Sleep Spindle Abnormalities as Neurophysiological Biomarkers of Schizophrenia Spectrum Disorders: From Cellular Mechanisms and Neural Circuits to Clinical Implications

Abstract

Although not included in current diagnostic criteria, sleep disturbances are common in patients with schizophrenia (SCZ) and significantly impact their cognitive function and clinical outcomes. Among sleep disturbances, abnormalities in sleep spindles-non-rapid eye movement thalamocortical oscillations essential for sleep stability and memory consolidation-have emerged as potential neurophysiological biomarkers of SCZ. Sleep spindle deficits, particularly reduced density and duration, are consistently observed across illness stages and correlate with cognitive impairments, including working memory and attentional deficits, in individuals with SCZ. Spindle abnormalities reflect disruptions in thalamocortical connectivity, especially within the thalamic reticular nucleus, and are linked to dysfunction in GABAergic (gamma-aminobutyric acidergic) and glutamatergic signaling. Genetic studies further indicate that sleep spindle characteristics are associated with SCZ risk variants, reinforcing their putative role as heritable biomarkers of the disorder. Despite strong evidence supporting the role of spindle deficits in the development and manifestation of SCZ, methodological inconsistencies and a lack of standardized assessment protocols limit their clinical application. In this review, we summarize the neurophysiological basis of spindle deficits in SCZ, discuss their cognitive and clinical implications, highlight the need for standardized spindle measurements, and evaluate emerging therapeutic strategies, including pharmacological modulation, transcranial stimulation, and closed-loop auditory stimulation. Although preliminary, the reviewed evidence suggests that future spindle-informed research could enhance diagnostic precision and potentially lead to the discovery of novel therapeutic strategies for SCZ.

Keywords: EEG; Endophenotype; NREM; Psychosis; Sleep microarchitecture; Thalamocortical dysfunction; Thalamocortical oscillations.