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Closed-loop optogenetic control of thalamus as a tool for interrupting seizures after cortical injury

Nature Neuroscience volume 16, pages 64–70 (2013)Cite this article

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Abstract

Cerebrocortical injuries such as stroke are a major source of disability. Maladaptive consequences can result from post-injury local reorganization of cortical circuits. For example, epilepsy is a common sequela of cortical stroke, but the mechanisms responsible for seizures following cortical injuries remain unknown. In addition to local reorganization, long-range, extra-cortical connections might be critical for seizure maintenance. In rats, we found that the thalamus, a structure that is remote from, but connected to, the injured cortex, was required to maintain cortical seizures. Thalamocortical neurons connected to the injured epileptic cortex underwent changes in HCN channel expression and became hyperexcitable. Targeting these neurons with a closed-loop optogenetic strategy revealed that reducing their activity in real-time was sufficient to immediately interrupt electrographic and behavioral seizures. This approach is of therapeutic interest for intractable epilepsy, as it spares cortical function between seizures, in contrast with existing treatments, such as surgical lesioning or drugs.

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Figure 1: Cortical stroke results in enhanced intrinsic excitability in thalamocortical neurons.
Figure 2: Cortical stroke alters biophysical properties of Ih in thalamocortical neurons.
Figure 3: Intra-thalamic network is hyperexcitable and generates epileptiform oscillations in injured animals and in a model.
Figure 4: Cortical stroke leads to late spontaneous epileptic activities in cortex and thalamus.
Figure 5: Selective optical inhibition of thalamocortical neurons interrupts ongoing epileptic seizures in awake, freely behaving animals.
Figure 6: Multiunit firing of thalamocortical neurons in awake, freely behaving animals.
Figure 7: Online detection and interruption of seizures via a 594-nm light illumination of thalamus in freely behaving animals.
Figure 8: Line-length calculation for real-time detection of seizures.

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Acknowledgements

We thank C. Pisaturo for designing and fabricating custom electronics, A. Herbert and S. Jin for their help with animal husbandry, and K. Graber and D. Prince for discussions related to clinical aspects of post-stroke epilepsy. J.T.P. is supported by the US National Institute of Neurological Disorders and Stroke (grant K99NS078118-01) and the Epilepsy Foundation. J.R.H. is supported by grants from the US National Institute of Neurological Disorders and Stroke (5R01NS006477 and 5R01NS034774). T.J.D. is supported by a Berry Foundation Postdoctoral fellowship. K.D. is supported by the Howard Hughes Medical Institute, the California Institute for Regenerative Medicine, the US National Institutes of Health and the Defence Advanced Research Projects Agency (DARPA) Reorganization and Plasticity to Accelerate Injury Recovery (REPAIR) Program. E.S.F. is supported by a Epilepsy Foundation Postdoctoral Fellowship.

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Authors and Affiliations

  1. Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA

    Jeanne T Paz, Eric S Frechette, Isabel Parada, Kathy Peng & John R Huguenard

  2. Department of Bioengineering, Stanford University School of Medicine, Stanford, California, USA

    Thomas J Davidson & Karl Deisseroth

  3. Institut des Systèmes Intelligents et de Robotique, Centre National de Recherche Scientifique, Unité Mixte de Recherche 7222, Université Pierre et Marie Curie, Paris, France

    Bruno Delord

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  1. Jeanne T Paz
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Contributions

J.T.P. and J.R.H. designed the experiments and wrote the manuscript. J.T.P. performed all of the in vitro experiments. J.T.P. and T.J.D. designed and performed the in vivo experiments. B.D. performed computational modeling. K.P. performed pilot EEG recordings. I.P. performed histology. J.T.P., J.R.H. and E.S.F. analyzed data. K.D. provided reagents and tools.

Corresponding authors

Correspondence to Jeanne T Paz or John R Huguenard.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–9 and Supplementary Table 1 (PDF 5764 kb)

Supplementary Movie 1

Synchronized multiunit bursts in thalamus during seizures (MP4 6502 kb)

Supplementary Movie 2

Real-time detection of seizures I (MP4 10064 kb)

Supplementary Movie 3

Real-time detection of seizures II (MP4 17429 kb)

Supplementary Movie 4

Manually triggered optogenetic interruption of seizures (MP4 7631 kb)

Supplementary Movie 5

Yellow light thalamic illumination does not affect sleep (MP4 3215 kb)

Supplementary Movie 6

Real-time detection and optogenetic interruption of seizures I (MP4 3249 kb)

Supplementary Movie 7

Real-time detection and optogenetic interruption of seizures II (MP4 9294 kb)

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Paz, J., Davidson, T., Frechette, E. et al. Closed-loop optogenetic control of thalamus as a tool for interrupting seizures after cortical injury. Nat Neurosci 16, 64–70 (2013). https://doi.org/10.1038/nn.3269

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