Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Early development of sleep and brain functional connectivity in term-born and preterm infants


The proper development of sleep and sleep-wake rhythms during early neonatal life is crucial to lifelong neurological well-being. Recent data suggests that infants who have poor quality sleep demonstrate a risk for impaired neurocognitive outcomes. Sleep ontogenesis is a complex process, whereby alternations between rudimentary brain states—active vs. wake and active sleep vs. quiet sleep—mature during the last trimester of pregnancy. If the infant is born preterm, much of this process occurs in the neonatal intensive care unit, where environmental conditions might interfere with sleep. Functional brain connectivity (FC), which reflects the brain’s ability to process and integrate information, may become impaired, with ensuing risks of compromised neurodevelopment. However, the specific mechanisms linking sleep ontogenesis to the emergence of FC are poorly understood and have received little investigation, mainly due to the challenges of studying causal links between developmental phenomena and assessing FC in newborn infants. Recent advancements in infant neuromonitoring and neuroimaging strategies will allow for the design of interventions to improve infant sleep quality and quantity. This review discusses how sleep and FC develop in early life, the dynamic relationship between sleep, preterm birth, and FC, and the challenges associated with understanding these processes.


  • Sleep in early life is essential for proper functional brain development, which is essential for the brain to integrate and process information. This process may be impaired in infants born preterm.

  • The connection between preterm birth, early development of brain functional connectivity, and sleep is poorly understood.

  • This review discusses how sleep and brain functional connectivity develop in early life, how these processes might become impaired, and the challenges associated with understanding these processes. Potential solutions to these challenges are presented to provide direction for future research.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Relationship between preterm birth, sleep ontogenesis, and functional brain connectivity.
Fig. 2: The parallel development of sleep, functional networks, and structural networks in the developing brain.
Fig. 3: Identifying, analyzing, and interpreting FCNs.


  1. 1.

    Feld, G. B. & Born, J. Sculpting memory during sleep: concurrent consolidation and forgetting. Curr. Opin. Neurobiol. 44, 20–27 (2017).

    CAS  PubMed  Article  Google Scholar 

  2. 2.

    Altena, E. et al. The bidirectional relation between emotional reactivity and sleep: From disruption to recovery. Behav. Neurosci. 130, 336–350 (2016).

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Lowe, C. J., Safati, A. & Hall, P. A. The neurocognitive consequences of sleep restriction: A meta-analytic review. Neurosci. Biobehav Rev. 80, 586–604 (2017).

    PubMed  Article  Google Scholar 

  4. 4.

    Cirelli, C. & Tononi, G. The sleeping brain. Cerebrum 2017, cer-07-17 (2017).

  5. 5.

    Dierker, L. J., Rosen, M. G., Pillay, S. & Sorokin, Y. Correlation between gestational age and fetal activity periods. Neonatology 42, 66–72 (1982).

    Article  Google Scholar 

  6. 6.

    de Vries, J. I., Visser, G. H. & Prechtl, H. F. The emergence of fetal behaviour. I. Qualitative aspects. Early Hum. Dev. 7, 301–322 (1982).

    PubMed  Article  Google Scholar 

  7. 7.

    de Vries, J. I. P., Visser, G. H. A. & Prechtl, H. F. R. The emergence of fetal behaviour. II. Quant. Asp. Early Hum. Dev. 12, 99–120 (1985).

    Article  Google Scholar 

  8. 8.

    Asaka, Y. & Takada, S. Activity-based assessment of the sleep behaviors of VLBW preterm infants and full-term infants at around 12 months of age. Brain Dev. 32, 150–155 (2010).

    PubMed  Article  Google Scholar 

  9. 9.

    Perkinson-Gloor, N. et al. The role of sleep and the hypothalamic-pituitary-adrenal axis for behavioral and emotional problems in very preterm children during middle childhood. J. Psychiatr. Res. 60, 141–147 (2015).

    PubMed  Article  Google Scholar 

  10. 10.

    Shellhaas, R. A. et al. Neonatal sleep-wake analyses predict 18-month neurodevelopmental outcomes. Sleep 40, zsx144 (2017).

  11. 11.

    Stangenes, K. M. et al. Children born extremely preterm had different sleeping habits at 11 years of age and more childhood sleep problems than term-born children. Acta Paediatr. 106, 1966–1972 (2017).

    PubMed  Article  Google Scholar 

  12. 12.

    Yiallourou, S. R. et al. Sleep: a window into autonomic control in children born preterm and growth restricted. Sleep (2017).

  13. 13.

    Back, S. A. White matter injury in the preterm infant: pathology and mechanisms. Acta Neuropathol. 134, 331–349 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. 14.

    Bennet, L., Walker, D. W. & Horne, R. S. C. Waking up too early - the consequences of preterm birth on sleep. Dev. J. Physiol. 596, 5687–5708 (2018).

    CAS  Article  Google Scholar 

  15. 15.

    van den Hoogen, A. et al. How to improve sleep in a neonatal intensive care unit: a systematic review. Early Hum. Dev. 113, 78–86 (2017).

    PubMed  Article  Google Scholar 

  16. 16.

    Levy, J. et al. Impact of hands-on care on infant sleep in the neonatal intensive care unit: impact of hands-on care on infant sleep. Pediatr. Pulmonol. 52, 84–90 (2017).

    PubMed  Article  Google Scholar 

  17. 17.

    Shellhaas, R. A., Burns, J. W., Barks, J. D. E., Hassan, F. & Chervin, R. D. Maternal voice and infant sleep in the neonatal intensive care unit. Pediatrics 144, e20190288 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  18. 18.

    Bertelle, V., Sevestre, A., Laou-Hap, K., Nagahapitiye, M. C. & Sizun, J. Sleep in the neonatal intensive care unit. J. Perinat. Neonatal Nurs. 21, 140–148 (2007). quiz 149–50.

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Varvara, B., Effrossine, T., Despoina, K., Konstantinos, D. & Matziou, V. Effects of neonatal intensive care unit nursing conditions in neonatal NREM. sleep. J. Neonatal Nurs. 22, 115–123 (2016).

    Article  Google Scholar 

  20. 20.

    Zores, C. et al. Observational study found that even small variations in light can wake up very preterm infants in a neonatal intensive care unit. Acta Paediatr. 107, 1191–1197 (2018).

    PubMed  Article  Google Scholar 

  21. 21.

    Orsi, K. C. S. C. et al. Effects of handling and environment on preterm newborns sleeping in incubators. J. Obstet. Gynecol. Neonatal Nurs. 46, 238–247 (2017).

    PubMed  Article  Google Scholar 

  22. 22.

    Hagmann-von Arx, P. et al. In school-age children who were born very preterm sleep efficiency is associated with cognitive function. Neuropsychobiology 70, 244–252 (2014).

    PubMed  Article  Google Scholar 

  23. 23.

    McCann, M. et al. The relationship between sleep problems and working memory in children born very preterm. Child Neuropsychol. 24, 124–144 (2018).

    PubMed  Article  Google Scholar 

  24. 24.

    Feng, P. & Ma, Y. Instrumental REM sleep deprivation in neonates leads to adult depression-like behaviors in rats. Sleep 26, 990–996 (2003).

    PubMed  Article  Google Scholar 

  25. 25.

    Frank, M. G., Morrissette, R. & Heller, H. C. Effects of sleep deprivation in neonatal rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 275, R148–R157 (1998).

    CAS  Article  Google Scholar 

  26. 26.

    Mirmiran, M. et al. Effects of experimental suppression of active (REM) sleep during early development upon adult brain and behavior in the rat. Dev. Brain Res. 7, 277–286 (1983).

    Article  Google Scholar 

  27. 27.

    Kidokoro, H. et al. Brain injury and altered brain growth in preterm infants: predictors and prognosis. Pediatrics 134, e444–e453 (2014).

    PubMed  Article  Google Scholar 

  28. 28.

    Blencowe, H. et al. Born too soon: the global epidemiology of 15 million preterm births. Reprod. Health 10, S2 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  29. 29.

    Bhutta, A. T., Cleves, M. A., Casey, P. H., Cradock, M. M. & Anand, K. J. S. Cognitive and behavioral outcomes of school-aged children who were born preterm: a meta-analysis. JAMA 288, 728 (2002).

    PubMed  Article  Google Scholar 

  30. 30.

    Raju, T. N. K., Buist, A. S., Blaisdell, C. J., Moxey-Mims, M. & Saigal, S. Adults born preterm: a review of general health and system-specific outcomes. Acta Paediatr. 106, 1409–1437 (2017).

    PubMed  Article  Google Scholar 

  31. 31.

    Gao, W., Lin, W., Grewen, K. & Gilmore, J. H. Functional connectivity of the infant human brain: plastic and modifiable. Neurosci. Rev. J. Bringing Neurobiol. Neurol. Psychiatry 23, 169–184 (2017).

    Google Scholar 

  32. 32.

    Mohammadi-Nejad, A.-R. et al. Neonatal brain resting-state functional connectivity imaging modalities. Photoacoustics 10, 1–19 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    Tokariev, A. et al. Large-scale brain modes reorganize between infant sleep states and carry prognostic information for preterms. Nat. Commun. 10, 2619 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  34. 34.

    Lee, C. W. et al. Sleep state modulates resting-state functional connectivity in neonates. Front Neurosci. 14, 347 (2020).

    PubMed  PubMed Central  Article  Google Scholar 

  35. 35.

    Dubois, J., Kostović, I. & Judas, M. in Brain Mapping: An Encyclopedic Reference 423–437. Accessed Mar 2020 (2015).

  36. 36.

    van den Heuvel, M. I. & Thomason, M. E. Functional connectivity of the human brain in utero. Trends Cogn. Sci. 20, 931–939 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  37. 37.

    Sporns, O. Structure and function of complex brain networks. Dialogues Clin. Neurosci. 15, 247–262 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    Spoormaker, V. I. et al. Development of a large-scale functional brain network during human non-rapid eye movement. Sleep. J. Neurosci. 30, 11379–11387 (2010).

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    Lombardi, F. et al. Critical dynamics and coupling in bursts of cortical rhythms indicate non-homeostatic mechanism for sleep-stage transitions and dual role of VLPO neurons in both sleep and wake. J. Neurosci. 40, 171–190 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. 40.

    Cao, M. et al. Early development of functional network segregation revealed by connectomic analysis of the preterm human brain. Cereb. Cortex 27, 1949–1963 (2017).

    PubMed  Google Scholar 

  41. 41.

    Fransson, P. et al. Resting-state networks in the infant brain. Proc. Natl Acad. Sci. USA 104, 15531–15536 (2007).

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    Doria, V. et al. Emergence of resting state networks in the preterm human brain. Proc. Natl Acad. Sci. USA 107, 20015–20020 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  43. 43.

    Fransson, P. et al. Spontaneous brain activity in the newborn brain during natural sleep—an fMRI study in infants born at full term. Pediatr. Res. 66, 301–305 (2009).

    PubMed  Article  PubMed Central  Google Scholar 

  44. 44.

    Smyser, C. D. et al. Longitudinal analysis of neural network development in preterm infants. Cereb. Cortex. 20, 2852–2862 (2010).

    PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    Fransson, P., Åden, U., Blennow, M. & Lagercrantz, H. The functional architecture of the infant brain as revealed by resting-state fMRI. Cereb. Cortex. 21, 145–154 (2011).

    PubMed  Article  PubMed Central  Google Scholar 

  46. 46.

    Nghiem, G. T. et al. Adverse effects of maternal dioxin exposure on fetal brain development before birth assessed by neonatal electroencephalography (EEG) leading to poor neurodevelopment; a 2-year follow-up study. Sci. Total Environ. 667, 718–729 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  47. 47.

    Batalle, D. et al. Early development of structural networks and the impact of prematurity on brain connectivity. NeuroImage 149, 379–392 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  48. 48.

    Videman, M. et al. Newborn brain function is affected by fetal exposure to maternal serotonin reuptake inhibitors. Cereb. Cortex 27, 3208–3216 (2017).

    PubMed  PubMed Central  Google Scholar 

  49. 49.

    Grieve, P. G. et al. EEG functional connectivity in term age extremely low birth weight infants. Clin. Neurophysiol. 119, 2712–2720 (2008).

    PubMed  PubMed Central  Article  Google Scholar 

  50. 50.

    Omidvarnia, A., Fransson, P., Metsäranta, M. & Vanhatalo, S. Functional bimodality in the brain networks of preterm and term human newborns. Cereb. Cortex 24, 2657–2668 (2014).

  51. 51.

    González, J. J. et al. Assessment of electroencephalographic functional connectivity in term and preterm neonates. Clin. Neurophysiol. 122, 696–702 (2011).

    PubMed  Article  Google Scholar 

  52. 52.

    Molnár, Z., Luhmann, H. J. & Kanold, P. O. Transient cortical circuits match spontaneous and sensory-driven activity during development. Science 370, eabb2153 (2020).

    PubMed  Article  CAS  Google Scholar 

  53. 53.

    Kostović, I. & Jovanov-Milošević, N. The development of cerebral connections during the first 20–45 weeks’ gestation. Semin. Fetal Neonat. Med. 11, 415–422 (2006).

    Article  Google Scholar 

  54. 54.

    Kostović, I. & Judaš, M. The development of the subplate and thalamocortical connections in the human foetal brain: Human foetal cortical circuitry. Acta Paediatr. 99, 1119–1127 (2010).

    PubMed  Article  Google Scholar 

  55. 55.

    Luhmann, H. J. et al. Spontaneous neuronal activity in developing neocortical networks: from single cells to large-scale interactions. Front. Neural Circuits 10, 40 (2016).

  56. 56.

    Vanhatalo, S. & Kaila, K. in The Newborn Brain: Neuroscience & Clinical Applications 2nd edn (eds Lagercrantz, H., Hanson, M., Ment, L. & Peebles, D.) 229–243 (2010).

  57. 57.

    Scher, M. S., Johnson, M. W. & Holditch-Davis, D. Cyclicity of neonatal sleep behaviors at 25 to 30 weeks’ postconceptional age. Pediatr. Res. 57, 879–882 (2005).

    PubMed  Article  Google Scholar 

  58. 58.

    Vanhatalo, S. et al. Slow endogenous activity transients and developmental expression of K+ -Cl cotransporter 2 in the immature human cortex. Eur. J. Neurosci. 22, 2799–2804 (2005).

    PubMed  Article  Google Scholar 

  59. 59.

    Kostovic, I. & Judaš, M. Prolonged coexistence of transient and permanent circuitry elements in the developing cerebral cortex of fetuses and preterm infants. Dev. Med. Child Neurol. 48, 388 (2006).

    PubMed  Article  Google Scholar 

  60. 60.

    Koolen, N. et al. Early development of synchrony in cortical activations in the human. Neuroscience 322, 298–307 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. 61.

    Stevenson, N. J. et al. Automated cot‐side tracking of functional brain age in preterm infants. Ann. Clin. Transl. Neurol. 7, 891–902 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. 62.

    O’Toole, J. M., Pavlidis, E., Korotchikova, I., Boylan, G. B. & Stevenson, N. J. Temporal evolution of quantitative EEG within 3 days of birth in early preterm infants. Sci. Rep. 9, 4859 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  63. 63.

    Pillay, K., Dereymaeker, A., Jansen, K., Naulaers, G. & De Vos, M. Applying a data-driven approach to quantify EEG maturational deviations in preterms with normal and abnormal neurodevelopmental outcomes. Sci. Rep. 10, 7288 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. 64.

    de Vries, J. I., Visser, G. H. & Prechtl, H. F. The emergence of fetal behaviour. III. Individual differences and consistencies. Early Hum. Dev. 16, 85–103 (1988).

    PubMed  Article  Google Scholar 

  65. 65.

    Hellström-Westas, L., Rosén, I. & Svenningsen, N. Cerebral function monitoring during the first week of life in extremely small low birthweight (ESLBW) infants. Neuropediatrics 22, 27–32 (1991).

    PubMed  Article  Google Scholar 

  66. 66.

    Scher, M. S. Ontogeny of EEG-sleep from neonatal through infancy periods. Sleep. Med. 9, 615–636 (2008).

    PubMed  Article  Google Scholar 

  67. 67.

    Dereymaeker, A. et al. Review of sleep-EEG in preterm and term neonates. Early Hum. Dev. 113, 87–103 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  68. 68.

    André, M. et al. Electroencephalography in premature and full-term infants. Developmental features and glossary. Neurophysiol. Clin. Clin. Neurophysiol. 40, 59–124 (2010).

    Article  Google Scholar 

  69. 69.

    Curzi-Dascalova, L. Between-sleep states transitions in premature babies. J. Sleep. Res. 10, 153–158 (2001).

    CAS  PubMed  Article  Google Scholar 

  70. 70.

    Tokariev, A., Videman, M., Palva, J. M. & Vanhatalo, S. Functional brain connectivity develops rapidly around term age and changes between vigilance states in the human newborn. Cereb. Cortex 26, 4540–4550 (2016).

    PubMed  Article  Google Scholar 

  71. 71.

    Caba, M., González-Mariscal, G. & Meza, E. Circadian rhythms and clock genes in reproduction: insights from behavior and the female rabbit’s brain. Front. Endocrinol. 9, 106 (2018).

    Article  Google Scholar 

  72. 72.

    Sims, R. E., Wu, H. H. T. & Dale, N. Sleep-wake sensitive mechanisms of adenosine release in the basal forebrain of rodents: an in vitro study. PLoS ONE 8, e53814 (2013).

  73. 73.

    Abbott, S. M. et al. Signals from the brainstem sleep/wake centers regulate behavioral timing via the circadian clock. PLoS ONE 8, e70481 (2013).

  74. 74.

    Blumberg, M. S., Gall, A. J. & Todd, W. D. The development of sleep-wake rhythms and the search for elemental circuits in the infant brain. Behav. Neurosci. 128, 250–263 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  75. 75.

    Hastings, M. H., Brancaccio, M. & Maywood, E. S. Circadian pacemaking in cells and circuits of the suprachiasmatic nucleus. J. Neuroendocrinol. 26, 2–10 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. 76.

    Saper, C. B., Fuller, P. M., Pedersen, N. P., Lu, J. & Scammell, T. E. Sleep state switching. Neuron 68, 1023–1042 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. 77.

    Bueno, C. & Menna-Barreto, L. Development of sleep/wake, activity and temperature rhythms in newborns maintained in a neonatal intensive care unit and the impact of feeding schedules. Infant Behav. Dev. 44, 21–28 (2016).

    PubMed  Article  Google Scholar 

  78. 78.

    Olischar, M. et al. Reference values for amplitude-integrated electroencephalographic activity in preterm infants younger than 30 weeks’ gestational age. Pediatrics 113, e61–e66 (2004).

    PubMed  Article  Google Scholar 

  79. 79.

    Parikh, N. A., Lasky, R. E., Kennedy, K. A., McDavid, G. & Tyson, J. E. Perinatal factors and regional brain volume abnormalities at term in a cohort of extremely low birth weight infants. PLoS ONE 8, e62804 (2013).

  80. 80.

    Inder, T. E. Abnormal cerebral structure is present at term in premature infants. Pediatrics 115, 286–294 (2005).

    PubMed  PubMed Central  Article  Google Scholar 

  81. 81.

    Padilla, N., Alexandrou, G., Blennow, M. & Lagercrantz, H. Ådén U. Brain growth gains and losses in extremely preterm infants at term. Cereb. Cortex 25, 1897–1905 (2015).

    PubMed  Article  Google Scholar 

  82. 82.

    Dimitrova, R. et al. Heterogeneity in brain microstructural development following preterm birth. Cereb. Cortex 30, 4800–4810 (2020).

  83. 83.

    Eiselt, M. et al. Quantitative analysis of discontinuous EEG in premature and full-term newborns during quiet sleep. Electroencephalogr. Clin. Neurophysiol. 103, 528–534 (1997).

    CAS  PubMed  Article  Google Scholar 

  84. 84.

    Horne, R. S., Sly, D. J., Cranage, S. M., Chau, B. & Adamson, T. M. Effects of prematurity on arousal from sleep in the newborn infant. Pediatr. Res. 47, 468–474 (2000).

    CAS  PubMed  Article  Google Scholar 

  85. 85.

    Huang, Y.-S., Paiva, T., Hsu, J.-F., Kuo, M.-C. & Guilleminault, C. Sleep and breathing in premature infants at 6 months post-natal age. BMC Pediatr. 14, 303 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  86. 86.

    Gössel-Symank, R., Grimmer, I., Korte, J. & Siegmund, R. Actigraphic monitoring of the activity-rest behavior of preterm and full-term infants at 20 months of age. Chronobiol. Int. 21, 661–671 (2004).

    PubMed  Article  Google Scholar 

  87. 87.

    Biggs, S. N. et al. Sleep/wake patterns and parental perceptions of sleep in children born preterm. J. Clin. Sleep. Med. 12, 711–717 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  88. 88.

    Yiallourou, S. R. et al. Being born too small and too early may alter sleep in childhood. Sleep 41, zsx193 (2018).

  89. 89.

    Caravale, B. et al. Sleep characteristics and temperament in preterm children at two years of age. J. Clin. Sleep. Med. 13, 1081–1088 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  90. 90.

    Iglowstein, I., Latal Hajnal, B., Molinari, L., Largo, R. & Jenni, O. Sleep behaviour in preterm children from birth to age 10 years: a longitudinal study. Acta Paediatr. 95, 1691–1693 (2006).

    PubMed  Article  Google Scholar 

  91. 91.

    Altimier, L., Kenner, C. & Damus, K. The Wee Care Neuroprotective NICU Program (Wee Care): the effect of a comprehensive developmental care training program on seven neuroprotective core measures for family-centered developmental care of premature neonates. Newborn Infant Nurs. Rev. 15, 6–16 (2015).

    Article  Google Scholar 

  92. 92.

    Pouraboli, B., Bazrgari, M., Mirlashari, J. & Ranjbar, H. The effect of clustered nursing care on sleep behaviors of preterm infants admitted to the neonatal intensive care unit. Iran J. Neonatol. (2019).

  93. 93.

    Collins, C. L., Barfield, C., Davis, P. G. & Horne, R. S. C. Randomized controlled trial to compare sleep and wake in preterm infants less than 32weeks of gestation receiving two different modes of non-invasive respiratory support. Early Hum. Dev. 91, 701–704 (2015).

    CAS  PubMed  Article  Google Scholar 

  94. 94.

    Olischar, M. et al. Progressive posthemorrhagic hydrocephalus leads to changes of amplitude-integrated EEG activity in preterm infants. Childs Nerv. Syst. 20, 41–45 (2004).

    CAS  PubMed  Article  Google Scholar 

  95. 95.

    Ogawa, S., Lee, T. M., Kay, A. R. & Tank, D. W. Brain magnetic resonance imaging with contrast dependent on blood oxygenation. Proc. Natl Acad. Sci. USA 87, 9868–9872 (1990).

    CAS  PubMed  Article  Google Scholar 

  96. 96.

    Jobsis, F. Noninvasive, infrared monitoring of cerebral and myocardial oxygen sufficiency and circulatory parameters. Science 198, 1264–1267 (1977).

    CAS  PubMed  Article  Google Scholar 

  97. 97.

    Matcher, S. J., Cope, M. & Delpy, D. T. Use of the water absorption spectrum to quantify tissue chromophore concentration changes in near-infrared spectroscopy. Phys. Med. Biol. 39, 177–196 (1994).

    CAS  PubMed  Article  Google Scholar 

  98. 98.

    Damoiseaux, J. S. et al. Consistent resting-state networks across healthy subjects. Proc. Natl Acad. Sci. USA 103, 13848–13853 (2006).

    CAS  PubMed  Article  Google Scholar 

  99. 99.

    Smith, S. M. et al. Correspondence of the brain’s functional architecture during activation and rest. Proc. Natl Acad. Sci. USA 106, 13040–13045 (2009).

    CAS  PubMed  Article  Google Scholar 

  100. 100.

    Fox, M. D. & Raichle, M. E. Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging. Nat. Rev. Neurosci. 8, 700–711 (2007).

    CAS  PubMed  Article  Google Scholar 

  101. 101.

    Blazejewska, A. I. et al. 3D in utero quantification of T2* relaxation times in human fetal brain tissues for age optimized structural and functional MRI: 3D T2* Relaxometry for Fetal Brain fMRI. Magn. Reson. Med. 78, 909–916 (2017).

    CAS  PubMed  Article  Google Scholar 

  102. 102.

    Jakab, A. et al. Fetal functional imaging portrays heterogeneous development of emerging human brain networks. Front. Hum. Neurosci. 8, 852 (2014).

  103. 103.

    Schopf, V. et al. The relationship between eye movement and vision develops before birth. Front. Hum. Neurosci. 8, 775 (2014).

  104. 104.

    Thomason, M. E. et al. Intrinsic functional brain architecture derived from graph theoretical analysis in the human fetus. PLoS ONE 9, e94423 (2014).

  105. 105.

    Thomason, M. E. et al. Age-related increases in long-range connectivity in fetal functional neural connectivity networks in utero. Dev. Cogn. Neurosci. 11, 96–104 (2015).

    PubMed  Article  Google Scholar 

  106. 106.

    Thomason, M. E. et al. Weak functional connectivity in the human fetal brain prior to preterm birth. Sci. Rep. 7, 39286 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  107. 107.

    Gao, W. et al. Evidence on the emergence of the brain’s default network from 2-week-old to 2-year-old healthy pediatric subjects. Proc. Natl Acad. Sci. USA 106, 6790–6795 (2009).

    CAS  PubMed  Article  Google Scholar 

  108. 108.

    Zhao, T., Xu, Y. & He, Y. Graph theoretical modeling of baby brain networks. NeuroImage 185, 711–727 (2019).

    PubMed  Article  Google Scholar 

  109. 109.

    Rubinov, M. & Sporns, O. Complex network measures of brain connectivity: uses and interpretations. NeuroImage 52, 1059–1069 (2010).

    PubMed  PubMed Central  Article  Google Scholar 

  110. 110.

    Omidvarnia, A., Metsäranta, M., Lano, A. & Vanhatalo, S. Structural damage in early preterm brain changes the electric resting state networks. NeuroImage 120, 266–273 (2015).

    PubMed  Article  Google Scholar 

  111. 111.

    Koolen, N. et al. Automated classification of neonatal sleep states using EEG. Clin. Neurophysiol. Off. J. Int. Fed. 128, 1100–1108 (2017).

    Article  Google Scholar 

  112. 112.

    Tóth, B. et al. Dynamics of EEG functional connectivity during statistical learning. Neurobiol. Learn Mem. 144, 216–229 (2017).

    PubMed  Article  Google Scholar 

  113. 113.

    De Vico Fallani, F., Richiardi, J., Chavez, M. & Achard, S. Graph analysis of functional brain networks: practical issues in translational neuroscience. Philos. Trans. R. Soc. Lond. B Biol. Sci. 369, 20130521 (2014).

  114. 114.

    Fornito, A., Zalesky, A. & Breakspear, M. Graph analysis of the human connectome: Promise, progress, and pitfalls. NeuroImage 80, 426–444 (2013).

    PubMed  Article  Google Scholar 

  115. 115.

    Stoecklein, S. et al. Variable functional connectivity architecture of the preterm human brain: Impact of developmental cortical expansion and maturation. Proc. Natl Acad. Sci. USA 117, 1201–1206 (2020).

    CAS  PubMed  Article  Google Scholar 

  116. 116.

    Farahani, F. V., Karwowski, W. & Lighthall, N. R. Application of graph theory for identifying connectivity patterns in human brain networks: a systematic review. Front. Neurosci. 13, 585 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  117. 117.

    Zalesky, A., Fornito, A. & Bullmore, E. T. Network-based statistic: identifying differences in brain networks. NeuroImage 53, 1197–1207 (2010).

    PubMed  Article  Google Scholar 

  118. 118.

    Bassett, D. S., Zurn, P. & Gold, J. I. On the nature and use of models in network neuroscience. Nat. Rev. Neurosci. 19, 566–578 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  119. 119.

    van den Heuvel, M. P. & Hulshoff Pol, H. E. Exploring the brain network: a review on resting-state fMRI functional connectivity. Eur. Neuropsychopharmacol. 20, 519–534 (2010).

    PubMed  Article  CAS  Google Scholar 

  120. 120.

    Telesford, Q. K., Simpson, S. L., Burdette, J. H., Hayasaka, S. & Laurienti, P. J. The brain as a complex system: using network science as a tool for understanding the brain. Brain Connect. 1, 295–308 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

  121. 121.

    Finc, K. et al. Dynamic reconfiguration of functional brain networks during working memory training. Nat. Commun. 11, 2435 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  122. 122.

    Zhang, G., Li, Y. & Zhang, J. Tracking the dynamic functional network interactions during goal-directed auditory tasks by brain state clustering. Front. Neurosci. 13, 1220 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  123. 123.

    Cai, L. et al. Functional integration and segregation in multiplex brain networks for Alzheimer’s disease. Front Neurosci. 14, 51 (2020).

    PubMed  PubMed Central  Article  Google Scholar 

  124. 124.

    Betzel, R. F. & Bassett, D. S. Multi-scale brain networks. NeuroImage 160, 73–83 (2017).

    PubMed  Article  Google Scholar 

  125. 125.

    Smyser, C. D. et al. Resting-state network complexity and magnitude are reduced in prematurely born infants. Cereb. Cortex 26, 322–333 (2016).

    PubMed  Article  Google Scholar 

  126. 126.

    Gozdas, E. et al. Altered functional network connectivity in preterm infants: antecedents of cognitive and motor impairments? Brain Struct. Funct. 223, 3665–3680 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  127. 127.

    Ball, G. et al. Machine-learning to characterise neonatal functional connectivity in the preterm brain. NeuroImage 124, 267–275 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  128. 128.

    Bouyssi-Kobar, M., De Asis-Cruz, J., Murnick, J., Chang, T. & Limperopoulos, C. Altered functional brain network integration, segregation, and modularity in infants born very preterm at term-equivalent age. J. Pediatr. 213, 13–21.e1 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  129. 129.

    Naoi, N. et al. Decreased right temporal activation and increased interhemispheric connectivity in response to speech in preterm infants at term-equivalent age. Front. Psychol. 4, 94 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  130. 130.

    Tóth, B. et al. Large-scale network organization of EEG functional connectivity in newborn infants. Hum. Brain Mapp. 38, 4019–4033 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  131. 131.

    Myers, M. M. et al. Family Nurture Intervention in preterm infants alters frontal cortical functional connectivity assessed by EEG coherence. Acta Paediatr. 104, 670–677 (2015).

    CAS  PubMed  Article  Google Scholar 

  132. 132.

    Taga, G., Watanabe, H. & Homae, F. Developmental changes in cortical sensory processing during wakefulness and sleep. NeuroImage 178, 519–530 (2018).

    PubMed  Article  Google Scholar 

  133. 133.

    Imai, M. et al. Functional connectivity of the cortex of term and preterm infants and infants with Down’s syndrome. NeuroImage 85, 272–278 (2014).

    PubMed  Article  Google Scholar 

  134. 134.

    Fuchino, Y. et al. Effects of preterm birth on intrinsic fluctuations in neonatal cerebral activity examined using optical imaging. PLoS ONE 8, e67432 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  135. 135.

    Spittle, A. J., Cameron, K., Doyle, L. W., Cheong, J. L. & Victorian Infant Collaborative Study Group. Motor impairment trends in extremely preterm children: 1991–2005. Pediatrics 141, e20173410 (2018).

  136. 136.

    Messerschmidt, A. et al. Disrupted cerebellar development in preterm infants is associated with impaired neurodevelopmental outcome. Eur. J. Pediatr. 167, 1141–1147 (2008).

    PubMed  Article  Google Scholar 

  137. 137.

    Bos, A. F., Van Braeckel, K. N. J. A., Hitzert, M. M., Tanis, J. C. & Roze, E. Development of fine motor skills in preterm infants. Dev. Med. Child Neurol. 55, 1–4 (2013).

  138. 138.

    Barnes-Davis, M. E., Williamson, B. J., Merhar, S. L., Holland, S. K. & Kadis, D. S. Rewiring the extremely preterm brain: Altered structural connectivity relates to language function. NeuroImage Clin. 25, 102194 (2020).

    PubMed  PubMed Central  Article  Google Scholar 

  139. 139.

    Rogers, C. E., Lean, R. E., Wheelock, M. D. & Smyser, C. D. Aberrant structural and functional connectivity and neurodevelopmental impairment in preterm children. J. Neurodev. Disord. 10, 38 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  140. 140.

    Scheinost, D. et al. Preterm birth alters neonatal, functional rich club organization. Brain Struct. Funct. 221, 3211–3222 (2016).

    PubMed  Article  Google Scholar 

  141. 141.

    Eyre, M. et al. The Developing Human Connectome Project: Typical and Disrupted Perinatal Functional Connectivity. Brain: A Journal of Neurology. (2021).

  142. 142.

    Tokariev, A. et al. Preterm birth changes networks of newborn cortical activity. Cereb. Cortex. 29, 1697–1697 (2019).

    PubMed  Article  Google Scholar 

  143. 143.

    White, B. R., Liao, S. M., Ferradal, S. L., Inder, T. E. & Culver, J. P. Bedside optical imaging of occipital resting-state functional connectivity in neonates. NeuroImage 59, 2529–2538 (2012).

    PubMed  Article  Google Scholar 

  144. 144.

    Ferradal, S. L. et al. Functional imaging of the developing brain at the bedside using diffuse optical tomography. Cereb. Cortex 26, 1558–1568 (2016).

    PubMed  Article  Google Scholar 

  145. 145.

    Homae, F. et al. Development of global cortical networks in early infancy. J. Neurosci. Off. 30, 4877–4882 (2010).

    CAS  Article  Google Scholar 

  146. 146.

    Vasung, L. et al. Exploring early human brain development with structural and physiological neuroimaging. NeuroImage 15, 226–254 (2019).

    Article  Google Scholar 

  147. 147.

    Scarapicchia, V., Brown, C., Mayo, C. & Gawryluk, J. R. Functional magnetic resonance imaging and functional near-infrared spectroscopy: insights from combined recording studies. Front. Hum. Neurosci. 11, 419 (2017).

  148. 148.

    Nourhashemi, M., Mahmoudzadeh, M., Goudjil, S., Kongolo, G. & Wallois, F. Neurovascular coupling in the developing neonatal brain at rest. Hum. Brain Mapp. 41, 503–519 (2020).

    PubMed  Article  Google Scholar 

  149. 149.

    Wong, F. Y., Barfield, C. P., Horne, R. S. C. & Walker, A. M. Dopamine therapy promotes cerebral flow-metabolism coupling in preterm infants. Intensive Care Med. 35, 1777–1782 (2009).

    CAS  PubMed  Article  Google Scholar 

  150. 150.

    Kozberg, M. & Hillman, E. Neurovascular coupling and energy metabolism in the developing brain. In: Progress in Brain Research [Internet] 213–242. (2016).

  151. 151.

    Pfurtscheller, K., Müller-Putz, G. R., Urlesberger, B., Müller, W. & Pfurtscheller, G. Relationship between slow-wave EEG bursts and heart rate changes in preterm infants. Neurosci. Lett. 385, 126–130 (2005).

    CAS  PubMed  Article  Google Scholar 

  152. 152.

    Aysin, B. & Aysin, E. Effect of respiration in heart rate variability (HRV) analysis. In: 2006 International Conference of the IEEE Engineering in Medicine and Biology Society [Internet] 1776–1779. (2006).

  153. 153.

    Holditch-Davis, D., Scher, M., Schwartz, T. & Hudson–Barr, D. Sleeping and waking state development in preterm infants. Early Hum. Dev. 80, 43–64 (2004).

    PubMed  Article  PubMed Central  Google Scholar 

  154. 154.

    Isler, J. R., Thai, T., Myers, M. M. & Fifer, W. P. An automated method for coding sleep states in human infants based on respiratory rate variability. Dev. Psychobiol. 58, 1108–1115 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  155. 155.

    Del Rio-Bermudez, C. & Blumberg, M. S. Active sleep promotes functional connectivity in developing sensorimotor networks. BioEssays 40, 1700234 (2018).

    Article  Google Scholar 

  156. 156.

    Arthurs, O. J., Edwards, A., Austin, T., Graves, M. J. & Lomas, D. J. The challenges of neonatal magnetic resonance imaging. Pediatr. Radiol. 42, 1183–1194 (2012).

    PubMed  Article  PubMed Central  Google Scholar 

  157. 157.

    van den Heuvel, M. P. et al. The neonatal connectome during preterm brain development. Cereb. Cortex 25, 3000–3013 (2015).

    PubMed  Article  Google Scholar 

  158. 158.

    Chalak, L. F. et al. Novel wavelet real time analysis of neurovascular coupling in neonatal encephalopathy. Sci. Rep. 7, 45958 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  159. 159.

    Mahmoudzadeh, M. et al. Consequence of intraventricular hemorrhage on neurovascular coupling evoked by speech syllables in preterm neonates. Dev. Cogn. Neurosci. 30, 60–69 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  160. 160.

    Li, X.-F., Zhou, Y.-X. & Zhang, L. Newborns’ sleep-wake cycle development on amplitude integrated electroencephalography. World J. Pediatr. 12, 327–334 (2016).

    PubMed  Article  Google Scholar 

  161. 161.

    Hellström-Westas, L. Amplitude-integrated electroencephalography for seizure detection in newborn infants. Semin. Fetal Neonatal Med. 23, 175–182 (2018).

    PubMed  Article  Google Scholar 

  162. 162.

    Hellstro m-Westas, L., Rosen, I., de Vries, L. S., Greisen, G. & Amplitude-integrated, E. E. G. Classification and interpretation in preterm and term infants. NeoReviews 7, e76–e87 (2006).

    Article  Google Scholar 

  163. 163.

    Klebermass, K. et al. Pattern predicts further outcome in preterm infants. Pediatr. Res. 70, 102–108 (2011).

    PubMed  Article  Google Scholar 

  164. 164.

    Bennet, L. et al. Discrimination of sleep states using continuous cerebral bedside monitoring (amplitude-integrated electroencephalography) compared to polysomnography in infants. Acta Paediatr. 105, e582–e587 (2016).

    PubMed  Article  Google Scholar 

  165. 165.

    Olischar, M., Klebermass, K., Waldhoer, T., Pollak, A. & Weninger, M. Background patterns and sleep-wake cycles on amplitude-integrated electroencephalography in preterms younger than 30 weeks gestational age with peri-/intraventricular haemorrhage. Acta Paediatr. 96, 1743–1750 (2007).

    PubMed  Article  Google Scholar 

  166. 166.

    Kidokoro, H., Inder, T., Okumura, A. & Watanabe, K. What does cyclicity on amplitude-integrated EEG mean? J. Perinatol. 32, 565–569 (2012).

    CAS  PubMed  Article  Google Scholar 

  167. 167.

    Stevenson, N. J., Palmu, K., Wikström, S., Hellström-Westas, L. & Vanhatalo, S. Measuring brain activity cycling (BAC) in long term EEG monitoring of preterm babies. Physiol. Meas. 35, 1493–508 (2014).

    PubMed  Article  Google Scholar 

  168. 168.

    Ghimatgar, H. et al. Neonatal EEG sleep stage classification based on deep learning and HMM. J. Neural Eng. 17, 036031 (2020).

    PubMed  Article  Google Scholar 

  169. 169.

    Ansari, A. H. et al. A convolutional neural network outperforming state-of-the-art sleep staging algorithms for both preterm and term infants. J. Neural Eng. 17, 016028 (2020).

    PubMed  Article  Google Scholar 

  170. 170.

    Terrill, P. I., Wilson, S. J., Suresh, S. & Cooper, D. M. Characterising infant inter-breath interval patterns during active and quiet sleep using recurrence plot analysis. In: 2009 Annual International Conference of the IEEE Engineering in Medicine and Biology Society [Internet] 6284–6287. (2009).

  171. 171.

    Werth, J. et al. Unobtrusive assessment of neonatal sleep state based on heart rate variability retrieved from electrocardiography used for regular patient monitoring. Early Hum. Dev. 113, 104–113 (2017).

    PubMed  Article  PubMed Central  Google Scholar 

  172. 172.

    Cooper, R. J. et al. Transient haemodynamic events in neurologically compromised infants: a simultaneous EEG and diffuse optical imaging study. NeuroImage 55, 1610–6 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  173. 173.

    Elisabetta Maria, F. et al. Functional imaging of the developing brain with wearable high-density diffuse optical tomography: a new benchmark for infant neuroimaging outside the scanner environment. NeuroImage 225, 117490 (2021).

  174. 174.

    Arichi, T. et al. Localization of spontaneous bursting neuronal activity in the preterm human brain with simultaneous EEG-fMRI. eLife 12, 6 (2017).

    Google Scholar 

  175. 175.

    Vanhatalo, S., Alnajjar, A., Nguyen, V. T., Colditz, P. & Fransson, P. Safety of EEG–fMRI recordings in newborn infants at 3T: a study using a baby-size phantom. Clin. Neurophysiol. 125, 941–946 (2014).

    PubMed  Article  Google Scholar 

  176. 176.

    González, J. J. et al. Assessment of Electroencephalographic Functional Connectivity in Term and Preterm Neonates. Clinical Neurophysiology 122, 696–702 (2011).

  177. 177.

    Burroughs, S. A., Morse R. P., Mott S. H. and Holmes G. L. Brain Connectivity in West Syndrome. Seizure 23, 576–79 (2014).

  178. 178.

    Grieve, P. G. et al. EEG Functional Connectivity in Term Age Extremely Low Birth Weight Infants. Clinical Neurophysiology 119, 2712–2720 (2008).

  179. 179.

    Scher, M. S., Steppe D. A., Dahl R. E., Asthana S. & Guthrie R. D. Comparison of EEG Sleep Measures in Healthy Full-Term and Preterm Infants at Matched Conceptional Ages. Sleep 15, 442–448 (1992).

  180. 180.

    Milde, T., Putsche P., Schwab K., Wacker M., Eiselt M. & Witte H. Dynamics of Directed Interactions between Brain Regions during Interburst–Burst EEG Patterns in Quiet Sleep of Full-Term Neonates. Neuroscience Letters 488, 148–53 (2011).

  181. 181.

    Räsänen, O., Metsäranta M. & Vanhatalo S. Development of a Novel Robust Measure for Interhemispheric Synchrony in the Neonatal EEG: Activation Synchrony Index (ASI). NeuroImage 69, 256–266 (2013).

  182. 182.

    Stefanski, M., Schulze, K., Bateman D., Kairam, R., Pedley T. A., Masterson, J. and L. S. James. A Scoring System for States of Sleep and Wakefulness in Term and Preterm Infants. Pediatric Research 18, 58–62 (1984).

  183. 183.

    Myers, M. M., Grieve P. G., Stark R. I., Isler, J. R., Hofer M. A., Yang, J., Ludwig R. J. & Welch M. G. Family Nurture Intervention in Preterm Infants Alters Frontal Cortical Functional Connectivity Assessed by EEG Coherence. Acta Paediatrica (Oslo, Norway: 1992) 104, 670–677 (2015).

  184. 184.

    Sahni, R., Schulze K. F., Stefanski, M., Myers M. M. & Fifer W. P. Methodological Issues in Coding Sleep States in Immature Infants. Developmental Psychobiology 28, 85–101 (1995).

  185. 185.

    Bulgarelli, C. et al. Dynamic Causal Modelling on Infant FNIRS Data: A Validation Study on a Simultaneously Recorded FNIRS-FMRI Dataset. Neuroimage 175, 413–424 (2018).

Download references


J.U. is funded by a Marshall Scholarship. The NIHR Cambridge Biomedical Research Centre (BRC) is a partnership between Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge, funded by the National Institute for Health Research (NIHR), T.A. is supported by the NIHR Cambridge Biomedical Research Centre (BRC). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.

Author information




J.U. drafted the manuscript for intellectual content, creating the figures for the manuscript, revised the manuscript for intellectual content, and prepared the manuscript for submission. S.V. drafted major components of the manuscript for intellectual content and revised the entire manuscript for intellectual content. T.A. planned the outline of the article, guided the drafting of the article, and contributed heavily to the revision of the manuscript for intellectual content and preparing the manuscript for submission.

Corresponding author

Correspondence to Topun Austin.

Ethics declarations

Competing interests

The authors declare no competing interests.

Consent statement

Patient consent was not needed in the preparation of this article.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Uchitel, J., Vanhatalo, S. & Austin, T. Early development of sleep and brain functional connectivity in term-born and preterm infants. Pediatr Res (2021).

Download citation


Quick links