Preterm birth results in alterations in neural connectivity at age 16 years
Research Highlights
►Recent studies in adults have proposed a dual system of language processing:bilateral ventral pathways process speech comprehension (semantic language) while a left dorsal pathway processes speech signals to phonological representations. ►This study shows for the first time that a dual system is present in preterm adolescents. ►In contrast to adults, preterm subjects show striking bilateral dorsal correlations. ►Preterm subjects rely more heavily on the right hemisphere than typically developing adults for phonological processing. ►These preterm findings may represent a delay in maturation or the engagement of alternative pathways for language.
Introduction
Premature birth is a pressing public health matter, as nearly 13% of infants in the United States are born preterm and infants weighing under 1500 g at birth comprise 1.5% of births (Beck et al., 2010, Martin et al., 2008). The brains of infants born prematurely face increased susceptibility to the challenges of ischemia and inflammation. Through the downstream effectors of excitotoxicity and free-radical attack, both glia and axons are disrupted, and the damage is compounded by secondary disturbance of growth patterns (Dyet et al., 2006, Hack et al., 2002, Miller et al., 2005). In addition to feared neurological complications of preterm birth such as cerebral palsy, a range of developmental deficits in cognitive function in preterm children have been observed to persist until early adulthood, indicating long-term disruption of brain function (Hack, 2009, Neubauer et al., 2008). Preterm children with severe brain injury such as periventricular hemorrhagic infarction and periventricular leukomalacia have the greatest risk of neurodevelopmental deficits; however, even those without these forms of brain injury are more likely than control term subjects to have lower IQ scores and require more support in language-based skills (Luu et al., 2009) during childhood and adolescence.
Recent investigations have proposed dual systems of language processing, analogous to dual pathways identified in visual processing (Friederici, 2009, Hickok and Poeppel, 2007, Saur et al., 2008). In this model, a ventral pathway processes comprehension of speech, with mapping of sounds to semantic representations, while a dorsal pathway is involved in matching speech signals to phonological and articulatory representations. The prototypical task calling upon the dorsal pathway is repetition, while the ventral pathway is vital in understanding meaningful speech. The arcuate fasciculus has been identified as the primary component of the dorsal pathway, while the ventral pathways are likely comprised of fibers traveling through both the extreme capsule and the uncinate fasciculus, a ventral pathway connecting the temporal and frontal lobes (Gozzo et al., 2009, Parker et al., 2005). The ventral pathway is thought to be bilateral, while the dorsal pathway tends to be strongly left-dominant (Hickok and Poeppel, 2007, Parker et al., 2005). Furthermore, since investigations of the dual pathway language systems have taken place in adult subjects, the developmental timing of specialization of these pathways is not fully understood. (Cao et al., 2009, Chou et al., 2006, Ment et al., 2006, Peterson et al., 2002).
Diffusion tensor imaging (DTI) provides a sensitive means of assessing the integrity of white matter tracts at a microstructural level. As part of DTI analyses, fractional anisotropy (FA) values provide a quantitative measure of the degree to which water diffusion is restricted along one axis relative to all others. Within cerebral white matter, water preferentially diffuses along axons, with diffusion perpendicular to this axis restricted by structural barriers including cell membranes. Higher FA values are a marker for the coherence of white matter tracts, as the constraints of the tissue organization into axon bundles within well-formed tracts limit the direction of water diffusion. Alterations in FA may result from changes in fiber organization, axonal size (Assaf et al., 2008), or activity-dependent changes in myelination (Als et al., 2004).
Previous studies have shown deficits in FA values in white matter tracts in premature infants at term-equivalent age as compared to term infants (Anjari et al., 2009, Anjari et al., 2007, Berman et al., 2005, Cheong et al., 2009, Dudink et al., 2007, Gimenez et al., 2008, Huppi et al., 1998, Huppi et al., 2001, Miller et al., 2002, Partridge et al., 2004, Rose et al., 2008), and changes in FA values can persist to late childhood and adolescence (Constable et al., 2008, Counsell et al., 2007, Counsell et al., 2008, Gimenez et al., 2006, Kontis et al., 2009, Murakami et al., 2008, Nagy et al., 2003, Reiss et al., 2004, Skranes et al., 2007, Vangberg et al., 2006, Yung et al., 2007). Moreover, FA values have been shown to correlate with multiple measures of neurodevelopmental function (Als et al., 2004, Arzoumanian et al., 2003, Bassi et al., 2008, Berman et al., 2009, Drobyshevsky et al., 2007, Krishnan et al., 2007, Peterson et al., 2000, Rose et al., 2009, Rose et al., 2007, Skranes et al., 2007).
Further, preterm children may develop language pathways differently than normally developing term children. For example, functional connectivity analyses have shown stronger connections between Wernicke's area and right-sided cortical regions in preterm children than in term children, implying changes in lateralization of language processing (Gozzo et al., 2009). This may represent increased utilization of compensatory alternative pathways in the right hemisphere in preterm children. Thus, for language tasks in particular, preterm children may engage alternative pathways, including increased utilization of the right hemisphere.
We hypothesize that preterm children at age 16 will continue to have deficits in both cognitive testing and microstructural integrity of multiple white matter tracts. By evaluating dorsal and ventral language pathways in preterm children, we will investigate whether preterm children demonstrate departures from the dual language pathway as described in typically developing adults, which may represent delays in maturation or compensations for changes in glio- and/or neurogenesis caused by the injury of preterm birth.
Section snippets
Methods
This study was performed at the Yale University School of Medicine, New Haven, CT and Brown Medical School, Providence, RI. The protocols were reviewed and approved by institutional review boards at each location. Children provided written assent; parent(s) provided written consent for the study. All scans were obtained at Yale University and were analyzed at Yale University and at Stanford University.
Subject population
Neonatal characteristics of the preterm population are shown in Table 1. The preterm subjects weighed between 600 and 1250 g at birth, with a mean birth weight of 994 ± 184 g and mean gestational age of 28.3 ± 1.9 weeks. One quarter of the subjects (26%) developed bronchopulmonary dysplasia.
Demographic data of the term and preterm cohorts are presented in Table 2. There were no significant differences between preterm and term cohorts in gender, age at scan, number of right-handed subjects, percentage
Discussion
These data support for the first time that the dual pathways underlying language function are present in prematurely-born subjects at late adolescence. Preterm subjects with no evidence of severe neonatal brain injury exhibit diffuse changes in cerebral white matter microstructure and total cerebral white matter volume compared to term controls at 16 years of age, yet our data show significant positive correlations between language measures and microstructural integrity in both the dorsal and
Acknowledgments
We thank Drs. Deborah Hirtz and Walter Allan for their scientific expertise; Marjorene Ainley for the follow-up coordination; Jill Maller-Kesselman, Susan Delancy and Victoria Watson for their neurodevelopmental testing; Hedy Sarofin and Terry Hickey for their technical assistance; Mai Manchanda for statistical analysis; and Cleo O'Brien-Udry and Julia Lubsen for their assistance in fiber tracking.
This work was supported by NS 27116 (LRM) and NCRR CTSA-T32 Medical Student Research Fellowship
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