*Clinical Neurophysiology of Epileptogenic Networks DOI: http://dx.doi.org/10.5772/intechopen.104952*

#### **Figure 24.**

*Following the background EEG attenuation lasting for 1–2 s, a widespread frontotemporal (maximum at midtemporal A1 electrode) rhythmical 3–4 Hz theta-range activity (with opening of her eyes), started building up indicating engagement of left limbo-cortical networks (left hippocampus and limbic system).*

#### **Figure 25.**

*Following the engagement of left limbo-cortical networks, there is an acceleration of the background activity over the left hemisphere into a rhythmical 8–9 Hz alpha-range (neocortical) activity predominantly over the left frontotemporal (maximum at A1 temporal electrode) region, before spreading to bilateral frontal regions and clinically manifesting with a generalized tonic-clonic seizure (the EEG gets obscured by muscle and movement artefact).*

In the focal type of epilepsies, there is either decreased inhibition and/or increased excitation and/or structural and functional connectivity changes (acquired or cumulated through life) in the local network that can alter the dynamic interaction of excitatory and inhibitory network components and/or result in increased network

synchronization processes [118]. The following fundamental mechanisms in different combinations can alter the dynamic interaction of excitatory and inhibitory network components resulting in focal-onset seizures:


#### *4.2.1 Mechanisms leading to decreased inhibition*

The release of γ-amino-butyric acid (GABA), the main inhibitory brain neurotransmitter, from presynaptic neuron terminals binds to GABA-A and GABA-B receptors and inhibits the postsynaptic neuron either by direct induction of an inhibitory postsynaptic potential (IPSP) via GABA-A receptor-mediated chloride currents, or by indirect inhibition of the release of excitatory neurotransmitter in the presynaptic afferent projection, with a GABA-B receptor-mediated potassium current [119].

GABA-A receptors (made of 2 alpha, 2 beta and 1 gamma subunits) are coupled to chloride channels which are modulated by several mechanisms, such as changes in the 3-dimensional conformation of subunits/proteins or phosphorylation at different sites of the channel. For example, chloride channels are modulated by benzodiazepines (e.g. diazepam, lorazepam, clonazepam, clobazam), barbiturates (e.g. phenobarbital, pentobarbital), Topiramate or Cenobamate or Stiripentol. Benzodiazepines increase the frequency of chloride channels opening, whereas barbiturates increase the duration of channels opening. Topiramate or Cenobamate or Stiripentol also increase the frequency of chloride channel opening, but they bind to a different site from benzodiazepines (allosteric modulators) [120].

The chloride equilibrium potential is roughly the same as the resting membrane potential equilibrium, about 70 mV. Therefore, the electromotive force for net chloride flux during the resting potential is minimal. As the summation of excitatory postsynaptic potentials (EPSPs) results in depolarization of the membrane potential, the influence of inhibitory postsynaptic potential (IPSP) mediated chloride currents on the membrane potential becomes even more crucial, as only these can increase the threshold for firing an action potential and decrease neuronal excitability [80–82, 85, 86, 90, 121].

#### *4.2.1.1 Defective GABA-A inhibition*

Mutations or lack of expression of appropriate GABA-A receptor complex subunits, their assembly molecules or the molecules that modulate their electrical properties can cause decreased inhibition [120, 122]. For example, hippocampal pyramidal neurons may not be able to assemble alpha-5, beta-3, gamma-3 receptors because of deletion of chromosome 15 (i.e. Angelman syndrome) [123]. Animal models of focal-onset epilepsy based on pilocarpine models, electrical or chemical kindling, have shown changes in the distribution of subunits of the GABA-A receptor complex [124].

#### *4.2.1.2 Defective GABA-B inhibition*

The GABA-B receptor complex, often located in the presynaptic excitatory nerve terminals, consists of 2 subunits (with 7 transmembrane domains each), coupled to potassium channels modulated via G proteins. Upon activation it drives a potassium current with longer latency and duration of action compared to the chloride current generated by activation of the GABA-A receptor. Thus, alterations in the GABA-B receptor complex may be crucial for ictal transformation [108, 125].

#### *4.2.1.3 Defective network function of GABAergic interneurons*

As we have demonstrated, in complex neuronal networks with recurrent feedforward and feedbackward projections from excitatory to inhibitory neurons, feedforward and feedbackward inhibition emerge from the critical time activation of GABAergic inhibitory neurons relative to the output of the Glutamatergic excitatory neurons of the network [35, 76–78, 126, 127]. The hippocampal model has been extensively investigated as the prototype neuronal network of focal epileptogenesis. Schaffer collateral axons from the CA3 pyramidal neurons (main afferent input) activate the CA1 principal neurons (hippocampal pyramidal cells). At the same time collateral feedforward projections to GABAergic inhibitory interneurons activate their somata, before or during activation of the apical dendrites of the CA1 pyramidal neurons [66, 79–82, 100, 128].

As a result of this crucial structural and functional connectivity, during passive transmission of the excitatory postsynaptic potential (EPSP) from the apical dendrites to the axon hillock of the CA1 pyramidal neurons, a concurrent GABAergic inhibitory postsynaptic potential (IPSP) inhibits the soma or axon hillock of the CA1 pyramidal neurons. This feedforward inhibitory projection simultaneously hinders pyramidal cell depolarization and firing of an action potential [129]. Recurrent axon collaterals from the CA1 pyramidal neurons activate GABAergic interneurons after the pyramidal neurons have fired an action potential. This creates a feedbackward inhibitory system (multiple inhibitory circuits with built-in timelags) that allows GABAergic cells to control repetitive firing in principal neurons (CA1 pyramidal cells) and also inhibit the surrounding hippocampal pyramidal cells. The critical timing of these excitatory-inhibitory cycles (push-and-pull mechanism) accounts for the generation of normal gamma-oscillatory and hippocampal sharp-wave ripples, or abnormal fast ripples and ultra-fast ripples [35, 36, 66, 76–79, 98–100, 126, 127, 130, 131].

The mossy cells of the hilar polymorphic region of the dentate gyrus of the hippocampus (which receive feedforward input from the Entorhinal Cortex and feedback activation from CA3) appear to activate GABAergic neurons and gate-control the inhibitory tone of the network. The mossy cells may be susceptible to seizure-related neuronal death [132, 133]. The loss of mossy cells results not only in impairment of GABAergic interneuron activation (deafferentation), but also in synaptic reorganization and changes in network plasticity, with formation of newly sprouted circuits of excitatory and inhibitory cells in an attempt to restore inhibition. However, with epilepsy progression the sprouted synaptic contacts also create recurrent excitatory circuitries that permanently alter the balance between excitatory and inhibitory tone in the hippocampal network [133, 134].

#### *4.2.1.4 Defective intracellular buffering of calcium*

In rodent hippocampal experiments, recurrent seizures can result in progressive loss of hyperpolarized resting membrane potentials in the hilar polymorphic region of the dentate gyrus and eventually loss of interneurons that lack the calcium-binding proteins parvalbumin and calbindin [135, 136]. Further experiments showed the critical role of adequate concentrations of calcium-binding proteins for neuronal survival in settings with sustained increases in intracellular calcium under neuronal cellular stress [137], such as in status epilepticus, febrile convulsions, brain hypoxia and other metabolic, toxic, ischaemic and inflammatory brain insults. Interindividual differences in these calcium-binding proteins may explain the variable susceptibility of different patients and with advancing age to epileptogenesis via the premature loss of critical interneurons, a process that alters inhibitory controls of local neuronal networks in favour of excitation [138–140].

#### *4.2.2 Mechanisms leading to increased excitation*

Similar concepts of structural and functional organisation to the chloride channels, with crucial electrophysiological implications, also hold for the voltage-gated sodium, potassium and calcium channels. Alterations or mutations in the chloride, potassium or sodium and calcium channel subunits or in the molecules that regulate their function may increase or decrease the membrane permeability and conductance of chloride, potassium or sodium and calcium ions forming the chloride-mediated and potassium-mediated hyperpolarizing currents (IPSPs) that counterbalance the sodium-mediated and calcium-mediated depolarizing currents created by the summation of EPSPs [94, 112–114]. The overall network balances and imbalances attained in excitatory and inhibitory components critically modulate the seizure-threshold or the tendency to seizures [33, 35, 36, 66, 69, 76–79, 85–90, 93, 97, 115].

A lower seizure-threshold and thus increased epileptogenesis may result from inappropriate activation of fast or long-acting NMDA channels or reduced intracellular calcium-buffering proteins (parvalbumin and calbindin), increasing the vulnerability of neurons to cellular stress-injury and death [134, 137, 140]. The release of the excitatory amino acid Glutamate from presynaptic neuron terminals mediates excitatory potentials (EPSPs) in the postsynaptic neuron membrane via: N-methyl-Daspartic acid (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/Kainate, and Metabotropic Glutamate receptors. These receptors are coupled by means of different postsynaptic membrane mechanisms to several depolarizing channels [33, 66, 69, 87–89, 116].

#### *4.2.2.1 Increased activation of NMDA receptors*

Fast glutamatergic neurotransmission is based on activation of AMPA/Kainate and NMDA receptors. The AMPA/Kainate receptors are coupled to channels that create currents of monovalent cations (sodium and potassium), whereas the NMDA receptors open channels that allow also divalent cations to pass through (calcium). Slow glutamatergic neurotransmission is also possible via metabotropic receptors, which alter postsynaptic membrane excitability with late-onset and more prolonged postsynaptic changes in phosphorylation and gene expression by means of a second-messenger system which uses calcium as a catalyst for various intracellular reactions. Normal NMDA receptor function is thought to be associated with learning and memory, whereas increased activation has been observed in several animal models of focal epilepsy, such as kindling, kainic acid, pilocarpine, etc. [116, 117, 141, 142].

### *4.2.2.2 Increased synchronization induced by ephaptic phenomena*

Widespread electrical fields emerging from synchronous activation of many pyramidal neurons in laminar hippocampal structures or local changes in extracellular ionic concentrations of potassium and calcium [97] or increased neuronal coupling due to more permanent changes in functional gap junctions [143] may further increase the excitability of neuronal assemblies by nonsynaptic (ephaptic) interactions, predisposing to focal-onset seizures or status.

#### *4.2.2.3 Increased synchronization and/or activation from recurrent excitatory collaterals*

Intractable focal-onset epilepsies are frequently accompanied by abnormalities in the limbic system, particularly in the hippocampal formation. Hippocampal atrophy and sclerosis are common lesions associated with neuronal loss and gliosis, particularly affecting the hilar polymorphic region and CA1 pyramidal regions, with relative sparing of the CA2 pyramidal region and only intermediate severity lesions in the CA3 pyramidal region and dentate granule neurons. About 2/3 of patients with intractable temporal-lobe epilepsy have marked hippocampal sclerosis, while animal models with >100 brief convulsions or epileptic status showed similar changes, suggesting that epileptogenesis or hippocampal/limbic system kindling can be a self-perpetuating process [132, 138, 139].

Perhaps subtler and more common than overt hippocampal sclerosis may be Mossy-fiber sprouting. The mossy fibers are the axons of the dentate granule neurons that mostly project to the hilar polymorphic region and CA3 pyramidal neurons. Progressive loss of neurons in the hilar polymorphic region and degeneration of their synaptic projections on dentate granule neurons, induce sprouting of the neighbouring mossy-fiber axons and formation of recurrent excitatory collaterals, with an overall increase in the excitatory drive of dentate granule neurons [133, 134, 140].

#### **4.3 Epileptogenicity: critical conditions and clinical implications**

As we have demonstrated in previous sections, epileptogenicity seems to be intricately related to the mechanisms that vary the level of consciousness and transition through sleep (cortico-thalamocortical circuits) and the processes of learning, memory, emotion and complex behaviour (cortico-limbocortical circuits). In our simulations of neocortical, thalamocortical and allocortical neuronal networks the following parameters or processes have emerged as most critical for epileptogenesis:
