Volumetric grey matter alterations in adolescents and adults born very preterm suggest accelerated brain maturation.

Previous research investigating structural neurodevelopmental alterations in individuals who were born very preterm demonstrated a complex pattern of grey matter changes that defy straightforward summary. Here we addressed this problem by characterising volumetric brain alterations in individuals who were born very preterm from adolescence to adulthood at three hierarchically related levels - global, modular and regional. We demarcated structural components that were either particularly resilient or vulnerable to the impact of very preterm birth. We showed that individuals who were born very preterm had smaller global grey matter volume compared to controls, with subcortical and medial temporal regions being particularly affected. Conversely, frontal and lateral parieto-temporal cortices were relatively resilient to the effects of very preterm birth, possibly indicating compensatory mechanisms. Exploratory analyses supported this hypothesis by showing a stronger association between lateral parieto-temporal volume and IQ in the very preterm group compared to controls. We then related these alterations to brain maturation processes. Very preterm individuals exhibited a higher maturation index compared to controls, indicating accelerated brain maturation and this was specifically associated with younger gestational age. We discuss how the findings of accelerated maturation might be reconciled with evidence of delayed maturation at earlier stages of development.

Subregional Hippocampal Morphology and Psychiatric Outcome in Adolescents Who Were Born Very Preterm and at Term.

BACKGROUND: The hippocampus has been reported to be structurally and functionally altered as a sequel of very preterm birth (<33 weeks gestation), possibly due its vulnerability to hypoxic-ischemic damage in the neonatal period. We examined hippocampal volumes and subregional morphology in very preterm born individuals in mid- and late adolescence and their association with psychiatric outcome. METHODS: Structural brain magnetic resonance images were acquired at two time points (baseline and follow-up) from 65 ex-preterm adolescents (mean age = 15.5 and 19.6 years) and 36 term-born controls (mean age=15.0 and 19.0 years). Hippocampal volumes and subregional morphometric differences were measured from manual tracings and with three-dimensional shape analysis. Psychiatric outcome was assessed with the Rutter Parents' Scale at baseline, the General Health Questionnaire at follow-up and the Peters Delusional Inventory at both time points. RESULTS: In contrast to previous studies we did not find significant difference in the cross-sectional or longitudinal hippocampal volumes between individuals born preterm and controls, despite preterm individual having significantly smaller whole brain volumes. Shape analysis at baseline revealed subregional deformations in 28% of total bilateral hippocampal surface, reflecting atrophy, in ex-preterm individuals compared to controls, and in 22% at follow-up. In ex-preterm individuals, longitudinal changes in hippocampal shape accounted for 11% of the total surface, while in controls they reached 20%. In the whole sample (both groups) larger right hippocampal volume and bilateral anterior surface deformations at baseline were associated with delusional ideation scores at follow-up. CONCLUSIONS: This study suggests a dynamic association between cross-sectional hippocampal volumes, longitudinal changes and surface deformations and psychosis proneness.

Alterations in cortical thickness development in preterm-born individuals: Implications for high-order cognitive functions.

Very preterm birth (gestational age <33 weeks) is associated with alterations in cortical thickness and with neuropsychological/behavioural impairments. Here we studied cortical thickness in very preterm born individuals and controls in mid-adolescence (mean age 15 years) and beginning of adulthood (mean age 20 years), as well as longitudinal changes between the two time points. Using univariate approaches, we showed both increases and decreases in cortical thickness in very preterm born individuals compared to controls. Specifically (1) very preterm born adolescents displayed extensive areas of greater cortical thickness, especially in occipitotemporal and prefrontal cortices, differences which decreased substantially by early adulthood; (2) at both time points, very preterm-born participants showed smaller cortical thickness, especially in parahippocampal and insular regions. We then employed a multivariate approach (support vector machine) to study spatially discriminating features between the two groups, which achieved a mean accuracy of 86.5%. The spatially distributed regions in which cortical thickness best discriminated between the groups (top 5%) included temporal, occipitotemporal, parietal and prefrontal cortices. Within these spatially distributed regions (top 1%), longitudinal changes in cortical thickness in left temporal pole, right occipitotemporal gyrus and left superior parietal lobe were significantly associated with scores on language-based tests of executive function. These results describe alterations in cortical thickness development in preterm-born individuals in their second decade of life, with implications for high-order cognitive processing.

Eating disorder psychopathology, brain structure, neuropsychological correlates and risk mechanisms in very preterm young adults.

This study investigates the prevalence of eating disorder (ED) psychopathology, neuropsychological function, structural brain correlates and risk mechanisms in a prospective cohort of very preterm (VPT) young adults. We assessed ED psychopathology and neuropsychological correlates in 143 cohort individuals born at <33 weeks of gestation. Structural brain correlates and risk factors at birth, in childhood and adolescence, were investigated using prospectively collected data throughout childhood/adolescence. VPT-born individuals had high levels of ED psychopathology at age 21 years. Executive function did not correlate with ED symptomatology. VPT adults presenting with ED psychopathology had smaller grey matter volume at age 14/15 years in the left posterior cerebellum and smaller white matter volume in the fusiform gyrus bilaterally, compared with VPT adults with no ED psychopathology. Caesarean delivery predicted engaging in compensatory behaviours, and severe eating difficulty at age 14 years predicted ED symptomatology in young adulthood. VPT individuals are at risk for ED symptomatology, with evidence of associated structural alterations in posterior brain regions. Further prospective studies are needed to clarify the pathways that lead from perinatal/obstetric complications to ED and relevant neurobiological mechanisms. © 2015 The Authors. European Eating Disorders Review published by John Wiley &Sons, Ltd.

Neural compensation in adulthood following very preterm birth demonstrated during a visual paired associates learning task.

Very preterm birth (VPT; < 33 weeks of gestation) is associated with an increased risk of learning disability, which contributes to more VPT-born children repeating grades and underachieving in school. Learning problems associated with VPT birth may be caused by pathophysiological alterations in neurodevelopment resulting from perinatal brain insult; however, adaptive neuroplastic processes may subsequently occur in the developing preterm brain which ameliorate, to an extent, the potential sequelae of altered neurophysiology. Here, we used functional magnetic resonance imaging (fMRI) to compare neuronal activation in 24 VPT individuals and 22 controls (CT) in young adulthood during a learning task consisting of the encoding and subsequent recognition of repeated visual paired associates. Structural MRI data were also collected and analysed in order to explore possible structure-function associations. Whilst the two groups did not differ in their learning ability, as demonstrated by their capacity to recognize previously-seen and previously-unseen visual pairs, between-group differences in linear patterns of Blood Oxygenation Level Dependant (BOLD) activity were observed across the four repeated blocks of the task for both the encoding and recognition conditions, suggesting that the way learning takes place differs between the two groups. During encoding, significant between-group differences in patterns of BOLD activity were seen in clusters centred on the cerebellum, the anterior cingulate gyrus, the midbrain/substantia nigra, medial temporal (including parahippocampal) gyrus and inferior and superior frontal gyri. During the recognition condition, significant between-group differences in patterns of BOLD activity were seen in clusters centred on the claustrum and the posterior cerebellum. Structural analysis revealed smaller grey matter volume in right middle temporal gyrus in VPT individuals compared to controls, however volume in this region was not significantly associated with functional activation. These results demonstrate that although cognitive task performance between VPT individuals and controls may be comparable on certain measures, differences in BOLD signal may also be evident, some of which could represent compensatory neural processes following VPT-related brain insult.

Preterm birth and structural brain alterations in early adulthood.

Alterations in cortical development and impaired neurodevelopmental outcomes have been described following very preterm (VPT) birth in childhood and adolescence, but only a few studies to date have investigated grey matter (GM) and white matter (WM) maturation in VPT samples in early adult life. Using voxel-based morphometry (VBM) we studied regional GM and WM volumes in 68 VPT-born individuals (mean gestational age 30 weeks) and 43 term-born controls aged 19-20 years, and their association with cognitive outcomes (Hayling Sentence Completion Test, Controlled Oral Word Association Test, Visual Reproduction test of the Wechsler Memory Scale-Revised) and gestational age. Structural MRI data were obtained with a 1.5 Tesla system and analysed using the VBM8 toolbox in SPM8 with a customized study-specific template. Similarly to results obtained at adolescent assessment, VPT young adults compared to controls demonstrated reduced GM volume in temporal, frontal, insular and occipital areas, thalamus, caudate nucleus and putamen. Increases in GM volume were noted in medial/anterior frontal gyrus. Smaller subcortical WM volume in the VPT group was observed in temporal, parietal and frontal regions, and in a cluster centred on posterior corpus callosum/thalamus/fornix. Larger subcortical WM volume was found predominantly in posterior brain regions, in areas beneath the parahippocampal and occipital gyri and in cerebellum. Gestational age was associated with GM and WM volumes in areas where VPT individuals demonstrated GM and WM volumetric alterations, especially in temporal, parietal and occipital regions. VPT participants scored lower than controls on measures of IQ, executive function and non-verbal memory. When investigating GM and WM alterations and cognitive outcome scores, subcortical WM volume in an area beneath the left inferior frontal gyrus accounted for 14% of the variance of full-scale IQ (F = 12.9, p < 0.0001). WM volume in posterior corpus callosum/thalamus/fornix and GM volume in temporal gyri bilaterally, accounted for 21% of the variance of executive function (F = 9.9, p < 0.0001) and WM in the posterior corpus callosum/thalamus/fornix alone accounted for 17% of the variance of total non-verbal memory scores (F = 9.9, p < 0.0001). These results reveal that VPT birth continues to be associated with altered structural brain anatomy in early adult life, although it remains to be ascertained whether these changes reflect neurodevelopmental delays or long lasting structural alterations due to prematurity. GM and WM alterations correlate with length of gestation and mediate cognitive outcome.

Dysconnectivity of neurocognitive networks at rest in very-preterm born adults.

Advances in neonatal medicine have resulted in a larger proportion of preterm-born individuals reaching adulthood. Their increased liability to psychiatric illness and impairments of cognition and behaviour intimate lasting cerebral consequences; however, the central physiological disturbances remain unclear. Of fundamental importance to efficient brain function is the coordination and contextually-relevant recruitment of neural networks. Large-scale distributed networks emerge perinatally and increase in hierarchical complexity through development. Preterm-born individuals exhibit systematic reductions in correlation strength within these networks during infancy. Here, we investigate resting-state functional connectivity in functional magnetic resonance imaging data from 29 very-preterm (VPT)-born adults and 23 term-born controls. Neurocognitive networks were identified with spatial independent component analysis conducted using the Infomax algorithm and employing Icasso procedures to enhance component robustness. Network spatial focus and spectral power were not generally significantly affected by preterm birth. By contrast, Granger-causality analysis of the time courses of network activity revealed widespread reductions in between-network connectivity in the preterm group, particularly along paths including salience-network features. The potential clinical relevance of these Granger-causal measurements was suggested by linear discriminant analysis of topological representations of connection strength, which classified individuals by group with a maximal accuracy of 86%. Functional connections from the striatal salience network to the posterior default mode network informed this classification most powerfully. In the VPT-born group it was additionally found that perinatal factors significantly moderated the relationship between executive function (which was reduced in the VPT-born as compared with the term-born group) and generalised partial directed coherence. Together these findings show that resting-state functional connectivity of preterm-born individuals remains compromised in adulthood; and present consistent evidence that the striatal salience network is preferentially affected. Therapeutic practices directed at strengthening within-network cohesion and fine-tuning between-network inter-relations may have the potential to mitigate the cognitive, behavioural and psychiatric repercussions of preterm birth.

Preterm birth and adolescent social functioning-alterations in emotion-processing brain areas.

OBJECTIVE: To investigate the relationship between preterm birth, adolescent, and adult psychosocial outcomes, and alterations in gray matter volume. STUDY DESIGN: Individuals (n = 73) born at <33 weeks of gestation (very preterm) and 49 controls completed the Child Behavior Checklist (CBCL) at age 15 years to identify 'social immaturity' (SI) cases. Voxel-based morphometry was used to investigate gray matter volumes according to CBCL-SI 'caseness.' The Clinical Interview Schedule-Revised (CIS-R) was administered at age 19 years. RESULTS: Very preterm adolescents were almost 4 times more likely to reach CBCL-SI 'caseness' compared with controls. Ex-preterm SI 'cases' had increased gray matter volume in the fusiform gyrus bilaterally (Talairach coordinates: x = 60, y = -27, z = -30; Z = 3.78; x = -61, y = -35, z = -27; Z = 3.56, after correction for multiple comparisons) compared with ex-preterm SI 'noncases.' Left fusiform volume displayed a stronger correlation with ipsilateral orbitofrontal cortex in SI 'cases' (x = -15, y = 22, z = -26; Z = 3.64). CIS-R total scores were slightly higher in ex-preterm individuals compared with controls. In the whole sample, SI 'cases' in midadolescence also had higher CIS-R scores in adulthood compared with 'noncases' (SI 'cases': mean = 5.7, 95% CI = 4.0-7.4; SI 'noncases': mean = 2.7, 95% CI = 1.1-4.3; F = 6.4, df = 74; P = .013). CONCLUSIONS: Ex-preterm adolescents had increased socialization problems in adolescence, which were associated with volumetric alterations in an emotion-processing brain network. Atypical social development is linked to an increased vulnerability to psychiatric disorder.

Neonatal brain injury and neuroanatomy of memory processing following very preterm birth in adulthood: an fMRI study.

Altered functional neuroanatomy of high-order cognitive processing has been described in very preterm individuals (born before 33 weeks of gestation; VPT) compared to controls in childhood and adolescence. However, VPT birth may be accompanied by different types of adverse neonatal events and associated brain injury, the severity of which may have differential effects on brain development and subsequent neurodevelopmental outcome. We conducted a functional magnetic resonance imaging (fMRI) study to investigate how differing degrees of neonatal brain injury, detected by neonatal ultrasounds, affect the functional neuroanatomy of memory processing in VPT young adults. We used a verbal paired associates learning task, consisting of four encoding, four cued-recall and four baseline condition blocks. To further investigate whether differences in neural activation between the groups were modulated by structural brain changes, structural MRI data were also collected. We studied 12 VPT young adults with a history of periventricular haemorrhage with associated ventricular dilatation, 17 VPT individuals with a history of uncomplicated periventricular haemorrhage, 12 individuals with normal ultrasonographic findings, and 17 controls. Results of a linear trend analysis demonstrated that during completion of the paired associates learning task right frontal and right parietal brain activation decreased as the severity of neonatal brain injury increased. There were no statistically significant between-group differences in on-line task performance and participants' intelligence quotient (IQ) at assessment. This pattern of differential activation across the groups was observed particularly in the right middle frontal gyrus during encoding and in the right posterior cingulate gyrus during recall. Structural MRI data analysis revealed that grey matter volume in the right superior temporal gyrus, right cerebellum, left middle temporal gyrus, right globus pallidus and right medial frontal gyrus decreased with increasing severity of neonatal brain injury. However, the significant between-group functional neuroanatomical differences were not directly attributable to the detected structural regional differences.