Characterize differences in sleep spindles between Clinical High Risk and healthy controls longitudinally Project summary: Schizophrenia and related disorders are one of leading causes of disability worldwide, thus making the early identification of neurobiological vulnerabilities, which may serve as treatment targets, a critical research priority. In recent work, we found that individuals with chronic schizophrenia had a striking deficit in sleep spindles. A hallmark of Stage 2 Non-Rapid Eye Movement (N2) Sleep, spindles are short (0.5-2 s), waxing/waning oscillations within the 12-16 Hz range. Spindle abnormalities are also present in early course and early onset schizophrenia, and spindle-related measures, including amplitude, duration, and density, are associated with cognitive ability, social functioning, and tendency for magical thinking in healthy individuals, including adolescents and young adults. By investigating individual spindle parameters, we established that reduced spindle density and amplitude are associated with severity of symptoms and cognitive impairments respectively, in chronic schizophrenia patients. We also found that Integrated Spindle Activity (ISA), which combines individual spindle parameters in a single value, was the most discriminating measure, yielding ~90% separation between schizophrenia and control groups. Youth at Clinical High Risk (CHR) are a unique population enriched for precursors of major psychiatric disorders, such as schizophrenia, who also experience emergent cognitive impairments, social dysfunction, and sub-syndromal clinical symptoms. What we do not know is when spindle impairments occur, and how they may affect the development of psychopathology in this population. Thus, the first broad aim of this project is to characterize the role of sleep spindle parameters in moderating cognitive, social, and clinical functioning trajectories, including transition to psychosis, among youth at CHR. Sleep spindles are initiated by the interplay of the Thalamic Reticular Nucleus (TRN) with the dorsal thalamus. Thalamic activity is then relayed to the cortex, where spindle oscillations are synchronized. Specific features of spindles?density, amplitude and duration?reflect neural function in the thalamus, cortex, and thalamo-cortical connections, respectively. Moreover, GABA neurotransmission and thalamo-cortical connectivity play a critical role in generating and sustaining spindle oscillations. In recent work, we found that spindle deficits were most prominent in frontal and prefrontal scalp regions, and that reduced medio-dorsal (MD) thalamic volumes were associated with decreased sleep spindles in source localized prefrontal cortex (PFC) in schizophrenia. Building on these findings, we will integrate data across multiple levels of analysis, from electrophysiology to neural to molecules, to characterize this spindle-related thalamo-cortical circuitry. Specifically, the second broad aim of this project is to identify the neuronal and molecular underpinnings of sleep spindle defects using sleep high density (hd)-EEG, 7T resting state (rs)-fMRI, and Magnetic Resonance Spectroscopy Imaging (MRSI). In order to address these general aims, we propose to conduct longitudinal studies in 45 CHR and 45 healthy controls (HC), with three assessments of clinical and cognitive function, hd-EEG, fMRI, and MRSI over two years.
Sleep spindles, a hallmark of Non-Rapid Eye Movement Sleep, are associated with cognitive ability, schizotypal traits, and social functioning in healthy controls (HC), including adolescents and young adults. Alterations in spindle number and electrophysiological features are present in chronic, early course, as well as early onset psychosis, and spindle deficits are inversely related to symptom severity and cognitive/social dysfunctions. By using a longitudinal design and multiple levels of analysis, from clinical to molecular, this project will characterize differences in sleep spindles between healthy subjects and individuals at Clinical High Risk for psychotic disorders, thus offering new insights into the vulnerability to, development of, and early intervention strategies for these devastating disorders.
