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

Abstract

Although schizophrenia 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. Here we review evidence that reduced spindle activity in schizophrenia 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 schizophrenia and that increasing spindles improves memory in healthy individuals suggest that treating spindle deficits in schizophrenia may improve cognition. Spindle activity is highly heritable and recent large-scale genome-wide association studies have identified schizophrenia risk genes that may contribute to spindle deficits and illuminate their mechanisms. For example, the schizophrenia risk gene CACNA1I encodes a calcium channel that is abundantly expressed in the thalamic spindle generator and plays a critical role in spindle activity in 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, through to endophenotypes, cognitive impairments, symptoms and diagnosis, has the potential to advance the mechanistic understanding, treatment and prevention of schizophrenia. This review highlights the importance of deficient sleep-dependent memory consolidation among the cognitive deficits of schizophrenia and implicates reduced sleep spindles as a potentially treatable mechanism.

Coordination of Slow Waves With Sleep Spindles Predicts Sleep-Dependent Memory Consolidation in Schizophrenia

“…We report N2 findings based on prior studies showing N2 spindle abnormalities in schizophrenia and correlations of N2 spindle activity with sleep-dependent memory consolidation 4,7,11 .…”

“…The neural bases of cognitive deficits are poorly understood and, consequently, effective treatments are lacking 3 . Recent work places deficient sleep-dependent memory consolidation among the cognitive deficits of schizophrenia and implicates reduced sleep spindles, a defining electroencephalographic (EEG) feature of Stage 2 non-rapid eye movement sleep (N2), as a potentially treatable mechanism 4 . Schizophrenia patients have deficient sleep-dependent consolidation of both procedural [5][6][7][8][9][10] and declarative 11 memory that, in some studies, correlates with reduced sleep spindle density (spindles per minute) and number 10,11 .…”

An Update on the Use of Sedative-Hypnotic Medications in Psychiatric Disorders

“…Patients with schizophrenia have demonstrated impairments in overnight improvement on a well-established finger-tapping motor sequence task (MST) (39). Because patients with schizophrenia demonstrate reductions in sleep spindles (40) and sleep-dependent improvement on the MST correlates with these waxing-waning electroencephalographic oscillations characteristic of non-rapid eye movement sleep (41), examining the effects of agents such as eszopiclone, which may increase sleep spindles through potentiation of the GABAergic thalamic reticular nucleus (the primary site of sleep spindle generation), is a promising line of inquiry. Wamsley and colleagues examined both the ability of eszopiclone to generate sleep spindles as well as its associative effects on overnight MST performance (42).…”

Investigation of sleep spindle activity and morphology as predictors of neurocognitive functioning in medicated patients with schizophrenia

“…The neurobiological basis for the profound deficits across cognitive domains is not fully understood, but deterioration of prefrontal cortex circuits is involved (Arnsten, ). Recently, a linkage between the cognitive deficits and disturbances in sleep microarchitecture has been proposed (Castelnovo, D'Agostino, Casetta, Sarasso, & Ferrarelli, ; Ferrarelli & Tononi, ; Manoach, Pan, Purcell, & Stickgold, ). Based on a number of studies published lately, there is now evidence that abnormalities in sleep spindle parameters are associated with disrupted sleep‐dependent consolidation of declarative and procedural memory (Ferrarelli & Tononi, ).…”