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Randomized Controlled Trial
. 2013 Sep 1;36(9):1317-26.
doi: 10.5665/sleep.2954.

Slow wave sleep induced by GABA agonist tiagabine fails to benefit memory consolidation

Gordon B Feld  1 , Ines Wilhelm, Ying Ma, Sabine Groch, Ferdinand Binkofski, Matthias Mölle, Jan Born
Affiliations
Randomized Controlled Trial

Slow wave sleep induced by GABA agonist tiagabine fails to benefit memory consolidation

Gordon B Feld et al. Sleep. .

Abstract

Study objectives: Slow wave sleep (SWS) plays a pivotal role in consolidating memories. Tiagabine has been shown to increase SWS in favor of REM sleep without impacting subjective sleep. However, it is unknown whether this effect is paralleled by an improved sleep-dependent consolidation of memory.

Design: This double-blind within-subject crossover study tested sensitivity of overnight retention of declarative neutral and emotional materials (word pairs, pictures) as well as a procedural memory task (sequence finger tapping) to oral administration of placebo or 10 mg tiagabine (at 22:30).

Participants: Fourteen healthy young men aged 21.9 years (range 18-28 years).

Measurements and results: Tiagabine significantly increased the time spent in SWS and decreased REM sleep compared to placebo. Tiagabine also enhanced slow wave activity (0.5-4.0 Hz) and density of < 1 Hz slow oscillations during NREM sleep. Fast (12-15 Hz) and slow (9-12 Hz) spindle activity, in particular that occurring phase-locked to the slow oscillation cycle, was decreased following tiagabine. Despite signs of deeper and more SWS, overnight retention of memory tested after sleep the next evening (19:30) was generally not improved after tiagabine, but on average even lower than after placebo, with this impairing effect reaching significance for procedural sequence finger tapping.

Conclusions: Our data show that increasing slow wave sleep with tiagabine does not improve memory consolidation. Possibly this is due to functional differences from normal slow wave sleep, i.e., the concurrent suppressive influence of tiagabine on phase-locked spindle activity.

Keywords: GABA; SWS; memory consolidation; skill memory; sleep spindles; tiagabine.

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Figures

Figure 1
Figure 1
Mean (± SEM) of overnight retention of memories (A) for word pair associates, (B) for neutral and emotional pictures, and (C) for sequence finger tapping skills in the tiagabine (empty bars) and placebo condition (black bars). Retention of word pairs is indicated by the difference in the number of word pairs recalled at retrieval testing after sleep minus recall performance on the criterion trial at learning before sleep. Recall of pictures is indicated by the total number of pictures recalled during retrieval testing after sleep. Overnight gains in sequence finger tapping (C, left panel) are indicated by the difference in performance (number of correctly tapped sequences per 30-sec trial) at retrieval testing after sleep minus average performance on the last trials during training before sleep. Right panel indicates performance after sleep on a control sequence not trained before sleep. *P ≤ 0.05, for pairwise comparisons between the effects of the treatments (n = 12).
Figure 2
Figure 2
Mean (± SEM) power spectra of EEG signal during NonREM sleep at Fz (left) and Cz (right) for the tiagabine (red thick line) and placebo condition (black thin line). Bottom panels indicate significance between the effects of tiagabine and placebo. (B) Average power for frequency bands of interest: 0.5-1 Hz slow oscillation, 1-4 Hz delta, 4-8 Hz theta, 9-12 Hz slow spindle, and 12-15 Hz fast spindle bands. ***P ≤ 0.001, **P ≤ 0.01 and *P ≤ 0.05, for pairwise comparisons between the effects of the treatment (n = 10).
Figure 3
Figure 3
(A) Mean (± SEM) density of (fast) spindles during entire NREM sleep, and separately for sleep stage 2 and SWS, and (B) slow oscillation density during NREM sleep, separately for recordings from Fz and Cz, in the tiagabine (empty bars) and placebo condition (black bars). ***P ≤ 0.001, **P ≤ 0.01, and *P ≤ 0.05 for pairwise comparisons between the effects of the treatment (n = 10).
Figure 4
Figure 4
(A) Averaged EEG signal within ± 1.3 sec around the negative half-wave peak (0.0 sec) of identified slow oscillations. (B) Mean (± SEM) root mean square fast spindle (12-15 Hz) and (C) slow spindle band (9-12 Hz) activity averaged time-locked to negative half-wave peak of identified slow oscillations. Data are shown separately for recordings from Fz (left) and Cz (right), and separately for the tiagabine (red thick lines, negative going error bars indicate SEM) and placebo (black thin lines, positive going error bars indicate SEM) conditions. Respective bottom panels indicate significance between the effects of the tiagabine and placebo treatment for consecutive 5-ms bins.
Figure 5
Figure 5
Schematic overview over the phase relationships between the slow oscillation and slow and fast sleep spindles; x-axis in milliseconds is relative to the (surface) negative slow oscillation peak. Fast spindle activity (12-15 Hz) increases during the down-to-up transition, is most pronounced during the up state of the slow oscillation and coincides with memory reactivations in the hippocampus and neocortex., Slow spindle activity (9-12 Hz), on the other hand, has its maximum during the up-to-down state transition. The surface EEG negative half-wave of the slow oscillation (down state), which is related to reduced neuronal fi ring, corresponds to a positive fi eld potential wave in deeper cortical layers, while the surface EEG positive half-wave (up state), which is related to increased neuronal fi ring, corresponds to a depth negative wave.,,
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