Advertisement

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

  • Dara S. Manoach
    Correspondence
    Address correspondence to Dara S. Manoach, Ph.D., Massachusetts General Hospital, 149 13th Street, Room 1.111, Charlestown, MA 02129.
    Affiliations
    Department of Psychiatry and Psychiatric and Neurodevelopmental Genetics Unit, Analytic, Boston

    Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown

    Stanley Center for Psychiatric Research, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts
    Search for articles by this author
  • Jen Q. Pan
    Affiliations
    Stanley Center for Psychiatric Research, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts
    Search for articles by this author
  • Shaun M. Purcell
    Affiliations
    Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston

    Stanley Center for Psychiatric Research, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts

    Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York
    Search for articles by this author
  • Robert Stickgold
    Affiliations
    Stanley Center for Psychiatric Research, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts

    Department of Psychiatry, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
    Search for articles by this author

      Abstract

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

      Keywords

      To read this article in full you will need to make a payment

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Tyler D.B.
        Psychological changes during experimental sleep deprivation.
        Dis Nerv Syst. 1955; 16: 293-299
        • Wehr T.A.
        • Sack D.A.
        • Rosenthal N.E.
        Sleep reduction as a final common pathway in the genesis of mania.
        Am J Psychiatry. 1987; 144: 201-204
        • Breslau N.
        • Roth T.
        • Rosenthal L.
        • Andreski P.
        Sleep disturbance and psychiatric disorders: A longitudinal epidemiological study of young adults.
        Biol Psychiatry. 1996; 39: 411-418
        • Huang Y.S.
        • Guilleminault C.
        • Li H.Y.
        • Yang C.M.
        • Wu Y.Y.
        • Chen N.H.
        Attention-deficit/hyperactivity disorder with obstructive sleep apnea: A treatment outcome study.
        Sleep Med. 2007; 8: 18-30
        • Germain A.
        • Buysse D.J.
        • Nofzinger E.
        Sleep-specific mechanisms underlying posttraumatic stress disorder: Integrative review and neurobiological hypotheses.
        Sleep Med Rev. 2008; 12: 185-195
        • Sateia M.J.
        Update on sleep and psychiatric disorders.
        Chest. 2009; 135: 1370-1379
        • Fava M.
        • McCall W.V.
        • Krystal A.
        • Wessel T.
        • Rubens R.
        • Caron J.
        • et al.
        Eszopiclone co-administered with fluoxetine in patients with insomnia coexisting with major depressive disorder.
        Biol Psychiatry. 2006; 59: 1052-1060
      1. Kraepelin E (1919): Dementia Praecox and Paraphrenia. Edinburgh, Scotland: E.S. Livingston.

        • Hofstetter J.R.
        • Lysaker P.H.
        • Mayeda A.R.
        Quality of sleep in patients with schizophrenia is associated with quality of life and coping.
        BMC Psychiatry. 2005; 5: 13
        • Goldman M.
        • Tandon R.
        • DeQuardo J.R.
        • Taylor S.F.
        • Goodson J.
        • McGrath M.
        Biological predictors of 1-year outcome in schizophrenia in males and females.
        Schizophr Res. 1996; 21: 65-73
        • Lieberman J.A.
        • Stroup T.S.
        • McEvoy J.P.
        • Swartz M.S.
        • Rosenheck R.A.
        • Perkins D.O.
        • et al.
        Effectiveness of antipsychotic drugs in patients with chronic schizophrenia.
        N Engl J Med. 2005; 353: 1209-1223
        • Lunsford-Avery J.R.
        • Orr J.M.
        • Gupta T.
        • Pelletier-Baldelli A.
        • Dean D.J.
        • Smith Watts A.K.
        • et al.
        Sleep dysfunction and thalamic abnormalities in adolescents at ultra high-risk for psychosis.
        Schizophr Res. 2013; 151: 148-153
        • Miller T.J.
        • Zipursky R.B.
        • Perkins D.
        • Addington J.
        • Woods S.W.
        • Hawkins K.A.
        • et al.
        The PRIME North America randomized double-blind clinical trial of olanzapine versus placebo in patients at risk of being prodromally symptomatic for psychosis. II. Baseline characteristics of the “prodromal” sample.
        Schizophr Res. 2003; 61: 19-30
        • Keshavan M.S.
        • Diwadkar V.A.
        • Montrose D.M.
        • Stanley J.A.
        • Pettegrew J.W.
        Premorbid characterization in schizophrenia: the Pittsburgh High Risk Study.
        World Psychiatry. 2004; 3: 163-168
        • Benson K.L.
        Sleep in schizophrenia: Pathology and treatment.
        Sleep Med Clin. 2015; 10: 49-55
        • Dencker S.J.
        • Malm U.
        • Lepp M.
        Schizophrenic relapse after drug withdrawal is predictable.
        Acta Psychiatr Scand. 1986; 73: 181-185
        • Chouinard S.
        • Poulin J.
        • Stip E.
        • Godbout R.
        Sleep in untreated patients with schizophrenia: A meta-analysis.
        Schizophr Bull. 2004; 30: 957-967
        • Krystal A.D.
        • Goforth H.W.
        • Roth T.
        Effects of antipsychotic medications on sleep in schizophrenia.
        Int Clin Psychopharmacol. 2008; 23: 150-160
        • Nofzinger E.A.
        • van Kammen D.P.
        • Gilbertson M.W.
        • Gurklis J.A.
        • Peters J.L.
        Electroencephalographic sleep in clinically stable schizophrenic patients: Two-weeks versus six-weeks neuroleptic-free.
        Biol Psychiatry. 1993; 33: 829-835
        • Chemerinski E.
        • Ho B.C.
        • Flaum M.
        • Arndt S.
        • Fleming F.
        • Andreasen N.C.
        Insomnia as a predictor for symptom worsening following antipsychotic withdrawal in schizophrenia.
        Compr Psychiatry. 2002; 43: 393-396
        • Benca R.M.
        • Obermeyer W.H.
        • Thisted R.A.
        • Gillin J.C.
        Sleep and psychiatric disorders. A meta-analysis.
        Arch Gen Psychiatry. 1992; 49 (discussion 669–670): 651-668
        • Rao M.L.
        • Gross G.
        • Strebel B.
        • Halaris A.
        • Huber G.
        • Braunig P.
        • et al.
        Circadian rhythm of tryptophan, serotonin, melatonin, and pituitary hormones in schizophrenia.
        Biol Psychiatry. 1994; 35: 151-163
        • Iber C.
        • Ancoli-Israel S.
        • Chesson A.L.
        • Quan S.F.
        The AASM Manual for the Scoring of Sleep and Associated Events: Rules.
        Terminology, and Technical Specifications. American Academy of Sleep Medicine, Westchester, IL2007
        • Feinberg I.
        • Braun M.
        • Koresko R.L.
        • Gottlieb F.
        Stage 4 sleep in schizophrenia.
        Arch Gen Psychiatry. 1969; 21: 262-266
        • Poulin J.
        • Daoust A.M.
        • Forest G.
        • Stip E.
        • Godbout R.
        Sleep architecture and its clinical correlates in first episode and neuroleptic-naive patients with schizophrenia.
        Schizophr Res. 2003; 62: 147-153
        • Yang C.
        • Winkelman J.W.
        Clinical significance of sleep EEG abnormalities in chronic schizophrenia.
        Schizophr Res. 2006; 82: 251-260
        • Keshavan M.S.
        • Reynolds 3rd, C.F.
        • Miewald M.J.
        • Montrose D.M.
        • Sweeney J.A.
        • Vasko Jr, R.C.
        • et al.
        Delta sleep deficits in schizophrenia: Evidence from automated analyses of sleep data.
        Arch Gen Psychiatry. 1998; 55: 443-448
        • Tandon R.
        • Shipley J.E.
        • Taylor S.
        • Greden J.F.
        • Eiser A.
        • DeQuardo J.
        • et al.
        Electroencephalographic sleep abnormalities in schizophrenia. Relationship to positive/negative symptoms and prior neuroleptic treatment.
        Arch Gen Psychiatry. 1992; 49: 185-194
        • Lauer C.J.
        • Schreiber W.
        • Pollmacher T.
        • Holsboer F.
        • Krieg J.C.
        Sleep in schizophrenia: A polysomnographic study on drug-naive patients.
        Neuropsychopharmacology. 1997; 16: 51-60
        • De Gennaro L.
        • Ferrara M.
        Sleep spindles: An overview.
        Sleep Med Rev. 2003; 7: 423-440
        • Wamsley E.
        • Tucker M.A.
        • Shinn A.K.
        • Ono K.E.
        • McKinley S.
        • Ely A.V.
        • et al.
        Reduced sleep spindles and spindle coherence in schizophrenia: Mechanisms of impaired memory consolidation?.
        Biol Psychiatry. 2012; 71: 154-161
        • Guillery R.W.
        • Harting J.K.
        Structure and connections of the thalamic reticular nucleus: Advancing views over half a century.
        J Comp Neurol. 2003; 463: 360-371
        • Houser C.R.
        • Vaughn J.E.
        • Barber R.P.
        • Roberts E.
        GABA neurons are the major cell type of the nucleus reticularis thalami.
        Brain Res. 1980; 200: 341-354
        • Jacobsen R.B.
        • Ulrich D.
        • Huguenard J.R.
        GABA(B) and NMDA receptors contribute to spindle-like oscillations in rat thalamus in vitro.
        J Neurophysiol. 2001; 86: 1365-1375
        • Fuentealba P.
        • Steriade M.
        The reticular nucleus revisited: Intrinsic and network properties of a thalamic pacemaker.
        Prog Neurobiol. 2005; 75: 125-141
        • Steriade M.
        • Domich L.
        • Oakson G.
        • Deschenes M.
        The deafferented reticular thalamic nucleus generates spindle rhythmicity.
        J Neurophysiol. 1987; 57: 260-273
        • Contreras D.
        • Destexhe A.
        • Sejnowski T.J.
        • Steriade M.
        Control of spatiotemporal coherence of a thalamic oscillation by corticothalamic feedback.
        Science. 1996; 274: 771-774
        • Sherman S.M.
        • Guillery R.W.
        Exploring the Thalamus and Its Role in Cortical Function.
        2nd ed. Cambridge, MA: The MIT Press, 2006
        • Contreras D.
        • Steriade M.
        Spindle oscillation in cats: The role of corticothalamic feedback in a thalamically generated rhythm.
        J Physiol. 1996; 490: 159-179
        • Zhang Y.
        • Llinas R.R.
        • Lisman J.E.
        Inhibition of NMDARs in the nucleus reticularis of the thalamus produces delta frequency bursting.
        Front Neural Circuits. 2009; 3: 20
        • Smith R.E.
        • Haroutunian V.
        • Davis K.L.
        • Meador-Woodruff J.H.
        Expression of excitatory amino acid transporter transcripts in the thalamus of subjects with schizophrenia.
        Am J Psychiatry. 2001; 158: 1393-1399
        • Dave A.S.
        • Yu A.C.
        • Margoliash D.
        Behavioral state modulation of auditory activity in a vocal motor system.
        Science. 1998; 282: 2250-2254
        • Siapas A.G.
        • Wilson M.A.
        Coordinated interactions between hippocampal ripples and cortical spindles during slow-wave sleep.
        Neuron. 1998; 21: 1123-1128
        • Frank M.G.
        • Issa N.P.
        • Stryker M.P.
        Sleep enhances plasticity in the developing visual cortex.
        Neuron. 2001; 30: 275-287
        • Stickgold R.
        • Walker M.P.
        Sleep-dependent memory triage: Evolving generalization through selective processing.
        Nat Neurosci. 2013; 16: 139-145
        • Sejnowski T.J.
        • Destexhe A.
        Why do we sleep?.
        Brain Res. 2000; 886: 208-223
        • Ghosh A.
        • Greenberg M.E.
        Calcium signaling in neurons: Molecular mechanisms and cellular consequences.
        Science. 1995; 268: 239-247
        • Rosanova M.
        • Ulrich D.
        Pattern-specific associative long-term potentiation induced by a sleep spindle-related spike train.
        J Neurosci. 2005; 25: 9398-9405
        • Walker M.P.
        • Brakefield T.
        • Morgan A.
        • Hobson J.A.
        • Stickgold R.
        Practice with sleep makes perfect: Sleep-dependent motor skill learning.
        Neuron. 2002; 35: 205-211
        • Nishida M.
        • Walker M.P.
        Daytime naps, motor memory consolidation and regionally specific sleep spindles.
        PLoS One. 2007; 2: e341
        • Rasch B.
        • Pommer J.
        • Diekelmann S.
        • Born J.
        Pharmacological REM sleep suppression paradoxically improves rather than impairs skill memory.
        Nat Neurosci. 2008; 12: 396-397
        • Tamaki M.
        • Matsuoka T.
        • Nittono H.
        • Hori T.
        Fast sleep spindle (13-15 Hz) activity correlates with sleep-dependent improvement in visuomotor performance.
        Sleep. 2008; 31: 204-211
        • Fogel S.M.
        • Smith C.T.
        Learning-dependent changes in sleep spindles and stage 2 sleep.
        J Sleep Res. 2006; 15: 250-255
        • Peters K.R.
        • Ray L.
        • Smith V.
        • Smith C.
        Changes in the density of stage 2 sleep spindles following motor learning in young and older adults.
        J Sleep Res. 2008; 17: 23-33
        • Clemens Z.
        • Fabo D.
        • Halasz P.
        Twenty-four hours retention of visuospatial memory correlates with the number of parietal sleep spindles.
        Neurosci Lett. 2006; 403: 52-56
        • Clemens Z.
        • Fabo D.
        • Halasz P.
        Overnight verbal memory retention correlates with the number of sleep spindles.
        Neuroscience. 2005; 132: 529-535
        • Schabus M.
        • Hoedlmoser K.
        • Pecherstorfer T.
        • Anderer P.
        • Gruber G.
        • Parapatics S.
        • et al.
        Interindividual sleep spindle differences and their relation to learning-related enhancements.
        Brain Res. 2008; 1191: 127-135
        • Tamaki M.
        • Huang T.R.
        • Yotsumoto Y.
        • Hamalainen M.
        • Lin F.H.
        • Nanez Sr, J.E.
        • et al.
        Enhanced spontaneous oscillations in the supplementary motor area are associated with sleep-dependent offline learning of finger-tapping motor-sequence task.
        J Neurosci. 2013; 33: 13894-13902
        • Johnson L.A.
        • Blakely T.
        • Hermes D.
        • Hakimian S.
        • Ramsey N.F.
        • Ojemann J.G.
        Sleep spindles are locally modulated by training on a brain-computer interface.
        Proc Natl Acad Sci U S A. 2012; 109: 18583-18588
        • Bang J.W.
        • Khalilzadeh O.
        • Hamalainen M.
        • Watanabe T.
        • Sasaki Y.
        Location specific sleep spindle activity in the early visual areas and perceptual learning.
        Vision Res. 2014; 99: 162-171
        • Fogel S.M.
        • Smith C.T.
        The function of the sleep spindle: A physiological index of intelligence and a mechanism for sleep-dependent memory consolidation.
        Neurosci Biobehav Rev. 2011; 35: 1154-1165
        • Schabus M.
        • Hodlmoser K.
        • Gruber G.
        • Sauter C.
        • Anderer P.
        • Klosch G.
        • et al.
        Sleep spindle-related activity in the human EEG and its relation to general cognitive and learning abilities.
        Eur J Neurosci. 2006; 23: 1738-1746
        • Lustenberger C.
        • Maric A.
        • Durr R.
        • Achermann P.
        • Huber R.
        Triangular relationship between sleep spindle activity, general cognitive ability and the efficiency of declarative learning.
        PLoS One. 2012; 7: e49561
        • Molle M.
        • Born J.
        Slow oscillations orchestrating fast oscillations and memory consolidation.
        Prog Brain Res. 2011; 193: 93-110
        • Clemens Z.
        • Molle M.
        • Eross L.
        • Barsi P.
        • Halasz P.
        • Born J.
        Temporal coupling of parahippocampal ripples, sleep spindles and slow oscillations in humans.
        Brain. 2007; 130: 2868-2878
        • Andrade K.C.
        • Spoormaker V.I.
        • Dresler M.
        • Wehrle R.
        • Holsboer F.
        • Samann P.G.
        • et al.
        Sleep spindles and hippocampal functional connectivity in human NREM sleep.
        J Neurosci. 2011; 31: 10331-10339
        • Phillips K.G.
        • Bartsch U.
        • McCarthy A.P.
        • Edgar D.M.
        • Tricklebank M.D.
        • Wafford K.A.
        • et al.
        Decoupling of sleep-dependent cortical and hippocampal interactions in a neurodevelopmental model of schizophrenia.
        Neuron. 2012; 76: 526-533
        • Ngo H.V.
        • Martinetz T.
        • Born J.
        • Molle M.
        Auditory closed-loop stimulation of the sleep slow oscillation enhances memory.
        Neuron. 2013; 78: 545-553
        • Forest G.
        • Poulin J.
        • Daoust A.M.
        • Lussier I.
        • Stip E.
        • Godbout R.
        Attention and non-REM sleep in neuroleptic-naive persons with schizophrenia and control participants.
        Psychiatry Res. 2007; 149: 33-40
        • Van Cauter E.
        • Linkowski P.
        • Kerkhofs M.
        • Hubain P.
        • L’Hermite-Baleriaux M.
        • Leclercq R.
        • et al.
        Circadian and sleep-related endocrine rhythms in schizophrenia.
        Arch Gen Psychiatry. 1991; 48: 348-356
        • Hiatt J.F.
        • Floyd T.C.
        • Katz P.H.
        • Feinberg I.
        Further evidence of abnormal non-rapid-eye-movement sleep in schizophrenia.
        Arch Gen Psychiatry. 1985; 42: 797-802
        • Goder R.
        • Graf A.
        • Ballhausen F.
        • Weinhold S.
        • Baier P.C.
        • Junghanns K.
        • et al.
        Impairment of sleep-related memory consolidation in schizophrenia: relevance of sleep spindles?.
        Sleep Med. 2015; 16: 564-569
        • Manoach D.S.
        • Thakkar K.N.
        • Stroynowski E.
        • Ely A.
        • McKinley S.K.
        • Wamsley E.
        • et al.
        Reduced overnight consolidation of procedural learning in chronic medicated schizophrenia is related to specific sleep stages.
        J Psychiatr Res. 2010; 44: 112-120
        • Ferrarelli F.
        • Huber R.
        • Peterson M.J.
        • Massimini M.
        • Murphy M.
        • Riedner B.A.
        • et al.
        Reduced sleep spindle activity in schizophrenia patients.
        Am J Psychiatry. 2007; 164: 483-492
        • Ferrarelli F.
        • Peterson M.J.
        • Sarasso S.
        • Riedner B.A.
        • Murphy M.J.
        • Benca R.M.
        • et al.
        Thalamic dysfunction in schizophrenia suggested by whole-night deficits in slow and fast spindles.
        Am J Psychiatry. 2010; 167: 1339-1348
        • Seeck-Hirschner M.
        • Baier P.C.
        • Sever S.
        • Buschbacher A.
        • Aldenhoff J.B.
        • Goder R.
        Effects of daytime naps on procedural and declarative memory in patients with schizophrenia.
        J Psychiatr Res. 2011; 44: 42-47
        • Tesler N.
        • Gerstenberg M.
        • Franscini M.
        • Jenni O.G.
        • Walitza S.
        • Huber R.
        Reduced sleep spindle density in early onset schizophrenia: A preliminary finding.
        Schizophr Res. 2015; 166: 355-357
        • Goder R.
        • Fritzer G.
        • Gottwald B.
        • Lippmann B.
        • Seeck-Hirschner M.
        • Serafin I.
        • et al.
        Effects of olanzapine on slow wave sleep, sleep spindles and sleep-related memory consolidation in schizophrenia.
        Pharmacopsychiatry. 2008; 41: 92-99
        • Hirshkowitz M.
        • Thornby J.I.
        • Karacan I.
        Sleep spindles: Pharmacological effects in humans.
        Sleep. 1982; 5: 85-94
        • Manoach D.S.
        • Demanuele C.
        • Wamsley E.J.
        • Vangel M.
        • Montrose D.M.
        • Miewald J.
        • et al.
        Sleep spindle deficits in antipsychotic-naïve early course schizophrenia and in non-psychotic first-degree relatives.
        Front Hum Neurosci. 2014; 8: 762
        • Plante D.T.
        • Goldstein M.R.
        • Landsness E.C.
        • Peterson M.J.
        • Riedner B.A.
        • Ferrarelli F.
        • et al.
        Topographic and sex-related differences in sleep spindles in major depressive disorder: A high-density EEG investigation.
        J Affect Disord. 2013; 146: 120-125
        • Shibagaki M.
        • Kiyono S.
        • Watanabe K.
        Spindle evolution in normal and mentally retarded children: A review.
        Sleep. 1982; 5: 47-57
        • De Giorgis G.F.
        • Nonnis E.
        • Crocioni F.
        • Gregori P.
        • Rosini M.P.
        • Leuzzi V.
        • et al.
        Evolution of daytime quiet sleep components in early treated phenylketonuric infants.
        Brain Dev. 1996; 18: 201-206
        • Bodizs R.
        • Gombos F.
        • Kovacs I.
        Sleep EEG fingerprints reveal accelerated thalamocortical oscillatory dynamics in Williams syndrome.
        Res Dev Disabil. 2012; 33: 153-164
        • Limoges E.
        • Mottron L.
        • Bolduc C.
        • Berthiaume C.
        • Godbout R.
        Atypical sleep architecture and the autism phenotype.
        Brain. 2005; 128: 1049-1061
        • Tessier S.
        • Lambert A.
        • Chicoine M.
        • Scherzer P.
        • Soulieres I.
        • Godbout R.
        Intelligence measures and stage 2 sleep in typically-developing and autistic children.
        Int J Psychophysiol. 2015; 97: 58-65
        • Latreille V.
        • Carrier J.
        • Lafortune M.
        • Postuma R.B.
        • Bertrand J.A.
        • Panisset M.
        • et al.
        Sleep spindles in Parkinson’s disease may predict the development of dementia.
        Neurobiol Aging. 2015; 36: 1083-1090
        • Gottesman II,
        • Gould T.D.
        The endophenotype concept in psychiatry: Etymology and strategic intentions.
        Am J Psychiatry. 2003; 160: 636-645
        • Chee M.W.
        • Chuah L.Y.
        Functional neuroimaging insights into how sleep and sleep deprivation affect memory and cognition.
        Curr Opin Neurol. 2008; 21: 417-423
        • Stickgold R.
        • Walker M.P.
        Sleep-dependent memory consolidation and reconsolidation.
        Sleep Med. 2007; 8: 331-343
        • Cipolli C.
        • Mazzetti M.
        • Plazzi G.
        Sleep-dependent memory consolidation in patients with sleep disorders.
        Sleep Med Rev. 2013; 17: 91-103
        • Karni A.
        • Meyer G.
        • Rey-Hipolito C.
        • Jezzard P.
        • Adams M.M.
        • Turner R.
        • et al.
        The acquisition of skilled motor performance: Fast and slow experience-driven changes in primary motor cortex.
        Proc Natl Acad Sci U S A. 1998; 95: 861-868
        • Gregory M.
        • Agam Y.
        • Selvadurai C.
        • Nagy A.
        • Vangel M.
        • Tucker M.
        • et al.
        Resting state connectivity immediately following learning correlates with subsequent sleep-dependent enhancement of motor task performance.
        Neuroimage. 2014; 102: 666-673
        • Walker M.P.
        • Brakefield T.
        • Seidman J.
        • Morgan A.
        • Hobson J.A.
        • Stickgold R.
        Sleep and the time course of motor skill learning.
        Learn Mem. 2003; 10: 275-284
        • Fischer S.
        • Nitschke M.F.
        • Melchert U.H.
        • Erdmann C.
        • Born J.
        Motor memory consolidation in sleep shapes more effective neuronal representations.
        J Neurosci. 2005; 25: 11248-11255
        • Barakat M.
        • Doyon J.
        • Debas K.
        • Vandewalle G.
        • Morin A.
        • Poirier G.
        • et al.
        Fast and slow spindle involvement in the consolidation of a new motor sequence.
        Behav Brain Res. 2011; 217: 117-121
        • Albouy G.
        • Fogel S.
        • Pottiez H.
        • Nguyen V.A.
        • Ray L.
        • Lungu O.
        • et al.
        Daytime sleep enhances consolidation of the spatial but not motoric representation of motor sequence memory.
        PLoS One. 2013; 8: e52805
        • Manoach D.S.
        • Cain M.S.
        • Vangel M.G.
        • Khurana A.
        • Goff D.C.
        • Stickgold R.
        A failure of sleep-dependent procedural learning in chronic, medicated schizophrenia.
        Biol Psychiatry. 2004; 56: 951-956
        • Genzel L.
        • Ali E.
        • Dresler M.
        • Steiger A.
        • Tesfaye M.
        Sleep-dependent memory consolidation of a new task is inhibited in psychiatric patients.
        J Psychiatr Res. 2011; 45: 555-560
        • Genzel L.
        • Dresler M.
        • Cornu M.
        • Jager E.
        • Konrad B.
        • Adamczyk M.
        • et al.
        Medial prefrontal-hippocampal connectivity and motor memory consolidation in depression and schizophrenia.
        Biol Psychiatry. 2015; 77: 177-186
        • Crick F.
        Function of the thalamic reticular complex: The searchlight hypothesis.
        Proc Natl Acad Sci U S A. 1984; 81: 4586-4590
        • Zikopoulos B.
        • Barbas H.
        Pathways for emotions and attention converge on the thalamic reticular nucleus in primates.
        J Neurosci. 2012; 32: 5338-5350
        • Pinault D.
        The thalamic reticular nucleus: Structure, function and concept.
        Brain Res Rev. 2004; 46: 1-31
        • Halassa M.M.
        • Chen Z.
        • Wimmer R.D.
        • Brunetti P.M.
        • Zhao S.
        • Zikopoulos B.
        • et al.
        State-dependent architecture of thalamic reticular subnetworks.
        Cell. 2014; 158: 808-821
        • Bramon E.
        • Rabe-Hesketh S.
        • Sham P.
        • Murray R.M.
        • Frangou S.
        Meta-analysis of the P300 and P50 waveforms in schizophrenia.
        Schizophr Res. 2004; 70: 315-329
        • Ahrens S.
        • Jaramillo S.
        • Yu K.
        • Ghosh S.
        • Hwang G.R.
        • Paik R.
        • et al.
        ErbB4 regulation of a thalamic reticular nucleus circuit for sensory selection.
        Nat Neurosci. 2015; 18: 104-111
        • McAlonan K.
        • Brown V.J.
        • Bowman E.M.
        Thalamic reticular nucleus activation reflects attentional gating during classical conditioning.
        J Neurosci. 2000; 20: 8897-8901
        • Uhlhaas P.J.
        • Singer W.
        Abnormal neural oscillations and synchrony in schizophrenia.
        Nat Rev Neurosci. 2010; 11: 100-113
        • Hashimoto T.
        • Volk D.W.
        • Eggan S.M.
        • Mirnics K.
        • Pierri J.N.
        • Sun Z.
        • et al.
        Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia.
        J Neurosci. 2003; 23: 6315-6326
        • Danos P.
        • Baumann B.
        • Bernstein H.G.
        • Franz M.
        • Stauch R.
        • Northoff G.
        • et al.
        Schizophrenia and anteroventral thalamic nucleus: selective decrease of parvalbumin-immunoreactive thalamocortical projection neurons.
        Psychiatry Res. 1998; 82: 1-10
        • Demjaha A.
        • Egerton A.
        • Murray R.M.
        • Kapur S.
        • Howes O.D.
        • Stone J.M.
        • et al.
        Antipsychotic treatment resistance in schizophrenia associated with elevated glutamate levels but normal dopamine function.
        Biol Psychiatry. 2014; 75: e11-e13
        • Keshavan M.S.
        Development, disease and degeneration in schizophrenia: A unitary pathophysiological model.
        J Psychiatr Res. 1999; 33: 513-521
        • Lustenberger C.
        • O’Gorman R.L.
        • Pugin F.
        • Tushaus L.
        • Wehrle F.
        • Achermann P.
        • et al.
        Sleep spindles are related to schizotypal personality traits and thalamic glutamine/glutamate in healthy subjects.
        Schizophr Bull. 2015; 41: 522-531
        • Vukadinovic Z.
        Sleep abnormalities in schizophrenia may suggest impaired trans-thalamic cortico-cortical communication: Towards a dynamic model of the illness.
        Eur J Neurosci. 2011; 34: 1031-1039
        • Green M.F.
        • Kern R.S.
        • Braff D.L.
        • Mintz J.
        Neurocognitive deficits and functional outcome in schizophrenia: Are we measuring the “right stuff”?.
        Schizophr Bull. 2000; 26: 119-136
        • Insel T.R.
        Translating scientific opportunity into public health impact: A strategic plan for research on mental illness.
        Arch Gen Psychiatry. 2009; 66: 128-133
        • Sergi M.J.
        • Green M.F.
        • Widmark C.
        • Reist C.
        • Erhart S.
        • Braff D.L.
        • et al.
        Social cognition [corrected] and neurocognition: Effects of risperidone, olanzapine, and haloperidol.
        Am J Psychiatry. 2007; 164: 1585-1592
      2. Shin H (2015): Optogenetic induced spindles alter sleep architecture in mice. Presented at the World Congress on Sleep Medicine, March 21–25, Seoul, Korea.

      3. McCarley R, Thankachan S, McNally J, McKenna J, Strecker R, Brown R (2014): Optogenetic study of the role of parvalbumin-containing thalamic reticular nucleus neurons in spindle generation: Implications for schizophrenia. Presented at the American College of Neuropsychopharmacology Annual Meeting, December 7–11, Phoenix, Arizona.

        • Kaestner E.J.
        • Wixted J.T.
        • Mednick S.C.
        Pharmacologically increasing sleep spindles enhances recognition for negative and high-arousal memories.
        J Cogn Neurosci. 2013; 25: 1597-1610
        • Mednick S.C.
        • McDevitt E.A.
        • Walsh J.K.
        • Wamsley E.
        • Paulus M.
        • Kanady J.C.
        • et al.
        The critical role of sleep spindles in hippocampal-dependent memory: A pharmacology study.
        J Neurosci. 2013; 33: 4494-4504
        • Marshall L.
        • Helgadottir H.
        • Molle M.
        • Born J.
        Boosting slow oscillations during sleep potentiates memory.
        Nature. 2006; 444: 610-613
        • Del Felice A.
        • Magalini A.
        • Masiero S.
        Slow-oscillatory transcranial direct current stimulation modulates memory in temporal lobe epilepsy by altering sleep spindle generators: A possible rehabilitation tool.
        Brain Stimul. 2015; 8: 567-573
        • Marshall L.
        • Kirov R.
        • Brade J.
        • Molle M.
        • Born J.
        Transcranial electrical currents to probe EEG brain rhythms and memory consolidation during sleep in humans.
        PLoS One. 2011; 6: e16905
        • Goder R.
        • Baier P.C.
        • Beith B.
        • Baecker C.
        • Seeck-Hirschner M.
        • Junghanns K.
        • et al.
        Effects of transcranial direct current stimulation during sleep on memory performance in patients with schizophrenia.
        Schizophr Res. 2013; 144: 153-154
        • Jia F.
        • Goldstein P.A.
        • Harrison N.L.
        The modulation of synaptic GABA(A) receptors in the thalamus by eszopiclone and zolpidem.
        J Pharmacol Exp Ther. 2009; 328: 1000-1006
        • Wamsley E.J.
        • Shinn A.K.
        • Tucker M.A.
        • Ono K.E.
        • McKinley S.K.
        • Ely A.V.
        • et al.
        The effects of eszopiclone on sleep spindles and memory consolidation in schizophrenia: A randomized placebo-controlled trial.
        Sleep. 2013; 36: 1369-1376
        • Tek C.
        • Palmese L.B.
        • Krystal A.D.
        • Srihari V.H.
        • DeGeorge P.C.
        • Reutenauer E.L.
        • et al.
        The impact of eszopiclone on sleep and cognition in patients with schizophrenia and insomnia: A double-blind, randomized, placebo-controlled trial.
        Schizophr Res. 2014; 160: 180-185
        • De Gennaro L.
        • Marzano C.
        • Fratello F.
        • Moroni F.
        • Pellicciari M.C.
        • Ferlazzo F.
        • et al.
        The electroencephalographic fingerprint of sleep is genetically determined: a twin study.
        Ann Neurol. 2008; 64: 455-460
        • Ambrosius U.
        • Lietzenmaier S.
        • Wehrle R.
        • Wichniak A.
        • Kalus S.
        • Winkelmann J.
        • et al.
        Heritability of sleep electroencephalogram.
        Biol Psychiatry. 2008; 64: 344-348
        • Hori A.
        Sleep characteristics in twins.
        Jpn J Psychiatry Neurol. 1986; 40: 35-46
        • Raizen D.M.
        • Wu M.N.
        Genome-wide association studies of sleep disorders.
        Chest. 2011; 139: 446-452
        • Parsons M.J.
        • Lester K.J.
        • Barclay N.L.
        • Nolan P.M.
        • Eley T.C.
        • Gregory A.M.
        Replication of genome-wide association studies (GWAS) loci for sleep in the British G1219 cohort.
        Am J Med Genet B Neuropsychiatr Genet. 2013; 162: 431-438
        • Byrne E.M.
        • Gehrman P.R.
        • Medland S.E.
        • Nyholt D.R.
        • Heath A.C.
        • Madden P.A.
        • et al.
        A genome-wide association study of sleep habits and insomnia.
        Am J Med Genet B Neuropsychiatr Genet. 2013; 162: 439-451
        • Landolt H.P.
        Genetic determination of sleep EEG profiles in healthy humans.
        Prog Brain Res. 2011; 193: 51-61
        • Veltman J.A.
        • Brunner H.G.
        De novo mutations in human genetic disease.
        Nat Rev Genet. 2012; 13: 565-575
        • Schizophrenia Working Group of the Psychiatric Genomics Consortium
        Biological insights from 108 schizophrenia-associated genetic loci.
        Nature. 2014; 511: 421-427
        • Gulsuner S.
        • Walsh T.
        • Watts A.C.
        • Lee M.K.
        • Thornton A.M.
        • Casadei S.
        • et al.
        Spatial and temporal mapping of de novo mutations in schizophrenia to a fetal prefrontal cortical network.
        Cell. 2013; 154: 518-529
        • Liu X.B.
        • Murray K.D.
        • Jones E.G.
        Low-threshold calcium channel subunit Ca(v) 3.3 is specifically localized in GABAergic neurons of rodent thalamus and cerebral cortex.
        J Comp Neurol. 2011; 519: 1181-1195
        • Cueni L.
        • Canepari M.
        • Lujan R.
        • Emmenegger Y.
        • Watanabe M.
        • Bond C.T.
        • et al.
        T-type Ca2+ channels, SK2 channels and SERCAs gate sleep-related oscillations in thalamic dendrites.
        Nat Neurosci. 2008; 11: 683-692
        • Astori S.
        • Wimmer R.D.
        • Prosser H.M.
        • Corti C.
        • Corsi M.
        • Liaudet N.
        • et al.
        The Ca(V)3.3 calcium channel is the major sleep spindle pacemaker in thalamus.
        Proc Natl Acad Sci U S A. 2011; 108: 13823-13828
        • Manoach D.S.
        • Stickgold R.
        Does abnormal sleep impair memory consolidation in schizophrenia?.
        Front Hum Neurosci. 2009; 3: 21
        • Atienza M.
        • Cantero J.L.
        • Stickgold R.
        Posttraining sleep enhances automaticity in perceptual discrimination.
        J Cogn Neurosci. 2004; 16: 53-64
        • Chapman L.J.
        • Chapman J.P.
        The measurement of differential deficit.
        J Psychiatr Res. 1978; 14: 303-311
        • Viviano J.D.
        • Schneider K.A.
        Interhemispheric interactions of the human thalamic reticular nucleus.
        J Neurosci. 2015; 35: 2026-2032
        • Evrard A.
        • Ropert N.
        Early development of the thalamic inhibitory feedback loop in the primary somatosensory system of the newborn mice.
        J Neurosci. 2009; 29: 9930-9940
        • Pinault D.
        Dysfunctional thalamus-related networks in schizophrenia.
        Schizophr Bull. 2011; 37: 238-243
        • Feinberg I.
        Schizophrenia: Caused by a fault in programmed synaptic elimination during adolescence?.
        J Psychiatr Res. 1982; 17: 319-334
        • Vukadinovic Z.
        Schizophrenia as a disturbance of cortical sensory maps.
        Transl Neurosci. 2012; 3: 388-398
        • Born J.
        • Wilhelm I.
        System consolidation of memory during sleep.
        Psychol Res. 2012; 76: 192-203