Structural network integrity of the central executive network is associated with the therapeutic effect of rTMS in treatment resistant depression

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

Large-scale structural network change correlates with clinical response to rTMS in depression.

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.

Disruptions in the inter-regional connective correlation within the brain are believed to contribute to memory impairment. To detect these corresponding correlation networks in Alzheimer's disease (AD), we conducted three types of inter-regional correlation analysis, including structural covariance, functional connectivity and group-level independent component analysis (group-ICA). The analyzed data were obtained from the Alzheimer's Disease Neuroimaging Initiative, comprising 52 cognitively normal (CN) participants without subjective memory concerns, 52 individuals with late mild cognitive impairment (LMCI) and 52 patients with AD. We firstly performed vertex-wise cortical thickness analysis to identify brain regions with cortical thinning in AD and LMCI patients using structural MRI data. These regions served as seeds to construct both structural covariance networks and functional connectivity networks for each subject. Additionally, group-ICA was performed on the functional data to identify intrinsic brain networks at the cohort level. Through a comparison of the structural covariance and functional connectivity networks with ICA networks, we identified several inter-regional correlation networks that consistently exhibited abnormal connectivity patterns among AD and LMCI patients. Our findings suggest that reduced inter-regional connectivity is predominantly observed within a subnetwork of the default mode network, which includes the posterior cingulate and precuneus regions, in both AD and LMCI patients. This disruption of connectivity between key nodes within the default mode network provides evidence supporting the hypothesis that impairments in brain networks may contribute to memory deficits in AD and LMCI.

Brain Connectivity: A Journal of Clinical Neurology, Neuroscience, & Neuroimaging Advancing the Field of Neurology.

Pediatric traumatic brain injury (TBI) is prevalent and can disrupt ongoing brain maturation. However, the long-term consequences of pediatric TBI on the brain’s network architecture are poorly understood. Structural covariance networks (SCN), based on anatomical correlations between brain regions, may provide important insights into brain topology following TBI. Changes in global SCN (default-mode network [DMN], central executive network [CEN], and salience network [SN]) were compared sub-acutely (<90 days) and in the long-term (approximately 12–24 months) after pediatric moderate-severe TBI (n = 16), and compared to typically developing children assessed concurrently (n = 15). Gray matter (GM) volumes from selected seeds (DMN: right angular gyrus [rAG], CEN: right dorsolateral prefrontal cortex [rDLPFC], SN: right anterior insula) were extracted from T1-weighted images at both timepoints. No group differences were found sub-acutely; at the second timepoint, the TBI group showed significantly reduced structural covariance within the DMN seeded from the rAG and the (1) right middle frontal gyrus, (2) left superior frontal gyrus, and (3) left fusiform gyrus. Reduced structural covariance was also found within the CEN, that is, between the rDLPFC and the (1) calcarine sulcus, and (2) right occipital gyrus. In addition, injury severity was positively associated with GM volumes in the identified CEN regions. Over time, there were no significant changes in SCN in either group. The findings, albeit preliminary, suggest for the first time a long-term effect of pediatric TBI on SCN. SCN may be a complementary approach to characterize the global effect of TBI on the developing brain. Future work needs to further examine how disruptions of these networks relate to behavioral and cognitive difficulties.

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.

Sex differences in episodic memory (EM), remembering past events based on when and where they occurred, have been reported, but the neural mechanisms are unclear. T1-weighted images of 111 females and 61 males were acquired from the Dallas Lifespan Brain Study. Using surface-based morphometry and structural covariance (SC) analysis, we constructed structural covariance networks (SCN) based on cortical volume, and the global efficiency (Eglob) was computed to characterize network integration. The relationship between SCN and EM was examined by SC analysis among the top-n brain regions that were most relevant to EM performance. The number of SC connections (females: 3306; males: 437, P = 0.0212) and Eglob (females: 0.1845; males: 0.0417, P = 0.0408) of SCN in females were higher than those in males. The top-n brain regions with the strongest SC in females were located in auditory network, cingulo-opercular network (CON), and default mode network (DMN), and in males, they were located in frontoparietal network, CON, and DMN. These results confirmed that the Eglob of SCN in females was higher than males, sex differences in EM performance might be related to the differences in network-level integration. Our study highlights the importance of sex as a research variable in brain science.

Structural covariance networks (SCNs) may offer unique insights into the developmental impact of childhood maltreatment (CM) because they are thought to reflect coordinated maturation of distinct gray matter regions. T1-weighted magnetic resonance images were acquired from 121 young people with emerging mental illness. Diffusion-weighted and resting-state functional imaging was also acquired from a random subset of participants (n = 62). Ten study-specific SCNs were identified using a whole-brain gray matter independent component analysis. The effects of CM and age on average gray matter density and the expression of each SCN were calculated. CM was linked to age-related decreases in gray matter density across an SCN that overlapped with the default mode network (DMN) and frontoparietal network. Resting-state functional connectivity (rsFC) and structural connectivity were calculated in the study-specific SCN and across the whole brain. Gray matter covariance was significantly correlated with rsFC across the SCN, and rsFC fully mediated the relationship between gray matter covariance and structural connectivity in the nonmaltreated group. A unique association of gray matter covariance with structural connectivity was detected among individuals with a history of CM. Perturbation of gray matter development across the DMN and frontoparietal network following CM may have significant implications for mental well-being, given the networks' roles in self-referential activity. Cross-modal comparisons suggest that reduced gray matter following CM could arise from deficient functional activity earlier in life.

Tinnitus is considered a neurological disorder affecting both auditory and nonauditory networks. This study aimed to investigate the structural brain covariance network in tinnitus patients and analyze its altered topological properties. Fifty three primary tinnitus patients and 67 age- and sex-matched healthy controls (HCs) were included. Gray matter volume (GMV) of each participant was extracted using voxel-based morphometry, a group-level structural covariance network (SCN) was constructed based on the GMV of each participant, and graph theoretic analyses were performed using graph analysis toolbox (GAT). The differences in the topological properties of SCN between both groups were compared and analyzed. Both groups exhibited small-world attributes. Compared with HCs, tinnitus patients had significantly higher characteristic path length, lambda, transitivity, and assortativity (p < 0.05), and significantly lower global efficiency (p < 0.05). Tinnitus patients had higher clustering coefficient and reduced gamma and modularity, but neither was remarkable. The hubs in tinnitus network focused on the temporal lobe. In addition, the tinnitus network was found to be reduced in robustness to targeted attacks compared with HCs. Besides, a significant negative correlation between Tinnitus Handicap Inventory (THI) score and GMV in the left angular gyrus (r = -0.283, p = 0.040) as well as left superior temporal pole (r = -0.282, p = 0.041) were identified. Tinnitus patients showed reduced small-world properties, altered hub nodes, and reduced ability to respond to targeted attacks in brain network. The GMV in the left angular gyrus and left superior temporal pole showed significant negative correlation with tinnitus distress (THI score), indicating potential therapeutic target.

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

Disease-specific patterns of gray matter atrophy in Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) overlap with distinct structural covariance networks (SCNs) in cognitively healthy controls. This suggests that both types of dementia target specific structural networks. Here, we study SCNs in AD and bvFTD. We used structural magnetic resonance imaging data of 31 AD patients, 24 bvFTD patients, and 30 controls from two centers specialized in dementia. Ten SCNs were defined based on structural covariance of gray matter density using independent component analysis. We studied group differences in SCNs using F-tests, with Bonferroni corrected t-tests, adjusted for age, gender, and study center. Associations with cognitive performance were studied using linear regression analyses. Cross-sectional group differences were found in three SCNs (all P < 0.0025). In bvFTD, we observed decreased anterior cingulate network integrity compared with AD and controls. Patients with AD showed decreased precuneal network integrity compared with bvFTD and controls, and decreased hippocampal network and anterior cingulate network integrity compared with controls. In AD, we found an association between precuneal network integrity and global cognitive performance (P = 0.0043). Our findings show that AD and bvFTD target different SCNs. The comparison of both types of dementia showed decreased precuneal (i.e., default mode) network integrity in AD and decreased anterior cingulate (i.e., salience) network integrity in bvFTD. This confirms the hypothesis that AD and bvFTD have distinct anatomical networks of degeneration and shows that structural covariance gives valuable insights in the understanding of network pathology in dementia.

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.

Background Treatment-resistant depression (TRD) is associated with gray matter volume reduction compared to healthy controls (HC). Since depression has increasingly been recognized as a disorder of dysregulated neural networks, it is important to evaluate these structural changes in terms of brain networks. Structural covariance is a measurement that gauges the association strength of structural measures between two regions, which is used to examine network-level alteration of brain structure. Although several studies reported abnormal structural covariance in depression, few studies have thus far investigated structural covariance alteration in relation to TRD. Aims and Objectives In this study, we aimed to examine structural covariance alteration in TRD compared to HC. Methods T1 images were obtained from 116 patients with TRD and 54 HC who were recruited at Keio University. Brain volume was calculated for each of 85 regions of the DK atlas using FreeSurfer 6.0. Group differences in brain volumes were examined by analysis of covariance controlling for age and sex. Structural covariances of brain volumes across 3570 pairs of brain regions were obtained by partial correlation analysis using age, sex, and total intracranial volume as covariates. Network-based statistics were used to extract networks with group differences in structural covariances. This study was conducted after obtaining approval from the respective ethics review committees. Results There were no significant differences in brain volumes between the TRD and HC groups. The null hypothesis of equality in structural covariance between them was rejected using network-based statistics. We found a single network comprising connections with elevated structural covariance in patients with TRD compared with HC. The left nucleus accumbens, bilateral pericalcarine, and supramarginal gyrus had high degree centrality in the structural covariance network. Discussion and Conclusion Patients with TRD showed coordinated brain volume alterations in comparison with HC, even though there was no difference in brain volumes between them. Nucleus accumbens, an integral hub in the reward circuit, was one of the hubs of extracted network with elevated structural covariance in TRD, which is in line with a previous study that reported higher structural covariance of nucleus accumbens in depression. Further studies are warranted to examine structural covariance differences among TRD, non-TRD, and HC in order to confirm the link between structural alteration and pathophysiology of treatment resistance in depression.

Grey Matter Covariance Predicts Response to rTMS in Depression