**4.1 Epileptogenic cortico-thalamo/ganglio-cortical networks (pathophysiology of typical absences, myoclonic jerks, primary generalized tonic-clonic seizures and photoparoxysmal responses)**

Idiopathic (genetic) generalized epilepsy is the prototypical phenotype of primary generalized epilepsies manifesting with a variable combination of absence, myoclonic *Clinical Neurophysiology of Epileptogenic Networks DOI: http://dx.doi.org/10.5772/intechopen.104952*

#### **Figure 21.**

*This particular seizure started in the right hippocampus with a brief period of broadband attenuation (desynchronization or phase-resetting of unit oscillators). After an initial synchronization phase (through recurrent cycles of depolarization and repolarization) it transitioned to a sustained broadband paroxysmal depolarization shift and lasted altogether for about 2 min and 15 s. It ended with a prolonged postictal period of broadband suppression of background rhythms for another 2.5 min. The spectrogram at the top shows the power per 1 Hz individual frequency component from 1 to 300 Hz (nonorthogonal continuous 3-cycle wavelet decomposition) versus time in x10<sup>5</sup> ms, while the spectrogram at the bottom shows log-spaced frequencies (pseudo-orthogonal decomposition) to help appreciate the concentration of power which is mostly <4 Hz but more sustained over time between 12 and 64 Hz (beta and low/high gamma range).*

and generalized tonic-clonic seizures, and photoparoxysmal responses (PPR) in the young population (<25 years). Absence epilepsy is one of the most common generalized epilepsies of childhood. It has a unique endo-phenotype based on perturbed corticothalamocortical circuitry with genetic and developmental features. It can appear in childhood (CAE) or juvenile ≥10 years (JAE) and can modify or improve its phenotype in adolescence. Typical absences can be triggered in more than >80% of patients with hyperventilation. CAE can even regress with or without treatment, while JAE that is more likely to present with generalized tonic-clonic seizures (up to 80% GTCS) compared to CAE (up to 20%) may also be more resistant to treatment [101].

Another relative endophenotype is that of juvenile myoclonic epilepsy (JAE) and of epilepsy with GTCS seizures alone or on awakening (EGTCS-a, Janz) with perhaps more permanent or pharmaco-resistant features, characterised more by motor myoclonic seizures (MJ) and generalized tonic-clonic seizures (GTCS) with or without absences and perhaps different engagement or imbalance of fronto-central (thalamobasoganglio-cortical) networks. Photosensitivity (PS) may coexist in roughly 1/5 of CAE, 1/4 of JAE or 1/3 of JME epilepsies [101].

The EEG hallmark of this wide spectrum of genetic/developmental epilepsies varying from less motor manifestations (absences) to more motor manifestations

#### **Figure 22.**

*Spike/polyspike and slow wave discharges in a patient with Juvenile Myoclonic Epilepsy. The spike is a recruiting wave associated with excitatory postsynaptic potentials (EPSPs) and the slow wave is an inhibitory wave associated with hyperpolarizing postsynaptic potentials (IPSPs) in cortical cells, essentially preventing the development of a generalized convulsive seizure.*

(myoclonic and generalized tonic-clonic seizures) is the epileptiform generalized spike-and-wave discharges (GSWD) (**Figure 22**). These can also vary in morphology across the different subtypes from a typical regular 3 Hz spike-and-slow-wave (often seen in CAE albeit some variations) to more irregular 3–6 Hz spikes/polyspikes-and- slow-wave patterns (often seen in JAE, JME and EGTCS-a) against a fairly normal background EEG (perhaps with some exceptions occasionally of more focal spikes, sharp waves, slow waves, OIRDA, etc.). The spike is a recruiting wave associated with excitatory postsynaptic potentials (EPSPs) from thalamic relay neurons on cortical cells and consequent phasic inhibition of the thalamic relay neurons. The slow wave is associated with tonic inhibition and hyperpolarizing postsynaptic potentials (IPSPs) on thalamic relay neurons resulting in secondary tonic inhibition of cortical cells (deafferentation), overriding cortical excitation and entraining pyramidal cortical neurons and thalamo-cortical networks in hypersynchronous paroxysmal activity.

The thalamocortical interaction implicated in primary or idiopathic (genetic) generalized epilepsies is one of the most studied epileptogenic networks. The basic thalamocortical circuitry is composed of pyramidal neocortical neurons, thalamic relay neurons, and neurons from the reticular nucleus of the thalamus (NRT) (**Figure 6**). The thalamic relay neurons receive ascending inputs from the Reticular Activation System (ARAS) and project to neocortical pyramidal neurons. Cholinergic pathways from the forebrain and ascending serotonergic, noradrenergic, and cholinergic brainstem pathways regulate the excitability of the thalamic relay neurons and the thalamocortical circuitry (**Figure 9**) [102]. As a result, thalamic relay neurons manifest oscillations in their resting membrane potential, which increase the probability of synchronous activation of neocortical pyramidal neurons (EPSPs) during depolarization states and lower the probability of neocortical activation (IPSPs) during hyperpolarization states. This generates thalamocortical oscillatory rhythms and

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

induces slow coherent oscillations in the cortex (resonance phenomena), characterised by periods of relatively increased excitation (up-states) and periods of relatively increased inhibition (down-states), such as the fast oscillations in sleep spindles and larger slower oscillations observed in sleep [103, 104].

Within a potential cortical area (sensorimotor cortex) medium-amplitude 5–9 Hz oscillations secondary to decreased phasic (GABAAR) inhibition [105–107] may entrain other cortical areas and the thalamus leading to a strong and synchronous cortical output that excites the GABAergic neurons of the Nucleus Reticularis of the Thalamus (NRT). The thalamic relay neurons have GABA-B receptors and receive GABAergic tonic inhibition from the neurons of the Nucleus Reticularis of the Thalamus (NRT) [108]. Also increased ambient (extrasynaptic) GABA levels around thalamic relay neurons due to reduced GABA uptake by GAT-1 (malfunction of thalamic astrocytes GABA transporter), may further enhance extrasynaptic GABAAR tonic inhibition [78]. Enhanced tonic inhibition persistently hyperpolarizes thalamic relay neurons and increases their membrane Cl conductance.

The hyperpolarization of thalamic relay neurons due to excessive or sustained GABAergic tonic inhibition of thalamic relay neurons shifts the T-calcium channels from the inactivated to the closed state and permits the synchronous opening of a large population of the T-calcium channels (about every 100 milliseconds). The rhythmic IPSP bursts on thalamic relay neurons, driven by a transient low-threshold calcium channel (transient T-calcium current) with intrinsic bursting behaviour, induce a widespread burst of excitation on neocortical pyramidal cells giving rise to the spike and secondary tonic cortical inhibition (following excessive excitatory bursting) which causes widespread cortical deafferentation, a phenomenon we macroscopically observe on scalp EEG as generalized slow wave complexes following the spike(s) (**Figure 22**) and as *absences* in patients' behaviour [85, 86, 90, 97]. A functional mutation in the CACNA1H gene encoding the Cav3.2 low-voltage activated Ca+2 channel has been found in the Genetic Absence Epilepsy Rats from Strasbourg (GAERS animal model of absence epilepsy) [109]. Alterations or mutations in the chloride channel subunits or molecules that regulate their function can increase membrane conductance of Cl. Increased Cl-mediated hyperpolarizing currents (IPSPs) increase the number of T-calcium channels available for activation, resulting in imbalanced networks of excitatory and inhibitory components with increased synchronization in the thalamocortical circuit and decreased seizurethreshold [94, 101–117]. Animal models of absence seizures have demonstrated that GABA-B receptor antagonists can suppress absence seizures, whereas GABA-B agonists can worsen them [111].

This explains why antiepileptic medications such as Ethosuximide, Valproic acid, Lamotrigine, Levetiracetam and Zonisamide, by blocking or suppressing the T-calcium channel currents, are more effective in preventing absence seizures. On the other hand, antiepileptic medications that indiscriminately increase GABA levels (e.g. Tiagabine, Vigabatrin) or Phenobarbital (prolongs Cl-channel opening duration) are associated with worsening of absence seizures. The effect of benzodiazepines (Diazepam, Lorazepam, Clonazepam and partial agonist: Clobazam) may be slightly more selective (increased frequency of Cl-channel opening), also manifested on the EEG often with increased fast cortical oscillatory activity (increased intracortical inhibition and synchronization) with more variable effects on the degree of synchronization (usually desynchronization) of the thalamocortical circuit [101–111].
