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1. Detection of resting-state functional connectivity in the lumbar spinal cord with 3T MRI

Author: Anna Combes, Lipika Narisetti, Anirban Sengupta, Baxter P. Rogers, Grace Sweeney, Logan Prock, Delaney Houston, Colin D. McKnight, John C. Gore, Seth A. Smith, and Kristin P. O’Grady
Subjects: Medicine, Science
Abstract: Abstract Functional MRI (fMRI) of the spinal cord is an expanding area of research with potential to investigate neuronal activity in the central nervous system. We aimed to characterize the functional connectivity features of the human lumbar spinal cord using resting-state fMRI (rs-fMRI) at 3T, using region-based and data-driven analysis approaches. A 3D multi-shot gradient echo resting-state blood oxygenation level dependent-sensitive rs-fMRI protocol was implemented in 26 healthy participants. Average temporal signal-to-noise ratio in the gray matter was 16.35 ± 4.79 after denoising. Evidence of synchronous signal fluctuations in the ventral and dorsal horns with their contralateral counterparts was observed in representative participants using interactive, exploratory seed-based correlations. Group-wise average in-slice Pearson’s correlations were 0.43 ± 0.17 between ventral horns, and 0.48 ± 0.16 between dorsal horns. Group spatial independent component analysis (ICA) was used to identify areas of coherent activity¸ and revealed components within the gray matter corresponding to anatomical regions. Lower-dimensionality ICA revealed bilateral components corresponding to ventral and dorsal networks. Additional separate ICAs were run on two subsets of the participant group, yielding two sets of components that showed visual consistency and moderate spatial overlap. This work shows feasibility of rs-fMRI to probe the functional features and organization of the lumbar spinal cord.
Published: 2023
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2. Cervical spinal cord susceptibility-weighted MRI at 7T: Application to multiple sclerosis

Author: Margareta A. Clarke, Atlee A. Witt, Ryan K. Robison, Sawyer Fleishman, Anna J.E. Combes, Delaney Houston, Logan E. Prock, Grace Sweeney, Kristin P. O'Grady, Colin D. McKnight, and Seth A. Smith
Subjects: Susceptibility-weighted imaging, Spinal cord, Multiple sclerosis, Ultra-high-field MRI, Central vein sign, Paramagnetic rim lesions, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: Background: Susceptibility-weighted imaging (SWI) has been extensively studied in the brain and in diseases of the central nervous system such as multiple sclerosis (MS) providing unique opportunities to visualize cerebral vasculature and disease-related pathology, including the central vein sign (CVS) and paramagnetic rim lesions (PRLs). However, similar studies evaluating SWI in the spinal cord of patients with MS remain severely limited. Purpose: Based on our previous findings of enlarged spinal vessels in MS compared to healthy controls (HCs), we developed high-field SWI acquisition and processing methods for the cervical spinal cord with application in people with MS (pwMS) and HCs. Here, we demonstrate the vascular variability between the two cohorts and unique MS lesion features in the cervical cord. Methods: In this retrospective, exploratory pilot study conducted between March 2021 and March 2022, we scanned 12 HCs and 9 pwMS using an optimized non-contrast 2D T2*-weighted gradient echo sequence at 7 tesla. The overall appearance of the white and gray matter as well as tissue vasculature were compared between the two cohorts and areas of MS pathology in the patient group were assessed using both the magnitude and processed SWI images. Results: We show improved visibility of vessels and more pronounced gray and white matter contrast in the MS group compared to HCs, hypointensities surrounding the cord in the MS cohort, and identify signal changes indicative of the CVS and paramagnetic rims in 66 % of pwMS with cervical spinal lesions. Conclusion: In this first study of SWI at 7T in the human spinal cord, SWI holds promise in advancing our understanding of disease processes in the cervical cord in MS.
Published: 2023
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3. Denoising of diffusion MRI in the cervical spinal cord – effects of denoising strategy and acquisition on intra-cord contrast, signal modeling, and feature conspicuity

Author: Kurt G. Schilling, Shreyas Fadnavis, Joshua Batson, Mereze Visagie, Anna J.E. Combes, Samantha By, Colin D. McKnight, Francesca Bagnato, Eleftherios Garyfallidis, Bennett A. Landman, Seth A. Smith, and Kristin P. O'Grady
Subjects: Spinal cord, Diffusion MRI, Diffusion tensor imaging, Image denoising, Multiple sclerosis, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: Quantitative diffusion MRI (dMRI) is a promising technique for evaluating the spinal cord in health and disease. However, low signal-to-noise ratio (SNR) can impede interpretation and quantification of these images. The purpose of this study is to evaluate several dMRI denoising approaches on their ability to improve the quality, reliability, and accuracy of quantitative diffusion MRI of the spinal cord. We evaluate three denoising approaches (Non-Local Means, Marchenko-Pastur PCA, and a newly proposed Patch2Self algorithm) and conduct five experiments to validate the denoising performance on clinical-quality and commonly-acquired dMRI acquisitions: 1) a phantom experiment to assess denoising error and bias; 2) a multi-vendor, multi-acquisition open experiment for both qualitative and quantitative evaluation of noise residuals; 3) a bootstrapping experiment to estimate uncertainty of parametric maps; 4) an assessment of spinal cord lesion conspicuity in a multiple sclerosis group; and 5) an evaluation of denoising for advanced parametric multi-compartment modeling. We find that all methods improve signal-to-noise ratio and conspicuity of MS lesions in individual diffusion weighted images (DWIs), but MPPCA and Patch2Self excel at improving the quality and intra-cord contrast of diffusion weighted images – removing signal fluctuations due to thermal noise while improving precision of estimation of diffusion parameters even with very few DWIs (i.e., 16-32) typical of clinical acquisitions. These denoising approaches hold promise for facilitating reliable diffusion observations and measurements in the spinal cord to investigate biological and pathological processes.
Published: 2023
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4. Open-access quantitative MRI data of the spinal cord and reproducibility across participants, sites and manufacturers

Author: Julien Cohen-Adad, Eva Alonso-Ortiz, Mihael Abramovic, Carina Arneitz, Nicole Atcheson, Laura Barlow, Robert L. Barry, Markus Barth, Marco Battiston, Christian Büchel, Matthew Budde, Virginie Callot, Anna J. E. Combes, Benjamin De Leener, Maxime Descoteaux, Paulo Loureiro de Sousa, Marek Dostál, Julien Doyon, Adam Dvorak, Falk Eippert, Karla R. Epperson, Kevin S. Epperson, Patrick Freund, Jürgen Finsterbusch, Alexandru Foias, Michela Fratini, Issei Fukunaga, Claudia A. M. Gandini Wheeler-Kingshott, Giancarlo Germani, Guillaume Gilbert, Federico Giove, Charley Gros, Francesco Grussu, Akifumi Hagiwara, Pierre-Gilles Henry, Tomáš Horák, Masaaki Hori, James Joers, Kouhei Kamiya, Haleh Karbasforoushan, Miloš Keřkovský, Ali Khatibi, Joo-Won Kim, Nawal Kinany, Hagen H. Kitzler, Shannon Kolind, Yazhuo Kong, Petr Kudlička, Paul Kuntke, Nyoman D. Kurniawan, Slawomir Kusmia, René Labounek, Maria Marcella Laganà, Cornelia Laule, Christine S. Law, Christophe Lenglet, Tobias Leutritz, Yaou Liu, Sara Llufriu, Sean Mackey, Eloy Martinez-Heras, Loan Mattera, Igor Nestrasil, Kristin P. O’Grady, Nico Papinutto, Daniel Papp, Deborah Pareto, Todd B. Parrish, Anna Pichiecchio, Ferran Prados, Àlex Rovira, Marc J. Ruitenberg, Rebecca S. Samson, Giovanni Savini, Maryam Seif, Alan C. Seifert, Alex K. Smith, Seth A. Smith, Zachary A. Smith, Elisabeth Solana, Y. Suzuki, George Tackley, Alexandra Tinnermann, Jan Valošek, Dimitri Van De Ville, Marios C. Yiannakas, Kenneth A. Weber II, Nikolaus Weiskopf, Richard G. Wise, Patrik O. Wyss, and Junqian Xu
Subjects: Science
Abstract: Measurement(s) spinal cord Technology Type(s) magnetic resonance imaging Factor Type(s) manufacturer • site Sample Characteristic - Organism Homo sapiens Sample Characteristic - Location Canada • Switzerland • Australia • United States of America • United Kingdom • Germany • French Republic • Czech Republic • Italy • Japan • Kingdom of Spain • China Machine-accessible metadata file describing the reported data: https://doi.org/10.6084/m9.figshare.14052269
Published: 2021
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5. Transcallosal and Corticospinal White Matter Disease and Its Association With Motor Impairment in Multiple Sclerosis

Author: Keejin Yoon, Derek B. Archer, Margareta A. Clarke, Seth A. Smith, Ipek Oguz, Gary Cutter, Junzhong Xu, and Francesca Bagnato
Subjects: multiple sclerosis, magnetic resonance imaging (MRI), neurite orientation dispersion and density imagining (NODDI), neurodegeneration, probabilistic tractography, Neurology. Diseases of the nervous system, RC346-429
Abstract: PurposeIn this cross-sectional, proof-of-concept study, we propose that using the more pathologically-specific neurite orientation dispersion and density imaging (NODDI) method, in conjunction with high-resolution probabilistic tractography, white matter tract templates can improve the assessment of regional axonal injury and its association with disability of people with multiple sclerosis (pwMS).MethodsParametric maps of the neurite density index, orientation dispersion index, and the apparent isotropic volume fraction (IVF) were estimated in 18 pwMS and nine matched healthy controls (HCs). Tract-specific values were measured in transcallosal (TC) fibers from the paracentral lobules and TC and corticospinal fibers from the ventral and dorsal premotor areas, presupplementary and supplementary motor areas, and primary motor cortex. The nonparametric Mann–Whitney U test assessed group differences in the NODDI-derived metrics; the Spearman's rank correlation analyses measured associations between the NODDI metrics and other clinical or radiological variables.ResultsIVF values of the TC fiber bundles from the paracentral, presupplementary, and supplementary motor areas were both higher in pwMS than in HCs (p ≤ 0.045) and in pwMS with motor disability compared to those without motor disability (p ≤ 0.049). IVF in several TC tracts was associated with the Expanded Disability Status Scale score (p ≤ 0.047), while regional and overall lesion burden correlated with the Timed 25-Foot Walking Test (p ≤ 0.049).ConclusionIVF alterations are present in pwMS even when the other NODDI metrics are still mostly preserved. Changes in IVF are biologically non-specific and may not necessarily drive irreversible functional loss. However, by possibly preceding downstream pathologies that are strongly associated with disability accretion, IVF changes are indicators of, otherwise, occult prelesional tissue injury.
Published: 2022
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6. Relaxation-Compensated Chemical Exchange Saturation Transfer MRI in the Brain at 7T: Application in Relapsing-Remitting Multiple Sclerosis

Author: Kristin P. O'Grady, Sanjana Satish, Quinn R. Owen, Bailey A. Box, Francesca Bagnato, Anna J. E. Combes, Sarah R. Cook, Holly James Westervelt, Haley R. Feiler, Richard D. Lawless, Asha Sarma, Shekinah D. Malone, Josephine M. Ndolo, Keejin Yoon, Richard D. Dortch, Baxter P. Rogers, and Seth A. Smith
Subjects: chemical exchange saturation transfer (CEST), glutamate, multiple sclerosis, metabolic imaging, ultrahigh field, apparent exchange-dependent relaxation (AREX), Neurology. Diseases of the nervous system, RC346-429
Abstract: Chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) can probe tissue biochemistry in vivo with high resolution and sensitivity without requiring exogenous contrast agents. Applying CEST MRI at ultrahigh field provides advantages of increasing spectral resolution and improving sensitivity to metabolites with faster proton exchange rates such as glutamate, a critical neurotransmitter in the brain. Prior magnetic resonance spectroscopy and CEST MRI studies have revealed altered regulation of glutamate in patients with multiple sclerosis (MS). While CEST imaging facilitates new strategies for investigating the pathology underlying this complex and heterogeneous neurological disease, CEST signals are contaminated or diluted by concurrent effects (e.g., semi-solid magnetization transfer (MT) and direct water saturation) and are scaled by the T1 relaxation time of the free water pool which may also be altered in the context of disease. In this study of 20 relapsing-remitting MS patients and age- and sex-matched healthy volunteers, glutamate-weighted CEST data were acquired at 7.0 T. A Lorentzian fitting procedure was used to remove the asymmetric MT contribution from CEST z-spectra, and the apparent exchange-dependent relaxation (AREX) correction was applied using an R1 map derived from an inversion recovery sequence to further isolate glutamate-weighted CEST signals from concurrent effects. Associations between AREX and cognitive function were examined using the Minimal Assessment of Cognitive Function in MS battery. After isolating CEST effects from MT, direct water saturation, and T1 effects, glutamate-weighted AREX contrast remained higher in gray matter than in white matter, though the difference between these tissues decreased. Glutamate-weighted AREX in normal-appearing gray and white matter in MS patients did not differ from healthy gray and white matter but was significantly elevated in white matter lesions. AREX in some cortical regions and in white matter lesions correlated with disability and measures of cognitive function in MS patients. However, further studies with larger sample sizes are needed to confirm these relationships due to potential confounding effects. The application of MT and AREX corrections in this study demonstrates the importance of isolating CEST signals for more specific characterization of the contribution of metabolic changes to tissue pathology and symptoms in MS.
Published: 2022
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7. Functional connectivity in the dorsal network of the cervical spinal cord is correlated with diffusion tensor imaging indices in relapsing-remitting multiple sclerosis

Author: Anna J.E. Combes, Kristin P. O'Grady, Baxter P. Rogers, Kurt G. Schilling, Richard D. Lawless, Mereze Visagie, Delaney Houston, Logan Prock, Shekinah Malone, Sanjana Satish, Atlee A. Witt, Colin D. McKnight, Francesca Bagnato, John C. Gore, and Seth A. Smith
Subjects: Spinal cord, Multiple sclerosis, Resting-state fMRI, Functional connectivity, Diffusion tensor imaging, Computer applications to medicine. Medical informatics, R858-859.7, Neurology. Diseases of the nervous system, RC346-429
Abstract: Focal lesions may affect functional connectivity (FC) of the ventral and dorsal networks in the cervical spinal cord of people with relapsing-remitting multiple sclerosis (RRMS). Resting-state FC can be measured using functional MRI (fMRI) at 3T. This study sought to determine whether alterations in FC may be related to the degree of damage in the normal-appearing tissue. Tissue integrity and FC in the cervical spinal cord were assessed with diffusion tensor imaging (DTI) and resting-state fMRI, respectively, in a group of 26 RRMS participants with high cervical lesion load, low disability, and minimally impaired sensorimotor function, and healthy controls. Lower fractional anisotropy (FA) and higher radial diffusivity (RD) were observed in the normal-appearing white matter in the RRMS group relative to controls. Average FC in ventral and dorsal networks was similar between groups. Significant associations were found between higher FC in the dorsal sensory network and several DTI markers of pathology in the normal-appearing tissue. In the normal-appearing grey matter, dorsal FC was positively correlated with axial diffusivity (AD) (r = 0.46, p = 0.020) and mean diffusivity (MD) (r = 0.43, p = 0.032). In the normal-appearing white matter, dorsal FC was negatively correlated with FA (r = −0.43, p = 0.028) and positively correlated with RD (r = 0.49, p = 0.012), AD (r = 0.42, p = 0.037) and MD (r = 0.53, p = 0.006). These results suggest that increased connectivity, while remaining within the normal range, may represent a compensatory mechanism in response to structural damage in support of preserved sensory function in RRMS.
Published: 2022
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8. Advanced spinal cord MRI in multiple sclerosis: Current techniques and future directions

Author: Anna J.E. Combes, Margareta A. Clarke, Kristin P. O'Grady, Kurt G. Schilling, and Seth A. Smith
Subjects: Spinal cord, Multiple sclerosis, advanced MRI, quantitative MRI, functional MRI, Computer applications to medicine. Medical informatics, R858-859.7, Neurology. Diseases of the nervous system, RC346-429
Abstract: Spinal cord magnetic resonance imaging (MRI) has a central role in multiple sclerosis (MS) clinical practice for diagnosis and disease monitoring. Advanced MRI sequences capable of visualizing and quantifying tissue macro- and microstructure and reflecting different pathological disease processes have been used in MS research; however, the spinal cord remains under-explored, partly due to technical obstacles inherent to imaging this structure. We propose that the study of the spinal cord merits equal ambition in overcoming technical challenges, and that there is much information to be exploited to make valuable contributions to our understanding of MS.We present a narrative review on the latest progress in advanced spinal cord MRI in MS, covering in the first part structural, functional, metabolic and vascular imaging methods. We focus on recent studies of MS and those making significant technical steps, noting the challenges that remain to be addressed and what stands to be gained from such advances. Throughout we also refer to other works that presend more in-depth review on specific themes. In the second part, we present several topics that, in our view, hold particular potential. The need for better imaging of gray matter is discussed. We stress the importance of developing imaging beyond the cervical spinal cord, and explore the use of ultra-high field MRI. Finally, some recommendations are given for future research, from study design to newer developments in analysis, and the need for harmonization of sequences and methods within the field.This review is aimed at researchers and clinicians with an interest in gaining an overview of the current state of advanced MRI research in this field and what is primed to be the future of spinal cord imaging in MS research.
Published: 2022
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9. Probing axons using multi‐compartmental diffusion in multiple sclerosis

Author: Francesca Bagnato, Giulia Franco, Hua Li, Enrico Kaden, Fei Ye, Run Fan, Amalie Chen, Daniel C. Alexander, Seth A. Smith, Richard Dortch, and Junzhong Xu
Subjects: Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract: Abstract Objects The diffusion‐based spherical mean technique (SMT) provides a novel model to relate multi‐b‐value diffusion magnetic resonance imaging (MRI) data to features of tissue microstructure. We propose the first clinical application of SMT to image the brain of patients with multiple sclerosis (MS) and investigate clinical feasibility and translation. Methods Eighteen MS patients and nine age‐ and sex‐matched healthy controls (HCs) underwent a 3.0 Tesla scan inclusive of clinical sequences and SMT images (isotropic resolution of 2 mm). Axial diffusivity (AD), apparent axonal volume fraction (Vax), and effective neural diffusivity (Dax) parametric maps were fitted. Differences in AD, Vax, and Dax between anatomically matched regions reflecting different tissues types were estimated using generalized linear mixed models for binary outcomes. Results Differences were seen in all SMT‐derived parameters between chronic black holes (cBHs) and T2‐lesions (P ≤ 0.0016), in Vax and AD between T2‐lesions and normal appearing white matter (NAWM) (P
Published: 2019
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10. Author Correction: Open-access quantitative MRI data of the spinal cord and reproducibility across participants, sites and manufacturers

Author: Julien Cohen-Adad, Eva Alonso-Ortiz, Mihael Abramovic, Carina Arneitz, Nicole Atcheson, Laura Barlow, Robert L. Barry, Markus Barth, Marco Battiston, Christian Büchel, Matthew Budde, Virginie Callot, Anna J. E. Combes, Benjamin De Leener, Maxime Descoteaux, Paulo Loureiro de Sousa, Marek Dostál, Julien Doyon, Adam Dvorak, Falk Eippert, Karla R. Epperson, Kevin S. Epperson, Patrick Freund, Jürgen Finsterbusch, Alexandru Foias, Michela Fratini, Issei Fukunaga, Claudia A. M. Gandini Wheeler-Kingshott, Giancarlo Germani, Guillaume Gilbert, Federico Giove, Charley Gros, Francesco Grussu, Akifumi Hagiwara, Pierre-Gilles Henry, Tomáš Horák, Masaaki Hori, James Joers, Kouhei Kamiya, Haleh Karbasforoushan, Miloš Keřkovský, Ali Khatibi, Joo-Won Kim, Nawal Kinany, Hagen H. Kitzler, Shannon Kolind, Yazhuo Kong, Petr Kudlička, Paul Kuntke, Nyoman D. Kurniawan, Slawomir Kusmia, René Labounek, Maria Marcella Laganà, Cornelia Laule, Christine S. Law, Christophe Lenglet, Tobias Leutritz, Yaou Liu, Sara Llufriu, Sean Mackey, Eloy Martinez-Heras, Loan Mattera, Igor Nestrasil, Kristin P. O’Grady, Nico Papinutto, Daniel Papp, Deborah Pareto, Todd B. Parrish, Anna Pichiecchio, Ferran Prados, Àlex Rovira, Marc J. Ruitenberg, Rebecca S. Samson, Giovanni Savini, Maryam Seif, Alan C. Seifert, Alex K. Smith, Seth A. Smith, Zachary A. Smith, Elisabeth Solana, Y. Suzuki, George Tackley, Alexandra Tinnermann, Jan Valošek, Dimitri Van De Ville, Marios C. Yiannakas, Kenneth A. Weber II, Nikolaus Weiskopf, Richard G. Wise, Patrik O. Wyss, and Junqian Xu
Subjects: Science
Published: 2021
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11. Application and evaluation of NODDI in the cervical spinal cord of multiple sclerosis patients

Author: Samantha By, Junzhong Xu, Bailey A. Box, Francesca R. Bagnato, and Seth A. Smith
Subjects: Computer applications to medicine. Medical informatics, R858-859.7, Neurology. Diseases of the nervous system, RC346-429
Abstract: Introduction: There is a need to develop imaging methods sensitive to axonal injury in multiple sclerosis (MS), given the prominent impact of axonal pathology on disability and outcome. Advanced multi-compartmental diffusion models offer novel indices sensitive to white matter microstructure. One such model, neurite orientation dispersion and density imaging (NODDI), is sensitive to neurite morphology, providing indices of apparent volume fractions of axons (vin), isotropic water (viso) and the dispersion of fibers about a central axis (orientation dispersion index, ODI). NODDI has yet to be studied for its sensitivity to spinal cord pathology. Here, we investigate the feasibility and utility of NODDI in the cervical spinal cord of MS patients. Methods: NODDI was applied in the cervical spinal cord in a cohort of 8 controls and 6 MS patients. Statistical analyses were performed to test the sensitivity of NODDI-derived indices to pathology in MS (both lesion and normal appearing white matter NAWM). Diffusion kurtosis imaging (DKI) and diffusion tensor imaging (DTI) analysis were also performed to compare with NODDI. Results: A decrease in NODDI-derived vin was observed at the site of the lesion (p
Published: 2017
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12. Evaluating single-point quantitative magnetization transfer in the cervical spinal cord: Application to multiple sclerosis

Author: Alex K. Smith, Samantha By, Bailey D. Lyttle, Richard D. Dortch, Bailey A. Box, Lydia J. Mckeithan, Saakshi Thukral, Francesca Bagnato, Siddharama Pawate, and Seth A. Smith
Subjects: Computer applications to medicine. Medical informatics, R858-859.7, Neurology. Diseases of the nervous system, RC346-429
Abstract: Spinal cord (SC) damage is linked to clinical deficits in patients with multiple sclerosis (MS), however, conventional MRI methods are not specific to the underlying macromolecular tissue changes that may precede overt lesion detection. Single-point quantitative magnetization transfer (qMT) is a method that can provide high-resolution indices sensitive to underlying macromolecular composition in a clinically feasible scan time by reducing the number of MT-weighted acquisitions and utilizing a two-pool model constrained by empirically determined constants. As the single-point qMT method relies on a priori constraints, it has not been employed extensively in patients, where these constraints may vary, and thus, the biases inherent in this model have not been evaluated in a patient cohort. We, therefore, addressed the potential biases in the single point qMT model by acquiring qMT measurements in the cervical SC in patient and control cohorts and evaluated the differences between the control and patient-derived qMT constraints (kmf, T2fR1f, and T2m) for the single point model. We determined that the macromolecular to free pool size ratio (PSR) differences between the control and patient-derived constraints are not significant (p>0.149 in all cases). Additionally, the derived PSR for each cohort was compared, and we reported that the white matter PSR in healthy volunteers is significantly different from lesions (p
Published: 2017
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13. ZOOM or Non-ZOOM? Assessing Spinal Cord Diffusion Tensor Imaging Protocols for Multi-Centre Studies.

Author: Rebecca S Samson, Simon Lévy, Torben Schneider, Alex K Smith, Seth A Smith, Julien Cohen-Adad, and Claudia A M Gandini Wheeler-Kingshott
Subjects: Medicine, Science
Abstract: The purpose of this study was to develop and evaluate two spinal cord (SC) diffusion tensor imaging (DTI) protocols, implemented at multiple sites (using scanners from two different manufacturers), one available on any clinical scanner, and one using more advanced options currently available in the research setting, and to use an automated processing method for unbiased quantification. DTI parameters are sensitive to changes in the diseased SC. However, imaging the cord can be technically challenging due to various factors including its small size, patient-related and physiological motion, and field inhomogeneities. Rapid acquisition sequences such as Echo Planar Imaging (EPI) are desirable but may suffer from image distortions. We present a multi-centre comparison of two acquisition protocols implemented on scanners from two different vendors (Siemens and Philips), one using a reduced field-of-view (rFOV) EPI sequence, and one only using options available on standard clinical scanners such as outer volume suppression (OVS). Automatic analysis was performed with the Spinal Cord Toolbox for unbiased and reproducible quantification of DTI metrics in the white matter. Images acquired using the rFOV sequence appear less distorted than those acquired using OVS alone. SC DTI parameter values obtained using both sequences at all sites were consistent with previous measurements made at 3T. For the same scanner manufacturer, DTI parameter inter-site SDs were smaller for the rFOV sequence compared to the OVS sequence. The higher inter-site reproducibility (for the same manufacturer and acquisition details, i.e. ZOOM data acquired at the two Philips sites) of rFOV compared to the OVS sequence supports the idea that making research options such as rFOV more widely available would improve accuracy of measurements obtained in multi-centre clinical trials. Future multi-centre studies should also aim to match the rFOV technique and signal-to-noise ratios in all sequences from different manufacturers/sites in order to avoid any bias in measured DTI parameters and ensure similar sensitivity to pathological changes.
Published: 2016
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14. Does the magnetization transfer effect bias chemical exchange saturation transfer effects? Quantifying chemical exchange saturation transfer in the presence of magnetization transfer

Author: Kevin J. Ray, Martin Craig, Michael A. Chappell, Seth A. Smith, James R. Larkin, and Alex K. Smith
Subjects: Full Papers—Imaging Methodology, qMT, Bootstrap analysis, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Nuclear magnetic resonance, quantitative, Bias, Healthy volunteers, Humans, Radiology, Nuclear Medicine and imaging, Magnetization transfer, NOE, Full Paper, Chemistry, Phantoms, Imaging, Chemical exchange, Phantom data, amide, Magnetic Resonance Imaging, Radiology Nuclear Medicine and imaging, Saturation transfer, MT, Protons, CEST, 030217 neurology & neurosurgery
Abstract: Purpose: Chemical exchange saturation transfer (CEST) is an MRI technique sensitive to the presence of low‐concentration solute protons exchanging with water. However, magnetization transfer (MT) effects also arise when large semisolid molecules interact with water, which biases CEST parameter estimates if quantitative models do not account for macromolecular effects. This study establishes under what conditions this bias is significant and demonstrates how using an appropriate model provides more accurate quantitative CEST measurements. Methods: CEST and MT data were acquired in phantoms containing bovine serum albumin and agarose. Several quantitative CEST and MT models were used with the phantom data to demonstrate how underfitting can influence estimates of the CEST effect. CEST and MT data were acquired in healthy volunteers, and a two‐pool model was fit in vivo and in vitro, whereas removing increasing amounts of CEST data to show biases in the CEST analysis also corrupts MT parameter estimates. Results: When all significant CEST/MT effects were included, the derived parameter estimates for each CEST/MT pool significantly correlated (P < .05) with bovine serum albumin/agarose concentration; minimal or negative correlations were found with underfitted data. Additionally, a bootstrap analysis demonstrated that significant biases occur in MT parameter estimates (P < .001) when unmodeled CEST data are included in the analysis. Conclusions: These results indicate that current practices of simultaneously fitting both CEST and MT effects in model‐based analyses can lead to significant bias in all parameter estimates unless a sufficiently detailed model is utilized. Therefore, care must be taken when quantifying CEST and MT effects in vivo by properly modeling data to minimize these biases.
Published: 2020

15. Open-access quantitative MRI data of the spinal cord and reproducibility across participants, sites and manufacturers

Author: Alexandra Tinnermann, Dimitri Van De Ville, Cornelia Laule, Sean Mackey, Robert L. Barry, Benjamin De Leener, Anna Pichiecchio, Eva Alonso-Ortiz, Giancarlo Germani, Ali Khatibi, Nico Papinutto, Marc J. Ruitenberg, René Labounek, Nawal Kinany, Francesco Grussu, Michela Fratini, Petr Kudlička, Christophe Lenglet, Kouhei Kamiya, Pierre-Gilles Henry, Julien Cohen-Adad, Richard G. Wise, Deborah Pareto, Tomáš Horák, Jürgen Finsterbusch, Alex Rovira, Todd B. Parrish, Y. Suzuki, George Tackley, Junqian Xu, Falk Eippert, Virginie Callot, Daniel Papp, Laura Barlow, Karla R. Epperson, Charley Gros, Nicole Atcheson, Akifumi Hagiwara, Jan Valošek, Yaou Liu, Patrick Freund, Maria Marcella Laganà, James M. Joers, Marco Battiston, Markus Barth, Adam V. Dvorak, Masaaki Hori, Joo Won Kim, Miloš Keřkovský, Paulo Loureiro de Sousa, Sara Llufriu, Mihael Abramovic, Igor Nestrasil, Kenneth A. Weber, Christine S. Law, Paul Kuntke, Elisabeth Solana, Kristin P. O’Grady, Alexandru Foias, Slawomir Kusmia, Claudia A. M. Wheeler-Kingshott, Hagen H. Kitzler, Alex K. Smith, Nyoman D. Kurniawan, Shannon H. Kolind, Marios C. Yiannakas, Seth A. Smith, Zachary A. Smith, Federico Giove, Tobias Leutritz, Matthew D. Budde, Rebecca S. Samson, Christian Büchel, Kevin S. Epperson, Marek Dostál, Giovanni Savini, Issei Fukunaga, Haleh Karbasforoushan, Loan Mattera, Nikolaus Weiskopf, Guillaume Gilbert, Yazhuo Kong, Ferran Prados, Maryam Seif, Anna J.E. Combes, Julien Doyon, P Wyss, Alan C. Seifert, Carina Arneitz, Eloy Martinez-Heras, Maxime Descoteaux, Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Exploration Métabolique par Résonance Magnétique [Hôpital de la Timone - AP-HM] (CEMEREM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS)- Hôpital de la Timone [CHU - APHM] (TIMONE), Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et nanosciences d'Alsace (FMNGE), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Universitat Oberta de Catalunya (UOC), Universitat Oberta de Catalunya. eHealth Center, Institut Català de la Salut, [Cohen-Adad J] NeuroPoly Lab, Institute of Biomedical Engineering, Polytechnique Montreal, Montreal, QC, Canada. Functional Neuroimaging Unit, CRIUGM, Université de Montréal, Montreal, QC, Canada. Mila - Quebec AI Institute, Montreal, QC, Canada. [Alonso-Ortiz E] NeuroPoly Lab, Institute of Biomedical Engineering, Polytechnique Montreal, Montreal, QC, Canada. [Abramovic M, Arneitz C] Department of Radiology, Swiss Paraplegic Centre, Nottwil, Switzerland. [Atcheson N] Centre for Advanced Imaging, The University of Queensland, Brisbane, Australia. [Barlow L] Department of Radiology, University of British Columbia, Vancouver, BC, Canada. [Grussu F] NMR Research Unit, Queen Square MS Centre, UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London, London, UK. Radiomics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Pareto D, Rovira À] Secció de Neuroradiologia, Vall d’Hebron Hospital Universitri, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Centre d'Exploration Métabolique par Résonance Magnétique [Hôpital de la Timone - APHM] (CEMEREM), Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, and Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Statistics and Probability, Data Descriptor, medicine.medical_specialty, Sciences du Vivant [q-bio]/Neurosciences [q-bio.NC], Investigació - Avaluació, Nervous System::Central Nervous System::Spinal Cord [ANATOMY], databases, Computer science, Science, of-the-art, Spinal cord diseases, Spinal Cord Diseases, Imaging techniques, Library and Information Sciences, 030218 nuclear medicine & medical imaging, Education, Databases, 03 medical and health sciences, 0302 clinical medicine, Diagnosis::Diagnostic Techniques and Procedures::Diagnostic Imaging::Tomography::Magnetic Resonance Imaging [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Investigative Techniques::Epidemiologic Methods::Epidemiologic Research Design::Reproducibility of Results [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], medicine, Medical physics, diagnóstico::técnicas y procedimientos diagnósticos::diagnóstico por imagen::tomografía::imagen por resonancia magnética [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Other subheadings::Other subheadings::/diagnostic imaging [Other subheadings], Protocol (science), Reproducibility, Extramural, Otros calificadores::Otros calificadores::/diagnóstico por imagen [Otros calificadores], técnicas de investigación::métodos epidemiológicos::diseño de la investigación epidemiológica::reproducibilidad de los resultados [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], white, Spinal cord, spinal cord diseases, Toolbox, imaging techniques, matter, Computer Science Applications, magnetization-transfer, medicine.anatomical_structure, Imatgeria per ressonància magnètica, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], sistema nervioso::sistema nervioso central::médula espinal [ANATOMÍA], Statistics, Probability and Uncertainty, Medul·la espinal - Malalties - Imatgeria, 030217 neurology & neurosurgery, Information Systems
Abstract: In a companion paper by Cohen-Adad et al. we introduce the spine generic quantitative MRI protocol that provides valuable metrics for assessing spinal cord macrostructural and microstructural integrity. This protocol was used to acquire a single subject dataset across 19 centers and a multi-subject dataset across 42 centers (for a total of 260 participants), spanning the three main MRI manufacturers: GE, Philips and Siemens. Both datasets are publicly available via git-annex. Data were analysed using the Spinal Cord Toolbox to produce normative values as well as inter/intra-site and inter/intra-manufacturer statistics. Reproducibility for the spine generic protocol was high across sites and manufacturers, with an average inter-site coefficient of variation of less than 5% for all the metrics. Full documentation and results can be found at https://spine-generic.rtfd.io/. The datasets and analysis pipeline will help pave the way towards accessible and reproducible quantitative MRI in the spinal cord., Measurement(s)spinal cordTechnology Type(s)magnetic resonance imagingFactor Type(s)manufacturer • siteSample Characteristic - OrganismHomo sapiensSample Characteristic - LocationCanada • Switzerland • Australia • United States of America • United Kingdom • Germany • French Republic • Czech Republic • Italy • Japan • Kingdom of Spain • China Machine-accessible metadata file describing the reported data: 10.6084/m9.figshare.14052269
Published: 2021

16. Resting state functional connectivity in the human spinal cord

Author: Robert L Barry, Seth A Smith, Adrienne N Dula, and John C Gore
Subjects: fMRI, spinal cord, 7 Tesla, resting state, functional connectivity, Medicine, Science, Biology (General), QH301-705.5
Abstract: Functional magnetic resonance imaging using blood oxygenation level dependent (BOLD) contrast is well established as one of the most powerful methods for mapping human brain function. Numerous studies have measured how low-frequency BOLD signal fluctuations from the brain are correlated between voxels in a resting state, and have exploited these signals to infer functional connectivity within specific neural circuits. However, to date there have been no previous substantiated reports of resting state correlations in the spinal cord. In a cohort of healthy volunteers, we observed robust functional connectivity between left and right ventral (motor) horns, and between left and right dorsal (sensory) horns. Our results demonstrate that low-frequency BOLD fluctuations are inherent in the spinal cord as well as the brain, and by analogy to cortical circuits, we hypothesize that these correlations may offer insight into the execution and maintenance of sensory and motor functions both locally and within the cerebrum.
Published: 2014
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17. Author Correction: Open-access quantitative MRI data of the spinal cord and reproducibility across participants, sites and manufacturers

Author: Ferran Prados, Alex Rovira, Ali Khatibi, Nico Papinutto, George Tackley, Maria Marcella Laganà, Akifumi Hagiwara, Kristin P. O’Grady, René Labounek, Nawal Kinany, Joo Won Kim, Loan Mattera, Christine S. Law, Seth A. Smith, Daniel Papp, Todd B. Parrish, Julien Cohen-Adad, Robert L. Barry, Nyoman D. Kurniawan, Sara Llufriu, Giancarlo Germani, Slawomir Kusmia, Miloš Keřkovský, Eloy Martinez-Heras, Matthew D. Budde, Richard G. Wise, Claudia A. M. Wheeler-Kingshott, P Wyss, Rebecca S. Samson, Karla R. Epperson, Y. Suzuki, Haleh Karbasforoushan, Issei Fukunaga, Igor Nestrasil, Virginie Callot, Maxime Descoteaux, Yazhuo Kong, Paul Kuntke, Kenneth A. Weber, Alexandru Foias, Marco Battiston, Hagen H. Kitzler, Charley Gros, Giovanni Savini, Michela Fratini, Guillaume Gilbert, Alan C. Seifert, Anna J.E. Combes, Carina Arneitz, Julien Doyon, Tobias Leutritz, Zachary A. Smith, Laura Barlow, James M. Joers, Kevin S. Epperson, Pierre-Gilles Henry, Markus Barth, Francesco Grussu, Deborah Pareto, Christophe Lenglet, Jürgen Finsterbusch, Shannon H. Kolind, Christian Büchel, Sean Mackey, Marios C. Yiannakas, Petr Kudlička, Mihael Abramovic, Benjamin De Leener, Elisabeth Solana, Anna Pichiecchio, Eva Alonso-Ortiz, Nikolaus Weiskopf, Kouhei Kamiya, Alexandra Tinnermann, Jan Valošek, Patrick Freund, Junqian Xu, Marek Dostál, Dimitri Van De Ville, Alex K. Smith, Federico Giove, Marc J. Ruitenberg, Falk Eippert, Nicole Atcheson, Paulo Loureiro de Sousa, Tomáš Horák, Masaaki Hori, Yaou Liu, Maryam Seif, Adam V. Dvorak, and Cornelia Laule
Subjects: Adult, Male, Statistics and Probability, Data descriptor, Science, MEDLINE, Spinal cord diseases, Neuroimaging, Spinal Cord Diseases, Imaging techniques, Library and Information Sciences, GeneralLiterature_MISCELLANEOUS, Education, Databases, Text mining, Image Processing, Computer-Assisted, Humans, Medicine, Author Correction, Reproducibility, business.industry, MT protocol, Reproducibility of Results, Spinal cord, Magnetic Resonance Imaging, Computer Science Applications, medicine.anatomical_structure, Spinal Cord, Female, Statistics, Probability and Uncertainty, business, Cartography, Information Systems
Abstract: In a companion paper by Cohen-Adad et al. we introduce the spine generic quantitative MRI protocol that provides valuable metrics for assessing spinal cord macrostructural and microstructural integrity. This protocol was used to acquire a single subject dataset across 19 centers and a multi-subject dataset across 42 centers (for a total of 260 participants), spanning the three main MRI manufacturers: GE, Philips and Siemens. Both datasets are publicly available via git-annex. Data were analysed using the Spinal Cord Toolbox to produce normative values as well as inter/intra-site and inter/intra-manufacturer statistics. Reproducibility for the spine generic protocol was high across sites and manufacturers, with an average inter-site coefficient of variation of less than 5% for all the metrics. Full documentation and results can be found at https://spine-generic.rtfd.io/ . The datasets and analysis pipeline will help pave the way towards accessible and reproducible quantitative MRI in the spinal cord.
Published: 2021

18. Extensive neurological recovery from a complete spinal cord injury: a case report and hypothesis on the role of cortical plasticity

Author: Ann S Choe, Visar eBelegu, Shoko eYoshida, Suresh eJoel, Cristina L Sadowsky, Seth A Smith, Peter C van Zijl, James J Pekar, and John W Mcdonald
Subjects: Diffusion Tensor Imaging, plasticity, spinal cord injury, Trauma, resting state fMRI, magnetization transfer imaging, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: Neurological recovery in patients with severe spinal cord injury (SCI) is extremely rare. We have identified a patient with chronic cervical traumatic SCI, who suffered a complete loss of motor and sensory function below the injury for six weeks after the injury, but experienced a progressive neurological recovery that continued for 17 years. The extent of the patient’s recovery from the severe trauma-induced paralysis is rare and remarkable. A detailed study of this patient using diffusion tensor imaging (DTI), magnetization transfer imaging (MTI), and resting state fMRI (rs-fMRI) revealed structural and functional changes in the central nervous system that may be associated with the neurological recovery. 62% cervical cord white matter atrophy was observed. DTI-derived quantities, more sensitive to axons, demonstrated focal changes, while MTI-derived quantity, more sensitive to myelin, showed a diffuse change. No significant cortical structural changes were observed, while rs-fMRI revealed increased brain functional connectivity between sensorimotor and visual networks. The study provides comprehensive description of the structural and functional changes in the patient using advanced MR imaging technique. This multimodal MR imaging study also shows the potential of rs-fMRI to measure the extent of cortical plasticity.
Published: 2013
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19. Discovering novel disease comorbidities using electronic medical records

Author: Lori L. Beason-Held, Thomas A. Lasko, Valerie F. Welty, Warren D. Taylor, Seth A. Smith, Jeffrey D. Blume, Michelle D. Failla, Shikha Chaganti, Bennett A. Landman, Louise A. Mawn, Francesca Bagnato, Carissa J. Cascio, Susan M. Resnick, and Kimberly Albert
Subjects: 0301 basic medicine, Pervasive Developmental Disorders, Autism Spectrum Disorder, Vision, Social Sciences, Electronic Medical Records, Datasets as Topic, Scientific literature, Disease, Comorbidity, Alzheimer's Disease, Database and Informatics Methods, 0302 clinical medicine, Medicine and Health Sciences, Psychology, Electronic Health Records, Database Searching, Multidisciplinary, Medical record, Neurodegenerative Diseases, 3. Good health, Neurology, Autism spectrum disorder, Alzheimer's Disease Diagnosis and Management, Physical Sciences, Medicine, Sensory Perception, Research Article, Multiple Sclerosis, Optic Neuritis, Science, Immunology, MEDLINE, Health Informatics, Research and Analysis Methods, Autoimmune Diseases, 03 medical and health sciences, Diagnostic Medicine, Alzheimer Disease, Mental Health and Psychiatry, medicine, Leverage (statistics), Humans, Biology and Life Sciences, medicine.disease, Probability Theory, Probability Distribution, Data science, Demyelinating Disorders, 030104 developmental biology, Developmental Psychology, Dementia, Clinical Immunology, Clinical Medicine, 030217 neurology & neurosurgery, Mathematics, Neuroscience
Abstract: Increasing reliance on electronic medical records at large medical centers provides unique opportunities to perform population level analyses exploring disease progression and etiology. The massive accumulation of diagnostic, procedure, and laboratory codes in one place has enabled the exploration of co-occurring conditions, their risk factors, and potential prognostic factors. While most of the readily identifiable associations in medical records are (now) well known to the scientific community, there is no doubt many more relationships are still to be uncovered in EMR data. In this paper, we introduce a novel finding index to help with that task. This new index uses data mined from real-time PubMed abstracts to indicate the extent to which empirically discovered associations are already known (i.e., present in the scientific literature). Our methods leverage second-generation p-values, which better identify associations that are truly clinically meaningful. We illustrate our new method with three examples: Autism Spectrum Disorder, Alzheimer's Disease, and Optic Neuritis. Our results demonstrate wide utility for identifying new associations in EMR data that have the highest priority among the complex web of correlations and causalities. Data scientists and clinicians can work together more effectively to discover novel associations that are both empirically reliable and clinically understudied.
Published: 2019

20. Spatial distribution of multiple sclerosis lesions in the cervical spinal cord

Author: Kouhei Kamiya, Massimo Filippi, Marios C. Yiannakas, Ferran Prados, Rohit Bakshi, Hugh Kearney, Sridar Narayanan, Pierre Labauge, Timothy M. Shepherd, Jean-Christophe Brisset, Russell Ouellette, Tobias Granberg, Ren Zhuoquiong, Caterina Mainero, Julien Cohen-Adad, Atef Badji, Jean Pelletier, Josefina Maranzano, Erik Charlson, Leszek Stawiarz, Seth A. Smith, Yasuhiko Tachibana, Yaou Liu, Charley Gros, Masaaki Hori, Dominique Eden, Olga Ciccarelli, Virginie Callot, Daniel S. Reich, Jennifer Lefeuvre, Gilles Edan, Sara M. Dupont, Govind Nair, Henitsoa Rasoanandrianina, Elise Bannier, Paola Valsasina, Jason F. Talbott, Shahamat Tauhid, Jan Hillert, Lydia Chougar, Anne Kerbrat, Constantina A. Treaba, Maria A. Rocca, Benjamin De Leener, Bertrand Audoin, École Polytechnique de Montréal (EPM), Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], Xuanwu Hospital of Capital, Deutsche Telekom Group, Department of Computer Science [Liverpool], University of Liverpool, Karolinska Institutet [Stockholm], Department of Radiology and Biomedical Imaging [San Francisco], University of California [San Francisco] (UC San Francisco), University of California (UC)-University of California (UC), Neuroimagerie: méthodes et applications (Empenn), Institut National de la Santé et de la Recherche Médicale (INSERM)-Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-SIGNAUX ET IMAGES NUMÉRIQUES, ROBOTIQUE (IRISA-D5), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Service de Neurologie [Rennes] = Neurology [Rennes], CHU Pontchaillou [Rennes], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Exploration Métabolique par Résonance Magnétique [Hôpital de la Timone - AP-HM] (CEMEREM), Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Observatoire Français de la Sclérose En Plaques [Lyon] (OFSEP), Vita-Salute San Raffaele University and Center for Translational Genomics and Bioinformatics, Brigham and Women's Hospital [Boston], Harvard Medical School [Boston] (HMS), Translational imaging group [London] (TIG), Centre for Medical Image Computing (CMIC), University College of London [London] (UCL)-University College of London [London] (UCL)-Department of Medical Physics and Biomedical Engineering (UCL), University College of London [London] (UCL), Vanderbilt University [Nashville], Athinoula A. Martinos Center for Biomedical Imaging, Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], National Institutes of Health [Bethesda] (NIH), New York University Langone Medical Center (NYU Langone Medical Center), NYU System (NYU), National Institute of Radiological Sciences (NIRS), Juntendo University Hospital [Tokyo], McConnell Brain Imaging Centre (MNI), McGill University = Université McGill [Montréal, Canada]-McGill University = Université McGill [Montréal, Canada], Funded by the Canada Research Chair in Quantitative Magnetic Resonance Imaging, CIHR-FDN-143263, FRQS-28826, FRQNT-2015-PR-182754, NSERC-435897–2013, QBIN, NMSS RG-1501–02840 (S.A.S.), NIH/NINDS R21 NS087465–01 (S.A.S.), NIH/NEI R01EY023240 (S.A.S.), DoD W81XWH-13–0073 (S.A.S.), the Intramural Research Program of NIH/NINDS (J.L., D.S.R., G.N.), PHRC (EMISEP), NIH/NINDS R01NS078322–02 (C.M.), ClinicalTrials.gov (NCT02117375), CNRS, 'Fondation A*midex-Investissements d’Avenir', the Stockholm County Council (ALF grant 20150166), Swedish Society for Medical Research (T.G.), Guarantors of Brain (F.P.), ANR-10-COHO-002, OFSEP, EDMUS Foundation against multiple sclerosis, UK MS Society and the National Institute for Health Research University College London Hospitals Biomedical Research Centre, EMD Serono (C.M., R.B.)., ANR-10-COHO-0002,OFSEP,Observatoire Français de la Sclérose en Plaques(2010), Bannier, Elise, Cohortes - Observatoire Français de la Sclérose en Plaques - - OFSEP2010 - ANR-10-COHO-0002 - COHO - VALID, University of California [San Francisco] (UCSF), University of California-University of California, Empenn, Université de Bretagne Sud (UBS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-CentraleSupélec-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Bretagne Sud (UBS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)- Hôpital de la Timone [CHU - APHM] (TIMONE), Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS), Centre d'Exploration Métabolique par Résonance Magnétique [Hôpital de la Timone - APHM] (CEMEREM), Eden, Dominique, Gros, Charley, Badji, Atef, Dupont, Sara M, De Leener, Benjamin, Maranzano, Josefina, Zhuoquiong, Ren, Liu, Yaou, Granberg, Tobia, Ouellette, Russell, Stawiarz, Leszek, Hillert, Jan, Talbott, Jason, Kerbrat, Anne, Edan, Gille, Labauge, Pierre, Callot, Virginie, Pelletier, Jean, Audoin, Bertrand, Rasoanandrianina, Henitsoa, Brisset, Jean-Christophe, Valsasina, Paola, Rocca, Maria A, Filippi, Massimo, Bakshi, Rohit, Tauhid, Shahamat, Prados, Ferran, Yiannakas, Mario, Kearney, Hugh, Ciccarelli, Olga, Smith, Seth A, Andrada Treaba, Constantina, Mainero, Caterina, Lefeuvre, Jennifer, Reich, Daniel S, Nair, Govind, Shepherd, Timothy M, Charlson, Erik, Tachibana, Yasuhiko, Hori, Masaaki, Kamiya, Kouhei, Chougar, Lydia, Narayanan, Sridar, and Cohen-Adad, Julien
Subjects: 0301 basic medicine, Adult, Male, medicine.medical_specialty, Cord, multicentre, Grey matter, multiple sclerosis, Spinal Cord Diseases, lesions, White matter, Lesion, 03 medical and health sciences, Disability Evaluation, 0302 clinical medicine, Multiple Sclerosis, Relapsing-Remitting, medicine, Humans, Gray Matter, 10. No inequality, [SDV.IB] Life Sciences [q-bio]/Bioengineering, Spatial Analysis, Expanded Disability Status Scale, Clinically isolated syndrome, business.industry, Multiple sclerosis, Brain, Cervical Cord, spinal cord, Original Articles, Middle Aged, Multiple Sclerosis, Chronic Progressive, medicine.disease, Spinal cord, Magnetic Resonance Imaging, White Matter, 030104 developmental biology, medicine.anatomical_structure, Disease Progression, Female, [SDV.IB]Life Sciences [q-bio]/Bioengineering, Neurology (clinical), Radiology, medicine.symptom, business, 030217 neurology & neurosurgery, MRI
Abstract: International audience; Spinal cord lesions detected on MRI hold important diagnostic and prognostic value for multiple sclerosis. Previous attempts to correlate lesion burden with clinical status have had limited success, however, suggesting that lesion location may be a contributor. Our aim was to explore the spatial distribution of multiple sclerosis lesions in the cervical spinal cord, with respect to clinical status. We included 642 suspected or confirmed multiple sclerosis patients (31 clinically isolated syndrome, and 416 relapsing-remitting, 84 secondary progressive, and 73 primary progressive multiple sclerosis) from 13 clinical sites. Cervical spine lesions were manually delineated on T2- and T2*-weighted axial and sagittal MRI scans acquired at 3 or 7 T. With an automatic publicly-available analysis pipeline we produced voxelwise lesion frequency maps to identify predilection sites in various patient groups characterized by clinical subtype, Expanded Disability Status Scale score and disease duration. We also measured absolute and normalized lesion volumes in several regions of interest using an atlas-based approach, and evaluated differences within and between groups. The lateral funiculi were more frequently affected by lesions in progressive subtypes than in relapsing in voxelwise analysis (P < 0.001), which was further confirmed by absolute and normalized lesion volumes (P < 0.01). The central cord area was more often affected by lesions in primary progressive than relapse-remitting patients (P < 0.001). Between white and grey matter, the absolute lesion volume in the white matter was greater than in the grey matter in all phenotypes (P < 0.001); however when normalizing by each region, normalized lesion volumes were comparable between white and grey matter in primary progressive patients. Lesions appearing in the lateral funiculi and central cord area were significantly correlated with Expanded Disability Status Scale score (P < 0.001). High lesion frequencies were observed in patients with a more aggressive disease course, rather than long disease duration. Lesions located in the lateral funiculi and central cord area of the cervical spine may influence clinical status in multiple sclerosis. This work shows the added value of cervical spine lesions, and provides an avenue for evaluating the distribution of spinal cord lesions in various patient groups.
Published: 2019

21. Automatic segmentation of the spinal cord and intramedullary multiple sclerosis lesions with convolutional neural networks

Author: Vincent Auclair, Ferran Prados, Jean-Christophe Brisset, Josefina Maranzano, Sridar Narayanan, Kouhei Kamiya, Constantina A. Treaba, Atef Badji, Hugh Kearney, Jean Pelletier, Pierre Labauge, Elise Bannier, Paola Valsasina, Erik Charlson, Daniel S. Reich, Olga Ciccarelli, Dominique Eden, Ren Zhuoquiong, Henitsoa Rasoanandrianina, Virginie Callot, Gilles Edan, Seth A. Smith, Marios C. Yiannakas, Jennifer Lefeuvre, Govind Nair, Allan R. Martin, Julien Cohen-Adad, Timothy M. Shepherd, Jason F. Talbott, Donald G. McLaren, Charley Gros, Masaaki Hori, Shahabeddin Vahdat, Julien Doyon, Yasuhiko Tachibana, Leszek Stawiarz, Shahamat Tauhid, Jan Hillert, Massimo Filippi, Lydia Chougar, Anne Kerbrat, Russell Ouellette, Caterina Mainero, Sara M. Dupont, Tobias Granberg, Bertrand Audoin, Ali Khatibi, Rohit Bakshi, Maria A. Rocca, Michael G. Fehlings, Benjamin De Leener, Yaou Liu, École Polytechnique de Montréal (EPM), Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], Department of Radiology and Biomedical Imaging [San Francisco], University of California [San Francisco] (UC San Francisco), University of California (UC)-University of California (UC), Xuanwu Hospital of Capital, Deutsche Telekom Group, Department of Computer Science [Liverpool], University of Liverpool, National Institute of Radiological Sciences (NIRS), Juntendo University Hospital [Tokyo], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Karolinska Institutet [Stockholm], CHU Pontchaillou [Rennes], Vision, Action et Gestion d'informations en Santé (VisAGeS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-SIGNAUX ET IMAGES NUMÉRIQUES, ROBOTIQUE (IRISA-D5), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de neurologie [Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université de Montpellier (UM), Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Exploration Métabolique par Résonance Magnétique [Hôpital de la Timone - AP-HM] (CEMEREM), Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Observatoire Français de la Sclérose En Plaques [Lyon] (OFSEP), Vita-Salute San Raffaele University and Center for Translational Genomics and Bioinformatics, Brigham and Women's Hospital [Boston], Harvard Medical School [Boston] (HMS), NMR Research Unit [London], Institute of Neurology [London], University College of London [London] (UCL)-University College of London [London] (UCL), University College of London [London] (UCL), Vanderbilt University [Nashville], Athinoula A. Martinos Center for Biomedical Imaging, Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], National Institutes of Health [Bethesda] (NIH), Biospective [Montréal], University of Toronto, Unité de Neuroimagerie Fonctionnelle [Montréal] (UNF-CRIUGM), Université de Montréal (UdeM)-Centre de Recherche de l'Institut Universitaire de Gériatrie de Montréal (CRIUGM), Stanford University, McConnell Brain Imaging Centre (MNI), McGill University = Université McGill [Montréal, Canada]-McGill University = Université McGill [Montréal, Canada], New York University Langone Medical Center (NYU Langone Medical Center), NYU System (NYU), CIHR FDN-143263, Canadian Institutes of Health Research, International Society of Regulatory Toxicology and Pharmacology, Svenska Sällskapet för Medicinsk Forskning, IVADO, EDMUS Foundation, TransMedTech, R01 EY023240 (SAS), NIH/NEI, RG-1501-02840 (SAS), National Multiple Sclerosis Society, Intramural Research Program, Hospital Programme of Clinical Research (PHRC), NCT02117375, EMISEP project, Fondation A*midex-Investissements d'Avenir, 435897-2013, Natural Sciences and Engineering Research Council of Canada, Observatoire Français de la Sclérose en plaques (OFSEP), 13034, MOP, Canada Research Chairs, National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre (BRC), 2015-PR-182754, Fonds de Recherche du Québec - Nature et Technologies, W81XWH-13-0073 (SAS), U.S. Department of Defense, ANR-10-COHO-002, Agence Nationale de la Recherche, R21 NS087465-01 (SAS), National Institute of Neurological Disorders and Stroke, Fondation Aix-Marseille Universite, SensoriMotor Rehabilitation Research Team (SMRRT), Wings for Life, 20150166, Stockholms Läns Landsting, Centre National de la Recherche Scientifique, 28826, Fonds de Recherche du Québec - Santé, 32454, Canada Foundation for Innovation, Centre d'Exploration Métabolique par Résonance Magnétique [Hôpital de la Timone - APHM] (CEMEREM), University of California [San Francisco] (UCSF), University of California-University of California, SIGNAUX ET IMAGES NUMÉRIQUES, ROBOTIQUE (IRISA-D5), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes 1 (UR1), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Gui de Chauliac [Montpellier]-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS)- Hôpital de la Timone [CHU - APHM] (TIMONE), Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS), Gros, Charley, De Leener, Benjamin, Badji, Atef, Maranzano, Josefina, Eden, Dominique, Dupont, Sara M., Talbott, Jason, Zhuoquiong, Ren, Liu, Yaou, Granberg, Tobia, Ouellette, Russell, Tachibana, Yasuhiko, Hori, Masaaki, Kamiya, Kouhei, Chougar, Lydia, Stawiarz, Leszek, Hillert, Jan, Bannier, Elise, Kerbrat, Anne, Edan, Gille, Labauge, Pierre, Callot, Virginie, Pelletier, Jean, Audoin, Bertrand, Rasoanandrianina, Henitsoa, Brisset, Jean-Christophe, Valsasina, Paola, Rocca, Maria A., Filippi, Massimo, Bakshi, Rohit, Tauhid, Shahamat, Prados, Ferran, Yiannakas, Mario, Kearney, Hugh, Ciccarelli, Olga, Smith, Seth, Treaba, Constantina Andrada, Mainero, Caterina, Lefeuvre, Jennifer, Reich, Daniel S., Nair, Govind, Auclair, Vincent, Mclaren, Donald G., Martin, Allan R., Fehlings, Michael G., Vahdat, Shahabeddin, Khatibi, Ali, Doyon, Julien, Shepherd, Timothy, Charlson, Erik, Narayanan, Sridar, and Cohen-Adad, Julien
Subjects: FOS: Computer and information sciences, Image Processing, Computer Vision and Pattern Recognition (cs.CV), Computer Science - Computer Vision and Pattern Recognition, Neurodegenerative, computer.software_genre, Convolutional neural network, Medical and Health Sciences, Pattern Recognition, Automated, 0302 clinical medicine, Computer-Assisted, Segmentation, Voxel, Image Processing, Computer-Assisted, Medicine, Spinal Cord Injury, Observer Variation, Spinal cord, medicine.diagnostic_test, 05 social sciences, Magnetic Resonance Imaging, 3. Good health, medicine.anatomical_structure, Neurology, Neurological, Biomedical Imaging, Convolutional neural networks, [SDV.IB]Life Sciences [q-bio]/Bioengineering, Radiology, medicine.symptom, MRI, Automated, medicine.medical_specialty, Cord, Multiple Sclerosis, Physical Injury - Accidents and Adverse Effects, Neural Networks, Cognitive Neuroscience, Bioengineering, Pattern Recognition, Sensitivity and Specificity, Autoimmune Disease, 050105 experimental psychology, Article, Lesion, Multiple sclerosis, 03 medical and health sciences, Computer, Humans, 0501 psychology and cognitive sciences, Multiple sclerosi, Traumatic Head and Spine Injury, Neurology & Neurosurgery, business.industry, Psychology and Cognitive Sciences, Neurosciences, Reproducibility of Results, Magnetic resonance imaging, medicine.disease, Brain Disorders, Neural Networks, Computer, business, computer, 030217 neurology & neurosurgery
Abstract: The spinal cord is frequently affected by atrophy and/or lesions in multiple sclerosis (MS) patients. Segmentation of the spinal cord and lesions from MRI data provides measures of damage, which are key criteria for the diagnosis, prognosis, and longitudinal monitoring in MS. Automating this operation eliminates inter-rater variability and increases the efficiency of large-throughput analysis pipelines. Robust and reliable segmentation across multi-site spinal cord data is challenging because of the large variability related to acquisition parameters and image artifacts. The goal of this study was to develop a fully-automatic framework, robust to variability in both image parameters and clinical condition, for segmentation of the spinal cord and intramedullary MS lesions from conventional MRI data. Scans of 1,042 subjects (459 healthy controls, 471 MS patients, and 112 with other spinal pathologies) were included in this multi-site study (n=30). Data spanned three contrasts (T1-, T2-, and T2*-weighted) for a total of 1,943 volumes. The proposed cord and lesion automatic segmentation approach is based on a sequence of two Convolutional Neural Networks (CNNs). To deal with the very small proportion of spinal cord and/or lesion voxels compared to the rest of the volume, a first CNN with 2D dilated convolutions detects the spinal cord centerline, followed by a second CNN with 3D convolutions that segments the spinal cord and/or lesions. When compared against manual segmentation, our CNN-based approach showed a median Dice of 95% vs. 88% for PropSeg, a state-of-the-art spinal cord segmentation method. Regarding lesion segmentation on MS data, our framework provided a Dice of 60%, a relative volume difference of -15%, and a lesion-wise detection sensitivity and precision of 83% and 77%, respectively. The proposed framework is open-source and readily available in the Spinal Cord Toolbox., Comment: 38 pages, 7 figures, 2 tables
Published: 2019

22. Quantitative characterization of optic nerve atrophy in patients with multiple sclerosis

Author: Bailey A. Box, Bailey Lyttle, Bennett A. Landman, Seth A. Smith, Francesca Bagnato, Alex K. Smith, Robert L. Harrigan, and Siddharama Pawate
Subjects: Pathology, medicine.medical_specialty, genetic structures, Neuritis, Axonal loss, multiple sclerosis, axonal loss, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Atrophy, atrophy, medicine, In patient, medicine.diagnostic_test, business.industry, Multiple sclerosis, Magnetic resonance imaging, Optic nerve atrophy, medicine.disease, eye diseases, Original Research Paper, 030221 ophthalmology & optometry, Neurology (clinical), business, 030217 neurology & neurosurgery, MRI
Abstract: Background Optic neuritis (ON) is one of the most common presentations of multiple sclerosis (MS). Magnetic resonance imaging (MRI) of the optic nerves is challenging because of retrobulbar motion, orbital fat and susceptibility artifacts from maxillary sinuses; therefore, axonal loss is investigated with the surrogate measure of a single heuristically defined point along the nerve as opposed to volumetric investigation. Objective The objective of this paper is to derive optic nerve volumetrics along the entire nerve length in patients with MS and healthy controls in vivo using high-resolution, clinically viable MRI. Methods An advanced, isotropic T2-weighted turbo spin echo MRI was applied to 29 MS patients with (14 patients ON+) or without (15 patients ON–) history of ON and 42 healthy volunteers. An automated tool was used to estimate and compare whole optic nerve and surrounding cerebrospinal fluid radii along the length of the nerve. Results and conclusion Only ON+ MS patients had a significantly reduced optic nerve radius compared to healthy controls in the central segment of the optic nerve. Using clinically available MRI methods, we show and quantify ON volume loss for the first time in MS patients.
Published: 2017

23. Dynamic Imaging of the Eye, Optic Nerve, and Extraocular Muscles With Golden Angle Radial MRI

Author: David S. Smith, Saikat Sengupta, E. Brian Welch, Seth A. Smith, and Alex K. Smith
Subjects: genetic structures, Computer science, Dynamic imaging, dynamic MRI, Image processing, Extraocular muscles, optic nerve, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Medical imaging, medicine, Accessory visual structures, Eye Movements, Strabismus, Amblyopia and Neuro-Ophthalmology, Magnetic resonance neurography, Anatomy, strabismus, eye diseases, medicine.anatomical_structure, extraocular muscles, 030221 ophthalmology & optometry, Optic nerve, Golden angle, sense organs, golden angle radial MRI, Biomedical engineering
Abstract: The eye and its accessory structures, the optic nerve and the extraocular muscles, form a complex dynamic system. In vivo magnetic resonance imaging (MRI) of this system in motion can have substantial benefits in understanding oculomotor functioning in health and disease, but has been restricted to date to imaging of static gazes only. The purpose of this work was to develop a technique to image the eye and its accessory visual structures in motion. Dynamic imaging of the eye was developed on a 3-Tesla MRI scanner, based on a golden angle radial sequence that allows freely selectable frame-rate and temporal-span image reconstructions from the same acquired data set. Retrospective image reconstructions at a chosen frame rate of 57 ms per image yielded high-quality in vivo movies of various eye motion tasks performed in the scanner. Motion analysis was performed for a left-right version task where motion paths, lengths, and strains/globe angle of the medial and lateral extraocular muscles and the optic nerves were estimated. Offline image reconstructions resulted in dynamic images of bilateral visual structures of healthy adults in only &Tilde;15-s imaging time. Qualitative and quantitative analyses of the motion enabled estimation of trajectories, lengths, and strains on the optic nerves and extraocular muscles at very high frame rates of &Tilde;18 frames/s. This work presents an MRI technique that enables high-frame-rate dynamic imaging of the eyes and orbital structures. The presented sequence has the potential to be used in furthering the understanding of oculomotor mechanics in vivo, both in health and disease.
Published: 2017

24. Spinal cord MRI at 7T

Author: Robert L. Barry, John C. Gore, S. Johanna Vannesjo, Seth A. Smith, and Samantha By
Subjects: Cord, Cognitive Neuroscience, Partial volume, Neuroimaging, Article, 030218 nuclear medicine & medical imaging, White matter, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, medicine.diagnostic_test, business.industry, Shim (magnetism), Magnetic resonance imaging, Spinal cord, Magnetic Resonance Imaging, Communication noise, medicine.anatomical_structure, Neurology, Spinal Cord, business, Neuroscience, 030217 neurology & neurosurgery, Radiofrequency coil, Biomedical engineering
Abstract: Magnetic resonance imaging (MRI) of the human spinal cord at 7 Tesla has been demonstrated by a handful of research sites worldwide, and the spinal cord remains one of the areas in which higher fields and resolution could have high impact. The small diameter of the cord (~1 cm) necessitates high spatial resolution to minimize partial volume effects between gray and white matter, and so MRI of the cord can greatly benefit from increased signal-to-noise ratio and contrasts at ultra-high field (UHF). Herein we review the current state of UHF spinal cord imaging. Technical challenges to successful UHF spinal cord MRI include radiofrequency (B(1)) nonuniformities and a general lack of optimized radiofrequency coils, amplified physiological noise, and an absence of methods for robust B(0) shimming along the cord to mitigate image distortions and signal losses. Numerous solutions to address these challenges have been and are continuing to be explored, and include novel approaches for signal excitation and acquisition, dynamic shimming and specialized shim coils, and acquisitions with increased coverage or optimal slice angulations.
Published: 2017

25. Bilateral Changes in Deep Tissue Environment After Manual Lymphatic Drainage in Patients with Breast Cancer Treatment-Related Lymphedema

Author: Ana M. Grau, Aditi A. Desai, Rondi M. Kauffmann, Sheila H. Ridner, Seth A. Smith, Paula M C Donahue, Raeshell S. Sweeting, Vaughn Braxton, Ingrid M. Meszoely, Allison O. Scott, Rachelle Crescenzi, John Jordi, Manus J. Donahue, and Kandace Spotanski
Subjects: Adult, medicine.medical_specialty, Breast Cancer Lymphedema, Breast Neoplasms, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Manual lymphatic drainage, medicine, Humans, Lymphatic Vessels, Massage, medicine.diagnostic_test, business.industry, Cancer, Magnetic resonance imaging, Original Articles, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Surgery, Axilla, medicine.anatomical_structure, Lymphatic system, Lymphedema, Treatment Outcome, 030220 oncology & carcinogenesis, Case-Control Studies, Lymph Node Excision, Female, Cardiology and Cardiovascular Medicine, business, Bioelectrical impedance analysis
Abstract: Background: Breast cancer treatment-related lymphedema (BCRL) arises from a mechanical insufficiency following cancer therapies. Early BCRL detection and personalized intervention require an improved understanding of the physiological processes that initiate lymphatic impairment. Here, internal magnetic resonance imaging (MRI) measures of the tissue microenvironment were paired with clinical measures of tissue structure to test fundamental hypotheses regarding structural tissue and muscle changes after the commonly used therapeutic intervention of manual lymphatic drainage (MLD). Methods and Results: Measurements to identify lymphatic dysfunction in healthy volunteers (n = 29) and patients with BCRL (n = 16) consisted of (1) limb volume, tissue dielectric constant, and bioelectrical impedance (i.e., non-MRI measures); (2) qualitative 3 Tesla diffusion-weighted, T1-weighted and T2-weighted MRI; and (3) quantitative multi-echo T2 MRI of the axilla. Measurements were repeated in patients immediately...
Published: 2017

26. Pool size ratio of the substantia nigra in Parkinson's disease derived from two different quantitative magnetization transfer approaches

Author: Luca Mainardi, Antonella Costa, Paula Trujillo, Sergio Cerutti, Daniel O. Claassen, Alex K. Smith, Paul Summers, and Seth A. Smith
Subjects: Male, Parkinson's disease, Red nucleus, Magnetization transfer, Neuromelanin, Parkinsonâs disease, Substantia nigra, Radiology, Nuclear Medicine and Imaging, Neurology (clinical), Cardiology and Cardiovascular Medicine, Sensitivity and Specificity, Article, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Nuclear magnetic resonance, Imaging, Three-Dimensional, Nuclear Medicine and Imaging, Cerebral crus, Image Interpretation, Computer-Assisted, medicine, Humans, Radiology, Nuclear Medicine and imaging, Parkinsonâ s disease, Aged, medicine.diagnostic_test, business.industry, Pars compacta, Magnetic resonance imaging, Parkinson Disease, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Case-Control Studies, Female, business, Radiology, 030217 neurology & neurosurgery, Biomarkers
Abstract: We sought to measure quantitative magnetization transfer (qMT) properties of the substantia nigra pars compacta (SNc) in patients with Parkinson’s disease (PD) and healthy controls (HCs) using a full qMT analysis and determine whether a rapid single-point measurement yields equivalent results for pool size ratio (PSR). Sixteen different MT-prepared MRI scans were obtained at 3 T from 16 PD patients and eight HCs, along with B1, B0, and relaxation time maps. Maps of PSR, free and macromolecular pool transverse relaxation times ( $$ {T}_2^f $$ , $$ {T}_2^m $$ ) and rate of MT exchange between pools (k mf ) were generated using a full qMT model. PSR maps were also generated using a single-point qMT model requiring just two MT-prepared images. qMT parameter values of the SNc, red nucleus, cerebral crus, and gray matter were compared between groups and methods. PSR of the SNc was the only qMT parameter to differ significantly between groups (p
Published: 2017

27. Magnetic Resonance Imaging of the Cervical Spinal Cord in Multiple Sclerosis at 7T

Author: Robert L. Barry, Bailey Lyttle, Lindsey M. Dethrage, Seth A. Smith, Kristen George-Durrett, Adrienne N. Dula, John C. Gore, Siddharama Pawate, and Richard D. Dortch
Subjects: Adult, Male, medicine.medical_specialty, Multiple Sclerosis, Article, 030218 nuclear medicine & medical imaging, Lesion, White matter, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Image Interpretation, Computer-Assisted, medicine, Humans, medicine.diagnostic_test, business.industry, Multiple sclerosis, Cervical Cord, Magnetic resonance imaging, Middle Aged, medicine.disease, Spinal cord, Image Enhancement, Magnetic Resonance Imaging, Image contrast, Sagittal plane, medicine.anatomical_structure, Neurology, Spinal Cord, Female, Neurology (clinical), Radiology, Lower field, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: Background: The clinical course of multiple sclerosis (MS) is mainly attributable to cervical and upper thoracic spinal cord dysfunction. High-resolution, 7T anatomical imaging of the cervical spinal cord is presented. Image contrast between gray/white matter and lesions surpasses conventional, clinical T1- and T2-weighted sequences at lower field strengths. Objective: To study the spinal cord of healthy controls and patients with MS using magnetic resonance imaging at 7T. Methods: Axial (C2–C5) T1- and T2*-weighted and sagittal T2*-/spin-density-weighted images were acquired at 7T in 13 healthy volunteers (age 22–40 years), and 15 clinically diagnosed MS patients (age 19–53 years, Extended Disability Status Scale, (EDSS) 0–3) in addition to clinical 3T scans. In healthy volunteers, a high-resolution multi-echo gradient echo scan was obtained over the same geometry at 3T. Evaluation included signal and contrast to noise ratios and lesion counts for healthy and patient volunteers, respectively. Results/conclusion: High-resolution images at 7T exceeded resolutions reported at lower field strengths. Gray and white matter were sharply demarcated and MS lesions were more readily visualized at 7T compared to clinical acquisitions, with lesions apparent at both fields. Nerve roots were clearly visualized. White matter lesion counts averaged 4.7 vs 3.1 (52% increase) per patient at 7T vs 3T, respectively ( p=0.05).
Published: 2015

28. Constructing a statistical atlas of the radii of the optic nerve and cerebrospinal fluid sheath in young healthy adults

Author: Seth A. Smith, Louise A. Mawn, Robert L. Harrigan, Robert L. Galloway, Bennett A. Landman, and Andrew J. Plassard
Subjects: medicine.medical_specialty, Visual acuity, genetic structures, Color vision, business.industry, Multiple sclerosis, Eye movement, medicine.disease, eye diseases, Article, Visual field, Optic neuropathy, Ophthalmology, medicine, Optic nerve, Optic neuritis, medicine.symptom, business
Abstract: Optic neuritis is a sudden inflammation of the optic nerve (ON) and is marked by pain on eye movement, and visual symptoms such as a decrease in visual acuity, color vision, contrast and visual field defects. The ON is closely linked with multiple sclerosis (MS) and patients have a 50% chance of developing MS within 15 years. Recent advances in multi-atlas segmentation methods have omitted volumetric assessment. In the past, measuring the size of the ON has been done by hand. We utilize a new method of automatically segmenting the ON to measure the radii of both the ON and surrounding cerebrospinal fluid (CSF) sheath to develop a normative distribution of healthy young adults. We examine this distribution for any trends and find that ON and CSF sheath radii do not vary between 20-35 years of age and between sexes. We evaluate how six patients suffering from optic neuropathy compare to this distribution of controls. We find that of these six patients, five of them qualitatively differ from the normative distribution which suggests this technique could be used in the future to distinguish between optic neuritis patients and healthy controls.
Published: 2015

29. A multimodal MRI approach to identify and characterize microstructural brain changes in neuropsychiatric systemic lupus erythematosus

Author: Tom W J Huizinga, Seth A. Smith, Ece Ercan, Carson Ingo, Oranan Tritanon, Itamar Ronen, Mark A. van Buchem, César Magro-Checa, and Alex K. Smith
Subjects: MTR, magnetization transfer ratio, Magnetization transfer imaging, Fluid-attenuated inversion recovery, Multimodal Imaging, lcsh:RC346-429, Normal appearing white matter, SLE, systemic lupus erythematosus, FA, fractional anisotropy, HC, healthy controls, medicine.diagnostic_test, Lupus Vasculitis, Central Nervous System, Middle Aged, White Matter, RD, radial diffusivity, Neuropsychiatric systemic lupus erythematosus, medicine.anatomical_structure, Diffusion tensor imaging, Neurology, NAWM, normal appearing white matter, NPSLE, neuropsychiatric systemic lupus erythematosus, FLAIR, fluid attenuated inversion recovery, lcsh:R858-859.7, Female, medicine.symptom, AD, axial diffusivity, Adult, Cognitive Neuroscience, ACR, American College of Rheumatology, lcsh:Computer applications to medicine. Medical informatics, Article, White matter, Lesion, Systemic lupus erythematosus, Magnetic resonance imaging, Fractional anisotropy, medicine, NP, neurological and psychiatric, Humans, Radiology, Nuclear Medicine and imaging, Magnetization transfer, WM, white matter, lcsh:Neurology. Diseases of the nervous system, MD, mean diffusivity, business.industry, WMH, white matter hyperintensities, TBSS, tract based spatial statistics, MTI, magnetization transfer imaging, Neurology (clinical), DTI, diffusion tensor imaging, business, Nuclear medicine, Diffusion MRI
Abstract: Systemic lupus erythematosus (SLE) is an autoimmune disease with multi-organ involvement and results in neurological and psychiatric (NP) symptoms in up to 40% of the patients. To date, the diagnosis of neuropsychiatric systemic lupus erythematosus (NPSLE) poses a challenge due to the lack of neuroradiological gold standards. In this study, we aimed to better localize and characterize normal appearing white matter (NAWM) changes in NPSLE by combining data from two quantitative MRI techniques, diffusion tensor imaging (DTI) and magnetization transfer imaging (MTI). 9 active NPSLE patients (37 ± 13 years, all females), 9 SLE patients without NP symptoms (44 ± 11 years, all females), and 14 healthy controls (HC) (40 ± 9 years, all females) were included in the study. MTI, DTI and fluid attenuated inversion recovery (FLAIR) images were collected from all subjects on a 3 T MRI scanner. Magnetization transfer ratio (MTR), mean diffusivity (MD), fractional anisotropy (FA), radial diffusivity (RD), axial diffusivity (AD) maps and white matter lesion maps based on the FLAIR images were created for each subject. MTR and DTI data were then co-analyzed using tract-based spatial statistics and a cumulative lesion map to exclude lesions. Significantly lower MTR and FA and significantly higher AD, RD and MD were found in NPSLE compared to HC in NAWM regions. The differences in DTI measures and in MTR, however, were only moderately co-localized. Additionally, significant differences in DTI measures, but not in MTR, were found between NPSLE and SLE patients, suggesting that the underlying microstructural changes detected by MD are linked to the onset of NPSLE. The co-analysis of the anatomical distribution of MTI and DTI measures can potentially improve the diagnosis of NPSLE and contribute to the understanding of the underlying microstructural damage., Graphical abstract, Highlights • NAWM is investigated in NPSLE and SLE using MTI and DTI. • Differences in DTI and MTR between NPSLE and HC are widespread but only moderately co-localized. • Significant differences in MD between SLE and NPSLE suggest link to onset of NPSLE.
Published: 2015

30. High-resolution quantitative imaging of the substantia nigra

Author: Antonella Costa, Paul Summers, Alex K. Smith, Seth A. Smith, Sergio Cerutti, Luca Mainardi, and Paula Trujillo
Subjects: Adult, Male, Quantitative imaging, Biomedical Engineering, High resolution, Neuroimaging, Substantia nigra, Health Informatics, Biology, Nuclear magnetic resonance, Humans, Signal Processing, Magnetization transfer, Melanins, Magnetic Phenomena, Dopaminergic, Progressive neurodegenerative disorder, Middle Aged, Magnetic Resonance Imaging, Substantia Nigra, Biomarker (medicine), Female, Neuroscience, Biomarkers
Abstract: There is a growing interest in identifying neuroimaging-based biomarkers for Parkinson's disease (PD), a progressive neurodegenerative disorder in which the major pathologic substrate is the loss of pigmented dopaminergic neurons in the substantia nigra (SN). Recently, an MRI technique dubbed "neuromelanin-sensitive MRI" (NM-MRI), has been found to provide notable contrast between the SN and surrounding brain tissues with potential applications as biomarker of PD. The contrast in NM-MRI has been associated with magnetization transfer (MT) effects, and thus the goal of this study was to characterize the impact of MT on NM-MRI, and to demonstrate the feasibility of performing quantitative MT (qMT) imaging in human SN. The results of this study demonstrate that high-resolution rapid qMT imaging of the SN can be reliably obtained within reasonable scan times, thereby can be translatable into clinical practice.
Published: 2015

31. Groupwise Multi-Atlas Segmentation of the Spinal Cord’s Internal Structure

Author: Bennett A. Landman, Frederick W. Bryan, Andrew J. Asman, Seth A. Smith, and Daniel S. Reich
Subjects: Computer science, Central nervous system, Health Informatics, Models, Biological, Sensitivity and Specificity, Article, Pattern Recognition, Automated, White matter, Image Interpretation, Computer-Assisted, medicine, Multi atlas segmentation, Humans, Radiology, Nuclear Medicine and imaging, Segmentation, Computer Simulation, Radiological and Ultrasound Technology, medicine.diagnostic_test, Tissue segmentation, business.industry, Reproducibility of Results, Pattern recognition, Magnetic resonance imaging, Limiting, Anatomy, Spinal cord, Image Enhancement, Computer Graphics and Computer-Aided Design, Magnetic Resonance Imaging, medicine.anatomical_structure, Spinal Cord, Subtraction Technique, Spinal Diseases, Computer Vision and Pattern Recognition, Artificial intelligence, business, Algorithms
Abstract: The spinal cord is an essential and vulnerable component of the central nervous system. Differentiating and localizing the spinal cord internal structure (i.e., gray matter vs. white matter) is critical for assessment of therapeutic impacts and determining prognosis of relevant conditions. Fortunately, new magnetic resonance imaging (MRI) sequences enable clinical study of the in vivo spinal cord's internal structure. Yet, low contrast-to-noise ratio, artifacts, and imaging distortions have limited the applicability of tissue segmentation techniques pioneered elsewhere in the central nervous system. Additionally, due to the inter-subject variability exhibited on cervical MRI, typical deformable volumetric registrations perform poorly, limiting the applicability of a typical multi-atlas segmentation framework. Thus, to date, no automated algorithms have been presented for the spinal cord's internal structure. Herein, we present a novel slice-based groupwise registration framework for robustly segmenting cervical spinal cord MRI. Specifically, we provide a method for (1) pre-aligning the slice-based atlases into a groupwise-consistent space, (2) constructing a model of spinal cord variability, (3) projecting the target slice into the low-dimensional space using a model-specific registration cost function, and (4) estimating robust segmentation susing geodesically appropriate atlas information. Moreover, the proposed framework provides a natural mechanism for performing atlas selection and initializing the free model parameters in an informed manner. In a cross-validation experiment using 67 MR volumes of the cervical spinal cord, we demonstrate sub-millimetric accuracy, significant quantitative and qualitative improvement over comparable multi-atlas frameworks, and provide insight into the sensitivity of the associated model parameters.
Published: 2014

32. Pathogenesis of multiple sclerosis: Insights from molecular and metabolic imaging

Author: Frederik Barkhof, Olga Ciccarelli, Seth A. Smith, Benedetta Bodini, Daniel Pelletier, Tarek A. Yousry, Claudia A. M. Wheeler-Kingshott, Nicola De Stefano, David Miller, Klaas Nicolay, Petra J. W. Pouwels, Xavier Golay, B. Stankoff, Radiology and nuclear medicine, Physics and medical technology, NCA - Neuroinflamation, and NCA - Brain imaging technology
Subjects: Pathology, medicine.medical_specialty, Animals, Humans, Multiple Sclerosis, Nerve Fibers, Myelinated, Magnetic Resonance Imaging, Molecular Imaging, Neurology (clinical), Central nervous system, Inflammation, Grey matter, White matter, Pathogenesis, Nerve Fibers, Medicine, Microglia, business.industry, Multiple sclerosis, Experimental autoimmune encephalomyelitis, medicine.disease, medicine.anatomical_structure, Myelinated, medicine.symptom, business, Neuroscience
Abstract: Summary The mechanisms underlying the pathogenesis of multiple sclerosis induce the changes that underpin relapse-associated and progressive disability. Disease mechanisms can be investigated in preclinical models and patients with multiple sclerosis by molecular and metabolic imaging techniques. Many insights have been gained from such imaging studies: persisting inflammation in the absence of a damaged blood–brain barrier, activated microglia within and beyond lesions, increased mitochondrial activity after acute lesions, raised sodium concentrations in the brain, increased glutamate in acute lesions and normal-appearing white matter, different degrees of demyelination in different patients and lesions, early neuronal damage in grey matter, and early astrocytic proliferation and activation in lesions and white matter. Clinical translation of molecular and metabolic imaging and extension of these techniques will enable the assessment of novel drugs targeted at these disease mechanisms, and have the potential to improve health outcomes through the stratification of patients for treatments.
Published: 2014

33. Quantitative magnetization transfer imaging of human brain at 7 T☆

Author: Jay Moore, Marcin Jankiewicz, Ke Li, Daniel F. Gochberg, Richard D. Dortch, John C. Gore, Seth A. Smith, and Jane Hirtle
Subjects: Adult, Male, Pathology, medicine.medical_specialty, Cognitive Neuroscience, Nerve Fibers, Myelinated, Sensitivity and Specificity, Article, White matter, Young Adult, Nuclear magnetic resonance, Image Interpretation, Computer-Assisted, medicine, Humans, Magnetization transfer imaging, Magnetization transfer, Physics, medicine.diagnostic_test, Brain, Reproducibility of Results, Magnetic resonance imaging, Human brain, Image Enhancement, Magnetic Resonance Imaging, medicine.anatomical_structure, Neurology, Free water, Size ratio, Female, Lower field, Algorithms
Abstract: Quantitative magnetization transfer (qMT) imaging yields indices describing the interactions between free water protons and immobile macromolecular protons. These indices include the macromolecular to free pool size ratio ( PSR ), which has been shown to be correlated with myelin content in white matter. Because of the long scan times required for whole-brain imaging (≈ 20–30 min), qMT studies of the human brain have not found widespread application. Herein, we investigated whether the increased signal-to-noise ratio available at 7.0 T could be used to reduce qMT scan times. More specifically, we developed a selective inversion recovery (SIR) qMT imaging protocol with a i ) novel transmit radiofrequency ( B 1 + ) and static field ( B 0 ) insensitive inversion pulse, ii ) turbo field-echo readout, and iii ) reduced TR. In vivo qMT data were obtained in the brains of healthy volunteers at 7.0 T using the resulting protocol (scan time ≈ 40 s/slice, resolution = 2 × 2 × 3 mm 3 ). Reliability was also assessed in repeated acquisitions. The results of this study demonstrate that SIR qMT imaging can be reliably performed within the radiofrequency power restrictions present at 7.0 T, even in the presence of large B 1 + and B 0 inhomogeneities. Consistent with qMT studies at lower field strengths, the observed PSR values were higher in white matter (mean ± SD = 17.6 ± 1.3%) relative to gray matter (10.3 ± 1.6%) at 7.0 T. In addition, regional variations in PSR were observed in white matter. Together, these results suggest that qMT measurements are feasible at 7.0 T and may eventually allow for the high-resolution assessment of changes in composition throughout the normal and diseased human brain in vivo.
Published: 2012

34. Reproducibility of tract-specific magnetization transfer and diffusion tensor imaging in the cervical spinal cord at 3 tesla

Author: Seth A. Smith, Peter A. Calabresi, B. Chodkowski, Craig K. Jones, Bennett A. Landman, Aliya Gifford, John W. McDonald, Jonathan A.D. Farrell, Visar Belegu, Peter C.M. van Zijl, and Daniel S. Reich
Subjects: Adult, Male, Time Factors, Central nervous system, Article, White matter, Diffusion, Magnetics, Young Adult, Nuclear magnetic resonance, Fractional anisotropy, medicine, Humans, Radiology, Nuclear Medicine and imaging, Magnetization transfer, Spectroscopy, Cerebrospinal Fluid, Physics, medicine.diagnostic_test, Reproducibility of Results, Magnetic resonance imaging, Middle Aged, Spinal cord, medicine.anatomical_structure, Diffusion Tensor Imaging, Spinal Cord, Organ Specificity, Cervical Vertebrae, Molecular Medicine, Female, Diffusion MRI, Tractography
Abstract: Damage to specific white matter tracts within the spinal cord can often result in the particular neurological syndromes that characterize myelopathies such as traumatic spinal cord injury. Noninvasive visualization of these tracts with imaging techniques that are sensitive to microstructural integrity is an important clinical goal. Diffusion tensor imaging (DTI)- and magnetization transfer (MT)-derived quantities have shown promise in assessing tissue health in the central nervous system. In this paper, we demonstrate that DTI of the cervical spinal cord can reliably discriminate sensory (dorsal) and motor (lateral) columns. From data derived from nine healthy volunteers, two raters quantified column-specific parallel (lambda(||)) and perpendicular (lambda(perpendicular)) diffusivity, fractional anisotropy (FA), mean diffusivity (MD), and MT-weighted signal intensity relative to cerebrospinal fluid (MTCSF) over two time-points separated by more than 1 week. Cross-sectional means and standard deviations of these measures in the lateral and dorsal columns were as follows: lambda(||): 2.13 +/- 0.14 and 2.14 +/- 0.11 microm(2)/ms; lambda(perpendicular): 0.67 +/- 0.16 and 0.61 +/- 0.09 microm(2)/ms; MD: 1.15 +/- 0.15 and 1.12 +/- 0.08 microm(2)/ms; FA: 0.68 +/- 0.06 and 0.68 +/- 0.05; MTCSF: 0.52 +/- 0.05 and 0.50 +/- 0.05. We examined the variability and interrater and test-retest reliability for each metric. These column-specific MR measurements are expected to enhance understanding of the intimate structure-function relationship in the cervical spinal cord and may be useful for the assessment of disease progression.
Published: 2010

35. Damage to the Optic Radiation in Multiple Sclerosis Is Associated with Retinal Injury and Visual Disability

Author: Daniel S. Reich, Arzu Ozturk, Brian Caffo, Eliza Gordon-Lipkin, Laura J. Balcer, Peter A. Calabresi, and Seth A. Smith
Subjects: Adult, Male, medicine.medical_specialty, Visual acuity, Multiple Sclerosis, Optic Neuritis, Nerve fiber layer, Vision Disorders, Visual Acuity, Article, Cohort Studies, Young Adult, Imaging, Three-Dimensional, Nerve Fibers, Arts and Humanities (miscellaneous), Ophthalmology, Fractional anisotropy, medicine, Image Processing, Computer-Assisted, Humans, Optic neuritis, Visual Pathways, Dominance, Cerebral, Aged, Visual Cortex, medicine.diagnostic_test, business.industry, Multiple sclerosis, Geniculate Bodies, Magnetic resonance imaging, Optic Nerve, Anatomy, Middle Aged, medicine.disease, medicine.anatomical_structure, Diffusion Magnetic Resonance Imaging, Optic Nerve Injuries, Optic nerve, Female, Neurology (clinical), medicine.symptom, business, Tomography, Optical Coherence, Optic radiation, Retinal Neurons
Abstract: To determine whether damage to the optic radiation (OR) in multiple sclerosis (MS) is associated with optic nerve injury and visual dysfunction.Case-control study.Referral center.Ninety referred patients with MS and 29 healthy volunteers.Magnetic resonance imaging indices along the OR were reconstructed with diffusion tensor tractography. Retinal nerve fiber layer thickness and visual acuity at high and low contrast were measured in a subset of the MS group (n = 36).All tested magnetic resonance imaging indices (fractional anisotropy [FA]; mean, parallel, and perpendicular [lambda( perpendicular)] diffusivity; T2 relaxation time; and magnetization transfer ratio) were significantly abnormal in patients with MS. Mean retinal nerve fiber layer thickness was significantly correlated with FA (r = 0.55; P.001) and lambda( perpendicular) (r = -0.37; P = .001). The retinal nerve fiber layer thickness in the nasal retinal quadrant was also specifically correlated with FA and lambda( perpendicular) in the synaptically connected contralateral OR. In individuals with less severely damaged optic nerves (mean retinal nerve fiber layer thickness80 mum), letter acuity scores at 2.5% contrast were correlated with OR-specific FA (r = 0.55; P = .004), lambda( perpendicular) (r = -0.40; P = .04), and magnetization transfer ratio (r = 0.54; P = .01), as well as the fraction of OR volume made up of lesions (r = -0.69; P.001).Fractional anisotropy and lambda( perpendicular) are potentially useful quantitative magnetic resonance imaging biomarkers of OR-specific damage in MS. Such damage is associated with retinal injury and visual disability.
Published: 2009

36. Sensorimotor dysfunction in multiple sclerosis and column-specific magnetization transfer-imaging abnormalities in the spinal cord

Author: Seth A. Smith, B. Chodkowski, Kathleen M. Zackowski, Amy J. Bastian, Eliza Gordon-Lipkin, Peter A. Calabresi, Daniel S. Reich, Divya R. Sambandan, Peter C.M. van Zijl, and Michael Shteyman
Subjects: Adult, Male, Multiple Sclerosis, Central nervous system, Grey matter, Vibration, White matter, Central nervous system disease, Multiple Sclerosis, Relapsing-Remitting, medicine, Image Processing, Computer-Assisted, Humans, Muscle Strength, Analysis of Variance, medicine.diagnostic_test, Multiple sclerosis, Brain, Magnetic resonance imaging, Anatomy, Original Articles, Middle Aged, Multiple Sclerosis, Chronic Progressive, Toes, Spinal cord, medicine.disease, Magnetic Resonance Imaging, medicine.anatomical_structure, Spinal Cord, Case-Control Studies, Sensory Thresholds, Corticospinal tract, Sensation Disorders, Cervical Vertebrae, Regression Analysis, Female, Neurology (clinical), Ankle, Psychology
Abstract: The human spinal cord contains segregated sensory and motor pathways that have been difficult to quantify using conventional magnetic resonance imaging (MRI) techniques. Multiple sclerosis is characterized by both focal and spatially diffuse spinal cord lesions with heterogeneous pathologies that have limited attempts at linking MRI and behaviour. We used a novel magnetization-transfer-weighted imaging approach to quantify damage to spinal white matter columns and tested its association with sensorimotor impairment. We studied 42 participants with multiple sclerosis who each underwent MRI at 3 Tesla and quantitative tests of sensorimotor function. We measured cerebrospinal-fluid-normalized magnetization-transfer signals in the dorsal and lateral columns and grey matter of the cervical cord. We also measured brain lesion volume, cervical spinal cord lesion number and cross-sectional area, vibration sensation, strength, walking velocity and standing balance. We used linear regression to assess the relationship between sensorimotor impairment and MRI abnormalities. We found that the dorsal column cerebrospinal-fluid-normalized magnetization-transfer signal specifically correlated with vibration sensation (R = 0.58, P < 0.001) and the lateral column signal with strength (R = −0.45, P = 0.003). Spinal cord signal measures also correlated with walking and balance dysfunction. A stepwise multiple regression showed that the dorsal column signal and diagnosis subtype alone explained a significant portion of the variance in sensation (R2 = 0.54, P < 0.001), whereas the lateral column signal and diagnosis subtype explained a significant portion of the variance in strength (R2 = 0.30, P < 0.001). These results help to understand the anatomic basis of sensorimotor disability in multiple sclerosis and have implications for testing the effects of neuroprotective and reparative interventions.
Published: 2009

37. Quantitative Description of the Asymmetry in Magnetization Transfer Effects around the Water Resonance in the Human Brain

Author: Jaishri O. Blakeley, Jun Hua, Craig K. Jones, Seth A. Smith, Peter C.M. van Zijl, and Jinyuan Zhou
Subjects: Chemistry, media_common.quotation_subject, Brain, Water, Pulse sequence, Tissue characterization, Human brain, Asymmetry, Magnetic Resonance Imaging, Article, Nuclear magnetic resonance, medicine.anatomical_structure, medicine, Frequency offset, Water proton, Humans, Radiology, Nuclear Medicine and imaging, Magnetization transfer, Irradiation, Protons, media_common
Abstract: Magnetization transfer (MT) imaging provides a unique method of tissue characterization by capitalizing on the interaction between solid-like tissue components and bulk water. We used a continuous-wave (CW) MT pulse sequence with low irradiation power to study healthy human brains in vivo at 3 T and quantified the asymmetry of the MT effects with respect to the water proton frequency. This asymmetry was found to be a difference of approximately a few percent from the water signal intensity, depending on both the RF irradiation power and the frequency offset. The experimental results could be quantitatively described by a modified two-pool MT model extended with a shift contribution for the semisolid pool with respect to water. For white matter, this shift was fitted to be 2.34 +/- 0.17 ppm (N = 5) upfield from the water signal.
Published: 2007

38. Generic acquisition protocol for quantitative MRI of the spinal cord

Author: René Labounek, Nawal Kinany, Michela Fratini, Laura Barlow, Markus Barth, P Wyss, Marco Battiston, Sean Mackey, Nyoman D. Kurniawan, Deborah Pareto, Kenneth A. Weber, Guillaume Gilbert, Robert L. Barry, Anna Pichiecchio, Eva Alonso-Ortiz, Matthew D. Budde, Mihael Abramovic, Alexandra Tinnermann, Giancarlo Germani, Dimitri Van De Ville, Falk Eippert, Anna J.E. Combes, Igor Nestrasil, Marios C. Yiannakas, Haleh Karbasforoushan, Julien Doyon, Cornelia Laule, Nicole Atcheson, Ali Khatibi, Nico Papinutto, Karla R. Epperson, Marek Dostál, Yazhuo Kong, Loan Mattera, Charley Gros, Paulo Loureiro de Sousa, Pierre-Gilles Henry, Alan C. Seifert, Richard G. Wise, Issei Fukunaga, Alexandru Foias, Shannon H. Kolind, Todd B. Parrish, Akifumi Hagiwara, Daniel Papp, Carina Arneitz, Virginie Callot, Christian Büchel, Maria Marcella Laganà, Tobias Leutritz, Slawomir Kusmia, Ferran Prados, Kevin S. Epperson, Marc J. Ruitenberg, Nikolaus Weiskopf, Kouhei Kamiya, Benjamin De Leener, Adam V. Dvorak, Giovanni Savini, Christine S. Law, Petr Kudlička, Paul Kuntke, Julien Cohen-Adad, Alex Rovira, Jan Valošek, Patrick Freund, George Tackley, Zachary A. Smith, Eloy Martinez-Heras, Maxime Descoteaux, Yaou Liu, Miloš Keřkovský, Joo Won Kim, Kristin P. O’Grady, Elisabeth Solana, Rebecca S. Samson, Junqian Xu, Alex K. Smith, Federico Giove, Maryam Seif, Claudia A. M. Wheeler-Kingshott, Tomáš Horák, James M. Joers, Francesco Grussu, Christophe Lenglet, Jürgen Finsterbusch, Sara Llufriu, Hagen H. Kitzler, Masaaki Hori, Yuichi Suzuki, Seth A. Smith, École Polytechnique de Montréal (EPM), Université du Québec à Montréal = University of Québec in Montréal (UQAM), Mila - Quebec AI Institute, Swiss Paraplegic Research = Schweizer Paraplegiker-Stiftung, University of Queensland [Brisbane], University of British Columbia (UBC), Massachusetts General Hospital [Boston], Harvard Medical School [Boston] (HMS), Massachusetts Institute of Technology (MIT), University College of London [London] (UCL), Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Medical College of Wisconsin [Milwaukee] (MCW), Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Exploration Métabolique par Résonance Magnétique [Hôpital de la Timone - AP-HM] (CEMEREM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS)- Hôpital de la Timone [CHU - APHM] (TIMONE), Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], CHU Sainte Justine [Montréal], Université de Sherbrooke (UdeS), Centre d'Imagerie Moléculaire de Sherbrooke, Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et nanosciences d'Alsace (FMNGE), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Masaryk University and University Hospital Brno, McGill University = Université McGill [Montréal, Canada], Max Planck Institute for Human Cognitive and Brain Sciences [Leipzig] (IMPNSC), Max-Planck-Gesellschaft, Stanford University School of Medicine [CA, USA], Universität Zürich [Zürich] = University of Zurich (UZH), IRCCS Santa Lucia Foundation, Juntendo University School of Medicine [Tokyo, Japan], University of Pavia, IRCCS Mondino Foundation, Philips Healthcare [Markham], Museo Storico della Fisica e Centro di Studi e Ricerche 'Enrico Fermi', Roma, Vall d'Hebron University Hospital [Barcelona], Center for Magnetic Resonance Research [Minneapolis] (CMRR), University of Minnesota Medical School, University of Minnesota System-University of Minnesota System, Central European Institute of Technology [Brno] (CEITEC MU), Brno University of Technology [Brno] (BUT), Toho University Omori Medical Center [Tokyo], The University of Tokyo (UTokyo), Northwestern University Feinberg School of Medicine, Stanford University, University of Birmingham [Birmingham], Icahn School of Medicine at Mount Sinai [New York] (MSSM), Ecole Polytechnique Fédérale de Lausanne (EPFL), University of Geneva [Switzerland], Technische Universität Dresden = Dresden University of Technology (TU Dresden), Chinese Academy of Sciences [Beijing] (CAS), University of Chinese Academy of Sciences [Beijing] (UCAS), University of Oxford [Oxford], University of Southern Queensland (USQ), Cardiff University, Epilepsy Society [Buckinghamshire] (MRI Unit), Departments of Ophthalmology and Pediatrics, University of Minnesota, Minneapolis, MN, University of Minnesota [Twin Cities] (UMN), University Hospital Olomouc [Czech Republic], Capital University of Medical Sciences [Beijing] (CUMS), Universitat de Barcelona (UB), University of California [San Francisco] (UCSF), University of California, Feinberg School of Medicine, Northwestern University [Evanston], Universitat Oberta de Catalunya [Barcelona] (UOC), University of Oklahoma Health Sciences Center (OUHSC), Palacky University Olomouc, Leipzig University, University 'G. d'Annunzio' of Chieti-Pescara [Chieti and Pescara, Italy], Centre d'Exploration Métabolique par Résonance Magnétique [Hôpital de la Timone - APHM] (CEMEREM), Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Masaryk University [Brno] (MUNI), Università degli Studi di Pavia = University of Pavia (UNIPV), Enrico Fermi Center for Study and Research | Museo Storico della Fisica e Centro Studi e Ricerche Enrico Fermi, Université de Genève = University of Geneva (UNIGE), University of Oxford, University of California [San Francisco] (UC San Francisco), University of California (UC), Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)- Hôpital de la Timone [CHU - APHM] (TIMONE), Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Matériaux et nanosciences d'Alsace (FMNGE), and Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Adult, Male, medicine.medical_specialty, Computer science, Neuroimaging, Article, General Biochemistry, Genetics and Molecular Biology, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Image Processing, Computer-Assisted, medicine, Humans, NeuroPoly, Medical physics, health care economics and organizations, Protocol (science), medicine.diagnostic_test, technology, industry, and agriculture, Healthy subjects, Magnetic resonance imaging, Spinal cord, Magnetic Resonance Imaging, White matter microstructure, humanities, 3. Good health, Acquisition Protocol, medicine.anatomical_structure, Spinal Cord, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], 030217 neurology & neurosurgery, Diffusion MRI
Abstract: Quantitative spinal cord (SC) magnetic resonance imaging (MRI) presents many challenges, including a lack of standardized imaging protocols. Here we present a prospectively harmonized quantitative MRI protocol, which we refer to as the spine generic protocol, for users of 3T MRI systems from the three main manufacturers: GE, Philips and Siemens. The protocol provides guidance for assessing SC macrostructural and microstructural integrity: T1-weighted and T2-weighted imaging for SC cross-sectional area computation, multi-echo gradient echo for gray matter cross-sectional area, and magnetization transfer and diffusion weighted imaging for assessing white matter microstructure. In a companion paper from the same authors, the spine generic protocol was used to acquire data across 42 centers in 260 healthy subjects. The key details of the spine generic protocol are also available in an open-access document that can be found at https://github.com/spine-generic/protocols . The protocol will serve as a starting point for researchers and clinicians implementing new SC imaging initiatives so that, in the future, inclusion of the SC in neuroimaging protocols will be more common. The protocol could be implemented by any trained MR technician or by a researcher/clinician familiar with MRI acquisition.
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39. Mapping of Adaptive Traits Enabled by a High-Density Linkage Map for Lake Trout

Author: Seth R. Smith, Stephen J. Amish, Louis Bernatchez, Jeremy Le Luyer, Chris C. Wilson, Olivia Boeberitz, Gordon Luikart, and Kim T. Scribner
Subjects: linkage map, salvelinus, qtl, rad, genomics, lake trout, Genetics, QH426-470
Abstract: Understanding the genomic basis of adaptative intraspecific phenotypic variation is a central goal in conservation genetics and evolutionary biology. Lake trout (Salvelinus namaycush) are an excellent species for addressing the genetic basis for adaptive variation because they express a striking degree of ecophenotypic variation across their range; however, necessary genomic resources are lacking. Here we utilize recently-developed analytical methods and sequencing technologies to (1) construct a high-density linkage and centromere map for lake trout, (2) identify loci underlying variation in traits that differentiate lake trout ecophenotypes and populations, (3) determine the location of the lake trout sex determination locus, and (4) identify chromosomal homologies between lake trout and other salmonids of varying divergence. The resulting linkage map contains 15,740 single nucleotide polymorphisms (SNPs) mapped to 42 linkage groups, likely representing the 42 lake trout chromosomes. Female and male linkage group lengths ranged from 43.07 to 134.64 centimorgans, and 1.97 to 92.87 centimorgans, respectively. We improved the map by determining coordinates for 41 of 42 centromeres, resulting in a map with 8 metacentric chromosomes and 34 acrocentric or telocentric chromosomes. We use the map to localize the sex determination locus and multiple quantitative trait loci (QTL) associated with intraspecific phenotypic divergence including traits related to growth and body condition, patterns of skin pigmentation, and two composite geomorphometric variables quantifying body shape. Two QTL for the presence of vermiculations and spots mapped with high certainty to an arm of linkage group Sna3, growth related traits mapped to two QTL on linkage groups Sna1 and Sna12, and putative body shape QTL were detected on six separate linkage groups. The sex determination locus was mapped to Sna4 with high confidence. Synteny analysis revealed that lake trout and congener Arctic char (Salvelinus alpinus) are likely differentiated by three or four chromosomal fissions, possibly one chromosomal fusion, and 6 or more large inversions. Combining centromere mapping information with putative inversion coordinates revealed that the majority of detected inversions differentiating lake trout from other salmonids are pericentric and located on acrocentric and telocentric linkage groups. Our results suggest that speciation and adaptive divergence within the genus Salvelinus may have been associated with multiple pericentric inversions occurring primarily on acrocentric and telocentric chromosomes. The linkage map presented here will be a critical resource for advancing conservation oriented genomic research on lake trout and exploring chromosomal evolution within and between salmonid species.
Published: 2020
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40. RAPTURE (RAD capture) panel facilitates analyses characterizing sea lamprey reproductive ecology and movement dynamics

Author: Nicholas M. Sard, Seth R. Smith, Jared J. Homola, Jeannette Kanefsky, Gale Bravener, Jean V. Adams, Christopher M. Holbrook, Peter J. Hrodey, Kevin Tallon, and Kim T. Scribner
Subjects: Great Lakes, pedigree reconstruction, population structure, RAD capture, Sea lamprey, Ecology, QH540-549.5
Abstract: Abstract Genomic tools are lacking for invasive and native populations of sea lamprey (Petromyzon marinus). Our objective was to discover single nucleotide polymorphism (SNP) loci to conduct pedigree analyses to quantify reproductive contributions of adult sea lampreys and dispersion of sibling larval sea lampreys of different ages in Great Lakes tributaries. Additional applications of data were explored using additional geographically expansive samples. We used restriction site‐associated DNA sequencing (RAD‐Seq) to discover genetic variation in Duffins Creek (DC), Ontario, Canada, and the St. Clair River (SCR), Michigan, USA. We subsequently developed RAD capture baits to genotype 3,446 RAD loci that contained 11,970 SNPs. Based on RAD capture assays, estimates of variance in SNP allele frequency among five Great Lakes tributary populations (mean FST 0.008; range 0.00–0.018) were concordant with previous microsatellite‐based studies; however, outlier loci were identified that contributed substantially to spatial population genetic structure. At finer scales within streams, simulations indicated that accuracy in genetic pedigree reconstruction was high when 200 or 500 independent loci were used, even in situations of high spawner abundance (e.g., 1,000 adults). Based on empirical collections of larval sea lamprey genotypes, we found that age‐1 and age‐2 families of full and half‐siblings were widely but nonrandomly distributed within stream reaches sampled. Using the genomic scale set of SNP loci developed in this study, biologists can rapidly genotype sea lamprey in non‐native and native ranges to investigate questions pertaining to population structuring and reproductive ecology at previously unattainable scales.
Published: 2020
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