The case of late preterm birth: sliding forwards the critical window for cognitive outcome risk

Many survivors of preterm birth experience neurodevelopmental disabilities, such as cerebral palsy, visual and hearing problems. However, even in the absence of major neurological complications, premature babies show significant neuropsychological and behavioural deficits during childhood and beyond. While the clinical tools routinely used to assess neurocognitive development in those infants have been useful in detecting major clinical complications in early infancy, they have not been equally sensitive in identifying subtle cognitive impairments emerging during childhood. These methodological concerns become even more relevant when considering the case of late preterm children (born between 34 and 36 gestational weeks). Although these children have been traditionally considered as having similar risks for developmental problems as neonates born at term, a recent line of research has provided growing evidence that even late preterm children display altered structural and functional brain maturation, with potential life-long implications for neurocognitive functioning. A recent study by Heinonen put forward the hypothesis that environmental factors, in this case educational attainment, could moderate the association between late preterm birth (LPT) and neuropsychological impairments commonly associated with aging. In this paper we bring together clinical literature and recent neuroimaging evidence in order to provide two different but complementary approaches for a better understanding of the "nature-nurture" interplay underlying the lifespan neurocognitive development of preterm babies

The Worsening Trajectory Of Social Impairment In Preterm Born Young Adults And Its Association With Altered Amygdalar Functional Connectivity

Survivors of preterm birth experience long-lasting behavioral problems characterized by increased risk of depression, anxiety, and impaired social functioning. The amygdala is a key region for social functioning, and alterations in amygdalar structure and connectivity are thought to underlie social functioning deficits in many disorders, including preterm birth. However, the trajectory of social impairments in PT and their association with functional connectivity of the amygdala are not well-studied in former preterm born individuals (PTs). It was hypothesized that PTs would show impaired social functioning compared to term controls beginning in early childhood and continuing to young adulthood. It was also hypothesized that amygdala resting state functional connectivity is altered in PT born young adults, and that alterations in amygdala functional connectivity would mediate increased internalizing behavior and socialization problems in PT born young adults. In a group of former very PT infants (600 to 1250 grams birth weight) and matched term (T) controls, measures of social and emotional behavior were examined using the Child Behavior Checklist (CBCL) administered at ages 8, 12, and 16, the Youth Self Report administered at age 16, and the Vineland Adaptive Behavior Scales (VABS) administered at ages 8 and 18. Amygdalar functional connectivity was examined using resting-state functional magnetic resonance imaging at age 20. By parent report, preterm-born children and adolescents exhibit behaviors demonstrating increased social impairment compared to their term-born peers, starting at school-age and becoming more prominent by young adulthood. PT demonstrate a worsening trajectory in CBCL Withdrawn scores from school-age to young adulthood compared to T (group*time interaction p=0.03), and maternal education has a protective effect on this trajectory in the PT population (withdrawn group*time interaction p=0.01). Furthermore, amygdalar connectivity is altered in the formerly prematurely-born, and markers of social impairment correlate negatively with altered amygdala-posterior cingulate cortex connectivity (Social competence r=-0.37, p=0.03; socialization r=-0.42, p=0.01). As this cohort of PTs does not include individuals who suffered any form of neurologic injury, their parent-reported increase in behavioral markers of social impairment may be attributable to prematurity rather than to neurologic injury. Moreover, these data suggest that previously established social impairments in PT as compared to T worsen during the critical period of transition from school-age to adolescence and suggest a possible neural underpinning for these impairments experienced by prematurely-born individuals

Attention and regional gray matter development in very preterm children at age 12 years

Objectives: This study examines the selective, sustained, and executive attention abilities of very preterm (VPT) born children in relation to concurrent structural magnetic resonance imaging (MRI) measures of regional gray matter development at age 12 years. Methods: A regional cohort of 110 VPT (≤32 weeks gestation) and 113 full term (FT) born children were assessed at corrected age 12 years on the Test of Everyday Attention-Children. They also had a structural MRI scan that was subsequently analyzed using voxel-based morphometry to quantify regional between-group differences in cerebral gray matter development, which were then related to attention measures using multivariate methods. Results: VPT children obtained similar selective (p=.85), but poorer sustained (p=.02) and executive attention (p=.01) scores than FT children. VPT children were also characterized by reduced gray matter in the bilateral parietal, temporal, prefrontal and posterior cingulate cortices, bilateral thalami, and left hippocampus; and increased gray matter in the occipital and anterior cingulate cortices (family-wise error-corrected

Born too early and too small: higher order cognitive function and brain at risk at ages 8–16

Prematurity presents a risk for higher order cognitive functions. Some of these deficits manifest later in development, when these functions are expected to mature. However, the causes and consequences of prematurity are still unclear. We conducted a longitudinal study to first identify clinical predictors of ultrasound brain abnormalities in 196 children born very preterm (VP; gestational age 32 weeks) and with very low birth weight (VLBW; birth weight 1500 g). At ages 8–16, the subset of VP-VLBW children without neurological findings (124) were invited for a neuropsychological assessment and an MRI scan (41 accepted). Of these, 29 met a rigorous criterion for MRI quality and an age, and gender-matched control group (n = 14) was included in this study. The key findings in the VP-VLBW neonates were: (a) 37% of the VP-VLBW neonates had ultrasound brain abnormalities; (b) gestational age and birth weight collectively with hospital course (i.e., days in hospital, neonatal intensive care, mechanical ventilation and with oxygen therapy, surgeries, and retinopathy of prematurity) predicted ultrasound brain abnormalities. At ages 8–16, VP-VLBW children showed: a) lower intelligent quotient (IQ) and executive function; b) decreased gray and white matter (WM) integrity; (c) IQ correlated negatively with cortical thickness in higher order processing cortical areas. In conclusion, our data indicate that facets of executive function and IQ are the most affected in VP-VLBW children likely due to altered higher order cortical areas and underlying WMThis study was supported by the Spanish Government Institute Carlos III (FIS Pl11/02860), Spanish Ministry of Health to MM-L, and the University of Castilla-La Mancha mobility Grant VA1381500149

Language at rest: A longitudinal study of intrinsic functional connectivity in preterm children

AbstractBackgroundPreterm (PT) children show early cognitive and language deficits and display altered cortical connectivity for language compared to term (T) children. Developmentally, functional connectivity networks become more segregated and integrated, through the weakening of short-range and strengthening of long-range connections.MethodsLongitudinal intrinsic connectivity distribution (ICD) values were assessed in PT (n=13) compared to T children (n=12) at ages 8 vs. 16 using a Linear Mixed Effects model. Connectivity values in regions generated by the group×age interaction analysis were then correlated to scores on full IQ (FSIQ), verbal IQ (VIQ), verbal comprehension IQ (VCIQ), performance IQ (PIQ), Peabody picture vocabulary test—revised (PPVT­R), and Rapid Naming Composite (RDRL_Cmp).ResultsNine regions were generated by the group×age interaction analysis. PT connectivity significantly increased over time in all but two regions, and they ultimately displayed greater relative connectivity at age 16 than Ts in all areas except the left occipito-temporal cortex (OTC). PTs underwent significant connectivity reductions in the left OTC, which corresponded with worse performance on FSIQ, VIQ, and PIQ. These findings differed from Ts, who did not undergo any significant changes in connectivity over time.ConclusionsThese findings suggest that the developmental alterations in connectivity in PT children at adolescence are both pervasive and widespread. The persistent and worsening cognitive and language deficits noted in the PT subjects may be attributed to the loss of connections in the left OTC

A Multivariate Surface-Based Analysis of the Putamen in Premature Newborns: Regional Differences within the Ventral Striatum

Many children born preterm exhibit frontal executive dysfunction, behavioral problems including attentional deficit/hyperactivity disorder and attention related learning disabilities. Anomalies in regional specificity of cortico-striato-thalamo-cortical circuits may underlie deficits in these disorders. Nonspecific volumetric deficits of striatal structures have been documented in these subjects, but little is known about surface deformation in these structures. For the first time, here we found regional surface morphological differences in the preterm neonatal ventral striatum. We performed regional group comparisons of the surface anatomy of the striatum (putamen and globus pallidus) between 17 preterm and 19 term-born neonates at term-equivalent age. We reconstructed striatal surfaces from manually segmented brain magnetic resonance images and analyzed them using our in-house conformal mapping program. All surfaces were registered to a template with a new surface fluid registration method. Vertex-based statistical comparisons between the two groups were performed via four methods: univariate and multivariate tensor-based morphometry, the commonly used medial axis distance, and a combination of the last two statistics. We found statistically significant differences in regional morphology between the two groups that are consistent across statistics, but more extensive for multivariate measures. Differences were localized to the ventral aspect of the striatum. In particular, we found abnormalities in the preterm anterior/inferior putamen, which is interconnected with the medial orbital/prefrontal cortex and the midline thalamic nuclei including the medial dorsal nucleus and pulvinar. These findings support the hypothesis that the ventral striatum is vulnerable, within the cortico-stiato-thalamo-cortical neural circuitry, which may underlie the risk for long-term development of frontal executive dysfunction, attention deficit hyperactivity disorder and attention-related learning disabilities in preterm neonates. © 2013 Shi et al

Language At Rest: A Longitudinal Study Of Intrinsic Functional Connectivity In Preterm Children

Preterm (PT) children show early cognitive and language deficits and display altered cortical connectivity for language compared to term (T) children. Developmentally, functional connectivity networks become more segregated and integrated through the weakening of short-range and strengthening of long-range connections. The specific aims of this study are: (1) To use residual fMRI data to investigate intrinsic connectivity development from ages 8 to 16 years in PT vs. T controls; and (2) To correlate intrinsic connectivity to cognitive and language scores. Longitudinal intrinsic connectivity distribution (ICD) values were assessed in PT (n = 13) compared to T children (n = 12) at ages 8 vs. 16 years using a Linear Mixed Effects model. Connectivity values in regions generated by the group x age interaction analysis were correlated with scores on full IQ (FSIQ), verbal IQ (VIQ), verbal comprehension IQ (VCIQ), performance IQ (PIQ), Peabody Picture Vocabulary Test­Revised (PPVT­R), and Rapid Naming Composite (RDRL_cmp). The group x age analysis revealed significant ICD differences in the following regions: bilateral Brodmann area (BA) 47­BA11­BA10­L BA45 (p=0.0002) and L fusiform­BA18­BA19 (p=0.008). The larger frontal region (bilateral BA47-BA11-BA10-L BA45) was separated into subregions for further analysis, which showed the following significant ICD group x age differences: L and R BA47 (p=0.03 and p=0.0006, respectively), bilateral BA11 (p=0.0008), L and R BA10 (p=0.0005 and 0.005, respectively), and L BA46 (p=0.03). Over time, PT ICD increased in: bilateral BA47­BA11­BA10­L BA45 (p\u3c0.0001), L and R BA47 (p=0.02 and \u3c0.0001, respectively), bilateral BA11 (p\u3c0.0001), L and R BA10 (p\u3c0.0001 for both), and L BA46 (p=0.002). In addition, PT showed decreased ICD in L fusiform­BA18­BA19 (p=0.002). In contrast, the T subjects had no significant changes in ICD values over time. At age 16, PT had greater ICD than T in: bilateral BA47­BA11­BA10­L BA45 (p=0.0002), L & R BA47 (p=0.03 & p=0.0007), bilateral BA11 (p=0.0009), L & R BA10 (p=0.0006 & p=0.005), and L BA46 (p=0.03). PT had less ICD than T in L fusiform­BA18­BA19 (p=0.04). L fusiform­BA18­BA19 ICD positively correlated to scores on VIQ (p=0.021), PIQ (p=0.041), and FSIQ (p=0.015). None of the other regions correlated to scores on the cognitive tasks. The L fusiform-BA18-BA19 region includes the visual word form area, which has long been associated with reading performance and complex visual processing. These data demonstrate for the first time that, over the course of adolescence, prematurely-born children undergo widespread developmental changes in intrinsic connectivity that differ from term-born children. The development of resting state connectivity in prematurely-born children does not reflect compensatory alterations but rather appears to underscore and perpetuate impairment in language and cognitive processing

Temporal ordering of input modulates connectivity formation in a developmental neuronal network model of the cortex

Preterm infant brain activity is discontinuous; bursts of activity recorded using EEG (electroencephalography), thought to be driven by subcortical regions, display scale free properties and exhibit a complex temporal ordering known as long-range temporal correlations (LRTCs). During brain development, activity-dependent mechanisms are essential for synaptic connectivity formation, and abolishing burst activity in animal models leads to weak disorganised synaptic connectivity. Moreover, synaptic pruning shares similar mechanisms to spike-timing dependent plasticity (STDP), suggesting that the timing of activity may play a critical role in connectivity formation. We investigated, in a computational model of leaky integrate-and-fire neurones, whether the temporal ordering of burst activity within an external driving input could modulate connectivity formation in the network. Connectivity evolved across the course of simulations using an approach analogous to STDP, from networks with initial random connectivity. Small-world connectivity and hub neurones emerged in the network structure—characteristic properties of mature brain networks. Notably, driving the network with an external input which exhibited LRTCs in the temporal ordering of burst activity facilitated the emergence of these network properties, increasing the speed with which they emerged compared with when the network was driven by the same input with the bursts randomly ordered in time. Moreover, the emergence of small-world properties was dependent on the strength of the LRTCs. These results suggest that the temporal ordering of burst activity could play an important role in synaptic connectivity formation and the emergence of small-world topology in the developing brain

Altered structural and functional connectivity in late preterm preadolescence: An anatomic seed-based study of resting state networks related to the posteromedial and lateral parietal cortex

Objective: Late preterm birth confers increased risk of developmental delay, academic difficulties and social deficits. The late third trimester may represent a critical period of development of neural networks including the default mode network (DMN), which is essential to normal cognition. Our objective is to identify functional and structural connectivity differences in the posteromedial cortex related to late preterm birth. Methods: Thirty-eight preadolescents (ages 9-13; 19 born in the late preterm period (≥32 weeks gestational age) and 19 at term) without access to advanced neonatal care were recruited from a low socioeconomic status community in Brazil. Participants underwent neurocognitive testing, 3-dimensional T1-weighted imaging, diffusion-weighted imaging and resting state functional MRI (RS-fMRI). Seed-based probabilistic diffusion tractography and RS-fMRI analyses were performed using unilateral seeds within the posterior DMN (posterior cingulate cortex, precuneus) and lateral parietal DMN (superior marginal and angular gyri). Results: Late preterm children demonstrated increased functional connectivity within the posterior default mode networks and increased anti-correlation with the central-executive network when seeded from the posteromedial cortex (PMC). Key differences were demonstrated between PMC components with increased anti-correlation with the salience network seen only with posterior cingulate cortex seeding but not with precuneus seeding. Probabilistic tractography showed increased streamlines within the right inferior longitudinal fasciculus and inferior fronto-occipital fasciculus within late preterm children while decreased intrahemispheric streamlines were also observed. No significant differences in neurocognitive testing were demonstrated between groups. Conclusion: Late preterm preadolescence is associated with altered functional connectivity from the PMC and lateral parietal cortex to known distributed functional cortical networks despite no significant executive neurocognitive differences. Selective increased structural connectivity was observed in the setting of decreased posterior interhemispheric connections. Future work is needed to determine if these findings represent a compensatory adaptation employing alternate neural circuitry or could reflect subtle pathology resulting in emotional processing deficits not seen with neurocognitive testing. Copyright

PRETERM BIRTH RESULTS IN ALTERATIONS IN NEURAL CONNECTIVITY AT AGE 16 YEARS

Very low birth weight preterm (PT) children are at high risk for brain injury. This study investigates microstructural differences in the brains of PT adolescents relative to term control subjects using diffusion tensor imaging (DTI), as well as studying their neurodevelopmental outcomes. Forty-four PT subjects (600 - 1250 grams birth weight) without neonatal brain injury and 41 term controls were evaluated at age 16 years with DTI, the Wechsler Intelligence Scale for Children - III (WISC), the Peabody Picture Vocabulary Test - Revised (PPVT), and the Comprehensive Test of Phonological Processing (CTOPP). PT subjects scored lower than term subjects on WISC full scale (p = 0.002), verbal (p = 0.027), and performance IQ tests (p = 0.001), as well as CTOPP phonological awareness (p = 0.005), but scored comparably to term subjects on PPVT and CTOPP Rapid Naming tests. PT subjects had lower fractional anisotropy (FA) values, suggestive of white matter disorganization, in multiple regions including bilateral uncinate fasciculi (left: p = 0.004; right: p = 0.002), bilateral external capsules (left: p \u3c 0.0001; right: p = 0.001), the splenium of the corpus callosum (p = 0.014), and white matter serving the inferior frontal gyrus bilaterally (left: p \u3c 0.0001; right: p = 0.005). FA values in both the left and right uncinate fasciculi correlated with PPVT scores (a semantic language task) in the PT subjects (left: R = 0.314, p = 0.038; right: R = 0.336, p = 0.026). FA values in the left and right arcuate fasciculi correlated with CTOPP Rapid Naming scores (a phonologic task) in the PT subjects (left: R = 0.424, p = 0.004; right: R = 0.301, p = 0.047). These data support for the first time that the recently proposed concept of dual pathways underlying language function are present in PT adolescents. These include a left-sided dorsal pathway associated with phonological and articulatory processing (arcuate fasciculus), and a bilateral ventral pathway for semantic, receptive language processing (uncinate fasciculus). The striking bilateral dorsal correlations for the PT group suggest that prematurely born subjects rely more heavily on the right hemisphere than typically developing adolescents for performance of phonological language tasks. These findings may represent either a delay in maturation or the engagement of alternative neural pathways for language in the developing PT brain