Consistently lower volumes across thalamus nuclei in very premature-born adults.

Lasting thalamus volume reduction after preterm birth is a prominent finding. However, whether thalamic nuclei volumes are affected differentially by preterm birth and whether nuclei aberrations are relevant for cognitive functioning remains unknown. Using T1-weighted MR-images of 83 adults born very preterm (≤ 32 weeks' gestation; VP) and/or with very low body weight (≤ 1,500 g; VLBW) as well as of 92 full-term born (≥ 37 weeks' gestation) controls, we compared thalamic nuclei volumes of six subregions (anterior, lateral, ventral, intralaminar, medial, and pulvinar) across groups at the age of 26 years. To characterize the functional relevance of volume aberrations, cognitive performance was assessed by full-scale intelligence quotient using the Wechsler Adult Intelligence Scale and linked to volume reductions using multiple linear regression analyses. Thalamic volumes were significantly lower across all examined nuclei in VP/VLBW adults compared to controls, suggesting an overall rather than focal impairment. Lower nuclei volumes were linked to higher intensity of neonatal treatment, indicating vulnerability to stress exposure after birth. Furthermore, we found that single results for lateral, medial, and pulvinar nuclei volumes were associated with full-scale intelligence quotient in preterm adults, albeit not surviving correction for multiple hypotheses testing. These findings provide evidence that lower thalamic volume in preterm adults is observable across all subregions rather than focused on single nuclei. Data suggest the same mechanisms of aberrant thalamus development across all nuclei after premature birth.

Human Claustrum Connections: Robust In Vivo Detection by DWI-Based Tractography in Two Large Samples.

Despite substantial neuroscience research in the last decade revealing the claustrum's prominent role in mammalian forebrain organization, as evidenced by its extraordinarily widespread connectivity pattern, claustrum studies in humans are rare. This is particularly true for studies focusing on claustrum connections. Two primary reasons may account for this situation: First, the intricate anatomy of the human claustrum located between the external and extreme capsule hinders straightforward and reliable structural delineation. In addition, the few studies that used diffusion-weighted-imaging (DWI)-based tractography could not clarify whether in vivo tractography consistently and reliably identifies claustrum connections in humans across different subjects, cohorts, imaging methods, and connectivity metrics. To address these issues, we combined a recently developed deep-learning-based claustrum segmentation tool with DWI-based tractography in two large adult cohorts: 81 healthy young adults from the human connectome project and 81 further healthy young participants from the Bavarian longitudinal study. Tracts between the claustrum and 13 cortical and 9 subcortical regions were reconstructed in each subject using probabilistic tractography. Probabilistic group average maps and different connectivity metrics were generated to assess the claustrum's connectivity profile as well as consistency and replicability of tractography. We found, across individuals, cohorts, DWI-protocols, and measures, consistent and replicable cortical and subcortical ipsi- and contralateral claustrum connections. This result demonstrates robust in vivo tractography of claustrum connections in humans, providing a base for further examinations of claustrum connectivity in health and disease.

Changes in social relationships from 26 to 34 years of age in adults born very preterm.

BACKGROUND: Very preterm and/or very low birthweight (VP/VLBW; <32 weeks' gestation and/or <1500 g birthweight) individuals rated their partner and peer relationships lower than term-born individuals in emerging adulthood, but their quality of relationships with parents has been rarely investigated. Moreover, it is unclear whether previously reported differences in social relationship characteristics persist or lessen from emerging to established adulthood. OBJECTIVES: To investigate changes in social relationship characteristics in VP/VLBW adults compared to term-born adults from 26 to 34 years and whether the association between VP/VLBW and social relationship characteristics varies according to sex. METHODS: In this prospective whole-population birth cohort study in South Bavaria, Germany, social relationship characteristics with parents, partners and peers, and overall social relationships across these domains were evaluated with a Life Course Interview at 26 and 34 years. Interview items related to these domains were extracted and scored as 0 (optimal) and 1 (non-optimal). Each score was summed into domain-specific composite scores and standardised according to the total sample. RESULTS: Participants included 262 VP/VLBW (52.7% males) and 230 term-born individuals (47.0% males). VP/VLBW adults had lower overall social relationship scores than term-born adults (ß = -.61, 95% CI -0.85, -0.37). Specifically, partner (ß = -.50, 95% CI-0.74, -0.27) and peer relationship scores (ß = -.55, 95% CI-0.78, -0.32) were lower than those of term-born adults, but scores did not differ for parent relationships. On average, partner (ß = .25, 95% CI 0.14, 0.35) and peer relationship scores increased (ß = .16, 95% CI 0.03, 0.29), while parent relationship scores decreased (ß = -.64, 95% CI-0.79, -0.49) from 26 to 34 years. These changes were similar for VP/VLBW and term-born individuals. CONCLUSIONS: Patterns of change for the improved partner and peer but worsening parental social relationship scores were common across VP/VLBW and term-born adults, but differences between the two groups persisted from 26 to 34 years.

Romantic and sexual relationships of young adults born very preterm: An individual participant data meta-analysis.

AIM: To compare romantic and sexual relationships between adults born very preterm (VP; <32 weeks of gestation) or with very low birth weight (VLBW; <1500 g) and at term, and to evaluate potential biological and environmental explanatory factors among VP/VLBW participants. METHODS: This individual participant data (IPD) meta-analysis included longitudinal studies assessing romantic and sexual relationships in adults (mean sample age ≥ 18 years) born VP/VLBW compared with term-born controls. Following PRISMA-IPD guidelines, 11 of the 13 identified cohorts provided IPD from 1606 VP/VLBW adults and 1659 term-born controls. IPD meta-analyses were performed using one-stage approach. RESULTS: Individuals born VP/VLBW were less likely to be in a romantic relationship (OR 0.49; 95% CI 0.31-0.76), to be married/cohabiting (OR 0.70, 95% CI 0.53-0.92), or to have had sexual intercourse (OR 0.21, 95% CI 0.09-0.36) than term-born adults. If sexually active, VP/VLBW participants were more likely to experience their first sexual intercourse after the age of 18 years (OR 1.93, 95% CI 1.24-3.01) than term-born adults. Among VP/VLBW adults, males, and those with neurosensory impairment were least likely to experience romantic relationships. CONCLUSIONS: These findings reflect less optimal social functioning and may have implications for socioeconomic and health outcomes of adults born VP/VLBW.

Indirect evidence for altered dopaminergic neurotransmission in very premature-born adults.

While animal models indicate altered brain dopaminergic neurotransmission after premature birth, corresponding evidence in humans is scarce due to missing molecular imaging studies. To overcome this limitation, we studied dopaminergic neurotransmission changes in human prematurity indirectly by evaluating the spatial co-localization of regional alterations in blood oxygenation fluctuations with the distribution of adult dopaminergic neurotransmission. The study cohort comprised 99 very premature-born (<32 weeks of gestation and/or birth weight below 1500 g) and 107 full-term born young adults, being assessed by resting-state functional MRI (rs-fMRI) and IQ testing. Normative molecular imaging dopamine neurotransmission maps were derived from independent healthy control groups. We computed the co-localization of local (rs-fMRI) activity alterations in premature-born adults with respect to term-born individuals to different measures of dopaminergic neurotransmission. We performed selectivity analyses regarding other neuromodulatory systems and MRI measures. In addition, we tested if the strength of the co-localization is related to perinatal measures and IQ. We found selectively altered co-localization of rs-fMRI activity in the premature-born cohort with dopamine-2/3-receptor availability in premature-born adults. Alterations were specific for the dopaminergic system but not for the used MRI measure. The strength of the co-localization was negatively correlated with IQ. In line with animal studies, our findings support the notion of altered dopaminergic neurotransmission in prematurity which is associated with cognitive performance.

ADHD symptoms and diagnosis in adult preterms: systematic review, IPD meta-analysis, and register-linkage study.

BACKGROUND: This study examined differences in ADHD symptoms and diagnosis between preterm and term-born adults (≥18 years), and tested if ADHD is related to gestational age, birth weight, multiple births, or neonatal complications in preterm borns. METHODS: (1) A systematic review compared ADHD symptom self-reports and diagnosis between preterm and term-born adults published in PubMed, Web of Science, and PROQUEST until April 2021; (2) a one-stage Individual Participant Data(IPD) meta-analysis (n = 1385 preterm, n = 1633 term; born 1978-1995) examined differences in self-reported ADHD symptoms[age 18-36 years]; and (3) a population-based register-linkage study of all live births in Finland (01/01/1987-31/12/1998; n = 37538 preterm, n = 691,616 term) examined ADHD diagnosis risk in adulthood (≥18 years) until 31/12/2016. RESULTS: Systematic review results were conflicting. In the IPD meta-analysis, ADHD symptoms levels were similar across groups (mean z-score difference 0.00;95% confidence interval [95% CI] -0.07, 0.07). Whereas in the register-linkage study, adults born preterm had a higher relative risk (RR) for ADHD diagnosis compared to term controls (RR = 1.26, 95% CI 1.12, 1.41, p < 0.001). Among preterms, as gestation length (RR = 0.93, 95% CI 0.89, 0.97, p < 0.001) and SD birth weight z-score (RR = 0.88, 95% CI 0.80, 0.97, p < 0.001) increased, ADHD risk decreased. CONCLUSIONS: While preterm adults may not report higher levels of ADHD symptoms, their risk of ADHD diagnosis in adulthood is higher. IMPACT: Preterm-born adults do not self-report higher levels of ADHD symptoms, yet are more likely to receive an ADHD diagnosis in adulthood compared to term-borns. Previous evidence has consisted of limited sample sizes of adults and used different methods with inconsistent findings. This study assessed adult self-reported symptoms across 8 harmonized cohorts and contrasted the findings with diagnosed ADHD in a population-based register-linkage study. Preterm-born adults may not self-report increased ADHD symptoms. However, they have a higher risk of ADHD diagnosis, warranting preventive strategies and interventions to reduce the presentation of more severe ADHD symptomatology in adulthood.

Comparative evaluation of the health utilities index mark 3 and the short form 6D: evidence from an individual participant data meta-analysis of very preterm and very low birthweight adults.

BACKGROUND: The most appropriate preference-based health-related quality of life (HRQoL) instruments for trials or research studies that ascertain the consequences of individuals born very preterm and/or low birthweight (VP/VLBW) are not known. Agreement between the HUI3 and SF-6D multi-attribute utility measures have not been previously investigated for VP/VLBW and normal birthweight or term-born controls. This study examined the agreement between the outputs of the HUI3 and SF-6D measures among adults born VP/VLBW and normal birthweight or term born controls. METHODS: We used two prospective cohorts of individuals born VP/VLBW and controls contributing to the 'Research on European Children and Adults Born Preterm' (RECAP) consortium which assessed HRQoL using two preference-based measures. The combined dataset of individual participant data (IPD) included 407 adult VP/VLBW survivors and 367 controls, ranging in age from 18 to 26 years. Bland-Altman plots, intra-class correlation coefficients, and generalized linear mixed models in a one-step approach were used to examine agreement between the measures. RESULTS: There was significant discordance between the HUI3 and SF-6D multi-attribute utility measures in the VP/VLBW sample, controls, and in the combined samples. Agreement between the HUI3 and SF-6D multi-attribute utility measures was weaker in controls compared with VP/VLBW individuals. CONCLUSIONS AND RELEVANCE: The HUI3 and SF-6D each provide unique information on different aspects of health status across the groups. The HUI3 better captures preterm-related changes to HRQoL in adulthood compared to SF-6D. Studies focused on measuring physical or cognitive aspects of health will likely benefit from using the HUI3 instead of the SF-6D, regardless of gestational age at birth and birthweight status.

Changes in neonatal morbidity, neonatal care practices, and length of hospital stay of surviving infants born very preterm in the Netherlands in the 1980s and in the 2000s: a comparison analysis with identical characteristics definitions.

BACKGROUND: This study evaluates changes in the neonatal morbidity, the neonatal care practices, and the length of hospital stay of surviving very preterm (VP) infants born in the Netherlands in the 1980s and in the 2000s; a period over which historical improvements were introduced into neonatal care. We, herein, also study whether these changes in neonatal morbidity, neonatal care practices and length of hospital stay are associated with sociodemographic, prenatal, and infant characteristics. METHODS: Two community-based cohorts from 1983 (POPS) and 2002-03 (LOLLIPOP) have provided the perinatal data for our study. The analysis enrolled 1,228 participants born VP (before the 32nd week of gestation) and surviving to 2 years of age without any severe congenital malformation. A rigorous harmonisation protocol ensured a precise comparison of the cohorts by using identical definitions of the perinatal characteristics. RESULTS: In 2003, mothers were older when giving birth, had higher multiple birth rates, and significantly more parents had received higher education. In 2003, less VP infants had severe intraventricular haemorrhage and sepsis and relatively more received continuous positive airway pressure, mechanical ventilation and caffeine therapy than in 1983. Antenatal corticosteroids and surfactant therapy were provided only in 2003. The length of the stay in the neonatal intensive care unit and in hospital had decreased in 2003 by 22 and 11 days, respectively. Differences persisted after adjustment for sociodemographic, prenatal, and infant characteristics. CONCLUSIONS: Neonatal morbidities of the surviving VP infants in this study have not increased, and exhibit improvements for various characteristics in two cohorts born 20 years apart with comparable gestational age and birth weight. Our data suggest that the improvements found are associated with more advanced therapeutic approaches and new national protocols in place, and less so with sociodemographic changes. This analysis provides a basis for further comparative analyses of the health and the development of VP children, particularly with regard to long-term outcomes.

Mathematical performance in childhood and early adult outcomes after very preterm birth: an individual participant data meta-analysis.

AIM: To investigate the strength of the independent associations of mathematics performance in children born very preterm (<32wks' gestation or <1500g birthweight) with attending postsecondary education and their current employment status in young adulthood. METHOD: We harmonized data from six very preterm birth cohorts from five different countries and carried out one-stage individual participant data meta-analyses (n=954, 52% female) using mixed effects logistic regression models. Mathematics scores at 8 to 11 years of age were z-standardized using contemporary cohort-specific controls. Outcomes included any postsecondary education, and employment/education status in young adulthood. All models were adjusted for year of birth, gestational age, sex, maternal education, and IQ in childhood. RESULTS: Higher mathematics performance in childhood was independently associated with having attended any postsecondary education (odds ratio [OR] per SD increase in mathematics z-score: 1.36 [95% confidence interval {CI}: 1.03, 1.79]) but not with current employment/education status (OR 1.14 per SD increase [95% CI: 0.87, 1.48]). INTERPRETATION: Among populations born very preterm, childhood mathematics performance is important for adult educational attainment, but not for employment status.

Aberrant Claustrum Microstructure in Humans after Premature Birth.

Several observations suggest an impact of prematurity on the claustrum. First, the claustrum's development appears to depend on transient subplate neurons of intra-uterine brain development, which are affected by prematurity. Second, the claustrum is the most densely connected region of the mammalian forebrain relative to its volume; due to its effect on pre-oligodendrocytes, prematurity impacts white matter connections and thereby the development of sources and targets of such connections, potentially including the claustrum. Third, due to its high connection degree, the claustrum contributes to general cognitive functioning (e.g., selective attention and task switching/maintaining); general cognitive functioning, however, is at risk in prematurity. Thus, we hypothesized altered claustrum structure after premature birth, with these alterations being associated with impaired general cognitive performance in premature born persons. Using T1-weighted and diffusion-weighted magnetic resonance imaging in 70 very preterm/very low-birth-weight (VP/VLBW) born adults and 87 term-born adults, we found specifically increased mean diffusivity in the claustrum of VP/VLBW adults, associated both with low birth weight and at-trend with reduced IQ. This result demonstrates altered claustrum microstructure after premature birth. Data suggest aberrant claustrum development, which is potentially related with aberrant subplate neuron and forebrain connection development of prematurity.

Exploiting Ultra-Wideband Channel Impulse Responses for Device-Free Localization.

In radio-frequency (RF)-based device-free localization (DFL), the number of sensors acting as RF transmitters and receivers is crucial for accuracy and system costs. Two promising approaches for DFL have been identified in the past: radio tomographic imaging (RTI) and multi-static radar (MSR). RTI in its basic version requires many sensors for high accuracy, which increases the cost. In this paper, we show how RTI benefits from multipath propagation. By evaluating the direct and echo paths, we increase the coverage of the target area, and by utilizing UWB signals, the RTI system is less susceptible to multipath propagation. MSR maps reflections that occur within the target area to reflectors such as persons or other objects. MSR does not require that the person is located near a signal path. Both suggested methods exploit ultra-wideband (UWB) channel impulse response (CIR) measurements. CIR measurements and the modeling of multipath effects either increase the accuracy or reduce the required number of sensors for localization with RTI. We created a test setup and measure UWB CIRs at different positions with a commercially available off-the-shelf UWB radio chip, the Decawave DW1000. We compare the localization results of RTI, multipath-assisted (MA)-RTI, and MSR and investigate a combined approach. We show that RTI is improved by the analysis of multipath propagation; furthermore, MA-RTI results in a better performance compared to MSR: with 50% of all cases, the localization error is better than 0.82 m and in 80% of all cases 1.34 m. The combined approach results in the best localization result with 0.64 m in 50% of all cases.

The fetal gastrointestinal tract is exposed to melatonin and superoxide dismutase rich amniotic fluid throughout prenatal development.

Amniotic fluid (AF) is the first fluid to enter the gastrointestinal tract. Preterm birth is leading to a sudden interruption of AF swallowing. Understanding the composition of amniotic fluid is crucial to implement strategies preventing intestinal injury in preterm infants. We hypothesized that the fetal gastrointestinal tract (GIT) is exposed to melatonin and antioxidant enzymes via amniotic fluid throughout prenatal development. Amniotic fluid samples from 76 pregnant women with a median (range) gestational age of 38.0 (14.3-40.1) weeks have been collected. Immediately after birth blood samples were collected from the umbilical vein (n = 53). Median (Interquartile range) melatonin concentration was 30.5 pg/ml (12.7-118.3) and superoxide dismutase 1 (SOD1) concentration was 84 ng/ml (59-123). Extracellular glutathione peroxidase concentration was either not detectable or exceptionally low. We found a positive correlation between melatonin concentration in amniotic fluid and gestational age (Spearman's correlation coefficient, r = 0.570, p<0.001), while SOD1 concentration in amniotic fluid was inversely correlated with gestational age (r = -0.246, p = 0.032). Compared to serum samples, melatonin concentration was statistically significantly higher in amniotic fluid (p<0.001). Our results indicate that the fetal gastrointestinal system is continuously exposed to melatonin and SOD1 via the amniotic fluid throughout prenatal development.

Testing the neurodevelopmental, trauma and developmental risk factor models of psychosis using a naturalistic experiment.

BACKGROUND: The neurodevelopmental and trauma theories are two widely cited models of psychosis. A third - the developmental risk factor model (DRFM) - recognises the combined role of neurodevelopmental risks and trauma. Our objective was to test these theories using preterm populations as a natural experiment, given the high prevalence of neurodevelopmental deficits and exposure to trauma. METHODS: Two population-based preterm birth cohorts, the Bavarian Longitudinal Study (BLS; N = 399) and EPICure Study (N = 184), were included with term-born controls. Peer victimisation in childhood was assessed by parent and child report and psychotic experiences (PE) were assessed in early adulthood. Different models of psychosis were tested using regression and mediation analyses. RESULTS: There was support for the trauma and DRFM in the BLS. Peer victimisation increased the risk of PE for preterm and term-born participants equally [odds ratio = 4.87, 95% confidence interval (CI) 1.96-12.08]. There was an indirect effect where preterm children were more likely to be victimised, which subsequently increased risk of PE [ß = 1.12 (s.e. = 0.61), 95% CI 0.11-2.48]. The results were replicated in EPICure. CONCLUSIONS: Exposure to trauma which is experienced more often by neurodevelopmental risk children rather than neurodevelopmental risk per se increases the risk of PE. The findings are consistent with the trauma model and DRFM. Interventions focused on reducing trauma may reduce the development of PE.

Preterm children's long-term academic performance after adaptive computerized training: an efficacy and process analysis of a randomized controlled trial.

BACKGROUND: Adaptive computerized interventions may help improve preterm children's academic success, but randomized trials are rare. We tested whether a math training (XtraMath®) versus an active control condition (Cogmed®; working memory) improved school performance. Training feasibility was also evaluated. METHODS: Preterm born first graders, N = 65 (28-35 + 6 weeks gestation) were recruited into a prospective randomized controlled multicenter trial and received one of two computerized trainings at home for 5 weeks. Teachers rated academic performance in math, reading/writing, and attention compared to classmates before (baseline), directly after (post), and 12 months after the intervention (follow-up). Total academic performance growth was calculated as change from baseline (hierarchically ordered-post test first, follow-up second). RESULTS: Bootstrapped linear regressions showed that academic growth to post test was significantly higher in the math intervention group (B = 0.25 [95% confidence interval: 0.04-0.50], p = 0.039), but this difference was not sustained at the 12-month follow-up (B = 0.00 [-0.31 to 0.34], p = 0.996). Parents in the XtraMath group reported higher acceptance compared with the Cogmed group (mean difference: -0.49, [-0.90 to -0.08], p = 0.037). CONCLUSIONS: Our findings do not show a sustained difference in efficacy between both trainings. Studies of math intervention effectiveness for preterm school-aged children are warranted. IMPACT: Adaptive computerized math training may help improve preterm children's short-term school performance. Computerized math training provides a novel avenue towards intervention after preterm birth. Well-powered randomized controlled studies of math intervention effectiveness for preterm school-aged children are warranted.

Very preterm birth and trajectories of domain-specific self-concept from childhood into adulthood.

Self-concept refers to individuals' perceptions of themselves in specific domains and is closely related with their overall self-esteem. Lower self-esteem has been reported in those born preterm (<37 weeks gestation), but the development of self-concept has not been studied in this population. This study investigates whether differences in trajectories of domain-specific self-concepts are explained by premature birth or other risk factors, using the Bavarian Longitudinal Study (N = 460), a population-based study of very preterm (VP; <32 weeks gestation)/very low birth weight (VLBW; <1500 g) cohort and term-born controls. Trajectories of body and social self-concept from 6 to 26 years of age were estimated using latent class growth analysis. Regression models examined the effects of VP/VLBW and other individual, social, and family factors. Two trajectories - one stable and one decreasing - were identified for both self-concepts. VP/VLBW birth was associated with decreasing self-concept in both domains, although the effect of VP/VLBW on social self-concept was weakened in the adjusted analysis. Furthermore, mediated pathways were found from VP/VLBW to decreasing social self-concept via chronic bullying (ß = 0.05, 95% CI [0.002, 0.12]) and motor impairments (ß = 0.04, 95% CI [0.01, 0.07]), suggesting that negative self-concept in the VP/VLBW population is partially modifiable through improving peer relationships and motor impairments in childhood.

An analysis of MRI derived cortical complexity in premature-born adults: Regional patterns, risk factors, and potential significance.

Premature birth bears an increased risk for aberrant brain development concerning its structure and function. Cortical complexity (CC) expresses the fractal dimension of the brain surface and changes during neurodevelopment. We hypothesized that CC is altered after premature birth and associated with long-term cognitive development. One-hundred-and-one very premature-born adults (gestational age <32 weeks and/or birth weight <1500 â€‹g) and 111 term-born adults were assessed by structural MRI and cognitive testing at 26 years of age. CC was measured based on MRI by vertex-wise estimation of fractal dimension. Cognitive performance was measured based on Griffiths-Mental-Development-Scale (at 20 months) and Wechsler-Adult-Intelligence-Scales (at 26 years). In premature-born adults, CC was decreased bilaterally in large lateral temporal and medial parietal clusters. Decreased CC was associated with lower gestational age and birth weight. Furthermore, decreased CC in the medial parietal cortices was linked with reduced full-scale IQ of premature-born adults and mediated the association between cognitive development at 20 months and IQ in adulthood. Results demonstrate that CC is reduced in very premature-born adults in temporoparietal cortices, mediating the impact of prematurity on impaired cognitive development. These data indicate functionally relevant long-term alterations in the brain's basic geometry of cortical organization in prematurity.

Hippocampal subfield volumes are nonspecifically reduced in premature-born adults.

Reduced global hippocampus volumes have been demonstrated in premature-born individuals, from newborns to adults; however, it is unknown whether hippocampus subfield (HCSF) volumes are differentially affected by premature birth and how relevant they are for cognitive performance. To address these questions, we investigated magnetic resonance imaging (MRI)-derived HCSF volumes in very premature-born adults, and related them with general cognitive performance in adulthood. We assessed 103 very premature-born (gestational age [GA] <32 weeks and/or birth weight <1,500 g) and 109 term-born individuals with cognitive testing and structural MRI at 26 years of age. HCSFs were automatically segmented based on three-dimensional T1- and T2-weighted sequences and studied both individually and grouped into three functional units, namely hippocampus proper (HP), subicular complex (SC), and dentate gyrus (DG). Cognitive performance was measured using the Wechsler-Adult-Intelligence-Scale (full-scale intelligence quotient [FS-IQ]) at 26 years. We observed bilateral volume reductions for almost all HCSF volumes in premature-born adults and associations with GA and neonatal treatment intensity but not birth weight. Left-sided HP, SC, and DG volumes were associated with adult FS-IQ. Furthermore, left DG volume was a mediator of the association between GA and adult FS-IQ in premature-born individuals. Results demonstrate nonspecifically reduced HCSF volumes in premature-born adults; but specific associations with cognitive outcome highlight the importance of the left DG. Data suggest that specific interventions toward hippocampus function might be promising to lower adverse cognitive effects of prematurity.

Decreased cortical thickness mediates the relationship between premature birth and cognitive performance in adulthood.

Cortical thickness (CTh) reflects cortical properties such as dendritic complexity and synaptic density, which are not only vulnerable to developmental disturbances caused by premature birth but also highly relevant for cognitive performance. We tested the hypotheses whether CTh in young adults is altered after premature birth and whether these aberrations are relevant for general cognitive abilities. We investigated CTh based on brain structural magnetic resonance imaging and surface-based morphometry in a large and prospectively collected cohort of 101 very premature-born adults (<32 weeks of gestation and/or birth weight [BW] below 1,500 g) and 111 full-term controls at 26 years of age. Cognitive performance was assessed by full-scale intelligence quotient (IQ) using the Wechsler Adult Intelligence Scale. CTh was reduced in frontal, parietal, and temporal associative cortices predominantly in the left hemisphere in premature-born adults compared to controls. We found a significant positive association of CTh with both gestational age and BW, particularly in the left hemisphere, and a significant negative association between CTh and intensity of neonatal treatment within limited regions bilaterally. Full-scale IQ and CTh in the left hemisphere were positively correlated. Furthermore, CTh in the left hemisphere acted as a mediator on the association between premature birth and full-scale IQ. Results provide evidence that premature born adults have widespread reduced CTh that is relevant for their general cognitive performance. Data suggest lasting reductions in cortical microstructure subserving CTh after premature birth.

IGF-I in cord blood is predictive of final height in monozygotic twins with intra-twin birth weight differences.

OBJECTIVE: Adverse prenatal conditions can exert a long-lasting impact on growth up to final height (FH). Due to different prenatal nutrient availability, monozygotic twin pairs with discordant birth weight (bw) provide an excellent model to examine the impact of genes and environment and to analyse the predictive value of bw, birth length (bl) and cord blood (cb) concentration of IGF-I on FH. PATIENTS AND METHODS: Twenty eight monozygotic twin pairs with intra-twin bw-/bl-differences were studied at birth and longitudinally until FH. Intra-twin bw difference >1 SDS was defined "discordant" (n = 10 pairs). IGF-I was analysed in cord blood in all twins. Intra-twin differences (∆) in bw, bl and cord blood IGF-I were correlated with ∆FH. RESULTS: Throughout growth and up until FH intra-twin length/height differences remained for all but two (26/28) twins and for all (10/10) discordant twins. In the discordant group, a highly significant intra-twin difference for FH-SDS was found with a mean intra-twin Δheight- SDS of 1.23 (range, 0.29-2.34). This corresponds to a mean Δintra-twin difference at FH of 7.9 cm (3.1 inch; range, 2-15 cm [0.79-5.9 inch]). Correlation coefficients were calculated to identify factors predicting FH: ∆bw (r = .678; P = .0005), ∆bl (r = .333; P = .0002) and ∆IGF-I in cb (r = .418; P = .0023). Interaction terms showed that IGF-I is an additional factor to the auxological data, leading to an improvement of the ∆FH modelling. CONCLUSION: Prenatal environment leading to bw-/bl- and cbIGF-I differences in monozygotic twins had a long-lasting impact on growth until FH. Both, anthropometric data at birth and cbIGF-I are predictive of FH.

Aberrant gyrification contributes to the link between gestational age and adult IQ after premature birth.

Gyrification is a hallmark of human brain development, starting in the second half of gestation in primary cortices, followed by unimodal and then transmodal associative cortices. Alterations in gyrification have been noted in premature-born newborns and children, suggesting abnormal cortical folding to be a permanent feature of prematurity. Furthermore, both gyrification and prematurity are tightly linked with cognitive performance, indicating a link between prematurity, gyrification, and cognitive performance. To investigate this triangular relation, we tested the following two hypotheses: (i) gyrification is aberrant in premature-born adults; and (ii) aberrant gyrification contributes to the impact of prematurity on adult cognitive performance. One hundred and one very premature-born adults (i.e. adults born before 32 weeks of gestation, and/or with birth weight <1500 g) and 111 mature-born adults were assessed by structural MRI and cognitive testing at 27 years of age. Gyrification was measured by local cortical absolute mean curvature (AMC), evaluated through structural MRI. Cognitive performance was assessed by the Wechsler Adult Intelligence Scale, full-scale IQ test. Two-sample t-tests, regression and mediation analyses were used to assess AMC group differences and the relation between AMC, birth-related variables, and full-scale IQ. Three key findings were identified. First, local AMC was widely increased in fronto-temporo-parietal primary and associative cortices of very premature-born adults. Increase of AMC was inversely associated with gestational age and birth weight and positively associated with medical complications at birth, respectively. Second, increased AMC of temporal associative cortices specifically contributed to the association between prematurity and reduced adult IQ (two-path mediation), indicating that aberrant gyrification of temporal associative cortices is critical for impaired cognitive performance after premature birth. Finally, further investigation of the relationship of gyrification between the early folding postcentral cortices and associative temporal cortices, folding later during neurodevelopment, revealed that the effect of gyrification abnormalities in associative temporal cortices on adult IQ is influenced itself by gyrification abnormalities occurring in the early folding postcentral cortices (three-path mediation). These results indicate that gyrification development across cortical areas in the brain conveys prematurity effects on adult IQ. Overall, these results provide evidence that premature birth leads to permanently aberrant gyrification patterns suggesting an altered neurodevelopmental trajectory. Statistical mediation modelling suggests that both aberrant gyrification itself as well as its propagation across the cortex express aspects of impaired neurodevelopment after premature birth and lead to reduced cognitive performance in adulthood. Thus, markers of gyrification appear as potential candidates for prognosis and treatment of prematurity effects.