Abstracts

Optical Interrogation of Neurovascular Dynamics in Seizure Progression and Epileptogenesis

Abstract number : 3.006
Submission category : 1. Basic Mechanisms / 1A. Epileptogenesis of acquired epilepsies
Year : 2019
Submission ID : 2421905
Source : www.aesnet.org
Presentation date : 12/9/2019 1:55:12 PM
Published date : Nov 25, 2019, 12:14 PM

Authors :
Andrew H. Chang, Gladstone Institutes; Chris Tsang, Inscopix; Bryan Higashikubo, Gladstone Institutes; Jeanne T. Paz, Gladstone Institutes

Rationale: Seizure prediction remains a critical interest in the epilepsy field. The ability to predict when seizures occur will significantly improve the quality of life in epilepsy patients and provide an avenue to pre-emptively abort seizures before they even begin. Seizure prediction efforts have primarily been focused on detecting characteristic pre-ictal electrical signals preceding seizure onset, while the cerebrovascular component and neurovascular responses have largely been understudied in this context. Here, we examine cerebrovascular dynamics during seizure progression and explore cerebrovascular changes after injuries that may contribute to epileptogenesis.  Methods: -Animal models: controlled cortical impact mouse model of post-traumatic epilepsy, neocortical photothrombosis mouse model of post-stroke epilepsy, pharmacologically induced seizures (pentylenetetrazole, kainic acid).-Simultaneous imaging, electrical recording and optogenetics using miniscopes (Inscopix nVoke) in freely behaving mice.-Electrocorticography (ECoG) in freely behaving mice.-Immunofluorescence labeling and imaging of cleared whole mouse brain (iDISCO).  Results: Using chronically implantable miniature microscopes (Inscopix nVoke devices) to image cortical vasculature at the single vessel level, we detected stereotypical vascular dynamics approximately 30 seconds prior to the onset of seizures in freely behaving mice, as well as before seizure termination. These events consisted of robust and sustained vasoconstriction of individual pial arteries, which have the potential to serve as a biomarker for seizure prediction. We hypothesize that these vasoconstrictive events act as a protective mechanism to restrict blood flow to neurons involved in hypersynchrony and tamper their activity. We have developed tools to selectively manipulate neuronal or vascular dynamics in mice undergoing seizures in order to determine to what extent decreasing cerebrovascular perfusion can prevent a seizure onset or terminate an ongoing seizure. Additionally, after focal neocortical lesions, such as a stroke and traumatic brain injury, we found a significant secondary structural remodeling of the cortical and thalamic vascular network during the latent phase preceding the chronic epilepsy. We hypothesize that this secondary vascular remodeling may negatively affect neurovascular dynamics and disrupt the protective role of the neurovascular unit leading to enhanced seizure susceptibility.  Conclusions: The cerebrovasculature and its behavior at the single vessel level is an understudied area in the epilepsy field. By understanding the neurovascular dynamics during seizures, we may be able to better predict and potentially prevent seizure progression. Understanding neurovascular dynamics during epileptogenesis may lead to novel disease-modifying strategies.  Funding: NIH R01 NS096369 (Paz, PI) 04/01/16–03/31/21The role of inflammation in post-stroke epileptogenesisW81XWH-16-1-0576 (Paz, PI) 09/30/16–09/29/19Department of DefenseDeconstruction and Control of Neural Circuits in Post-traumatic Epilepsy
Basic Mechanisms