Electrophysiologic Sleep Phenotyping and Sleep-Dependent Neuro-maturation in Clinical and Healthy Pediatric Populations

This is a multisite longitudinal study with NIH as the lead site. The other sites: Texas Children s Hospital, Boston Children s Hospital, Geisinger Medical Center, NYU and the NHLBI- supported, area specific repository, National Sleep Research Repository (NSRR). This study will address the data gap established by two NIMH sponsored intramural/extramural workshops (2017 and 2018) in the field of sleep and neurodevelopment by establishing a standardized, reliable protocol for real time acquisition of research data on the normal and abnormal neuro-maturational changes that are sleep-dependent. It will facilitate data-sharing in this area and speed the pace of discovery. Sleep EEG is a highly advantageous modality to provide non-invasive, reliable, robust and reproducible imaging of the brain in young and neurodevelopmentally disordered populations. Sleep EEG affords data acquisition of functional network microstructure with a decreased signal to noise ratio compared to acquisition in the awake state. In addition, potential deviations from the natural ultradian and other sleep oscillatory patterns of the sleep process have the potential to inform on underlying developing neuropathology of various microstructures and neurotransmitter systems prior to the emergence of putatively associated behavioral phenomenon. Ideally, these oscillatory trajectories will not only map to developmental behavioral phenotypes but also to clinical disorders of the sleep state itself, such as the malignant insomnias that are prevalent in neuropsychiatric and neurodevelopmental syndromes. The protocol will initiate the establishment of a normative database for electrophysiologic sleep data in the developing brain. Disorders of particular interest include autism, disorders of social cognition and other neurodevelopmental disorders, childhood psychiatric disorders, and unique clinical presentations of neurogenetic syndromes, such as those associated with genetic disorders or those with a unique family history. The study plans to use a quantitative, dimensional approach to outcome measurement with respect to adaptive functioning in children and to symptoms of behavioral and/or neurodevelopmental problems, irrespective of diagnosis.

While specific differences in the architecture of sleep (e.g., stages, movement abnormalities, cyclicity, spindles and other bio-signatures that reflect anatomical microstructure) may be used to differentiate neurodevelopmental cohorts, the enormous potential of this proposed database lies in the ability to track functional connectivity (coherence) during sleep in the developing brain in a longitudinal, prospective manner, thereby establishing both normal and aberrant trajectories. Predictive relationships can be determined once these trajectories are established. Coherence studies would allow for the potential recreation of neural circuits that sub-serve various brain functions, such as language and attention. Tracking the trajectory of neural development prior to and during the developmental window when these circuits are maturing will allow for an understanding of best potential windows of intervention.

Objectives: The long term, primary objective of this protocol is to evaluate the degree to which the development and maturation of sleep patterns, with an emphasis on the relationship of those patterns to electrophysiologic signals, can predict cognitive and behavioral outcomes. Assessing participants over time will allow researchers to gain additional knowledge about the role of abnormal sleep, measured both clinically and by polysomnogram, in various childhood neuropsychiatric/ neurodevelopmental disorders and behavioral syndromes.

Study Population: The total number of participants to be enrolled will be set at N = 244 (6 months to 8 years old) and will include the following:

1. Study 1: N = 90 with no known risk for neurodevelopmental disorders. These include children without identified neurodevelopmental problems who score within age-expected ranges on cognitive and behavioral screeners.

2. Study 2: N = 154 children at risk for or known to have selected neurodevelopmental/neuropsychiatric disorders, based on any one or more of the following criteria:

   1. Enrolled in early intervention

   2. Getting any targeted therapies

   3. Neurodevelopmental or neuropsychiatric disorder

   4. Failed Infant Toddler Checklist (ITC) (ages 6 months 24 months)

   5. Failed the Early Intervention (EI) screener (>24 months)

Design: Study 1 (N = 90) and Study 2 (N = 154) use the same accelerated longitudinal design.

Outcome Measures: The primary outcome measure in Study 1 is sleep spindle activity. Study 2 has an additional primary outcome, the Vineland Adaptive Behavior (VABS) Socialization growth scale. In both studies, secondary outcome measures will include:other characteristics of sleep spindles, sleep rhythms (ultradian, circadian), macroarchitecture (stages and latencies), microarchitecture (measures of connectivity and network analyses).

Predictors include other neurodevelopmental variables, including other domain scores from the Vineland, IQ, and quantitative measurement of behavioral problems and social communicative development.