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

Nature Neuroscience volume 16, pages 6470 (2013) | Download Citation

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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References

  1. 1.

    , , , & Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke. Nature 468, 305–309 (2010).

  2. 2.

    & Epilepsy after stroke. Epilepsia 33, 495–498 (1992).

  3. 3.

    Animal modeling of poststroke seizures and epilepsy: 5-year update. Epilepsy Curr. 7, 159–162 (2007).

  4. 4.

    et al. Seizures in childhood ischemic stroke in Taiwan. Brain Dev. 31, 294–299 (2009).

  5. 5.

    & Early identification of refractory epilepsy. N. Engl. J. Med. 342, 314–319 (2000).

  6. 6.

    Pathologic processes in the elderly and their association with seizures. in Seizures and Epilepsy in the Elderly (eds. Rowan, A.J. & Ramsay, E.) 63–85 (Butterworth-Heinemann, 1997).

  7. 7.

    , & Chronic neocortical epileptogenesis in vitro. J. Neurophysiol. 71, 1762–1773 (1994).

  8. 8.

    & Basic mechanisms of epileptic discharges in the thalamus. in The Thalamus: Experimental and Clinical Aspects (eds. Steriade, M., Jones, E.G. & McCormick, D.) 295–330 (Elsevier, 1997).

  9. 9.

    , , , & Regional hypometabolism in an acute model of focal epileptic activity in the rat. Eur. J. Neurosci. 7, 192–197 (1995).

  10. 10.

    , , & Coupling of cortical and thalamic ictal activity in human partial epilepsy: demonstration by functional magnetic resonance imaging. Epilepsia 37, 657–661 (1996).

  11. 11.

    , , , & Coupling of cortical and thalamic metabolism in experimentally induced visual and somatosensory focal epilepsy. Epilepsy Res. 27, 127–137 (1997).

  12. 12.

    , & Interictal afterdischarge in focal penicillin epilepsy: block by thalamic cooling. Exp. Neurol. 88, 349–359 (1985).

  13. 13.

    & Suppression of motor seizures after specific thalamotomy in chronic epileptic monkeys. Epilepsy Res. 5, 137–145 (1990).

  14. 14.

    & Optogenetic investigation of neural circuits underlying brain disease in animal models. Nat. Rev. Neurosci. 13, 251–266 (2012).

  15. 15.

    et al. A new mode of corticothalamic transmission revealed in the Gria4−/− model of absence epilepsy. Nat. Neurosci. 14, 1167–1173 (2011).

  16. 16.

    , , , & Optogenetic control of epileptiform activity. Proc. Natl. Acad. Sci. USA 106, 12162–12167 (2009).

  17. 17.

    et al. Photothrombotic brain infarction results in seizure activity in aging Fischer 344 and Sprague Dawley rats. Epilepsy Res. 47, 189–203 (2001).

  18. 18.

    , , & Electrobehavioral characteristics of epileptic rats following photothrombotic brain infarction. Epilepsy Res. 56, 185–203 (2003).

  19. 19.

    , , , & Focal cortical infarcts alter intrinsic excitability and synaptic excitation in the reticular thalamic nucleus. J. Neurosci. 30, 5465–5479 (2010).

  20. 20.

    , & HCN channelopathies: pathophysiology in genetic epilepsy and therapeutic implications. Br. J. Pharmacol. 165, 49–56 (2012).

  21. 21.

    & Intrathalamic rhythmicity studied in vitro: nominal T-current modulation causes robust antioscillatory effects. J. Neurosci. 14, 5485–5502 (1994).

  22. 22.

    , , & A gain in GABAA receptor synaptic strength in thalamus reduces oscillatory activity and absence seizures. Proc. Natl. Acad. Sci. USA 106, 7630–7635 (2009).

  23. 23.

    , , & Maintenance of thalamic epileptiform activity depends on the astrocytic glutamate-glutamine cycle. J. Neurophysiol. 102, 2880–2888 (2009).

  24. 24.

    et al. Epileptogenesis after cortical photothrombotic brain lesion in rats. Neuroscience 148, 314–324 (2007).

  25. 25.

    et al. Molecular and cellular approaches for diversifying and extending optogenetics. Cell 141, 154–165 (2010).

  26. 26.

    et al. Neocortical excitation/inhibition balance in information processing and social dysfunction. Nature 477, 171–178 (2011).

  27. 27.

    , , , & Line length: an efficient feature for seizure onset detection. Eng. Med. Biol. Soc. Proc. 23rd Ann. Int. Conf. IEEE 2, 1707–1710 (2001).

  28. 28.

    & A versatile means of intracellular labeling: injection of biocytin and its detection with avidin conjugates. J. Neurosci. Methods 25, 1–11 (1988).

  29. 29.

    , & Double-labelling with rhodamine beads and biocytin: a technique for studying corticospinal and other projection neurons in vitro. J. Neurosci. Methods 37, 121–131 (1991).

  30. 30.

    & Properties of a hyperpolarization-activated cation current and its role in rhythmic oscillation in thalamic relay neurones. J. Physiol. (Lond.) 431, 291–318 (1990).

  31. 31.

    & A practical guide to wavelet analysis. Bull. Am. Meteorol. Soc. 79, 61–78 (1997).

  32. 32.

    Multiple dynamical modes of thalamic relay neurons: rhythmic bursting and intermittent phase-locking. Neuroscience 59, 21–31 (1994).

  33. 33.

    & Simulation of the currents involved in rhythmic oscillations in thalamic relay neurons. J. Neurophysiol. 68, 1373–1383 (1992).

  34. 34.

    & Variability, compensation and homeostasis in neuron and network function. Nat. Rev. Neurosci. 7, 563–574 (2006).

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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.

Author information

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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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.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Jeanne T Paz or John R Huguenard.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–9 and Supplementary Table 1

Videos

  1. 1.

    Supplementary Movie 1

    Synchronized multiunit bursts in thalamus during seizures

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    Supplementary Movie 2

    Real-time detection of seizures I

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    Supplementary Movie 3

    Real-time detection of seizures II

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    Supplementary Movie 4

    Manually triggered optogenetic interruption of seizures

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    Supplementary Movie 5

    Yellow light thalamic illumination does not affect sleep

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    Supplementary Movie 6

    Real-time detection and optogenetic interruption of seizures I

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    Supplementary Movie 7

    Real-time detection and optogenetic interruption of seizures II

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DOI

https://doi.org/10.1038/nn.3269

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