Long-term effects of preterm birth on large-scale brain organization

Being born preterm (< 37 weeks of gestation)increases the risk for several psychiatric disorders, cognitive impairments, and academic underachievement. It is hypothesized that this is due to perinatal brain injury and subsequent alterations in brain development. Structural and functional magnetic resonance imaging allows the identification of such brain abnormalities in-vivo. Accordingly, previous MRI studies have shown that preterm Born infants, children and adolescents demonstrate both structural and functional alterations when compared to their term born peers. However, it is unclear whether such changes persist into adulthood. Therefore, the present doctoral Thesis aimed to investigate the long-term effects of preterm birth on large-scale brain organization. Study I: in 95 preterm and 83 full-term Born adults, structural and functional magnetic resonance imaging at-rest was used to analyze both voxel-based morphometry and spatial Patterns of intrinsic functional connectivity (iFC) in ongoing blood oxygenation level–dependent activity. We found widespread iFC differences that overlapped and correlated with aberrant regional gray matter volume in subcortical and temporal areas. Overlapping changes were predicted by the degree of prematurity and neonatal medical complications. The second study investigated functional brain organization in 73 adults born very preterm and/or with very low birth weight (VP/VLBW), and 73 termborn controls, while participants were involved in a verbal N-Back paradigm with varying workload. Although behavioral performance was comparable between groups, VP/VLBW adults showed significantly stronger deactivations of posterior default mode network regions during the most demanding 2-back condition. Our results suggest long-term effects of preterm birth on both structural and functional brain organization and imply compensatory brain activity as a mechanism to help overcome functional deficits.Eine Frühgeburt (d.h. Geburt vor der 37. Schwangerschaftswoche) erhöht das Risiko für psychiatrische Erkrankungen, kognitive Defizite und schwächere akademische Leistungen. Es wird vermutet, dass dies auf perinatale Hirnschädigungen und nachfolgende Veränderungen in der Gehirnentwicklung zurückzuführen ist. Die strukturelle und funktionelle Magnetresonanztomographie ermöglicht es solche Gehirnveränderungen in-vivo darzustellen. Frühere MRT-Studien haben gezeigt, dass frühgeborene Säuglinge, Kinder und Jugendliche sowohl strukturelle als auch funktionelle Unterschiede im Vergleich zu reifgeborenen Gleichaltrigen aufweisen. Jedoch ist unklar, ob solche Veränderungen bis ins Erwachsenenalter bestehen. Das Ziel der vorliegenden Doktorarbeit war es daher, die langfristigen Auswirkungen einer Frühgeburt auf die Gehirnorganisation im Erwachsenenalter zu untersuchen. Zu diesem Zweck wurden in der ersten Studie strukturelle und Ruhe-fMRT Daten von 95 frühgeborenen und 83 reifgeborenen Erwachsen erhoben und mittels Voxel-basierter Morphometrie und „Independent Component Analysis“ analysiert. Bei frühgeborenen Erwachsenen zeigten sich ausgedehnte Veränderungen in der funktionellen Konnektivität intrinsischer Hirnnetzwerke, die mit subkortikalen und temporalen Veränderungen im Volumen der grauen Substanz überlappten und korrelierten. Überlappende Veränderungen wurden durch den Grad der Frühgeburtlichkeit und das Ausmaß an perinatalen medizinischen Komplikationen vorhergesagt. Die zweite Studie untersuchte die funktionelle Gehirnorganisation von 73 Erwachsenen, die sehr frühgeboren und/oder ein sehr geringes Geburtsgewicht (SF/SGG) hatten, und 73 reifgeborenen Kontrollen, während diese ein verbales N-Back Paradigma mit variierendem Schwierigkeitsgrad absolvierten. Beide Gruppen meisterten die Aufgabe gleich gut. Jedoch zeigten die SF/SGG Erwachsenen während der schwierigsten 2-back Bedingung eine signifikant stärkere Deaktivierung von Regionen, die zum posterioren „default mode“ Netzwerk gezählt werden. Unsere Ergebnisse lassen langfristige Effekte einer Frühgeburt auf die strukturelle und funktionelle Gehirnorganisation im Erwachsenenalter vermuten und deuten an, dass kompensatorische Gehirnaktivität ein möglicher Mechanismus ist, um funktionelle Defizite auszugleichen

Univariate and multivariate pattern analysis of preterm subjects: a multimodal neuroimaging study

Background: Widespread lasting functional connectivity (FC) and brain volume changes in cortices and subcortices after premature birth have been researched in recent studies. However, the relationship remains unclear between spontaneously slow blood oxygen dependent level (BOLD) fluctuations and gray matter volume (GMV) changes in specific brain areas, such as temporal insular cortices, and whether classification methods based on MRI could be successfully applied to the identification of preterm individuals. In this thesis I hypothesized that in prematurely born adults 1. Ongoing neural excitability and brain activity, as estimated by regional functional connectivity of resting state functional MRI (rs-fMRI) is accompanied with altered low-frequency fluctuations and neonatal complications; 2. Altered regional functional connectivity is connected with superimposed cerebral structural reductions; and 3. multivariate neuroanatomical and functional brain patterns could be treated as features to identify preterm subjects from term subjects individually. Methods: To investigate these hypotheses, the principal results of structural alterations were measured with voxel-based morphometry (VBM), while rs-fMRI outcomes were estimated with amplitude of low-frequency fluctuations (ALFF) in analysis with ninety-four very preterm/very low birth weight (VP/VLBW) and ninety-two full-term (FT) born young adults. Results: The results of the thesis support the hypotheses by showing that, in univariate results, first in VP/VLBW grownups, ALFF was decreased in the left lateral temporal cortices no matter with global signal regression, and this reduction was closely associated with neonatal complications and cognitive variables. Second overlapped brain regions were found between reduced ALFF and reduced brain volumes in the left temporal cortices, and positively associated with each other, demonstrating a potential relationship between VBM and ALFF in this brain area. In multimodal multivariate pattern recognition analysis (MVPA), the gray matter volume (GMV) classifier displayed a higher accuracy (80.7%) contrast with the ALFF classifier (77.4%). The late fusion of GMV and ALFF did not outperform single GMV modality classification by reaching 80.4% accuracy. Moderator analysis from both rs-fMRI and structural MRI (sMRI) uncovered that the neuro-prematurity performance was predominantly determined by neonatal complications. Conclusions: In conclusion, these outcomes exhibit the long term effects of premature labour on lateral temporal cortices, which changed in both ongoing BOLD fluctuations and decreased cerebral structural volumes. This thesis further provided evidence that multivariate pattern analysis such as support vector machine (SVM) may identify imaging-based biomarkers and reliably detect signatures of preterm birth

Univariate and multivariate pattern analysis of preterm subjects: a multimodal neuroimaging study

Background: Widespread lasting functional connectivity (FC) and brain volume changes in cortices and subcortices after premature birth have been researched in recent studies. However, the relationship remains unclear between spontaneously slow blood oxygen dependent level (BOLD) fluctuations and gray matter volume (GMV) changes in specific brain areas, such as temporal insular cortices, and whether classification methods based on MRI could be successfully applied to the identification of preterm individuals. In this thesis I hypothesized that in prematurely born adults 1. Ongoing neural excitability and brain activity, as estimated by regional functional connectivity of resting state functional MRI (rs-fMRI) is accompanied with altered low-frequency fluctuations and neonatal complications; 2. Altered regional functional connectivity is connected with superimposed cerebral structural reductions; and 3. multivariate neuroanatomical and functional brain patterns could be treated as features to identify preterm subjects from term subjects individually. Methods: To investigate these hypotheses, the principal results of structural alterations were measured with voxel-based morphometry (VBM), while rs-fMRI outcomes were estimated with amplitude of low-frequency fluctuations (ALFF) in analysis with ninety-four very preterm/very low birth weight (VP/VLBW) and ninety-two full-term (FT) born young adults. Results: The results of the thesis support the hypotheses by showing that, in univariate results, first in VP/VLBW grownups, ALFF was decreased in the left lateral temporal cortices no matter with global signal regression, and this reduction was closely associated with neonatal complications and cognitive variables. Second overlapped brain regions were found between reduced ALFF and reduced brain volumes in the left temporal cortices, and positively associated with each other, demonstrating a potential relationship between VBM and ALFF in this brain area. In multimodal multivariate pattern recognition analysis (MVPA), the gray matter volume (GMV) classifier displayed a higher accuracy (80.7%) contrast with the ALFF classifier (77.4%). The late fusion of GMV and ALFF did not outperform single GMV modality classification by reaching 80.4% accuracy. Moderator analysis from both rs-fMRI and structural MRI (sMRI) uncovered that the neuro-prematurity performance was predominantly determined by neonatal complications. Conclusions: In conclusion, these outcomes exhibit the long term effects of premature labour on lateral temporal cortices, which changed in both ongoing BOLD fluctuations and decreased cerebral structural volumes. This thesis further provided evidence that multivariate pattern analysis such as support vector machine (SVM) may identify imaging-based biomarkers and reliably detect signatures of preterm birth

Decreased BOLD fluctuations in lateral temporal cortices of premature born adults

Lasting volume reductions in subcortical and temporal-insular cortices after premature birth suggest altered ongoing activity in these areas. We hypothesized altered fluctuations in ongoing neural excitability and activity, as measured by slowly fluctuating blood oxygenation of restingstate functional MRI (rs-fMRI), in premature born adults, with altered fluctuations being linked with underlying brain volume reductions. To investigate this hypothesis, 94 very preterm/very low birth weight (VP/VLBW) and 92 full-term born young adults underwent structural and rsfMRI data acquisition with voxel-based morphometry and amplitude of low-frequency fluctuations (ALFF) as main outcome measure. In VP/VLBW adults, ALFF was reduced in lateral temporal cortices, and this reduction was positively associated with lower birth weight. Regions of reduced ALFF overlapped with reduced brain volume. On the one hand, ALFF reduction remained after controlling for volume loss, supporting the functional nature of ALFF reductions. On the other hand, ALFF decreases were positively associated with underlying brain volume loss, indicating a relation between structural and functional changes. Furthermore, within the VP/VLBW group, reduced ALFF was associated with reduced IQ, indicating the behavioral relevance of ALFF decreases in temporal cortices. These results demonstrate long-term impact of premature birth on ongoing BOLD fluctuations in lateral temporal cortices, which are linked with brain volume reductions. Data suggest permanently reduced fluctuations in ongoing neural excitability and activity in structurally altered lateral temporal cortices after premature birth

In utero exposure to transient ischemia-hypoxemia promotes long-term neurodevelopmental abnormalities in male rat offspring

The impact of transient ischemic-hypoxemic insults on the developing fetal brain is poorly understood despite evidence suggesting an association with neurodevelopmental disorders such as schizophrenia and autism. To address this, we designed an aberrant uterine hypercontractility paradigm with oxytocin to better assess the consequences of acute, but transient, placental ischemia-hypoxemia in term pregnant rats. Using MRI, we confirmed that oxytocin-induced aberrant uterine hypercontractility substantially compromised uteroplacental perfusion. This was supported by the observation of oxidative stress and increased lactate concentration in the fetal brain. Genes related to oxidative stress pathways were significantly upregulated in male, but not female, offspring 1 hour after oxytocin-induced placental ischemia-hypoxemia. Persistent upregulation of select mitochondrial electron transport chain complex proteins in the anterior cingulate cortex of adolescent male offspring suggested that this sex-specific effect was enduring. Functionally, offspring exposed to oxytocin-induced uterine hypercontractility showed male-specific abnormalities in social behavior with associated region-specific changes in gene expression and functional cortical connectivity. Our findings, therefore, indicate that even transient but severe placental ischemia-hypoxemia could be detrimental to the developing brain and point to a possible mitochondrial link between intrauterine asphyxia and neurodevelopmental disorders

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

Impaired structural connectivity between dorsal attention network and pulvinar mediates the impact of premature birth on adult visual–spatial abilities

The dorsal attention network (DAN), including frontal eye fields and posterior parietal cortices, and its link with the posterior thalamus, contribute to visual–spatial abilities. Very premature birth impairs both visual–spatial abilities and cortico‐thalamic structural connectivity. We hypothesized that impaired structural DAN‐pulvinar connectivity mediates the effect of very premature birth on adult visual–spatial abilities. Seventy very premature (median age 26.6 years) and 57 mature born adults (median age 26.6 years) were assessed with cognitive tests and diffusion tensor imaging. Perceptual organization (PO) index of the Wechsler Adult Intelligence Scale‐III was used as a proxy for visual–spatial abilities, and connection probability maps in the thalamus, derived from probabilistic tractography from the DAN, were used as a proxy for DAN‐thalamic connectivity. Premature born adults showed decreases in both PO‐index and connection probability from DAN into the pulvinar, with both changes being positively correlated. Moreover, path analysis revealed that DAN‐pulvinar connectivity mediates the relationship between very premature birth and PO‐index. Results provide evidence for long‐term effects of very premature birth on structural DAN‐pulvinar connectivity, mediating the effect of prematurity on adult visual–spatial impairments. Data suggest DAN‐pulvinar connectivity as a specific target of prognostic and diagnostic procedures for visual–spatial abilities after premature birth

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

Analysis of brain structure in premature-born adults

My master’s thesis with the title “Analysis of brain structure in premature-born adults” is based on the discoveries of various developmental differences that have been found in premature-born individuals, both shortly after birth and in adults. However, it was not known to what extent these developmental differences are correlated and whether there might even be a causal relationship between structural differences and cognitive performance. To investigate these questions, MRI derived information on brain structure is combined in order to compute dependencies between different affected developmental processes. The analyses include statistical testing, correlation analysis as well as causal inference on a dataset consisting of 101 very preterm-born/ very low birth weight adults and 111 term-born control subjects. We found significant differences in very preterm- compared to term-born adults in multiple developmental processes, and these processes can be grouped by similarity into four main clusters. Furthermore, we found causal relationships between several developmental processes and cognitive performance. These findings pave the way for further research with the goal to improve risk prediction and the development of drug targets for preterm-born neonates

The association of children’s mathematic abilities with both adults’ cognitive abilities and intrinsic fronto-parietal networks is altered in preterm-born individuals

Mathematic abilities in childhood are highly predictive for long-term neurocognitive outcomes. Preterm-born individuals have an increased risk for both persistent cognitive impairments and long-term changes in macroscopic brain organization. We hypothesized that the association of childhood mathematic abilities with both adulthood general cognitive abilities and associated fronto-parietal intrinsic networks is altered after preterm delivery. 72 preterm- and 71 term-born individuals underwent standardized mathematic and IQ testing at 8 years and resting-state fMRI and full-scale IQ testing at 26 years of age. Outcome measure for intrinsic networks was intrinsic functional connectivity (iFC). Controlling for IQ at age eight, mathematic abilities in childhood were significantly stronger positively associated with adults’ IQ in preterm compared with term-born individuals. In preterm-born individuals, the association of children’s mathematic abilities and adults’ fronto-parietal iFC was altered. Likewise, fronto-parietal iFC was distinctively linked with preterm- and term-born adults’ IQ. Results provide evidence that preterm birth alters the link of mathematic abilities in childhood and general cognitive abilities and fronto-parietal intrinsic networks in adulthood. Data suggest a distinct functional role of intrinsic fronto-parietal networks for preterm individuals with respect to mathematic abilities and that these networks together with associated children’s mathematic abilities may represent potential neurocognitive targets for early intervention