Should stimulation parameters be individualized to stop seizures: Evidence in support of this approach

Abstract

Objective: Deep-brain electrical stimulation (DBS) is a treatment modality being explored for many neurologic diseases and is a potentially potent means of disrupting the aberrant rhythms that arise during the epileptic seizures that afflict >1% of the population. However, current DBS protocols typically employed are formulated a priori and do not reflect the electrophysiologic dynamics within the brain as seizures arise, which may underlie their limited efficacy. This study investigates how the efficacy of DBS could be improved using endogenous dynamics to inform stimulation protocols.

Methods: Multisite brain dynamics within the circuit of Papez were calculated in a chronic rat limbic epilepsy model induced via lithium chloride/pilocarpine intraperitoneal injections. Stimulation/recording electrodes were placed in the CA3 region of the left and right hippocampi and the anteromedial nucleus of the left thalamus. Deconvolution of local field potentials using empirical mode decomposition (EMD) and phase synchrony analysis revealed multisite coherence as seizures approached natural termination that could not be detected with Fourier analysis. Multisite stimulation used charge-neutral biphasic square waves at frequencies observed during natural termination.

Results: Synchronization of electrical activity across sites occurred as both spontaneous and evoked seizures naturally terminated. Furthermore, the location and frequency of the synchrony varied between subjects but was stable in time within each animal. DBS protocols were significantly more effective at rapidly stopping seizures when the frequency and location of multisite stimulation reflected the endogenous synchrony dynamics observed in each subject as seizures naturally terminated.

Significance: These results strongly support the approach of tailoring DBS protocols to individual endogenous rhythms that may represent how brains naturally resolve epileptic seizures. This approach may significantly improve the overall efficacy of this potentially important therapy.

Keywords: Chronic epilepsy; Deep brain stimulation; Empirical mode decomposition; Rat; Temporal lobe.

Figure 1.

Endogenous synchrony dynamics within circuit of Papez during temporal lobe seizures. (A) LFPs and corresponding Teager energy (TE) recorded in a rat from both hippocampi and left thalamus during a spontaneous seizure. Red bars indicate period of seizure activity. (B) In three different rats, LFP is plotted during evoked seizures and, below, the time, location, and frequency of synchronized activity. Red arrows mark the end of each seizure.

Figure 2.

Therapeutic stimulation at target frequencies observed by synchrony analysis terminates evoked seizures faster than stimulation at non-target frequencies. The time course of LFPs during evoked seizures in four rats (one animal per row) stimulated at either target (left) or nontarget (right) frequencies. Horizontal bars indicate evoked (green) and therapeutic (red) stimulations. End of each seizure indicated with red arrow.

Figure 3.

Summary of responses to therapeutic DBS as a function of stimulation frequency during temporal lobe seizures. Seizure duration PS (poststimulation; i.e., after therapeutic stimulation ends) and DBS efficacy after 10 s therapeutic stimulation at target (circled) and nontarget frequencies in nine different rats. Means with standard error of the mean (SEM) bars; n shown in histogram bar. Brackets compare significant differences (*p < 0.05; **p < 0.01; ANOVA followed by Holm-Sidak or Student-Newman-Keuls test). (A) Effects of therapeutic stimulation shown for five rats with low target frequencies (<30 Hz) and (B) effects of therapeutic stimulation for four rats with high target frequencies (>100 Hz) Circled inset shows the relationship of efficacy to relative seizure duration following therapeutic stimulation (TS) to duration under no stimulation (NS).

Figure 4.

Endogenous synchrony dynamics and frequency-sensitivity of therapeutic stimulation are similar in spontaneous versus evoked seizures. Left, spontaneous and right, evoked seizures in the same animal. (A) Time course of LFP during a seizure and the corresponding sites and frequencies of synchrony during natural termination. Target frequency was 7 Hz for both seizure induction methods. (B) Seizure duration and (C) efficacy following therapeutic stimulation at target (circled) and nontarget frequencies. Means with SEM bars; n shown in each histogram group. Brackets compare significant differences (*p < 0.05; **p < 0.01; ANOVA followed by Holm-Sidak or Student-Newman-Keuls test).

Figure 5.

Fourier-derived spectrograms in rats with different endogenous termination dynamics. Energy of the frequency components of the LFP during spontaneous seizures recorded at each of the three recording sites is shown for three different animals with target frequencies of 7, 15, and 300 Hz, respectively. Red arrows indicate seizure termination. Range of frequencies displayed are centered around the target frequencies for clarity. The relatively brief (≥100 ms) but significant periods of multisite coherence found with EMD and Hilbert analysis could not be readily detected using Fourier techniques.

Figure 6.

Sensitivity of efficacy to DBS stimulation locations depends on where coherence at natural termination occurs. Temporal progression of coherence at the three recording sites at natural termination shown for two different rats. LH, left hippocampus; RH, right hippocampus; T, anteromedial thalamus. State transitions indicated by arrows with transition time shown above arrows. (A) High coherence was seen across bilateral hippocampi that evolved to include thalamus. Stimulation at both hippocampi or at one hippocampus + thalamus yielded high therapeutic efficacy. However, stimulation solely at the thalamus in this animal produced nearly zero efficacy. In contrast, (B) when high coherence at termination included all three sites, efficacy was nearly identical between thalamus alone and that observed with stimulation at one or both hippocampi.