Reduced sleep spindle density in adolescent patients with early-onset schizophrenia compared to major depressive disorder and healthy controls

Abstract

OBJECTIVES: During adolescence schizophrenia and major depressive disorder (MDD) increasingly emerge. Overlapping symptomatology during first presentation challenges the diagnostic process. Reduced sleep spindle density (SSD) was suggested as a biomarker in adults, discerning patients with schizophrenia from patients with depression or healthy controls (HC). We aimed to compare SSD in early-onset schizophrenia (EOS), with MDD, and HC, and to analyse associations of SSD with symptomatology and neurocognitive measures. METHODS: Automatic sleep spindle detection was performed on all-night high-density EEG (128 electrodes) data of 12 EOS, 19 MDD, and 57 HC (age range 9.8-19), allowing an age-and sex-matching of 1:2 (patients vs. HC). Severity of current symptoms and neurocognitive variables were assessed in all patients. RESULTS: SSD was defined between 13.75 and 14.50 Hz as within this frequency range SSD differed between EOS vs. HC in bin by bin analyses (12-15 Hz). In EOS, SSD was lower over 27 centro-temporal electrodes compared to HC and over 9 central electrodes compared to MDD. Reduced SSD in EOS compared to MDD and HC was accompanied by a high variability of SSD in all adolescents. SSD did not differ between MDD and HC. In the pooled sample of patients, lower SSD was associated with more severe Positive and Negative Symptoms Scale total score, more impaired memory consolidation and processing speed. CONCLUSION: A high variability of SSD in all adolescents may reflect the evolving character of SSD. The association of reduced SSD with the symptom dimension of impaired cognition cuts across diagnostical entities.

Sleep and Memory Consolidation Dysfunction in Psychiatric Disorders: Evidence for the Involvement of Extracellular Matrix Molecules

“…Sleep spindle deficits have been reported in several independent studies (Ferrarelli et al, 2007;Manoach et al, 2014Manoach et al, , 2016Ferrarelli, 2015Ferrarelli, , 2020Ferrarelli and Tononi, 2017;D'Agostino et al, 2018;Baran et al, 2019;Manoach and Stickgold, 2019;Merikanto et al, 2019;Gerstenberg et al, 2020;Markovic et al, 2020) including in unmedicated patients with SZ, and in first-degree relatives, suggesting that this represents a core genetic component of the disease rather than medication effects or a degenerative consequence of disease progression. Sleep spindle deficits are highly associated with psychosis, and disease prognosis (Manoach et al, 2016;Gerstenberg et al, 2020;Markovic et al, 2020).…”

“…Recent studies point to sleep and circadian rhythm disturbances as key aspects of schizophrenia (SZ) (Ferrarelli et al, 2007;Manoach et al, 2014Manoach et al, , 2016Ferrarelli, 2015Ferrarelli, , 2020Ferrarelli and Tononi, 2017;D'Agostino et al, 2018;Baran et al, 2019;Manoach and Stickgold, 2019;Merikanto et al, 2019;Seney et al, 2019;Delorme T.C. et al, 2020;Gerstenberg et al, 2020;Markovic et al, 2020;Meyer et al, 2020). Furthermore, altered diurnal molecular expression rhythms have been recently reported in the prefrontal cortex of subjects with SZ using RNAseq profiling of postmortem brain samples, suggesting broad molecular circadian rhythm disturbances in this disease (Seney et al, 2019).…”

“…Disrupted sleep and circadian rhythms may impair synaptic downscaling of unnecessary spines during sleep Cirelli, 2006, 2014), and strengthening of selective spines for enhancement of specific memories (Rasch and Born, 2013;Yang et al, 2014;Dudai et al, 2015). Despite the clinical and genetic heterogeneity of SZ (Fanous et al, 2012; Cross-Disorder Group of the Psychiatric Genomics Consortium et al, 2013), sleep dysfunction, specifically decreased sleep spindles and memory consolidation deficits, is emerging as a consistent characteristic of the disease (Ferrarelli et al, 2007;Manoach et al, 2014Manoach et al, , 2016Ferrarelli, 2015Ferrarelli, , 2020Ferrarelli and Tononi, 2017;D'Agostino et al, 2018;Baran et al, 2019;Manoach and Stickgold, 2019;Merikanto et al, 2019;Gerstenberg et al, 2020;Markovic et al, 2020). Decreases in sleep spindles are found together with memory consolidation deficits in patients with SZ (Ferrarelli et al, 2007;Manoach et al, 2010Manoach et al, , 2014.…”

The Engram’s Dark Horse: How Interneurons Regulate State-Dependent Memory Processing and Plasticity

“…Attenuated sleep oscillations, altered sleep patterns, and dysfunctional PV+ and SST+ GABAergic interneurons have also been observed in schizophrenia (Lewis and Sweet, 2009), which is a multifaceted mental disorder characterized by cognitive deficits. NREM sleep spindle disruption and suppression is a highly consistent finding in schizophrenic patients, and has predictive value of cognitive, positive, and negative symptoms (Kaskie et al, 2019;Au and Harvey, 2020;Gerstenberg et al, 2020;Markovic et al, 2020;Zhang et al, 2020). This selective disruption of sleep spindles is linked to loss of PV+ interneurons in the thalamic reticular nucleus of schizophrenic patients (Steullet et al, 2018).…”

An Infant Sleep Electroencephalographic Marker of Thalamocortical Connectivity Predicts Behavioral Outcome in Late Infancy

“…Spindles were detected using a procedure adapted from (Ferrarelli et al, 2007;Gerstenberg et al, 2020): After low-pass filtering below 40 Hz and re-referencing to the average across all electrodes, the signal was band-pass filtered (10 -16 Hz, stopband 6 and 30 Hz, Chebyshev Type II filter) and rectified. Whenever the signal exceeded an upper threshold of 5-fold the mean signal amplitude, a spindle was detected.…”