Generation Of Human Focal Interictal Discharges

Focal seizures are classified according to severity and their site of initiation in the brain. In general, severity is contingent upon whether or not consciousness is maintained throughout the event and if the seizure manifests in convulsions. In terms of site of initiation, the temporal, frontal, parietal and occipital lobes are all examined and when possible more specific structures are examined to determine as specifically as possible the region of seizure onset (Alarcon, 2012). The more specific the descri ption of seizure onset is, the more likely it is that surgery can be considered as an option, and by extension the odds of success in surgery are greater as well. Focal seizures are classified as either idiopathic, which includes those seizures with a proposed genetic cause, or symptomatic, consisting of those that arise spontaneously with no known or identifiable cause. Interictal epileptiform discharges include any electrical discharges such as spikes, polyspikes, and spike and wave discharges identified on an EEG that occur between the subject's attacks or convulsions. The generation of human focal interictal epileptiform discharges is usually attributed to enhanced excitatory interactions within glutamatergic neuronal networks, however inhibitory networks also play a central role. Interictal discharges are important indicators of epileptogenicity in the subject's brain and are therefore regularly used for both the diagnosis of epilepsy and even the localization of the seizure focus despite the fact that interictal epileptiform discharges are generated in both the epileptogenic and irritative zones and can spread to other brain structures. EEG data presented by Curtis et al (2012) indicates that interictal epileptiform discharges are usually present with superimposed high frequency activity, are usually followed by an inhibition of background activity, can generate delayed excitatory components, and finally can be sustained by either glutamatergic or GABAergic signaling. Interictal spikes have been examined both in vivo and in vitro. In vivo experimental animal models that utilize the application of convulsants have shown that interictal spikes correlate with paroxysmal depolarizing shifts of the membrane potential which in turn leads to sustained action potential firing. In vivo animal models have also demonstrated that the transition to seizure is characterized by interictal epileptiform discharge acceleration and post-burst hyperpolarizing potential deceleration (Curtis, 2012). In addition to in vivo seizure models, in vitro brain slice models have shown that interictal epileptiform discharges are initiated by the gradual enhancement of synaptic excitation that reaches the threshold for regenerative calcium currents. This action in turn begins a persistent process by setting off further recurrent excitation and by promoting the synchronous firing of a large number of neurons that contribute to the buildup of a population spike/sharp wave. Excitatory postsynaptic potentials associated with these interictal epileptiform discharges are mediated by both AMPA and NMDA glutamate receptors. The epileptic cortex is characterized by suddenly recurring electrical discharges. These discharges manifest as spike and wave complexes on the EEG. Interictal discharges play a critical role in the diagnosis of epilepsy, and while some understanding of the cellular mechanisms behind their generation exists, a complete picture of the neurophysiological mechanisms generating discharges in human focal seizures is not yet definitive. Human single cell recordings allow for the examination of the relationship between single unit activity and interictal discharges. In a research protocol by Keller et al (2010), patients (n=20) with medically intractable focal epilepsy were fitted with systems of microelectrodes to record both local field potentials as well as single cell action potentials throughout ten different cortical areas and the hippocampus during interictal periods. Brain regions both inside and outside of the assumed seizure focus were studied. Changes in the firing rates of individual neurons during interictal discharges were compared to a median baseline firing rate that was representative of discharge free periods during the interictal phase. 48% of the recorded units had a modulated firing rate within 500ms of the discharge. The single cell units that did show a modulation displayed significantly higher baseline firing and bursting rates as compared to the unmodulated units. Many of the units also displayed an increase in firing rate during the fast segment of the discharge and half showed a decrease during the slow wave. This comparison of single cell activity to a baseline derived from local field potentials displays heterogeneity in single unit activity suggesting that interictal epileptiform discharges in patients with focal epilepsy are representative of multiple distinct neuronal types within a complicated network of neurons both inside and outside of the epileptic foci (Keller, 2010). The vast diversity of responses and changes in firing displayed, including changes that occurred before the defining interictal discharge itself, support the hypothesis that interictal discharges reflect a complex network phenomenon, and are not simply the result of a single physiological event within a population of neurons. More recent studies have continually added evidence to support the hypothesis that neuronal spiking activity during seizure initiation is a highly heterogeneous phenomenon and not hypersynchronous as was the traditional view derived through the use of human single cell recordings. An additional comparison of interictal discharges carried out by Jirsch et al (2006) measured both grid electrodes and single-unit recordings in patients (n=4) with intractable epilepsy. The heterogeneity of activity reported in this example of human epilepsy appears simultaneously in small patches of neocortex. This means that different groups of neurons must have entered different states of excitation not only at different times but also for different durations. It is important to remember that EEG recordings measure an average of electrical activity amongst large populations of neurons. As a consequence they can only provide a vague, or best guess, depiction of the behavior of single neurons. Human single cell recordings that provide a means of measuring electrophysiological activity within single neurons offer insight into the mechanisms that generate not only interictal activity but also seizure events in general. In addition to principles of heterogeneity of activity in discharge generation, human single cell recordings have also supported the hypothesis that inhibition in neuronal dendrites supports epileptic fast activity including the generation of both interictal spikes and focal seizures. High-frequency EEG activity is the most characteristic electrophysiological pattern in focal seizure recordings in human subjects. Both the non-uniform alteration of GABAergic inhibition in human epilepsy models and the depression of GABA circuit activity by GABA inhibitory postsynaptic currents show that interictal activity and the transition from interictal fast activity to ictal activity can be explained by dendritic inhibition (Wendling 2002). Additional evidence supporting the concept that GABA inhibition plays a significant role in both receptor-mediated inhibition and enhanced excitatory synaptic interactions is provided by Prince (2000). Using both an in vivo rat model as well as in vitro patch-clamp methods Prince provided evidence that altered intra-cortical circuitry involving a decrease in GABA inhibition is a plausible mechanism by which hyperexicability has the potential to create both interictal and ictal discharges. Mechanisms involving a possible role for gap junctions in the generation of fast EEG activity, specifically activity that occurs immediately before ictal activity, have also been proposed, particularly for the generation of focal seizures. Subdural EEG recordings were taken from paediatric subjects with both focal cortical dysplasias and intractable seizures. During the interictal phase prior to seizure onset very fast oscillations were found in children and also superimposed on bursts during the seizure. These oscillations were credited to electrical coupling between principal neurons through axonal gap junctions. This phenonmenon is thought to underlie very fast population oscillations in a seizure-prone brain but could also be a cause of oscillations in a normal brain (Traub 2008). Additionally, Nilsen et al (2006) found that gap-junction blockers such as carbenoxolone applied focally are effective at suppressing seizures and as evidenced by this experimental protocol represent a possible solution for seizure control (Nilsen 2006). In a separate protocol looking at gap junctions by Traub et al (2008), recordings were performed in vitro with hippocampal slices from rats treated with either tetramethylamine to open gap junctions, a cholinergic agonist mean to mimic the action of acetylcholine in the cell, or a hypertonic K+ solution used both in order to facilitate and accelerate the rate of potassium ion transport. Very fast oscillations were seen in interictal-like discharges induced by the hypertonic K+ solution and became continuous when the chemical synapses were purposefully blocked. The same results are obtained when axonal gap junctions are included. High frequency oscillations were recorded at seizure onset providing evidence that not only are they involved in seizure generation but they also provide relevant information regarding the physiologic factors involved in seizure initiation. In general terms, seizure activity is generated by specific subcortical circuits. Gale (2007) studied two substrates identified for the control of seizures which were the substantia nigra (SN) and the area tempestas (AT). Inhibition of the substantia nigra has been shown to suppress absence and clonic seizures in mammalian experimental models through the forced dysfunction of GABAergic neurotransmission. In another protocol focused on the role of GABAA carried out by Deransart (2001) when the density of GABAA was reduced by 40% seizures were found to be suppressed highlighting the role that GABA plays in seizure generation. In the case of the area tempestas, which is actually a part of the prepiriform cortex, injecting GABA induced generalized motor seizures prompting both the suggestion that this area is a crucial epileptogenic site but also that GABA, specifically GABAA, plays a significant role in generating multiple types of seizures in multiple areas of the brain (Wahnschaffe & Loscher 1990). Neuroactive peptides and excitatory amino acids are thought to work with GABA in the SN to control propagation of various epilepsy types including focal seizures. The AT is known to be a site that triggers bilaterally synchronous convulsions in response to alterations of cholingergic, GABAergic, and excitatory amino acid receptors (Gale, 2007). The success of this research in exploring different mechanisms of various neurotransmitters and their role in the propagation of seizures makes apparent the potential for further research in the area to aid in the complete understanding of seizure generation. By extension these findings could be extrapolated to aid in the development of anti-epileptic drugs. Recurrent excitatory circuits arise in subjects with focal epilepsy developed in damaged areas of the cortex producing spike discharges. As a result of this, normal membrane conductance and inhibitory synaptic currents break down allowing excitability to spread in excess. This could result in a focal seizure, or even a more widespread generalized seizure. The original synchronous activation that leads to a seizure and the spread of the event both use normal synaptic pathways and mechanisms steering the focus of trying to understand their mechanisms towards the modulation of excitatory and inhibitory synaptic effects. Voltage-dependent currents are also an important component of the pathophysiology of the epileptic processes. Specifically, calcium currents act to amplify neuronal depolarization during hypersynchronous activation and become engaged in neurotransmitter release playing a role in the development of longer-term changes in synaptic efficacy. In addition peptides, purines, cytokines, and steroid hormones amongst other neuromodulatory agents play important roles in regulating brain excitability and take an active role in the generation of both interictal spikes and focal seizures (Dichter, 1994). The study of the mechanisms of generation of both focal seizures and interictal discharges can be extrapolated to a broader understanding of all forms of epileptic seizures and aid in the development of anti-epileptic drugs. Human single cell records both enhance and accelerate the understanding of these mechanisms of generation of interictal spikes and focal seizures in single neurons as opposed to average electrical activity of populations of neurons, surpassing the gains that could be made in the understanding of generation mechanisms that can be made from current standard electroencephalography techniques.