Adolescent depression presented higher risk of suicide than adult depression. However, the neurophysiological mechanisms underlying this phenomenon have not been elucidated. We aimed to identify structural covariance network alterations in depressed adolescents with suicidal behaviors to provide novel neuroimaging evidence for this condition. 64 first-episode, treatment-naïve depressed adolescent patients with suicidal behaviors and 48 healthy controls were enrolled. Nonnegative matrix factorization was used to identify the structural covariance networks. The Kullback-Leibler divergence method was applied to estimate the interregional relationships between the altered brain networks. Correlation analyses were conducted between altered brain networks and clinical characteristics. Patients had lower gray matter volumes in the anterior default mode network (DMN), visual network, sensorimotor network, and right executive control network than healthy controls. Morphological connections were altered in the anterior DMN, visual network, and right executive control network in patients. Correlation analyses revealed negative associations between morphological connections in anterior DMN-visual networks and illness duration in the patient group. This study revealed abnormal gray matter attributes in the anterior DMN, visual network, sensorimotor network, and executive control network in first-episode and treatment-naïve adolescent depression with suicide, which might reflect disease traits and provide essential neurobiological evidence for behavioral disturbances in depression.

BackgroundThe thalamus, along with its component nuclei, possesses extensive connections with various brain regions and is engaged in diverse functions. However, it is unknown whether the gray matter volume (GMV) covariance networks of thalamic subfields are selectively affected in chronic capsular stroke.MethodsWe recruited 45 patients with chronic right capsular strokes (CS) and 93 normal controls (NC) from three centers. The thalamus was segmented into 25 subfields using FreeSurfer (v7.1.1). A general linear model was applied to investigate intergroup differences in the GMV covariance network of each thalamic subfield with each voxel of the entire brain between CS and NC, correcting for confounders such as age, gender, total intracranial volume (TIV), and scanners (voxel-wise p < 0.001, cluster-wise FWE corrected p < 0.05).ResultsOur findings revealed that all 25 ipsilesional thalamic subfields in CS were atrophied (p < 0.05, FDR correction). Among these, 16 ipsilesional thalamic subfields (including AV, LD, LP, VLa, VLp, VPL, VM, CeM, CL, MDm, LGN, PuM, PuI, CM, Pf, and Pt) exhibited significantly subfield-specific increased GMV covariance connectivity with the anterior orbital gyrus, superior occipital gyrus, calcarine, anterior cingulate cortex, precentral gyrus, and other regions. Additionally, although none of the contralesional thalamic subfields demonstrated regional GMV changes, 3/25 showed subfield-specific increased GMV covariance connectivity with the ipsilesional anterior orbital gyrus and subcortex.ConclusionThe GMV covariance networks of thalamic subfields are selectively involved in patients with chronic capsular stroke, which affect not only the ipsilesional thalamic subfields but also the contralesional ones.

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

This study investigated brain structural covariance network (SCN) topological changes and alertness in temporal lobe epilepsy (TLE) with and without focal to bilateral tonic-clonic seizures (FBTCS). Seventy-eight subjects, including 32 TLE patients with FBTCS (TLE-FBTCS), 46 TLE patients without FBTCS (TLE-FS), and 42 healthy controls (HCs), underwent the Attention Network Test to assess alertness and volumetric MRI scans. SCNs were constructed and analyzed using graph theory. Results showed that TLE-FS patients had lower total cerebral volume than HCs, and the lowest volume was observed in the TLE-FBTCS group. Compared to HCs and TLE-FBTCS patients, TLE-FS patients exhibited increased small-worldness, normalized clustering coefficient, global efficiency, and modularity, but decreased normalized characteristic shortest path length and assortativity. Specific brain regions, such as the hippocampus, thalamus, and superior temporal sulcus, showed changes in nodal clustering coefficients and efficiency in TLE-FS patients. Further analysis revealed decreased intrinsic/phasic alertness in TLE-FBTCS patients. Correlation analysis indicated that SCN topological properties were associated with alertness in TLE-FS patients but not in TLE-FBTCS patients. These findings suggest that TLE-FS and TLE-FBTCS patients show different changes in SCN integration and segregation, with TLE-FS alertness linked to SCN topological properties, providing insights into TLE's neuropathological mechanisms.

Parkinson's disease (PD) typically presents with unilateral symptoms in early stages, starting on one side and progressing, with the onset side showing more severe motor symptoms even after bilateralization. This asymmetry may reflect complex interactions among multiple brain regions and their network connections. In this study, we aimed to use surface-based morphometry (SBM) and structural covariance networks (SCNs) to investigate the differences in brain structure and network characteristics between patients with left-onset PD (LPD) and right-onset PD (RPD). A total of 51 LPD and 49 RPD patients were recruited. Clinical assessments included the Unified Parkinson's Disease Rating Scale motor section, Hoehn and Yahr stage, Mini-Mental State Examination, Parkinson's Disease Questionnaire, and Beck Depression Inventory. All participants underwent 3 T structural MRI. FreeSurfer was used to perform vertex-wise comparisons of cortical surface area (CSA) and cortical thickness (CT), whereas the Brain Connectivity Toolbox was implemented to construct and analyze the structural covariance networks. In patients with LPD, we found reduced CSA in the right supramarginal gyrus (SMG), right precuneus (PCUN), left inferior parietal lobule (IPL), and left lingual gyrus (LING) compared to RPD, while no significant differences in CT were found between the two groups. The CSA of the right PCUN showed a significant positive correlation with MMSE score in LPD patients. In our SCNs analysis, LPD patients exhibited increased normalized characteristic path length and decreased small-world index in CSA-based networks, while in CT-based networks, they showed increased small-world index and global efficiency compared to RPD. No significant differences in nodal characteristics were observed in either CSA-based or CT-based networks between the two groups. In patients with LPD, reductions in CSA observed in the right PCUN, right SMG, left IPL, and left LING may be associated with cognitive impairments and hallucinations among non-motor symptoms of PD. Additionally, the SCNs of LPD and RPD patients show significant differences in global topology, but regional node characteristics do not reflect lateralization differences. These findings offer new insights into the mechanisms of symptom lateralization in PD from the perspective of brain regional structure and network topology.

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.

Cognitive impairment (CI) is common in Parkinson's disease (PD). Multiple brain regions and their interactions are involved in PD associated CI. Magnetic resonance imaging (MRI) technology is a non-invasive method in investigating brain structure and inter-regional connections. In this study, by comparing cortical thickness, subcortical volume, and brain network topology properties in PD patients with and without CI, we aimed to understand the changes of brain structure and structural covariance network properties in PD associated CI. A total of 18 PD patients with CI and 33 PD patients without CI were recruited. Movement Disorder Society Unified Parkinson's Disease Rating Scale, Hoehn and Yahr stage, Mini Mental State Examination Scale, Non-motor Symptom Rating Scale, Hamilton Anxiety Scale, and Hamilton Depression Scale were assessed. All participants underwent structural 3T MRI. Cortical thickness, subcortical volume, global and nodal network topology properties were measured. Compared with PD patients without CI, the volumes of white matter, thalamus and hippocampus were lower in PD patients with CI. And decreased whole-brain local efficiency is associated with CI in PD patients. While the cortical thickness and nodal network topology properties were comparable between PD patients with and without CI. Our findings support the alterations of brain structure and disruption of structural covariance network are involved in PD associated CI, providing a new insight into the association between graph properties and PD associated CI.

Transcriptional Patterns of Brain Structural Covariance Network Abnormalities Associated With Suicidal Thoughts and Behaviors in Major Depressive Disorder

Recently, we demonstrated that a distinct pattern of structural covariance networks (SCN) from magnetic resonance imaging (MRI)-derived measurements of brain cortical thickness characterized young adults with alcohol use disorder (AUD) and predicted current and future problematic drinking in adolescents relative to controls. Here, we establish the robustness and value of SCN for identifying heavy alcohol users in three additional independent studies. Cross-sectional and longitudinal studies using data from the Pediatric Imaging, Neurocognition and Genetics (PING) study (n = 400, age range = 14-22 years), the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) (n = 272, age range = 17-22 years) and the Human Connectome Project (HCP) (n = 375, age range = 22-37 years). Cases were defined based on heavy alcohol use patterns or former alcohol use disorder (AUD) diagnoses: 50, 68 and 61 cases were identified. Controls had none or low alcohol use or absence of AUD: 350, 204 and 314 controls were selected. Graph theory metrics of segregation and integration were used to summarize SCN. Mirroring our prior findings, and across the three data sets, cases had a lower clustering coefficient [area under the curve (AUC) = -0.029, P = 0.002], lower modularity (AUC = -0.14, P = 0.004), lower average shortest path length (AUC = -0.078, P = 0.017) and higher global efficiency (AUC = 0.007, P = 0.010). Local efficiency differences were marginal (AUC = -0.017, P = 0.052). That is, cases exhibited lower network segregation and higher integration, suggesting that adjacent nodes (i.e. brain regions) were less similar in thickness whereas spatially distant nodes were more similar. Structural covariance network (SCN) differences in the brain appear to constitute an early marker of heavy alcohol use in three new data sets and, more generally, demonstrate the utility of SCN-derived metrics to detect brain-related psychopathology.

The neurobiological pathogenesis of major depression disorder (MDD) remains largely controversial. Previous literatures with limited sample size utilizing group-level structural covariance networks (SCN) commonly generated mixed findings regarding the topology of brain networks. We analyzed T1 images from a high-powered multisite sample including 1173 patients with MDD and 1019 healthy controls (HCs). We used regional gray matter volume to construct individual SCN by utilizing a novel approach based on the interregional effect size difference. We further investigated MDD-related structural connectivity alterations using topological metrics. Compared to HCs, the MDD patients showed a shift toward randomization characterized by increased integration. Further subgroup analysis of patients in different stages revealed this randomization pattern was also observed in patients with recurrent MDD, while the first-episode drug naïve patients exhibited decreased segregation. Altered nodal properties in several brain regions which have a key role in both emotion regulation and executive control were also found in MDD patients compared with HCs. The abnormalities in inferior temporal gyrus were not influenced by any specific site. Moreover, antidepressants increased nodal efficiency in the anterior ventromedial prefrontal cortex. The MDD patients at different stages exhibit distinct patterns of randomization in their brain networks, with increased integration during illness progression. These findings provide valuable insights into the disruption in structural brain networks that occurs in patients with MDD and might be useful to guide future therapeutic interventions.

BackgroundThe extensive functional and structural remodeling that occurs in the brain after amputation often results in phantom limb pain (PLP). These closely related phenomena are still not fully understood.MethodsUsing magnetic resonance imaging (MRI) and graph theoretical analysis (GTA), we explored how alterations in brain cortical thickness (CTh) and structural covariance networks (SCNs) in upper limb amputees (ULAs) relate to PLP. In all, 45 ULAs and 45 healthy controls (HCs) underwent structural MRI. Regional network properties, including nodal degree, betweenness centrality (BC), and node efficiency, were analyzed with GTA. Similarly, global network properties, including global efficiency (Eglob), local efficiency (Eloc), clustering coefficient (Cp), characteristic path length (Lp), and the small‐worldness index, were evaluated.ResultsCompared with HCs, ULAs had reduced CThs in the postcentral and precentral gyri contralateral to the amputated limb; this decrease in CTh was negatively correlated with PLP intensity in ULAs. ULAs showed varying degrees of change in node efficiency in regional network properties compared to HCs (p < 0.005). There were no group differences in Eglob, Eloc, Cp, and Lp properties (all p > 0.05). The real‐worldness SCN of ULAs showed a small‐world topology ranging from 2% to 34%, and the area under the curve of the small‐worldness index in ULAs was significantly different compared to HCs (p < 0.001).ConclusionThese results suggest that the topological organization of human CNS functional networks is altered after amputation of the upper limb, providing further support for the cortical remapping theory of PLP.

ObjectiveIschemic moyamoya (MMD) disease could alter the cerebral structure, but little is known about the topological organization of the structural covariance network (SCN). This study employed structural magnetic resonance imaging and graph theory to evaluate SCN reorganization in ischemic MMD patients.MethodForty-nine stroke-free ischemic MMD patients and 49 well-matched healthy controls (HCs) were examined by T1-MPRAGE imaging. Structural images were pre-processed using the Computational Anatomy Toolbox 12 (CAT 12) based on the diffeomorphic anatomical registration through exponentiated lie (DARTEL) algorithm and both the global and regional SCN parameters were calculated and compared using the Graph Analysis Toolbox (GAT).ResultsMost of the important metrics of global network organization, including characteristic path length (Lp), clustering coefficient (Cp), assortativity, local efficiency, and transitivity, were significantly reduced in MMD patients compared with HCs. In addition, the regional betweenness centrality (BC) values of the bilateral medial orbitofrontal cortices were significantly lower in MMD patients than in HCs after false discovery rate (FDR) correction for multiple comparisons. The BC was also reduced in the left medial superior frontal gyrus and hippocampus, and increased in the bilateral middle cingulate gyri of patients, but these differences were not significant after FDR correlation. No differences in network resilience were detected by targeted attack analysis or random failure analysis.ConclusionsBoth global and regional properties of the SCN are altered in MMD, even in the absence of major stroke or hemorrhagic damage. Patients exhibit a less optimal and more randomized SCN than HCs, and the nodal BC of the bilateral medial orbitofrontal cortices is severely reduced. These changes may account for the cognitive impairments in MMD patients.

Structural covariance changes in major cortico-basal ganglia and thalamic networks in amyloid-positive patients with white matter hyperintensities

Small average differences in the left-right asymmetry of cerebral cortical thickness have been reported in individuals with autism spectrum disorder (ASD) compared to typically developing controls, affecting widespread cortical regions. The possible impacts of these regional alterations in terms of structural network effects have not previously been characterized. Inter-regional morphological covariance analysis can capture coordinated maturational-trophic networks between different cortical areas at macroscale.

Graph theoretic analysis of structural covariance networks (SCN) provides an assessment of brain organization that has not yet been applied to alcohol dependence (AD). We estimated whether SCN differences are present in adults with AD and heavy-drinking adolescents at age 19 and age 14, prior to substantial exposure to alcohol. Cross-sectional sample of adults and a cohort of adolescents. Correlation matrices for cortical thicknesses across 68 regions were summarized with graph theoretic metrics. A total of 745 adults with AD and 979 non-dependent controls from 24 sites curated by the Enhancing NeuroImaging Genetics through Meta Analysis (ENIGMA)-Addiction consortium, and 297 hazardous drinking adolescents and 594 controls at ages 19 and 14 from the IMAGEN study, all from Europe. Metrics of network segregation (modularity, clustering coefficient and local efficiency) and integration (average shortest path length and global efficiency). The younger AD adults had lower network segregation and higher integration relative to non-dependent controls. Compared with controls, the hazardous drinkers at age 19 showed lower modularity [area-under-the-curve (AUC) difference = -0.0142, 95% confidence interval (CI) = -0.1333, 0.0092; P-value = 0.017], clustering coefficient (AUC difference = -0.0164, 95% CI = -0.1456, 0.0043; P-value = 0.008) and local efficiency (AUC difference = -0.0141, 95% CI = -0.0097, 0.0034; P-value = 0.010), as well as lower average shortest path length (AUC difference = -0.0405, 95% CI = -0.0392, 0.0096; P-value = 0.021) and higher global efficiency (AUC difference = 0.0044, 95% CI = -0.0011, 0.0043; P-value = 0.023). The same pattern was present at age 14 with lower clustering coefficient (AUC difference = -0.0131, 95% CI = -0.1304, 0.0033; P-value = 0.024), lower average shortest path length (AUC difference = -0.0362, 95% CI = -0.0334, 0.0118; P-value = 0.019) and higher global efficiency (AUC difference = 0.0035, 95% CI = -0.0011, 0.0038; P-value = 0.048). Cross-sectional analyses indicate that a specific structural covariance network profile is an early marker of alcohol dependence in adults. Similar effects in a cohort of heavy-drinking adolescents, observed at age 19 and prior to substantial alcohol exposure at age 14, suggest that this pattern may be a pre-existing risk factor for problematic drinking.

Small average differences in the left-right asymmetry of cerebral cortical thickness have been reported in individuals with autism spectrum disorder (ASD) compared to typically developing controls, affecting widespread cortical regions. The possible impacts of these regional alterations in terms of structural network effects have not previously been characterized. Inter-regional morphological covariance analysis can capture network connectivity between different cortical areas at the macroscale level. Here, we used cortical thickness data from 1455 individuals with ASD and 1560 controls, across 43 independent datasets of the ENIGMA consortium’s ASD Working Group, to assess hemispheric asymmetries of intra-individual structural covariance networks, using graph theory-based topological metrics. Compared with typical features of small-world architecture in controls, the ASD sample showed significantly altered average asymmetry of networks involving the fusiform, rostral middle frontal, and medial orbitofrontal cortex, involving higher randomization of the corresponding right-hemispheric networks in ASD. A network involving the superior frontal cortex showed decreased right-hemisphere randomization. Based on comparisons with meta-analyzed functional neuroimaging data, the altered connectivity asymmetry particularly affected networks that subserve executive functions, language-related and sensorimotor processes. These findings provide a network-level characterization of altered left-right brain asymmetry in ASD, based on a large combined sample. Altered asymmetrical brain development in ASD may be partly propagated among spatially distant regions through structural connectivity.

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

Introduction:Autism is a heterogeneous neurodevelopmental disorder associated with social, cognitive and behavioral impairments. These impairments are often reported along with alteration of the brain structure such as abnormal changes in the grey matter (GM) density. However, it is not yet clear whether these changes could be used to differentiate various subtypes of autism spectrum disorder (ASD).Method:We compared the regional changes of GM density in ASD, Asperger's Syndrome (AS) individuals and a group of healthy controls (HC). In addition to regional changes itself, the amount of GM density changes in one region as compared to other brain regions was also calculated. We hypothesized that this structural covariance network could differentiate the AS individuals from the ASD and HC groups. Therefore, statistical analysis was performed on the MRI data of 70 male subjects including 26 ASD (age=14–50, IQ=92–132), 16 AS (age=7–58, IQ=93–133) and 28 HC (age=9–39, IQ=95–144).Result:The one-way ANOVA on the GM density of 116 anatomically separated regions showed significant differences among the groups. The pattern of structural covariance network indicated that covariation of GM density between the brain regions is altered in ASD.Conclusion:This changed structural covariance could be considered as a reason for less efficient segregation and integration of information in the brain that could lead to cognitive dysfunctions in autism. We hope these findings could improve our understanding about the pathobiology of autism and may pave the way towards a more effective intervention paradigm.

Altered topological organization of brain structural covariance networks has been observed in attention deficit hyperactivity disorder (ADHD). However, results have been inconsistent, potentially related to confounding medication effects. In addition, since structural networks are traditionally constructed at the group level, variabilities in individual structural features remain to be well characterized. Structural brain imaging with MRI was performed on 84 drug‐naïve children with ADHD and 83 age‐matched healthy controls. Single‐subject gray matter (GM) networks were obtained based on areal similarities of GM, and network topological properties were analyzed using graph theory. Group differences in each topological metric were compared using nonparametric permutation testing. Compared with healthy subjects, GM networks in ADHD patients demonstrated significantly altered topological characteristics, including higher global and local efficiency and clustering coefficient, and shorter path length. In addition, ADHD patients exhibited abnormal centrality in corticostriatal circuitry including the superior frontal gyrus, orbitofrontal gyrus, medial superior frontal gyrus, precentral gyrus, middle temporal gyrus, and pallidum (all p < .05, false discovery rate [FDR] corrected). Altered global and nodal topological efficiencies were associated with the severity of hyperactivity symptoms and the performance on the Stroop and Wisconsin Card Sorting Test tests (all p < .05, FDR corrected). ADHD combined and inattention subtypes were differentiated by nodal attributes of amygdala (p < .05, FDR corrected). Alterations in GM network topologies were observed in drug‐naïve ADHD patients, in particular in frontostriatal loops and amygdala. These alterations may contribute to impaired cognitive functioning and impulsive behavior in ADHD.

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.