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

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

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.

Targeted rhythmic visual stimulation at individual participants' intrinsic alpha frequency causes selective increase of occipitoparietal BOLD-fMRI and EEG functional connectivity.

Neural oscillations in distinct frequency bands are ubiquitous in the brain and play a role in many cognitive processes. The "communication by coherence" hypothesis, poses that the synchronization through phase coupling of frequency-specific neural oscillations regulate information flow across distribute brain regions. Specifically, the posterior alpha frequency band (7-12 Hz) is thought to gate bottom-up visual information flow by inhibition during visual processing. Evidence shows that increased alpha phase coherency positively correlates with functional connectivity in resting state connectivity networks, supporting alpha mediates neural communication through coherency. However, these findings have mainly been derived from spontaneous changes in the ongoing alpha rhythm. In this study, we experimentally modulate the alpha rhythm by targeting individuals' intrinsic alpha frequency with sustained rhythmic light to investigate alpha-mediated synchronous cortical activity in both EEG and fMRI. We hypothesize increased alpha coherency and fMRI connectivity should arise from modulation of the intrinsic alpha frequency (IAF) as opposed to control frequencies in the alpha range. Sustained rhythmic and arrhythmic stimulation at the IAF and at neighboring frequencies within the alpha band range (7-12 Hz) was implemented and assessed in a separate EEG and fMRI study. We observed increased cortical alpha phase coherency in the visual cortex during rhythmic stimulation at the IAF as in comparison to rhythmic stimulation of control frequencies. In the fMRI, we found increased functional connectivity for stimulation at the IAF in visual and parietal areas as compared to other rhythmic control frequencies by correlating time courses from a set of regions of interest for the different stimulation conditions and applying network-based statistics. This suggests that rhythmic stimulation at the IAF frequency induces a higher degree of synchronicity of neural activity across the occipital and parietal cortex, which supports the role of the alpha oscillation in gating information flow during visual processing.

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.

Magnetic resonance imaging of the dopamine system in schizophrenia - A scoping review.

For decades, aberrant dopamine transmission has been proposed to play a central role in schizophrenia pathophysiology. These theories are supported by human in vivo molecular imaging studies of dopamine transmission, particularly positron emission tomography. However, there are several downsides to such approaches, for example limited spatial resolution or restriction of the measurement to synaptic processes of dopaminergic neurons. To overcome these limitations and to measure complementary aspects of dopamine transmission, magnetic resonance imaging (MRI)-based approaches investigating the macrostructure, metabolism, and connectivity of dopaminergic nuclei, i.e., substantia nigra pars compacta and ventral tegmental area, can be employed. In this scoping review, we focus on four dopamine MRI methods that have been employed in patients with schizophrenia so far: neuromelanin MRI, which is thought to measure long-term dopamine function in dopaminergic nuclei; morphometric MRI, which is assumed to measure the volume of dopaminergic nuclei; diffusion MRI, which is assumed to measure fiber-based structural connectivity of dopaminergic nuclei; and resting-state blood-oxygenation-level-dependent functional MRI, which is thought to measure functional connectivity of dopaminergic nuclei based on correlated blood oxygenation fluctuations. For each method, we describe the underlying signal, outcome measures, and downsides. We present the current state of research in schizophrenia and compare it to other disorders with either similar (psychotic) symptoms, i.e., bipolar disorder and major depressive disorder, or dopaminergic abnormalities, i.e., substance use disorder and Parkinson's disease. Finally, we discuss overarching issues and outline future research questions.

Within amygdala: Basolateral parts are selectively impaired in premature-born adults.

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.

Aberrant cortico-thalamic structural connectivity in premature-born adults.

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.

Increased Brain Age Gap Estimate (BrainAGE) in Young Adults After Premature Birth.

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.

Decreased amygdala volume in adults after premature birth.

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.

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.

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.