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 ​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

Sequelae of premature birth in young adults

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

Inter-ictal assay of peripheral circulating inflammatory mediators in migraine patients under adjunctive cervical non-invasive vagus nerve stimulation (nVNS) : A proof-of-concept study

Objective: To assay peripheral inter-ictal cytokine serum levels and possible relations with non-invasive vagus nerve stimulation (nVNS) responsiveness in migraineurs. Methods: This double-blinded, sham-controlled study enrolled 48 subjects and measured headache severity, frequency [headache days/month, number of total and mild/moderate/severe classified attacks/month], functional state [sleep, mood, body weight, migraine-associated disability] and serum levels of inflammatory markers [inter-ictal] using enzyme-linked immunoassays at baseline and after 2 months of adjunctive nVNS compared to sham stimulation and suitably matched controls. Results: No significant differences were observed at baseline and after 2 months for headache severity, total attacks/month, headache days/month and functional outcome [sleep, mood, disability] between verum and sham nVNS. However, the number of severe attacks/month significantly decreased in the verum nVNS group and circulating pro-inflammatory IL-1 beta was elevated significantly in the sham group compared to nVNS. Levels of anti-inflammatory IL-10 were significantly higher at baseline in both groups compared to healthy controls, but not at 2 months follow-up [p 0.05]. No severe device-/stimulation-related adverse events occurred. Conclusion: 2 months of adjunctive cervical nVNS significantly declined the number of severe attacks/month. Pro-inflammatory IL-1 beta plasma levels [inter-ictal] were higher in sham-treated migraine patients compared to verum nVNS. However, pro- [IL-6, HMGB-1, TNF-alpha, leptin] and anti-inflammatory [IL-10, adiponectin, ghrelin] mediators did not differ statistically. Profiling of neuroinflammatory circuits in migraine to predict nVNS responsiveness remains an experimental approach, which may be biased by pre-analytic variables warranting large-scale biobank-based systematic investigations [omics]. (C) 2019 Elsevier Inc. All rights reserved.Peer reviewe

Neural correlates of executive attention in adults born very preterm

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

Reduced cholinergic basal forebrain integrity links neonatal complications and adult cognitive deficits after premature birth

Background Premature-born individuals have an increased risk for long-term neurocognitive impairments. In animal models, the development of the cholinergic basal forebrain (cBF) is selectively vulnerable to adverse effects of perinatal stressors, and impaired cBF integrity results in lasting cognitive deficits. We hypothesized that in premature-born individuals cBF integrity is impaired and mediates adult cognitive impairments associated with prematurity. Methods We used MRI-based volumetric assessments of a cytoarchitectonically defined cBF region-of-interest to determine differences in cBF integrity between 99 adults who were born very preterm and/or with very low birth weight (VP/VLBW) and 106 term born controls from the same birth cohort. MRI-derived cBF volumes were studied in relation to neonatal clinical complications after delivery as well as intelligence measures (IQ) in adulthood. Results In VP/VLBW adults, cBF volumes were significantly reduced compared to term-born adults (-4.5%, F(1, 202) = 11.82, p = 0.001). Lower cBF volume in VP/VLBW adults was specifically associated with both neonatal complications (rpart(92) = -0.35, p < 0.001) and adult IQ (rpart(88) = 0.33, p = 0.001) even after controlling for global gray matter and white matter volume. In an additional path analytic model, cBF volume significantly mediated the association between neonatal complications and adult cognitive deficits. Conclusions Results provide first time evidence in humans that cBF integrity is impaired after premature birth and links neonatal complications with long-term cognitive outcome. Data suggest that cholinergic system abnormalities may play a relevant role for long-term neurocognitive impairments associated with premature delivery

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

White matter alterations of the corticospinal tract in adults born very preterm and/or with very low birth weight

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

Automated quantitative evaluation of brain MRI may be more accurate for discriminating preterm born adults

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

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