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Articles, Behavioral/Cognitive

The Critical Role of Sleep Spindles in Hippocampal-Dependent Memory: A Pharmacology Study

Sara C. Mednick, Elizabeth A. McDevitt, James K. Walsh, Erin Wamsley, Martin Paulus, Jennifer C. Kanady and Sean P. A. Drummond
Journal of Neuroscience 6 March 2013, 33 (10) 4494-4504; DOI: https://doi.org/10.1523/JNEUROSCI.3127-12.2013
Sara C. Mednick
1Department of Psychology, University of California Riverside, Riverside, California 92521,
2Department of Psychiatry, University of California San Diego, La Jolla, California 92093,
3VA San Diego Healthcare System, La Jolla, California 92161,
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Elizabeth A. McDevitt
1Department of Psychology, University of California Riverside, Riverside, California 92521,
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James K. Walsh
4St. Luke's Hospital, St. Louis, Missouri 64111,
5Department of Psychiatry, Stanford University, Palo Alto, California 94305,
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Erin Wamsley
6Department of Psychiatry, Harvard Medical School, Boston, Massachusetts 02115, and
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Martin Paulus
2Department of Psychiatry, University of California San Diego, La Jolla, California 92093,
3VA San Diego Healthcare System, La Jolla, California 92161,
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Jennifer C. Kanady
7Department of Psychology, University of California Berkeley, Berkeley, California 94720
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Sean P. A. Drummond
2Department of Psychiatry, University of California San Diego, La Jolla, California 92093,
3VA San Diego Healthcare System, La Jolla, California 92161,
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  • Figure 1.
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    Figure 1.

    Study time line. The experimental time line for each session for Study 1 (a) and Study 2 (b). On the eve of the experimental day, subjects slept in the laboratory with a bedtime of 11:00 P.M. and a wake time of 5:00 A.M. In study 2, participants took cognitive tests between 6:00 and 8:00 A.M. At 8:30 A.M., subjects were reattached to the PSG monitor, given their medication, and allowed to nap until 90 min of total sleep time was obtained. At 3:00 P.M., subjects were retested on the cognitive tasks.

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    Figure 2.

    Drug effects on minutes in each sleep stage and spindle density. a, Study 1 compares 5 and 10 mg of ZOL (black bars), 2.5 and 3 g of SO (gray bars), and placebo (white bars). b, Study 2 compares 10 mg of ZOL (black bars), 2.5 g of SO (gray bars), and placebo (white bars). Statistical comparisons are between drug conditions and placebo. ***p < 0.001; **p < 0.01; *p < 0.05.

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    Figure 3.

    Cognitive performance by drug condition. Difference scores for the verbal paired associate task, the visual texture discrimination task, and the motor sequence task for the three drug conditions: 10 mg of ZOL, 2.5 g of SO, and placebo. Statistical comparisons are between drug conditions and placebo. **p < 0.005; *p < 0.05.

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    Figure 4.

    Sleep features and memory performance. a, Spindle density in each drug condition (ZOL, black circle; SO, gray circle; placebo, white circle) is shown relative to change scores in verbal memory. b, REM minutes in each drug are shown relative to change scores in perceptual learning. c, Spindle density in each drug condition is shown relative to change scores in motor learning.

Tables

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    Table 1.

    Nocturnal sleep: week prior (actigraphy)

    PlaceboSodium oxybate (2.5 g)Sodium oxybate (3 g)Zolpidem (5 mg)Zolpidem (10 mg)Statistic
    Study 1
        TSTact (min)397 ± 59396 ± 52388 ± 63413 ± 56408 ± 59F(4,44) = 0.70, p = 0.60
        SEact77 ± 878 ± 876 ± 980 ± 778 ± 7F(4,44) = 0.68, p = 0.62
        WASOact (min)98 ± 4389 ± 3596 ± 3683 ± 3491 ± 36F(4,44) = 0.38, p = 0.81
    Study 2
        TSTact (min)376 ± 7.2381 ± 6.5372 ± 6.9F(2,54) = 0.80, p = 0.45
        SEact81 ± 1.281 ± 1.080 ± 1.3F(2,54) = 1.14, p = 0.32
        WASOact (min)71 ± 4.671 ± 4.775 ± 4.9F(2,54) = 0.63, p = 0.53
    • View popup
    Table 2.

    Nocturnal sleep: experimental night (polysomnography)

    PlaceboSodium oxybate (2.5 g)Sodium oxybate (3 g)Zolpidem (5 mg)Zolpidem (10 mg)Statistic
    Study 1
        TSTnight (min)322 ± 30313 ± 44333 ± 17321 ± 29323 ± 42F(4,72) = 1.38, p = 0.28
        SEnight89 ± 786 ± 1292 ± 489 ± 889 ± 11F(4,72) = 1.06, p = 0.41
        SLnight (min)16 ± 1618 ± 269 ± 512 ± 1515 ± 24F(4,72) = 1.00, p = 0.43
        WASOnight (min)20 ± 1729 ± 3218 ± 1125 ± 2721 ± 27F(4,72) = 0.49, p = 0.73
        Stage 1 (min)12 ± 613 ± 712 ± 812 ± 512 ± 6F(4,72) = 0.23, p = 0.92
        Stage 2 (min)175 ± 21171 ± 23183 ± 24166 ± 24172 ± 34F(4,72) = 2.32, p = 0.10
        SWS (min)77 ± 2677 ± 2580 ± 2479 ± 2281 ± 28F(4,72) = 0.25, p = 0.90
        REM (min)57 ± 1750 ± 1957 ± 1762 ± 1856 ± 20F(4,72) = 2.07, p = 0.13
    Study 2
        TSTnight (min)319 ± 26317 ± 30321 ± 24F(2,58) = 0.46, p = 0.62
        SEnight86 ± 1888 ± 887 ± 18F(2,58) = 0.19, p = 0.82
        SLnight (min)13 ± 918 ± 1414 ± 12F(2,58) = 0.46, p = 0.62
        WASOnight (min)23 ± 2125 ± 2623 ± 18F(2,58) = 0.06, p = 0.93
        Stage 1 (min)14 ± 915 ± 1013 ± 9F(2,58) = 0.71, p = 0.49
        Stage 2 (min)190 ± 34190 ± 36192 ± 31F(2,58) = 0.11, p = 0.89
        SWS (min)71 ± 2270 ± 3071 ± 25F(2,58) = 0.07, p = 0.92
        REM (min)45 ± 2042 ± 1446 ± 13F(2,58) = 0.53, p = 0.59
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    Table 3.

    Study 1: experimental nap (polysomnography)

    PlaceboSodium oxybate (2.5 g)Sodium oxybate (3 g)Zolpidem (5 mg)Zolpidem (10 mg)Statistic
    TSTnap (min)86 ± 4.591 ± 1.791 ± 4.685 ± 2.595 ± 1.4F(4,72) = 2.00, p = 0.10, partial eta2 = 0.1
    Sleep latencynap (min)11.7 ± 2.08.2 ± 1.09.0 ± 2.113.4 ± 1.710.6 ± 1.5F(4,72) = 3.00, p = 0.06, partial eta2 = 0.11
    WASOnap (min)16.7 ± 4.910 ± 5.05.5 ± 3.014.6 ± 4.86.5 ± 1.3F(4,71) = 3.26, p = 0.01, partial eta2 = 0.15
    Sleep efficiencynap76 ± 4.285.4 ± 2.987.1 ± 4.577.4 ± 3.785.5 ± 1.8F(4,72) = 3.97, p = 0.006, partial eta2 = 0.18
    C4 spindle density2.70 ± 0.201.32 ± 0.201.14 ± 0.233.12 ± 0.393.49 ± 0.46F(4,72) = 24.84, p < 0.001, partial eta2 = 0.58
    C3 spindle density3.11 ± 0.361.71 ± 0.251.44 ± 0.253.55 ± 0.404.08 ± 0.48F(4,72) = 19.99, p < 0.001, partial eta2 = 0.52
    Stage 1 (min)9.73 ± 0.834.08 ± 0.634.00 ± 0.697.08 ± 0.886.24 ± 0.69F(4,72) = 11.97, p < 0.001, partial eta2 = 0.4
    Stage 2 (min)44.37 ± 3.740.13 ± 3.3046.28 ± 4.344.89 ± 2.644.10 ± 2.9F(4,72) = 0.57, p < 0.67, partial eta2 = 0.03
    SWS (min)9.00 ± 2.723.07 ± 3.523.03 ± 4.918.87 ± 3.622.37 ± 4.1F(4,72) = 4.36, p = 0.003, partial eta2 = 0.19
    REM (min)23.71 ± 3.224.05 ± 2.918.21 ± 2.514.61 ± 1.923.13 ± 2.9F(4,72) = 2.68, p = 0.03, partial eta2 = 0.13
    • View popup
    Table 4.

    Study 2: experimental nap (polysomnography)

    PlaceboSodium oxybate (2.5 g)Zolpidem (10 mg)Statistic
    TSTnap (min)92 ± 3.291 ± 2.393 ± 1.3F(2,58) = 0.08, p = 0.91, partial eta2= 0.003
    Sleep latencynap (min)9.2 ± 1.28.8 ± 0.9410.5 ± 1.3F(2,58) = 0.65, p = 0.52, partial eta2= 0.02
    WASOnap (min)17.7 ± 3.813.7 ± 2.413.8 ± 2.7F(2,58) = 0.08, p = 0.91, partial eta2= 0.003
    Sleep efficiencynap78.9 ± 3.180.8 ± 2.280.5 ± 1.8F(2,58) = 0.14, p = 0.86, partial eta2= 0.005
    Stage 1 (min)8.3 ± 0.876.1 ± 0.687.88 ± 0.95F(2,58) = 2.26, p = 0.11, partial eta2= 0.07
    Stage 2 (min)43.6 ± 2.640.47 ± 2.8839.2 ± 3.0F(2,58) = 1.0, p = 0.34, partial eta2= 0.03
    SWS (min)9.8 ± 1.519.26 ± 3.024.3 ± 2.0F(2,58) = 10.6, p < 0.001, partial eta2= 0.26
    REM (min)30.7 ± 2.325.9 ± 2.422.6 ± 2.4F(2,58) = 4.55, p = 0.01, partial eta2= 0.13
    • View popup
    Table 5.

    Study 2: experimental nap (spindle analysis)

    Spindle featureChannelPlaceboSodium oxybate (2.5 g)Zolpidem (10 mg)Statistic
    DensityC42.40 ± 0.141.68 ± 0.213.13 ± 0.24F(2,58) = 19.64, p < 0.001, partial eta2 = 0.40
    C32.78 ± 0.172.03 ± 0.253.45 ± 0.27F(2,58) = 12.45, p < 0.001, partial eta2 = 0.30
    AmplitudeC416.96 ± 0.4517.31 ± 0.4616.43 ± 0.48F(2,56) = 3.75, p = 0.03, partial eta2 = 0.11
    C316.78 ± 0.5217.01 ± 0.4915.63 ± 0.44F(2,56) = 7.39, p = 0.001, partial eta2 = 0.17
    FrequencyC413.58 ± 0.0913.49 ± 0.0913.49 ± 0.08F(2,50) = 10.81, p < 0.001, partial eta2 = 0.20
    C313.49 ± 0.1013.48 ± 0.0913.43 ± 0.09F(2,56) = 1.33, p = 0.27, partial eta2 = 0.04
    Fast spindle densityC41.59 ± 0.231.23 ± 0.222.23 ± 0.27F(2,52) = 10.81, p < 0.001, partial eta2 = 0.29
    C31.85 ± 0.291.45 ± 0.252.40 ± 0.30F(2,54) = 7.35, p = 0.002, partial eta2 = 0.21
    Slow spindle densityC40.77 ± 0.130.64 ± 0.111.46 ± 0.26F(2,56) = 9.49, p < 0.001, partial eta2 = 0.25
    C31.18 ± 0.220.80 ± 0.131.84 ± 0.39F(2,52) = 5.46, p = 0.007, partial eta2 = 0.17
    Fast spindle amplitudeC416.34 ± 0.5016.77 ± 0.4815.88 ± 0.56F(2,50) = 2.49, p = 0.09, partial eta2 = 0.09
    C316.49 ± 0.6816.32 ± 0.5515.16 ± 0.50F(2,54) = 2.74, p = 0.07, partial eta2 = 0.09
    Slow spindle amplitudeC417.20 ± 0.5217.30 ± 0.4316.66 ± 0.50F(2,56) = 1.84, p = 0.168, partial eta2 = 0.06
    C316.94 ± 0.5217.28 ± 0.4815.64 ± 0.42F(2,56) = 10.36, p < 0.001, partial eta2 = 0.27
    • View popup
    Table 6.

    Study 2: task performance for encoding and test sessions

    PlaceboSodium oxybate (2.5 g)Zolpidem (10 mg)
    A.M.P.M.A.M.P.M.A.M.P.M.
    Verbal memory: word-pair associates (number of correct pairs recalled out of 48 pairs)24.5 ± 1.528.9 ± 1.326.7 ± 1.230.1 ± 1.024.1 ± 1.530.4 ± 1.0*
    Perceptual learning: texture discrimination (threshold in ms)153.1 ± 16.9133.4 ± 13.0149.6 ± 16.4132.1 ± 13.0151.3 ± 17.0163.4 ± 17.0*
    Motor learning: motor sequence (number of correct sequences)20.0 ± 0.9724.7 ± 1.021.5 ± 1.025.2 ± 1.120.8 ± 0.8324.4 ± 0.91
    • ↵*p < 0.05.

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The Critical Role of Sleep Spindles in Hippocampal-Dependent Memory: A Pharmacology Study
Sara C. Mednick, Elizabeth A. McDevitt, James K. Walsh, Erin Wamsley, Martin Paulus, Jennifer C. Kanady, Sean P. A. Drummond
Journal of Neuroscience 6 March 2013, 33 (10) 4494-4504; DOI: 10.1523/JNEUROSCI.3127-12.2013

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The Critical Role of Sleep Spindles in Hippocampal-Dependent Memory: A Pharmacology Study
Sara C. Mednick, Elizabeth A. McDevitt, James K. Walsh, Erin Wamsley, Martin Paulus, Jennifer C. Kanady, Sean P. A. Drummond
Journal of Neuroscience 6 March 2013, 33 (10) 4494-4504; DOI: 10.1523/JNEUROSCI.3127-12.2013
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