Dyscoordination of non-rapid eye movement sleep oscillations in autism spectrum disorder

Abstract

Study Objectives Converging evidence from neuroimaging, sleep, and genetic studies suggests that dysregulation of thalamocortical interactions mediated by the thalamic reticular nucleus (TRN) contribute to autism spectrum disorder (ASD). Sleep spindles assay TRN function, and their coordination with cortical slow oscillations (SOs) indexes thalamocortical communication. These oscillations mediate memory consolidation during sleep. In the present study, we comprehensively characterized spindles and their coordination with SOs in relation to memory and age in children with ASD. Methods Nineteen children and adolescents with ASD, without intellectual disability, and 18 typically developing (TD) peers, aged 9-17, completed a home polysomnography study with testing on a spatial memory task before and after sleep. Spindles, SOs, and their coordination were characterized during stages 2 (N2) and 3 (N3) non-rapid eye movement sleep. Results ASD participants showed disrupted SO-spindle coordination during N2 sleep. Spindles peaked later in SO upstates and their timing was less consistent. They also showed a spindle density (#/min) deficit during N3 sleep. Both groups showed significant sleep-dependent memory consolidation, but its relations with spindle density differed. While TD participants showed the expected positive correlations, ASD participants showed the opposite. Conclusions The disrupted SO-spindle coordination and spindle deficit provide further evidence of abnormal thalamocortical interactions and TRN dysfunction in ASD. The inverse relations of spindle density with memory suggest a different function for spindles in ASD than TD. We propose that abnormal sleep oscillations reflect genetically mediated disruptions of TRN-dependent thalamocortical circuit development that contribute to the manifestations of ASD and are potentially treatable.

Increased resting‐state thalamocortical functional connectivity in children and young adults with autism spectrum disorder

“…This hypothesis is consistent with findings that in ASD, lower concentrations of the inhibitory neurotransmitter GABA in the thalamus predict sensory sensitivities and increased thalamic functional connectivity with sensory cortices (Wood et al, 2021). Reduced thalamic inhibition in ASD may also contribute to reduced sleep spindles in ASD (Tessier et al, 2015), oscillations that require powerful inhibition of thalamocortical relay neurons for their generation (Steriade, 2003), and reduced spindle coordination with cortical slow oscillations (Mylonas et al, 2022; Tessier et al, 2015), which relies on thalamocortical circuitry. Our findings that in both health and schizophrenia sleep spindle rate inversely correlates with thalamocortical connectivity with regions in sensorimotor cortex and superior and middle temporal gyri support the hypothesis that both measures reflect the degree of thalamic inhibition (Baran et al, 2019).…”

Sleep spindles in primates: modelling the effects of distinct laminar thalamocortical connectivity in core, matrix, and reticular thalamic circuits

“…For example, medicated individuals with chronic schizophrenia show deficits in spindle density (Ferrarelli et al, 2007; Manoach et al, 2010), which parallel impaired memory consolidation during stage 2 sleep (Göder et al, 2015; Wamsley et al, 2012), and increased thalamocortical functional connectivity (Baran et al, 2019; Manoach and Stickgold, 2019). Moreover, spindle density and duration are significantly decreased in autism spectrum disorders (ASD) and show negative correlation with sleep-dependent memory consolidation (Farmer et al, 2018; Mylonas et al, 2022). Both disorders differentially affect sensory processing, attention, and emotional processing likely involving at variable degrees first-order, primary networks that participate in core TC circuits, or high-order, association networks that participate in matrix or mix TC circuits.…”

“…Sleep spindles are widespread oscillations associated with the beginning of deep NREM sleep, learning, and memory consolidation (Luthi, 2014; Steriade, 2005; Steriade et al, 1987). Because sleep spindles are disrupted in a variety of neurological and psychiatric conditions, they are an important clinical marker of atypical brain function in several disorders, including schizophrenia and autism (Farmer et al, 2018; Ferrarelli et al, 2007; Manoach et al, 2010; Mylonas et al, 2022).…”

Are sleep disturbances a cause or consequence of autism spectrum disorder?

“…generated sleep spindles in ASD individuals, suggesting altered thalamic reticular nucleus function. 209 As discussed in the previous section, sleep problems might be closely related to the etiology of ASD. In this sense, clarification and subcategorization of sleep problems in ASD may be helpful for future subcategorization of ASD heterogeneity.…”