Sleep links hippocampal propensity for epileptiform activity to its viscerosensory inputs

Abstract

The development of a seizure relies on two factors. One is the existence of an overexcitable neuronal network and the other is a trigger that switches normal activity of that network into a paroxysmal state. While mechanisms of local overexcitation have been the focus of many studies, the process of triggering remains poorly understood. We suggest that, apart from the known exteroceptive sources of reflex epilepsy such as visual, auditory or olfactory signals, there is a range of interoceptive triggers, which are relevant for seizure development in Temporal Lobe Epilepsy (TLE). The hypothesis proposed here aims to explain the prevalence of epileptic activity in sleep and in drowsiness states and to provide a detailed mechanism of seizures triggered by interoceptive signals.

Keywords: Hippocampus; circadian rhythm; epilepsy; ipRGC (intrinsically photosensitive retinal ganglion cells); sleep; vagus.

Figure 1

Schematic depiction of the brain structures known to be involved in viscerosensory and/or visceromotoric functions. The upper panel demonstrates medial view of the brain, and the lower panel shows lateral view. ipIGC, intrinsically photosensitive retinal ganglion cells; S, somatosensory cortical areas; mPFC, medial prefrontal cortex; OFC, orbitofrontal cortex; Ci, cingulate cortex; In, insula; Th, thalamus; Hip, hippocampus; Hyp, hypothalamus; Ms, medial septum; Pb, parabrachial nucleus; NTS, nucleus tractus solitarius.

Figure 2

Model of functional connectivity changes occurring upon transition from light to dark phase of a sleep–wake cycle. Left panel represents subjective light phase, and right panel represents subjective dark phase. During the light phase, ipRGCs of the retina are activated by light and send their signals to SCN. SCN stops producing melatonin, thus enhancing sympathetic activity (dashed gray arrow). As a result, predominantly parasympathetic vagal activity (dashed purple and green arrows) is attenuated. SCN also does not inhibit medial septum during the light phase; that allows disinhibited septal areas to send cholinergic signals to the hippocampus (orange arrow, Ach+), promoting arousal and supporting tonic type of hippocampal inhibition. Medial septum also “closes the gate” for the vagal signals, reducing chances for hippocampal triggering by the vagal input. In contrast, during the dark phase, when SCN does not receive ipRGC input, it increases melatonin production, supporting parasympathetic activity (dashed purple arrows) and so the vagal activity is enhanced. SCN also inhibits medial septum (open purple arrow), which decreases the medial septum’s cholinergic input to the hippocampus, causing switching of the hippocampus to a phasic inhibition mode with increased susceptibility to low frequency entrainment. Medial septum also “opens the gate” for the vagal signals, thus increasing the influence of the visceral activity on hippocampus and allowing the triggering of paroxysmal responses to occur.

Figure 3

Outcomes of the resonant and phase-amplitude CFC mechanisms of seizure triggering. Both mechanisms require visceral input (purple); however, the resonance mechanism (left side of the picture) implies similarity between frequencies of the hippocampal oscillation and the visceral input or a harmonic relationship between them, while phase-amplitude CFC (right side) leads to an amplitude modulation of any prevailing higher-frequency hippocampal activity.