The relationship between negative life events and cortical structural connectivity in adolescents.

Adolescence is a crucial period for physical and psychological development. The impact of negative life events represents a risk factor for the onset of neuropsychiatric disorders. This study aims to investigate the relationship between negative life events and structural brain connectivity, considering both graph theory and connectivity strength. A group (n = 487) of adolescents from the IMAGEN Consortium was divided into Low and High Stress groups. Brain networks were extracted at an individual level, based on morphological similarity between grey matter regions with regions defined using an atlas-based region of interest (ROI) approach. Between-group comparisons were performed with global and local graph theory measures in a range of sparsity levels. The analysis was also performed in a larger sample of adolescents (n = 976) to examine linear correlations between stress level and network measures. Connectivity strength differences were investigated with network-based statistics. Negative life events were not found to be a factor influencing global network measures at any sparsity level. At local network level, between-group differences were found in centrality measures of the left somato-motor network (a decrease of betweenness centrality was seen at sparsity 5%), of the bilateral central visual and the left dorsal attention network (increase of degree at sparsity 10% at sparsity 30% respectively). Network-based statistics analysis showed an increase in connectivity strength in the High stress group in edges connecting the dorsal attention, limbic and salience networks. This study suggests negative life events alone do not alter structural connectivity globally, but they are associated to connectivity properties in areas involved in emotion and attention.

Life After Mild Traumatic Brain Injury: Widespread Structural Brain Changes Associated With Psychological Distress Revealed With Multimodal Magnetic Resonance Imaging.

Background: Traumatic brain injury (TBI) can alter brain structure and lead to onset of persistent neuropsychological symptoms. This study investigates the relationship between brain injury and psychological distress after mild TBI using multimodal magnetic resonance imaging. Methods: A total of 89 patients with mild TBI from the TRACK-TBI (Transforming Research and Clinical Knowledge in Traumatic Brain Injury) pilot study were included. Subscales of the Brief Symptoms Inventory 18 for depression, anxiety, and somatization were used as outcome measures of psychological distress approximately 6 months after the traumatic event. Glasgow Coma Scale scores were used to evaluate recovery. Magnetic resonance imaging data were acquired within 2 weeks after injury. Perivascular spaces (PVSs) were segmented using an enhanced PVS segmentation method, and the volume fraction was calculated for the whole brain and white matter regions. Cortical thickness and gray matter structures volumes were calculated in FreeSurfer; diffusion imaging indices and multifiber tracts were extracted using the Quantitative Imaging Toolkit. The analysis was performed considering age, sex, intracranial volume, educational attainment, and improvement level upon discharge as covariates. Results: PVS fractions in the posterior cingulate, fusiform, and postcentral areas were found to be associated with somatization symptoms. Depression, anxiety, and somatization symptoms were associated with the cortical thickness of the frontal-opercularis and occipital pole, putamen and amygdala volumes, and corticospinal tract and superior thalamic radiation. Analyses were also performed on the two hemispheres separately to explore lateralization. Conclusions: This study shows how PVS, cortical, and microstructural changes can predict the onset of depression, anxiety, and somatization symptoms in patients with mild TBI.

Perivascular spaces in Alzheimer's disease are associated with inflammatory, stress-related, and hypertension biomarkers.

Perivascular spaces (PVS) are fluid-filled spaces surrounding the brain vasculature. Literature suggests that PVS may play a significant role in aging and neurological disorders, including Alzheimer's disease (AD). Cortisol, a stress hormone, has been implicated in the development and progression of AD. Hypertension, a common condition in older adults, has been found to be a risk factor for AD. Hypertension may contribute to PVS enlargement, impairing the clearance of waste products from the brain and promoting neuroinflammation. This study aims to understand the potential interactions between PVS, cortisol, hypertension, and inflammation in the context of cognitive impairment. Using MRI scans acquired at 1.5T, PVS were quantified in a cohort of 465 individuals with cognitive impairment. PVS was calculated in the basal ganglia and centrum semiovale using an automated segmentation approach. Levels of cortisol and angiotensin-converting enzyme (ACE) (an indicator of hypertension) were measured from plasma. Inflammatory biomarkers, such as cytokines and matrix metalloproteinases, were analyzed using advanced laboratory techniques. Main effect and interaction analyses were performed to examine the associations between PVS severity, cortisol levels, hypertension, and inflammatory biomarkers. In the centrum semiovale, higher levels of inflammation reduced cortisol associations with PVS volume fraction. For ACE, an inverse association with PVS was seen only when interacting with TNFr2 (a transmembrane receptor of TNF). There was also a significant inverse main effect of TNFr2. In the PVS basal ganglia, a significant positive association was found with TRAIL (a TNF receptor inducing apoptosis). These findings show for the first time the intricate relationships between PVS structure and the levels of stress-related, hypertension, and inflammatory biomarkers. This research could potentially guide future studies regarding the underlying mechanisms of AD pathogenesis and the potential development of novel therapeutic strategies targeting these inflammation factors.

Imaging perivascular space structure and function using brain MRI.

In this article, we provide an overview of current neuroimaging methods for studying perivascular spaces (PVS) in humans using brain MRI. In recent years, an increasing number of studies highlighted the role of PVS in cerebrospinal/interstial fluid circulation and clearance of cerebral waste products and their association with neurological diseases. Novel strategies and techniques have been introduced to improve the quantification of PVS and to investigate their function and morphological features in physiological and pathological conditions. After a brief introduction on the anatomy and physiology of PVS, we examine the latest technological developments to quantitatively analyze the structure and function of PVS in humans with MRI. We describe the applications, advantages, and limitations of these methods, providing guidance and suggestions on the acquisition protocols and analysis techniques that can be applied to study PVS in vivo. Finally, we review the human neuroimaging studies on PVS across the normative lifespan and in the context of neurological disorders.

Age differences in diffusivity in the locus coeruleus and its ascending noradrenergic tract.

The noradrenergic locus coeruleus (LC) is a small brainstem nucleus that promotes arousal and attention. Recent studies have examined the microstructural properties of the LC using diffusion-weighted magnetic resonance imaging and found unexpected age-related differences in fractional anisotropy - a measure of white matter integrity. Here, we used two datasets (Berlin Aging Study-II, N = 301, the Leipzig Study for Mind-Body-Emotion Interactions, N = 220), to replicate published findings and expand them by investigating diffusivity in the LC's ascending noradrenergic bundle. In younger adults, LC fractional anisotropy was significantly lower, compared to older adults. However, in the LC's ascending noradrenergic bundle, we observed significantly higher fractional anisotropy in younger adults, relative to older adults. These findings indicate that diffusivity in the LC versus the ascending noradrenergic bundle are both susceptible to structural changes in aging that have opposing effects on fractional anisotropy.

Examining the Role of the Noradrenergic Locus Coeruleus for Predicting Attention and Brain Maintenance in Healthy Old Age and Disease: An MRI Structural Study for the Alzheimer's Disease Neuroimaging Initiative.

The noradrenergic theory of Cognitive Reserve (Robertson, 2013-2014) postulates that the upregulation of the locus coeruleus-noradrenergic system (LC-NA) originating in the brainstem might facilitate cortical networks involved in attention, and protracted activation of this system throughout the lifespan may enhance cognitive stimulation contributing to reserve. To test the above-mentioned theory, a study was conducted on a sample of 686 participants (395 controls, 156 mild cognitive impairment, 135 Alzheimer's disease) investigating the relationship between LC volume, attentional performance and a biological index of brain maintenance (BrainPAD-an objective measure, which compares an individual's structural brain health, reflected by their voxel-wise grey matter density, to the state typically expected at that individual's age). Further analyses were carried out on reserve indices including education and occupational attainment. Volumetric variation across groups was also explored along with gender differences. Control analyses on the serotoninergic (5-HT), dopaminergic (DA) and cholinergic (Ach) systems were contrasted with the noradrenergic (NA) hypothesis. The antithetic relationships were also tested across the neuromodulatory subcortical systems. Results supported by Bayesian modelling showed that LC volume disproportionately predicted higher attentional performance as well as biological brain maintenance across the three groups. These findings lend support to the role of the noradrenergic system as a key mediator underpinning the neuropsychology of reserve, and they suggest that early prevention strategies focused on the noradrenergic system (e.g., cognitive-attentive training, physical exercise, pharmacological and dietary interventions) may yield important clinical benefits to mitigate cognitive impairment with age and disease.

No relationship between fornix and cingulum degradation and within-network decreases in functional connectivity in prodromal Alzheimer's disease.

INTRODUCTION: The earliest changes in the brain due to Alzheimer's disease are associated with the neural networks related to memory function. We investigated changes in functional and structural connectivity among regions that support memory function in prodromal Alzheimer's disease, i.e., during the mild cognitive impairment (MCI) stage. METHODS: Twenty-three older healthy controls and 25 adults with MCI underwent multimodal MRI scanning. Limbic white matter tracts-the fornix, parahippocampal cingulum, retrosplenial cingulum, subgenual cingulum and uncinate fasciculus-were reconstructed in ExploreDTI using constrained spherical deconvolution-based tractography. Using a network-of-interest approach, resting-state functional connectivity time-series correlations among sub-parcellations of the default mode and limbic networks, the hippocampus and the thalamus were calculated in Conn. ANALYSIS: Controlling for age, education, and gender between group linear regressions of five diffusion-weighted measures and of resting state connectivity measures were performed per hemisphere. FDR-corrections were performed within each class of measures. Correlations of within-network Fisher Z-transformed correlation coefficients and the mean diffusivity per tract were performed. Whole-brain graph theory measures of cluster coefficient and average path length were inspecting using the resting state data. RESULTS & CONCLUSION: MCI-related changes in white matter structure were found in the fornix, left parahippocampal cingulum, left retrosplenial cingulum and left subgenual cingulum. Functional connectivity decreases were observed in the MCI group within the DMN-a sub-network, between the hippocampus and sub-areas -a and -c of the DMN, between DMN-c and DMN-a, and, in the right hemisphere only between DMN-c and both the thalamus and limbic-a. No relationships between white matter tract 'integrity' (mean diffusivity) and within sub-network functional connectivity were found. Graph theory revealed that changes in the MCI group was mostly restricted to diminished between-neighbour connections of the hippocampi and of nodes within DMN-a and DMN-b.

Aging-Related Microstructural Alterations Along the Length of the Cingulum Bundle.

The aim of this study was to investigate the aging-related structural changes of the cingulum, one of the major components of the limbic network, which has a critical role in emotion, attention, and memory. Thirty-five healthy young adults (22.3 ± 2.7 years) and 33 healthy older adults (69.5 ± 3.5 years) were recruited. Diffusion weighted imaging data were acquired with a b-value = 2000 sec/mm2 and 61 diffusion directions and 4 non-weighted images. The fiber directions in each voxel were based on the constrained spherical deconvolution model. The cingulum was segmented into three branches using deterministic tractography (subgenual, retrosplenial, and parahippocampal), using a region-of-interest-based approach. Atlas-based tractography was the method used to obtain the output tracts of each branch of the cingulum. Along-tract analysis was performed on each branch. We found a statistically significant change with aging in the left subgenual branch of the cingulum with a decrease in fractional anisotropy and axial diffusivity, as well as an increase in radial diffusivity. No statistically significant differences were found between young and older groups in the other two branches. This study adds to knowledge about how the cingulum changes structurally along its entire length during aging in a more detailed way, thanks to an advanced methodological approach.