Targeting sleep oscillations to improve memory in schizophrenia

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.