Differential effects on fast and slow spindle activity, and the sleep slow oscillation in humans with carbamazepine and flunarizine to antagonize voltage-dependent Na+ and Ca2+ channel activity

Abstract

Study objectives: Sleep spindles play an important functional role in sleep-dependent memory consolidation. They are a hallmark of non-rapid eye movement (NREM) sleep and are grouped by the sleep slow oscillation. Spindles are not a unitary phenomenon but are differentiated by oscillatory frequency and topography. Yet, it is still a matter of debate whether these differences relate to different generating mechanisms. As corticothalamic networks are known to be involved in the generation of spindles and the slow oscillation, with Ca2+ and Na+ conductances playing crucial roles, we employed the actions of carbamazepine and flunarizine to reduce the efficacy of Na+ and Ca2+ channels, respectively, for probing in healthy human subjects mechanisms of corticothalamocortical excitability.

Design: For each pharmacologic substance a within-design study was conducted on 2 experimental nights in young, healthy adults.

Measurements and results: Results indicate differential effects for slow frontocortical (approximately 10 Hz) and fast centroparietal (approximately 14 Hz) spindles. Carbamazepine enhanced slow frontal spindle activity conjointly with an increment in slow oscillation power (approximately 0.75 Hz) during deep NREM sleep. In contrast, fast centroparietal spindle activity (approximately 14 Hz) was decreased by carbamazepine. Flunarizine also decreased fast-spindle electroencephalogram power, but affected neither slow frontal spindle nor slow oscillation frequency bands.

Conclusions: Our findings indicate a differential pharmacologic response of the two types of sleep spindles and underscore a close linkage of the generating mechanisms underlying the sleep slow oscillation and the slow frontal sleep spindles for the signal transmission processes manipulated in the current study.

Keywords: EEG; ion channels; sleep spindles; slow oscillations; theta.

Figure 1

Mean (± standard error of the mean) power spectra for Stage 2 sleep (S2) and slow wave sleep (SWS) after the Na⁺ channel blocker carbamazepine, Na⁺ blocker CBZ (A) and the Ca²⁺ channel blocker flunarizine, Ca²⁺ blocker FLU (B). Frontal, central, and parietal correspond to the midline electroencephalographic recording sites Fz, Cz, and Pz. Gray areas indicate frequency bands revealing differences between verum and placebo in paired t-tests. Inserted bar charts give power on linear scale for significantly different frequency bands (*P < 0.05, **P < 0.01).

Figure 2

Mean (± standard error of the mean) time course of selected successive slow oscillation negative half-waves and positive half-waves time locked to the zero-crossing between negative and positive half-waves. The peak of the positive half-wave and the positive-half-wave downward slope are indicated. Black dots along the line at 0 μV demarcate beginning and end of the selected successive half-waves. Dashed lines represent the means of all previous and subsequent electroencephalographic activity.