A new study reveals that when a baby is born prematurely, their cerebellum, the part of the brain with a critical role in motor function, language and cognition, grows and develops in a different way than it would if the baby remains in utero full term.
The findings, published in Science, solve a long-standing medical puzzle: Why so many premature infants go on to face challenges with movement, language and learning in childhood, even though they have no detectable brain injuries. In short, the study overturns the decades-old view that premature birth slows down brain growth but that early arrivals "catch-up" by their original due date and beyond.
"We could always see the developmental differences that premature children faced, but we could not see the cellular machinery driving them," says senior author Panagiotis Kratimentos, MD, PhD , a physician-scientist, neonatologist and director of Research and the Neonatal Neurocritical Care Program at Children's National Hospital. "We now have a biological explanation thanks to a unique combination of data from both living participants and from existing brain tissue samples."
Why it matters
Between 24 and 40 weeks of pregnancy, the human cerebellum undergoes its most rapid period of development, expanding fivefold in size as its primary neurons wire together into complex communication networks. This entire growth period happens inside the protective environment of the uterus for a full-term infant. When the baby is born prematurely, this rapid brain construction phase is forced to happen outside the womb.
- Smaller cerebellar volume: Each week spent outside the womb before full term was associated with about 230 cubic millimeters less cerebellar volume — roughly the size of a pea.
- Developmental delays: At 9 to 36 months of age, smaller cerebellar volume correlated with delays in movement, language and thinking skills.
- Potential to influence growth: Although birth timing sets the baseline molecular program, physiological stressors, illness and specific aspects of care in the neonatal intensive care unit (NICU) significantly altered cerebellar growth rates.
"With this human cellular map in hand, we are moving into a new era of precision neurocritical care for premature newborns," says Dr. Kratimenos. "Instead of treating the preterm brain as a black box, we can now design and time neuroprotective strategies to match the exact biological state of a baby's brain cells in the NICU, helping them transition smoothly from early adaptation to healthy circuit-building."
"Assessment and treatment of preterm infants should be guided by developmental maturity rather than chronological age," said Vittorio Gallo, PhD, a joint senior author who began the research while at Children's National. "The identified molecular markers will improve risk stratification, advance maturity biomarkers and optimize the timing of neuroprotective therapies." Gallo continued the research collaboration after joining Seattle Children's , where he now serves as senior vice president and chief scientific officer.
How the research was conducted
Study co-first authors Georgios Sanidas, MD, a physician-scientist, and Gabriele Simonti, a translational neuroscientist, from Children's National's Center for Neuroscience Research and Sheikh Zayed Institute for Pediatric Surgical Innovation , led the study. Drs. Sanidas and Simonti combined multiyear brain imaging and developmental tracking of 176 living infants with cellular analysis of pre-existing brain tissue from 83 preterm and term human infants. Samples came from tissue repositories, including the NIH NeuroBioBank, for spatial transcriptomics. This technology maps exact gene activity across intact tissue layers, revealing how major cerebellar neurons — Purkinje and granule cells — develop outside the womb compared with normal gestation.
"Studying human tissue alongside living patients allowed us to connect the molecular programs set at birth directly to how children grow and develop years later," says Dr. Sanidas.
"By decoding these mechanisms directly in human datasets, we were able to see how the molecular programs governing Purkinje and granule cells respond not just to the timing of birth, but also to the clinical environment after birth," adds Simonti. "We are now actively investigating targeted interventions based on these findings to steer the premature brain toward healthy maturation."
This study was supported by the Raynor Cerebellum Project Foundation.
