A comprehensive evaluation of multicentric reliability of single-subject cortical morphological networks on traveling subjects.

Despite the prevalence of research on single-subject cerebral morphological networks in recent years, whether they can offer a reliable way for multicentric studies remains largely unknown. Using two multicentric datasets of traveling subjects, this work systematically examined the inter-site test-retest (TRT) reliabilities of single-subject cerebral morphological networks, and further evaluated the effects of several key factors. We found that most graph-based network measures exhibited fair to excellent reliabilities regardless of different analytical pipelines. Nevertheless, the reliabilities were affected by choices of morphological index (fractal dimension > sulcal depth > gyrification index > cortical thickness), brain parcellation (high-resolution > low-resolution), thresholding method (proportional > absolute), and network type (binarized > weighted). For the factor of similarity measure, its effects depended on the thresholding method used (absolute: Kullback-Leibler divergence > Jensen-Shannon divergence; proportional: Jensen-Shannon divergence > Kullback-Leibler divergence). Furthermore, longer data acquisition intervals and different scanner software versions significantly reduced the reliabilities. Finally, we showed that inter-site reliabilities were significantly lower than intra-site reliabilities for single-subject cerebral morphological networks. Altogether, our findings propose single-subject cerebral morphological networks as a promising approach for multicentric human connectome studies, and offer recommendations on how to determine analytical pipelines and scanning protocols for obtaining reliable results.

Single-subject cortical morphological brain networks: Phenotypic associations and neurobiological substrates.

Although single-subject morphological brain networks provide an important way for human connectome studies, their roles and origins are poorly understood. Combining cross-sectional and repeated structural magnetic resonance imaging scans from adults, children and twins with behavioral and cognitive measures and brain-wide transcriptomic, cytoarchitectonic and chemoarchitectonic data, this study examined phenotypic associations and neurobiological substrates of single-subject morphological brain networks. We found that single-subject morphological brain networks explained inter-individual variance and predicted individual outcomes in Motor and Cognition domains, and distinguished individuals from each other. The performance can be further improved by integrating different morphological indices for network construction. Low-moderate heritability was observed for single-subject morphological brain networks with the highest heritability for sulcal depth-derived networks and higher heritability for inter-module connections. Furthermore, differential roles of genetic, cytoarchitectonic and chemoarchitectonic factors were observed for single-subject morphological brain networks. Cortical thickness-derived networks were related to the three factors with contributions from genes enriched in membrane and transport related functions, genes preferentially located in supragranular and granular layers, overall thickness in the molecular layer and thickness of wall in the infragranular layers, and metabotropic glutamate receptor 5 and dopamine transporter; fractal dimension-, gyrification index- and sulcal depth-derived networks were only associated with the chemoarchitectonic factor with contributions from different sets of neurotransmitter receptors. Most results were reproducible across different parcellation schemes and datasets. Altogether, this study demonstrates phenotypic associations and neurobiological substrates of single-subject morphological brain networks, which provide intermediate endophenotypes to link molecular and cellular architecture and behavior and cognition.

Single-subject cortical morphological brain networks across the adult lifespan.

Age-related changes in focal cortical morphology have been well documented in previous literature; however, how interregional coordination patterns of the focal cortical morphology reorganize with advancing age is not well established. In this study, we performed a comprehensive analysis of the topological changes in single-subject morphological brain networks across the adult lifespan. Specifically, we constructed four types of single-subject morphological brain networks for 650 participants (aged from 18 to 88 years old), and characterized their topological organization using graph-based network measures. Age-related changes in the network measures were examined via linear, quadratic, and cubic models. We found profound age-related changes in global small-world attributes and efficiency, local nodal centralities, and interregional similarities of the single-subject morphological brain networks. The age-related changes were mainly embodied in cortical thickness networks, involved in frontal regions and highly connected hubs, concentrated on short-range connections, characterized by linear changes, and susceptible to connections between limbic, frontoparietal, and ventral attention networks. Intriguingly, nonlinear (i.e., quadratic or cubic) age-related changes were frequently found in the insula and limbic regions, and age-related cubic changes preferred long-range morphological connections. Finally, we demonstrated that the morphological similarity in cortical thickness between two frontal regions mediated the relationship between age and cognition measured by Cattell scores. Taken together, these findings deepen our understanding of adaptive changes of the human brain with advancing age, which may account for interindividual variations in behaviors and cognition.

Surface-based single-subject morphological brain networks: Effects of morphological index, brain parcellation and similarity measure, sample size-varying stability and test-retest reliability.

Morphological brain networks, in particular those at the individual level, have become an important approach for studying the human brain connectome; however, relevant methodology is far from being well-established in their formation, description and reproducibility. Here, we extended our previous study by constructing and characterizing single-subject morphological similarity networks from brain volume to surface space and systematically evaluated their reproducibility with respect to effects of different choices of morphological index, brain parcellation atlas and similarity measure, sample size-varying stability and test-retest reliability. Using the Human Connectome Project dataset, we found that surface-based single-subject morphological similarity networks shared common small-world organization, high parallel efficiency, modular architecture and bilaterally distributed hubs regardless of different analytical strategies. Nevertheless, quantitative values of all interregional similarities, global network measures and nodal centralities were significantly affected by choices of morphological index, brain parcellation atlas and similarity measure. Moreover, the morphological similarity networks varied along with the number of participants and approached stability until the sample size exceeded ~70. Using an independent test-retest dataset, we found fair to good, even excellent, reliability for most interregional similarities and network measures, which were also modulated by different analytical strategies, in particular choices of morphological index. Specifically, fractal dimension and sulcal depth outperformed gyrification index and cortical thickness, higher-resolution atlases outperformed lower-resolution atlases, and Jensen-Shannon divergence-based similarity outperformed Kullback-Leibler divergence-based similarity. Altogether, our findings propose surface-based single-subject morphological similarity networks as a reliable method to characterize the human brain connectome and provide methodological recommendations and guidance for future research.

Multiparametric and multilevel characterization of morphological alterations in patients with transient ischemic attack.

Transient ischemic attack (TIA), an important risk factor for stroke, is associated with widespread disruptions of functional brain architecture. However, TIA-related structural alterations are not well established. By analyzing structural MRI data from 50 TIA patients versus 40 healthy controls (HCs), here we systematically investigated TIA-related morphological alterations in multiple cortical surface-based indices (cortical thickness [CT], fractal dimension [FD], gyrification index [GI], and sulcal depth [SD]) at multiple levels (local topography, interregional connectivity and whole-brain network topology). For the observed alterations, their associations with clinical risk factors and abilities as diagnostic and prognostic biomarkers were further examined. We found that compared with the HCs, the TIA patients showed widespread morphological alterations and the alterations depended on choices of morphological index and analytical level. Specifically, the patients exhibited: (a) regional CT decreases in the transverse temporal gyrus and lateral sulcus; (b) impaired FD- and GI-based connectivity mainly involving visual, somatomotor and ventral attention networks and interhemispheric connections; and (c) altered GI-based whole-brain network efficiency and decreased FD-based nodal centrality in the middle frontal gyrus. Moreover, the impaired morphological connectivity showed high sensitivities and specificities for distinguishing the patients from HCs. Altogether, these findings demonstrate the emergence of morphological index-dependent and analytical level-specific alterations in TIA, which provide novel insights into neurobiological mechanisms underlying TIA and may serve as potential biomarkers to help diagnosis of the disease. Meanwhile, our findings highlight the necessity of using multiparametric and multilevel approaches for a complete mapping of cerebral morphology in health and disease.

Neural network correlates of high-altitude adaptive genetic variants in Tibetans: A pilot, exploratory study.

Although substantial progress has been made in the identification of genetic substrates underlying physiology, neuropsychology, and brain organization, the genotype-phenotype associations remain largely unknown in the context of high-altitude (HA) adaptation. Here, we related HA adaptive genetic variants in three gene loci (EGLN1, EPAS1, and PPARA) to interindividual variance in a set of physiological characteristics, neuropsychological tests, and topological attributes of large-scale structural and functional brain networks in 135 indigenous Tibetan highlanders. Analyses of individual HA adaptive single-nucleotide polymorphisms (SNPs) revealed that specific SNPs selectively modulated physiological characteristics (erythrocyte level, ratio between forced expiratory volume in the first second to forced vital capacity, arterial oxygen saturation, and heart rate) and structural network centrality (the left anterior orbital gyrus) with no effects on neuropsychology or functional brain networks. Further analyses of genetic adaptive scores, which summarized the overall degree of genetic adaptation to HA, revealed significant correlations only with structural brain networks with respect to local interconnectivity of the whole networks, intermodule communication between the right frontal and parietal module and the left occipital module, nodal centrality in several frontal regions, and connectivity strength of a subnetwork predominantly involving in intramodule edges in the right temporal and occipital module. Moreover, the associations were dependent on gene loci, weight types, or topological scales. Together, these findings shed new light on genotype-phenotype interactions under HA hypoxia and have important implications for developing new strategies to optimize organism and tissue responses to chronic hypoxia induced by extreme environments or diseases.

Subregion-specific, modality-dependent and timescale-sensitive hippocampal connectivity alterations in patients with first-episode, drug-naïve major depression disorder.

BACKGROUND: Despite accumulating evidence for the hippocampus as a key dysfunctional node in major depressive disorder (MDD), previous findings are controversial possibly due to heterogeneous and small clinical samples, complicated hippocampal structure, and different imaging modalities and analytical methods. METHODS: We collected structural and resting-state functional MRI data from 100 first-episode, drug-naïve MDD patients and 99 healthy controls. A subset of the participants (34 patients and 33 controls) also completed a battery of neuropsychological tests and childhood trauma questionnaires. Seed-based morphological and functional (static and dynamic) connectivity were calculated for ten hippocampal subregions, followed by analyses of dynamic functional connectivity states (k-means clustering), connectivity cross-modality relationships (cosine similarity), and connectivity associations with clinical and neuropsychological variables (Spearman correlation). RESULTS: Between-group comparisons revealed abnormal hippocampal connectivity in the patients that depended on 1) hippocampal subdivisions: the cornu ammonis (CA) was the most seriously affected subregion, in particular the right CA1 for functional connectivity alterations; 2) imaging modality: morphological connectivity revealed seldom and sporadic alterations with different lobes, while functional connectivity identified numerous and convergent alterations with prefrontal regions; and 3) time scale: dynamic functional connectivity was more sensitive than static functional connectivity, in particular in revealing alterations between the right CA1 and contralateral prefrontal cortex. Among the 34 patients, functional connectivity alterations of the CA1 were related to the history of childhood trauma in the patients. LIMITATIONS: Only a subset of the patients completed the neuropsychological tests, which may cause underestimation of cognitive relevance of hippocampal connectivity alterations. CONCLUSIONS: Disrupted hippocampal CA1 functional connectivity plays key roles in the pathophysiology of MDD and may act as a potential diagnostic biomarker for the disease.

Aberrant multimodal brain networks in patients with anti-NMDA receptor encephalitis.

AIMS: To explore large-scale brain network alterations and examine their clinical and neuropsychological relevance in patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. METHODS: Twenty-four patients with anti-NMDAR encephalitis and 26 matched healthy controls (HCs) were enrolled in our study. Based on the multimodal MRI dataset, individual morphological, structural, and functional brain networks were constructed and compared between the two groups at multiple levels. The associations with clinical/neuropsychological variables and the discriminant ability of significant alterations were further studied. RESULTS: Multimodal network analysis revealed that anti-NMDAR encephalitis mainly affected morphological and structural networks, but subtle alterations were observed in functional networks. Intriguingly, decreased network local efficiency was observed for both morphological and structural networks and increased nodal centrality in the lateral orbital gyrus was convergently observed among the three types of networks in the patients. Moreover, the alterations, particularly those from structural networks, accounted largely for cognitive deficits of the patients and could distinguish the diseased individuals from the HCs with excellent performance (area under the curve =0.933). CONCLUSIONS: The current study provides a comprehensive view of characteristic multimodal network dysfunction in anti-NMDAR encephalitis, which is crucial to establish new diagnostic biomarkers and promising therapeutic targets for the disease.