Brain Stimulation for Epilepsy: Of Mice and Man

Commentary Berényi et al. describe an experiment in which transcranial stimulation is applied in a rodent model with spontaneously occurring generalized spike-wave (SW) discharges. Stimulation electrodes were placed over thinned skull bitemporally. Multiunit and field potentials were recorded via tripolar electrodes in the frontal and parietal cortex. Initially, sinusoidal stimulation was delivered independent of spontaneous spike-wave activity in an ON–OFF mode at 1 Hz. Multi-unit neuronal activity was modulated with stimulation regardless of whether SW discharges occurred or not. With this stimulation paradigm, the amplitude of the spikes was altered but not the duration of the SW discharges. The stimulation configuration with the highest modulation index of multi-unit activity was chosen for closed-loop (responsive) stimulation. Responsive stimulation was triggered by the spike component of the discharge as detected by a combined measure of current source density. A Gaussian 50-millisecond stimulus was applied after every detected spike. This stimulation paradigm resulted in significant reduction in the duration of SW discharges and the overall percentage of time spent in SW activity. The therapeutic effect on SW activity was dependent on the size of the voltage gradient applied. What can we learn or deduct from this experiment and translate to human epilepsy? Electrical brain stimulation has evolved into a new treatment venue for intractable epilepsy (1–3). There are systems that stimulate in an ON-OFF mode in the anterior nucleus of the thalamus or hippocampus (2, 4) and systems that deliver responsive stimulation triggered by seizures or epileptiform activity occurring in the seizure onset zone (3, 5). Both systems have already proven to be effective in human focal epilepsy (2, 3). The above study provides evidence that electrical stimulation in some form modulates multi-unit activity. This is reassuring and confirms that neuromodulation is achieved with stimulation. However, in the rodent, SW activity was only reduced with closed-loop stimulation. The authors conclude that the stimulation has to be timed to the underlying rhythm. They hypothesize that the reverberation of the thalamo-cortical loop can be suppressed by cortical excitation during the wave period of the SW activity. Cortical excitation “quenches” more or less the reverberating loop. The authors try to confirm this with another experiment embedded into the study utilizing optogenetic suppression of cortical circuits in mice (Figure S6). One could conclude that the use of responsive systems is of greater advantage than mere ON-OFF stimulation independent of the underlying rhythm. However, this conclusion is not valid if directly translated into human use. Human systems with ONOFF stimulation are not delivering stimuli at the cortex but in the deeper structures of the brain and may affect the thalamocortical circuits in a different way. Another significant difference to the animal study is that ON-OFF stimulation was delivered at 1 Hz, while in humans, higher frequency stimulation is applied. All systems for brain stimulation in humans have been studied in focal epilepsy, not for generalized epilepsy with spike-wave discharges. Focal seizures frequently do not have an SW pattern. Stimulating non–spike-wave seizure patterns may not be as effective if approached in the same way as the study by Berényi et al. Stimulation in the animal persisted as long as SW persisted. Systems in humans are limited to a certain number of stimuli if used in a responsive mode (3). Furthermore, SW discharges in the rodent are well defined and easier to detect by composite measures than epileptiform activity in humans. Epileptiform activity in humans is frequently heterogeneous, variable, and specific to the patient (6). Reliable detection requires intracranial recordings (3, 7). Automated systems that reliably detect scalp epileptiform activity have not been overly successful and are still not considered reliable by clinicians (7). Closed-Loop Control of Epilepsy by Transcranial Electrical Stimulation.