Predicting cognitive aging through brain structural covariance networks: A decade of longitudinal insights using source-based morphometry.

Identifying Subgroups of Major Depressive Disorder Using Brain Structural Covariance Networks and Mapping of Associated Clinical and Cognitive Variables

Radiation-induced brain injury (RBI) is a common complication in patients with nasopharyngeal carcinoma (NPC) who have undergone radiotherapy (RT), which is characterized by significant cognitive and psychological impairments. Although radiation-induced regional structural abnormalities have been well-reported, the effects of RT on the whole brain structural covariance networks are mostly unknown. Here, we performed a source-based morphometry (SBM) study to solve this issue. In this cross-sectional study, 131 NPC patients with pre- and post-RT were stratified into pre-RT (n=47) and post-RT (n=84) groups. The SBM method was adopted to investigate the radiation-induced alterations in structural covariance networks in patients with NPC. Compared to the pre-RT group, our SBM analyses revealed increased z-scores in the independent component 05 (IC05; mainly located in the posterior cingulate, precuneus areas, and superior parietal lobe) (P=0.040) and decreased z-scores in the temporal-occipital network (P=0.015) and cerebellar network (P=0.023) in post-RT NPC patients. Compared to the pre-RT group, voxel-based morphometry (VBM) revealed reduced gray matter volume in the left temporal lobe, cerebellum, bilateral thalamus, left insular, and occipital lobe in the post-RT group. Notably, a significant negative correlation was observed between the mean radiation doses of the right temporal lobe and the z-score of the cerebellar network (r=-0.349, P=0.027). This present study revealed radiation-induced changes in structural covariance networks and cortical volume in patients with NPC. These findings shed some light on the neural basis of symptom patterns in RBI and may support the development of new intervention strategies to prevent progression to radiation-induced brain necrosis.

Decision letter: Stage-dependent differential influence of metabolic and structural networks on memory across Alzheimer’s disease continuum

Abnormal structural covariance network in major depressive disorder: Evidence from the REST-meta-MDD project

Brain structural covariance networks (SCNs) based on pairwise statistical associations of cortical thickness data across brain areas reflect underlying physical and functional connections between them. SCNs capture the complexity of human brain cortex structure and are disrupted in neurodegenerative conditions. However, the longitudinal assessment of SCN dynamics has not yet been explored, despite its potential to unveil mechanisms underlying neurodegeneration. Here, we evaluated the changes of SCNs over 12 months in patients with a first inflammatory-demyelinating attack of the Central Nervous System and assessed their clinical relevance by comparing SCN dynamics of patients with and without conversion to multiple sclerosis (MS) over one year. All subjects underwent clinical and brain MRI assessments over one year. Brain cortical thicknesses for each subject and time point were used to obtain group-level between-area correlation matrices from which nodal connectivity metrics were obtained. Robust bootstrap-based statistical approaches (allowing sampling with replacement) assessed the significance of longitudinal changes. Patients who converted to MS exhibited significantly greater network connectivity at baseline than non-converters (p = 0.02) and a subsequent connectivity loss over time (p = 0.001–0.02), not observed in non-converters’ network. These findings suggest SCN analysis is sensitive to brain tissue changes in early MS, reflecting clinically relevant aspects of the condition. However, this is preliminary work, indicated by the low sample sizes, and its results and conclusions should be treated with caution and confirmed with larger cohorts.

Brain structural covariance networks (SCNs) composed of regions with correlated variation are altered in neuropsychiatric disease and change with age. Little is known about the development of SCNs in early childhood, a period of rapid cortical growth. We investigated the development of structural and maturational covariance networks, including default, dorsal attention, primary visual and sensorimotor networks in a longitudinal population of 118 children after birth to 2 years old and compared them with intrinsic functional connectivity networks. We found that structural covariance of all networks exhibit strong correlations mostly limited to their seed regions. By Age 2, default and dorsal attention structural networks are much less distributed compared with their functional maps. The maturational covariance maps, however, revealed significant couplings in rates of change between distributed regions, which partially recapitulate their functional networks. The structural and maturational covariance of the primary visual and sensorimotor networks shows similar patterns to the corresponding functional networks. Results indicate that functional networks are in place prior to structural networks, that correlated structural patterns in adult may arise in part from coordinated cortical maturation, and that regional co-activation in functional networks may guide and refine the maturation of SCNs over childhood development.

Brain structural covariance networks reflect covariation in morphology of different brain areas and are thought to reflect common trajectories in brain development and maturation. Large-scale investigation of structural covariance networks in obsessive-compulsive disorder (OCD) may provide clues to the pathophysiology of this neurodevelopmental disorder. Using T1-weighted MRI scans acquired from 1616 individuals with OCD and 1463 healthy controls across 37 datasets participating in the ENIGMA-OCD Working Group, we calculated intra-individual brain structural covariance networks (using the bilaterally-averaged values of 33 cortical surface areas, 33 cortical thickness values, and six subcortical volumes), in which edge weights were proportional to the similarity between two brain morphological features in terms of deviation from healthy controls (i.e. z-score transformed). Global networks were characterized using measures of network segregation (clustering and modularity), network integration (global efficiency), and their balance (small-worldness), and their community membership was assessed. Hub profiling of regional networks was undertaken using measures of betweenness, closeness, and eigenvector centrality. Individually calculated network measures were integrated across the 37 datasets using a meta-analytical approach. These network measures were summated across the network density range of K = 0.10-0.25 per participant, and were integrated across the 37 datasets using a meta-analytical approach. Compared with healthy controls, at a global level, the structural covariance networks of OCD showed lower clustering (P < 0.0001), lower modularity (P < 0.0001), and lower small-worldness (P = 0.017). Detection of community membership emphasized lower network segregation in OCD compared to healthy controls. At the regional level, there were lower (rank-transformed) centrality values in OCD for volume of caudate nucleus and thalamus, and surface area of paracentral cortex, indicative of altered distribution of brain hubs. Centrality of cingulate and orbito-frontal as well as other brain areas was associated with OCD illness duration, suggesting greater involvement of these brain areas with illness chronicity. In summary, the findings of this study, the largest brain structural covariance study of OCD to date, point to a less segregated organization of structural covariance networks in OCD, and reorganization of brain hubs. The segregation findings suggest a possible signature of altered brain morphometry in OCD, while the hub findings point to OCD-related alterations in trajectories of brain development and maturation, particularly in cingulate and orbitofrontal regions.

Previous neuroimaging studies have suggested that cerebral changes over normal aging are not simply characterized by regional alterations, but rather by the reorganization of cortical connectivity patterns. The investigation of structural covariance networks (SCNs) using voxel-based morphometry is an advanced approach to examining the pattern of covariance in gray matter (GM) volumes among different regions of the human cortex. To date, how the organization of critical SCNs change during normal aging remains largely unknown. In this study, we used an SCN mapping approach to investigate eight large-scale networks in 240 healthy participants aged 18–89 years. These participants were subdivided into young (18–23 years), middle aged (30–58 years), and older (61–89 years) subjects. Eight seed regions were chosen from widely reported functional intrinsic connectivity networks. The voxels showing significant positive associations with these seed regions were used to describe the topological organization of an SCN. All of these networks exhibited non-linear patterns in their spatial extent that were associated with normal aging. These networks, except the primary motor network, had a distributed topology in young participants, a sharply localized topology in middle aged participants, and were relatively stable in older participants. The structural covariance derived using the primary motor cortex was limited to the ipsilateral motor regions in the young and older participants, but included contralateral homologous regions in the middle aged participants. In addition, there were significant between-group differences in the structural networks associated with language-related speech and semantics processing, executive control, and the default-mode network (DMN). Taken together, the results of this study demonstrate age-related changes in the topological organization of SCNs, and provide insights into normal aging of the human brain.

Alzheimer disease (AD) is defined by cortical β-amyloid (Aβ), tau, and neurodegeneration, which contribute to cognitive decline, in part, by altering large-scale functional brain networks. While cortical Aβ and tau have been associated with changes in functional brain connectivity, it is unknown whether plasma biomarkers relate to such changes. In a healthy community sample of cognitively unimpaired adults free from major CNS disease from the Baltimore Longitudinal Study of Aging, we examined whether plasma biomarkers of AD pathology (Aβ42/40, phosphorylated tau [pTau-181]), astrogliosis (glial fibrillary acidic protein [GFAP]), and neuronal injury (neurofilament light chain [NfL]) were associated with longitudinal changes in functional connectivity and whether changes in functional connectivity were related to longitudinal cognition. Plasma biomarkers were measured using the Quanterix SIMOA assays. Intranetwork connectivity (3T resting-state fMRI) from 7 functional networks was derived using a predefined cortical parcellation mask for each participant visit. Cognitive performance was assessed concurrently with fMRI scan. Covariate-adjusted linear mixed-effect models were used to determine (1) whether plasma biomarkers were associated with longitudinal changes in connectivity, (2) whether the magnitude of the biomarker-connectivity relationships differed by amyloid status, and (3) whether changes in connectivity co-occurred with longitudinal changes in cognition. Our primary findings (n = 486; age = 65.5 ± 16.2 years; 54% female; mean follow-up time = 4.3 ± 1.7 years) showed that higher baseline GFAP was associated with faster declines in somatomotor (β = -0.04, p = 0.01, 95% CI -0.06 to -0.01), limbic (β = -0.03, p = 0.02, 95% CI -0.06 to -0.005), and frontoparietal (β = -0.04, p = 0.02, 95% CI -0.07 to -0.01) network connectivity. Amyloid status moderated several biomarker-connectivity associations. For instance, higher baseline NfL was related to faster declines in visual and limbic network connectivity, but only among amyloid-positive participants. Among 421 participants with ≥2 fMRI visits (age = 71.7 ± 11.4 years; 55% female; follow-up time = 3.9 ± 1.6 years), longitudinal changes in connectivity were associated with concurrent declines in cognition; however, these results did not survive multiple comparison correction. Among cognitively unimpaired participants, plasma biomarkers of amyloidosis, astrogliosis, and neuronal injury are associated with declines in network connectivity, particularly among amyloid-positive participants. Major limitations include the lack of inclusion of the sensitive pTau-217 and pTau-231 isoforms and comparative PET biomarkers.

Child maltreatment is a major cause of pediatric posttraumatic stress disorder (PTSD). Previous studies have not investigated potential differences in network architecture in maltreated youth with PTSD and those resilient to PTSD. High-resolution magnetic resonance imaging brain scans at 3 T were completed in maltreated youth with PTSD (n = 31), without PTSD (n = 32), and nonmaltreated controls (n = 57). Structural covariance network architecture was derived from between-subject intraregional correlations in measures of cortical thickness in 148 cortical regions (nodes). Interregional positive partial correlations controlling for demographic variables were assessed, and those correlations that exceeded specified thresholds constituted connections in cortical brain networks. Four measures of network centrality characterized topology, and the importance of cortical regions (nodes) within the network architecture were calculated for each group. Permutation testing and principle component analysis method were employed to calculate between-group differences. Principle component analysis is a methodological improvement to methods used in previous brain structural covariance network studies. Differences in centrality were observed between groups. Larger centrality was found in maltreated youth with PTSD in the right posterior cingulate cortex; smaller centrality was detected in the right inferior frontal cortex compared to youth resilient to PTSD and controls, demonstrating network characteristics unique to pediatric maltreatment-related PTSD. Larger centrality was detected in right frontal pole in maltreated youth resilient to PTSD compared to youth with PTSD and controls, demonstrating structural covariance network differences in youth resilience to PTSD following maltreatment. Smaller centrality was found in the left posterior cingulate cortex and in the right inferior frontal cortex in maltreated youth compared to controls, demonstrating attributes of structural covariance network topology that is unique to experiencing maltreatment. This work is the first to identify cortical thickness-based structural covariance network differences between maltreated youth with and without PTSD. We demonstrated network differences in both networks unique to maltreated youth with PTSD and those resilient to PTSD. The networks identified are important for the successful attainment of age-appropriate social cognition, attention, emotional processing, and inhibitory control. Our findings in maltreated youth with PTSD versus those without PTSD suggest vulnerability mechanisms for developing PTSD.

The relationship between age-related changes in brain structural connectivity (SC) and functional connectivity (FC) with cognition is not well understood. Furthermore, it is not clear whether cognition is represented via a similar spatial pattern of FC and SC or instead is mapped by distinct sets of distributed connectivity patterns. To this end, we used a longitudinal, within-subject, multimodal approach aiming to combine brain data from diffusion-weighted MRI (DW-MRI), and functional MRI (fMRI) with behavioral evaluation, to better understand how changes in FC and SC correlate with changes in cognition in a sample of older adults. FC and SC measures were derived from the multimodal scans acquired at two time points. Change in FC and SC was correlated with 13 behavioral measures of cognitive function using Partial Least Squares Correlation (PLSC). Two of the measures indicate an age-related change in cognition and the rest indicate baseline cognitive performance. FC and SC—cognition correlations were expressed across several cognitive measures, and numerous structural and functional cortical connections, mainly cingulo-opercular, dorsolateral prefrontal, somatosensory and motor, and temporo-parieto-occipital, contributed both positively and negatively to the brain-behavior relationship. Whole-brain FC and SC captured distinct and independent connections related to the cognitive measures. Overall, we examined age-related function-structure associations of the brain in a comprehensive and integrated manner, using a multimodal approach. We pointed out the behavioral relevance of age-related changes in FC and SC. Taken together, our results highlight that the heterogeneity in distributed FC and SC connectivity patterns provide unique information about the variable nature of healthy cognitive aging.

Purpose: To investigate the structural covariance network disruption in Parkinson’s disease (PD), and explore the functional alterations of disrupted structural covariance network.Methods: A cohort of 100 PD patients and 70 healthy participants underwent structural and functional magnetic resonance scanning. Independent component analysis (ICA) was applied separately to both deformation-based morphometry (DBM) maps and functional maps with the same calculating parameters (both decomposed into 20 independent components (ICs) and computed 20 times the Infomax algorithm in ICASSO). Disrupted structural covariance network in PD patients was identified, and then, we performed goodness of fit analysis to obtain the functional network that showed the highest spatial overlap with it. We investigated the relationship between structural covariance network and functional network alterations. Finally, to further understand the structural and functional alterations over time, we performed a longitudinal subgroup analysis (51 patients were followed up for 2 years) with the same procedures.Results: In a cross-sectional analysis, PD patients showed decreased structural covariance between anterior and posterior cingulate subnetworks. The functional components showed best overlap with anterior and posterior cingulate structural subnetworks were selected as anterior and posterior cingulate functional subnetworks. The functional connectivity between them was significantly increased [assessed by Functional Network Connectivity (FNC) toolbox]; and the increased functional connectivity was negatively correlated with cingulate structural covariance network integrity. Longitudinal subgroup analysis showed cingulate structural covariance network disruption was worse at follow-up, while the functional connectivity between anterior and posterior cingulate network was increased at baseline and decreased at follow-up.Conclusion: This study indicated that the cingulate structural covariance network displayed a high susceptibility in PD patients. This study indicated that the cingulate structural covariance network displayed a high susceptibility in PD patients. Considering that disrupted structural covariance network coexisted with enhanced/remained functional activity during disease development, enhanced functional activity underlying the disrupted cingulate structural covariance network might represent a temporal compensation for maintaining clinical performance.

Carpal tunnel syndrome (CTS) is a common peripheral entrapment neuropathy. However, CTS-related changes of brain structural covariance and structural covariance networks (SCNs) patterns have not been clearly studied. To explore CTS-related brain changes from perspectives of structural connectivity and SCNs. Brain structural magnetic resonance images were acquired from 27 CTS patients and 19 healthy controls (HCs). Structural covariance and SCNs were constructed based on gray matter volume. The global network properties including clustering coefficient (Cp), characteristic path length (Lp), small-worldness index, global efficiency (Eglob), and local efficiency (Eloc) and regional network properties including degree, betweenness centrality (BC), and Eloc of a given node were calculated with graph theoretical analysis. Compared with HCs, the strength of structural connectivity between the dorsal anterior insula and medial prefrontal thalamus decreased (P <.001) in CTS patients. There was no intergroup difference of area under the curve for Cp, Lp¸ Eglob, and Eloc (all P >.05). The real-world SCN of CTS patients showed a small-world topology ranging from 2% to 32%. CTS patients showed lower nodal degrees of the dorsal anterior insula and medial prefrontal thalamus, and higher Eloc of a given node and BC in the lateral occipital cortex (P <.001) and the dorsolateral middle temporal gyrus (P <.001) than HCs, respectively. CTS had a profound impact on brain structures from perspectives of structural connectivity and SCNs.

We investigated the changes in structural connectivity (using diffusion tensor imaging [DTI]) and the structural covariance network based on structural volume using graph theory in patients with neurofibromatosis type 1 (NF1) compared to a healthy control group. We included 14 patients with NF1, according to international consensus recommendations, and 16 healthy individuals formed the control group. This was retrospectively observational study followed STROBE guideline. Both groups underwent brain magnetic resonance imaging including DTI and 3-dimensional T1-weighted imaging. We analyzed structural connectivity using DTI and Diffusion Spectrum Imaging Studio software and evaluated the structural covariance network based on the structural volumes using FreeSurfer and Brain Analysis Using Graph Theory software. There were no differences in the global structural connectivity between the 2 groups, but several brain regions showed significant differences in local structural connectivity. Additionally, there were differences between the global structural covariance networks. The characteristic path length was longer and the small-worldness index was lower in patients with NF1. Furthermore, several regions showed significant differences in the local structural covariance networks. We observed changes in structural connectivity and covariance networks in patients with NF1 compared to a healthy control group. We found that global structural efficiency is decreased in the brains of patients with NF1, and widespread changes in the local structural network were found. These results suggest that NF1 is a brain network disease, and our study provides direction for further research to elucidate the biological processes of NF1.

Prenatal stress and its association with amygdala-related structural covariance patterns in youth