Preterm Infants Need Their Sleep, Especially Active (REM) Sleep

March 2024

Introduction

A recent report1 from a distinguished group in the field of sleep in infancy concludes that active sleep is related beneficially to cerebral white matter development in preterm infants. The findings suggest potential value of incorporating sleep monitoring into routine caregiving practices in NICU settings (see later). Recall that in the neonatal period sleep is divided generally into two main periods, quiet sleep, a precursor to non-rapid eye movement sleep, and active sleep, a precursor to rapid eye movement (REM) sleep.2 In general, preterm infants, when uninterrupted, spend approximately 80-90% of the time asleep (see later), and the majority of this time is in active sleep.3 

Sleep and Brain Development—Animal Studies

The possibility that altered sleep behaviors in infants could be related to impaired brain development has been raised by a variety of animal studies.3-6 In particular, deprivation of active sleep during development has been followed by smaller brain size, reduced brain growth and subsequent alterations of brain function. At the microstructural level, depending on the model, active sleep has been associated with synaptogenesis, maintenance of dendritic spines, and strengthening of synapses.3  At the electrophysiological level, REM sleep in early development has been associated with a number of effects indicative of functional maturation of neural circuits. As summarized by Knoop et al., “During early maturation REM sleep seems to provide the stimulation needed for preliminary development and survival of sensorimotor neural networks. It does this by driving the generation of endogenous, intense and generalized neural activity across sensorimotor systems.”3 This phenomenon is reminiscent of activity-dependent differentiation of neuronal circuits in a variety of sensory systems during brain development.7 (Although beyond the scope of this discussion, animal studies support the notion that non-REM sleep is more important for regulating synaptic homeostasis and later brain maturation.2) 

Several concerns could be raised about the animal studies. First, the models generally involved animals that are more mature than human infants.4,5,8 Additionally, experimental paradigms often decreased active sleep by pharmacological methods and did not control for such factors as stress (as in experiments utilizing ocular deprivation). Moreover, study of brain maturation in the animal models has often not been sufficiently detailed, especially at the regional and cellular levels. Nevertheless, the findings are compelling.

Sleep and Brain Development—Human Studies

The few relevant studies in human preterm infants have been of interest but have been limited by methodological challenges. Several reports describe an association of decreased active sleep during the preterm or term period to later cognitive impairments.9-12 Correlation with imaging markers of brain development was not reported. Moreover, the most prevalent methodologies utilized for sleep assessment, i.e., behavioral observation or polysomnography, limit daily sleep assessments to only a few minutes to hours.13,14

Current Study

Study Design. The study that stimulated this Commentary is entitled: “Machine learning-derived active sleep as an early predictor of white matter development in preterm infants,” by Wang et al., and as noted earlier, was published in the Journal of Neuroscience (January 2024). (The senior author, Jeroen Dudink, is a well-established leader in the field.) Stimulated by the experimental and human studies reviewed earlier, this study “aimed to determine the potential of sleep as an early predictor for subsequent white matter development in preterm infants.” To overcome the deficiencies of conventional sleep studies, after an initial study of infants for multiple consecutive hours by visual sleep scoring by trained sleep observers, the group was able to utilize heart and respiratory rates as routinely monitored in the NICU to develop a machine learning-based automated sleep stage classifier. This automated classifier subsequently was applied to a cohort of 58 preterm infants to extract sleep percentage over 5-7 consecutive days from 29-32 weeks of postmenstrual age. Excluded from the cohort were infants with major congenital malformations and such overt brain injury as grade III IVH or cystic periventricular leukomalacia. Also excluded were infants on mechanical ventilation. The study infants then had an MRI scan at term equivalent age on a clinical 3-Tesla scanner to assess volumetric tissue segmentation.

Principal Finding. The results were very interesting. The infants spent most of their time asleep (mean percentage of 90% per 24 hours), and on average, time in active sleep and in quiet sleep were approximately equal.1 Notably, higher active sleep percentage was significantly associated with larger white matter volume at term after adjusting for potential confounding covariates (standardized regression coefficient, 0.31; 95% CI, 0.09, 0.53; adjusted P-value 0.021). 

Data Implications. The data raise the critical question concerning the basis for increased cerebral white matter volume in the infants with higher active sleep percentages. Cerebral white matter volume during the last 10 weeks of brain development in the premature infant increases nearly 80%, and approximately 80% of this increase is unmyelinated white matter.15,16 The latter is composed principally of rapidly developing axons and premyelinating oligodendrocytes. Indeed, the period of observation of the sleep parameters in the study of Wang et al.,1 29 to 32 weeks postmenstrual age, is the time of onset of ensheathment of developing axons by immature oligodendrocytes in human cerebral white matter.17 This ensheathment is important for the subsequent development of the abundant growing axons in cerebral white matter at this time.7 In turn, the resulting axonal activity stimulates the further development of these ensheathing immature oligodendroglia.18 Analysis of developing cerebral white matter during this period with GAP-43, a marker of growing axons, shows marked expression in the third trimester.19,20 Anatomical studies have elucidated the details of thalamacortical, commissural cortical and cortico-cerebral axonal development during this period.7,21,22 Similarly, state-of-the-art diffusion-based MRI study of human fetal brain in utero shows changes consistent with exuberant axonal development during the last trimester of gestation, although the regional changes vary in magnitude and timing.23

Notably, during the developmental period just described, accompanying these changes in cerebral white matter are increases in cerebral cortical surface area and gyrification.24 Anatomical and diffusion MRI studies are indicative of marked cortical dendritic and synaptic development also during this time.7 Additionally, functional MRI studies show the onset of cortical neuronal activation and connectivity after visual, auditory and somatosensory stimulation at this time.25 Assessment of these individual events in future studies of the role of active sleep in premature infants in subsequent brain development will be of great interest.

Which of the developmental processes just reviewed could underlie the increase in cerebral white matter volume related to time in active sleep in the study of Wang et al.?1 Based on the likelihood that the increase in cerebral white matter volume during the 30-40 week gestational period is related largely to axonal development, an important possibility is that active sleep in some way leads to enhanced axonal development. One critical driving force for axonal development during this period from 30-40 weeks is the development of synaptic connections in cerebral cortex by terminals of axons coursing through cerebral white matter from thalamus, subplate, and other cortical sites via commissural-cortical and cortico-cortical connections (see earlier). These events are especially prominent in the period from 30-40 weeks’ gestation.7 Studies in animal models (see earlier) indicate that active sleep is important in synaptic development and maintenance. Taken together, the findings suggest that cerebral white matter volume may increase with active sleep because of an increase in axonal development stimulated in an activity-dependent manner by the synaptic effects of this sleep state. As noted earlier, the period of the study, 29-32 weeks postmenstrual age, is the onset of pre-oligodendroglial ensheathment of axons, a process critical for axonal function.7 Future studies of cerebral connectivity in the context of active sleep will be important.

Clinical Implications

The authors of the interesting report by Wang et al.1 conclude that the discovery of a positive association between the percentage of machine learning-derived active sleep during the preterm period and white matter volume at term-equivalent age: (1) “provides new insights into the role of active sleep in early human brain development, confirming and extending findings from animal research,” and (2) “further indicates the potential benefit of integrating automated sleep monitoring into routine caregiving practices in NICU settings.”1 I agree with both of these conclusions.

Concerning caregiving practices, a review of studies assessing interventions to promote “sleep” in NICU settings identified fourteen, of which 10 were RCT.26 Approaches studied include kangaroo care, gentle human touch, different sleep surfaces, sound, cycled light, and LED light. None of the studies showed marked benefit, although methodological concerns, including the means of assessment of sleep state, render comparisons difficult. One study utilizing an instrument that creates a sound effect similar to the sound of moving fluids did show an increase in time spent in active sleep.27 The authors of this review concluded that there is insufficient evidence to recommend any new intervention to promote neonatal sleep in the NICU.26 However, with the recent work of Wang et al.1 an important breakthrough may be apparent. Automated sleep monitoring in the NICU could allow caregivers to carry out various daily interventions in such a way as to safeguard active sleep and, presumably, to promote growth of cerebral white matter and the likely anatomical correlates describe earlier. 

Currently, rational changes in caregiving would be difficult if sleep assessment is carried out by observation by individuals not highly trained in such assessment. REM sleep in the premature infant often can be difficult to detect because of its close resemblance to an awake state, a resemblance that results from the spontaneous activity generated during the sleep state (Jereon Dudink, personal communication). Thus, as communicated to me by Dr. Dudink, caretakers “will more likely disturb the infants during this sleep state than during quiet sleep. … Our extended monitoring indicates that sleep is disrupted many times in an NICU and that in a less intrusive environment, the duration of active sleep in preterm infants increases, underscoring the profound impact of the NICU setting on their sleep architecture.” Thus, the value for the continuous assessment of sleep state afforded by the approach described by Wang et al.1 is particularly apparent.

A final caveat—it should be noted that the role of non-REM sleep during the preterm period in promoting brain development is unclear. Available data suggest that non-REM sleep is related more to later brain development, rather than to that occurring during the NICU period for preterm infants.3 More research is needed on the issue of non-REM sleep in preterm infants and brain development.

Conclusion

The methodological advances concerning sleep monitoring and the correlation with enhanced cerebral white matter development, as shown by MRI described here,1 could lead to caregiving practices that enhance specific sleep behavior in the preterm infant, promote cerebral white matter development, and perhaps most importantly, improve neurological outcome. My view is that such improved sleep management, carefully devised, could prove to be a safe, readily applied, and beneficial management approach. Future research that includes assessment of cerebral cortical and white matter microstructure by advanced diffusion-based MRI methods28,29 and of subsequent neurodevelopmental outcomes will be of particular interest.

Joseph J. Volpe, MD

Department of Neurology, Boston Children’s Hospital

Bronson Crothers Professor of Neurology, Emeritus, Harvard Medical School

Boston MA

References

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