Elsevier

NeuroImage

Volume 108, March 2015, Pages 144-150
NeuroImage

Adaptive mechanisms of developing brain: Cerebral lateralization in the prematurely-born

https://doi.org/10.1016/j.neuroimage.2014.12.032Get rights and content

Highlights

  • We compare cerebral lateralization in preterm and term neonates at term age.

  • Preterm neonates have altered lateralization in left hemisphere language areas.

  • L BA22, Wernicke's area, is more strongly connected to R BA39 in preterm neonates.

  • Results foreshadow findings in preterm children, adolescents and young adults.

  • Preterm birth at very low postmenstrual age alters corticogenesis.

Abstract

Preterm birth results in alterations in neural connectivity, but the impact of prematurity on the functional organization of the developing brain has yet to be explored. To test the hypothesis that preterm birth alters cortical organization during the late second and third trimesters of gestation, we interrogated cerebral lateralization at rest in 26 very preterm subjects (birth weight 500–1500 g) with no evidence of brain injury and 25 healthy term control subjects at term equivalent age. Employing an unbiased voxel-based measure of functional connectivity, these data demonstrated that cerebral lateralization is impaired in the prematurely-born. At term equivalent age, preterm neonates showed significantly less lateralization in regions subserving both receptive and expressive language, left Brodmann (BA) areas insula–BA22–BA21 and L BA45–BA47 (p < 0.05 corrected for multiple comparisons for both). Exploratory region of interest analyses demonstrated significantly less inter-hemispheric connectivity from L BA22 to R BA22 in preterm infants compared to term controls (p < 0.005) and from R BA22 to its homolog (p < 0.005). L BA22, Wernicke's area, was more strongly connected to R BA39, foreshadowing neural networks for language in preterm subjects at school age, adolescence and young adulthood. For these very preterm neonates born at less than 30 weeks' PMA, the degree of prematurity had no influence on lateralization in these differential regions.

Introduction

While it has been known for many years that prematurity results in disordered neural connectivity (Huppi et al., 1998, Inder et al., 2003, Nosarti et al., 2006, Smyser et al., 2010, White et al., 2014), emerging data suggest that preterm (PT) birth alters the fundamental functional organization of developing brain. Multiple studies across the past decade suggest that alterations in neural networks contribute to the cognitive and behavioral difficulties of the prematurely-born (Doesburg et al., 2011, Ment et al., 2009, Myers et al., 2010, Nosarti, 2013, Salvan et al., 2014), but recent reports demonstrate alterations in the genetically-determined process of cerebral lateralization in PT subjects at adolescence and young adulthood (Scheinost et al., 2014, Wilke et al., 2014). Lateralization implies localization of a cognitive task to a specific cerebral region, and lateralization of language is a critical characteristic of developing brain (Power et al., 2010, Renteria, 2012).

Functional MRI studies suggest that those regions known to constitute the neural network for language in adults, children and older infants are also activated in newborns in response to language stimulation (Dehaene-Lambertz et al., 2002, Dehaene-Lambertz et al., 2004, Dehaene-Lambertz et al., 2010). Consistent with neuropathologic studies (Chi et al., 1977), this network involves both frontal and temporal regions with a clear dominance of the left hemisphere (Pena et al., 2003, Perani et al., 2011), and those regions sub-serving language are functionally connected (Hickok and Poeppel, 2007).

Likewise, studies across the putative third trimester of gestation suggest that healthy PT neonates develop the structural basis for language during this time interval (Dubois et al., 2009, Leroy et al., 2011). Similarly, functional imaging demonstrates the emergence of auditory networks in PT subjects between 30 and 40 weeks of gestation (Doria et al., 2010, Omidvarnia et al., 2013, Smyser et al., 2011). However, relative to term controls, PT neonates exhibit altered discrimination of speech sounds and deficits in auditory memory at term equivalent age and long term deficits in language processing (Luu et al., 2009, Taylor et al., 2004, Therien et al., 2004).

These data suggest that PT birth results in both proximate and long-lasting changes in cerebral functional organization. To test the hypothesis that PT birth alters cortical organization during the late second and third trimesters of gestation, we interrogated cerebral lateralization at rest in very PT subjects and term control subjects at term-equivalent age employing a novel data-driven voxel-based connectivity analysis strategy. Secondary seed-based analyses provided information about neural networks for language in the preterm brain.

Section snippets

Methods

This study was approved by the Yale University Human Investigation Committee.

Results

Thirty PT infants and 32 term controls met all inclusion criteria, and data from 26 PT and 25 term infants were analyzed after exclusion of 11 infants due to motion artifact. There was no significant difference in motion between the PT and term groups (p = 0.61). Although there was no gender difference between the two groups, PMA at scan and TBV were significantly less for PT subjects compared to term controls (p < 0.001 for both; Table 2).

As shown in Fig. 2, voxel-wise, whole brain analyses

Discussion

Lateralization of language is an essential characteristic of the developing human brain, and these data suggest that this most fundamental process is impaired in the prematurely-born. At term equivalent age, PT neonates show significant lack of lateralization to regions subserving both receptive and expressive language, L insula–BA22–BA21 and L lateral BA45–BA47. ROI analyses demonstrate a significant decrease in inter-hemispheric connectivity from L BA22 to its homolog — and back again from R

Conclusions

Preterm birth is a major pediatric public health problem in the world today (Blencowe et al., 2013a, Blencowe et al., 2013b), and almost 40% of preterm subjects experience language disorders (Northam et al., 2012, Pritchard et al., 2014). If a major aim of perinatal intensive care is to promote typical development in the prematurely born (Bauer and Msall, 2010), then interrogation of molecular mechanisms responsible for language in the developing brain is critically important for this goal (

Acknowledgments

We thank Drs. Richard Ehrenkranz and Deborah Hirtz for their scientific expertise; Hedy Sarofin and Terry Hickey for their technical assistance; and the families who participated in this study.

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    Supported by NIH NS074022, T32 HD07094, T32 DA022975, UL1 TR000142

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