PURPOSE: To optimize diffusion-relaxation MRI with tensor-valued diffusion encoding for precise estimation of compartment-specific fractions, diffusivities, and T values within a two-compartment model of white matter, and to explore the approach in vivo. METHODS: Sampling protocols featuring different b-values (b), b-tensor shapes (b ), and echo times (TE) were optimized using Cram\ er-Rao lower bounds (CRLB). Whole-brain data were acquired in children, adults, and elderly with white matter lesions. Compartment fractions, diffusivities, and T values were estimated in a model featuring two microstructural compartments represented by a "stick" and a "zeppelin." RESULTS: Precise parameter estimates were enabled by sampling protocols featuring seven or more "shells" with unique b/b /TE-combinations. Acquisition times were approximately 15 minutes. In white matter of adults, the "stick" compartment had a fraction of approximately 0.5 and, compared with the "zeppelin" compartment, featured lower isotropic diffusivities (0.6 vs. 1.3 μm /ms) but higher T values (85 vs. 65 ms). Children featured lower "stick" fractions (0.4). White matter lesions exhibited high "zeppelin" isotropic diffusivities (1.7 μm /ms) and T values (150 ms). CONCLUSIONS: Diffusion-relaxation MRI with tensor-valued diffusion encoding expands the set of microstructure parameters that can be precisely estimated and therefore increases their specificity to biological quantities.

The corticospinal tract (CST) is one of the most well studied tracts in human neuroanatomy. Its clinical significance can be demonstrated in many notable traumatic conditions and diseases such as stroke, spinal cord injury (SCI) or amyotrophic lateral sclerosis (ALS). With the advent of diffusion MRI and tractography the computational representation of the human CST in a 3D model became available. However, the representation of the entire CST and, specifically, the hand motor area has remained elusive. In this paper we propose a novel method, using manually drawn ROIs based on robustly identifiable neuroanatomic structures to delineate the entire CST and isolate its hand motor representation as well as to estimate their variability and generate a database of their volume, length and biophysical parameters. Using 37 healthy human subjects we performed a qualitative and quantitative analysis of the CST and the hand-related motor fiber tracts (HMFTs). Finally, we have created variability heat maps from 37 subjects for both the aforementioned tracts, which could be utilized as a reference for future studies with clinical focus to explore neuropathology in both trauma and disease states.

BACKGROUND: Extracellular free water within cerebral white matter tissue has been shown to increase with age and pathology, yet the cognitive consequences of free water in typical aging prior to the development of neurodegenerative disease remains unclear. Understanding the contribution of free water to cognitive function in older adults may provide important insight into the neural mechanisms of the cognitive aging process. METHODS: A diffusion-weighted MRI measure of extracellular free water as well as a commonly used diffusion MRI metric (fractional anisotropy) along nine bilateral white matter pathways were examined for their relationship with cognitive function assessed by the NIH Toolbox Cognitive Battery in 47 older adults (mean age ​= ​74.4 years, SD ​= ​5.4 years, range ​= ​65-85 years). Probabilistic tractography at the 99th percentile level of probability (Tracts Constrained by Underlying Anatomy; TRACULA) was utilized to produce the pathways on which microstructural characteristics were overlaid and examined for their contribution to cognitive function independent of age, education, and gender. RESULTS: When examining the 99th percentile probability core white matter pathway derived from TRACULA, poorer fluid cognitive ability was related to higher mean free water values across the angular and cingulum bundles of the cingulate gyrus, as well as the corticospinal tract and the superior longitudinal fasciculus. There was no relationship between cognition and mean FA or free water-adjusted FA across the 99th percentile core white matter pathway. Crystallized cognitive ability was not associated with any of the diffusion measures. When examining cognitive domains comprising the NIH Toolbox Fluid Cognition index relationships with these white matter pathways, mean free water demonstrated strong hemispheric and functional specificity for cognitive performance, whereas mean FA was not related to age or cognition across the 99th percentile pathway. CONCLUSIONS: Extracellular free water within white matter appears to increase with normal aging, and higher values are associated with significantly lower fluid but not crystallized cognitive functions. When using TRACULA to estimate the core of a white matter pathway, a higher degree of free water appears to be highly specific to the pathways associated with memory, working memory, and speeded decision-making performance, whereas no such relationship existed with FA. These data suggest that free water may play an important role in the cognitive aging process, and may serve as a stronger and more specific indicator of early cognitive decline than traditional diffusion MRI measures, such as FA.

BACKGROUND: Auditory verbal hallucinations (AVH) are a cardinal feature of schizophrenia, but they can also appear in otherwise healthy individuals. Imaging studies implicate language networks in the generation of AVH; however, it remains unclear if alterations reflect biologic substrates of AVH, irrespective of diagnostic status, age, or illness-related factors. We applied multimodal imaging to identify AVH-specific pathology, evidenced by overlapping gray or white matter deficits between schizophrenia patients and healthy voice-hearers. METHODS: Diffusion-weighted and T1-weighted magnetic resonance images were acquired in 35 schizophrenia patients with AVH (SCZ-AVH), 32 healthy voice-hearers (H-AVH), and 40 age- and sex-matched controls without AVH. White matter fractional anisotropy (FA) and gray matter thickness (GMT) were computed for each region comprising ICBM-DTI and Desikan-Killiany atlases, respectively. Regions were tested for significant alterations affecting both SCZ-AVH and H-AVH groups, relative to controls. RESULTS: Compared with controls, the SCZ-AVH showed widespread FA and GMT reductions; but no significant differences emerged between H-AVH and control groups. While no overlapping pathology appeared in the overall study groups, younger (<40 years) H-AVH and SCZ-AVH subjects displayed overlapping FA deficits across four regions (p < 0.05): the genu and splenium of the corpus callosum, as well as the anterior limbs of the internal capsule. Analyzing these regions with free-water imaging ascribed overlapping FA abnormalities to tissue-specific anisotropy changes. CONCLUSIONS: We identified white matter pathology associated with the presence of AVH, independent of diagnostic status. However, commonalities were constrained to younger and more homogenous groups, after reducing pathologic variance associated with advancing age and chronicity effects.

OBJECTIVE: Accurate biopsy sampling of the suspected lesions is critical for the diagnosis and clinical management of prostate cancer. Transperineal in-bore MRI-guided prostate biopsy (tpMRgBx) is a targeted biopsy technique that was shown to be safe, efficient, and accurate. Our goal was to develop an open source software platform to support evaluation, refinement, and translation of this biopsy approach. METHODS: We developed SliceTracker, a 3D Slicer extension to support tpMRgBx. We followed modular design of the implementation to enable customization of the interface and interchange of image segmentation and registration components to assess their effect on the processing time, precision, and accuracy of the biopsy needle placement. The platform and supporting documentation were developed to enable the use of software by an operator with minimal technical training to facilitate translation. Retrospective evaluation studied registration accuracy, effect of the prostate segmentation approach, and re-identification time of biopsy targets. Prospective evaluation focused on the total procedure time and biopsy targeting error (BTE). RESULTS: Evaluation utilized data from 73 retrospective and ten prospective tpMRgBx cases. Mean landmark registration error for retrospective evaluation was 1.88 ± 2.63 mm, and was not sensitive to the approach used for prostate gland segmentation. Prospectively, we observed target re-identification time of 4.60 ± 2.40 min and BTE of 2.40 ± 0.98 mm. CONCLUSION: SliceTracker is modular and extensible open source platform for supporting image processing aspects of the tpMRgBx procedure. It has been successfully utilized to support clinical research procedures at our site.

OBJECTIVE: Delineation of malformations of cortical development (MCD) is central in presurgical evaluation of drug-resistant epilepsy. Delineation using magnetic resonance imaging (MRI) can be ambiguous, however, because the conventional T - and T -weighted contrasts depend strongly on myelin for differentiation of cortical tissue and white matter. Variations in myelin content within both cortex and white matter may cause MCD findings on MRI to change size, become undetectable, or disagree with histopathology. The novel tensor-valued diffusion MRI (dMRI) technique maps microscopic diffusion anisotropy, which is sensitive to axons rather than myelin. This work investigated whether tensor-valued dMRI may improve differentiation of cortex and white matter in the delineation of MCD. METHODS: Tensor-valued dMRI was performed on a 7 T MRI scanner in 13 MCD patients (age = 32 ± 13 years) featuring periventricular heterotopia, subcortical heterotopia, focal cortical dysplasia, and polymicrogyria. Data analysis yielded maps of microscopic anisotropy that were compared with T -weighted and T -fluid-attenuated inversion recovery images and with the fractional anisotropy from diffusion tensor imaging. RESULTS: Maps of microscopic anisotropy revealed large white matter-like regions within MCD that were uniformly cortex-like in the conventional MRI contrasts. These regions were seen particularly in the deep white matter parts of subcortical heterotopias and near the gray-white boundaries of focal cortical dysplasias and polymicrogyrias. SIGNIFICANCE: By being sensitive to axons rather than myelin, mapping of microscopic anisotropy may yield a more robust differentiation of cortex and white matter and improve MCD delineation in presurgical evaluation of epilepsy.

PURPOSE: Zero-footprint Web architecture enables imaging applications to be deployed on premise or in the cloud without requiring installation of custom software on the user’s computer. Benefits include decreased costs and information technology support requirements, as well as improved accessibility across sites. The Open Health Imaging Foundation (OHIF) Viewer is an extensible platform developed to leverage these benefits and address the demand for open-source Web-based imaging applications. The platform can be modified to support site-specific workflows and accommodate evolving research requirements. MATERIALS AND METHODS: The OHIF Viewer provides basic image review functionality (eg, image manipulation and measurement) as well as advanced visualization (eg, multiplanar reformatting). It is written as a client-only, single-page Web application that can easily be embedded into third-party applications or hosted as a standalone Web site. The platform provides extension points for software developers to include custom tools and adapt the system for their workflows. It is standards compliant and relies on DICOMweb for data exchange and OpenID Connect for authentication, but it can be configured to use any data source or authentication flow. Additionally, the user interface components are provided in a standalone component library so that developers can create custom extensions. RESULTS: The OHIF Viewer and its underlying components have been widely adopted and integrated into multiple clinical research platforms (e,g Precision Imaging Metrics, XNAT, LabCAS, ISB-CGC) and commercial applications (eg, Osirix). It has also been used to build custom imaging applications (eg, ProstateCancer.ai, Crowds Cure Cancer [presented as a case study]). CONCLUSION: The OHIF Viewer provides a flexible framework for building applications to support imaging research. Its adoption could reduce redundancies in software development for National Cancer Institute-funded projects, including Informatics Technology for Cancer Research and the Quantitative Imaging Network.

RATIONALE AND OBJECTIVES: To explore a role for multiparametric MRI (mpMRI) as a biomarker of response to neoadjuvant androgen deprivation therapy (ADT) for prostate cancer (PCa). MATERIALS AND METHODS: This prospective study was approved by the institutional review board and was HIPAA compliant. Eight patients with localized PCa had a baseline mpMRI, repeated after 6-months of ADT, followed by prostatectomy. mpMRI indices were extracted from tumor and normal regions of interest (TROI/NROI). Residual cancer burden (RCB) was measured on mpMRI and on the prostatectomy specimen. Paired t-tests compared TROI/NROI mpMRI indices and pre/post-treatment TROI mpMRI indices. Spearman’s rank tested for correlations between MRI/pathology-based RCB, and between pathological RCB and mpMRI indices. RESULTS: At baseline, TROI apparent diffusion coefficient (ADC) was lower and dynamic contrast enhanced (DCE) metrics were higher, compared to NROI (ADC: 806 ± 137 × 10 vs. 1277 ± 213 × 10 mm/sec, p = 0.0005; K: 0.346 ± 0.16 vs. 0.144 ± 0.06 min, p = 0.002; AUC: 0.213 ± 0.08 vs. 0.11 ± 0.03, p = 0.002). Post-treatment, there was no change in TROI ADC, but a decrease in TROI K (0.346 ± 0.16 to 0.188 ± 0.08 min; p = 0.02) and AUC (0.213 ± 0.08 to 0.13 ± 0.06; p = 0.02). Tumor volume decreased with ADT. There was no difference between mpMRI-based and pathology-based RCB, which positively correlated (⍴ = 0.74-0.81, p < 0.05). Pathology-based RCB positively correlated with post-treatment DCE metrics (⍴ = 0.76-0.70, p < 0.05) and negatively with ADC (⍴ = -0.79, p = 0.03). CONCLUSION: Given the heterogeneity of PCa, an individualized approach to ADT may maximize potential benefit. This pilot study suggests that mpMRI may serve as a biomarker of ADT response and as a surrogate for RCB at prostatectomy.

The etiology of bipolar disorder (BD) is unknown and the neurobiological underpinnings are not fully understood. Both genetic and environmental factors contribute to the risk of BD, which may be linked through epigenetic mechanisms, including those regulated by histone deacetylase (HDAC) enzymes. This study measures in vivo HDAC expression in individuals with BD for the first time using the HDAC-specific radiotracer [C]Martinostat. Eleven participants with BD and 11 age- and sex-matched control participants (CON) completed a simultaneous magnetic resonance - positron emission tomography (MR-PET) scan with [C]Martinostat. Lower [C]Martinostat uptake was found in the right amygdala of BD compared to CON. We assessed uptake in the dorsolateral prefrontal cortex (DLPFC) to compare previous findings of lower uptake in the DLPFC in schizophrenia and found no group differences in BD. Exploratory whole-brain voxelwise analysis showed lower [C]Martinostat uptake in the bilateral thalamus, orbitofrontal cortex, right hippocampus, and right amygdala in BD compared to CON. Furthermore, regional [C]Martinostat uptake was associated with emotion regulation in BD in fronto-limbic areas, which aligns with findings from previous structural, functional, and molecular neuroimaging studies in BD. Regional [C]Martinostat uptake was associated with attention in BD in fronto-parietal and temporal regions. These findings indicate a potential role of HDACs in BD pathophysiology. In particular, HDAC expression levels may modulate attention and emotion regulation, which represent two core clinical features of BD.

PURPOSE: We summarize Quantitative Imaging Informatics for Cancer Research (QIICR; U24 CA180918), one of the first projects funded by the National Cancer Institute (NCI) Informatics Technology for Cancer Research program. METHODS: QIICR was motivated by the 3 use cases from the NCI Quantitative Imaging Network. 3D Slicer was selected as the platform for implementation of open-source quantitative imaging (QI) tools. Digital Imaging and Communications in Medicine (DICOM) was chosen for standardization of QI analysis outputs. Support of improved integration with community repositories focused on The Cancer Imaging Archive (TCIA). Priorities included improved capabilities of the standard, toolkits and tools, reference datasets, collaborations, and training and outreach. RESULTS: Fourteen new tools to support head and neck cancer, glioblastoma, and prostate cancer QI research were introduced and downloaded over 100,000 times. DICOM was amended, with over 40 correction proposals addressing QI needs. Reference implementations of the standard in a popular toolkit and standalone tools were introduced. Eight datasets exemplifying the application of the standard and tools were contributed. An open demonstration/connectathon was organized, attracting the participation of academic groups and commercial vendors. Integration of tools with TCIA was improved by implementing programmatic communication interface and by refining best practices for QI analysis results curation. CONCLUSION: Tools, capabilities of the DICOM standard, and datasets we introduced found adoption and utility within the cancer imaging community. A collaborative approach is critical to addressing challenges in imaging informatics at the national and international levels. Numerous challenges remain in establishing and maintaining the infrastructure of analysis tools and standardized datasets for the imaging community. Ideas and technology developed by the QIICR project are contributing to the NCI Imaging Data Commons currently being developed.