹⁴⁵. Indeed, elevating extracellular potassium can disclose seizure activity both in vivo ¹⁴⁶ and in vitro ¹⁴⁷;¹⁴⁸. It should be emphasized that a similar 4AP treatment in human neocortical tissue without obvious structural abnormality induces only periodic, synchronous, interictal-like GABA receptor-mediated potentials (Figure 5A) ¹⁴⁹. Therefore, these in vitro data support the view that epileptogenicity is a functional feature of FCD tissue.

Figure 5

Synchronous activity induced by bath application of 4AP in neocortical slices obtained from TLE (i.e., presenting with no architectural anomaly) and FCD patients. A: Isolated field potentials (arrow) occur spontaneously in a TLE slice analyzed with field (more...)

The role of GABA receptor-mediated synchronization in initiating ictal activity in FCD tissue is further supported by pharmacological manipulations aimed at decreasing or enhancing the function of GABA_A receptors. GABA_A receptor antagonists or activation of μ-opioid receptors (which blocks the release of GABA from interneuron terminals) made ictal discharges and GABA receptor-mediated interictal events disappear (Figure 6A). Under both conditions, FCD slices generated recurrent epileptiform activity that lacked the features of an electrographic ictal event. Conversely, potentiating GABA_A receptor function with minimal concentrations of phenobarbital ¹⁵⁰;¹⁵¹ caused a prolongation of the ictal discharges along with potentiation of the slow interictal events (Figure 6B).

Figure 6

GABA_A receptor function modulates ictal discharges in brain FCD slices. A: Bath application of the μ-opioid receptor agonist DAGO (10 μM) reduces the amplitude of the isolated negative field events (arrows in a) and transforms ictal activity (more...)

Conclusions

Evidence reviewed in this chapter indicates that IEDs are heterogeneous in terms of both pattern and underlying mechanisms. It has been proposed that the core region in which focal seizures are generated is surrounded by an area that generates hypersynchronous activity (denominated the ‘irritative region’) interposed between the seizure-onset area and the surrounding normal tissue ¹³⁴. IEDs are generated both in the epileptogenic zone and in the irritative region and can spread to (and thus be recorded from) adjacent ‘healthy’ brain structures. Therefore, it is reasonable to conclude that interictal events are sustained by cellular and pharmacological mechanisms that vary according to the site of generation. Indeed, these differences may result in a different functional role with respect to seizure generation. The existence of pre-ictal spikes and their recognition as GABA-mediated events in some experimental models suggest that different IEDs may have a different temporal correlation and possibly functional role with respect to seizure initiation. According to this view, post-IED depression could be a selective feature of IEDs that occur in brain regions (such as the irritative region) in which neuronal homeostasis and synaptic networks are not drastically altered by the epileptogenic process. In seizure-onset regions, tissue damage could be more intense and post-IED depression may not be present or insufficient to dampen excitability, allowing IED’s to effectively trigger seizures.

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The authors declare no conflicts of interest.