Background Sleep spindles are thought to induce synaptic changes and thereby contribute to memory consolidation during sleep. Patients with schizophrenia show dramatic reductions of both spindles and sleep-dependent memory consolidation, which may be causally related. Methods To examine the relations of sleep spindle activity to sleep-dependent consolidation of motor procedural memory, 21 chronic, medicated schizophrenia outpatients and 17 healthy volunteers underwent polysomnography on two consecutive nights. On the second night, participants were trained on the finger tapping Motor Sequence Task (MST) at bedtime and tested the following morning. The number, density, frequency, duration, amplitude, spectral content, and coherence of stage 2 sleep spindles were compared between groups and examined in relation to overnight changes in MST performance. Results Patients failed to show overnight improvement on the MST and differed significantly from controls who did improve. Patients also exhibited marked reductions in the density (reduced 38% relative to controls), number (reduced 36%), and coherence (reduced 19%) of sleep spindles, but showed no abnormalities in the morphology of individual spindles or of sleep architecture. In patients, reduced spindle number and density predicted less overnight improvement on the MST. In addition, reduced amplitude and sigma power of individual spindles correlated with greater severity of positive symptoms. Conclusions The observed sleep spindle abnormalities implicate thalamocortical network dysfunction in schizophrenia. In addition, our findings suggest that abnormal spindle generation impairs sleep-dependent memory consolidation in schizophrenia, contributes to positive symptoms, and is a promising novel target for the treatment of cognitive deficits in schizophrenia.

We previously reported that patients with schizophrenia failed to demonstrate normal sleepdependent improvement in motor procedural learning. Here, we tested whether this failure was associated with the duration of Stage 2 sleep in the last quartile of the night (S2q4) and with spindle activity during this epoch. Fourteen patients with schizophrenia and 15 demographically matched controls performed a motor sequence task (MST) before and after a night of polysomnographically monitored sleep. Patients showed no significant overnight task improvement and significantly less than controls, who did show significant improvement. While there were no group differences in © 2009 Elsevier Ltd. All rights reserved.Corresponding author: D. S. Manoach, Massachusetts General Hospital-East, 36 First Avenue, Room 420, Charlestown, MA 02129; dara@nmr.mgh.harvard.edu ; phone: 617-724-6148; fax: 617-726-0504. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Disclosures:This was not an industry-supported study. Dr. Manoach has received research funding and consulting fees from Sepracor Inc. Dr. Stickgold has received research funding from Merck & Co., Actelion Pharmaceuticals Ltd., and Sepracor Inc., as well as consulting fees from Actelion Pharmaceuticals Ltd. and Sepracor Inc, speaking fees from Epix Pharmaceuticals, and an educational grant from Takeda Inc. Ms. Stroynowski is presently employed by Alkermes. Dr. Goff has received honoraria or research support over the past year from Organon, Xytis, Wyeth, Forest Labs, Eli Lilly, Pfizer, and Ortho-McNeil-Janssen. None of the other authors have any conflicts of interest to disclose.Contributors: Dara S. Manoach: is an expert on cognition in schizophrenia and was responsible for all aspects of the present study including the design and execution of the study, data analysis, and manuscript preparation. Katharine N. Thakkar: data acquisition and analysis of MST findings. Eva Stroynowski: data acquisition and scoring and analysis of PSG data. Alice Ely: data acquisition and scoring, analysis, and quality control of PSG data. Sophia K. McKinley: analysis and interpretation of actigraphy data. Erin Wamsley: analysis and interpretation of spectral PSG data. Ina Djonlagic: consultant regarding medication effects on sleep parameters. Mark G. Vangel: provided statistical consultation to all aspects of data analysis. Donald C. Goff: responsible for patient recruitment and characterization. Contributed to interpretation of the findings. Robert Stickgold: is an expert on sleep dependent cognition and participated with Dr. Manoach on all aspects of...

Eszopiclone significantly increased sleep spindles, which correlated with overnight motor sequence task improvement. These findings provide partial support for the hypothesis that the spindle deficit in schizophrenia impairs sleep-dependent memory consolidation and may be ameliorated by eszopiclone. Larger samples may be needed to detect a significant effect on memory. Given the general role of sleep spindles in cognition, they offer a promising novel potential target for treating cognitive deficits in schizophrenia.