Publications by Year: 2022

2022
Pujol S, Cabeen RP, Yelnik J, François C, Fernandez Vidal S, Karachi C, Bardinet E, Cosgrove RG, Kikinis R. Somatotopic Organization of Hyperdirect Pathway Projections From the Primary Motor Cortex in the Human Brain. Front Neurol. 2022;13 :791092.Abstract
Background: The subthalamic nucleus (STN) is an effective neurosurgical target to improve motor symptoms in Parkinson's Disease (PD) patients. MR-guided Focused Ultrasound (MRgFUS) subthalamotomy is being explored as a therapeutic alternative to Deep Brain Stimulation (DBS) of the STN. The hyperdirect pathway provides a direct connection between the cortex and the STN and is likely to play a key role in the therapeutic effects of MRgFUS intervention in PD patients. Objective: This study aims to investigate the topography and somatotopy of hyperdirect pathway projections from the primary motor cortex (M1). Methods: We used advanced multi-fiber tractography and high-resolution diffusion MRI data acquired on five subjects of the Human Connectome Project (HCP) to reconstruct hyperdirect pathway projections from M1. Two neuroanatomy experts reviewed the anatomical accuracy of the tracts. We extracted the fascicles arising from the trunk, arm, hand, face and tongue area from the reconstructed pathways. We assessed the variability among subjects based on the fractional anisotropy (FA) and mean diffusivity (MD) of the fibers. We evaluated the spatial arrangement of the different fascicles using the Dice Similarity Coefficient (DSC) of spatial overlap and the centroids of the bundles. Results: We successfully reconstructed hyperdirect pathway projections from M1 in all five subjects. The tracts were in agreement with the expected anatomy. We identified hyperdirect pathway fascicles projecting from the trunk, arm, hand, face and tongue area in all subjects. Tract-derived measurements showed low variability among subjects, and similar distributions of FA and MD values among the fascicles projecting from different M1 areas. We found an anterolateral somatotopic arrangement of the fascicles in the corona radiata, and an average overlap of 0.63 in the internal capsule and 0.65 in the zona incerta. Conclusion: Multi-fiber tractography combined with high-resolution diffusion MRI data enables the identification of the somatotopic organization of the hyperdirect pathway. Our preliminary results suggest that the subdivisions of the hyperdirect pathway projecting from the trunk, arm, hand, face, and tongue motor area are intermixed at the level of the zona incerta and posterior limb of the internal capsule, with a predominantly overlapping topographical organization in both regions. Subject-specific knowledge of the hyperdirect pathway somatotopy could help optimize target definition in MRgFUS intervention.
Cole AP, Langbein BJ, Giganti F, Fennessy FM, Tempany CM, Emberton M. Is Perfect the Enemy of Good? Weighing the Evidence for Biparametric MRI in Prostate Cancer. Br J Radiol. 2022;95 (1131) :20210840.Abstract
The role of multiparametric MRI in diagnosis, staging and treatment planning for prostate cancer is well established. However, there remain several challenges to widespread adoption. One such challenge is the duration and cost of the examination. Abbreviated exams omitting contrast-enhanced sequences may help address this challenge. In this review, we will discuss the rationale for biparametric MRI for detection and characterization of clinically significant prostate cancer prior to biopsy and synthesize the published literature. We will weigh up the advantages and disadvantages to this approach and lay out a conceptual cost/benefit analysis regarding adoption of biparametric MRI.
Sebastian C, Ferrer C, Serra M, Choi J-E, Ducano N, Mira A, Shah MS, Stopka SA, Perciaccante AJ, Isella C, et al. A Non-Dividing Cell Population With High Pyruvate Dehydrogenase Kinase Activity Regulates Metabolic Heterogeneity and Tumorigenesis in the Intestine. Nat Commun. 2022;13 (1) :1503.Abstract
Although reprogramming of cellular metabolism is a hallmark of cancer, little is known about how metabolic reprogramming contributes to early stages of transformation. Here, we show that the histone deacetylase SIRT6 regulates tumor initiation during intestinal cancer by controlling glucose metabolism. Loss of SIRT6 results in an increase in the number of intestinal stem cells (ISCs), which translates into enhanced tumor initiating potential in APCmin mice. By tracking down the connection between glucose metabolism and tumor initiation, we find a metabolic compartmentalization within the intestinal epithelium and adenomas, where a rare population of cells exhibit features of Warburg-like metabolism characterized by high pyruvate dehydrogenase kinase (PDK) activity. Our results show that these cells are quiescent cells expressing +4 ISCs and enteroendocrine markers. Active glycolysis in these cells suppresses ROS accumulation and enhances their stem cell and tumorigenic potential. Our studies reveal that aerobic glycolysis represents a heterogeneous feature of cancer, and indicate that this metabolic adaptation can occur in non-dividing cells, suggesting a role for the Warburg effect beyond biomass production in tumors.
Abdelmoula WM, Stopka SA, Randall EC, Regan M, Agar JN, Sarkaria JN, Wells WM, Kapur T, Agar NYR. massNet: Integrated Processing and Classification of Spatially Resolved Mass Spectrometry Data Using Deep Learning for Rapid Tumor Delineation. Bioinformatics. 2022;38 (7) :2015-21.Abstract
MOTIVATION: Mass spectrometry imaging (MSI) provides rich biochemical information in a label-free manner and therefore holds promise to substantially impact current practice in disease diagnosis. However, the complex nature of MSI data poses computational challenges in its analysis. The complexity of the data arises from its large size, high dimensionality, and spectral non-linearity. Preprocessing, including peak picking, has been used to reduce raw data complexity, however peak picking is sensitive to parameter selection that, perhaps prematurely, shapes the downstream analysis for tissue classification and ensuing biological interpretation. RESULTS: We propose a deep learning model, massNet, that provides the desired qualities of scalability, non-linearity, and speed in MSI data analysis. This deep learning model was used, without prior preprocessing and peak picking, to classify MSI data from a mouse brain harboring a patient-derived tumor. The massNet architecture established automatically learning of predictive features, and automated methods were incorporated to identify peaks with potential for tumor delineation. The model's performance was assessed using cross-validation, and the results demonstrate higher accuracy and a substantial gain in speed compared to the established classical machine learning method, support vector machine. AVAILABILITY AND IMPLEMENTATION: https://github.com/wabdelmoula/massNet. AVAILABILITY OF DATA: The data underlying this article are available in the NIH Common Fund's National Metabolomics Data Repository (NMDR) Metabolomics Workbench under project id (PR001292) with http://dx.doi.org/10.21228/M8Q70T. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Zheng J, Yang Q, Makris N, Huang K, Liang J, Ye C, Yu X, Tian M, Ma T, Mou T, et al. Three-Dimensional Digital Reconstruction of the Cerebellar Cortex: Lobule Thickness, Surface Area Measurements, and Layer Architecture. Cerebellum. 2022.Abstract
The cerebellum is ontogenetically one of the first structures to develop in the central nervous system; nevertheless, it has been only recently reconsidered for its significant neurobiological, functional, and clinical relevance in humans. Thus, it has been a relatively under-studied compared to the cerebrum. Currently, non-invasive imaging modalities can barely reach the necessary resolution to unfold its entire, convoluted surface, while only histological analyses can reveal local information at the micrometer scale. Herein, we used the BigBrain dataset to generate area and point-wise thickness measurements for all layers of the cerebellar cortex and for each lobule in particular. We found that the overall surface area of the cerebellar granular layer (including Purkinje cells) was 1,732 cm2 and the molecular layer was 1,945 cm2. The average thickness of the granular layer is 0.88 mm (± 0.83) and that of the molecular layer is 0.32 mm (± 0.08). The cerebellum (both granular and molecular layers) is thicker at the depth of the sulci and thinner at the crowns of the gyri. Globally, the granular layer is thicker in the lateral-posterior-inferior region than the medial-superior regions. The characterization of individual layers in the cerebellum achieved herein represents a stepping-stone for investigations interrelating structural and functional connectivity with cerebellar architectonics using neuroimaging, which is a matter of considerable relevance in basic and clinical neuroscience. Furthermore, these data provide templates for the construction of cerebellar topographic maps and the precise localization of structural and functional alterations in diseases affecting the cerebellum.
Sefcikova V, Sporrer JK, Juvekar P, Golby A, Samandouras G. Converting Sounds to Meaning With Ventral Semantic Language Networks: Integration of Interdisciplinary Data on Brain Connectivity, Direct Electrical Stimulation and Clinical Disconnection Syndromes. Brain Struct Funct. 2022;227 (5) :1545-64.Abstract
Numerous traditional linguistic theories propose that semantic language pathways convert sounds to meaningful concepts, generating interpretations ranging from simple object descriptions to communicating complex, analytical thinking. Although the dual-stream model of Hickok and Poeppel is widely employed, proposing a dorsal stream, mapping speech sounds to articulatory/phonological networks, and a ventral stream, mapping speech sounds to semantic representations, other language models have been proposed. Indeed, despite seemingly congruent models of semantic language pathways, research outputs from varied specialisms contain only partially congruent data, secondary to the diversity of applied disciplines, ranging from fibre dissection, tract tracing, and functional neuroimaging to neuropsychiatry, stroke neurology, and intraoperative direct electrical stimulation. The current review presents a comprehensive, interdisciplinary synthesis of the ventral, semantic connectivity pathways consisting of the uncinate, middle longitudinal, inferior longitudinal, and inferior fronto-occipital fasciculi, with special reference to areas of controversies or consensus. This is achieved by describing, for each tract, historical concept evolution, terminations, lateralisation, and segmentation models. Clinical implications are presented in three forms: (a) functional considerations derived from normal subject investigations, (b) outputs of direct electrical stimulation during awake brain surgery, and (c) results of disconnection syndromes following disease-related lesioning. The current review unifies interpretation of related specialisms and serves as a framework/thinking model for additional research on language data acquisition and integration.
Madore B, Belsley G, Cheng C-C, Preiswerk F, Kijewski MF, Wu P-H, Martell LB, Pluim JPW, Di Carli M, Moore SC. Ultrasound-Based Sensors for Respiratory Motion Assessment in Multimodality PET Imaging. Phys Med Biol. 2022;67 (2).Abstract
Breathing motion can displace internal organs by up to several cm; as such, it is a primary factor limiting image quality in medical imaging. Motion can also complicate matters when trying to fuse images from different modalities, acquired at different locations and/or on different days. Currently available devices for monitoring breathing motion often do so indirectly, by detecting changes in the outline of the torso rather than the internal motion itself, and these devices are often fixed to floors, ceilings or walls, and thus cannot accompany patients from one location to another. We have developed small ultrasound-based sensors, referred to as 'organ configuration motion' (OCM) sensors, that attach to the skin and provide rich motion-sensitive information. In the present work we tested the ability of OCM sensors to enable respiratory gating duringin vivoPET imaging. A motion phantom involving an FDG solution was assembled, and two cancer patients scheduled for a clinical PET/CT exam were recruited for this study. OCM signals were used to help reconstruct phantom andin vivodata into time series of motion-resolved images. As expected, the motion-resolved images captured the underlying motion. In Patient #1, a single large lesion proved to be mostly stationary through the breathing cycle. However, in Patient #2, several small lesions were mobile during breathing, and our proposed new approach captured their breathing-related displacements. In summary, a relatively inexpensive hardware solution was developed here for respiration monitoring. Because the proposed sensors attach to the skin, as opposed to walls or ceilings, they can accompany patients from one procedure to the next, potentially allowing data gathered in different places and at different times to be combined and compared in ways that account for breathing motion.
Zhou H, Jayender J. EMDQ: Removal of Image Feature Mismatches in Real-Time. IEEE Trans Image Process. 2022;31 :706-20.Abstract
This paper proposes a novel method for removing image feature mismatches in real-time that can handle both rigid and smooth deforming environments. Image distortion, parallax and object deformation may cause the pixel coordinates of feature matches to have non-rigid deformations, which cannot be represented using a single analytical rigid transformation. To solve this problem, we propose an algorithm based on the re-weighting and 1-point RANSAC strategy (R1P-RNSC), which operates under the assumption that a non-rigid deformation can be approximately represented by multiple rigid transformations. R1P-RNSC is fast but suffers from the drawback that local smoothing information cannot be considered, thus limiting its accuracy. To solve this problem, we propose a non-parametric algorithm based on the expectation-maximization algorithm and the dual quaternion-based representation (EMDQ). EMDQ generates dense and smooth deformation fields by interpolating among the feature matches, simultaneously removing mismatches that are inconsistent with the deformation field. It relies on the rigid transformations obtained by R1P-RNSC to improve its accuracy. The experimental results demonstrate that EMDQ has superior accuracy compared to other state-of-the-art mismatch removal methods. The ability to build correspondences for all image pixels using the dense deformation field is another contribution of this paper.
Lopez BGC, Kohale IN, Du Z, Korsunsky I, Abdelmoula WM, Dai Y, Stopka SA, Gaglia G, Randall EC, Regan MS, et al. Multimodal Platform for Assessing Drug Distribution and Response in Clinical Trials. Neuro Oncol. 2022;24 (1) :64-77.Abstract
BACKGROUND: Response to targeted therapy varies between patients for largely unknown reasons. Here, we developed and applied an integrative platform using mass spectrometry imaging (MSI), phosphoproteomics, and multiplexed tissue imaging for mapping drug distribution, target engagement, and adaptive response to gain insights into heterogeneous response to therapy. METHODS: Patient-derived xenograft (PDX) lines of glioblastoma were treated with adavosertib, a Wee1 inhibitor, and tissue drug distribution was measured with MALDI-MSI. Phosphoproteomics was measured in the same tumors to identify biomarkers of drug target engagement and cellular adaptive response. Multiplexed tissue imaging was performed on sister sections to evaluate spatial co-localization of drug and cellular response. The integrated platform was then applied on clinical specimens from glioblastoma patients enrolled in the phase 1 clinical trial. RESULTS: PDX tumors exposed to different doses of adavosertib revealed intra- and inter-tumoral heterogeneity of drug distribution and integration of the heterogeneous drug distribution with phosphoproteomics and multiplexed tissue imaging revealed new markers of molecular response to adavosertib. Analysis of paired clinical specimens from patients enrolled in the phase 1 clinical trial informed the translational potential of the identified biomarkers in studying patient's response to adavosertib. CONCLUSIONS: The multimodal platform identified a signature of drug efficacy and patient-specific adaptive responses applicable to preclinical and clinical drug development. The information generated by the approach may inform mechanisms of success and failure in future early phase clinical trials, providing information for optimizing clinical trial design and guiding future application into clinical practice.
Maier-Hein L, Eisenmann M, Sarikaya D, März K, Collins T, Malpani A, Fallert J, Feussner H, Giannarou S, Mascagni P, et al. Surgical Data Science - From Concepts Toward Clinical Translation. Med Image Anal. 2022;76 :102306.Abstract
Recent developments in data science in general and machine learning in particular have transformed the way experts envision the future of surgery. Surgical Data Science (SDS) is a new research field that aims to improve the quality of interventional healthcare through the capture, organization, analysis and modeling of data. While an increasing number of data-driven approaches and clinical applications have been studied in the fields of radiological and clinical data science, translational success stories are still lacking in surgery. In this publication, we shed light on the underlying reasons and provide a roadmap for future advances in the field. Based on an international workshop involving leading researchers in the field of SDS, we review current practice, key achievements and initiatives as well as available standards and tools for a number of topics relevant to the field, namely (1) infrastructure for data acquisition, storage and access in the presence of regulatory constraints, (2) data annotation and sharing and (3) data analytics. We further complement this technical perspective with (4) a review of currently available SDS products and the translational progress from academia and (5) a roadmap for faster clinical translation and exploitation of the full potential of SDS, based on an international multi-round Delphi process.
Zekelman LR, Zhang F, Makris N, He J, Chen Y, Xue T, Liera D, Drane DL, Rathi Y, Golby AJ, et al. White Matter Association Tracts Underlying Language and Theory of Mind: An Investigation of 809 Brains from the Human Connectome Project. Neuroimage. 2022;246 :118739.Abstract
Language and theory of mind (ToM) are the cognitive capacities that allow for the successful interpretation and expression of meaning. While functional MRI investigations are able to consistently localize language and ToM to specific cortical regions, diffusion MRI investigations point to an inconsistent and sometimes overlapping set of white matter tracts associated with these two cognitive domains. To further examine the white matter tracts that may underlie these domains, we use a two-tensor tractography method to investigate the white matter microstructure of 809 participants from the Human Connectome Project. 20 association white matter tracts (10 in each hemisphere) are uniquely identified by leveraging a neuroanatomist-curated automated white matter tract atlas. The mean fractional anisotropy (FA), mean diffusivity (MD), and number of streamlines (NoS) are measured for each white matter tract. Performance on neuropsychological assessments of semantic memory (NIH Toolbox Picture Vocabulary Test, TPVT) and emotion perception (Penn Emotion Recognition Test, PERT) are used to measure critical subcomponents of the language and ToM networks, respectively. Regression models are constructed to examine how structural measurements of left and right white matter tracts influence performance across these two assessments. We find that semantic memory performance is influenced by the number of streamlines of the left superior longitudinal fasciculus III (SLF-III), and emotion perception performance is influenced by the number of streamlines of the right SLF-III. Additionally, we find that performance on both semantic memory & emotion perception is influenced by the FA of the left arcuate fasciculus (AF). The results point to multiple, overlapping white matter tracts that underlie the cognitive domains of language and ToM. Results are discussed in terms of hemispheric dominance and concordance with prior investigations.
Robles DJ, Dharani A, Rostowsky KA, Chaudhari NN, Ngo V, Zhang F, O'Donnell LJ, Green L, Sheikh-Bahaei N, Chui HC, et al. Older Age, Male Sex, and Cerebral Microbleeds Predict White Matter Loss After Traumatic Brain Injury. Geroscience. 2022;44 (1) :83-102.Abstract
Little is known on how mild traumatic brain injury affects white matter based on age at injury, sex, cerebral microbleeds, and time since injury. Here, we study the fractional anisotropy of white matter to study these effects in 109 participants aged 18-77 (46 females, age μ ± σ = 40 ± 17 years) imaged within [Formula: see text] 1 week and [Formula: see text] 6 months post-injury. Age is found to be linearly associated with white matter degradation, likely due not only to injury but also to cumulative effects of other pathologies and to their interactions with injury. Age is associated with mean anisotropy decreases in the corpus callosum, middle longitudinal fasciculi, inferior longitudinal and occipitofrontal fasciculi, and superficial frontal and temporal fasciculi. Over [Formula: see text] 6 months, the mean anisotropies of the corpus callosum, left superficial frontal fasciculi, and left corticospinal tract decrease significantly. Independently of other predictors, age and cerebral microbleeds contribute to anisotropy decrease in the callosal genu. Chronically, the white matter of commissural tracts, left superficial frontal fasciculi, and left corticospinal tract degrade appreciably, independently of other predictors. Our findings suggest that large commissural and intra-hemispheric structures are at high risk for post-traumatic degradation. This study identifies detailed neuroanatomic substrates consistent with brain injury patients' age-dependent deficits in information processing speed, interhemispheric communication, motor coordination, visual acuity, sensory integration, reading speed/comprehension, executive function, personality, and memory. We also identify neuroanatomic features underlying white matter degradation whose severity is associated with the male sex. Future studies should compare our findings to functional measures and other neurodegenerative processes.
Yu Y, Bourantas G, Zwick B, Joldes G, Kapur T, Frisken S, Kikinis R, Nabavi A, Golby A, Wittek A, et al. Computer Simulation of Tumour Resection-Induced Brain Deformation by a Meshless Approach. Int J Numer Method Biomed Eng. 2022;38 (1) :e3539.Abstract
Tumour resection requires precise planning and navigation to maximise tumour removal while simultaneously protecting nearby healthy tissues. Neurosurgeons need to know the location of the remaining tumour after partial tumour removal before continuing with the resection. Our approach to the problem uses biomechanical modelling and computer simulation to compute the brain deformations after the tumour is resected. In this study, we use Meshless Total Lagrangian Explicit Dynamics (MTLED) as the solver. The problem geometry is extracted from the patient-specific MRI data and includes the parenchyma, tumour, cerebrospinal fluid (CSF) and skull. Appropriate nonlinear material formulation is used. Loading is performed by imposing intra-operative conditions of gravity and reaction forces between the tumour and surrounding healthy parenchyma tissues. A finite frictionless sliding contact is enforced between the skull (rigid) and parenchyma. The meshless simulation results are compared to intra-operative MRI sections. We also calculate Hausdorff distances between the computed deformed surfaces (ventricles and tumour cavities) and surfaces observed intra-operatively. Over 80% of points on ventricle surface and 95% of points on tumour cavity surface were successfully registered (results within the limits of two times the original in-plane resolution of the intra-operative image). Computed results demonstrate the potential for our method in estimating the tissue deformation and tumour boundary during the resection. This article is protected by copyright. All rights reserved.
Dominas C, Bhagavatula S, Stover EH, Deans K, Larocca C, Colson YL, Peruzzi PP, Kibel AS, Hata N, Tsai LL, et al. The Translational and Regulatory Development of an Implantable Microdevice for Multiple Drug Sensitivity Measurements in Cancer Patients. IEEE Trans Biomed Eng. 2022;69 (1) :412-21.Abstract
OBJECTIVE: The purpose of this article is to report the translational process of an implantable microdevice platform with an emphasis on the technical and engineering adaptations for patient use, regulatory advances, and successful integration into clinical workflow. METHODS: We developed design adaptations for implantation and retrieval, established ongoing monitoring and testing, and facilitated regulatory advances that enabled the administration and examination of a large set of cancer therapies simultaneously in individual patients. RESULTS: Six applications for oncology studies have successfully proceeded to patient trials, with future applications in progress. CONCLUSION: First-in-human translation required engineering design changes to enable implantation and retrieval that fit with existing clinical workflows, a regulatory strategy that enabled both delivery and response measurement of up to 20 agents in a single patient, and establishment of novel testing and quality control processes for a drug/device combination product without clear precedents. SIGNIFICANCE: This manuscript provides a real-world account and roadmap on how to advance from animal proof-of-concept into the clinic, confronting the question of how to use research to benefit patients.
Yao S, Rigolo L, Yang F, Vangel MG, Wang H, Golby AJ, Liebenthal E, Tie Y. Movie-Watching fMRI for Presurgical Language Mapping in Patients With Brain Tumour. J Neurol Neurosurg Psychiatry. 2022;93 (2) :220-1.