Klaus H. Maier-Hein

Methodological considerations on tract-based spatial statistics (TBSS)

Having gained a tremendous amount of popularity since its introduction in 2006, tract-based spatial statistics (TBSS) can now be considered as the standard approach for voxel-based analysis (VBA) of diffusion tensor imaging (DTI) data. Aiming to improve the sensitivity, objectivity, and interpretability of multi-subject DTI studies, TBSS includes a skeletonization step that alleviates residual image misalignment and obviates the need for data smoothing. Although TBSS represents an elegant and user-friendly framework that tackles numerous concerns existing in conventional VBA methods, it has limitations of its own, some of which have already been detailed in recent literature. In this work, we present general methodological considerations on TBSS and report on pitfalls that have not been described previously. In particular, we have identified specific assumptions of TBSS that may not be satisfied under typical conditions. Moreover, we demonstrate that the existence of such violations can severely affect the reliability of TBSS results. With TBSS being used increasingly, it is of paramount importance to acquaint TBSS users with these concerns, such that a well-informed decision can be made as to whether and how to pursue a TBSS analysis. Finally, in addition to raising awareness by providing our new insights, we provide constructive suggestions that could improve the validity and increase the impact of TBSS drastically.

The challenge of mapping the human connectome based on diffusion tractography

Tractography based on non-invasive diffusion imaging is central to the study of human brain connectivity. To date, the approach has not been systematically validated in ground truth studies. Based on a simulated human brain data set with ground truth tracts, we organized an open international tractography challenge, which resulted in 96 distinct submissions from 20 research groups. Here, we report the encouraging finding that most state-of-the-art algorithms produce tractograms containing 90% of the ground truth bundles (to at least some extent). However, the same tractograms contain many more invalid than valid bundles, and half of these invalid bundles occur systematically across research groups. Taken together, our results demonstrate and confirm fundamental ambiguities inherent in tract reconstruction based on orientation information alone, which need to be considered when interpreting tractography and connectivity results. Our approach provides a novel framework for estimating reliability of tractography and encourages innovation to address its current limitations.Though tractography is widely used, it has not been systematically validated. Here, authors report results from 20 groups showing that many tractography algorithms produce both valid and invalid bundles.

Radiomic Profiling of Glioblastoma: Identifying an Imaging Predictor of Patient Survival with Improved Performance over Established Clinical and Radiologic Risk Models

Purpose To evaluate whether radiomic feature-based magnetic resonance (MR) imaging signatures allow prediction of survival and stratification of patients with newly diagnosed glioblastoma with improved accuracy compared with that of established clinical and radiologic risk models. Materials and Methods Retrospective evaluation of data was approved by the local ethics committee and informed consent was waived. A total of 119 patients (allocated in a 2:1 ratio to a discovery [n = 79] or validation [n = 40] set) with newly diagnosed glioblastoma were subjected to radiomic feature extraction (12 190 features extracted, including first-order, volume, shape, and texture features) from the multiparametric (contrast material-enhanced T1-weighted and fluid-attenuated inversion-recovery imaging sequences) and multiregional (contrast-enhanced and unenhanced) tumor volumes. Radiomic features of patients in the discovery set were subjected to a supervised principal component (SPC) analysis to predict progression-free survival (PFS) and overall survival (OS) and were validated in the validation set. The performance of a Cox proportional hazards model with the SPC analysis predictor was assessed with C index and integrated Brier scores (IBS, lower scores indicating higher accuracy) and compared with Cox models based on clinical (age and Karnofsky performance score) and radiologic (Gaussian normalized relative cerebral blood volume and apparent diffusion coefficient) parameters. Results SPC analysis allowed stratification based on 11 features of patients in the discovery set into a low- or high-risk group for PFS (hazard ratio [HR], 2.43; P = .002) and OS (HR, 4.33; P < .001), and the results were validated successfully in the validation set for PFS (HR, 2.28; P = .032) and OS (HR, 3.45; P = .004). The performance of the SPC analysis (OS: IBS, 0.149; C index, 0.654; PFS: IBS, 0.138; C index, 0.611) was higher compared with that of the radiologic (OS: IBS, 0.175; C index, 0.603; PFS: IBS, 0.149; C index, 0.554) and clinical risk models (OS: IBS, 0.161, C index, 0.640; PFS: IBS, 0.139; C index, 0.599). The performance of the SPC analysis model was further improved when combined with clinical data (OS: IBS, 0.142; C index, 0.696; PFS: IBS, 0.132; C index, 0.637). Conclusion An 11-feature radiomic signature that allows prediction of survival and stratification of patients with newly diagnosed glioblastoma was identified, and improved performance compared with that of established clinical and radiologic risk models was demonstrated. (©) RSNA, 2016 Online supplemental material is available for this article.

Deep MRI brain extraction: A 3D convolutional neural network for skull stripping

Brain extraction from magnetic resonance imaging (MRI) is crucial for many neuroimaging workflows. Current methods demonstrate good results on non-enhanced T1-weighted images, but struggle when confronted with other modalities and pathologically altered tissue. In this paper we present a 3D convolutional deep learning architecture to address these shortcomings. In contrast to existing methods, we are not limited to non-enhanced T1w images. When trained appropriately, our approach handles an arbitrary number of modalities including contrast-enhanced scans. Its applicability to MRI data, comprising four channels: non-enhanced and contrast-enhanced T1w, T2w and FLAIR contrasts, is demonstrated on a challenging clinical data set containing brain tumors (N=53), where our approach significantly outperforms six commonly used tools with a mean Dice score of 95.19. Further, the proposed method at least matches state-of-the-art performance as demonstrated on three publicly available data sets: IBSR, LPBA40 and OASIS, totaling N=135 volumes. For the IBSR (96.32) and LPBA40 (96.96) data set the convolutional neuronal network (CNN) obtains the highest average Dice scores, albeit not being significantly different from the second best performing method. For the OASIS data the second best Dice (95.02) results are achieved, with no statistical difference in comparison to the best performing tool. For all data sets the highest average specificity measures are evaluated, whereas the sensitivity displays about average results. Adjusting the cut-off threshold for generating the binary masks from the CNNs probability output can be used to increase the sensitivity of the method. Of course, this comes at the cost of a decreased specificity and has to be decided application specific. Using an optimized GPU implementation predictions can be achieved in less than one minute. The proposed method may prove useful for large-scale studies and clinical trials.

Large-scale Radiomic Profiling of Recurrent Glioblastoma Identifies an Imaging Predictor for Stratifying Anti-Angiogenic Treatment Response.

Purpose: Antiangiogenic treatment with bevacizumab, a mAb to the VEGF, is the single most widely used therapeutic agent for patients with recurrent glioblastoma. A major challenge is that there are currently no validated biomarkers that can predict treatment outcome. Here we analyze the potential of radiomics, an emerging field of research that aims to utilize the full potential of medical imaging. Experimental Design: A total of 4,842 quantitative MRI features were automatically extracted and analyzed from the multiparametric tumor of 172 patients (allocated to a discovery and validation set with a 2:1 ratio) with recurrent glioblastoma prior to bevacizumab treatment. Leveraging a high-throughput approach, radiomic features of patients in the discovery set were subjected to a supervised principal component (superpc) analysis to generate a prediction model for stratifying treatment outcome to antiangiogenic therapy by means of both progression-free and overall survival (PFS and OS). Results: The superpc predictor stratified patients in the discovery set into a low or high risk group for PFS (HR = 1.60; P = 0.017) and OS (HR = 2.14; P < 0.001) and was successfully validated for patients in the validation set (HR = 1.85, P = 0.030 for PFS; HR = 2.60, P = 0.001 for OS). Conclusions: Our radiomic-based superpc signature emerges as a putative imaging biomarker for the identification of patients who may derive the most benefit from antiangiogenic therapy, advances the knowledge in the noninvasive characterization of brain tumors, and stresses the role of radiomics as a novel tool for improving decision support in cancer treatment at low cost. Clin Cancer Res; 22(23); 5765–71. ©2016 AACR.

The DTI Challenge: Toward Standardized Evaluation of Diffusion Tensor Imaging Tractography for Neurosurgery

Diffusion tensor imaging (DTI) tractography reconstruction of white matter pathways can help guide brain tumor resection. However, DTI tracts are complex mathematical objects and the validity of tractography‐derived information in clinical settings has yet to be fully established. To address this issue, we initiated the DTI Challenge, an international working group of clinicians and scientists whose goal was to provide standardized evaluation of tractography methods for neurosurgery. The purpose of this empirical study was to evaluate different tractography techniques in the first DTI Challenge workshop.

ISLES 2015 - A public evaluation benchmark for ischemic stroke lesion segmentation from multispectral MRI

&NA; Ischemic stroke is the most common cerebrovascular disease, and its diagnosis, treatment, and study relies on non‐invasive imaging. Algorithms for stroke lesion segmentation from magnetic resonance imaging (MRI) volumes are intensely researched, but the reported results are largely incomparable due to different datasets and evaluation schemes. We approached this urgent problem of comparability with the Ischemic Stroke Lesion Segmentation (ISLES) challenge organized in conjunction with the MICCAI 2015 conference. In this paper we propose a common evaluation framework, describe the publicly available datasets, and present the results of the two sub‐challenges: Sub‐Acute Stroke Lesion Segmentation (SISS) and Stroke Perfusion Estimation (SPES). A total of 16 research groups participated with a wide range of state‐of‐the‐art automatic segmentation algorithms. A thorough analysis of the obtained data enables a critical evaluation of the current state‐of‐the‐art, recommendations for further developments, and the identification of remaining challenges. The segmentation of acute perfusion lesions addressed in SPES was found to be feasible. However, algorithms applied to sub‐acute lesion segmentation in SISS still lack accuracy. Overall, no algorithmic characteristic of any method was found to perform superior to the others. Instead, the characteristics of stroke lesion appearances, their evolution, and the observed challenges should be studied in detail. The annotated ISLES image datasets continue to be publicly available through an online evaluation system to serve as an ongoing benchmarking resource (www.isles‐challenge.org). HighlightsEvaluation framework for automatic stroke lesion segmentation from MRIPublic multi‐center, multi‐vendor, multi‐protocol databases releasedOngoing fair and automated benchmark with expert created ground truth setsComparison of 14+7 groups who responded to an open challenge in MICCAISegmentation feasible in acute and unsolved in sub‐acute cases Graphical abstract Figure. No caption available.

Prediction of treatment response in head and neck carcinomas using IVIM-DWI: Evaluation of lymph node metastasis.

PURPOSE To obtain diffusion and microperfusion measures in lymph node metastases of head and neck squamous cell carcinomas (HNSCC) using intravoxel incoherent motion (IVIM) imaging. The obtained IVIM parameters were used to characterize lymph nodes in the staging phase and longitudinal follow-up was performed to evaluate the potential predictive value of these parameters considering therapy response. METHODS Fifteen patients with lymph node metastases of histologically confirmed locally advanced HNSCC were examined using diffusion weighted imaging (DWI) before a nonsurgical organ preserving therapy. DWI imaging was performed at 3T using eight different b-values ranging from 0 to 800s/mm(2). Using the IVIM-approach, the perfusion fraction f and the diffusion coefficient D were extracted using a biexponential fit. A follow-up period of 13.5 months was available for all patients. One patient with a macroscopically necrotic lymph node was excluded from analyses. A region of interest (ROI)-analysis was performed in all patients. RESULTS Locoregional failure (LRF) was present in 3 of 15 patients within 13.5 months follow-up. The initial f-value was significantly higher (p=0.01) in patients with LRF (14.5±0.6% vs. 7.7±2.6%) compared to patients with locoregional control (LRC). The initial diffusion coefficient D did not differ significantly (p=0.30) between the two groups (0.97±0.15×10(-3)mm(2)/s vs. 0.88±0.13×10(-3)mm(2)/s). CONCLUSIONS Our results indicate that a high initial perfusion fraction f in lymph nodes may predict poor treatment response in patients with HNSCC due to locoregional failure.

Disorder-Specific White Matter Alterations in Adolescent Borderline Personality Disorder

BACKGROUND The pathogenesis of borderline personality disorder (BPD) is complex and not fully understood. Using diffusion tensor imaging, recent studies suggest that white matter abnormalities may occur in adult patients with BPD. However, deeper insight into the disorder-specific developmental psychobiology (e.g., analysis of adolescents with BPD; inclusion of clinical control groups) is missing. METHODS Twenty adolescent patients with BPD (aged 14-18 years), 20 healthy, and 20 clinical control subjects were assessed using diffusion tensor imaging. All subjects were right-handed girls, matched for age and IQ. Microstructural parameters were analyzed via tractography of the main bundles in the limbic system and using Tract-Based Spatial Statistics, an explorative, global approach. RESULTS BPD was associated with decreased fractional anisotropy in the fornix when compared with clinical (p < .001) or healthy (nonsignificant trend) control subjects. Using Tract-Based Spatial Statistics, significant disorder-specific white matter alterations were found in the long association bundles interconnecting the heteromodal association cortex and in connections between the thalamus and hippocampus. CONCLUSIONS The study strongly supports the hypothesis that white matter alterations play a key role in the pathogenesis of BPD. These disorder-specific alterations include white matter pathways involved in emotion regulation but also affect parts of the heteromodal association cortex that are related to emotion recognition. Our findings unify previously documented deficits in emotion recognition and regulation and suggest that a large-scale network of emotion processing is disrupted in BPD. Continued research is essential to evaluate the predictive value of these early disruptions in a clinical context.

Tractography-based connectomes are dominated by false-positive connections

Fiber tractography based on non-invasive diffusion imaging is at the heart of connectivity studies of the human brain. To date, the approach has not been systematically validated in ground truth studies. Based on a simulated human brain dataset with ground truth white matter tracts, we organized an open international tractography challenge, which resulted in 96 distinct submissions from 20 research groups. While most state-of-the-art algorithms reconstructed 90% of ground truth bundles to at least some extent, on average they produced four times more invalid than valid bundles. About half of the invalid bundles occurred systematically in the majority of submissions. Our results demonstrate fundamental ambiguities inherent to tract reconstruction methods based on diffusion orientation information, with critical consequences for the approach of diffusion tractography in particular and human connectivity studies in general.