Intrinsic optical signals (in vitro): Analysis of onset and propagation of epileptic activity
In brain slices of rats and humans (specimen from resective epilepsy surgery), we deploy optical methods in addition to electrophysiological measurements in order to provide a better understanding of pathophysiological mechanisms of ictogenesis (i.e. generation of seizures). By use of intrinsic opical signals, i.e. activity-dependent alterations of optical properties of brain tissue, onset and propagation of epileptic activity can be visualised and analysed subsequently. In previous works, we were able to demonstrate significant differences in epileptic activity in juvenile or senile neuronal tissue and during epileptogenesis following status epilepticus. Furthermore, we currently assess epileptiform discharges and seizure patterns in brain slices of chronic epileptic animals by means of high-resolution voltage sensitive dye imaging.
Deep brain stimulation (in vivo)
Based on the model system of electrically induced self-sustaining status epilepticus, we developed an approach to induce single limbic epileptic seizures in naïve and chronically epileptic rats by 20 Hz stimulation of the perforant path for 5 sec. Using this methodological approach, pharmacological and non-pharmacological treatments can be tested in naïve animals first (“screening”) and, if successful, afterwards may be translated to the chronic condition characterised by spontaneous seizures. Using this new technique, we currently assess various parameters of deep brain stimulation (DBS) in well-defined brain areas. Beyond the direct anti-seizure effect, we analyse DBS-mediated alterations of excitation and inhibition in mesio-temporal structures working with the paired-pulse paradigm. Stimulation sites and parameters that are successful in animal models, may be translated to neurostimulation in patients with intractable epilepsy.
Novel treatments in status epilepticus (in vivo)
We analyse the anticonvulsant properties of pharmacological and non- pharmacological treatment approaches using the model system of self-sustaining status epilepticus. At an early stage, we were able to demonstrate the strong anticonvulsant effect of the anaesthetic propofol, but also that of the loop diuretic furosemide. Furthermore, we investigate the impact of various degrees of hypothermia on status epilepticus and thus collected experimental data for clinical use of cooling in patients with refractory status epilepticus.
Pathophysiology and preventive approaches in epileptogenesis (in vivo)
The current concept in the „treatment“ of epilepsy is prevention of further seizures. Formally, this is a secondary prophylaxis. So far, epilepsy itself cannot be treated pharmacologically, the only causal therapeutic approach is surgical removal of the seizure focus. The aim of this project is to prevent development or at least to decrease the extent of epilepsy following acquired brain lesions. However, the prerequisite for this is a better pathophysiological understanding of epileptogenesis (i.e. the development of epilepsy). Many drugs that are given to prevent further seizures have been tested regarding their antiepileptogenic properties, but all failed to prove efficacy. A research grant from the Deutsche Forschungsgemeinschaft enables us to investigate antiepileptogenic effects of hypothermia applied subsequent to status epilepticus.
Cellular and network mechanisms of cerebral excitability (in vitro)
Ion channel proteins are decisive for generation and propagation of epileptic activity. Ion channels are membrane proteins that transport charged compounds between the intracellular and the extracellular compartments and thus majorly contribute to signal conduction and excitability of neurons. Pharmacological impact on ion channel activity may suppress epileptic seizures, and is currently one out of many mechanisms in the treatment of epilepsy. To improve understanding of the mechanisms involved and thus to develop new treatment approaches, we study electric properties of single cell and neuronal networks by use of high-resolution electrophysiological methods (patch-clamp technique). In this regard, we apply specific pharmaceutical substances that have the capability to interfere with the activity of well-defined proteins. We work on brain slices of rats and mouse models in which single ion channel proteins are knocked out or altered regarding their function. By knocking out a specific subunit of the potassium channel, we were able to demonstrate that, in contrast to all other subunits, this is not involved in epileptogenesis, but that it enhances inhibitory neuronal processes. Currently, we investigate if knock-out of the potassium channel subunit also has protective properties in chronic epilepsy.
- Prof. Dr. Douglas Coulter (Children’s Hospital of Philadelphia, USA)
- Prof. Dr. Uwe Heinemann (Institut für Neurophysiologie, Charité, Berlin)
- Prof. Dr. Thomas Jentsch (Max Delbrück Center for Molecular Medicine, Berlin-Buch)
- Dr. Julia Matzen, Dr. Friedhelm Schmitt (Klinik für Neurologie, Universität Magdeburg)
- Dr. Lars Büntjen, Prof. Dr. Jürgen Voges (Klinik für Stereotaktische Neurochirurgie, Universität Magdeburg)
- Dr. Sabine Oertelt-Prigione (Institut für Geschlechterforschung in der Medizin, Charité – Universitätsmedizin Berlin)
- Prof. Dr. Michael Sperling (Jefferson Comprehensive Epilepsy Center, Thomas Jefferson University, Philadelphia, USA)
- Prof. Dr. Matthew Walker (Institute of Neurology, University College London, UK)