Malta neuroscientists and European colleagues unveil network dynamics behind absence epilepsy

“EPILEFREE” R&I – 2013-14 researchers discover the cortico-thalamo-cortical network firing dynamics that underlies absence epilepsy, paving the way for new treatments.

A research study part of “EPILEFREE” R&I – 2013-14 grant on Absence Epilepsy, the most common form of paediatric and juvenile epilepsy, by Professor Giuseppe Di Giovanni (MNS vice-president) and Professor Vincenzo Crunelli, from of the Department of Physiology and Biochemistry in the Faculty of Medicine and Surgery of University of Malta, has been published in the prestigious journal Nature Neuroscience.

The full article can be found here.

Absence Epilepsy is a condition that affects 10 to 17% of all children and adolescents with epilepsy. It is manifested by brief, but very frequent, episodes of altered consciousness characterized by a break in communication with the external world and cessation of on-going. These clinical symptoms are associated with the appearance of a particular oscillatory waves (called spike and wave discharges) in the electroencephalogram. Together with these behavioural problems, patients with absence epilepsy also experience learning difficulties and other neuropsychiatric problems. Notably, control of seizures when using a single drug only occurs in 50% of sufferers, while potential additional improvements with a second drug are always accompanied by a marked increase in serious side effects.

Although the origin of absence-epilepsy remains poorly understood, it has been shown that synchronous neuronal oscillations of the thalamocortical network underlie the appearance of spike-wave discharges. This thalamocortical network is organized in a loop: cortical and thalamocortical excitatory neurons are reciprocally connected and the thalamic inhibitory neurons receive projections from both the cortex and the thalamocortical neurons (Fig. 1a). The respective role of these different neuronal types in the hyperexcitability of this loop is strongly debated.
Vincenzo Crunelli and Giuseppe Di Giovanni, together with research support officers Francis Delicata and Gergely Orban supported by “EPILEFREE” R&I – 2013-14 in Malta, in collaboration with researchers in the UK, France and Hungary recorded simultaneously for the first time the activity of several cortical and thalamic neurons during absence seizures in two animal model of this epilepsy under vigilant freely moving conditions.

They discovered that the activity of thalamocortical neurons, which constitute the thalamus output to the cortex, is controlled and synchronized by the combination of an excitation from the cortex and an inhibition from the neurons of the thalamic reticular nucleus. On the other hand, contrary to the commonly accepted idea, the intrinsic excitability mechanisms of thalamocortical neurons contribute very little to the hyperexcitability of the thalamocortical loop at the origin of the spike and wave discharges.

This work is the first cellular description of cortical and thalamic network dynamics during absence seizures in vigilant animals, and puts an end to long-lasting controversies on the role of the excitatory and thalamic neurons in the generation of spike-wave discharges. Moreover, this research is fundamental for the future development of innovative therapies for disabling childhood and juvenile disease.

This study, a follow-up of the previous research published in Nature Medicine in 2009 by Professor Giuseppe Di Giovanni and Professor Vincenzo Crunelli, was supported by the Malta Council for Science and Technology grant “EPILEFREE” R&I – 2013-14.

Figure MCST NN
a) Left: Diagram of the thalamocortical loop (Cx: cortex, TC: thalamocortical nuclei, NRT: thalamic crosslinked nucleus). Right: Simultaneous recordings of the electrical activity of two thalamocortical (TC) neurons and a Thalamus Reticulari Nucleus (NRT) neuron during EEG tip-to-wave discharges. b). Left: Section of a rat brain showing the location of the local application of a pharmacological blocker (same colour code as the graph on the right). Right: The modification of the excitability of cortical and NRT neurons by the local application of a calcium channel blocker blocks seizures. This same blocker has no effect in other thalamic nuclei.