Elsevier

Biological Psychiatry

Volume 80, Issue 8, 15 October 2016, Pages 599-608
Biological Psychiatry

Review
Reduced Sleep Spindles in Schizophrenia: A Treatable Endophenotype That Links Risk Genes to Impaired Cognition?

https://doi.org/10.1016/j.biopsych.2015.10.003Get rights and content

Abstract

Although schizophrenia (SZ) is defined by waking phenomena, abnormal sleep is a common feature. In particular, there is accumulating evidence of a sleep spindle deficit. Sleep spindles, a defining thalamocortical oscillation of non–rapid eye movement stage 2 sleep, correlate with IQ and are thought to promote long-term potentiation and enhance memory consolidation. We review evidence that reduced spindle activity in SZ is an endophenotype that impairs sleep-dependent memory consolidation, contributes to symptoms, and is a novel treatment biomarker. Studies showing that spindles can be pharmacologically enhanced in SZ and that increasing spindles improves memory in healthy individuals suggest that treating spindle deficits in patients with SZ may improve cognition. Spindle activity is highly heritable, and recent large-scale genome-wide association studies have identified SZ risk genes that may contribute to spindle deficits and illuminate their mechanisms. For example, the SZ risk gene CACNA1I encodes a calcium channel that is abundantly expressed in the thalamic spindle generator and plays a critical role in spindle activity based on a mouse knockout. Future genetic studies of animals and humans can delineate the role of this and other genes in spindles. Such cross-disciplinary research, by forging empirical links in causal chains from risk genes to proteins and cellular functions to endophenotypes, cognitive impairments, symptoms, and diagnosis, has the potential to advance the mechanistic understanding, treatment, and prevention of SZ. This review highlights the importance of deficient sleep-dependent memory consolidation among the cognitive deficits of SZ and implicates reduced sleep spindles as a potentially treatable mechanism.

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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