Can quantitative susceptibility mapping help diagnose and predict recovery of concussion in children? An A-CAP study.

BACKGROUND: Quantitative susceptibility mapping (QSM) is an MRI technique that is a potential biomarker for concussion. We performed QSM in children following concussion or orthopaedic injury (OI), to assess QSM performance as a diagnostic and prognostic biomarker. METHODS: Children aged 8-17 years with either concussion (N=255) or OI (N=116) were recruited from four Canadian paediatric emergency departments and underwent QSM postacutely (2-33 days postinjury) using 3 Tesla MRI. QSM Z-scores within nine regions of interest (ROI) were compared between groups. QSM Z-scores were also compared with the 5P score, the current clinical benchmark for predicting persistent postconcussion symptoms (PPCS), at 4 weeks postinjury, with PPCS defined using reliable change methods based on both participant and parent reports. RESULTS: Concussion and OI groups did not differ significantly in QSM Z-scores for any ROI. Higher QSM Z-scores within frontal white matter (WM) independently predicted PPCS based on parent ratings of cognitive symptoms (p=0.001). The combination of frontal WM QSM Z-score and 5P score was better at predicting PPCS than 5P score alone (p=0.004). The area under the curve was 0.72 (95% CI 0.63 to 0.81) for frontal WM susceptibility, 0.69 (95% CI 0.59 to 0.79) for the 5P score and 0.74 (95% CI 0.65 to 0.83) for both. CONCLUSION: The findings suggest that QSM is a potential MRI biomarker that can help predict PPCS in children with concussion, over and above the current clinical benchmark, and thereby aid in clinical management. They also suggest a frontal lobe substrate for PPCS, highlighting the potential for QSM to clarify the neurophysiology of paediatric concussion.

Short-term repeatability and long-term reproducibility of quantitative MR imaging biomarkers in a single centre longitudinal study.

Quantitative imaging biomarkers (QIBs) can be defined as objective measures that are sensitive and specific to changes in tissue physiology. Provided the acquired QIBs are not affected by scanner changes, they could play an important role in disease diagnosis, prognosis, management, and treatment monitoring. The precision of selected QIBs was assessed from data collected on a 3-T scanner in four healthy participants over a 5-year period. Inevitable scanner changes and acquisition protocol revisions occurred during this time. Standard and custom processing pipelines were used to calculate regional brain volume, cortical thickness, T2, T2*, quantitative susceptibility, cerebral blood flow, axial, radial and mean diffusivity, peak width of skeletonized mean diffusivity, and fractional anisotropy from the acquired images. Coefficient of variation (CoV) and intra-class correlation (ICC) indices were determined in the short-term (i.e., repeatable over three acquisitions within 4 weeks) and in the long-term (i.e., reproducible over four acquisition sessions in 5 years). Precision indices varied based on acquisition technique, processing pipeline, and anatomical region. Good repeatability (average CoV=2.40% and ICC=0.78) and reproducibility (average CoV=8.86 % and ICC=0.72) were found over all QIBs. The best performance indices were obtained for diffusion derived biomarkers (CoV∼0.96% and ICCs=0.87); conversely, the poorest indices were found for the cerebral blood flow biomarker (CoV>10% and ICC<0.5). These results demonstrate that changes in protocol, along with hardware and software upgrades, did not affect the estimates of the selected biomarkers and their precision. Further characterization of the QIB is necessary to understand meaningful changes in the biomarkers in longitudinal studies of normal brain aging and translation to clinical research.

An open, multi-vendor, multi-field-strength brain MR dataset and analysis of publicly available skull stripping methods agreement.

This paper presents an open, multi-vendor, multi-field strength magnetic resonance (MR) T1-weighted volumetric brain imaging dataset, named Calgary-Campinas-359 (CC-359). The dataset is composed of images of older healthy adults (29-80 years) acquired on scanners from three vendors (Siemens, Philips and General Electric) at both 1.5 T and 3 T. CC-359 is comprised of 359 datasets, approximately 60 subjects per vendor and magnetic field strength. The dataset is approximately age and gender balanced, subject to the constraints of the available images. It provides consensus brain extraction masks for all volumes generated using supervised classification. Manual segmentation results for twelve randomly selected subjects performed by an expert are also provided. The CC-359 dataset allows investigation of 1) the influences of both vendor and magnetic field strength on quantitative analysis of brain MR; 2) parameter optimization for automatic segmentation methods; and potentially 3) machine learning classifiers with big data, specifically those based on deep learning methods, as these approaches require a large amount of data. To illustrate the utility of this dataset, we compared to the results of a supervised classifier, the results of eight publicly available skull stripping methods and one publicly available consensus algorithm. A linear mixed effects model analysis indicated that vendor (p-value<0.001) and magnetic field strength (p-value<0.001) have statistically significant impacts on skull stripping results.

SimITK: visual programming of the ITK image-processing library within Simulink.

The Insight Segmentation and Registration Toolkit (ITK) is a software library used for image analysis, visualization, and image-guided surgery applications. ITK is a collection of C++ classes that poses the challenge of a steep learning curve should the user not have appropriate C++ programming experience. To remove the programming complexities and facilitate rapid prototyping, an implementation of ITK within a higher-level visual programming environment is presented: SimITK. ITK functionalities are automatically wrapped into "blocks" within Simulink, the visual programming environment of MATLAB, where these blocks can be connected to form workflows: visual schematics that closely represent the structure of a C++ program. The heavily templated C++ nature of ITK does not facilitate direct interaction between Simulink and ITK; an intermediary is required to convert respective data types and allow intercommunication. As such, a SimITK "Virtual Block" has been developed that serves as a wrapper around an ITK class which is capable of resolving the ITK data types to native Simulink data types. Part of the challenge surrounding this implementation involves automatically capturing and storing the pertinent class information that need to be refined from an initial state prior to being reflected within the final block representation. The primary result from the SimITK wrapping procedure is multiple Simulink block libraries. From these libraries, blocks are selected and interconnected to demonstrate two examples: a 3D segmentation workflow and a 3D multimodal registration workflow. Compared to their pure-code equivalents, the workflows highlight ITK usability through an alternative visual interpretation of the code that abstracts away potentially confusing technicalities.

Quantitative Susceptibility Mapping in Adults with Persistent-Post Concussion Symptoms after Mild Traumatic Brain Injury: An Exploratory Study.

BACKGROUND AND PURPOSE: It is estimated that 18-30% of concussion sufferers experience symptoms lasting more than 1 month, known as persistent post-concussion symptoms (PPCS). Symptoms can be debilitating, and include headache, dizziness, nausea, problems with memory and concentration, sleep and mood disruption, and exercise intolerance. Previous studies have used quantitative susceptibility mapping (QSM) to show altered tissue susceptibility levels in adults acutely following concussion, however this finding has yet to be investigated in participants with PPCS. MATERIALS AND METHODS: In this exploratory case-controlled study, we measured tissue susceptibility using quantitative susceptibility mapping (QSM) in 24 participants with PPCS following mild traumatic brain injury (mTBI) and 23 healthy controls with no history of concussion. We compute tissue susceptibility for seven white matter tracts and three deep grey matter regions and compare tissue susceptibility between groups using ANCOVA models controlling for age and sex. We also assess the relationship between regional tissue susceptibility and symptoms. RESULTS: There were no significant differences between tissue susceptibility in participants with PPCS compared to control subjects in any of the evaluated regions. However, we show lower tissue susceptibility across four white matter tracts was generally associated with worse symptoms in the PPCS group. Specifically, we saw relationships between white matter susceptibility and headache (p=0.006), time since injury (p=0.03), depressive symptoms (p=0.021) and daytime fatigue (p=0.01) in participants with PPCS. CONCLUSIONS: These results provide evidence in support of persistent changes in the brain months-to-years following injury and highlight the need to further understand the pathophysiology of PPCS, to determine effective prevention and treatment options. ABBREVIATIONS: ATR: Anterior Thalamic Radiation; Caud: Caudate; CCB: Corpus Callosum Body; CCG: Corpus Callosum Genus; CCS: Corpus Callosum Splenium; CH: Cingulum; DHI: Dizziness Handicap Inventory; ESS: Epworth Sleepiness Scale; FM: Forceps Minor; FSS: Fatigue Severity Scale; GAD: Generalized Anxiety Disorder; HIT-6: Headache Impact Test 6; IFOF: Inferior Fronto-Occipital Fasciculus; ILF: Inferior Longitudinal Fasciculus; mTBI: mild traumatic brain injury; Pal: Pallidum; PPCS: Persistent Post-Concussive Symptoms; PCSC: Postconcussional Syndrone Checklist; PHQ: Patient Health Questionnaire; Put: Putamen; RPQ: Rivermead Post Concussion Symptoms Questionnaire; SLF: Superior Longitudinal Fasciculus; QSM: Quantitative Susceptibility Mapping.

Brain iron content in cerebral amyloid angiopathy using quantitative susceptibility mapping.

Introduction: Cerebral amyloid angiopathy (CAA) is a small vessel disease that causes covert and symptomatic brain hemorrhaging. We hypothesized that persons with CAA would have increased brain iron content detectable by quantitative susceptibility mapping (QSM) on magnetic resonance imaging (MRI), and that higher iron content would be associated with worse cognition. Methods: Participants with CAA (n = 21), mild Alzheimer's disease with dementia (AD-dementia; n = 14), and normal controls (NC; n = 83) underwent 3T MRI. Post-processing QSM techniques were applied to obtain susceptibility values for regions of the frontal and occipital lobe, thalamus, caudate, putamen, pallidum, and hippocampus. Linear regression was used to examine differences between groups, and associations with global cognition, controlling for multiple comparisons using the false discovery rate method. Results: No differences were found between regions of interest in CAA compared to NC. In AD, the calcarine sulcus had greater iron than NC (ß = 0.99 [95% CI: 0.44, 1.53], q < 0.01). However, calcarine sulcus iron content was not associated with global cognition, measured by the Montreal Cognitive Assessment (p > 0.05 for all participants, NC, CAA, and AD). Discussion: After correcting for multiple comparisons, brain iron content, measured via QSM, was not elevated in CAA compared to NC in this exploratory study.

Calgary Normative Study: design of a prospective longitudinal study to characterise potential quantitative MR biomarkers of neurodegeneration over the adult lifespan.

INTRODUCTION: A number of MRI methods have been proposed to be useful, quantitative biomarkers of neurodegeneration in ageing. The Calgary Normative Study (CNS) is an ongoing single-centre, prospective, longitudinal study that seeks to develop, test and assess quantitative magnetic resonance (MR) methods as potential biomarkers of neurodegeneration. The CNS has three objectives: first and foremost, to evaluate and characterise the dependence of the selected quantitative neuroimaging biomarkers on age over the adult lifespan; second, to evaluate the precision, variability and repeatability of quantitative neuroimaging biomarkers as part of biomarker validation providing proof-of-concept and proof-of-principle; and third, provide a shared repository of normative data for comparison to various disease cohorts. METHODS AND ANALYSIS: Quantitative MR mapping of the brain including longitudinal relaxation time (T1), transverse relaxation time (T2), T2*, magnetic susceptibility (QSM), diffusion and perfusion measurements, as well as morphological assessments are performed. The Montreal Cognitive Assessment (MoCA) and a brief, self-report medical history will be collected. Mixed regression models will be used to characterise changes in quantitative MR biomarker measures over the adult lifespan. In this report, we describe the study design, strategies to recruit and perform changes to the acquisition protocol from inception to 31 December 2018, planned statistical approach and data sharing procedures for the study. ETHICS AND DISSEMINATION: Participants provide signed informed consent. Changes in quantitative MR biomarkers measured over the adult lifespan as well as estimates of measurement variance and repeatability will be disseminated through peer-reviewed scientific publication.

Tract-based analysis of target engagement by subcallosal cingulate deep brain stimulation for treatment resistant depression.

BACKGROUND: Deep brain stimulation (DBS) of subcallosal cingulate cortex (SCC) is a promising investigational therapy for treatment-resistant depression (TRD). However, outcomes vary, likely due to suboptimal DBS placement. Ideal placement is proposed to stimulate 4 SCC white matter bundles; however, no quantitative data have linked activation of these target tracts to response. OBJECTIVE: Here we used the volume of tissue activated (VTA) and probabilistic diffusion tensor imaging (DTI) to quantify tract activation relating to response. METHODS: DTI was performed in 19 TRD patients who received SCC-DBS. We defined clinical response as >48% reduction from baseline in the Hamilton Depression Rating Scale. Bilateral VTAs were generated based on subject-specific stimulation parameters. Patient-specific tract maps emanating from the VTAs were calculated using whole-brain probabilistic DTI. The four target tracts were isolated using tract-specific quantification and examined for overlap with DBS activated tissue. RESULTS: Medial frontal and temporal projections were stimulated in all responders at 6 and 12 months. Individual tract-based generalized linear mixed model analysis revealed a significant tract-by-response interaction at both 6 (F(1,135) = 3.828, p = 0.001) and 12 (F(1,135) = 5.688, p < 0.001) months, with post hoc tests revealing a response-related increase in cingulum activation at 6 months (t(135) = 2.418, p = 0.017) and decrease in forceps minor activation at 12 months (t(135) = -2.802, p = 0.006). CONCLUSIONS: A wider profile of white matter tracts, particularly to the medial frontal, was associated with DBS response. Cingulum bundle stimulation may promote early response and excess stimulation of the forceps minor might be detrimental. Our work supports prospective patient-specific targeting to inform personalized DBS.

Tactics: an open-source platform for planning, simulating and validating stereotactic surgery.

Frame-based stereotaxy is widely used for planning and implanting deep-brain electrodes. In 2013, as part of a clinical study on deep-brain stimulation for treatment-resistant depression, our group identified a need for software to simulate and plan stereotactic procedures. Shortcomings in extant commercial systems encouraged us to develop Tactics. Tactics is purpose-designed for frame-based stereotactic placement of electrodes. The workflow is far simpler than commercial systems. By simulating specific electrode placement, immediate in-context view of each electrode contact, and the cortical entry site are available within seconds. Post implantation, electrode placement is verified by linearly registering post-operative images. Tactics has been particularly helpful for invasive electroencephalography electrodes where as many as 20 electrodes are planned and placed within minutes. Currently, no commercial system has a workflow supporting the efficient placement of this many electrodes. Tactics includes a novel implementation of automated frame localization and a user-extensible mechanism for importing electrode specifications for visualization of individual electrode contacts. The system was systematically validated, through comparison against gold-standard techniques and quantitative analysis of targeting accuracy using a purpose-built imaging phantom mountable by a stereotactic frame. Internal to our research group, Tactics has been used to plan over 300 depth-electrode targets and trajectories in over 50 surgical cases, and to plan dozens of stereotactic biopsies. Source code and pre-built binaries for Tactics are public and open-source, enabling use and contribution by the extended community.

Automatic fusion of freehand endoscopic brain images to three-dimensional surfaces: creating stereoscopic panoramas.

A major limitation of the use of endoscopes in minimally invasive surgery is the lack of relative context between the endoscope and its surroundings. The purpose of this work was to fuse images obtained from a tracked endoscope to surfaces derived from three-dimensional (3-D) preoperative magnetic resonance or computed tomography (CT) data, for assistance in surgical planning, training and guidance. We extracted polygonal surfaces from preoperative CT images of a standard brain phantom and digitized endoscopic video images from a tracked neuro-endoscope. The optical properties of the endoscope were characterized using a simple calibration procedure. Registration of the phantom (physical space) and CT images (preoperative image space) was accomplished using fiducial markers that could be identified both on the phantom and within the images. The endoscopic images were corrected for radial lens distortion and then mapped onto the extracted surfaces via a two-dimensional 2-D to 3-D mapping algorithm. The optical tracker has an accuracy of about 0.3 mm at its centroid, which allows the endoscope tip to be localized to within 1.0 mm. The mapping operation allows multiple endoscopic images to be "painted" onto the 3-D brain surfaces, as they are acquired, in the correct anatomical position. This allows panoramic and stereoscopic visualization, as well as navigation of the 3-D surface, painted with multiple endoscopic views, from arbitrary perspectives.

Generalized 3D nonlinear transformations for medical imaging: an object-oriented implementation in VTK.

We have contributed an efficient, object-oriented implementation of 3D nonlinear transformations to the Visualization Toolkit that can be applied to a wide variety of data types, including images and polygonal meshes. The transformations are performed via thin-plate splines or via interpolation of a regular lattice of displacement vectors, and are part of a framework that is easily extensible to other nonlinear transformation types. In this paper we demonstrate application of these transformations in medical imaging in general and image-guided surgery in particular, and present a series of performance benchmarks.

Integrated navigation and control software system for MRI-guided robotic prostate interventions.

A software system to provide intuitive navigation for MRI-guided robotic transperineal prostate therapy is presented. In the system, the robot control unit, the MRI scanner, and the open-source navigation software are connected together via Ethernet to exchange commands, coordinates, and images using an open network communication protocol, OpenIGTLink. The system has six states called "workphases" that provide the necessary synchronization of all components during each stage of the clinical workflow, and the user interface guides the operator linearly through these workphases. On top of this framework, the software provides the following features for needle guidance: interactive target planning; 3D image visualization with current needle position; treatment monitoring through real-time MR images of needle trajectories in the prostate. These features are supported by calibration of robot and image coordinates by fiducial-based registration. Performance tests show that the registration error of the system was 2.6mm within the prostate volume. Registered real-time 2D images were displayed 1.97 s after the image location is specified.

Quantification of edematic effects in prostate brachytherapy interventions.

We present a quantitative model to analyze the detrimental effects of for edema on the quality of prostate brachytherapy implants We account for both tissue expansion and implant migration by mapping intra-operative ultrasound and post-implant CT. We pre-process the ultrasound with a phase congruency filter, and map it to the volume CT using a B-spline deformable mutual information similarity metric. To test the method, we implanted a standard training phantom with 48 seeds, imaged the phantom with ultrasound and CT and registered the two for ground truth. Edema was simulated by distorting the CT volume by known transformations. The objective was to match the distorted implant to the intra-operative ultrasound. Performance was measured relative to ground truth. We successfully mapped 100% of deformed seeds to ground truth under edematic expansion up to 40% of volume growth. Seed matching performance was 98% with random seed migration of 3mm superimposed on 10% edematic volume growth. This method promises to be clinically applicable as the first quantitative analysis tool to measure edematic implant deformations occurring between the operating room and post-operative CT imaging.

Designing Tracking Software for Image-Guided Surgery Applications: IGSTK Experience.

OBJECTIVE: Many image-guided surgery applications require tracking devices as part of their core functionality. The Image-Guided Surgery Toolkit (IGSTK) was designed and developed to interface tracking devices with software applications incorporating medical images. METHODS: IGSTK was designed as an open source C++ library that provides the basic components needed for fast prototyping and development of image-guided surgery applications. This library follows a component-based architecture with several components designed for specific sets of image-guided surgery functions. At the core of the toolkit is the tracker component that handles communication between a control computer and navigation device to gather pose measurements of surgical instruments present in the surgical scene. The representations of the tracked instruments are superimposed on anatomical images to provide visual feedback to the clinician during surgical procedures. RESULTS: The initial version of the IGSTK toolkit has been released in the public domain and several trackers are supported. The toolkit and related information are available at www.igstk.org. CONCLUSION: With the increased popularity of minimally invasive procedures in health care, several tracking devices have been developed for medical applications. Designing and implementing high-quality and safe software to handle these different types of trackers in a common framework is a challenging task. It requires establishing key software design principles that emphasize abstraction, extensibility, reusability, fault-tolerance, and portability. IGSTK is an open source library that satisfies these needs for the image-guided surgery community.

Software strategy for robotic transperineal prostate therapy in closed-bore MRI.

A software strategy to provide intuitive navigation for MRI-guided robotic transperineal prostate therapy is presented. In the system, the robot control unit, the MRI scanner, and open-source navigation software are connected to one another via Ethernet to exchange commands, coordinates, and images. Six states of the system called "workphases" are defined based on the clinical scenario to synchronize behaviors of all components. The wizard-style user interface allows easy following of the clinical workflow. On top of this framework, the software provides features for intuitive needle guidance: interactive target planning; 3D image visualization with current needle position; treatment monitoring through real-time MRI. These features are supported by calibration of robot and image coordinates by the fiducial-based registration. The performance test shows that the registration error of the system was 2.6 mm in the prostate area, and it displayed real-time 2D image 1.7 s after the completion of image acquisition.

The image-guided surgery toolkit IGSTK: an open source C++ software toolkit.

This paper presents an overview of the image-guided surgery toolkit (IGSTK). IGSTK is an open source C++ software library that provides the basic components needed to develop image-guided surgery applications. It is intended for fast prototyping and development of image-guided surgery applications. The toolkit was developed through a collaboration between academic and industry partners. Because IGSTK was designed for safety-critical applications, the development team has adopted lightweight software processes that emphasizes safety and robustness while, at the same time, supporting geographically separated developers. A software process that is philosophically similar to agile software methods was adopted emphasizing iterative, incremental, and test-driven development principles. The guiding principle in the architecture design of IGSTK is patient safety. The IGSTK team implemented a component-based architecture and used state machine software design methodologies to improve the reliability and safety of the components. Every IGSTK component has a well-defined set of features that are governed by state machines. The state machine ensures that the component is always in a valid state and that all state transitions are valid and meaningful. Realizing that the continued success and viability of an open source toolkit depends on a strong user community, the IGSTK team is following several key strategies to build an active user community. These include maintaining a users and developers' mailing list, providing documentation (application programming interface reference document and book), presenting demonstration applications, and delivering tutorial sessions at relevant scientific conferences.

Challenges in image-guided therapy system design.

System development for image-guided therapy (IGT), or image-guided interventions (IGI), continues to be an area of active interest across academic and industry groups. This is an emerging field that is growing rapidly: major academic institutions and medical device manufacturers have produced IGT technologies that are in routine clinical use, dozens of high-impact publications are published in well regarded journals each year, and several small companies have successfully commercialized sophisticated IGT systems. In meetings between IGT investigators over the last two years, a consensus has emerged that several key areas must be addressed collaboratively by the community to reach the next level of impact and efficiency in IGT research and development to improve patient care. These meetings culminated in a two-day workshop that brought together several academic and industrial leaders in the field today. The goals of the workshop were to identify gaps in the engineering infrastructure available to IGT researchers, develop the role of research funding agencies and the recently established US-based National Center for Image Guided Therapy (NCIGT), and ultimately to facilitate the transfer of technology among research centers that are sponsored by the National Institutes of Health (NIH). Workshop discussions spanned many of the current challenges in the development and deployment of new IGT systems. Key challenges were identified in a number of areas, including: validation standards; workflows, use-cases, and application requirements; component reusability; and device interface standards. This report elaborates on these key points and proposes research challenges that are to be addressed by a joint effort between academic, industry, and NIH participants.