Dynamics of networks during absence seizure's on- and offset in rodents and man

Abstract

Network mechanisms relevant for the generation, maintenance and termination of spike-wave discharges (SWD), the neurophysiological hallmark of absence epilepsy, are still enigmatic and widely discussed. Within the last years, however, improvements in signal analytical techniques, applied to both animal and human fMRI, EEG, MEG, and ECoG data, greatly increased our understanding and challenged several, dogmatic concepts of SWD. This review will summarize these recent data, demonstrating that SWD are not primary generalized, are not sudden and unpredictable events. It will disentangle different functional contributions of structures within the cortico-thalamo-cortical system, relevant for the generation, generalization, maintenance, and termination of SWD and will present a new "network based" scenario for these oscillations. Similarities and differences between rodent and human data are presented demonstrating that in both species a local cortical onset zone of SWD exists, although with different locations; that in both some forms of cortical and thalamic precursor activity can be found, and that SWD occur through repetitive cyclic activity between cortex and thalamus. The focal onset zone in human data could differ between patients with varying spatial and temporal dynamics; in rats the latter is still poorly investigated.

Keywords: Granger causality; childhood absence epilepsy; cortico-thalamo-cortical system; genetic absence models; network interactions; non-linear-association analysis; pairwise-phase-consistency; seizure dynamics.

Figure 1

Electrode locations (A) and summary of results (B+C) obtained in the study by Meeren et al. (2002) inspiring the formulation of the cortical focus theory. In A different symbol-shapes indicate the recording positions of 8 different rats (H11 to H21, respectively) across anterior-posterior and medial lateral coordinates of one hemisphere of a rat brain. Filled symbols represent the SWD onset sites of the different rats as determined by non-linear association analysis. It can be noted that that the onset zone of the individual rats are exclusively positioned in the most ventrolateral recording positions. In (B,C) strength and direction of coupling are represented by arrows, with the thickness of the arrow representing a different degree of coupling strength. It can be noted that during the first 500 ms of the SWD, the S1-upper lip region drives all other recorded areas (B), while thereafter (C) a bidirectional crosstalk between cortical focus and thalamus can be detected. Figure adapted from Meeren et al. (2002).

Figure 2

Schematical overview of anatomical connectivity of the somatosensory cortico-thalamic loop. Excitatory, glutamatergic connections are displayed in gray while inhibitory, GABAergic projections are displayed in blue. Note that thalamic nuclei are chategorized as either higher order nuclei (HO), which receive their driving input from the cortex and project widespreadly to other cortical regions, and first order nuclei (FO), which receive their driving input from sensory organs and project to a defined/restricted cortical area (Sherman and Guillery, 2005). Po, Posterior thalamic nucleus; VPM, Venral-Postero-Medial thalamic nucleus; RTN, Reticular thalamic nucleus; C-T cell, cortico-thalamic cell; T-C cell, thalamo-cortical cell.

Figure 3

Changes (as compared to non-epileptic control) in network interactions seen with SWD generation. All pre-ictal changes are represented in (A). Earliest pre-ictal changes were detected up 1.25 s prior to SWD onset or better the FCTS (first cortico-thalamic spike of the SWD). (B) Represents network coupling seen within the first 500 ms following FCTS. Solid lines represent changes between anatomically connected structures, dashed lines changes between structures that do not possess a direct, anatomical connection. The direction of coupling is indicated by arrowheads, which can either be unidirectional (→) or bidirectional (↔). Orange indicates a significant increase that did not yet reach its maximal value at that time point, red indicates that the coupling reached its maximal value and blue indicates a decrease in coupling.

Figure 4

Changes (as compared to non-epileptic control) in network interactions seen with SWD maintenance. These are detected following the first 500 ms after SWD onset until 3 s following FCTS (= end of analysis interval) as well as 3 to 1.5 s prior to SWD termination or better the LCTS (last cortico-thalamic spike of the SWD). Solid lines represent changes between anatomically connected structures, dashed lines changes between structures that do not possess a direct, anatomical connection. The direction of coupling is indicated by arrowheads, which can either be unidirectional (→) or bidirectional (↔). Red indicates a significant increase that is at its maximal value.

Figure 5

Changes in network interactions seen with SWD termination. (A) Represents changes seen from about 1.5 s prior to the LTCS (last cortico-thalamic spike of the SWD) until LCTS. (B) Represents changes from LCTS until about 1.5 s following it. Solid lines represent changes between anatomically connected structures, dashed lines changes between structures that do not possess a direct, anatomical connection. The direction of coupling is indicated by arrowheads, which can either be unidirectional (→) or bidirectional (↔). Orange indicates a significant increase that is not at its maximal value at that time point, red indicates that the coupling is at its maximal value.

Figure 6

Schematic interpretation of the importance of a bidirectional crosstalk between cortical, epileptic focus and posterior thalamic nucleus for the generation of “full blown” SWD (see text for details). Po, Posterior thalamic nucleus; VPM, Venral-Postero-Medial thalamic nucleus; RTN, Reticular thalamic nucleus; ATN, Anterior thalamic nucleus.

Figure 7

Association strength between MEG sensors assessed across SWD onset with the aid of non-linear association analysis. Note the local clusters accompanying the spike component of SWD and the broad generalization accompanying the wave components of SWD as well as the early, local cluster of connectivity preceeding the first generalized spike. Figure adapted from Westmijse et al. (2009).