Temporally Targeted Interactions With Pathologic Oscillations as Therapeutical Targets in Epilepsy and Beyond.

Self-organized neuronal oscillations rely on precisely orchestrated ensemble activity in reverberating neuronal networks. Chronic, non-malignant disorders of the brain are often coupled to pathological neuronal activity patterns. In addition to the characteristic behavioral symptoms, these disturbances are giving rise to both transient and persistent changes of various brain rhythms. Increasing evidence support the causal role of these "oscillopathies" in the phenotypic emergence of the disease symptoms, identifying neuronal network oscillations as potential therapeutic targets. While the kinetics of pharmacological therapy is not suitable to compensate the disease related fine-scale disturbances of network oscillations, external biophysical modalities (e.g., electrical stimulation) can alter spike timing in a temporally precise manner. These perturbations can warp rhythmic oscillatory patterns via resonance or entrainment. Properly timed phasic stimuli can even switch between the stable states of networks acting as multistable oscillators, substantially changing the emergent oscillatory patterns. Novel transcranial electric stimulation (TES) approaches offer more reliable neuronal control by allowing higher intensities with tolerable side-effect profiles. This precise temporal steerability combined with the non- or minimally invasive nature of these novel TES interventions make them promising therapeutic candidates for functional disorders of the brain. Here we review the key experimental findings and theoretical background concerning various pathological aspects of neuronal network activity leading to the generation of epileptic seizures. The conceptual and practical state of the art of temporally targeted brain stimulation is discussed focusing on the prevention and early termination of epileptic seizures.