Elsevier

NeuroImage

Volume 51, Issue 4, 15 July 2010, Pages 1445-1452
NeuroImage

Functional connectivity to a right hemisphere language center in prematurely born adolescents

https://doi.org/10.1016/j.neuroimage.2010.03.049Get rights and content

Abstract

Prematurely born children are at increased risk for language deficits at school age and beyond, but the neurobiological basis of these findings remains poorly understood. Thirty-one PT adolescents (600–1250 g birth weight) and 36 T controls were evaluated using an fMRI passive language task and neurodevelopmental assessments including: the Wechsler Intelligence Scale for Children-III (WISC-III), the Peabody Picture Vocabulary Test-Revised (PPVT-R), the Comprehensive Test of Phonological Processing (CTOPP) and the Test of Word Reading Efficiency (TOWRE) at 16 years of age. Neural activity was assessed for language processing and the data were evaluated for connectivity and correlations to cognitive outcomes. PT subjects scored significantly lower on all components of the WISC-III (p < 0.05) compared to term subjects, but there was no significant difference in PPVT-R scores between the groups. Functional connectivity (fcMRI) between Wernicke's area (left BA 22) and the right supramarginal gyrus (BA 40) was increased in preterm subjects relative to term controls (p = 0.03), and the strength of this connection was inversely related to performance on both the PPVT-R (R2 = 0.553, p = 0.002), and the verbal comprehension index (R2 = 0.439, p = 0.019). Preterm adolescents engage a dorsal right hemisphere region for language at age 16 years. Those with the greatest cognitive deficits demonstrate increasing reliance on this alternate pathway.

Introduction

Preterm birth represents a major pediatric public health problem in the United States and Europe today(Behrman and Stith Butler, 2007). The neurocognitive sequelae of preterm birth have been well described (Allin et al., 2008, Hack et al., 2009, Hille et al., 2007, Saigal & Doyle, 2008, Verrips et al., 2008), and the development of sophisticated magnetic resonance imaging (MRI) strategies has provided significant information about the impact of preterm birth on the developing brain. Preterm subjects have widespread structural and microstructural changes when compared to term control subjects in studies ranging from the newborn period to adolescence and young adulthood (Anjari et al., 2009, Dubois et al., 2008, Gimenez et al., 2008, Nagy & Jonsson, 2009, Skranes et al., 2009). In contrast to these presumptive markers of adverse outcome, functional MRI (fMRI) strategies from several investigators demonstrate the recruitment of alternative neural systems for language in the prematurely born (Ment et al., 2006b, Narberhaus et al., 2009, Nosarti et al., 2009, Rushe et al., 2004), and several recent reports suggest that cognitive outcomes for this vulnerable population may depend not only on the gestational age at birth but also on the maternal level of education (Hack et al., 2009, Weisglas-Kuperus et al., 2009). Functional connectivity (fcMRI), which assesses the functional organization of the developing brain, has been less well studied than other imaging strategies in the preterm population. By identifying those regions that activate together either during a particular task or at resting state, fcMRI may provide important information about the differential engagement of alternative neural systems in the developing preterm brain.

Numerous cohort studies have revealed inferior educational outcomes in preterm subjects. At school entry, minor developmental impairment is diagnosed in 30–40% and major disabilities are found in almost 20% of preterm children (Allen, 2008, Larroque et al., 2008, Neubauer et al., 2008, Saigal & Doyle, 2008, Voss et al., 2007). Over half require special assistance in the classroom, 20% are in special education and 15% have repeated at least one grade in school (Aylward, 2005, Bhutta et al., 2002). Furthermore, although a majority of prematurely born neonates have recently been shown to become independent adults, the intellectual deficits of preterm subjects may persist through adolescence and young adulthood (Saigal et al., 2006).

Imaging plays an important role in understanding the neurobiology underlying the cognitive deficits of preterm children. When compared to term control subjects, preterm subjects have global and regional decreases in cortical gray and deep gray matter, less myelinated white matter, smaller corpus callosal areas and significant ventriculomegaly (Allin et al., 2004, Boardman et al., 2007, Huppi et al., 1998, Inder et al., 1999, Inder et al., 2005, Mewes et al., 2006, Peterson et al., 2003). Diffusion tensor imaging (DTI) provides information about the microstructure of the developing brain through measures such as fractional anisotropy (FA). FA increases with increasing myelination, axonal diameter and fiber bundle packing. Widespread decreases in FA have been reported in PT children compared to term controls in studies ranging from infancy through young adulthood (Anjari et al., 2007, Anjari et al., 2009, Skranes et al., 2007) and DTI parameters have been shown to significantly correlate with cognitive and motor outcomes for the prematurely born (Constable et al., 2008, Counsell et al., 2008, Skranes et al., 2009).

More recently, studies using fMRI have identified differences in the brain areas activated during language and executive tasks in preterm children when compared to term control subjects, and preliminary studies investigating fcMRI in preterm subjects during the newborn period and at school age suggest that, when compared to term control subjects, preterm subjects exhibit different patterns of connectivity between brain areas both at rest and during a functional task (Doria et al., 2008, Doria et al., 2009, Fransson et al., 2007, Gozzo et al., 2009, Smyser et al., 2009). Resting state literature suggests that functional connectivity is at least partially anatomically determined, but the role of these alternative pathways remains poorly understood.

In order to test the hypothesis that the alternative neural connections found in prematurely born subjects at adolescence may be associated with cognitive measures including language skills, the connectivity between language regions during an fMRI language task was investigated in preterm and term subjects by correlating the strength of the differential connections with language measures. Wernicke's area, in the left superior temporal gyrus (left Brodmann's area 22), was chosen as a reference region for functional connectivity analysis based on findings from a previous study showing significant differences in functional connectivity levels between eight year old preterms and terms. Functional connectivity to Wernicke's area was evaluated in other primary language regions in the left hemisphere and their right-sided homologues.

Because intraventricular hemorrhage, periventricular leukomalacia and low-pressure ventriculomegaly have been associated with adverse cognitive outcomes in the prematurely born (Ment et al., 1996), our a priori hypothesis was tested in preterm subjects who were free of these lesions in both neonatal cranial ultrasound studies and magnetic resonance images at age 16 years.

Section snippets

Methods

This study was performed at Yale University School of Medicine, New Haven, CT, and Warren Alpert Brown Medical School, Providence RI. The protocols were reviewed and approved by institutional review boards at each location. All scans were obtained and analyzed at Yale University.

Subjects and neurodevelopmental assessment

Thirty-one preterm children and 36 term controls participated in this study. Perinatal data for preterm children are described in Table 2. As shown in Table 3, there were no significant differences between the preterm and term groups in the number of males, minority status, special services received or handedness. There were differences between the groups in maternal education (p = 0.03) and participant age at the time of scan (p = 0.04). Although preterm adolescents scored significantly lower than

Discussion

Preterm birth and, by extension, the longterm neurocognitive sequelae of the prematurely born represent major public health problems in the United States today. Thus, understanding the influence of birth at an early gestational age on brain development becomes a priority for neonatologists and neuroscientists alike. The development of sophisticated neuroimaging strategies has facilitated this goal, and we report alterations in neural connectivity for language in preterm adolescents when

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; and Hedy Sarofin and Terry Hickey for their technical assistance.

This work was supported in part by NS 27116, T32 HD007094, R01 HD 048830 and P50 HD1994.

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