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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., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Multiple or persistent crying, sleeping, or feeding problems in early childhood (regulatory problems, RPs) predict increased risk for self-regulation difficulties. Sensitive parenting may protect children from trajectories of dysregulation. Considering self-regulation from a life-course perspective, are children with early multiple and/or persistent RPs affected similarly by parenting as those without (main effects model, ME), or are they more vulnerable (diathesis-stress, DIA-S), or more susceptible (differential susceptibility theory, DST) to variations in sensitive parenting at age 6 years? Participants (N = 302) were studied prospectively from birth to 28 years. RPs were assessed from 5 to 56 months. Sensitive parenting was observed at 6 years. Attention regulation was observed at 8 and 28 years. Internalizing and externalizing problems were rated by parents at 8 years, and by adults at 28 years. Confirmatory-comparative modelling tested whether associations of sensitive parenting with outcomes at 8 and 28 years among individuals with early multiple and/or persistent RPs (n = 74) versus those without (n = 228) were best explained by ME, DIA-S, or DST models. Best fitting models differed according to age at assessment. For childhood attention regulation, the statistically parsimonious DIA-S provided the best fit to the data. At age 28, two additive main effects (ME, RP group and sensitive parenting) fit best. DIA-S and ME explained internalizing and externalizing problems. Using a comprehensive life-span approach, DIA-S and ME models but not DST explained how early RPs and sensitive parenting predicted attention, internalizing, and externalizing outcomes. Individuals with early RPs are vulnerable to insensitive parenting., (© 2020. Springer-Verlag GmbH Germany, part of Springer Nature.)

Premature birth is associated with alterations in brain structure, particularly in white matter. Among white matter, alterations in cortico-thalamic connections are present in premature-born infants, and they have been suggested both to last until adulthood and to contribute to impaired cognitive functions. To test these hypotheses, 70 very premature-born adults and 67 full-term controls underwent cognitive testing and diffusion-weighted imaging. Each cortical hemisphere was parcellated into six lobes, from which probabilistic tractography was performed to the thalamus. Connection probability was chosen as metric of structural connectivity. We found increased cortico-thalamic connection probability between left prefrontal cortices and left medio-dorsal thalamus and reduced connection probability between bilateral temporal cortices and bilateral anterior thalami in very premature-born adults. Aberrant prefronto- and temporo-thalamic connection probabilities were correlated with birth weight and days on ventilation, respectively, supporting the suggestion that these connectivity changes relate with the degree of prematurity. Moreover, an increase in left prefronto-thalamic connection probability also correlated with lower verbal comprehension index indicating its relevance for verbal cognition. Together, our results demonstrate that cortico-thalamic structural connectivity is aberrant in premature-born adults, with these changes being linked with impairments in verbal cognitive abilities. Due to corresponding findings in infants, data suggest aberrant development of cortico-thalamic connectivity after premature birth with lasting effects into adulthood., Competing Interests: Declaration of competing interest The authors report no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background and Purpose: Qualitative studies about the abnormalities appreciated on routine magnetic resonance imaging (MRI) sequences in prematurely born adults are lacking. This article aimed at filling this knowledge gap by (1) qualitatively describing routine imaging findings in prematurely born adults, (2) evaluating measures for routine image interpretation and (3) investigating the impact of perinatal variables related to premature birth., Methods: In this study two board-certified radiologists assessed T1-weighted and FLAIR-weighted images of 100 prematurely born adults born very preterm (VP <32 weeks) and/or at very low birth weight (VLBW <1500 g) and 106 controls born at full term (FT) (mean age 26.8 ± 0.7 years). The number of white matter lesions (WML) was counted according to localization. Lateral ventricle volume (LVV) was evaluated subjectively and by measurements of Evans' index (EI) and frontal-occipital-horn ratio (FOHR). Freesurfer-based volumetry served as reference standard. Miscellaneous incidental findings were noted as free text., Results: The LVV was increased in 24.7% of VP/VLBW individuals and significantly larger than in FT controls. This was best identified by measurement of FOHR (AUC = 0.928). Ventricular enlargement was predicted by low gestational age (odds ratio: 0.71, 95% CI 0.51-0.98) and presence of neonatal intracranial hemorrhage (odds ratio: 0.26, 95% CI 0.07-0.92). The numbers of deep and periventricular WML were increased while subcortical WMLs were not., Conclusion: Enlargement of the LVV and deep and periventricular WMLs are typical sequelae of premature birth that can be appreciated on routine brain MRI. To increase sensitivity of abnormal LVV detection, measurement of FOHR seems feasible in clinical practice.

Recent evidence suggests increased metabolic and physiologic aging rates in premature-born adults. While the lasting consequences of premature birth on human brain development are known, its impact on brain aging remains unclear. We addressed the question of whether premature birth impacts brain age gap estimates (BrainAGE) using an accurate and robust machine-learning framework based on structural MRI in a large cohort of young premature-born adults ( n = 101) and full-term (FT) controls ( n = 111). Study participants are part of a geographically defined population study of premature-born individuals, which have been followed longitudinally from birth until young adulthood. We investigated the association between BrainAGE scores and perinatal variables as well as with outcomes of physical (total intracranial volume, TIV) and cognitive development (full-scale IQ, FS-IQ). We found increased BrainAGE in premature-born adults [median (interquartile range) = 1.4 (-1.3-4.7 years)] compared to full-term controls ( p = 0.002, Cohen's d = 0.443), which was associated with low Gestational age (GA), low birth weight (BW), and increased neonatal treatment intensity but not with TIV or FS-IQ. In conclusion, results demonstrate elevated BrainAGE in premature-born adults, suggesting an increased risk for accelerated brain aging in human prematurity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hedderich, Menegaux, Schmitz-Koep, Nuttall, Zimmermann, Schneider, Bäuml, Daamen, Boecker, Wilke, Zimmer, Wolke, Bartmann, Sorg and Gaser.)

Premature-born infants have impaired amygdala structure, presumably due to increased stress levels of premature birth mediated by the amygdala. However, accounting for lifelong plasticity of amygdala, it is unclear whether such structural changes persist into adulthood. To address this problem, we stated the following questions: first, are whole amygdala volumes reduced in premature-born adults? And second, as adult anxiety traits are often increased after prematurity and linked with amygdala structure, are alterations in amygdala associated with adults' anxiety traits after premature birth? We addressed these questions by automated amygdala segmentation of MRI volumes in 101 very premature-born adults (< 32 weeks of gestation and/or birth weight below 1500 g) and 108 full-term controls at 26 years of age of a prospectively and longitudinally collected cohort. We found significantly lower whole amygdala volumes in premature-born adults. While premature-born adults had significantly higher T score for avoidant personality reflecting increased social anxiety trait, this trait was not correlated with amygdala volume alterations. Results demonstrate reduced amygdala volumes in premature born adults. Data suggest lasting effects of prematurity on amygdala structure.

While it is known that whole amygdala volume is lastingly reduced after premature birth, it is unknown whether different amygdala nuclei are distinctively affected by prematurity. This question is motivated by two points: First, the observation that developmental trajectories of superficial, centromedial and basolateral amygdala nuclei are different. And second, the expectation that these different developmental pathways are distinctively affected by prematurity. Furthermore, we stated the question whether alterations in amygdala nuclei are associated with increased adults' anxiety traits after premature birth. We investigated 101 very premature-born adults (<32 weeks of gestation and/or birth weight below 1500 g) and 108 full-term controls of a prospectively and longitudinally collected cohort at 26 years of age using automated amygdala nuclei segmentation based on structural MRI. We found selectively reduced volumes of bilateral accessory basal nuclei (pertaining to the basolateral amygdala of claustral developmental trajectory) adjusted for whole amygdala volume. Volumes of bilateral accessory basal nuclei were positively associated with gestational age and negatively associated with duration of ventilation. Furthermore, structural covariance within the basolateral amygdala was increased in premature-born adults. We did not find an association between reduced volumes of basolateral amygdala and increased social anxiety in the prematurity group. These results demonstrate specifically altered basolateral amygdala structure in premature-born adults. Data suggest that prematurity has distinct effects on amygdala nuclei., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

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., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

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., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Premature-born adults exhibit lasting white matter alterations as demonstrated by widespread reduction in fractional anisotropy (FA) based on diffusion-weighted imaging (DWI). FA reduction, however, is non-specific for microscopic underpinnings such as aberrant myelination or fiber density (FD). Using recent advances in DWI, we tested the hypothesis of reduced FD in premature-born adults and investigated its link with the degree of prematurity and cognition. 73 premature- and 89 mature-born adults aged 25-27 years underwent single-shell DWI, from which a FD measure was derived using convex optimization modeling for microstructure informed tractography (COMMIT). Premature-born adults exhibited lower FD in numerous tracts including the corpus callosum and corona radiata compared to mature-born adults. These FD alterations were associated with both the degree of prematurity, as assessed via gestational age and birth weight, as well as with reduced cognition as measured by full-scale IQ. Finally, lower FD overlapped with lower FA, suggesting lower FD underlie unspecific FA reductions. Results provide evidence that premature birth leads to lower FD in adulthood which links with lower full-scale IQ. Data suggest that lower FD partly underpins FA reductions of premature birth but that other processes such as hypomyelination might also take place.

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 ​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., Competing Interests: Declaration of competing interest None., (Copyright © 2019. Published by Elsevier Inc.)

This study investigated if crying, sleeping or feeding problems that co-occur (multiple regulatory problems [RPs]) or are persistent predict attention problems and diagnoses of attention deficit hyperactivity disorder (ADHD) in childhood and adulthood. Participants were 342 individuals who were assessed at 5, 20, and 56 months for crying, sleeping, and feeding (RPs) and at 6, 8, and 28 years for ADHD diagnoses, attention problems, and attention span. Infants/toddlers with multiple/persistent RPs had an increased risk of receiving an ADHD diagnosis both in childhood and adulthood compared to those who never had RPs. Multiple/persistent RPs were further associated with a high-decreasing attention problems trajectory from childhood to adulthood. Interventions to alleviate early RPs may prevent the development of attention problems., (© 2018 Society for Research in Child Development.)

Imaging studies have characterized functional and structural brain abnormalities in adults after premature birth, but these investigations have mostly used univariate methods that do not account for hypothesized interdependencies between brain regions or quantify accuracy in identifying individuals. To overcome these limitations, we used multivariate machine learning to identify gray matter volume (GMV) and amplitude of low frequency fluctuations (ALFF) brain patterns that best classify young adults born very preterm/very low birth weight (VP/VLBW; n = 94) from those born full-term (FT; n = 92). We then compared the spatial maps of the structural and functional brain signatures and validated them by assessing associations with clinical birth history and basic cognitive variables. Premature birth could be predicted with a balanced accuracy of 80.7% using GMV and 77.4% using ALFF. GMV predictions were mediated by a pattern of subcortical and middle temporal reductions and volumetric increases of the lateral prefrontal, medial prefrontal, and superior temporal gyrus regions. ALFF predictions were characterized by a pattern including increases in the thalamus, pre- and post-central gyri, and parietal lobes, in addition to decreases in the superior temporal gyri bilaterally. Decision scores from each classification, assessing the degree to which an individual was classified as a VP/VLBW case, were predicted by the number of days in neonatal hospitalization and birth weight. ALFF decision scores also contributed to the prediction of general IQ, which highlighted their potential clinical significance. Combined, the results clarified previous research and suggested that primary subcortical and temporal damage may be accompanied by disrupted neurodevelopment of the cortex., (© 2019 Wiley Periodicals, Inc.)

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., (© 2019 Wiley Periodicals, Inc.)

Regulatory problems in infancy and toddlerhood have previously been associated with an increased risk of developing attention problems in childhood. We hypothesized that early regulatory problems are associated with attention problems via reduced inhibitory control. This prospective study assessed 1,459 children from birth to 8 years. Crying, feeding, and sleeping problems were assessed at 5 and 20 months via parent interviews and neurological examinations. At 20 months, inhibitory control was tested with a behavioral (snack delay) task. Attention regulation was assessed at 6 and 8 years using multiple instruments and informants. Detrimental effects of crying, feeding, and sleeping problems on attention regulation were partly mediated by children's ability to inhibit unwanted behaviors (β = -0.04, p = 0.013). Accounting for cognition diminished this indirect effect (β = -0.01, p = 0.209). Instead, the effects of crying, feeding, and sleeping problems on attention regulation were fully mediated by children's cognitive functioning (β = -0.10, p < 0.001). These results support that inhibitory control abilities partly mediate effects of crying, feeding, and sleeping problems. However, these effects may be accounted for by children's general cognitive abilities. Early regulatory problems may set infants on a course of under control of behavior into school age, and such trajectories are highly associated with general cognitive development., (© International Congress of Infant Studies (ICIS).)

Objective: To investigate the structural brain abnormalities and their diagnostic accuracy through qualitative and quantitative analysis in term born and very preterm birth or with very low birth weight (VP/VLBW) adults., Methods: We analyzed 3-T MRIs acquired in 2011-2013 from 67 adults (27 term born controls, mean age 26.4 years, 8 females; 40 VP/VLBWs, mean age 26.6 years, 16 females). We compared automatic segmentations of the white matter, deep gray matter and cortical gray matter, manual corpus callosum measurements and visual ratings of the ventricles and white matter with t tests, logistic regression, and receiver operator characteristic (ROC) curves., Results: Automatic segmentation correctly classified 84% of cases; visual ratings correctly classified 63%. Quantitative volumetry based on automatic segmentation revealed higher ventricular volume, lower posterior corpus callosum, and deep gray matter volumes in VP/VLBW subjects compared to controls (p < 0.01). Visual rating and manual measurement revealed a thinner corpus callosum in VP/VLBW adults (p = 0.04) and deformed lateral ventricles (p = 0.03) and tendency towards more "dirty" white matter (p = 0.06). Automatic/manual measures combined with visual ratings correctly classified 87% of cases. Stepwise logistic regression identified three independent features that correctly classify 81% of cases: ventricular volume, deep gray matter volume, and white matter aspect., Conclusion: Enlarged and deformed lateral ventricles, thinner corpus callosum, and "dirty" white matter are prevalent in preterm born adults. Their visual evaluation has low diagnostic accuracy. Automatic volume quantification is more accurate but time consuming. It may be useful to ask for prematurity before initiating further diagnostics in subjects with these alterations., Key Points: • Our study confirms prior reports showing that structural brain abnormalities related to preterm birth persist into adulthood. • In the clinical practice, if large and deformed lateral ventricles, small and thin corpus callosum, and "dirty" white matter are visible on MRI, ask for prematurity before considering other diagnoses. • Although prevalent, visual findings have low accuracy; adding automatic segmentation of lateral ventricles and deep gray matter nuclei improves the diagnostic accuracy.

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., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Infant regulatory problems (RPs), i.e., problems with crying, feeding, and/or sleeping, are associated with behavioral and emotional problems in childhood. It is unclear, however, whether these behavioral and emotional problems persist into adulthood. The default mode network (DMN) and salience network (SN) support both interoceptive regulation and social and emotional abilities. We thus hypothesized that adults who had experienced RPs in infancy have more behavioral and emotional problems, which are mediated by DMN and/or SN alterations., Methods: Within the scope of the Bavarian Longitudinal Study, adults (mean age 28 years; 50% female subjects) with (n = 79) and without (n = 254) a history of multiple and/or persistent infant RPs were assessed by the Young Adult Self Report to measure behavioral and emotional problems, and-in a subsample (n = 49 with and n = 71 without a history of infant RPs)-by resting-state functional magnetic resonance imaging to measure DMN/SN integrity via intrinsic functional connectivity (iFC)., Results: Compared with adults with no history of infant RPs, adults who had experienced infant RPs had more total problems (p = .002), more internalizing problems (p = .005), and more avoidant personality traits (p < .001). They showed decreased iFC of the DMN and SN. DMN iFC decreases were strongest in adults with multiple and persistent RPs, and they were linked with avoidant personality traits (r = -.42, p = .006). Remarkably, DMN iFC decrements fully mediated the association between infant RPs and adult avoidant personality traits., Conclusions: Adults who had experienced infant RPs have more avoidant personality traits that are mediated by the DMN. Persistent and/or multiple infant RPs and the DMN may be targets to attenuate behavioral and emotional problems., (Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

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 resting-state 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 rs-fMRI 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., (© 2018 Wiley Periodicals, Inc.)

Background and Aims: To determine the combined impact of infant multiple/persistent regulatory problems (RPs), parenting quality and maternal mental health on childhood attention problems., Study Design: A prospective, population-based cohort study including 16 paediatric hospitals in Southern Bavaria (Germany)., Subjects: 1459 infants were followed from birth to 8 years of age., Outcome Measures: RPs were assessed at 5 and 20 months using interviews by trained paediatricians; parenting quality was assessed between birth and 5 months using parent interviews and nurses' observations; maternal mental health was assessed at birth and 5 months using standardized parents' interviews; childhood data on attention problems were collected at 8 years, using parent reports and expert behaviour observation ratings., Results: After correction for gestational age, sex, and socioeconomic status, early RPs (β = 0.079) and low parenting quality (β = 0.175) predicted later attention problems (R 2  = 0.272). Their impact was additive, such that infants with both multiple/persistent RPs and poor parenting quality showed the highest attention problems 8 years later. However, the impact of RPs on attention was strongest for preterm children. Maternal mental health was a significant moderator of the relationship between parenting quality and attention problems. With adequate maternal mental health, good parenting quality was related to lower attention problems, yet with mental health problems present, the effect of good parenting on attention problems diminished., Conclusions: Guidance and support for parents of infants with multiple/persistent crying, sleeping or feeding problems may be essential to prevent the development of childhood attention problems, especially when maternal mental health problems are present., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Preterm birth is associated with an increased risk for lasting changes in both the cortico-thalamic system and attention; however, the link between cortico-thalamic and attention changes is as yet little understood. In preterm newborns, cortico-cortical and cortico-thalamic structural connectivity are distinctively altered, with increased local clustering for cortico-cortical and decreased integrity for cortico-thalamic connectivity. In preterm-born adults, among the various attention functions, visual short-term memory (vSTM) capacity is selectively impaired. We hypothesized distinct associations between vSTM capacity and the structural integrity of cortico-thalamic and cortico-cortical connections, respectively, in preterm-born adults. A whole-report paradigm of briefly presented letter arrays based on the computationally formalized Theory of Visual Attention (TVA) was used to quantify parameter vSTM capacity in 26 preterm- and 21 full-term-born adults. Fractional anisotropy (FA) of posterior thalamic radiations and the splenium of the corpus callosum obtained by diffusion tensor imaging were analyzed by tract-based spatial statistics and used as proxies for cortico-thalamic and cortico-cortical structural connectivity. The relationship between vSTM capacity and cortico-thalamic and cortico-cortical connectivity, respectively, was significantly modified by prematurity. In full-term-born adults, the higher FA in the right posterior thalamic radiation the higher vSTM capacity; in preterm-born adults this FA-vSTM-relationship was inversed. In the splenium, higher FA was correlated with higher vSTM capacity in preterm-born adults, whereas no significant relationship was evident in full-term-born adults. These results indicate distinct associations between cortico-thalamic and cortico-cortical integrity and vSTM capacity in preterm-and full-term-born adults. Data suggest compensatory cortico-cortical fiber re-organization for attention deficits after preterm delivery., (Copyright © 2017 Elsevier Inc. All rights reserved.)

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.

Preterm birth is a leading cause for impaired neurocognitive development with an increased risk for persistent cognitive deficits in adulthood. In newborns, preterm birth is associated with interrelated white matter (WM) alterations and deep gray matter (GM) loss; however, little is known about the persistence and relevance of these subcortical brain changes. We tested the hypothesis that the pattern of correspondent subcortical WM and GM changes is present in preterm-born adults and has a brain-injury-like nature, i.e., it predicts lowered general cognitive performance. Eighty-five preterm-born and 69 matched term-born adults were assessed by diffusion- and T1-weighted MRI and cognitive testing. Main outcome measures were fractional anisotropy of water diffusion for WM property, GM volume for GM property, and full-scale IQ for cognitive performance. In preterm-born adults, reduced fractional anisotropy was widely distributed ranging from cerebellum to brainstem to hemispheres. GM volume was reduced in the thalamus, striatum, temporal cortices, and increased in the cingulate cortices. Fractional anisotropy reductions were specifically associated with GM loss in thalamus and striatum, with correlation patterns for both regions extensively overlapping in the WM of brainstem and hemispheres. For overlap regions, fractional anisotropy was positively related with both gestational age and full-scale IQ. Results provide evidence for extensive, interrelated, and adverse WM and GM subcortical changes in preterm-born adults. Data suggest persistent brain-injury-like changes of subcortical-cortical connectivity after preterm delivery.

White matter (WM) injury, either visible on conventional magnetic resonance images (MRI) or measurable by diffusion tensor imaging (DTI), is frequent in preterm born individuals and often affects the corticospinal tract (CST). The relation between visible and invisible white mater alterations in the reconstructed CST of preterm subjects has so far been studied in infants, children and up to adolescence. Therefore, we probabilistically tracked the CST in 53 term-born and 56 very preterm and/or low birth weight (VP/VLBW, < 32 weeks of gestation and/or birth weight < 1,500 g) adults (mean age 26 years) and compared their DTI parameters (axial, radial, mean diffusivity--AD, RD, MD, fractional anisotropy--FA) in the whole CST and slice-wise along the CST. Additionally, we used the automatic, tract-based-spatial-statistics (TBSS) as an alternative to tractography. We compared control and VP/VLBW and subgroups with and without CST WM lesions visible on conventional MRI. Compared to controls, VP/VLBW subjects had significantly higher diffusivity (AD, RD, MD) in the whole CST, slice-wise along the CST, and in multiple regions along the TBSS skeleton. VP/VLBW subjects also had significantly lower (TBSS) and higher (tractography) FA in regions along the CST, but no different mean FA in the tracked CST as a whole. Diffusion changes were weaker, but remained significant for both, tractography and TBSS, when excluding subjects with visible CST lesions. Chronic CST injury persists in VP/VLBW adults even in the absence of visible WM lesions, indicating long-term structural WM changes induced by premature birth., (© 2015 Wiley Periodicals, Inc.)

Widespread brain changes are present in preterm born infants, adolescents, and even adults. While neurobiological models of prematurity facilitate powerful explanations for the adverse effects of preterm birth on the developing brain at microscale, convincing linking principles at large-scale level to explain the widespread nature of brain changes are still missing. We investigated effects of preterm birth on the brain's large-scale intrinsic networks and their relation to brain structure in preterm born adults. 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 functional connectivity in ongoing blood oxygenation level-dependent activity. Differences in intrinsic functional connectivity (iFC) were found in cortical and subcortical networks. Structural differences were located in subcortical, temporal, and cingulate areas. Critically, for preterm born adults, iFC-network differences were overlapping and correlating with aberrant regional gray-matter (GM) volume specifically in subcortical and temporal areas. Overlapping changes were predicted by prematurity and in particular by neonatal medical complications. These results provide evidence that preterm birth has long-lasting effects on functional connectivity of intrinsic networks, and these changes are specifically related to structural alterations in ventral brain GM., (© The Author 2014. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Very preterm birth is associated with an increased prevalence of attention problems and may especially impair executive attention, i.e., top-down control of attentional selection in situations where distracting information interferes with the processing of task-relevant stimuli. While there are initial findings linking structural brain alterations in preterm-born individuals with attention problems, the functional basis of these problems are not well understood. The present study used an fMRI adaptation of the Attentional Network Test to examine the neural correlates of executive attention in a large sample of N = 86 adults born very preterm and/or with very low birth weight (VP/VLBW), and N = 100 term-born controls. Executive attention was measured by comparing task behavior and brain activations associated with the processing of incongruent vs. congruent arrow flanker stimuli. Consistent with subtle impairments of executive attention, the VP/VLBW group showed lower accuracy and a tendency for increased response times during the processing of incongruent stimuli. Both groups showed similar activation patters, especially within expected fronto-cingulo-parietal areas, but no significant between-group differences. Our results argue for a maintained attention-relevant network organization in high-functioning preterm born adults in spite of subtle deficits in executive attention. Gestational age and neonatal treatment variables showed associations with task behavior, and brain activation in the dorsal ACC and lateral occipital areas, suggesting that the degree of prematurity (and related neonatal complications) has subtle modulatory influences on executive attention processing.

Premature birth is associated with an increased risk of cognitive performance deficits that are dependent on working memory (WM) load in childhood. Less clear is whether preterm-born adults show similar WM impairments, or develop compensatory brain mechanisms that help to overcome prematurity-related functional deficits, for example, by a workload-dependent over-recruitment of WM-typical areas, and/or engagement of alternative brain networks. In this functional magnetic resonance imaging study, 73 adults born very preterm and/or with very low birth weight (VP/VLBW) and 73 term-born controls (CON, mean age: 26.5 years) performed a verbal N-Back paradigm with varying workload (0-back, 1-back, 2-back). Generally, both groups showed similar performance accuracy and task-typical patterns of brain activations (especially in fronto-cingulo-parietal, thalamic, and cerebellar areas) and deactivations (especially in mesial frontal and parietal aspects of the default mode network [DMN]). However, VP/VLBW adults showed significantly stronger deactivations (P < 0.05, cluster-level corrected) than CON in posterior DMN regions, including right ventral precuneus, and right parahippocampal areas (with adjacent cerebellar areas), which were specific for the most demanding 2-back condition. Consistent with a workload-dependent effect, VP/VLBW adults with stronger deactivations (1-back > 2-back) in the parahippocampal/cerebellar cluster also presented a greater slowing of response latencies with increasing WM load (2-back > 1-back), indicative of higher effort. In conclusion, VP/VLBW adults recruited similar anatomical networks as controls during N-back performance, but showed an enhanced suppression of posterior DMN regions during higher workload, which may reflect a temporary suppression of stimulus-independent thoughts that helps to maintain adequate task performance with increasing attentional demands., (© 2014 Wiley Periodicals, Inc.)

Although pronounced and lasting deficits in selective attention have been observed for preterm born individuals it is unknown which specific attentional sub-mechanisms are affected and how they relate to brain networks. We used the computationally specified 'Theory of Visual Attention' together with whole- and partial-report paradigms to compare attentional sub-mechanisms of pre- (n=33) and full-term (n=32) born adults. Resting-state fMRI was used to evaluate both between-group differences and inter-individual variance in changed functional connectivity of intrinsic brain networks relevant for visual attention. In preterm born adults, we found specific impairments of visual short-term memory (vSTM) storage capacity while other sub-mechanisms such as processing speed or attentional weighting were unchanged. Furthermore, changed functional connectivity was found in unimodal visual and supramodal attention-related intrinsic networks. Among preterm born adults, the individual pattern of changed connectivity in occipital and parietal cortices was systematically associated with vSTM in such a way that the more distinct the connectivity differences, the better the preterm adults' storage capacity. These findings provide first evidence for selectively changed attentional sub-mechanisms in preterm born adults and their relation to altered intrinsic brain networks. In particular, data suggest that cortical changes in intrinsic functional connectivity may compensate adverse developmental consequences of prematurity on visual short-term storage capacity., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Schizophrenia is characterized by aberrant intrinsic functional connectivity (iFC) within and between intrinsic connectivity networks (ICNs), including the Default Mode- (DMN), Salience- (SN), and Central Executive Network (CEN). The anterior insula (AI) of the SN has been demonstrated to modulate DMN/CEN interactions. Recently, we found that the dependence of DMN/CEN interactions on SN's right AI activity is altered in patients with schizophrenia in acute psychosis and related to psychotic symptoms, indicating a link between aberrant AI, DMN, CEN, and psychosis. However, since structural alterations of the insula are also present during psychotic remission and associated with negative symptoms, impaired AI interaction might be relevant even for psychotic remission and corresponding symptoms. Twelve patients with schizophrenia during psychotic remission (SR) and 12 healthy controls were assessed using resting-state fMRI and psychometric examination. High-model-order independent component analysis of fMRI data revealed ICNs including DMN, SN, and CEN. Scores of iFC within (intra-iFC) and between (inter-iFC) distinct subsystems of the DMN, SN, and CEN were calculated, compared between groups and correlated with the severity of symptoms. Intra-iFC was altered in patients' SN, DMN, and CEN, including decreased intra-iFC in the left AI within the SN. Patients' inter-iFC between SN and CEN was increased and correlated with the severity of negative symptoms. Furthermore, decreased intra-iFC of the left AI correlated with both severity of negative symptoms and increased inter-iFC between SN and CEN. Our result provides first evidence for a relationship between AI dysfunction and altered between-network interactions in schizophrenia during psychotic remission, which is related to the severity of negative symptoms. Together with our previous results, data suggest specific SN/DMN/CEN reorganization in schizophrenia with distinct insular pathways for distinct symptom dimensions.