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Fast sleep spindle reduction in schizophrenia and healthy first-degree relatives: association with impaired cognitive function and potential intermediate phenotype

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Abstract

Several studies in patients with schizophrenia reported a marked reduction in sleep spindle activity. To investigate whether the reduction may be linked to genetic risk of the illness, we analysed sleep spindle activity in healthy volunteers, patients with schizophrenia and first-degree relatives, who share an enriched set of schizophrenia susceptibility genes. We further investigated the correlation of spindle activity with cognitive function in first-degree relatives and whether spindle abnormalities affect both fast (12–15 Hz) and slow (9–12 Hz) sleep spindles. We investigated fast and slow sleep spindle activity during non-rapid eye movement sleep in a total of 47 subjects comprising 17 patients with schizophrenia, 13 healthy first-degree relatives and 17 healthy volunteers. Groups were balanced for age, gender, years of education and estimated verbal IQ. A subsample of relatives received additional testing for memory performance. Compared to healthy volunteers, fast spindle density was reduced in patients with schizophrenia and healthy first-degree relatives following a pattern consistent with an assumed genetic load for schizophrenia. The deficit in spindle density was specific to fast spindles and was associated with decreased memory performance. Our findings indicate familial occurrence of this phenotype and thus support the hypothesis that deficient spindle activity relates to genetic liability for schizophrenia. Furthermore, spindle reductions predict impaired cognitive function and are specific to fast spindles. This physiological marker should be further investigated as an intermediate phenotype of schizophrenia. It could also constitute a target for drug development, especially with regard to cognitive dysfunction.

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Acknowledgments

We thank Ines Wilhelm, Amr Ayoub, Matthias Mölle (Center of Brain, Behavior and Metabolism, University of Luebeck, 23562 Luebeck, Germany) and Jan Born (Institute for Medical Psychology and Behavioural Neurobiology, University of Tuebingen, 72076 Tuebingen, Germany) for their valuable support with the spindle detection algorithm. CS acknowledges grant support from the Olympia-Morata-Programme of the University of Heidelberg, Germany. AM-L acknowledges funding from the German Federal Ministry of Education and Research (BMBF) Grant No. 01ZX1314G and partly Grant No. 01GS08147 (MooDs). HT gratefully acknowledges grant support by the German Federal Ministry of Education and Research (BMBF) Grant No. 01GQ1102. SE acknowledges grant support from the University of Heidelberg.

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  1. Manuel Schlipf

    Present address: Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Square J5, 68159, Mannheim, Germany

  2. Simone Spietzack

    Present address: Department of Radiology, Radiological Centre Speyer, Paul-Egell-Strasse 33, 67346, Speyer, Germany

  3. Oliver Grimm

    Present address: Department of Psychiatry, Psychotherapy and Psychosomatic, Psychiatric University Clinic Zurich, Lengstrasse 31, Postfach 1931, 8032, Zurich, Switzerland

Authors and Affiliations

  1. Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Square J5, 68159, Mannheim, Germany

    Claudia Schilling, Manuel Schlipf, Simone Spietzack, Franziska Rausch, Sarah Eisenacher, Susanne Englisch, Iris Reinhard, Leila Haller, Oliver Grimm, Michael Deuschle, Heike Tost, Mathias Zink, Andreas Meyer-Lindenberg & Michael Schredl

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Conflict of interest

There are no conflicts of interest to declare related to this work. There was no funding for this study. A. Meyer-Lindenberg received the following Grants: ECNP Neuropsychopharmacology Award, Prix ROGER DE SPOELBERCH. A. Meyer-Lindenberg received consultancy fees from Astra Zeneca, Elsevier, F. Hoffmann-La Roche, Gerson Lehrman Group, Lundbeck foundation, Outcome Europe Sárl, Outcome Sciences, Roche Pharma, Servier International and Thieme Verlag, and lecture fees—including the travel fees—from Abbott, Astra Zeneca, Aula Médica Congresos, BASF, Groupo Ferrer International, Janssen-Cilag, Lilly Deutschland, LVR Klinikum Düsseldorf, Servier Deutschland and Otsuka Pharmaceuticals. C. Schilling received remuneration for advisory board participation from Vanda Pharmaceuticals. M. Deuschle received speaker fees from Astra-Zeneca, Bristol-Myers Squibb and Lundbeck, Mundipharma and honoraria for consultation from Lundbeck. M. Deuschle participated in phase II/III trials by Janssen and Lilly. M. Zink received unrestricted scientific grants of the German Research Foundation (DFG) and Servier; further speaker and travel grants were provided from Pfizer Pharma GmbH, Bristol Myers Squibb Pharmaceuticals, Otsuka, Servier, Lundbeck, Janssen Cilag, Roche, Ferrer and Trommsdorff. S. Englisch received travel expenses and consultant fees from AstraZeneca, Bristol-Myers Squibb GmbH & CoKGaA, Eli-Lilly, Janssen Cilag, Otsuka Pharma, Pfizer Pharma and Servier.

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The study was approved by the local ethic committee of the Medical Faculty Mannheim of the University of Heidelberg (AZ 2010-208 N-MA and 2007-250 N-MA) and has therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. All participants were informed about the aims and procedures of the study and gave their written consent prior to the investigation.

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Schilling, C., Schlipf, M., Spietzack, S. et al. Fast sleep spindle reduction in schizophrenia and healthy first-degree relatives: association with impaired cognitive function and potential intermediate phenotype. Eur Arch Psychiatry Clin Neurosci 267, 213–224 (2017). https://doi.org/10.1007/s00406-016-0725-2

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