Stronger influence of systemic than local hemodynamic-vascular factors on resting-state BOLD functional connectivity.

Correlated fluctuations in the blood oxygenation level dependent (BOLD) signal of resting-state functional MRI (i.e., BOLD-functional connectivity, BOLD-FC) reflect a spectrum of neuronal and non-neuronal processes. In particular, there are multiple hemodynamic-vascular influences on BOLD-FC on both systemic (e.g., perfusion delay) and local levels (e.g., neurovascular coupling). While the influence of individual factors has been studied extensively, combined and comparative studies of systemic and local hemodynamic-vascular factors on BOLD-FC are scarce, notably in humans. We employed a multi-modal MRI approach to investigate and compare distinct hemodynamic-vascular processes and their impact on homotopic BOLD-FC in healthy controls and patients with unilateral asymptomatic internal carotid artery stenosis (ICAS). Asymptomatic ICAS is a cerebrovascular disorder, in which neuronal functioning is largely preserved but hemodynamic-vascular processes are impaired, mostly on the side of stenosis. Investigated indicators for local hemodynamic-vascular processes comprise capillary transit time heterogeneity (CTH) and cerebral blood volume (CBV) from dynamic susceptibility contrast (DSC) MRI, and cerebral blood flow (CBF) from pseudo-continuous arterial spin labeling (pCASL). Indicators for systemic processes are time-to-peak (TTP) from DSC MRI and BOLD lags from functional MRI. For each of these parameters, their influence on BOLD-FC was estimated by a comprehensive linear mixed model. Equally across groups, we found that individual mean BOLD-FC, local (CTH, CBV, and CBF) and systemic (TTP and BOLD lag) hemodynamic-vascular factors together explain 40.7% of BOLD-FC variance, with 20% of BOLD-FC variance explained by hemodynamic-vascular factors, with an about two-times larger contribution of systemic versus local factors. We conclude that regional differences in blood supply, i.e., systemic perfusion delays, exert a stronger influence on BOLD-FC than impairments in local neurovascular coupling.

Resting-state BOLD functional connectivity depends on the heterogeneity of capillary transit times in the human brain A combined lesion and simulation study about the influence of blood flow response timing.

Functional connectivity (FC) derived from blood oxygenation level dependent (BOLD) functional magnetic resonance imaging at rest (rs-fMRI), is commonly interpreted as indicator of neuronal connectivity. In a number of brain disorders, however, metabolic, vascular, and hemodynamic impairments can be expected to alter BOLD-FC independently from neuronal activity. By means of a neurovascular coupling (NVC) model of BOLD-FC, we recently demonstrated that aberrant timing of cerebral blood flow (CBF) responses may influence BOLD-FC. In the current work, we support and extend this finding by empirically linking BOLD-FC with capillary transit time heterogeneity (CTH), which we consider as an indicator of delayed and broadened CBF responses. We assessed 28 asymptomatic patients with unilateral high-grade internal carotid artery stenosis (ICAS) as a hemodynamic lesion model with largely preserved neurocognitive functioning and 27 age-matched healthy controls. For each participant, we obtained rs-fMRI, arterial spin labeling, and dynamic susceptibility contrast MRI to study the dependence of left-right homotopic BOLD-FC on local perfusion parameters. Additionally, we investigated the dependency of BOLD-FC on CBF response timing by detailed simulations. Homotopic BOLD-FC was negatively associated with increasing CTH differences between homotopic brain areas. This relation was more pronounced in asymptomatic ICAS patients even after controlling for baseline CBF and relative cerebral blood volume influences. These findings match simulation results that predict an influence of delayed and broadened CBF responses on BOLD-FC. Results demonstrate that increasing CTH differences between homotopic brain areas lead to BOLD-FC reductions. Simulations suggest that CTH increases correspond to broadened and delayed CBF responses to fluctuations in ongoing neuronal activity.

Visual processing speed is linked to functional connectivity between right frontoparietal and visual networks.

Visual information processing requires an efficient visual attention system. The neural theory of visual attention (TVA) proposes that visual processing speed depends on the coordinated activity between frontoparietal and occipital brain areas. Previous research has shown that the coordinated activity between (i.e., functional connectivity and "inter-FC") cingulo-opercular (COn) and right-frontoparietal (RFPn) networks is linked to visual processing speed. However, how inter-FC of COn and RFPn with visual networks links to visual processing speed has not been directly addressed yet. Forty-eight healthy adult participants (27 females) underwent resting-state (rs-)fMRI and performed a whole-report psychophysical task. To obtain inter-FC, we analyzed the entire frequency range available in our rs-fMRI data (i.e., 0.01-0.4 Hz) to avoid discarding neural information. Following previous approaches, we analyzed the data across frequency bins (Hz): Slow-5 (0.01-0.027), Slow-4 (0.027-0.073), Slow-3 (0.073-0.198), and Slow-2 (0.198-0.4). We used the mathematical TVA framework to estimate an individual, latent-level visual processing speed parameter. We found that visual processing speed was negatively associated with inter-FC between RFPn and visual networks in Slow-5 and Slow-2, with no corresponding significant association for inter-FC between COn and visual networks. These results provide the first empirical evidence that links inter-FC between RFPn and visual networks with the visual processing speed parameter. These findings suggest that direct connectivity between occipital and right frontoparietal, but not frontoinsular, regions support visual processing speed.

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.

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.

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.