Single-pulse stimulation of cerebellar nuclei stops epileptic thalamic activity

Oscar H.J. Eelkman Rooda, Lieke Kros, Sade J. Faneyte, P.J. Holland, Simona V. Gornati, Huub J. Poelman, Nico A. Jansen, Else A. Tolner, Arn M.J.M. van den Maagdenberg, C.I. De Zeeuw, Freek E. Hoebeek*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

13 Citations (Scopus)

Abstract

Background: Epileptic (absence) seizures in the cerebral cortex can be stopped by pharmacological and optogenetic stimulation of the cerebellar nuclei (CN) neurons that innervate the thalamus. However, it is unclear how such stimulation can modify underlying thalamo-cortical oscillations. Hypothesis: Here we tested whether rhythmic synchronized thalamo-cortical activity during absence seizures can be desynchronized by single-pulse optogenetic stimulation of CN neurons to stop seizure activity. Methods: We performed simultaneous thalamic single-cell and electrocorticographical recordings in awake tottering mice, a genetic model of absence epilepsy, to investigate the rhythmicity and synchronicity. Furthermore, we tested interictally the impact of single-pulse optogenetic CN stimulation on thalamic and cortical recordings. Results: We show that thalamic firing is highly rhythmic and synchronized with cortical spike-and-wave discharges during absence seizures and that this phase-locked activity can be desynchronized upon single-pulse optogenetic stimulation of CN neurons. Notably, this stimulation of CN neurons was more effective in stopping seizures than direct, focal stimulation of groups of afferents innervating the thalamus. During interictal periods, CN stimulation evoked reliable but heterogeneous responses in thalamic cells in that they could show an increase or decrease in firing rate at various latencies, bi-phasic responses with an initial excitatory and subsequent inhibitory response, or no response at all. Conclusion: Our data indicate that stimulation of CN neurons and their fibers in thalamus evokes differential effects in its downstream pathways and desynchronizes phase-locked thalamic neuronal firing during seizures, revealing a neurobiological mechanism that may explain how cerebellar stimulation can stop seizures.

Original languageEnglish
Pages (from-to)861-872
Number of pages12
JournalBrain Stimulation
Volume14
Issue number4
DOIs
Publication statusPublished - 1 Jul 2021

Bibliographical note

Funding Information:
This research was supported by funding from ERC-Adv , ERC-PoC to C.I.D.Z., NWO-Veni and Erasmus MC fellowship to L.K., various ZonMw and NWO-ALW grants to A.M.J.M.v.d.M., C.I.D.Z. and F.E.H, FP7 “EUROHEADPAIN” to A.M.J.M.v.d.M. and EU IAPP “BRAINPATH” to A.M.J.M.v.d.M. and E.A.T., EU Marie Curie Career Integration Grant to E.A.T. and the Dutch National Epilepsy Foundation to A.M.J.M.v.d.M. and E.A.T. L.K., E.A.T., A.M.J.M.V.D.M, C.I.D.Z. and F.E.H. are supported by the national medical delta (‘Medical Neurodelta)’ scientific program , and finally C.I.D.Z. and L.K. are supported by the Crossover LSH-NWO grant INTENSE. F.E.H. is supported by the C.J. Vaillant Fund .

Publisher Copyright:
© 2021 The Author(s)

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