Targeting sleep oscillations to improve memory in schizophrenia

Abstract

Although schizophrenia is defined by waking phenomena, a growing literature documents a deficit in sleep spindles, a defining oscillation of stage 2 non-rapid eye movement sleep. Compelling evidence supports an important role for spindles in cognition, and particularly memory. In schizophrenia, although the spindle deficit correlates with impaired sleep-dependent memory consolidation, recent clinical trials find that increasing spindles does not improve memory. This may reflect that sleep-dependent memory consolidation relies not on spindles alone, but also on their precise temporal coordination with cortical slow oscillations and hippocampal sharp-wave ripples. Consequently, interventions to improve memory in schizophrenia must not only increase spindles, but also preserve or enhance slow oscillations, hippocampal ripples and their temporal relations. Because hippocampal ripples and the activity of the thalamic spindle generator are difficult to measure noninvasively, screening potential interventions requires complementary animal and human studies. In this review we (i) propose that sleep oscillations are novel pathophysiological targets for therapy to improve cognition in schizophrenia; (ii) summarize our understanding of how these oscillations interact to consolidate memory; (iii) suggest that a systems neuroscience strategy is essential to selecting and evaluating effective treatments, and illustrate this with findings from clinical trials; and (iv) selectively review the interventional literature relevant to sleep and cognition, covering both pharmacological and noninvasive brain stimulation approaches. We conclude that coordinated sleep oscillations are promising targets for improving cognition in schizophrenia and that effective therapies will need to preserve or enhance sleep oscillatory dynamics and restore function at the network level.

Keywords: Brain stimulation; Hippocampal ripples; Memory; Schizophrenia; Sleep spindles; Slow oscillations.

Figure 1:

The coordination of sleep spindles with hippocampal ripples and neocortical slow oscillations in the service of consolidating new memories during sleep (adapted from Born and Wilhelm, 2012). During NREM sleep, neocortical slow oscillations drive the reactivation of hippocampal memory representations during sharp wave ripples (green) in the hippocampus together with spindles (blue) in the TRN. Hippocampal ripples nest in the troughs of spindles, which occur during the up states of slow oscillations. This dialogue between slow oscillations, spindles and hippocampal ripples is thought to mediate the transfer of selected new memories from temporary dependence on the hippocampus to longer-term representation in the neocortex (Siapas and Wilson, 1998).

Figure 2:

The temporal coordination of spindles with slow oscillations (SOs) in relation to sleep-dependent memory consolidation. a) SO phase at spindle peak. Top row: Topographical maps show mean SO phase at the peak of the spindle averaged across schizophrenia and healthy control participants. The circular plot shows the SO phase distributions across participants at Cz. Lines represent the mean SO phase for each participant. Arrows represent group means and their length represents the consistency of the SO phase across participants. Bottom row: Mapping of SO phase to the topographical map. b) Overnight improvement on a procedural motor memory task it is plotted against the density of coupled spindle-SO events in the electrode cluster showing a significant correlation (inset shows the electrodes comprising the significant cluster). The regression line for the combined groups is shown.

Figure 3:

Example of a closed-loop auditory stimulation paradigm and data from a single subject (pilot data courtesy of Dr. Baxter). Closed-loop auditory stimulation during slow oscillation upstates may increase spindle density. EEG trace at Fz filtered in the sigma (12-15 Hz) and slow wave (0.5-4 Hz) bands time-locked to the auditory stimulus. Slow oscillations were detected at Fz in real-time. The auditory stimulus (a 50 ms burst of pink noise) was delivered during the slow oscillation upstate (red vertical line). The light blue line indicates a detected spindle peak. The grey shading indicates the time window after sham/stimulation over which the probability of evoking a spindle was calculated. (Inset) Probability of evoking a spindle following stimulation/sham.