Abstract
Sophisticated neuroimaging strategies demonstrate alterations in functional connectivity at school age, adolescence, and young adulthood in individuals born preterm. Recent data suggest these alterations are present in the postnatal period prior to term-equivalent age in neonates born preterm. Likewise, functional organization increases across development, but the influence of preterm birth on this fundamental infrastructure is immediate and unchanging. This article briefly reviews the current methodsof measuring functional connectivity throughout development in those born preterm, and the association of functional connectivity with language disorders. Taken together, these data suggest that the effects of preterm birth on the functional organization of language in the developing brain are both proximate and long-lasting.
Preterm birth represents one of the most important public health problems in the world today. In 2010, there were 2.4 million neonates born at less than or at 31 weeks postmenstrual age (PMA) worldwide,1 and 27% of survivors will experience significant long-term neurodevelopmental disability.2 The cost of preterm birth is high, with estimated new education and care costs of over 4 billion dollars annually in the US alone.3
Long-term neurodevelopmental outcomes in children born preterm, especially those born extremely preterm, range in severity – from major disabilities such as cerebral palsy and intellectual disability, to more subtle developmental disorders including language disorders, learning disabilities, attention-deficit-hyperactivity disorder, minor neuromotor dysfunction, behavioral problems, and socialemotional difficulties.4 Of particular importance for children born preterm are deficits in language processing. Almost 20% are diagnosed with language disability, over half require special services at school age, and a recent analysis suggests a left-shift of the ‘normal’ distribution curves for language and cognition for children born very preterm, with an effect size 0.60SD for IQ, or 9 IQ points.5
Sophisticated neuroimaging strategies provide important information about the impact of preterm birth on both functional and structural connectivity. Functional connectivity, as measured by functional connectivity magnetic resonance imaging (fcMRI), is based on the blood oxygen level dependent signal and assesses ‘temporal correlations between spatially remote neurophysiological events’6 to map neural activity in the brain.
The objective of this article is to review both the fcMRI alterations reported in individuals born preterm across development and their association with language outcome measures. To address this aim, we (1) provide a short description of different techniques of measuring resting-state fcMRI, (2) discuss studies that have measured changes in functional connectivity from infancy to adulthood, and (3) review investigations correlating fcMRI findings with language disabilities in children and adolescents born preterm.
METHOD
A search of the scientific literature for fcMRI studies in infants born preterm using PubMed (with a combination of search terms: preterm, connectivity, brain, networks) yielded 167 references from January 2005 to January 2015. The search was limited to human studies in those born preterm that used fcMRI techniques, and excluded other MRI modalities (such as structural MRI and diffusion tensor imaging) and electroencephalography. All potential references were manually reviewed to determine eligibility. In total, 22 fcMRI studies met the inclusion criteria and are included in this review, organized by age at scan (Tables I–III).
Table I:
Functional connectivity studies – preterm neonates
| Author | Population (n) |
Age at birth (preterm) |
Age at scan | Method | Summary of findings |
|---|---|---|---|---|---|
| Doria et al.8 | 62 preterm 8 term |
30.1wks PMA |
Preterm: 3 groups at 30.1, 33.4, and 40.4wks PMA Term: 40.5wks |
ICA | •Infants born preterm showed fragmentary functional networks in the youngest gestational age individuals •Networks included sensory and attention networks, and formed at different rates across gestation •These networks resembled connectivity patterns found in term infants at term equivalent age |
| Smyser et al.9 | 53 preterm 10 term |
27.8wks PMA |
Preterm: Longitudinal – 26wks PMA to term equivalent age Term: at birth |
Seed | •Inter-hemispheric connections between homotopic counterparts increased with gestational age •Infants born preterm showed reduced connectivity compared with term infants in several networks, including thalamo-cortical connections •Putative default mode was only observed in infants born at term |
| Smith et al.16 | 44 preterm 10 term |
26.8wks PMA |
Preterm: 38wks PMA Term: 39.5wks PMA |
Seed | •Infants born preterm with high stress did not show robust inter-hemispheric connectivity compared with those with low stress or term infants •These differences were not correlated with severity of illness |
| Smyser et al.15 | 39 preterm 25 term |
26.8wks PMA |
Preterm: 37.7wks PMA Term: 39.5wks PMA |
Seed | •Infants born preterm with white matter injury showed reduced inter-hemispheric connectivity when compared with both infants born preterm without white matter injury and infants born at term •The severity of white matter injury was correlated with the loss of connectivity |
| Kwon et al.11 | 12 preterm 16 term |
27wks PMA |
Preterm: 42.6wks PMA Term: 42.6wks PMA |
Voxel-wise | •Reduced concentration of gamma-aminobutyric acid in the right frontal lobe of infants born preterm was positively correlated with reduced connectivity in the same right frontal region |
| Kwon et al.14 | 26 preterm 25 term |
27wks PMA |
Preterm: 42.6wks PMA Term: 42.3wks PMA |
Voxel-wise | •Infants born preterm showed decreased lateralization of connectivity in left frontal-temporal language areas compared with infants born at term •Infants born at term infants demonstrated significant connectivity between left and right Broadmann area 22 compared with infants born preterm who showed no significant connections |
| Smyser et al.13 | 25 preterm 25 term |
26.8wks PMA |
Preterm: 38.1wks PMA Term: 39.5wks PMA |
Seed | •Infants born preterm showed reduced correlation and covariance in language, default mode, and frontal- parietal networks, suggesting that functional connections in infants born preterm are less complex than those in infants born at term |
| van den Heuvel et al.12 | 27 preterm | 27wks PMA |
Preterm: 30wks PMA and/or 40wks PMA |
Matrix | •Functional networks in infants born preterm are positively correlated with structural networks and this coupling increases with age •Similarly, inter-hemispheric connections increase with age |
PMA, postmenstrual age.
Table III:
Functional connectivity studies – adults born preterm
| Author | Population | Age at scan | Age at birth (preterm) |
Method | Summary of findings |
|---|---|---|---|---|---|
| Scheinost et al.25 | 21 preterm 19 term | 20y | 28.2wks PMA | Voxel-wise | •Adults born preterm showed increased whole brain connectivity in left and right temporal parietal language regions compared with adults born at term |
| Constable et al.24 | 19 preterm 19 term | 20y | 28.2wks PMA | Voxel-wise | •In adults born preterm, the left cerebellum showed increased connectivity compared with adults born at term •Connectivity from this region was increased to bilateral inferior frontal gyrus in adults born preterm and was positively correlated with language scores for adults born preterm |
| Bäuml et al.29 | 95 preterm 83 term | 26.5y | 30.8wks PMA | ICA | •For adults born preterm compared with adults born at term, overlapping regions of greater functional connectivity and reduced gray matter volume were found in language regions of the superior temporal gyrus, caudate, and thalamus. |
| Finke et al.28 | 33 preterm 32 term | 26.5y | 30.5wks PMA | ICA | •Adults born preterm have both greater and weaker connectivity in parietal attention and visual networks compared with adults born at term •Changes were correlated with visual working memory in the same direction of connectivity differences |
| White et al.26 | 29 preterm 23 term | Preterm: 27.6y Term: 28.6y | <33wks PMA | ICA | •Adults born at term had significantly reduced between-network connectivity, particularly alongside those that included thalamo-cortical connections •No differences in spatial focus and spectral power were observed |
PMA, postmenstrual age.
Methods of measuring resting-state functional connectivity
As shown in Figure 1, there are several ways to measure and analyze functional connectivity in the brain. The most commonly used technique is seed-based connectivity. The seed-based connectivity approach utilizes region of interest time series that are selected a priori, and voxel-wise crosscorrelation is then computed across the whole brain. The second approach is independent component analysis (ICA), a data-driven approach that deconstructs the data into a set of statistically independent signals. Matrix connectivity involves parcellating the brain into approximately 100 to 400 distinct regions and assessing connectivity among the regions. These connectivity matrices are typically analyzed using graph theory. Finally, voxel-wise connectivity assesses the connectivity of every voxel in the brain to every other voxel and summarizes these correlations with a summary statistic.
Figure 1:
Overview of functional connectivity. (a) Functional connectivity is defined as the correlation between blood oxygen level dependent time course for any two regions or voxels in the brain. A higher correlation between time course implies higher functional connectivity between the regions. Common methods for functional connectivity include seed, matrix, and voxel-wise connectivity. (b) Seed connectivity involves identifying key regions or seeds and assessing connectivity between these seeds and all other voxels in the brain. This analysis is the most common. (c) Matrix connectivity involves parcellating the brain in ~100 to 400 distinct regions and assessing connectivity between each of these regions. These connectivity matrices typically use graph theory. (d) Voxel-wise connectivity involves assessing connectivity for every voxel in the brain to every other voxel in the brain and summarizing these correlations with a summary statistic. This method is highly data driven as no a priori region needs to be specified (unlike seed and matrix connectivity). However, any information about a specific connection is lost.
Preterm birth is associated with altered network architecture in neonates
Initial studies of functional connectivity in neonates showed the presence of functionally connected neural networks at rest, or ‘resting-state networks’. Although not detected by the search criteria because of the omission of ‘preterm’, Fransson et al. were the first to identify resting-state networks in preterm neonates at term-equivalent age. These included the occipital, somatosensory, temporal parietal, anterior prefrontal cortices – some of which are involved in visual, auditory, and sensorimotor processing. Additionally, the preterm brain was predominantly nonlateralized and exhibited a strong functional correlation across hemispheres.7 In a subsequent report of 62 preterm neonates and 8 term controls studied between 30 and 40 weeks’ PMA, Doria et al. demonstrated resting-state networks in preterm infants that were fragmentary in the youngest gestational age participants. Notably, different resting-state networks formed at significantly different rates across gestation.8
In contrast, Smyser et al.’s longitudinal study of 53 neonates born preterm from 26 weeks’ PMA to term-equivalent age and 10 control infants born at term demonstrated reduced connectivity in preterm infants compared with controls born at term in several networks, including inter-hemispheric temporal lobe and thalamo-cortical networks. Inter-hemispheric connections between homotopic counterparts increased with PMA, and the putative default mode network was only found in controls born at term controls.9
Recent investigations have addressed both the structure-function correlation in developing networks and the complexity of these systems.9–12 Graph theory analyses suggest that the topology of networks in preterm infants is positively correlated with structural ones, and this coupling increases with gestational age.12 Similarly, employing correlation and covariance analyses in 25 preterm and 25 term controls, Smyser et al.13 demonstrated reduced covariance in both language and fronto-parietal networks in the preterm group, suggesting that functional connections in individuals born preterm are less complex than those in neonates born at term. Further, despite reports demonstrating that individuals born preterm develop the classic asymmetry for language regions described in infants born at term, older children, and adults, infants born preterm showed decreased lateralization in left frontal-temporal language areas.14
Finally, reduced connectivity between homologs observed in individuals born preterm appears to be related to both white matter injury and neonatal environment. Smyser et al. investigated the effects of white matter injury on resting-state functional connectivity. Infants born preterm with white matter injury showed reduced connectivity between homologs when compared with both infants born preterm without white matter injury and controls born at term, and the severity of white matter injury was correlated with the loss of connectivity.15 Additionally, Smith et al. showed a link between inter-hemispheric connectivity and neonatal stress measured by the Neonatal Infant Stressor scale. High stress infants failed to demonstrate robust inter-hemispheric connectivity, especially in temporal lobe language regions, compared with infants born preterm with low stress and controls born at term.16
Differences in functional connectivity persist in childhood
Despite having reduced connectivity as neonates, typical patterns of connectivity do develop by late infancy and early childhood for those born preterm. Investigating preterm infants scanned in the newborn period and during early childhood, Lee et al.10 showed that network development for children born preterm was qualitatively similar to children born at term; in addition, most networks were formed by 4 years of age. Similarly, in a sample of 18 to 24 month and 3 to 4 year old preterm children, Damaraju et al.17 suggest that typical functional networks are well developed by 18 months of age for children born preterm and their spatial locations are not distinguishable between children born preterm and at term at either age.
In contrast to preterm infants, older children born preterm show evidence of both increased and decreased connectivity compared with age-matched term controls. When compared with term children at 35 months, preterm children had increased spectral energy in the basal ganglia network, but still exhibited weaker overall connectivity between networks.17 A study of language networks by Gozzo et al., showed that functional connectivity from Wernicke’s region was increased to the right inferior frontal gyrus and bilateral supramarginal gyri in preterm children compared with term controls at 8 years of age.18 Degnan et al. showed increased connectivity between the frontal cortex (right and left) and the salience network, default mode network, and the central executive network in preterm children at 10 years of age, while the left frontal cortex showed decreased connectivity with the limbic system.19
Finally, similar to findings in infants born preterm, white matter injury is a persistent risk factor for reduced functional connectivity. Lee et al.20 demonstrated that children born (10y old) with diffuse periventricular white matter injury have reduced motor connectivity compared with controls born at term.
Alternate pathways for language in preterm adolescents and adults
Language is a major problem for some individuals born preterm, and many studies of functional connectivity in adolescents born preterm involve language networks.
Three reports suggest that those born preterm have increased strength of connectivity from the left hemisphere language networks to other regions of the brain compared with age-matched controls born at term. Compared with control individuals, adolescents born preterm showed increased connectivity between language and sensorimotor areas,21 between Wernicke’s area and right supramarginal gyrus,22 and from superior temporal lobe regions to nonsuperior temporal regions within both the left and right hemispheres.23 In studies of preterm adults compared with age-matched term controls, increased connectivity has been reported between the left cerebellum and bilateral inferior frontal gyri.24 Similarly, preterm adults showed increased whole brain connectivity in left and right temporo-parietal language regions compared with term controls.25
In contrast, when analyzing overall functional network strength in adolescents born preterm, Wilke showed local and global network strength was greater in adolescents born at term than in individuals born preterm.23 Between-net-work connectivity, particularly that which included thalamo-cortical connections, was also reduced in adults born preterm.26 Further, Scheinost et al.27 demonstrated that those born preterm had decreased lateralization in right hemisphere language homologs compared with term controls. Finke et al.28 studied preterm adults and found greater and weaker connectivity in the parietal attention and visual networks. Finally, preterm adults had greater connectivity and reduced gray matter volume in language regions of the superior temporal gyrus and caudate, suggesting that changes in connectivity are related to structural alterations secondary to injury and/or recovery from preterm birth.29
Functional connectivity in preterm adolescents and adults correlates with language scores
Despite the range of analysis methods used to study functional connectivity in the population born preterm through development, many studies have correlated differences in functional connectivity in language regions to language outcomes. Adolescents born preterm exhibit less lateralization in right hemisphere language homologs than controls born at term, and cerebral lateralization in these right hemisphere language homologs inversely correlates with receptive language.27 Similarly, lateralization of functional connectivity in the superior temporal lobe language areas inversely correlated with verbal comprehension abilities.23 When investigating more specific language pathways in adolescent and adults born preterm, the strengths of specific connections between the left cerebellum and bilateral inferior frontal gyrus,24 and between Wernicke’s area and right supramarginal gyrus, correlate with receptive vocabulary and verbal comprehension scores respectively.22
LIMITATIONS
Functional connectivity in the population born preterm is a developing field with a limited number of published reports. Further study is needed to confirm and integrate the current findings with broader research on preterm birth. Two critical issues include the imaging methodologies used and the patient population selected for the studies, including the age at which they are imaged.
The first challenge is the rapid advances in imaging technology, making it difficult to integrate past, current, and new research. In addition, many connectivity methods exist, and results from one method may not be directly comparable with another. A second challenge is the patient population investigated. Connectivity studies generally only include the healthiest of individuals born preterm, which may bias the literature and underestimate altered connectivity in participants born preterm.
Data from diffusion tensor imaging studies and emerging functional connectivity reports suggest that connectivity in the developing preterm brain is both plastic and experiential. Therefore, as functional connectivity continues to develop into young adulthood, studies comparing preterm individuals with term controls should include a well-matched population within a well-defined age range.
CONCLUSIONS
Preterm birth has long-lasting effects on the functional connectivity of neural networks. The alterations in neural connectivity that characterize individuals born preterm at school age, adolescence, and young adulthood are both systemically pervasive and clinically significant. Emerging data suggest that these changes are found as early as the third trimester of gestation, and persist through young adulthood. If the goal of neonatal intensive care is to develop targeted interventions for the optimal development of individuals born preterm, future studies should assess the critical periods and regions involved in the functional reorganization of the preterm brain.
Table II:
Functional connectivity studies – children and adolescents born preterm
| Author | Population | Age at scan | Age at birth (preterm) |
Method | Summary of findings |
|---|---|---|---|---|---|
| Gozzo et al.18 | 54 preterm 24 term | 8y | 28.2wks PMA | Seed | •Connectivity from Wernicke's region was increased to the right inferior frontal gyrus and bilateral supramarginal gyri in children born preterm compared with controls born at term |
| Schafer et al.21 | 22 preterm 26 term | 12y | 28.6wks PMA | Seed | •When performing a lexical semantic processing task, children born preterm showed greater connectivity between language and sensory/motor areas, but weaker connectivity within the frontal lobes when compared with controls born at term |
| Damaraju et al.17 | 31 preterm 18 term | 18mo and 36mo | 29.5wks PMA | ICA | •Typical networks develop by 18mo for children born preterm and their spatial locations are not distinguishable between groups born preterm and at term at either age •At 36mo, children born preterm had increased spectral energy in the basal ganglia network, but weaker overall connectivity between networks |
| Myers et al.22 | 31 preterm 36 term | 16y | 27.7wks PMA | Seed | •Adolescents born preterm showed greater connectivity between Wernicke's area and the right supramarginal gyrus compared with adolescents born at term •For adolescent born preterm, strength of connection inversely correlated with language scores and maternal education |
| Lee et al.20 | 11 preterm 11 term | Preterm: 10.2y Term: 12.4y | 30.9wks PMA | Seed | •Children born preterm with diffuse periventricular white matter injury showed reduced motor connectivity compared with children born at term |
| Lee et al.10 | 36 preterm | Preterm: Longitudinal - at birth, term equivalent age, 2y, 4y | 28.7wks PMA | Seed | •Functional network development in infants born preterm was qualitatively similar to that found in infants born at term. •Most networks were formed by 4y of age |
| Scheinost et al.27 | 20 preterm 23 term | Preterm: 17.8y Term: 16.6y | 28.2wks PMA | Voxel-wise | •Lateralization of connectivity in right hemisphere language homologs was decreased in adolescents born preterm compared with adolescents born at term •For adolescents born preterm, lateralization was correlated with language scores |
| Wilke et al.23 | 29 preterm 19 term | Preterm: 14.7y Term: 12.8y | 28.3wks PMA | Seed and Matrix | •Adolescents born preterm showed stronger connectivity of STL regions with non-STL regions both within the left hemisphere and to the right hemisphere compared with adolescents born at term •Both local and global network strength were greater in adolescents born at term than in individuals born preterm •Lateralization of functional connectivity was inversely correlated with verbal comprehension •abilities |
| Degnan et al.19 | 19 preterm 19 term | 10y | 35wks PMA | Seed | •Hyper-connectivity from medial prefrontal regions to control, salience, and default mode networks was observed in children born preterm compared with children born at term |
PMA, postmenstrual age; STL, superior temporal lobe; TEA, term-equivalent age.
What this paper adds.
Preterm birth alters functional organization in developing brain.
These changes occur early in life, prior to term-equivalent age.
Alterations in neural networks correlate with language testing scores in childhood, adolescence and adulthood.
These alterations in connectivity are both proximate and long-lasting.
ACKNOWLEDGEMENTS
This work was supported by NIH NS074022 (LRM), T32 HD07094 (SHK), and T32 DA022975 (DS). The author has stated that they had no interests that might be perceived as posing a conflict or bias.
ABBREVIATIONS
- fcMRI
Functional connectivity magnetic resonance imaging
- ICA
Independent component analysis
- PMA
Postmenstrual age
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