Sleep spindles across youth affected by schizophrenia or anti- N-methyl-D-aspartate-receptor encephalitis

Maria E Dimitriades; Andjela Markovic; Silvano R Gefferie; Ashura Buckley; David I Driver; Judith L Rapoport; Margherita Nosadini; Kevin Rostasy; Stefano Sartori; Agnese Suppiej; Salome Kurth; Maurizia Franscini; Susanne Walitza; Reto Huber; Leila Tarokh; Bigna K Bölsterli; Miriam Gerstenberg

doi:10.3389/fpsyt.2023.1055459

Sleep spindles across youth affected by schizophrenia or anti- N-methyl-D-aspartate-receptor encephalitis

Front Psychiatry. 2023 Jun 7:14:1055459. doi: 10.3389/fpsyt.2023.1055459. eCollection 2023.

Authors

Maria E Dimitriades^{1

2}, Andjela Markovic^{3

4

5}, Silvano R Gefferie^{6

7}, Ashura Buckley⁸, David I Driver⁹, Judith L Rapoport⁹, Margherita Nosadini^{10

11}, Kevin Rostasy¹², Stefano Sartori^{10

11}, Agnese Suppiej¹³, Salome Kurth⁵, Maurizia Franscini¹⁴, Susanne Walitza^{14

15

16}, Reto Huber^{1

2

14

15}, Leila Tarokh^{4

17}, Bigna K Bölsterli^{1

2

18

19}, Miriam Gerstenberg^{2

14}

Affiliations

¹ Child Development Center, University Children's Hospital Zurich, Zurich, Switzerland.
² Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.
³ Department of Pulmonology, University Hospital Zurich, Zurich, Switzerland.
⁴ University Hospital of Child and Adolescent Psychiatry and Psychotherapy, University of Bern, Bern, Switzerland.
⁵ Department of Psychology, University of Fribourg, Fribourg, Switzerland.
⁶ Stichting Epilepsie Instellingen Nederland, Heemstede, Netherlands.
⁷ Department of Neurology, Leiden University Medical Center, Leiden, Netherlands.
⁸ Pediatrics and Neurodevelopmental Neuroscience, National Institute of Mental Health, Bethesda, MD, United States.
⁹ Child Psychiatry Branch, National Institute of Mental Health, Bethesda, MD, United States.
¹⁰ Paediatric Neurology and Neurophysiology Unit, Department of Women's and Children's Health, University Hospital of Padova, Padova, Italy.
¹¹ Neuroimmunology Group, Paediatric Research Institute Città della Speranza, Padova, Italy.
¹² Department of Pediatric Neurology, Children's Hospital Datteln, Witten/Herdecke University, Datteln, Germany.
¹³ Department of Medical Sciences, Pediatric Section, University of Ferrara, Ferrara, Italy.
¹⁴ Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric University Hospital Zurich, University of Zurich, Zurich, Switzerland.
¹⁵ Neuroscience Center Zurich, University of Zurich and Swiss Federal Institute of Technology Zurich, Zurich, Switzerland.
¹⁶ Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
¹⁷ Translational Research Center, University Hospital of Psychiatry and Psychotherapy, University of Bern, Bern, Switzerland.
¹⁸ Department of Pediatric Neurology, University Children's Hospital Zurich, Zurich, Switzerland.
¹⁹ Department of Pediatric Neurology, Children's Hospital of Eastern Switzerland, St. Gallen, Switzerland.

Abstract

Background: Sleep disturbances are intertwined with the progression and pathophysiology of psychotic symptoms in schizophrenia. Reductions in sleep spindles, a major electrophysiological oscillation during non-rapid eye movement sleep, have been identified in patients with schizophrenia as a potential biomarker representing the impaired integrity of the thalamocortical network. Altered glutamatergic neurotransmission within this network via a hypofunction of the N-methyl-D-aspartate receptor (NMDAR) is one of the hypotheses at the heart of schizophrenia. This pathomechanism and the symptomatology are shared by anti-NMDAR encephalitis (NMDARE), where antibodies specific to the NMDAR induce a reduction of functional NMDAR. However, sleep spindle parameters have yet to be investigated in NMDARE and a comparison of these rare patients with young individuals with schizophrenia and healthy controls (HC) is lacking. This study aims to assess and compare sleep spindles across young patients affected by Childhood-Onset Schizophrenia (COS), Early-Onset Schizophrenia, (EOS), or NMDARE and HC. Further, the potential relationship between sleep spindle parameters in COS and EOS and the duration of the disease is examined.

Methods: Sleep EEG data of patients with COS (N = 17), EOS (N = 11), NMDARE (N = 8) aged 7-21 years old, and age- and sex-matched HC (N = 36) were assessed in 17 (COS, EOS) or 5 (NMDARE) electrodes. Sleep spindle parameters (sleep spindle density, maximum amplitude, and sigma power) were analyzed.

Results: Central sleep spindle density, maximum amplitude, and sigma power were reduced when comparing all patients with psychosis to all HC. Between patient group comparisons showed no differences in central spindle density but lower central maximum amplitude and sigma power in patients with COS compared to patients with EOS or NMDARE. Assessing the topography of spindle density, it was significantly reduced over 15/17 electrodes in COS, 3/17 in EOS, and 0/5 in NMDARE compared to HC. In the pooled sample of COS and EOS, a longer duration of illness was associated with lower central sigma power.

Conclusions: Patients with COS demonstrated more pronounced impairments of sleep spindles compared to patients with EOS and NMDARE. In this sample, there is no strong evidence that changes in NMDAR activity are related to spindle deficits.

Keywords: anti-NMDAR encephalitis; psychosis; schizophrenia; sleep EEG; sleep spindles; thalamocortical network.

Grants and funding

This work was supported by the Frutiger Foundation (to MG), Swiss National Science Foundation 320030_153387 (to RH), PCEFP1-181279 (to SK), and 32003B_184943 (to LT), radiz—Rare Disease Initiative Zurich (to SG), Interfaculty Research Cooperation: Decoding Sleep (to LT), the Anna Müller Grocholski foundation (to BB), and the EMDO foundation (to BB and MG). This research was also supported in part by the Intramural Research Program of the National Institute of Mental Health (Annual Report Number ZIAMH002581, ClinicalTrials.gov identifier NCT00001198, protocol ID 84-M-0050). Additionally, MN and SS were supported by the project DOR2008453/20, University of Padova (systematic literature review and evidence-based international consensus recommendations for the treatment of pediatric anti-NMDAR encephalitis, MN).