Thesis defense Annika Lüttjohann (Donders Series 138)

11 November 2013

Promotor: Prof.dr. G. van Luijtelaar

The role of the cortico-thalamo-cortical system in absence epilepsy

Absence epilepsy is a neurological disorder, which can be found in young children. It is characterized by sudden lapses op consciousness, which can occur up to several hundred times a day. The main electroencephalographic hallmark of absence epilepsy are the bilateral, synchronous spike and wave discharges (SWD), which can be recorded in the electroencephalogram of patients. While there is a general agreement that SWD are generated within the thalamo-cortical system, network interactions, relevant for the occurrence of SWD are still enigmatic and the relative functional contribution for cortex and thalamus is highly debated, resulting in a total of five different theories on SWD generation. The in Nijmegen developed cortical focus theory is currently in the forefront of experimental investigation. It proposes that SWD in patients originate from restricted cortical areas cortex; in genetic epileptic rats from the deep layers of the perioral somatosensory cortex. This area should contain a hyperexcitable area where SWD are generated, whereas the thalamus functions as a resonator for SWD sustainment. Aim of the current thesis was to investigate in genetic epileptic rats the excitability of the focal zone and the dynamics of cortico-thalamo-cortical network interactions, relevant for the generation and sustainment and the termination of SWD. The latter cannot be done with the modern brain imaging tools, considering that they lack the necessary temporal refinement. Therefore, the studies were done in a well characterized and validated animal model. Experimental approaches: Different types of electrical deep brain stimulation protocols were locally applied to structures within the cortico-thalamo-cortical system. This was done to assess local excitability, to induce and to interrupt ongoing epileptic activity. For the latter an online SWD detection algorithm was developed, evaluated and applied: it allowed to stimulate the brain as soon as a SWD was detected. Signal analytical approach: Multisite local field potential recordings were obtained from several thalamic nuclei and different layers of the somatosensory cortex of freely moving epileptic rats. Signals of pre-SWD->SWD and SWD->post SWD transition periods were dynamically analyzed with several advanced connectivity analysis (non-linear association analysis, Granger Causality, Pairwise-Phase Consistency analysis) in order to investigate changes in network communication associated with the generation, sustainment and termination of SWD.

We established that the deep somatosensory cortex contains indeed a local region, which possesses multiple characteristics of an epileptic focus: it is more excitable than other cortical areas, it can generate local epileptic discharges, it shows SWD earlier than in the thalamus, and electrical stimulation induces self-sustained afterdischarges mimicking SWDs. In all, we confirmed the cortical focus theory.

We discovered that high-frequent, closed loop stimulation is effective in disrupting SWD, open loop low-frequency stimulation was found to, structure dependent, induces epileptic activity.

We extended the cortical focus theory by showing that the thalamus is not only a passive resonator for cortical induced SWD; different functional roles were attributed to various thalamic nuclei in the initiation, sustainment and end phase and a detailed SWD generation and termination scenario was proposed. We discovered also that the posterior nucleus of the thalamus is a key-player in SWD generation: it helps to prepare the system into a pro-epileptic state and decides whether locally generated SWD activity can come to ‘full blown’ cortico-thalamo-cortical expression. Changes in network interactions could already be seen more than a second prior to SWD onset, which challenges the long-lasting belief that SWD are sudden and unpredictable phenomena.

These outcomes have strong scientific and clinical relevance. They open the possibility of an improved clinical treatment of SWD and their prevention via precursor locked high frequency deep brain stimulation. The improved knowledge on network interactions of SWD generation and termination and the functional contributions of the different structures, as described in this thesis, is suited to guide the search for the most optimal stimulation sites.