Brain stimulation treatments in epilepsy: Basic mechanisms and clinical advances

Abstract

Drug-resistant epilepsy, characterized by ongoing seizures despite appropriate trials of anti-seizure medications, affects approximately one-third of people with epilepsy. Brain stimulation has recently become available as an alternative treatment option to reduce symptomatic seizures in short and long-term follow-up studies. Several questions remain on how to optimally develop patient-specific treatments and manage therapy over the long term. This review aims to discuss the clinical use and mechanisms of action of Responsive Neural Stimulation and Deep Brain Stimulation in the treatment of epilepsy and highlight recent advances that may both improve outcomes and present new challenges. Finally, a rational approach to device selection is presented based on current mechanistic understanding, clinical evidence, and device features.

Keywords: Deep brain stimulation; Epilepsy; Neurostimulation; Responsive neural stimulation; Seizure.

Fig. 1

Neurostimulation overview. (A) The stimulation waveform is primarily defined by the amplitude of stimulation (μA-mA), stimulation pulse width (μs-ms), burst duration (ms-s), stimulation frequency (Hz), and burst frequency (<1 Hz) (B) Open-loop stimulation devices (e.g., Deep Brain Stimulation). Deliver continuous periodic stimulation (I_stim) to the brain (C) Closed-loop stimulation devices (e.g., Responsive Neural Stimulation). Deliver stimulation only when seizure activity is detected from the recorded EEG signal (V_eeg).

Fig. 2

Representation of chronic effects of neurostimulation (A) In established epilepsy, seizure suppression (shaded region) temporarily reduces the probability of seizures, with no permanent effect on disease state of epilepsy. (B) In established epilepsy, disease modification (shaded region) results in permanent reduction in seizure frequency, ideally resulting in seizure freedom or “cure”, even after stimulation is stopped. The black bar represent the time period of stimulation.

Fig. 3

Representation of acute seizure-termination effects of neurostimulation. In this simulated EEG tracing, seizure activity is interrupted by a brief pulse of electrical neurostimulation.

Fig. 4

Schematic representation of stimulation fields from conventional and directional electrodes. (A) A single active symmetric ring contact (red) creates a roughly spherical volume of modulated tissue (green sphere), as seen from oblique (left) and axial (right) directions. (B) A single active directional contact creates an asymmetric volume of modulated tissue (green), as seen from oblique (left) and axial (right) directions, which could be designed to avoid brain regions associated with undesirable side effects.

Fig. 5

A proposed clinical approach to neuromodulation selection. Highly localized focal epilepsy arising from 1 to 2 foci are preferentially treated with RNS to benefit from continuous monitoring. ANT DBS is an approved alternative. Hippocampal DBS for temporal lobe epilepsy is a reasonable alternative. Multifocal (3+ foci) or poorly-localized focal epilepsy are preferentially treated with ANT DBS, though regional RNS is a reasonable alternative. Brain stimulation is not currently approved for generalized epilepsies, though CMN stimulation is reasonable based on recent studies. ANT: Anterior nucleus of the thalamus. CM: Centro-median nucleus of the thalamus. DBS: Deep Brain Stimulation. HC: Hippocampus. RNS: Responsive Neurostimulation. US FDA approved indications are in bold. Off-label investigational treatments are in italics.