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

millivolts, a rather unique prediction of our model (right bottom of **Figure 15**). Translating this early abnormality in a critical subpopulation of inhibitory cells in biological terms, raises two possibilities. These would allow an initial wave of over-excitation due to stochastic noise and critical time coincidences in a potentially hyperexcitable system of unit oscillators to rapidly or progressively attain an oscillation of maximal amplitude (resonance) in depolarizing and hyperpolarizing directions while going through consecutive synchronization cycles of excitation and inhibition [85–89]. One possibility is that some of the inhibitory interneurons can go into an actual *depolarization block*, leaving effectively unchecked the excitatory oscillators (unopposed EPSPs on pyramidal cells) to rapidly or progressively evolve into a paroxysmal depolarization (this is likely to occur towards the end of a seizure due to metabolic depletion). The other possibility is that excessive initial phasic inhibitory GABAergic activity, sometimes in combination with GABA transporter (GAT-1) malfunction in astrocytes, releases too much extrasynaptic GABA which facilitates concurrent extrasynaptic GABABR activation. This results in enhanced/sustained tonic GABAA currents that persistently hyperpolarize and increase membrane Cl conductance causing bursts of IPSPs to override the depolarizing currents in thalamocortical [85, 86] or pyramidal neurons [90]. Such rhythmical bursts of IPSPs can entrain thalamocortical/gangliocortical (**Figure 16**) and limbocortical (**Figures 17-19**) networks to paroxysmal and/or hypersynchronous activity.

The neuronal network attains a paroxysmal depolarization state when the different excitatory and inhibitory oscillatory components reach maximal

#### **Figure 17.**

*A left-side mesial temporal onset seizure on the EEG with a rhythmical theta activity build-up over the left temporal region. The MRI scan at the right top corner of the figure indicates severe right mesial temporal lobe sclerosis. Because of lack of concordance between scalp Electroencephalography and MR imaging, we had to undertake intracranial iEEG recordings in this case to determine the exact ictal-onset (potential epileptogenic zone).*

#### **Figure 18.**

*Human intracranial EEG recordings of bilateral hippocampi to demonstrate baseline (DC) shifts and high-frequency oscillations (HFOs) as surrogate markers of the ictal onset zone. In this patient they always started from the most atrophic and sclerotic (burnt out) right hippocampus and subsequently spread to the left hippocampus. Resection of the right hippocampus in this case conferred seizure freedom and confirmed the epileptogenic zone.*

depolarization and hyperpolarization potentials or when excitatory and inhibitory oscillatory units synchronize via depolarizing and hyperpolarizing currents into an oscillation of maximal amplitude. Epileptogenic depolarizing currents can emerge from abnormal or excessive ionic Na<sup>+</sup> [91] and Ca++ [92] channel-conductances or excessive excitatory (Glutamate) and neuromodulatory (Acetylcholine, Noradrenaline, Dopamine, Serotonin, etc) neurotransmitter release and receptor function [87– 89]. Epileptogenic afterhyperpolarizing currents can emerge from abnormal, insufficient or excessive ionic Cl [93] and K<sup>+</sup> [94–96] channel-conductances or abnormal, insufficient or excessive inhibitory (GABA) neurotransmitter release and receptor function [85, 86]. Multiple combinations of the above epileptogenic mechanisms are plausible.

Critical synchronization, resonant oscillation and massive depolarization of excitatory and inhibitory neurons seem to account for a massive release of potassium ions (K<sup>+</sup> ) from the principal (pyramidal) and supportive glial cells [97]. These shift the resting electrochemical/equilibrium gradients of the cell membrane from 65 mV probably closer to 50 mV, where voltage-gated Na<sup>+</sup> channels are still active and much more likely to open (they are also less likely to be inactivated because of increased Cl conductance and sustained tonic GABAergic currents). The membrane conductances essentially change to levels that allow for a massive sustained depolarization shift of the principal/pyramidal cells (massive influx of Na+ and slower Ca2+ inward currents) to take place [83, 84]. Paroxysmal depolarization shifts manifest

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

#### **Figure 19.**

*Within the right posterior hippocampus (Channel 3 Spectrogram) an initial wave of over-excitation (high-frequency ripple synchronization) with ripples/fast ripples followed by excessive feedback inhibition and brief period of attenuation (broadband suppression/desynchronization or phase-resetting of unit oscillators) of the right middle hippocampus (Channel 2 Spectrogram) and recurrent excitation-inhibition oscillatory cycles (synchronization process) before a sustained paroxysmal depolarization shift develops with pathological low/high gamma, ripple and fast ripple oscillations. The inset figure shows the interaction of hippocampal pyramidal cells with parvalbumin-positive basket-cells (interneurons) generating high-frequency gamma-oscillations (PING mechanism) and ripple-frequency phase-modulations (FINO mechanism), reproduced from [66].*

electrophysiologically with huge baseline (DC) shifts and very high amplitude pathological high-frequency oscillations (pHFOs) known as pathological beta/gamma oscillations (15–80 Hz), (fast) ripples (80–150 Hz) and (ultra)fast ripples (150–500 Hz) (**Figures 18**–**20**) [66, 98–100].

Obviously, as this excessive and hypersynchronous overdrive of excitatory and inhibitory neurons goes on, the membrane depolarization shifts towards a more 'toxic'

#### **Figure 20.**

*Spreading of pathological/epileptogenic gamma oscillatory activity in man from the right hippocampus (top spectrogram) to the left hippocampus (bottom spectrogram) with subsequent fast ripples in the left hippocampus. Hilar mossy cells and CA3 pyramidal cells give rise not only to ipsilateral associational hippocampal fibers but also some contralateral commissural fibers (terminating on principal cells and interneurons to CA3, CA2 and CA1 regions), passing through the posterior and anterior hippocampal commissures to reach the contralateral hippocampus and dentate gyrus. More extensive polysynaptic pathways via the entorhinal and perirhinal cortex integrate the hippocampus with the ipsilateral and contralateral hemispheres and homologous hippocampal network. This particular focal motor unaware seizure died out in the right hippocampus/hemisphere but propagated and continued in the left hippocampus/hemisphere, declaring itself on the scalp EEG as seen in Figure 15.*

range of less negative potentials (around 35 mV or above) which will eventually render all voltage-gated Na-channels inactivated. At that point, as the Na-K-ATPase pumps and ion-transporters require sufficient energy and time to restore the electrochemical membrane gradients, a combination of inactivated Na-channels and metabolic depletion will bring the activity of the excitatory and inhibitory cells to sub physiological levels or to a halt (depolarization block and metabolic depletion) during the postictal phase (**Figure 21**) [73, 74].
