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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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.
Synchronized multiunit bursts in thalamus during seizures
Real-time detection of seizures I
Real-time detection of seizures II
Manually triggered optogenetic interruption of seizures
Yellow light thalamic illumination does not affect sleep
Real-time detection and optogenetic interruption of seizures I
Real-time detection and optogenetic interruption of seizures II
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