Stop lights for temporal lobe seizures

Unlike electrical stimulation, optogenetics allows neuronal manipulation with great cell-type specificity, with light directly affecting only those cells expressing opsins. In a recent report in Nature Communications, Krook-Magnuson et al harnessed this specificity to stop seizures in vivo in a mouse model of temporal lobe epilepsy. Mice were implanted with electrodes to record brain activity and 200µm thick optical fibers to deliver light to the brain. A closed-loop, on-demand responsive system detected seizures in real time, allowing temporal specificity, in addition to the cell-type specificity achieved through selective opsin expression. Specifically, the authors either selectively inhibited excitatory principal cells or, alternatively, excited a subpopulation of GABAergic inhibitory neurons in the hippocampus by delivering light at the time of a seizure. Both approaches proved successful, despite the less than 5% of illuminated neurons expressing opsins in the latter approach. Light arrested ongoing electrical seizure activity and reduced the incidence of events progressing to overt behavioral seizures.

EEG input (blue) from the mouse hippocampus is amplified (Amp), digitized (A/D) and relayed to a PC running a custom-designed real-time seizure detection software. The signal is fed into a number of possible detection algorithms, which utilize features of signal power, spikes or frequency (sample schematics are presented here; detailed methodology is provided in Supplementary Methods). Thresholds for power and spike properties (green) are determined using tunable leaky integrators acting as low-pass filters. Top: Amplitude Correlation (purple, during an example seizure, shown in grey); Middle: spike characteristics (for example, amplitude, rate, regularity and spike width, shown in red); Bottom: power of the signal in specific frequency bands during the same seizure, with warmer colours representing higher energy. Once a seizure has been detected using the selected criteria, for 50% of the events in a random fashion (RND), the software activates the optical output (orange) delivered to the hippocampus of the mouse, via a TTL signal from the digitizer to the laser. All trigger events, however, are flagged for later off-line analysis. COMP, digital comparator. USB, universal serial bus.

EEG input (blue) from the mouse hippocampus is amplified (Amp), digitized (A/D) and relayed to a PC running a custom-designed real-time seizure detection software. The signal is fed into a number of possible detection algorithms, which utilize features of signal power, spikes or frequency (sample schematics are presented here; detailed methodology is provided in Supplementary Methods). Thresholds for power and spike properties (green) are determined using tunable leaky integrators acting as low-pass filters. Top: Amplitude Correlation (purple, during an example seizure, shown in grey); Middle: spike characteristics (for example, amplitude, rate, regularity and spike width, shown in red); Bottom: power of the signal in specific frequency bands during the same seizure, with warmer colours representing higher energy. Once a seizure has been detected using the selected criteria, for 50% of the events in a random fashion (RND), the software activates the optical output (orange) delivered to the hippocampus of the mouse, via a TTL signal from the digitizer to the laser. All trigger events, however, are flagged for later off-line analysis. COMP, digital comparator. USB, universal serial bus. From Krook-Magnuson et al, 2013.

Epilepsy, a condition of recurrent, spontaneous seizures, is a prevalent disorder, with 1 out of 26 people developing epilepsy during their lifetime. Unfortunately, for over 40% of patients, seizures cannot be controlled with current treatment options. Temporal lobe epilepsy, the most common form of epilepsy in adults, is often pharmacoresistant, and current systemic treatments have major side-effects. By demonstrating the successful use of optogenetics in a mouse model of temporal lobe epilepsy, Krook-Magnuson et al highlight the potential of an intervention for this devastating disease which would directly affect only a minimum number of cells, and only at the time of seizures.

(a) Crossing CamK-Cre and Cre-dependent HR mouse lines generated mice expressing the inhibitory opsin HR in excitatory cells (Cam-HR mice). (b) Experimental timeline. (c–e) Example electrographic seizures detected (vertical green bars), activating amber light (589 nm) randomly for 50% of events (light: amber line, example in d; no-light example in e). (f) Typical example distribution of postdetection seizure durations (5 s bin size) during light (solid amber) and no-light internal control conditions (hashed grey). Inset: first 5 s bin expanded, 1 s bin size. Note that most seizures stop within 1 s of light delivery. (g–i) Group Cam-HR data showing the per cent of seizures stopping within 5 s of detection (g), within 1 s of detection (h), and the average postdetection seizure duration (normalized to average no-light postdetection duration for each animal) (i). Note that in one animal (shown in c–e), all seizures were stopped within 1 s of light delivery. Averaged data: filled circles. Error bars represent s.e.m. Scale bars in c–e, 100 μV, 5 s.

(a) Crossing CamK-Cre and Cre-dependent HR mouse lines generated mice expressing the inhibitory opsin HR in excitatory cells (Cam-HR mice). (b) Experimental timeline. (c–e) Example electrographic seizures detected (vertical green bars), activating amber light (589 nm) randomly for 50% of events (light: amber line, example in d; no-light example in e). (f) Typical example distribution of postdetection seizure durations (5 s bin size) during light (solid amber) and no-light internal control conditions (hashed grey). Inset: first 5 s bin expanded, 1 s bin size. Note that most seizures stop within 1 s of light delivery. (g–i) Group Cam-HR data showing the per cent of seizures stopping within 5 s of detection (g), within 1 s of detection (h), and the average postdetection seizure duration (normalized to average no-light postdetection duration for each animal) (i). Note that in one animal (shown in c–e), all seizures were stopped within 1 s of light delivery. Averaged data: filled circles. Error bars represent s.e.m. Scale bars in c–e, 100 μV, 5 s. From Krook-Magnuson et al, 2013.

Previous work in other laboratories further supports the use of these techniques in the treatment of epilepsy. Responsive electrical stimulation devices for the treatment of epilepsy are in clinical trials (Morrell 2011), and recent reports have used optogenetics to stop seizure activity both in vitro (Tonnesen et al 2009) as well as in other models of epilepsy in vivo (Wykes et al, 2012; Paz et al, 2013). Taken together, these findings suggest that we may one day be able to use optogenetic stop lights for the treatment of epilepsy.

This entry was posted in Journal Club, News and tagged , , , , . Bookmark the permalink.
Add Comment Register



Leave a Reply