Authors :
First Author: Ryan Jamiolkowski, MD PhD – Stanford
Presenting Author: Quynh Anh Nguyen, PhD – Stanford University
Quynh Anh Nguyen, PhD – Instructor, Neurosurgery, Stanford; Jordan Farrell, PhD – Instructor, Neurosurgery, Stanford; Ryan McGinn, MD – Epilepsy Fellow, Neurology, Stanford; Jeff Nirschl, MD PhD – Neuropathology Fellow, Pathology, Stanford; Alice Ting, PhD – Professor, Genetics, Stanford; Vivek Buch, MD – Assistant Professor, Neurosurgery, Stanford; Ivan Soltesz, PhD – Professor, Neurosurgery, Stanford
Rationale:
The posterior-medial tail of the hippocampus is not thought to be a significant seizure source and is rarely a target in temporal lobe epilepsy (TLE) surgery. However, stereo electroencephalograpy (sEEG) identified it as the source of recurrence in a patient who had previously undergone mesial temporal laser interstitial thermal ablation, and it was also a site of high frequency oscillations in five other TLE patients prior to surgical intervention. That part of the hippocampal tail contains the fasciola cinereum (FC), an under-studied subfield. Based on these clinical observations, we used the intrahippocampal kainate mouse model of temporal lobe epilepsy (TLE) to investigate the FC’s role in epilepsy and determine if it is a therapeutic target.
Methods:
1) A light and Ca2+-dependent molecular integrator was used to identify seizure-active neurons in freely-behaving mice. Using this tool, a fluorescent reporter is expressed only in cells that have high Ca2+ (consistent with rapid firing) when light is delivered via optical fiber (timed to occur during seizures via closed-loop system).
2) 2-photon calcium imaging through an implanted gradient index (GRIN) lens recorded individual neuron activity, while a wire electrode recorded LFP.
3) An inhibitory opsin was expressed in the FC for closed-loop seizure intervention; an optical fiber delivered light to the FC at the start of half of randomly chosen seizure events.
Results:
1) The light and Ca2+-dependent molecular integrator prominently labeled cells in the FC suggesting they are highly active during seizures.
2) Ca2+-imaging of FC neurons showed dramatically increased firing during ictal/inter-ictal spikes, as well as overall increased activity when a seizure starts and decreased activity once a seizure concludes.
3) Closed-loop optogenetic inhibition of FC neurons suppressed seizures in chronically epileptic mice.
4) Repeat ablation of the initial patient’s residual hippocampal tail containing the FC reduced seizure frequency and severity.
Conclusions:
The FC is a major (and intervenable) seizure focus in both mice and human. These human and mouse findings together demonstrate that the FC may be an important source of seizure recurrence for many of the 30-40% of patients with inadequate seizure control after surgery for temporal lobe epilepsy.
Funding:
NIH R25 NS065741, MCHRI Tashia and John Morgridge Endowed Postdoctoral Fellowship to RJ, NIH K99NS121399 to QAN, NIH K99NS126725 to JF, NIH R01MH119353, Chan Zuckerberg Biohub, Beckman Technology Development Seed Grant to AT, NIH 1U19NS104590 to IS