A Candidate Mechanism Underlying the Variance of Interictal Spike Propagation

Abstract

Synchronous activation of neural networks is an important physiological mechanism, and dysregulation of synchrony forms the basis of epilepsy. We analyzed the propagation of synchronous activity through chronically epileptic neural networks. Electrocortigraphic recordings from epileptic patients demonstrate remarkable variance in the pathways of propagation between sequential interictal spikes (IIS). Calcium imaging in chronically epileptic slice cultures demonstrates that pathway variance depends on the presence of GABAergic inhibition and that spike propagation becomes stereotyped following GABA-R blockade. Computer modeling suggests that GABAergic quenching of local network activations leaves behind regions of refractory neurons, whose late recruitment forms the anatomical basis of variability during subsequent network activation. Targeted path scanning of slice cultures confirmed local activations, while ex vivo recordings of human epileptic tissue confirmed the dependence of interspike variance on GABA-mediated inhibition. These data support the hypothesis that the paths by which synchronous activity spread through an epileptic network change with each activation, based on the recent history of localized activity that has been successfully inhibited.

Evolution of Network Synchronization during Early Epileptogenesis Parallels Synaptic Circuit Alterations

“…The topology of network synchronization remains hypothetical. For example, seizures could coalesce from smaller scattered nodes of physiological (Ikegaya et al, 2004;Bonifazi et al, 2009) or pathological (Huberfeld et al, 2011;Sabolek et al, 2012) synchrony. Alternatively, the fraction of neurons in the network participating could increase regardless of spatial constraints.…”

Microcircuits in Epilepsy: Heterogeneity and Hub Cells in Network Synchronization

“…Instead, the pattern of cluster recruitment was nonuniform, showing large heterogeneity between macroscopically "recurrent" epileptiform events at the scale of microcircuits (Feldt Muldoon et al 2013). This heterogeneity is not limited to laboratory models, as patients have shown nonuniform recruitment of neuronal populations during initiation and progression of epileptiform events (Keller et al 2010;Truccolo et al 2011;Sabolek et al 2012). Even between sequential seizures, the fraction of active neurons was highly variable, with different populations of neurons participating in sequential events; this appeared independent of neuronal class type, as it was evident for interneurons and principal neurons (Keller et al 2010;Truccolo et al 2011).…”

“…Even between sequential seizures, the fraction of active neurons was highly variable, with different populations of neurons participating in sequential events; this appeared independent of neuronal class type, as it was evident for interneurons and principal neurons (Keller et al 2010;Truccolo et al 2011). Additionally, even among neurons that were frequently active during sei- zures, the spiking patterns of those cells did not repeat between consecutive seizures (Truccolo et al 2011), and the path of propagation during large-scale bursts of activity changed between episodes (Sabolek et al 2012). These results highlight the existence of variable paths of epileptiform synchronization dynamics in the recruitment of pathological neuronal clusters.…”

“…Instead, there is complex circuit communication associated with epileptiform activity (Truccolo et al 2011;Feldt Muldoon et al 2013). Contributions of specific neuronal populations have been observed to be variable, and certain well-connected networks appear to play a greater role in the ini-tiation and progression of large-scale network events (Morgan and Soltesz 2008;Keller et al 2010;Sabolek et al 2012). In addition, work from high-level network theory and data-driven computational studies have modeled how altered neural circuit connections can trigger seizure activity (Santhakumar et al 2005;Dyhrfjeld-Johnsen et al 2007;Morgan and Soltesz 2008;Bullmore and Sporns 2009).…”

Staged anticonvulsant screening for chronic epilepsy

“…Recently, it has been proposed that this lack of progress is a consequence of the method by which compounds are screened 3, 4. To date, initial screening is based on acute application of convulsant conditions to normal brain tissue,2, 4 but this produces patterns of epileptic activity that are substantially different from spontaneous epileptiform activity in chronically epileptic brain tissue 5. Thus, we considered the hypothesis that screening for anticonvulsants in chronically epileptic tissue would uncover agents that may be uniquely effective in medically intractable epilepsy 6…”