Reduced overnight consolidation of procedural learning in chronic medicated schizophrenia is related to specific sleep stages
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.
References (55)
Sleep in schizophrenia: impairments, correlates, and treatment
Psychiatric Clinics of North America
(2006)Sleep in schizophrenia
Sleep Medicine Clinics
(2008)- et al.
The measurement of differential deficit
Journal of Psychiatry Research
(1978) - et al.
EEGLAB: an open source toolbox for analysis of single-trial EEG dynamics including independent component analysis
Journal of Neuroscience Methods
(2004) - et al.
Dissociable learning-dependent changes in REM and non-REM sleep in declarative and procedural memory systems
Behavioural Brain Research
(2007) - et al.
Attention and non-REM sleep in neuroleptic-naive persons with schizophrenia and control participants
Psychiatry Research
(2007) - et al.
Impairment of visuospatial memory is associated with decreased slow wave sleep in schizophrenia
Journal of Psychiatry Research
(2004) - et al.
Biological predictors of 1-year outcome in schizophrenia in males and females
Schizophrenia Research
(1996) - et al.
Sleep in schizophrenia: a polysomnographic study on drug-naive patients
Neuropsychopharmacology
(1997) Prefrontal cortex dysfunction during working memory performance in schizophrenia: reconciling discrepant findings
Schizophrenia Research
(2003)