Reduced overnight consolidation of procedural learning in chronic medicated schizophrenia is related to specific sleep stages

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Abstract

We previously reported that patients with schizophrenia failed to demonstrate normal sleep-dependent 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 overall sleep architecture, patients showed significant reductions in fast sigma frequency power (45%) and in spindle density (43%) during S2q4 sleep at the electrode proximal to the motor cortex controlling the hand that performed the MST. Although spindle activity did not correlate with overnight improvement in either group, S2q4 sleep duration in patients significantly correlated with the plateau level of overnight improvement seen at the end of the morning testing session, and slow wave sleep (SWS) duration correlated with the delay in reaching this plateau. SWS and S2q4 sleep each predicted the initial level of overnight improvement in schizophrenia, and their product explained 77% of the variance, suggesting that both sleep stages are necessary for consolidation. These findings replicate our prior observation of reduced sleep-dependent consolidation of motor procedural learning in schizophrenia and link this deficit to specific sleep stages. They provide further evidence that sleep is an important contributor to cognitive deficits in schizophrenia.

Introduction

Sleep disturbances in schizophrenia have been described since Kraepelin (1919) and are associated with poor coping skills and diminished quality of life (Goldman et al., 1996, Hofstetter et al., 2005). Accumulating evidence suggests that abnormal sleep also contributes to cognitive deficits in schizophrenia (e.g., Forest et al., 2007, Goder et al., 2004, Goder et al., 2008, Yang and Winkelman, 2006). In a prior study, we reported that chronic medicated patients with schizophrenia failed to demonstrate normal improvements in procedural learning after a night of sleep, in spite of showing intact practice-dependent learning during training the previous day (Manoach et al., 2004). The goal of the present study was to determine whether this reduced overnight consolidation of procedural learning in schizophrenia is associated with alterations in specific sleep stages or their characteristics, which could provide insight into the mechanisms underlying this cognitive deficit.

Subjective sleep disturbance is common in patients with schizophrenia and often presages psychotic decompensation (Benson, 2006, Lieberman et al., 2005). The presence of sleep abnormalities in antipsychotic-naïve and unmedicated patients indicates that abnormal sleep is not merely a side-effect of medications (for meta-analysis see Chouinard et al. (2004)). While there are reports of diverse abnormalities of sleep architecture in schizophrenia, reduced slow wave sleep (SWS) is the most consistent (e.g., Keshavan et al., 1998, Monti and Monti, 2004, Yang and Winkelman, 2006), but not universal (e.g., Chouinard et al., 2004, Lauer et al., 1997), finding. In spite of its ubiquity, abnormal sleep has generally been overlooked as a potential contributor to cognitive deficits in schizophrenia. This neglect may stem from a tendency to regard disturbed sleep as secondary to other factors and from difficulty specifying the exact nature of the disturbance. There is now overwhelming evidence that sleep plays a critical role in memory consolidation (e.g., Stickgold, 2005) and recent studies of schizophrenia report associations between sleep and cognitive performance in medicated (Goder et al., 2004, Goder et al., 2008) and antipsychotic-naïve (Forest et al., 2007) patients. These findings support the hypothesis that abnormal sleep contributes to cognitive deficits in schizophrenia and highlight the need for further study.

In the present study, we employed the same simple, well-characterized test of motor skill learning, the finger tapping motor sequence test (MST) (Karni et al., 1998, Walker et al., 2002) that we used in our previous study of schizophrenia (Manoach et al., 2004). When healthy young participants are trained on this task, they show significant improvements in speed after a night of sleep, but not after an equivalent period of daytime wake (Walker et al., 2002). Additional nights of sleep lead to more improvement, even with no additional practice (Walker et al., 2003b), but sleep deprivation the first night after training blocks all subsequent non-practice related improvement (Fischer et al., 2002). These findings demonstrate that overnight improvement on this task depends on sleep rather than the mere passage of time. Sleep following MST training also leads to increased functional MRI activation in right primary motor cortex, contralateral to the hand performing the task, and to decreased activation in regions that mediate the conscious monitoring of performance (Walker et al., 2005). These and other findings suggest that sleep-dependent consolidation leads to task automation, resulting in performance that is faster, less variable, and less dependent on voluntary attention (Atienza et al., 2004, Kuriyama et al., 2004, Walker et al., 2005).

Overnight improvement on the MST and other simple motor skill tasks specifically correlates with the amount of Stage 2 sleep in the last quartile of the night (S2q4, Fogel et al., 2007, Smith and MacNeill, 1994, Walker et al., 2002). MST improvement also correlates with the number and density of fast spindles (Rasch et al., 2008), and since the MST is performed with the left hand, it is interesting to note that it is associated with right > left asymmetry of spindle density and power at central electrodes proximal to primary motor cortex (Nishida and Walker, 2007). Sleep spindles are brief, powerful bursts of synchronous neural firing that reach peak density late in the night (De Gennaro et al., 2000) and are hypothesized to mediate the consolidation of procedural memory on the MST (Nishida and Walker, 2007, Rasch et al., 2008, Walker et al., 2002) and other motor tasks (Fogel and Smith, 2006, Tamaki et al., 2008). Studies of schizophrenia show reduced spindle activity (Ferrarelli et al., 2007), and positive relations between Stage 2 spindle density and verbal declarative memory performance (Goder et al., 2008). Here, we expected to replicate our finding of reduced overnight improvement of motor procedural learning in schizophrenia and to correlate it with the duration of S2q4 sleep (Walker et al., 2002), reduced sigma frequency power, which corresponds to sleep spindles, and spindle density during S2q4 sleep, specifically at the right central (C4) electrode, and reduced right > left sigma asymmetry at central electrodes (C4–C3) during S2q4 sleep (Nishida and Walker, 2007, Rasch et al., 2008, Walker et al., 2005).

Section snippets

Participants

All participants were screened to exclude substance abuse or dependence within the past six months, diagnosed sleep disorders, or any independent conditions that might affect brain function. Outpatients with schizophrenia (n = 16) were recruited from an urban mental health center. Two patients were excluded for failing to type a single correct sequence during training. The remaining 14 patients had all been maintained on stable doses of antipsychotic medications for at least six weeks, 12 on

MST performance (Fig. 2, Table 2)

Practice-Dependent Improvement: Both groups showed significant improvement across Training. While the groups did not differ in absolute improvement, patients showed greater proportional improvement (45 vs. 115%, t(27) = 2.27, p = .03).

Overnight Improvement: While controls showed significant plateau improvement overnight, patients did not, and improvement was significantly greater in controls (15.2% vs. 5.0%). This is similar to our previous study (Manoach et al., 2004) in which only controls showed

Discussion

Consistent with our previous report (Manoach et al., 2004), in the context of intact practice-dependent learning, chronic medicated schizophrenia patients failed to demonstrate significant overnight improvement of motor procedural memory. In this respect, they differed significantly from healthy controls, who did show significant improvement. The present study extends these findings by demonstrating that in schizophrenia, overnight improvement is correlated with the amount of time spent in

Role of funding sources

Study sponsors had no role in the acquisition, analysis, or presentation of study data.

Contributors

Dara S. Manoach 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

Conflict of interest

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

Acknowledgements

Support from: Mallinckrodt General Clinical Research Centers Program at Massachusetts General Hospital (M01-RR-01066); NIMH (MH48832) and NIH T32 training grant HL07901-10 to the Harvard Division of Sleep Medicine. We are grateful to the staff of the Mallinckrodt GCRC program, particularly Mary Sullivan, RN, for their support.

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