Epilepsy
The first description of epileptic seizures was made around 4000 B.C. and later Hippocrates already acknowledged the fact the epilepsy must be related to morphological and functional changes in the central nervous system. Unfortunately even today we must admit that far too little is known about the development of epilepsy and the treatment of this disease.
We know that epileptic seizures are caused by complex neurochemical, physiopathological and anatomical alterations of the brain. It's also acknowledged that epilepsy cannot be considered and treated as a homogenous disease. That's why both in fundamental research as well as the clinical practice instead "epilepsy" is better to use "epileptic syndromes". By this term we refer to a series of diseases different from many points of view but sharing two criteria: (1) the presence of epileptic modifications on electroencephalographic recordings and (2) the recurrence of fairly similar clinical symptoms, which start and end abruptly - called convulsions or ictus. At the very foundation of these symptoms lies the hyperexcitability of a population of neurons with transient abnormally synchronized activity.
Epilepsy causes both suffering and stigmatization of patients and relatives representing in the same time an important socio-economic burden for the society. Epileptic syndromes are one of the most frequent neurological diseases affecting 0.5-3% of the globe's population. The hyperexcitability of the developing brain explains the higher incidence of the disease in children. The number of people affected indirectly by this disease (i.e. family members, etc) is actually much higher. Although usually the disease is not lethal the loss of consciousness can lead do dangerous situations (i.e. when driving, etc). Almost indifferently of the type of epilepsy the disease will lead to psychopathological complications (hiposexuality, memory loss, depression) as well as the stigmatization of the patients. Thus epilepsy causes an important socio-economic burden as well as affecting the quality of life for both patients and relatives. Therefore revealing the mechanisms of epileptogenesis and creating new drug targets is essential and it is worth the intellectual and financial effort.
A better understanding of the fundamental processes that lie at the basis of epileptogenesis is essential for the improvement of the treatment of these patients which in term leads to the amelioration of the quality of life. This research application studies the hyperexcitability of neuronal populations during the development of epilepsy. The results of the study should lead to changes in the therapeutic strategies for epileptic patients.
High-frequency oscillations
Short epochs of high-frequency oscillations (HFO) are considered physiological phenomena implicated in hippocampal information processing and synaptic plasticity. HFO does occur spontaneously in the hippocampus in vivo and in vitro. HFOs were suggested to reflect synchronous neuronal firing and their occurrence was reported both in epileptic human patients and animal models of epilepsy. As HFOs are often found at the seizure onset they are assumed to contribute to its initiation. Furthermore a specific class of HFOs (above 250 Hz, termed fast ripples) was proposed to reflect the formation of pathologically interconnected neuronal networks contributing to epileptogenesis. In vitro, nonsynaptic mechanisms, like gap junction coupling and field effects were proposed to be sufficient for the development of HFOs and synchronously firing neuronal aggregates. Synaptic activity was shown to contribute to ictal activity; however its impact on HFO formation has not been elucidated sufficiently. Recently was described the temporal relationship of HFO and status epilepticus in the dentate gyrus of the rat as well as the fact that HFO may precede a seizure-like event in a in vitro epileptic experimental paradigm. In conclusion one can state that HFO can be reproduced in a large number of experimental and/or clinical paradigms and that HFOs seem to be related to normal and pathological synchronization of the central nervous system.
Activitatea interictală
Interictal spikes (ISp) are morphologically defined, episodic, transient discharges of a neuronal population. During an interictal spike, local neurons undergo a synchronous, paroxysmal depolarization of the membrane potential that triggers a series of action potentials. The relationship of interictal spikes to seizures is not as straightforward as one would expect, based on their reliable presence in the EEG of epileptic patients. Spikes are observed in the setting of an increased probability for spontaneous seizures. In local-onset epilepsy, interictal spikes are localized to the epileptic brain region and frequently disappear after resection of the epileptogenic brain tissue or spontaneous resolution of epilepsy. Thus, generally it is believed that interictal spikes are associated with an increased risk for spontaneous seizures, though some contradictory reports exist - post ISp inhibition being protective as it maintains a low level of excitability. Interictal spike frequency increases after rather than before a seizure. These findings do not support the "damp kindling" theory of interictal spikes, in which each spike represents the unsuccessful initiation of a seizure, just as multiple sparks might be required to ignite damp kindling. If that were the case, then spike frequency should be more strongly correlated with seizure probability. One could argue that how wet the kindling is might be a more important determinant of seizure frequency than the number of ignition trials, in which case, the conditions that favor the evolution of a spike into a seizure would be the feature most highly correlated with seizure frequency. Some seizures start with a "sentinel spike", so this idea cannot be discarded, but there is currently not enough data to support this mechanism. Another possible reason for the coexistence of these two types of synchronous activity is causation: seizures could cause spikes, or spikes could cause seizures. This hypothesis has been studied but the mechanism was not elucidated especially because although ISp does appear both in human and experimental animal models of epilepsy almost immediately after traumatic brain injury the first seizure usually occurs several months to several years after the initial injury. When we consider the mechanisms for epileptogenesis, it is important to remember this slow time scale. A possible explanation could be found in the normal plasticity of the brain. During development, many circuits in the brain self-organize with the aid of synchronous bursts of activity that is nearly identical to interictal spikes. New axon branches grow and synaptic connections are formed in the epileptic brain (processes called sprouting and synaptic reorganization) by the growth of axons back into their network of origin (a local synaptic circuit called recurrent excitation). Increasing and unmasking of positive feedback is associated with spontaneous, synchronous activation of the sprouted neural networks in vitro and in vivo. Suppressing activity in the experimentally injured cortex can reduce the incidence of subsequent epileptiform activity. Thus, interictal spikes are likely to both guide the growth of sprouting axons and increase and maintain the strength of the newly formed recurrent connections in the epileptic network. If interictal spikes are epileptogenic, this would dramatically alter the goals of anticonvulsant therapy. More generally, recognition that interictal activity may develop and sustain the epileptic condition suggests a new antiepileptogenic strategy: suppression of interictal spikes.
Morphological and molecular basis
Seizure activity reflects the hypersynchrony of a local neuronal network that ultimately recruits adjacent networks until the activity generalizes. Kindling as a model of epilepsy produces permanent changes in excitatory and inhibitory transmission. It has been suggested that hypersynchrony may arise from altered inhibitory synaptic transmission owing to inappropriate GABA-A receptor expression. On the other hand, in other models of epilepsy altered expression of GABA-A receptor subunits was proposed to be compensatory to interneuronal loss and not causative. It has been suggested that differences in GABA-A receptor expression on interneurons may have a significant impact on the control of synchronous behavior and as such could be an important pathophysiological mechanism for seizure induction. Interneurons in several areas have an important role in controlling (or causing) seizure spread from which the most important probably are: the hilus of the dentate gyrus and the perirhinal cortex. Hilar interneurons control the excitatory synchronization of dentate granule cells, which are thought to gate the spread of seizures in the hippocampus. The perirhinal cortex is thought to be an effective path for seizure propagation both within the limbic system and to the frontal cortex, which ultimately results in generalization of the seizure.
Computer modelling
New experimental models provide such a great amount of physiological and morphological information that their separate interpretation, in order to understand the function o neural circuits, has become impossible. Lately the number of researches using computational models as a means to understand the functioning of different neural systems has significantly increased. The combination of experimental research and computational modelling produced a new discipline called computational neuroscience. The models based on detailed physiological and anatomical information about the studied brain region synthesize all that is known about that region. In the same time determine the most significant deficiencies, the information indispensable for functional interpretation, showing new directions for experimental research. Synchronization in hippocampal neural networks was intensely studied also using computational models. There have been created models which state the conditions for the emergence of high frequency oscillations in networks of neurons connected with gap junctions. It has been shown that pyramidal cells interconnected with axon-axon gap junctions and connected with chemical synapses to interneurons generate ripple-type oscillations superimposed on the depolarization caused by synaptic inputs. There are many models of hippocampal pyramidal cells with active dendritic conductances published on the Internet, but detailed models of interneurons are not available. Likewise there are very few models describing extracellular potentials and their relation to intracellular phenomena.