Comapping Cellular Content and Extracellular Matrix with Hemodynamics in Intact Arterial Tissues Using Scanning Immunofluorescent Multiphoton Microscopy.

Deviation of blood flow from an optimal range is known to be associated with the initiation and progression of vascular pathologies. Important open questions remain about how the abnormal flow drives specific wall changes in pathologies such as cerebral aneurysms where the flow is highly heterogeneous and complex. This knowledge gap precludes the clinical use of readily available flow data to predict outcomes and improve treatment of these diseases. As both flow and the pathological wall changes are spatially heterogeneous, a crucial requirement for progress in this area is a methodology for acquiring and comapping local vascular wall biology data with local hemodynamic data. Here, we developed an imaging pipeline to address this pressing need. A protocol that employs scanning multiphoton microscopy was developed to obtain three-dimensional (3D) datasets for smooth muscle actin, collagen, and elastin in intact vascular specimens. A cluster analysis was introduced to objectively categorize the smooth muscle cells (SMC) across the vascular specimen based on SMC actin density. Finally, direct quantitative comparison of local flow and wall biology in 3D intact specimens was achieved by comapping both heterogeneous SMC data and wall thickness to patient-specific hemodynamic results.

Calcification in Human Intracranial Aneurysms Is Highly Prevalent and Displays Both Atherosclerotic and Nonatherosclerotic Types.

OBJECTIVE: Although the clinical and biological importance of calcification is well recognized for the extracerebral vasculature, its role in cerebral vascular disease, particularly, intracranial aneurysms (IAs), remains poorly understood. Extracerebrally, 2 distinct mechanisms drive calcification, a nonatherosclerotic, rapid mineralization in the media and a slower, inflammation driven, atherosclerotic mechanism in the intima. This study aims to determine the prevalence, distribution, and type (atherosclerotic, nonatherosclerotic) of calcification in IAs and assess differences in occurrence between ruptured and unruptured IAs. Approach and Results: Sixty-five 65 IA specimens (48 unruptured, 17 ruptured) were resected perioperatively. Calcification and lipid pools were analyzed nondestructively in intact samples using high resolution (0.35 µm) microcomputed tomography. Calcification is highly prevalent (78%) appearing as micro (<500 µm), meso (500 µm-1 mm), and macro (>1 mm) calcifications. Calcification manifests in IAs as both nonatherosclerotic (calcification distinct from lipid pools) and atherosclerotic (calcification in the presence of lipid pools) with 3 wall types: Type I-only calcification, no lipid pools (20/51, 39%), Type II-calcification and lipid pools, not colocalized (19/51, 37%), Type III-calcification colocalized with lipid pools (12/51, 24%). Ruptured IAs either had no calcifications or had nonatherosclerotic micro- or meso-calcifications (Type I or II), without macro-calcifications. CONCLUSIONS: Calcification in IAs is substantially more prevalent than previously reported and presents as both nonatherosclerotic and atherosclerotic types. Notably, ruptured aneurysms had only nonatherosclerotic calcification, had significantly lower calcification fraction, and did not contain macrocalcifications. Improved understanding of the role of calcification in IA pathology should lead to new therapeutic targets.

Incorporating variability of patient inflow conditions into statistical models for aneurysm rupture assessment.

BACKGROUND: Hemodynamic patterns have been associated with cerebral aneurysm instability. For patient-specific computational fluid dynamics (CFD) simulations, the inflow rates of a patient are typically not known. The aim of this study was to analyze the influence of inter- and intra-patient variations of cerebral blood flow on the computed hemodynamics through CFD simulations and to incorporate these variations into statistical models for aneurysm rupture prediction. METHODS: Image data of 1820 aneurysms were used for patient-specific steady CFD simulations with nine different inflow rates per case, capturing inter- and intra-patient flow variations. Based on the computed flow fields, 17 hemodynamic parameters were calculated and compared for the different flow conditions. Next, statistical models for aneurysm rupture were trained in 1571 of the aneurysms including hemodynamic parameters capturing the flow variations either by defining hemodynamic "response variables" (model A) or repeatedly randomly selecting flow conditions by patients (model B) as well as morphological and patient-specific variables. Both models were evaluated in the remaining 249 cases. RESULTS: All hemodynamic parameters were significantly different for the varying flow conditions (p < 0.001). Both the flow-independent "response" model A and the flow-dependent model B performed well with areas under the receiver operating characteristic curve of 0.8182 and 0.8174 ± 0.0045, respectively. CONCLUSIONS: The influence of inter- and intra-patient flow variations on computed hemodynamics can be taken into account in multivariate aneurysm rupture prediction models achieving a good predictive performance. Such models can be applied to CFD data independent of the specific inflow boundary conditions.

Associations of hemodynamics, morphology, and patient characteristics with aneurysm rupture stratified by aneurysm location.

PURPOSE: The mechanisms of cerebral aneurysm rupture are not fully understood. We analyzed the associations of hemodynamics, morphology, and patient age and gender with aneurysm rupture stratifying by location. METHODS: Using image-based models, 20 hemodynamic and 17 morphological parameters were compared in 1931 ruptured and unruptured aneurysms with univariate logistic regression. Rupture rates were compared between males and females as well as younger and older patients and bifurcation versus sidewall aneurysms for different aneurysm locations. Subsequently, associations between hemodynamics and morphology and patient as well as aneurysm characteristics were analyzed for aneurysms at five locations. RESULTS: Compared to unruptured aneurysms, ruptured aneurysms were characterized by a more irregular shape and were exposed to a more adverse hemodynamic environment described by faster flow, higher wall shear stress, more oscillatory shear, and more unstable and complex flows. These associations with rupture status were consistent for different aneurysm locations. Rupture rates were significantly higher in males at the internal carotid artery (ICA) bifurcation, ophthalmic ICA, and the middle cerebral artery (MCA) bifurcation. At the anterior communicating artery (ACOM) and MCA bifurcation, they were significantly higher for younger patients. Bifurcation aneurysms had significantly larger rupture rates at the MCA and posterior communicating artery (PCOM). In these groups with higher rupture rates, aneurysms were characterized by adverse hemodynamics and more complex shapes. CONCLUSION: Hemodynamic and morphological differences between ruptured and unruptured aneurysms are consistent across locations. Adverse morphology and hemodynamics are related to rupture as well as younger age, male gender, and bifurcation aneurysms.

Extending statistical learning for aneurysm rupture assessment to Finnish and Japanese populations using morphology, hemodynamics, and patient characteristics.

OBJECTIVE: Incidental aneurysms pose a challenge for physicians, who need to weigh the rupture risk against the risks associated with treatment and its complications. A statistical model could potentially support such treatment decisions. A recently developed aneurysm rupture probability model performed well in the US data used for model training and in data from two European cohorts for external validation. Because Japanese and Finnish patients are known to have a higher aneurysm rupture risk, the authors' goals in the present study were to evaluate this model using data from Japanese and Finnish patients and to compare it with new models trained with Finnish and Japanese data. METHODS: Patient and image data on 2129 aneurysms in 1472 patients were used. Of these aneurysm cases, 1631 had been collected mainly from US hospitals, 249 from European (other than Finnish) hospitals, 147 from Japanese hospitals, and 102 from Finnish hospitals. Computational fluid dynamics simulations and shape analyses were conducted to quantitatively characterize each aneurysm's shape and hemodynamics. Next, the previously developed model's discrimination was evaluated using the Finnish and Japanese data in terms of the area under the receiver operating characteristic curve (AUC). Models with and without interaction terms between patient population and aneurysm characteristics were trained and evaluated including data from all four cohorts obtained by repeatedly randomly splitting the data into training and test data. RESULTS: The US model's AUC was reduced to 0.70 and 0.72, respectively, in the Finnish and Japanese data compared to 0.82 and 0.86 in the European and US data. When training the model with Japanese and Finnish data, the average AUC increased only slightly for the Finnish sample (to 0.76 ± 0.16) and Finnish and Japanese cases combined (from 0.74 to 0.75 ± 0.14) and decreased for the Japanese data (to 0.66 ± 0.33). In models including interaction terms, the AUC in the Finnish and Japanese data combined increased significantly to 0.83 ± 0.10. CONCLUSIONS: Developing an aneurysm rupture prediction model that applies to Japanese and Finnish aneurysms requires including data from these two cohorts for model training, as well as interaction terms between patient population and the other variables in the model. When including this information, the performance of such a model with Japanese and Finnish data is close to its performance with US or European data. These results suggest that population-specific differences determine how hemodynamics and shape associate with rupture risk in intracranial aneurysms.

External validation of cerebral aneurysm rupture probability model with data from two patient cohorts.

BACKGROUND: For a treatment decision of unruptured cerebral aneurysms, physicians and patients need to weigh the risk of treatment against the risk of hemorrhagic stroke caused by aneurysm rupture. The aim of this study was to externally evaluate a recently developed statistical aneurysm rupture probability model, which could potentially support such treatment decisions. METHODS: Segmented image data and patient information obtained from two patient cohorts including 203 patients with 249 aneurysms were used for patient-specific computational fluid dynamics simulations and subsequent evaluation of the statistical model in terms of accuracy, discrimination, and goodness of fit. The model's performance was further compared to a similarity-based approach for rupture assessment by identifying aneurysms in the training cohort that were similar in terms of hemodynamics and shape compared to a given aneurysm from the external cohorts. RESULTS: When applied to the external data, the model achieved a good discrimination and goodness of fit (area under the receiver operating characteristic curve AUC = 0.82), which was only slightly reduced compared to the optimism-corrected AUC in the training population (AUC = 0.84). The accuracy metrics indicated a small decrease in accuracy compared to the training data (misclassification error of 0.24 vs. 0.21). The model's prediction accuracy was improved when combined with the similarity approach (misclassification error of 0.14). CONCLUSIONS: The model's performance measures indicated a good generalizability for data acquired at different clinical institutions. Combining the model-based and similarity-based approach could further improve the assessment and interpretation of new cases, demonstrating its potential use for clinical risk assessment.

Development of a statistical model for discrimination of rupture status in posterior communicating artery aneurysms.

BACKGROUND: Intracranial aneurysms at the posterior communicating artery (PCOM) are known to have high rupture rates compared to other locations. We developed and internally validated a statistical model discriminating between ruptured and unruptured PCOM aneurysms based on hemodynamic and geometric parameters, angio-architectures, and patient age with the objective of its future use for aneurysm risk assessment. METHODS: A total of 289 PCOM aneurysms in 272 patients modeled with image-based computational fluid dynamics (CFD) were used to construct statistical models using logistic group lasso regression. These models were evaluated with respect to discrimination power and goodness of fit using tenfold nested cross-validation and a split-sample approach to mimic external validation. RESULTS: The final model retained maximum and minimum wall shear stress (WSS), mean parent artery WSS, maximum and minimum oscillatory shear index, shear concentration index, and aneurysm peak flow velocity, along with aneurysm height and width, bulge location, non-sphericity index, mean Gaussian curvature, angio-architecture type, and patient age. The corresponding area under the curve (AUC) was 0.8359. When omitting data from each of the three largest contributing hospitals in turn, and applying the corresponding model on the left-out data, the AUCs were 0.7507, 0.7081, and 0.5842, respectively. CONCLUSIONS: Statistical models based on a combination of patient age, angio-architecture, hemodynamics, and geometric characteristics can discriminate between ruptured and unruptured PCOM aneurysms with an AUC of 84%. It is important to include data from different hospitals to create models of aneurysm rupture that are valid across hospital populations.

The Computational Fluid Dynamics Rupture Challenge 2013--Phase II: Variability of Hemodynamic Simulations in Two Intracranial Aneurysms.

With the increased availability of computational resources, the past decade has seen a rise in the use of computational fluid dynamics (CFD) for medical applications. There has been an increase in the application of CFD to attempt to predict the rupture of intracranial aneurysms, however, while many hemodynamic parameters can be obtained from these computations, to date, no consistent methodology for the prediction of the rupture has been identified. One particular challenge to CFD is that many factors contribute to its accuracy; the mesh resolution and spatial/temporal discretization can alone contribute to a variation in accuracy. This failure to identify the importance of these factors and identify a methodology for the prediction of ruptures has limited the acceptance of CFD among physicians for rupture prediction. The International CFD Rupture Challenge 2013 seeks to comment on the sensitivity of these various CFD assumptions to predict the rupture by undertaking a comparison of the rupture and blood-flow predictions from a wide range of independent participants utilizing a range of CFD approaches. Twenty-six groups from 15 countries took part in the challenge. Participants were provided with surface models of two intracranial aneurysms and asked to carry out the corresponding hemodynamics simulations, free to choose their own mesh, solver, and temporal discretization. They were requested to submit velocity and pressure predictions along the centerline and on specified planes. The first phase of the challenge, described in a separate paper, was aimed at predicting which of the two aneurysms had previously ruptured and where the rupture site was located. The second phase, described in this paper, aims to assess the variability of the solutions and the sensitivity to the modeling assumptions. Participants were free to choose boundary conditions in the first phase, whereas they were prescribed in the second phase but all other CFD modeling parameters were not prescribed. In order to compare the computational results of one representative group with experimental results, steady-flow measurements using particle image velocimetry (PIV) were carried out in a silicone model of one of the provided aneurysms. Approximately 80% of the participating groups generated similar results. Both velocity and pressure computations were in good agreement with each other for cycle-averaged and peak-systolic predictions. Most apparent "outliers" (results that stand out of the collective) were observed to have underestimated velocity levels compared to the majority of solutions, but nevertheless identified comparable flow structures. In only two cases, the results deviate by over 35% from the mean solution of all the participants. Results of steady CFD simulations of the representative group and PIV experiments were in good agreement. The study demonstrated that while a range of numerical schemes, mesh resolution, and solvers was used, similar flow predictions were observed in the majority of cases. To further validate the computational results, it is suggested that time-dependent measurements should be conducted in the future. However, it is recognized that this study does not include the biological aspects of the aneurysm, which needs to be considered to be able to more precisely identify the specific rupture risk of an intracranial aneurysm.

Evaluation of predictive models of aneurysm focal growth and bleb development using machine learning techniques.

BACKGROUND: The presence of blebs increases the rupture risk of intracranial aneurysms (IAs). OBJECTIVE: To evaluate whether cross-sectional bleb formation models can identify aneurysms with focalized enlargement in longitudinal series. METHODS: Hemodynamic, geometric, and anatomical variables derived from computational fluid dynamics models of 2265 IAs from a cross-sectional dataset were used to train machine learning (ML) models for bleb development. ML algorithms, including logistic regression, random forest, bagging method, support vector machine, and K-nearest neighbors, were validated using an independent cross-sectional dataset of 266 IAs. The models' ability to identify aneurysms with focalized enlargement was evaluated using a separate longitudinal dataset of 174 IAs. Model performance was quantified by the area under the receiving operating characteristic curve (AUC), the sensitivity and specificity, positive predictive value, negative predictive value, F1 score, balanced accuracy, and misclassification error. RESULTS: The final model, with three hemodynamic and four geometrical variables, along with aneurysm location and morphology, identified strong inflow jets, non-uniform wall shear stress with high peaks, larger sizes, and elongated shapes as indicators of a higher risk of focal growth over time. The logistic regression model demonstrated the best performance on the longitudinal series, achieving an AUC of 0.9, sensitivity of 85%, specificity of 75%, balanced accuracy of 80%, and a misclassification error of 21%. CONCLUSIONS: Models trained with cross-sectional data can identify aneurysms prone to future focalized growth with good accuracy. These models could potentially be used as early indicators of future risk in clinical practice.

Phenotyping calcification in vascular tissues using artificial intelligence.

Vascular calcification is implicated as an important factor in major adverse cardiovascular events (MACE), including heart attack and stroke. A controversy remains over how to integrate the diverse forms of vascular calcification into clinical risk assessment tools. Even the commonly used calcium score for coronary arteries, which assumes risk scales positively with total calcification, has important inconsistencies. Fundamental studies are needed to determine how risk is influenced by the diverse calcification phenotypes. However, studies of these kinds are hindered by the lack of high-throughput, objective, and non-destructive tools for classifying calcification in imaging data sets. Here, we introduce a new classification system for phenotyping calcification along with a semi-automated, non-destructive pipeline that can distinguish these phenotypes in even atherosclerotic tissues. The pipeline includes a deep-learning-based framework for segmenting lipid pools in noisy µ-CT images and an unsupervised clustering framework for categorizing calcification based on size, clustering, and topology. This approach is illustrated for five vascular specimens, providing phenotyping for thousands of calcification particles across as many as 3200 images in less than seven hours. Average Dice Similarity Coefficients of 0.96 and 0.87 could be achieved for tissue and lipid pool, respectively, with training and validation needed on only 13 images despite the high heterogeneity in these tissues. By introducing an efficient and comprehensive approach to phenotyping calcification, this work enables large-scale studies to identify a more reliable indicator of the risk of cardiovascular events, a leading cause of global mortality and morbidity.

Description of the local hemodynamic environment in intracranial aneurysm wall subdivisions.

Intracranial aneurysms (IAs) pose severe health risks influenced by hemodynamics. This study focuses on the intricate characterization of hemodynamic conditions within the IA walls and their influence on bleb development, aiming to enhance understanding of aneurysm stability and the risk of rupture. The methods emphasized utilizing a comprehensive dataset of 359 IAs and 213 IA blebs from 268 patients to reconstruct patient-specific vascular models, analyzing blood flow using finite element methods to solve the unsteady Navier-Stokes equations, the segmentation of aneurysm wall subregions and the hemodynamic metrics wall shear stress (WSS), its metrics, and the critical points in WSS fields were computed and analyzed across different aneurysm subregions defined by saccular, streamwise, and topographical divisions. The results revealed significant variations in these metrics, correlating distinct hemodynamic environments with wall features on the aneurysm walls, such as bleb formation. Critical findings indicated that regions with low WSS and high OSI, particularly in the body and central regions of aneurysms, are prone to conditions that promote bleb formation. Conversely, areas exposed to high WSS and positive divergence, like the aneurysm neck, inflow, and outflow regions, exhibited a different but substantial risk profile for bleb development, influenced by flow impingements and convergences. These insights highlight the complexity of aneurysm behavior, suggesting that both high and low-shear environments can contribute to aneurysm pathology through distinct mechanisms.

Distribution of rupture sites and blebs on intracranial aneurysm walls suggests distinct rupture patterns in ACom and MCA aneurysms.

The mechanisms behind intracranial aneurysm formation and rupture are not fully understood, with factors such as location, patient demographics, and hemodynamics playing a role. Additionally, the significance of anatomical features like blebs in ruptures is debated. This highlights the necessity for comprehensive research that combines patient-specific risk factors with a detailed analysis of local hemodynamic characteristics at bleb and rupture sites. Our study analyzed 359 intracranial aneurysms from 268 patients, reconstructing patient-specific models for hemodynamic simulations based on 3D rotational angiographic images and intraoperative videos. We identified aneurysm subregions and delineated rupture sites, characterizing blebs and their regional overlap, employing statistical comparisons across demographics, and other risk factors. This work identifies patterns in aneurysm rupture sites, predominantly at the dome, with variations across patient demographics. Hypertensive and anterior communicating artery (ACom) aneurysms showed specific rupture patterns and bleb associations, indicating two pathways: high-flow in ACom with thin blebs at impingement sites and low-flow, oscillatory conditions in middle cerebral artery (MCA) aneurysms fostering thick blebs. Bleb characteristics varied with gender, age, and smoking, linking rupture risks to hemodynamic factors and patient profiles. These insights enhance understanding of the hemodynamic mechanisms leading to rupture events. This analysis elucidates the role of localized hemodynamics in intracranial aneurysm rupture, challenging the emphasis on location by revealing how flow variations influence stability and risk. We identify two pathways to wall failure-high-flow and low-flow conditions-highlighting the complexity of aneurysm behavior. Additionally, this research advances our knowledge of how inherent patient-specific characteristics impact these processes, which need further investigation.

Digital reconstruction and morphometric analysis of human brain arterial vasculature from magnetic resonance angiography.

Characterization of the complex branching architecture of cerebral arteries across a representative sample of the human population is important for diagnosing, analyzing, and predicting pathological states. Brain arterial vasculature can be visualized by magnetic resonance angiography (MRA). However, most MRA studies are limited to qualitative assessments, partial morphometric analyses, individual (or small numbers of) subjects, proprietary datasets, or combinations of the above limitations. Neuroinformatics tools, developed for neuronal arbor analysis, were used to quantify vascular morphology from 3T time-of-flight MRA high-resolution (620 µm isotropic) images collected in 61 healthy volunteers (36/25 F/M, average age=31.2 ± 10.7, range=19-64 years). We present in-depth morphometric analyses of the global and local anatomical features of these arbors. The overall structure and size of the vasculature did not significantly differ across genders, ages, or hemispheres. The total length of the three major arterial trees stemming from the circle of Willis (from smallest to largest: the posterior, anterior, and middle cerebral arteries; or PCAs, ACAs, and MCAs, respectively) followed an approximate 1:2:4 proportion. Arterial size co-varied across individuals: subjects with one artery longer than average tended to have all other arteries also longer than average. There was no net right-left difference across the population in any of the individual arteries, but ACAs were more lateralized than MCAs. MCAs, ACAs, and PCAs had similar branch-level properties such as bifurcation angles. Throughout the arterial vasculature, there were considerable differences between branch types: bifurcating branches were significantly shorter and straighter than terminating branches. Furthermore, the length and meandering of bifurcating branches increased with age and with path distance from the circle of Willis. All reconstructions are freely distributed through a public database to enable additional analyses and modeling (cng.gmu.edu/brava).

Differences Between Ruptured Aneurysms With and Without Blebs: Mechanistic Implications.

PURPOSE: Blebs are known risk factors for intracranial aneurysm (IA) rupture. We analyzed differences between IAs that ruptured with blebs and those that ruptured without developing blebs to identify distinguishing characteristics among them and suggest possible mechanistic implications. METHODS: Using image-based models, 25 hemodynamic and geometric parameters were compared between ruptured IAs with and without blebs (n = 673), stratified by location. Hemodynamic and geometric differences between bifurcation and sidewall aneurysms and for aneurysms at five locations were also analyzed. RESULTS: Ruptured aneurysms harboring blebs were exposed to higher flow conditions than aneurysms that ruptured without developing blebs, and this was consistent across locations. Bifurcation aneurysms were exposed to higher flow conditions than sidewall aneurysms. They had larger maximum wall shear stress (WSS), more concentrated WSS distribution, and larger numbers of critical points than sidewall aneurysms. Additionally, bifurcation aneurysms were larger, more elongated, and had more distorted shapes than sidewall aneurysms. Aneurysm morphology was associated with aneurysm location (p < 0.01). Flow conditions were different between aneurysm locations. CONCLUSION: Aneurysms at different locations are likely to develop into varying morphologies and thus be exposed to diverse flow conditions that may predispose them to follow distinct pathways towards rupture with or without bleb development. This could explain the diverse rupture rates and bleb presence in aneurysms at different locations.

Computational fluid dynamics-based virtual angiograms for the detection of flow stagnation in intracranial aneurysms.

The goal of this study was to test if CFD-based virtual angiograms could be used to automatically discriminate between intracranial aneurysms (IAs) with and without flow stagnation. Time density curves (TDC) were extracted from patient digital subtraction angiography (DSA) image sequences by computing the average gray level intensity inside the aneurysm region and used to define injection profiles for each subject. Subject-specific 3D models were reconstructed from 3D rotational angiography (3DRA) and computational fluid dynamics (CFD) simulations were performed to simulate the blood flow inside IAs. Transport equations were solved numerically to simulate the dynamics of contrast injection into the parent arteries and IAs and then the contrast retention time (RET) was calculated. The importance of gravitational pooling of contrast agent within the aneurysm was evaluated by modeling contrast agent and blood as a mixture of two fluids with different densities and viscosities. Virtual angiograms can reproduce DSA sequences if the correct injection profile is used. RET can identify aneurysms with significant flow stagnation even when the injection profile is not known. Using a small sample of 14 IAs of which seven were previously classified as having flow stagnation, it was found that a threshold RET value of 0.46 s can successfully identify flow stagnation. CFD-based prediction of stagnation was in more than 90% agreement with independent visual DSA assessment of stagnation in a second sample of 34 IAs. While gravitational pooling prolonged contrast retention time it did not affect the predictive capabilities of RET. CFD-based virtual angiograms can detect flow stagnation in IAs and can be used to automatically identify aneurysms with flow stagnation even without including gravitational effects on contrast agents.

Understanding development of jugular bulb stenosis in vein of galen malformations: identifying metrics of complex flow dynamics in the cerebral venous vasculature of infants.

Introduction: Computational fluid dynamics (CFD) assess biological systems based on specific boundary conditions. We propose modeling more advanced hemodynamic metrics, such as core line length (CL) and critical points which characterize complexity of flow in the context of cerebral vasculature, and specifically cerebral veins during the physiologically evolving early neonatal state of vein of Galen malformations (VOGM). CFD has not been applied to the study of arteriovenous shunting in Vein of Galen Malformations but could help illustrate the pathophysiology of this malformation. Methods: Three neonatal patients with VOGM at Boston Children's Hospital met inclusion criteria for this study. Structural MRI data was segmented to generate a mesh of the VOGM and venous outflow. Boundary condition flow velocity was derived from PC-MR sequences with arterial and venous dual velocity encoding. The mesh and boundary conditions were applied to model the cerebral venous flow. We computed flow variables including mean wall shear stress (WSSmean), mean OSI, CL, and the mean number of critical points (nCrPointsmean) for each patient specific model. A critical point is defined as the location where the shear stress vector field is zero (stationary point) and can be used to describe complexity of flow. Results: The division of flow into the left and right venous outflow was comparable between PC-MR and CFD modeling. A high complexity recirculating flow pattern observed on PC-MR was also identified on CFD modeling. Regions of similar WSSmean and OSImean (<1.3 fold) in the left and right venous outflow channels of a single patient have several-fold magnitude difference in higher order hemodynamic metrics (> 3.3 fold CL, > 1.7 fold nCrPointsmean). Specifically, the side which developed JBS in each model had greater nCrPointsmean compared to the jugular bulb with no stenosis (VOGM1: 4.49 vs. 2.53, VOGM2: 1.94 vs. 0, VOGM3: 1 vs. 0). Biologically, these regions had subsequently divergent development, with increased complexity of flow associating with venous stenosis. Discussion: Advanced metrics of flow complexity identified in computational models may reflect observed flow phenomena not fully characterized by primary or secondary hemodynamic parameters. These advanced metrics may indicate physiological states that impact development of jugular bulb stenosis in VOGM.

Flow reversal in distal collaterals as a possible mechanism of delayed intraparenchymal hemorrhage after flow diversion treatment of cerebral aneurysms.

Background and Purpose: Delayed intraparenchymal hemorrhages (DIPHs) are one of the most serious complications of cerebral aneurysm treatment with flow diverters (FD), yet their causes are largely unknown. This study analyzes distal hemodynamic alterations induced by the treatment of intracranial aneurysms with FDs. Methods: A realistic model of the brain arterial network was constructed from MRA images and extended with a constrained constructive optimization technique down to vessel diameters of approximately 50 µ m . Different variants of the circle of Willis were created by alternatively occluding communicating arteries. Collateral vessels connecting different arterial trees were then added to the model, and a distributed lumped parameter approach was used to model the pulsatile blood flow in the arterial network. The treatment of an ICA aneurysm was modeled by changing the local resistance, flow inertia, and compliance of the aneurysmal segment. Results: The maximum relative change in distal pressure induced by the aneurysm treatment was below 1%. However, for certain combinations of the circle of Willis and distal collateralization, important flow reversals (with a wall shear stress larger than approximately 1.0   d y n e / c m 2 ) were observed in collateral vessels, both ipsilaterally and contralaterally to the treated aneurysm. Conclusion: This study suggests the hypothesis that flow diverters treatment of intracranial aneurysms could cause important flow reversal in distal collaterals. Flow reversal has previously been shown to be pro-inflammatory and pro-atherogenic and could therefore have a detrimental effect on these collateral vessels, and thus could be a suitable explanation of DIPHs, while the small distal pressure increase is not.

Prediction of bleb formation in intracranial aneurysms using machine learning models based on aneurysm hemodynamics, geometry, location, and patient population.

BACKGROUND: Bleb presence in intracranial aneurysms (IAs) is a known indication of instability and vulnerability. OBJECTIVE: To develop and evaluate predictive models of bleb development in IAs based on hemodynamics, geometry, anatomical location, and patient population. METHODS: Cross-sectional data (one time point) of 2395 IAs were used for training bleb formation models using machine learning (random forest, support vector machine, logistic regression, k-nearest neighbor, and bagging). Aneurysm hemodynamics and geometry were characterized using image-based computational fluid dynamics. A separate dataset with 266 aneurysms was used for model evaluation. Model performance was quantified by the area under the receiving operating characteristic curve (AUC), true positive rate (TPR), false positive rate (FPR), precision, and balanced accuracy. RESULTS: The final model retained 18 variables, including hemodynamic, geometrical, location, multiplicity, and morphology parameters, and patient population. Generally, strong and concentrated inflow jets, high speed, complex and unstable flow patterns, and concentrated, oscillatory, and heterogeneous wall shear stress patterns together with larger, more elongated, and more distorted shapes were associated with bleb formation. The best performance on the validation set was achieved by the random forest model (AUC=0.82, TPR=91%, FPR=36%, misclassification error=27%). CONCLUSIONS: Based on the premise that aneurysm characteristics prior to bleb formation resemble those derived from vascular reconstructions with their blebs virtually removed, machine learning models can identify aneurysms prone to bleb development with good accuracy. Pending further validation with longitudinal data, these models may prove valuable for assessing the propensity of IAs to progress to vulnerable states and potentially rupturing.

Quantification of the Rupture Potential of Patient-Specific Intracranial Aneurysms under Contact Constraints.

Intracranial aneurysms (IAs) are localized enlargements of cerebral blood vessels that cause substantial rates of mortality and morbidity in humans. The rupture possibility of these aneurysms is a critical medical challenge for physicians during treatment planning. This treatment planning while assessing the rupture potential of aneurysms becomes more complicated when they are constrained by an adjacent structure such as optic nerve tissues or bones, which is not widely studied yet. In this work, we considered and studied a constitutive model to investigate the bio-mechanical response of image-based patient-specific IA data using cardiovascular structural mechanics equations. We performed biomechanical modeling and simulations of four different patient-specific aneurysms' data (three middle cerebral arteries and one internal carotid artery) to assess the rupture potential of those aneurysms under a plane contact constraint. Our results suggest that aneurysms with plane contact constraints produce less or almost similar maximum wall effective stress compared to aneurysms with no contact constraints. In our research findings, we observed that a plane contact constraint on top of an internal carotid artery might work as a protective wall due to the 16.6% reduction in maximum wall effective stress than that for the case where there is no contact on top of the aneurysm.

Hemodynamic conditions that favor bleb formation in cerebral aneurysms.

BACKGROUND: Although it is generally believed that blebs represent weaker spots in the walls of intracranial aneurysms (IAs), it is largely unknown which aneurysm characteristics favor their development. OBJECTIVE: To investigate possible associations between aneurysm hemodynamic and geometric characteristics and the development of blebs in intracranial aneurysms. METHODS: A total of 270 IAs in 199 patients selected for surgical clipping were studied. Blebs were visually identified and interactively marked on patient-specific vascular models constructed from presurgical images. Blebs were then deleted from the vascular reconstruction to approximate the aneurysm before bleb formation. Computational fluid dynamics studies were performed in these models and in cases without blebs. Hemodynamic and geometric characteristics of aneurysms with and without blebs were compared. RESULTS: A total of 173 aneurysms had no blebs, while 97 aneurysms had a total of 122 blebs. Aneurysms favoring bleb formation had stronger (p<0.0001) and more concentrated inflow jets (p<0.0001), higher flow velocity (p=0.0061), more complex (p<0.0001) and unstable (p=0.0157) flow patterns, larger maximum wall shear stress (WSS; p<0.0001), more concentrated (p=0.0005) and oscillatory (p=0.0004) WSS distribution, and a more heterogeneous WSS field (p<0.0001), than aneurysms without blebs. They were also larger (p<0.0001), more elongated (p<0.0001), had wider necks (p=0.0002), and more distorted and irregular shapes (p<0.0001). CONCLUSIONS: Strong and concentrated inflow jets, high-speed, complex, and unstable flow patterns, and concentrated, oscillatory, and heterogeneous WSS patterns favor the formation of blebs in IAs. Blebs are more likely to form in large, elongated, and irregularly shaped aneurysms. These adverse characteristics could be considered signs of aneurysm instability when evaluating aneurysms for conservative observation or treatment.