Background Large-scale Granger causality (lsGC) is a recently developed, resting-state functional MRI (fMRI) connectivity analysis approach that estimates multivariate voxel-resolution connectivity. Unlike most commonly used multivariate approaches, which establish coarse-resolution connectivity by aggregating voxel time-series avoiding an underdetermined problem, lsGC estimates voxel-resolution, fine-grained connectivity by incorporating an embedded dimension reduction. New Method We investigate application of lsGC on realistic fMRI simulations, modeling smoothing of neuronal activity by the hemodynamic response function and repetition time (TR), and empirical resting-state fMRI data. Subsequently, functional subnetworks are extracted from lsGC connectivity measures for both datasets and validated quantitatively. We also provide guidelines to select lsGC free parameters. Results Results indicate that lsGC reliably recovers underlying network structure with Area Under receiver operator characteristic Curve (AUC) of 0.93 at TR=1.5s for a 10-minute session of fMRI simulations. Furthermore, subnetworks of closely interacting modules are recovered from the aforementioned lsGC networks. Results on empirical resting-state fMRI data demonstrate recovery of visual and motor cortex in close agreement with spatial maps obtained from (i) visuo-motor fMRI stimulation task-sequence (Accuracy=0.76) and (ii) independent component analysis (ICA) of resting-state fMRI (Accuracy=0.86). Comparison with Existing Method(s) Compared with conventional Granger causality approach (AUC=0.75), lsGC produces better network recovery on fMRI simulations. Furthermore, it cannot recover functional subnetworks from empirical fMRI data, since quantifying voxel-resolution connectivity is not possible as consequence of encountering an underdetermined problem. Conclusions Functional network recovery from fMRI data suggests that lsGC gives useful insight into connectivity patterns from resting-state fMRI at a multivariate voxel-resolution.

Visualization of ex vivo human patellar cartilage matrix through the phase contrast imaging X-ray computed tomography (PCI-CT) has been previously demonstrated. Such studies revealed osteoarthritis-induced changes to chondrocyte organization in the radial zone. This study investigates the application of texture analysis to characterizing such chondrocyte patterns in the presence and absence of osteoarthritic damage. Texture features derived from Minkowski functionals (MF) and gray-level co-occurrence matrices (GLCM) were extracted from 842 regions of interest (ROI) annotated on PCI-CT images of ex vivo human patellar cartilage specimens. These texture features were subsequently used in a machine learning task with support vector regression to classify ROIs as healthy or osteoarthritic; classification performance was evaluated using the area under the receiver operating characteristic curve (AUC). The best classification performance was observed with the MF features perimeter (AUC: 0.94 ± 0.08) and “Euler characteristic” (AUC: 0.94 ± 0.07), and GLCM-derived feature “Correlation” (AUC: 0.93 ± 0.07). These results suggest that such texture features can provide a detailed characterization of the chondrocyte organization in the cartilage matrix, enabling classification of cartilage as healthy or osteoarthritic with high accuracy.

Characterizing the dignity of breast lesions as benign or malignant is specifically difficult for small lesions; they don’t exhibit typical characteristics of malignancy and are harder to segment since margins are harder to visualize. Previous attempts at using dynamic or morphologic criteria to classify small lesions (mean lesion diameter of about 1 cm) have not yielded satisfactory results. The goal of this work was to improve the classification performance in such small diagnostically challenging lesions while concurrently eliminating the need for precise lesion segmentation. To this end, we introduce a method for topological characterization of lesion enhancement patterns over time. Three Minkowski Functionals were extracted from all five post-contrast images of sixty annotated lesions on dynamic breast MRI exams. For each Minkowski Functional, topological features extracted from each post-contrast image of the lesions were combined into a high-dimensional texture feature vector. These feature vectors were classified in a machine learning task with support vector regression. For comparison, conventional Haralick texture features derived from gray-level co-occurrence matrices (GLCM) were also used. A new method for extracting thresholded GLCM features was also introduced and investigated here. The best classification performance was observed with Minkowski Functionals area and perimeter, thresholded GLCM features f8 and f9, and conventional GLCM features f4 and f6. However, both Minkowski Functionals and thresholded GLCM achieved such results without lesion segmentation while the performance of GLCM features significantly deteriorated when lesions were not segmented (p < 0.05). This suggests that such advanced spatio-temporal characterization can improve the classification performance achieved in such small lesions, while simultaneously eliminating the need for precise segmentation.

Detecting changes of spatially high-resolution functional connectivity patterns in the brain is crucial for improving the fundamental understanding of brain function in both health and disease, yet still poses one of the biggest challenges in computational neuroscience. Currently, classical multivariate Granger Causality analyses of directed interactions between single process components in coupled systems are commonly restricted to spatially low- dimensional data, which requires a pre-selection or aggregation of time series as a preprocessing step. In this paper we propose a new fully multivariate Granger Causality approach with embedded dimension reduction that makes it possible to obtain a representation of functional connectivity for spatially high-dimensional data. The resulting functional connectivity networks may consist of several thousand vertices and thus contain more detailed information compared to connectivity networks obtained from approaches based on particular regions of interest. Our large scale Granger Causality approach is applied to synthetic and resting state fMRI data with a focus on how well network community structure, which represents a functional segmentation of the network, is preserved. It is demonstrated that a number of different community detection algorithms, which utilize a variety of algorithmic strategies and exploit topological features differently, reveal meaningful information on the underlying network module structure.

The results indicate that advanced topological texture features derived from MFs can provide superior classification performance in computer-assisted diagnosis of fibrotic interstitial lung disease patterns when compared to standard texture analysis methods.

Phase-contrast computed tomography (PCI-CT) has shown tremendous potential as an imaging modality for visualizing human cartilage with high spatial resolution. Previous studies have demonstrated the ability of PCI-CT to visualize (1) structural details of the human patellar cartilage matrix and (2) changes to chondrocyte organization induced by osteoarthritis. This study investigates the use of highdimensional geometric features in characterizing such chondrocyte patterns in the presence or absence of osteoarthritic damage. Geometrical features derived from the scaling index method (SIM) and statistical features derived from gray-level co-occurrence matrices were extracted from 842 regions of interest (ROI) annotated on PCI-CT images of ex vivo human patellar cartilage specimens. These features were subsequently used in a machine learning task with support vector regression to classify ROIs as healthy or osteoarthritic; classification performance was evaluated using the area under the receiveroperating characteristic curve (AUC). SIM-derived geometrical features exhibited the best classification performance (AUC, 0.95±0.06) and were most robust to changes in ROI size. These results suggest that such geometrical features can provide a detailed characterization of the chondrocyte organization in the cartilage matrix in an automated and nonsubjective manner, while also enabling classification of cartilage as healthy or osteoarthritic with high accuracy. Such features could potentially serve as imaging markers for evaluating osteoarthritis progression and its response to different therapeutic intervention strategies.

HIV is capable of invading the brain soon after seroconversion. This ultimately can lead to deficits in multiple cognitive domains commonly referred to as HIV-associated neurocognitive disorders (HAND). Clinical diagnosis of such deficits requires detailed neuropsychological assessment but clinical signs may be difficult to detect during asymptomatic injury of the central nervous system (CNS). Therefore neuroimaging biomarkers are of particular interest in HAND. In this study, we constructed brain connectivity profiles of 40 subjects (20 HIV positive subjects and 20 age-matched seronegative controls) using two different methods: a non-linear mutual connectivity analysis approach and a conventional method based on Pearson's correlation. These profiles were then summarized using graph-theoretic methods characterizing their topological network properties. Standard clinical and laboratory assessments were performed and a battery of neuropsychological (NP) tests was administered for all participating subjects. Based on NP testing, 14 of the seropositive subjects exhibited mild neurologic impairment. Subsequently, we analyzed associations between the network derived measures and neuropsychological assessment scores as well as common clinical laboratory plasma markers (CD4 cell count, HIV RNA) after adjusting for age and gender. Mutual connectivity analysis derived graph-theoretic measures, Modularity and Small Worldness, were significantly (p < 0.05, FDR adjusted) associated with the Executive as well as Overall z-score of NP performance. In contrast, network measures derived from conventional correlation-based connectivity did not yield any significant results. Thus, changes in connectivity can be captured using advanced time-series analysis techniques. The demonstrated associations between imaging-derived graph-theoretic properties of brain networks with neuropsychological performance, provides opportunities to further investigate the evolution of HAND in larger, longitudinal studies. Our analysis approach, involving non-linear time-series analysis in conjunction with graph theory, is promising and it may prove to be useful not only in HAND but also in other neurodegenerative disorders.

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