Epilepsy, a disorder of recurrent, spontaneous seizures actually comprises a number of distinct clinical disease entities, each with different phenotypes, underlying mechanisms, involved brain structures and prognoses1
. In part because of their unpredictable nature, seizures can dramatically interfere with the daily lives of patients. This same feature poses an obvious challenge to the development of ideal therapeutic strategies that act only on an ‘as-needed’ basis, which would avoid disrupting normal interictal behaviours and reduce the frequently debilitating negative side-effects of currently available medications.
Epilepsies are often categorized as being either generalized or partial. In generalized epilepsies such as absence epilepsy, seizures begin with an immediate change in level of consciousness, and electroencephalography (EEG) abnormalities appear across widespread brain areas simultaneously. In partial epilepsies such as temporal lobe epilepsy (TLE), however, early seizure activity appears in a restricted region and may or may not progress to involve the entire brain or affect level of consciousness2
. This feature of TLE is clinically significant because it provides a theoretical time window for intervention between electrographic seizure onset and the onset of altered mental status. Thus, it is hypothetically possible to implement a temporally restricted therapeutic strategy for TLE and other partial epilepsies during early ictal activity, which could prevent consciousness-altering seizure progression without disrupting brain function during interictal time periods. While there is currently no Food and Drug Administration-approved on-demand treatment for epilepsy, clinical trials using closed-loop electrical stimulation have shown promise3
Optogenetic techniques provide immediate, temporary control of specific cell populations using light-sensitive opsins4
, making them ideal candidates for on-demand seizure control. Indeed, in vitro
and in vivo
studies support the use of optogenetics to control seizure activity7
. However, temporal specificity in epilepsy treatment additionally requires an accurate, fast method of detecting and responding to unpredictable seizures. This poses an additional challenge for on-demand treatment for TLE, because unlike in thalamocortical epilepsy, the electrographic appearance of seizures varies considerably between individuals. Additionally, the presence of interictal spiking makes rapid and selective detection of ictal events more challenging.
We developed a novel, tunable closed-loop seizure-detection programme to identify and rapidly respond to seizures. Seizures were detected in real-time, triggering light delivery which was randomized, such that 50% of events received light and 50% served as no-light internal controls. When inhibitory opsins were expressed in excitatory principal cells, light application rapidly stopped seizures. Moreover, seizure control was also achieved when excitatory opsins were selectively expressed only in a subpopulation of inhibitory cells, which make up <5% of neurons in the hippocampus10
. These results demonstrate that spontaneous temporal lobe seizures can be detected and stopped even by directly affecting only specific cell populations in a spatially restricted manner. The insight obtained from exploring seizure cessation by on-demand optogenetics provides an approach, based on direct modulation of a minimum number of cells and only at the time of a seizure, for the development of less disruptive interventions than are currently available for treating TLE.