ReviewReduced Sleep Spindles in Schizophrenia: A Treatable Endophenotype That Links Risk Genes to Impaired Cognition?
Section snippets
Abnormal Sleep is a Key Feature of Sz and Potential Target for Treatment
In SZ, sleep disturbances have been described since Kraepelin’s work (8) and are associated with poorer coping skills and diminished quality of life (9, 10). They are common in patients throughout the course of SZ (11), in individuals with prodromal symptoms (12, 13), and in young relatives (14). Sleep disturbances are associated with the initial onset of psychosis and predict relapse in remitted patients (15, 16). Findings of sleep disturbances in unmedicated and antipsychotic drug (APD)-naïve
Sleep Abnormalities in SZ
The most common subjective sleep disturbances in SZ are difficulty initiating and maintaining sleep (i.e., insomnia) (15, 17). Polysomnography studies variably show reduced sleep efficiency (the fraction of time in bed spent asleep), increased sleep onset latencies, and increased wake time after sleep onset in patients with SZ compared with healthy individuals (17, 21). Studies also reported altered circadian rhythms (22) and increased rates of sleep disorders, including obstructive sleep
Spindle Mechanisms
There is considerable cross-species knowledge about sleep spindle mechanisms. Spindles are generated in the thalamic reticular nucleus (TRN) (32), a thin net-like structure around the thalamus comprised entirely of gamma-aminobutyric acid (GABA)-ergic neurons (33). TRN neurons project to glutamatergic thalamic neurons that project to the cortex. Cortical neurons send glutamatergic inputs back to N-methyl-D-aspartate (NMDA) receptors on TRN neurons (Figure 2). Thus, spindles are the product of a
Sleep Spindles Mediate Memory Consolidation
After encoding, memories undergo “consolidation” processes that stabilize, enhance, integrate, and reorganize memory traces in the brain. These processes operate outside of conscious awareness while awake and during sleep. A wealth of molecular cellular, neural network, brain activation, and behavioral data from birds (42), rodents (43), cats (44), and humans (45) suggest an evolutionarily conserved function for sleep in the consolidation of multiple forms of memory.
Animal studies suggest that
Sleep Spindle Deficit in SZ
Three early studies of small samples (n ≤ 11) of APD-naïve patients with a first episode of SZ (25, 69) and unmedicated patients with SZ (70, 71) did not find a spindle deficit (Table 1). However, a growing literature has reported marked reductions of spindle activity in medicated patients with chronic SZ (31, 72, 73, 74, 75, 76) and medicated adolescents with early-onset SZ spectrum disorder (77). With the exception of increased sleep onset latency in two studies (74, 75), the spindle deficit
Reduced Spindles are Associated with Impaired Cognition and Positive Symptoms in SZ
Although sleep is critical for memory, disrupted sleep impairs memory (89, 90, 91), and SZ is characterized by both abnormal sleep and impaired memory, few studies have examined the connection. Emerging evidence suggests that reduced sleep spindles contribute to procedural and declarative memory impairments in SZ.
Using a well-validated probe of sleep-dependent motor procedural memory, the finger-tapping motor sequence task (Figure 4) (49, 92), several studies demonstrated deficient
Sleep Spindles as a Novel Treatment Biomarker for Improving Cognition in SZ
Cognitive deficits are the strongest predictor of functional outcome in SZ (115). Even after florid psychotic symptoms are controlled with APDs, debilitating cognitive deficits persist, and only ~20% of individuals with SZ are able to work (116). Although ameliorating cognitive deficits is a priority of the SZ research community, effective treatments are lacking (117). A better understanding of the pathophysiology of cognitive deficits is needed to guide the development of new treatments.
Genetic Mechanisms of Sleep Spindles
In twin studies, EEG sigma power is highly heritable (heritability estimate of 96%) (129) and shows high interindividual variability and within-individual stability, leading to its description as an “electrophysiological fingerprint” (129, 130, 131). Despite their high heritability, little is known about the genetic underpinnings of sleep spindles. Genome-wide association studies (GWAS) have been conducted for sleep disorders (132), sleep duration (133), and insomnia (134), but genetic studies
Conclusions
This review expands current models of cognitive deficits in SZ by highlighting the importance of deficient sleep–dependent consolidation of procedural and declarative memory. It implicates reduced sleep spindles as a mechanism and suggests novel pathophysiologic targets for treatment. Going forward, we propose several potentially fruitful avenues of research.
First, it will be important to define the scope and consequences of the sleep-dependent memory deficit in SZ. Findings of dissociations
Acknowledgments and Disclosures
This work was supported by the National Institutes of Health Grant Nos. K24MH099421 (DSM), R01 MH092638 (DSM, RS), R01MH048832 (RS), and R21MH099448 (JQP) and Stanley Research Center (JQP).
We thank Steven Hyman for his comments on the manuscript.
The authors report no biomedical financial interests or potential conflicts of interest.
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