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

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

Distinct Volume Alterations of Thalamic Nuclei Across the Schizophrenia Spectrum.

BACKGROUND AND HYPOTHESIS: Abnormal thalamic nuclei volumes and their link to cognitive impairments have been observed in schizophrenia. However, whether and how this finding extends to the schizophrenia spectrum is unknown. We hypothesized a distinct pattern of aberrant thalamic nuclei volume across the spectrum and examined its potential associations with cognitive symptoms. STUDY DESIGN: We performed a FreeSurfer-based volumetry of T1-weighted brain MRIs from 137 healthy controls, 66 at-risk mental state (ARMS) subjects, 89 first-episode psychosis (FEP) individuals, and 126 patients with schizophrenia to estimate thalamic nuclei volumes of six nuclei groups (anterior, lateral, ventral, intralaminar, medial, and pulvinar). We used linear regression models, controlling for sex, age, and estimated total intracranial volume, both to compare thalamic nuclei volumes across groups and to investigate their associations with positive, negative, and cognitive symptoms. STUDY RESULTS: We observed significant volume alterations in medial and lateral thalamic nuclei. Medial nuclei displayed consistently reduced volumes across the spectrum compared to controls, while lower lateral nuclei volumes were only observed in schizophrenia. Whereas positive and negative symptoms were not associated with reduced nuclei volumes across all groups, higher cognitive scores were linked to lower volumes of medial nuclei in ARMS. In FEP, cognition was not linked to nuclei volumes. In schizophrenia, lower cognitive performance was associated with lower medial volumes. CONCLUSIONS: Results demonstrate distinct thalamic nuclei volume reductions across the schizophrenia spectrum, with lower medial nuclei volumes linked to cognitive deficits in ARMS and schizophrenia. Data suggest a distinctive trajectory of thalamic nuclei abnormalities along the course of schizophrenia.

Altered gray-to-white matter tissue contrast in preterm-born adults.

AIMS: To investigate cortical organization in brain magnetic resonance imaging (MRI) of preterm-born adults using percent contrast of gray-to-white matter signal intensities (GWPC), which is an in vivo proxy measure for cortical microstructure. METHODS: Using structural MRI, we analyzed GWPC at different percentile fractions across the cortex (0%, 10%, 20%, 30%, 40%, 50%, and 60%) in a large and prospectively collected cohort of 86 very preterm-born (<32 weeks of gestation and/or birth weight <1500 g, VP/VLBW) adults and 103 full-term controls at 26 years of age. Cognitive performance was assessed by full-scale intelligence quotient (IQ) using the Wechsler Adult Intelligence Scale. RESULTS: GWPC was significantly decreased in VP/VLBW adults in frontal, parietal, and temporal associative cortices, predominantly in the right hemisphere. Differences were pronounced at 20%, 30%, and 40%, hence, in middle cortical layers. GWPC was significantly increased in right paracentral lobule in VP/VLBW adults. GWPC in frontal and temporal cortices was positively correlated with birth weight, and negatively with duration of ventilation (p < 0.05). Furthermore, GWPC in right paracentral lobule was negatively correlated with IQ (p < 0.05). CONCLUSIONS: Widespread aberrant gray-to-white matter contrast suggests lastingly altered cortical microstructure after preterm birth, mainly in middle cortical layers, with differential effects on associative and primary cortices.

Aberrant allometric scaling of cortical folding in preterm-born adults.

A universal allometric scaling law has been proposed to describe cortical folding of the mammalian brain as a function of the product of cortical surface area and the square root of cortical thickness across different mammalian species, including humans. Since these cortical properties are vulnerable to developmental disturbances caused by preterm birth in humans and since these alterations are related to cognitive impairments, we tested (i) whether cortical folding in preterm-born adults follows this cortical scaling law and (ii) the functional relevance of potential scaling aberrances. We analysed the cortical scaling relationship in a large and prospectively collected cohort of 91 very premature-born adults (<32 weeks of gestation and/or birthweight <1500 g, very preterm and/or very low birth weight) and 105 full-term controls at 26 years of age based on the total surface area, exposed surface area and average cortical thickness measured with structural magnetic resonance imaging and surface-based morphometry. We found that the slope of the log-transformed cortical scaling relationship was significantly altered in adults (very preterm and/or very low birth weight: 1.24, full-term: 1.14, P = 0.018). More specifically, the slope was significantly altered in male adults (very preterm and/or very low birth weight: 1.24, full-term: 1.00, P = 0.031), while there was no significant difference in the slope of female adults (very preterm and/or very low birth weight: 1.27, full-term: 1.12, P = 0.225). Furthermore, offset was significantly lower compared with full-term controls in both male (very preterm and/or very low birth weight: -0.546, full-term: -0.538, P = 0.001) and female adults (very preterm and/or very low birth weight: -0.545, full-term: -0.538, P = 0.023), indicating a systematic shift of the regression line after preterm birth. Gestational age had a significant effect on the slope in very preterm and/or very low birth weight adults and more specifically in male very preterm and/or very low birth weight adults, indicating that the difference in slope is specifically related to preterm birth. The shape or tension term of the scaling law had no significant effect on cognitive performance, while the size of the cortex did. Results demonstrate altered scaling of cortical surface and cortical thickness in very premature-born adults. Data suggest altered mechanical forces acting on the cortex after preterm birth.

Altered Gray Matter Cortical and Subcortical T1-Weighted/T2-Weighted Ratio in Premature-Born Adults.

BACKGROUND: Microscopic studies in newborns and animal models indicate impaired myelination after premature birth, particularly for cortical myelination; however, it remains unclear whether such myelination impairments last into adulthood and, if so, are relevant for impaired cognitive performance. It has been suggested that the ratio of T1-weighted (T1w) and T2-weighted (T2w) magnetic resonance imaging signal intensity (T1w/T2w ratio) is a proxy for myelin content. We hypothesized altered gray matter (GM) T1w/T2w ratio in premature-born adults, which is associated with lower cognitive performance after premature birth. METHODS: We analyzed GM T1w/T2w ratio in 101 adults born very premature (VP) and/or at very low birth weight (VLBW) (<32 weeks of gestation and/or birth weight <1500 g) and 109 full-term control subjects at 26 years of age, controlled for voxelwise volume alterations. Cognitive performance was assessed by verbal, performance, and full scale IQ using the Wechsler Adult Intelligence Scale. RESULTS: Significantly higher T1w/T2w ratio in VP/VLBW subjects was found bilaterally in widespread cortical areas, particularly in frontal, parietal, and temporal cortices, and in putamen and pallidum. In these areas, T1w/T2w ratio was not related to birth variables, such as gestational age, or IQ scores. In contrast, significantly lower T1w/T2w ratio in VP/VLBW subjects was found in bilateral clusters in superior temporal gyrus, which was associated with birth weight in the VP/VLBW group. Furthermore, lower T1w/T2w ratio in left superior temporal gyrus was associated with lower full scale and verbal IQ. CONCLUSIONS: Results demonstrate GM T1w/T2w ratio alterations in premature-born adults and suggest altered GM myelination development after premature birth with lasting and functionally relevant effects into early adulthood.

Aberrant claustrum structure in preterm-born neonates: an MRI study.

The human claustrum is a gray matter structure in the white matter between insula and striatum. Previous analysis found altered claustrum microstructure in very preterm-born adults associated with lower cognitive performance. As the claustrum development is related to hypoxia-ischemia sensitive transient cell populations being at-risk in premature birth, we hypothesized that claustrum structure is already altered in preterm-born neonates. We studied anatomical and diffusion-weighted MRIs of 83 preterm- and 83 term-born neonates at term-equivalent age. Additionally, claustrum development was analyzed both in a spectrum of 377 term-born neonates and longitudinally in 53 preterm-born subjects. Data was provided by the developing Human Connectome Project. Claustrum development showed increasing volume, increasing fractional anisotropy (FA), and decreasing mean diffusivity (MD) around term both across term- and preterm-born neonates. Relative to term-born ones, preterm-born neonates had (i) increased absolute and relative claustrum volumes, both indicating increased cellular and/or extracellular matter and being in contrast to other subcortical gray matter regions of decreased volumes such as thalamus; (ii) lower claustrum FA and higher claustrum MD, pointing at increased extracellular matrix and impaired axonal integrity; and (iii) aberrant covariance between claustrum FA and MD, respectively, and that of distributed gray matter regions, hinting at relatively altered claustrum microstructure. Results together demonstrate specifically aberrant claustrum structure in preterm-born neonates, suggesting altered claustrum development in prematurity, potentially relevant for later cognitive performance.

Barcoded DNA origami structures for multiplexed optimization and enrichment of DNA-based protein-binding cavities.

Simultaneous binding of molecules by multiple binding partners is known to strongly reduce the apparent dissociation constant of the corresponding molecular complexes, and can be used to achieve strong, non-covalent molecular interactions. Based on this principle, efficient binding of proteins to DNA nanostructures has been achieved previously by placing several aptamers in close proximity to each other onto DNA scaffolds. Here, we develop an approach for exploring design parameters, such as the geometric arrangement or the nanomechanical properties of the binding sites, that use two-dimensional DNA origami-based nanocavities that bear aptamers with known mechanical properties at defined distances and orientations. The origami structures are labelled with barcodes, which enables large numbers of binding cavities to be investigated in parallel and under identical conditions, and facilitates a direct and reliable quantitative comparison of their binding yields. We demonstrate that binding geometry and mechanical properties have a dramatic effect on origami-based multivalent binding sites, and that optimization of linker spacings and flexibilities can improve the effective binding strength of the sites substantially.