The effects of eszopiclone on sleep spindles and memory consolidation in schizophrenia: a randomized clinical trial

Abstract

Sleep spindles, defining oscillations of stage 2 non-rapid eye movement sleep (N2), mediate memory consolidation. Schizophrenia is characterized by reduced spindle activity that correlates with impaired sleep-dependent memory consolidation. In a small, randomized, placebo-controlled pilot study of schizophrenia, eszopiclone (Lunesta®), a nonbenzodiazepine sedative hypnotic, increased N2 spindle density (number/minute) but did not significantly improve memory. This larger double-blind crossover study that included healthy controls investigated whether eszopiclone could both increase N2 spindle density and improve memory. Twenty-six medicated schizophrenia outpatients and 29 healthy controls were randomly assigned to have a placebo or eszopiclone (3 mg) sleep visit first. Each visit involved two consecutive nights of high density polysomnography with training on the Motor Sequence Task (MST) on the second night and testing the following morning. Patients showed a widespread reduction of spindle density and, in both groups, eszopiclone increased spindle density but failed to enhance sleep-dependent procedural memory consolidation. Follow-up analyses revealed that eszopiclone also affected cortical slow oscillations: it decreased their amplitude, increased their duration, and rendered their phase locking with spindles more variable. Regardless of group or visit, the density of coupled spindle-slow oscillation events predicted memory consolidation significantly better than spindle density alone, suggesting that they are a better biomarker of memory consolidation. In conclusion, sleep oscillations are promising targets for improving memory consolidation in schizophrenia, but enhancing spindles is not enough. Effective therapies also need to preserve or enhance cortical slow oscillations and their coordination with thalamic spindles, an interregional dialog that is necessary for sleepdependent memory consolidation.

Sleep spindles preferentially consolidate weakly encoded memories

“…It is important to note that our findings are correlational in nature. Other work has shown that it is possible to enhance spindle activity pharmacologically to alter memory function, (Kaestner et al, 2013; Niknazar et al, 2015), though potentially at the cost of disrupting slow oscillation-spindle coupling processes (Mylonas et al, 2020). Furthermore, commonly used pharmacological agents such as zolpidem and eszopiclone have been shown to induce widespread alterations in the sleep EEG, and as such do not solely target changes in sleep spindles (Aeschbach et al, 1994; Monti et al, 2000; Struyk et al, 2016).…”

Slow oscillation‐spindle coupling is negatively associated with emotional memory formation following stress

“…It is important to consider that coupling events are just one neurophysiological event that occurs during SWS and is a particularly rare event. Only ~15% of spindles couple to slow oscillations, and coupled spindle density has been reported as being around 0.5 per minute (Denis, Mylonas, et al, 2020;Mylonas et al, 2020). As such, coupling is a rare event in the broader SWS sleep state.…”

“…This approach to slow oscillation spindle coupling has been widely used elsewhere (e.g. Staresina et al, 2015;Helfrich et al, 2018;Mylonas et al, 2020). We extracted the percentage of all spindles coupled with a slow oscillation at each electrode, the average phase of the slow oscillation at the peak of each coupled spindle, and the overall coupling strength (mean vector length).…”

Slow oscillation-spindle coupling is negatively associated with emotional memory formation following stress

“…It is important to consider that coupling events are just one neurophysiological event that occurs during SWS and is a particularly rare event. Only ~15% of spindles couple to slow oscillations, and coupled spindle density has been reported as being around 0.5 per minute (Denis, Mylonas, et al , 2020; Mylonas et al , 2020). As such, coupling is a rare event in the broader SWS sleep state.…”