Differential contribution of excitatory and inhibitory neurons in shaping neurovascular coupling in different epileptic neural states

Abstract

Understanding the neurovascular coupling (NVC) underlying hemodynamic changes in epilepsy is crucial to properly interpreting functional brain imaging signals associated with epileptic events. However, how excitatory and inhibitory neurons affect vascular responses in different epileptic states remains unknown. We conducted real-time in vivo measurements of cerebral blood flow (CBF), vessel diameter, and excitatory and inhibitory neuronal calcium signals during recurrent focal seizures. During preictal states, decreases in CBF and arteriole diameter were closely related to decreased γ-band local field potential (LFP) power, which was linked to relatively elevated excitatory and reduced inhibitory neuronal activity levels. Notably, this preictal condition was followed by a strengthened ictal event. In particular, the preictal inhibitory activity level was positively correlated with coherent oscillating activity specific to inhibitory neurons. In contrast, ictal states were characterized by elevated synchrony in excitatory neurons. Given these findings, we suggest that excitatory and inhibitory neurons differentially contribute to shaping the ictal and preictal neural states, respectively. Moreover, the preictal vascular activity, alongside with the γ-band, may reflect the relative levels of excitatory and inhibitory neuronal activity, and upcoming ictal activity. Our findings provide useful insights into how perfusion signals of different epileptic states are related in terms of NVC.

Microvascular changes associated with epilepsy: A narrative review

“…In addition, the authors observed a slow increase of [Ca 2þ ] following repetitive seizures in astrocytic endfeet. This resulted in a stronger arteriolar constriction in the focal and perifocal tissues, which is in line with the reduced interictal vascular and neuronal activity as described by Lim et al 101 Using 2-photon [Ca 2þ ] imaging, it has been shown that seizures result in vasoconstriction of cortical penetrating arterioles. This postictal vasoconstriction in the NVU was associated with seizure-induced hypoxia.…”

Two-Photon Imaging to Unravel the Pathomechanisms Associated with Epileptic Seizures: A Review

“…In terms of temporal characteristics, vasodilation in the focus occurred almost immediately after seizure onset whereas preictal vasoconstriction of vessels in distal regions occurred 5.3 ± 0.5 s before seizure onset (see Figure 4). Preictal vasoconstriction was also observed in the study by Lim et al [61], and this was found to be correlated with increased excitatory and reduced inhibitory neuronal activity levels, as shown with [Ca 2+ ] 2PI.…”

“…By using 2PI, changes in blood flow were visualized, with different states of vasoconstriction and vasodilation surrounding the epileptogenic focus [59][60][61]. Preictal vasoconstriction was found to be correlated with increased excitatory and reduced inhibitory neuronal activity levels [61]. These findings indicate that excitatory and inhibitory neurons affect surrounding neurons during epileptiform activity leading to dysfunctional local inhibition, which is supportive of the aforementioned "inhibitory model" of seizure propagation.…”

“…Most studies used rodent models, except for Cozzolino et al [39], and Verdugo et al [47], who both used zebrafish models, while Kerekes et al [40], Chia et al [66], and Hakvoort et al [21] examined human brain tissue. Twenty-three studies used mouse models [31][32][33][34]36,37,41,42,45,46,48,49,[53][54][55]58,60,61,63,64], seven used rat models [50][51][52]59,62,65,66], three used both rat and mouse models [29,35,38], and one used a guinea pig model [56]. In addition, fourteen of the studies applied 2PI to visualize ex vivo cells in brain slices [21,29,34,35,38,[40][41][42]45,48,[50]…”

“…Given the recent change in epilepsy research from a neuronal-centered toward a vascular-centered concept of epileptogenesis [9][10][11][12], neurovascular alterations in epilepsy are of major interest. By using 2PI, changes in blood flow were visualized, with different states of vasoconstriction and vasodilation surrounding the epileptogenic focus [59][60][61]. Preictal vasoconstriction was found to be correlated with increased excitatory and reduced inhibitory neuronal activity levels [61].…”