**Abstract**

Current theories and models of brain rhythm generation are based on (1) the excitability of individual neurons and whole networks, (2) the structural and functional connectivity of neuronal ensembles, (3) the dynamic interaction of excitatory and inhibitory network components, and (4) the importance of transient local and global states. From the interplay of the above, systemic network properties arise which account for activity overdrive or suppression, and critical-level synchronization. Under certain conditions or states, small-to-large scale neuronal networks can be entrained into excessive and/or hypersynchronous electrical brain activity (epileptogenesis). In this chapter we demonstrate with artificial neuronal network simulations how physiological brain oscillations (delta, theta, alpha, beta and gamma range, and transients thereof, including sleep spindles and larger sleep waves) are generated and how epileptiform phenomena can potentially emerge, as observed at a macroscopic scale on scalp and intracranial EEG recordings or manifested with focal and generalized, aware and unaware, motor and nonmotor or absence seizures in man. Fast oscillations, ripples and sharp waves, spike and slow wave discharges, sharp and rhythmical slow waves, paroxysmal depolarization and DC shifts or attenuation and electrodecremental responses seem to underlie key mechanisms of epileptogenesis across different scales of neural organization and bear clinical implications for the pharmacological and surgical treatment of the various types of epilepsy.

**Keywords:** epilepsy, seizure, epileptogenic networks, epileptogenesis, focal and generalized epilepsies, epileptic syndromes, cortico-thalamo/ganglio-cortical networks (primary generalized tonic-clonic seizures, myoclonic jerks, photoparoxysmal responses, typical and atypical absences), focal neocortical and allocortical or limbocortical networks (focal [auto]motor, aware or unaware seizures with secondary propagation, bilateral spreading and/or generalization), nerve action potential, depolarization and repolarization, excitatory and inhibitory postsynaptic potentials, neuronal and network excitability, structural and functional network connectivity, physiological brain oscillations (delta, theta, alpha, beta and gamma oscillations, sleep spindles, sleep waves), fast oscillations and synchronization, ripples and sharp waves, paroxysmal depolarization and DC shifts, spike and slow wave discharges, sharp and rhythmical slow waves, electrodecremental responses and desynchronization, stochastic resonance, phasic and tonic inhibition, critical-level synchronization, depolarization block, critical global and local transient brain states, decreased network inhibition or defective activation of GABAergic transmission,

increased network excitation (glutamatergic, cholinergic and monoaminergic transmission) or excitability and synchronization, biological and artificial neuronal networks, excitatory and inhibitory network components, recurrent neuronal networks with inhibitory feedback, pulse-coupled neural networks and neuronal spiking models, cerebral cortex, neocortex and allocortex, thalamus and basal ganglia, hippocampus, entorhinal cortex and limbic system, brainstem, ascending reticular activation system, intracellular and extracellular recordings, local-field potentials, intracranial and scalp-surface electroencephalography, antiseizure or antiepileptic medications, epileptogenesis-modifying medications, pharmacological, neurostimulation, neurosurgical treatments of epilepsy

## **1. Introduction**

A seizure is the clinical manifestation of an abnormal, excessive or hypersynchronous discharge of a population of neurons [1]. Epileptogenesis is the sequence of underlying processes and/or events that can turn a neuronal network into an epileptogenic (hyperexcited or hypersynchronous) one [1–6].

*Generalized epileptic seizures* are considered to originate at some point within, and rapidly engage bilaterally distributed networks, including cortical (not necessarily the entire cortex) and subcortical structures (diencephalon/thalamus, basal ganglia, limbic system). Even if individual seizure onsets appear localised or asymmetric, the location and lateralisation may not be consistent from one seizure to another [1–6].

*Focal epileptic seizures* are considered to originate primarily within networks limited to one cerebral hemisphere. These are more discretely localised or distributed, and can originate or involve cortical and subcortical structures independently in either hemisphere. Ictal onset is consistent from one seizure to another with preferential propagation patterns, usually slower when compared to generalized epilepsies, which can potentially evolve and spread to the contralateral hemisphere or eventually engage bilateral hemispheres (bilateral spreading or secondary generalisation). In cases where there are more than one local epileptogenic networks involved corresponding to more than one seizure types, each individual seizure type has a consistent site of onset [1–6].

The fundamental principle of causality implies that both processes, 'focal' and 'generalized', start somewhere locally in the brain. The particular propagation pathways, how rapidly they spread and engage bilateral cortical networks are crucial for the distinction of 'focal' and 'generalized' epileptogenic networks, which may be more of an operational rather than a pragmatic dichotomy.

All diverse clinical patterns of seizures with either focal or generalized underlying pathomechanisms can be classified into a few categorical types of stereotypical epileptic features: seizures with preserved, impaired or lost *awareness* or *consciousness* and with predominantly *motor* (clonic/myoclonic, tonic/myotonic/dystonic, hyperkinetic/ paretic or spasms), *limited-motor* (subtle automatisms, negative myoclonus, atonia, behavioural changes) or *non-motor* (sensory, autonomic, perceptual, behavioural arrest or absences) manifestations (**Table 1**) [1–6].

*Seizure propagation* takes preferential faster or slower pathways through the same neural/cerebral substrate in terms of neocortical structural connections (short-range and long-range association fibers: arcuate fasciculus, uncinate fasciculus, superior and inferior fronto-occipital fasciculi, etc. and interhemispheric association fibers: corpus

**I. Generalized onset** - usually compromised consciousness/awareness with variable degrees of motor manifestations, as a result of rapid bilateral hemispheric spread from the very beginning of the seizure and involvement of key (not necessarily all) *neocortical and subcortical structures (diencephalon, basal ganglia and limbic system, brainstem and cerebellum)*


**II. Focal onset** – may or may not (to a variable extent) compromise consciousness/awareness, and show variable degrees of motor and sensory manifestations implying more focal involvement, at least initially confined only to one cerebral hemisphere, of key *neocortical [frontal, temporal, insular, parietal, occipital] and/or subcortical structures (diencephalon, basal ganglia and limbic system, brainstem and cerebellum)*, with potential for ipsilateral, contralateral and/or bilateral hemispheric spreading and/or secondary generalisation

#### **A. Localised** to:

**1.** *Neocortical* **- without local spread** (focal clonic, myoclonic or inhibitory-motor seizures, focal sensory seizures with elementary symptoms) or **with local spread** (jacksonian march-seizures, focal tonic [asymmetric] seizures, dysphasic/aphasic seizures or focal sensory seizures with experiential symptoms)

**2.** *Limbic-system* **predominantly** (hippocampal, parahippocampal)

**B. With ipsilateral propagation** to:


#### **C. With contralateral spreading** to:

**1.** *Neocortical areas* (hyperkinetic seizures)


#### **Table 1.**

*Basic seizure categorization scheme [1–6].*

callosum, anterior and posterior commissures) and functional network connectivities (sensorimotor, central-executive, default-mode, salience, visuospatial attention, language, visual networks, etc.), as well as subcortical structures (thalamus, limbic system and ascending reticular activating system [ARAS]) or subcortical network connections and functional connectivities (thalamocortical, limbic system fibers [cingulum, fornix, medial forebrain bundle, etc.]) [7].

Across diverse seizure patterns the following fundamental seizure types emerge with fairly distinct pathomechanisms in the underlying epileptogenic networks (**Table 2**) [1–5].

Based on further patient and epilepsy characteristics, in particular age at onset and remission (where applicable), seizure triggers, diurnal variation, distinctive comorbidities such as intellectual, neurological and psychiatric abnormalities, evolution and progression of the condition or not, correlated with the underlying brain pathology, aetiology and pathophysiology, electroclinical, neuroimaging and genetic investigations, epilepsies can be organized into more complex clinical diagnostic entities, so-called epilepsy syndromes. Such syndromes have a typical age of seizure onset,


#### **Table 2.**

*Fundamental seizure types emerging from seizure semiology and distinct pathophysiological processes.*

specific seizure types and EEG characteristics and other electroclinical and neuroimaging features which, when taken together, allow the specific syndromic epilepsy diagnosis [8, 9]. The identification of an epilepsy syndrome is useful as it provides information on which underlying aetiologies should be considered, what is the current and future prognosis, which pharmacological anti-seizure medications and/or neurosurgical or neurostimulation interventions might be most useful. Certain epilepsy syndromes may manifest seizure exacerbation, modification or ineffective control with particular anti-seizure medications, which can be avoided and seizure-control outcomes can be optimized through early syndromic diagnosis [2–6, 8–11]

The differential effectiveness of antiepileptic drugs across seizure types highlights likely distinct seizure pathomechanisms and the underlying pathophysiological processes of different epileptic syndromes (**Table 3**) [8–11].

Antiseizure medications in *italics* are generally avoided or contraindicated for the treatment of idiopathic (genetic) generalized epilepsies (**Table 3**). **Carbamazepine, Oxcarbazepine, (Fos)Phenytoin** (mainly voltage-dependent sodium channel blockers binding in the inactivated sodium channels and preventing high-frequency action potentials) may be used in the rare pure forms of primarily generalized tonicclonic seizures (GTCS) but are not indicated as first-line for idiopathic generalized epilepsies, either because they are ineffective or may exaggerate/exacerbate certain types of seizures. Carbamazepine may treat manic and depressive symptoms in bipolar disorder by increasing dopamine turnover and GABA transmission. **Eslicarbazepine** has lower affinity for inactive voltage-gated sodium channels in the resting state compared to Carbamazepine and Oxcarbazepine, thereby selectively inhibits repeated neuronal firing in the epileptic focus, as well as T-type calcium channels in vitro. **Lacosamide** may be selective for inhibiting depolarized neurons (slow inactivation gating of sodium channels), affecting only those neurons (at the epileptic focus) which are depolarized or active for long periods of time. **Lamotrigine** (acting as voltage-gated inactivated sodium channel and R-type calcium channel blocker, suppressing glutamate release and stabilising membranes) may exaggerate myoclonic jerks in juvenile myoclonic epilepsy and some progressive myoclonic epilepsies. **Ethosuximide** (T-type calcium channel blocker) is only effective for absences and may be effective in negative myoclonus. **Levetiracetam** is an inhibitor of synaptic vesicle protein 2A (SVP2A) and presynaptic neurotransmitter release in highfrequency firing neurons and inhibitor of N-type calcium channels. It may indirectly enhance GABAergic neurotransmission via GABA-A receptors and decrease glutaminergic excitation via modulation of NMDA and AMPA receptors or upregulation of glial glutamate transporters. **Brivaracetam** is the racetam derivative of Levetiracetam with 20 times higher affinity for binding SVP2A, while also inhibiting sodium channels and impairing epileptogenesis through modulation of

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


#### **Table 3.**

*Adapted from Panayiotopoulos [5] and adjusted based on updated publicly available information from https:// www.medicines.org.uk/emc and https://www.fda.gov/drugs and https://go.drugbank.com/drugs and https://bnf. nice.org.uk/*

synaptic GABA. **Zonisamide** (blocking repetitive firing of voltage-gated sodium channels, reducing T-type calcium channel currents or binding allosterically to GABA receptors inhibits the uptake of GABA and enhances the uptake of glutamate) and **Topiramate** (voltage-dependent sodium channel blocker, allosteric stimulator of GABA-A receptors and inhibitor of AMPA and Kainate glutamate receptors) are effective in all types of epilepsy. **Cenobamate** reduces repetitive neuronal firing in the epileptic focus by enhancing the inactivation of sodium channels and inhibiting the persistent component of the sodium current and acts as a positive allosteric modulator of GABA-A ion channel subtypes. **Gabapentin** (presynaptic voltage-dependent calcium channel inhibitor and dose-dependent inducer of L-glutamic acid decarboxylase that enhances GABA synthesis) and **Pregabalin** used as adjunctive for focal seizures may have pro-myoclonic effects. **Clonazepam** (1,4-benzodiazepine, full agonist of GABA-A receptors resulting in increase in the frequency of chloride-channel opening) is mainly used for myoclonic jerks, but it may not suppress GTCS of juvenile myoclonic epilepsy. **Clobazam** (1,5-benzodiazepine, partial agonist of GABA-A receptors) licensed as adjunctive therapy may be more efficacious in focal than generalized epilepsies. **Phenobarbital** is a potentiator agonist of GABA-A receptors resulting in increased duration of chloride-channel opening and may also act on Glutamate receptors. **Perampanel** (non-competitive AMPA glutamate receptor antagonist) is mostly used for focal epilepsies and only as adjunctive for primary generalized ones. **Valproate** (directly suppresses voltage-gated sodium channel activities and influences many other channels and neurotransmitters and indirectly enhances GABAergic neurotransmission as inhibitor of succinic semialdehyde dehydrogenase [GABA transaminase]) is effective against all types of epilepsy [5, 8–11]. **Fenfluramine** (a serotonin-releasing agent that stimulates multiple 5-HT receptor subtypes) is used as an adjunctive treatment in Dravet syndrome. **Rufinamide** (prolonging the inactive state of voltage-gated sodium channels and inhibiting mGluR5 subtype receptors at high concentration) is used as an adjunctive treatment of seizures in Lennox-Gastaut syndrome. **Stiripentol** potentiates GABAergic transmission by elevating the levels of GABA and acting as a positive allosteric modulator of GABA-A receptors and is used as an adjunctive treatment in Dravet syndrome. **Cannabidiol** (**CBD Oil)**, the major component of the resin of *Cannabis sativa* plant (marijuana), is devoid of the psychoactive, euphoric or intrusive effects and abuse liability of the tetrahydrocannabinol (THC) component. Endocannabinoid receptors regulate cognition, pain sensation, appetite, memory, sleep, immune function, fear, emotion or mood and are mostly localized in the hippocampus and amygdala. Cannabidiol may have low affinity for endocannabinoid receptors but may indirectly modulate these receptors by blocking the breakdown of Anandamide. It could also activate the transient receptor potential of Vanilloid type-1 (TRPV1), antagonise the G protein-coupled receptor 55 (GPR55), target abnormal sodium channels, block T-type calcium channels, modulate adenosine receptors or adenosine reuptake, voltage-dependent anion selective channel protein (VDAC1) or tumor necrosis factor alpha (TNFa) release. It has been licenced as adjunctive treatment in Tuberous Sclerosis and (together with Clobazam) in Lennox-Gastaut and Dravet syndromes. (publicly available information at: https://go.drugba nk.com/drugs and https://bnf.nice.org.uk/).
