*4.3.1 Excitability of individual neurons and entire networks*

The intrinsic/inherent cell membrane and synaptic membrane excitability properties, influence the electrochemical ionic gradients/equilibriums and ionic transmembrane conductances (presynaptic, synaptic, extrasynaptic and postsynaptic receptors, ionic channels and ligands/neurotransmitters, transporters, ion pumps and exchangers, channelopathies and antiepileptic drug effects). These ultimately determine the intrinsic excitability and oscillatory dynamics of the individual neuron and its interactions with other structurally/functionally interconnected neurons.

#### **Figure 26.**

*A summary of the interaction of multiple neurophysiological epileptogenic mechanisms.*

The membrane excitability characteristics and shortening of time integration constant (via a "push-and-pull" mechanism) of synchronized, coincidental or critically interacting excitatory (EPSP) and inhibitory (IPSP) postsynaptic potentials can increase or decrease the excitability of the entire network (**Figure 26**) [79, 85–97].

The intrinsic excitability of the neuron directly increases excitation or the number of fast or transient oscillations by reducing the relative refractory period of the firing neurons and/or increase the probability of spatiotemporal summation or integration of synchronous/coincidental EPSPs and/or IPSPs. These mechanisms can drive the firing rates of neurons broadband, the amplitude of the postsynaptic oscillations high and the time/phase dynamics of their firing complex. They can thus generate a range of physiological transient and rhythmical cortical neuronal activities (in delta, theta, alpha, beta and gamma frequencies as reflected in extracellular recordings, local field potentials, intracranial and scalp surface EEG) and can drive local or widespread networks in paroxysmal/hypersynchronous activity [85–97, 126, 127].

#### *4.3.2 Structural connectivity of neuronal networks*

The structural connectivity (spatial network geometry) of neurons is critical for the dynamic interaction of excitatory and inhibitory network components. The spatial distribution of excitatory and inhibitory neurons reflects how sharpened or spread out the inhibition may be around excitatory neurons. Changing the relative distribution of the inhibition, that is, how locally vs. widespread the inhibition acts, shapes up and critically determines individual neuronal and collective oscillatory network behavior, generating a range of physiological transient and rhythmical cortical neuronal activities and can drive local or widespread networks in paroxysmal or hypersynchronous activity (**Figures 13**–**15**) [76, 79, 126, 127, 144].

Early developmental and life-long brain changes induce progressive small-to-large scale structural changes in cortical networks (and thus in epilepsies with age) via migration and branching-off patterns of neurons, plasticity changes via sprouting or pruning of neuronal processes, reinforcement or attenuation of synaptic contacts.

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

Cortical network development and life-long plasticity changes determine long-term episodic memory formation or retrieval and operational learning memory, and may be responsible for the development of thalamocortical (e.g. idiopathic/genetic generalized epilepsies) or build-up of neocortical and limbocortical epileptogenic networks (e.g. abnormal excitatory recurrent collaterals) [1–6, 101, 126, 127, 144].

#### *4.3.3 Functional connectivity of neuronal networks*

The functional connectivity (synaptic strengths/weights) of the network is critical for the dynamic interaction of excitatory and inhibitory network components. Changing the relative strength of synaptic connections, critically determines the oscillatory behavior of the network, and can produce a range of physiological transient and rhythmical cortical neuronal activities and collective behaviors, from local spatiotemporal to systemic synchronization phenomena. These can sustain the excitatory up-states of cortical neurons, shape and enhance plasticity, memory, structural and functional connectivity of thalamocortical, limbocortical and neocortical neuronal networks (**Figures 13**–**15**) [43–53, 126, 127, 144].

Memory and learning (new memory formation and retrieval, short-term working memory and operational learning), diurnal variations in brain function (spindle waves and slow sleep oscillations) and longer lasting plasticity changes emerge from the short to long-term potentiation and/or depression of synaptic connections. Developmental brain changes are also associated with progressive plasticity changes, affecting brain rhythms and epilepsies with age including the build-up (e.g. through abnormal excitatory recurrent collaterals) or shape up of epileptogenic networks (e.g. through recurrent seizures, high firing-rate and/or hypersynchronous synaptic activations) [1–6, 126, 127, 144].

#### *4.3.4 Critical global and local transient brain states (microstates)*

Neocortical activation is driven by thalamic/reticular input and the level of consciousness rises or drops with a varying reticular, thalamic, septal or neocortical drive. As higher numbers of thalamic input neurons engage larger numbers of cortical neurons, this physiologically brings about thalamocortical arousal, thalamosensory afferentation and amplifies cortical cognitive processing upon multi-modal sensory stimulation of the cortex. Cortical rhythms speed up and modulate from slow oscillatory (delta and theta range) activities during sleep and low consciousness states to faster oscillatory activities (alpha with closed eyes and beta/gamma with open eyes) in the awake and alert brain (**Figures 13**–**15**) [43–53].

In a similar fashion, limbocortical activation is externally driven by varying septal, reticular, thalamic, or neocortical input. While internally limbocortical activation is driven by CA3/modulatory Mossy-fiber input into CA1/Subiculum and further into entorhinal cortex that interfaces with the neocortical parahippocampal gyrus and perirhinal cortex, anterior nucleus of the thalamus, the posterior and anterior cingulate cortex, temporal association cortex (for stimulus perception) and frontal association cortex (for planning behavioural responses) and other subcortical structures. This gives rise to physiological high-frequency gamma oscillations (nHFO) and sharp-wave ripples (SWR) for memory storage/retrieval and arousal respectively (**Figure 26**) [33, 34, 49, 60–66, 68, 69].

When critical local and global conditions are met, transitions across different global and local brain states (microstates) become a powerful modulator of small-tolarge scale neocortical, ganglio-thalamocortical and/or limbocortical networks that elicit or unmask epileptogenic network activity in the form of pathological gammaoscillations (pHFO), ripples and fast ripples, paroxysmal depolarizations and DC shifts at the microscopic/mesoscopic level (extracellular and local-field potentials) or spike-and-waves discharges, sharp and rhythmical fast and slow waves or attenuation/electrodecremental responses at the macroscopic level (EEG) (**Figure 26**) [33, 34, 60–66, 68, 69, 98–100, 126, 127]

#### *4.3.5 Epileptogenicity and clinical implications*

The above have crucial clinical implications for our current practice and future approach to epileptic disorders. We need to identify focal lesions or more widespread abnormalities of structural and/or functional connectivity (focal cortical dysplasias, developmental dysplasias/malformations, previous or perinatal brain injuries, hypoxic or metabolic and toxic insults, ischaemic or vascular lesions and malformations, tumours, space-occupying lesions, infiltrative, (para)neoplastic, inflammatory, infective/postinfective, autoimmune, vasculitic, (epi)genetic, neurodegenerative, etc) and modify the local and global, structural and/or functional connectivity and network excitability [1–6, 98–100, 127].

A common approach to modifying the local and global functional connectivity and network excitability is by means of antiepileptic medications (**Figure 27**). For this

#### **Figure 27.**

*Mechanism of action of clinically approved anti-seizure drugs. Published in Löscher et al. [145] under CC BY-NC 4.0 license. The updated and modified figure has been reproduced with permission from Löscher and Schmidt [146]. The initial figure was modified with permission from Macmillan Publishers Ltd © Bialer, M. & White, H. S. Nat. Rev. Drug Discov. 9, 68–82 (2010). Drugs marked with asterisks indicate that these compounds act by multiple mechanisms (not all mechanisms shown here). GABA-T: GABA aminotransferase, GAT: GABA transporter, SV2A: synaptic vesicle protein 2A, GABA: gamma-aminobutyric acid, NMDA: N-methyl-D-aspartate, AMPA: α-amino-3-hydroxy-5 methyl-4-isoxazolepropionic acid, KCNQ: a family of voltage-gated potassium channels (also known as the Kv7 family).* purpose, we employ different antiseizure medications as monotherapy or in various optimal combinations (polytherapy):


An alternative approach to modifying the local and global, structural and functional network connectivity and excitability is by means of neurosurgery (with resection or thermocoagulation of highly epileptogenic lesions/zones and disruption or disconnection of epileptogenic networks, etc) [98] and neurostimulation (vagus nerve, electrical/magnetic or optogenetic cortical stimulation or deep brain stimulation of the thalamus [anterior, centromedian, subthalamic nuclei]/basal ganglia, hippocampus, etc.) [71].

Current antiseizure medications (**Figure 27**) are mostly effective at preventing initiation, propagation, spreading or generalization of epileptic seizures. Modelling epileptogenesis across all scales of neuronal organization will further our understanding of the mechanisms of epileptogenesis, leading to better pharmacological and neurosurgical or neurostimulation treatment strategies and the development of new antiepileptic and epileptogenesis-modifying medications [1–11, 71, 98].
