While schizophrenia is defined primarily by symptoms that occur during wakefulness, recent research indicates that patients with schizophrenia have characteristic changes in sleep rhythms. Dara Manoach, PhD and colleagues at the Sleep, Cognition, and Neuropsychiatry (SCAN) Lab have observed that a specific sleep abnormality observed in patients with schizophrenia – reduced sleep spindle activity – predates the onset of schizophrenia, is present throughout the course of illness and correlates with worse cognitive functioning. This leads to the hypothesis that reduced sleep spindle activity contributes to the cognitive deficits seen in individuals with schizophrenia. The finding that increasing spindle activity via drugs or noninvasive brain stimulation during sleep improves memory in healthy people (without schizophrenia) provides the impetus to target spindles as a means of improving cognition in individuals with schizophrenia.
Sleep and Memory Consolidation
During non-REM sleep, slow waves, sleep spindles and sharp-wave ripples are the main oscillatory activities seen in the brain. Slow waves are ∼1 Hz, high amplitude oscillations that are primarily generated and coordinated within the cortex. Sleep spindles are 12-16 Hz, waxing and waning oscillations that are initiated within the thalamus and are regulated by thalamo-cortical circuits. Sharp-wave ripples are high frequency oscillations (~100 Hz) emanating from the hippocampus that are associated with the replay of recent memories during sleep. In healthy adults, the dialogue between these three cardinal oscillations of non-REM sleep — spindles, slow waves and ripples — mediates memory consolidation.
After learning, memories undergo “consolidation”, processes that stabilize, enhance, integrate and reorganize memory traces in the brain. Sleep is critical for memory consolidation, and disrupted sleep impairs memory. We have learned from animal studies that sleep spindles, in coordination with slow wave and ripples, facilitate the synaptic plasticity involved in memory consolidation. In humans, sleep spindles correlate with the sleep-dependent consolidation of both procedural and declarative memory.
Sleep and Cognition in Schizophrenia
Few studies have attempted to improve cognition in patients with schizophrenia by manipulating sleep spindles. Recent clinical trials find that while certain drugs increase sleep spindles in patients with schizophrenia, there is no improvement in memory. Complementary rodent and human studies from the SCAN Lab and collaborators provide an explanation: these drugs interfere with the precise temporal coordination of sleep spindles with cortical slow oscillations and hippocampal sharp-wave ripples. The SCAN lab is now developing and evaluating interventions that both increase spindles and preserve or enhance their coordination with slow waves and ripples in patients with schizophrenia in an effort to improve sleep-dependent memory consolidation.
This body of work brings us closer to understanding the cognitive deficits experienced by patients with schizophrenia. While antipsychotic medications may effectively treat psychotic symptoms, many patients with schizophrenia experience persistent cognitive deficits. Because cognitive deficits are the strongest predictor of functional outcomes in patients with schizophrenia, improving cognitive functioning in this population is a priority. However, effective treatments are lacking. Continuing research into the pathophysiology of these cognitive deficits is vital to the development of new treatments that can improve functioning and quality-of-life in individuals suffering from schizophrenia.
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Lai M, Hegde R, Kelly S, Bannai D, Lizano P, Stickgold R, Manoach DS, Keshavan M. Investigating sleep spindle density and schizophrenia: A meta-analysis. Psychiatry Res. 2022 Jan;307:114265.
Manoach DS, Mylonas D, Baxter B. Targeting sleep oscillations to improve memory in schizophrenia. Schizophr Res. 2020 Jul;221:63-70.
Manoach DS, Stickgold R. Abnormal Sleep Spindles, Memory Consolidation, and Schizophrenia. Annu Rev Clin Psychol. 2019 May 7;15:451-479.
Dara Manoach, PhD is Director of theSleep, Cognition, and Neuropsychiatry (SCAN) Laband a Professor of Psychology in the Department of Psychiatry at MGH and Harvard Medical School. Her research uses multimodal neuroimaging techniques to illuminate the neural basis and nature of fundamental cognitive deficits in neuropsychiatric disorders, particularly schizophrenia and autism, so that they can be effectively treated.
