Publications

Hope Center Member Publications

List of publications for September 12, 2022

Organization of the gravity-sensing system in zebrafish
(2022) Nature Communications

Organization of the gravity-sensing system in zebrafish
(2022) Nature Communications, 13 (1), art. no. 5060, . 

Liu, Z.a , Hildebrand, D.G.C.b , Morgan, J.L.c , Jia, Y.a , Slimmon, N.a , Bagnall, M.W.a

a Dept. of Neuroscience, Washington University in St. Louis, St. Louis, MO, United States
b Laboratory of Neural Systems, The Rockefeller University, New York, NY, United States
c Dept. of Ophthalmology, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Motor circuits develop in sequence from those governing fast movements to those governing slow. Here we examine whether upstream sensory circuits are organized by similar principles. Using serial-section electron microscopy in larval zebrafish, we generated a complete map of the gravity-sensing (utricular) system spanning from the inner ear to the brainstem. We find that both sensory tuning and developmental sequence are organizing principles of vestibular topography. Patterned rostrocaudal innervation from hair cells to afferents creates an anatomically inferred directional tuning map in the utricular ganglion, forming segregated pathways for rostral and caudal tilt. Furthermore, the mediolateral axis of the ganglion is linked to both developmental sequence and neuronal temporal dynamics. Early-born pathways carrying phasic information preferentially excite fast escape circuits, whereas later-born pathways carrying tonic signals excite slower postural and oculomotor circuits. These results demonstrate that vestibular circuits are organized by tuning direction and dynamics, aligning them with downstream motor circuits and behaviors. © 2022, The Author(s).

Funding details
National Institutes of HealthNIHEY029313, EY030623, R01 DC016413
Brain and Behavior Research FoundationBBRF
Research to Prevent BlindnessRPB
McKnight Foundation
Leon Levy Foundation
Foundation for Barnes-Jewish HospitalFBJH3770, 4642
National Alliance for Research on Schizophrenia and DepressionNARSAD
St. Louis Children’s HospitalSLCHCDI-CORE-2015-505, CDI-CORE-2019-813

Document Type: Article
Publication Stage: Final
Source: Scopus

Human induced pluripotent stem cell engineering establishes a humanized mouse platform for pediatric low-grade glioma modeling” (2022) Acta Neuropathologica Communications

Human induced pluripotent stem cell engineering establishes a humanized mouse platform for pediatric low-grade glioma modeling
(2022) Acta Neuropathologica Communications, 10 (1), art. no. 120, . 

Anastasaki, C.a , Chatterjee, J.a , Cobb, O.a , Sanapala, S.a , Scheaffer, S.M.a , De Andrade Costa, A.a , Wilson, A.F.a , Kernan, C.M.a , Zafar, A.H.a , Ge, X.b , Garbow, J.R.b , Rodriguez, F.J.c , Gutmann, D.H.a

a Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue, Box 8111, St. Louis, MO 63110, United States
b Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Pathology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, United States

Abstract
A major obstacle to identifying improved treatments for pediatric low-grade brain tumors (gliomas) is the inability to reproducibly generate human xenografts. To surmount this barrier, we leveraged human induced pluripotent stem cell (hiPSC) engineering to generate low-grade gliomas (LGGs) harboring the two most common pediatric pilocytic astrocytoma-associated molecular alterations, NF1 loss and KIAA1549:BRAF fusion. Herein, we identified that hiPSC-derived neuroglial progenitor populations (neural progenitors, glial restricted progenitors and oligodendrocyte progenitors), but not terminally differentiated astrocytes, give rise to tumors retaining LGG histologic features for at least 6 months in vivo. Additionally, we demonstrated that hiPSC-LGG xenograft formation requires the absence of CD4 T cell-mediated induction of astrocytic Cxcl10 expression. Genetic Cxcl10 ablation is both necessary and sufficient for human LGG xenograft development, which additionally enables the successful long-term growth of patient-derived pediatric LGGs in vivo. Lastly, MEK inhibitor (PD0325901) treatment increased hiPSC-LGG cell apoptosis and reduced proliferation both in vitro and in vivo. Collectively, this study establishes a tractable experimental humanized platform to elucidate the pathogenesis of and potential therapeutic opportunities for childhood brain tumors. © 2022, The Author(s).

Author Keywords
BRAF;  Human induced pluripotent stem cells;  Low-grade glioma;  NF1;  Pediatric brain tumor;  Pilocytic astrocytoma

Funding details
National Eye InstituteNEIP30EY002687
National Cancer InstituteNCI1-R50-CA233164-01, P30-CA091842
National Institute of Neurological Disorders and StrokeNINDS1-R35-NS07211-01
Pediatric Brain Tumor FoundationPBTFP20-00873
Ian’s Friends FoundationIFF
Alvin J. Siteman Cancer Center

Document Type: Article
Publication Stage: Final
Source: Scopus

Tralesinidase Alfa Enzyme Replacement Therapy Prevents Disease Manifestations in a Canine Model of Mucopolysaccharidosis Type IIIB” (2022) The Journal of Pharmacology and Experimental Therapeutics

Tralesinidase Alfa Enzyme Replacement Therapy Prevents Disease Manifestations in a Canine Model of Mucopolysaccharidosis Type IIIB
(2022) The Journal of Pharmacology and Experimental Therapeutics, 382 (3), pp. 277-286. 

Ellinwood, N.M.a , Valentine, B.N.b , Hess, A.S.b , Jens, J.K.b , Snella, E.M.b , Jamil, M.b , Hostetter, S.J.b , Jeffery, N.D.b , Smith, J.D.b , Millman, S.T.b , Parsons, R.L.b , Butt, M.T.b , Chandra, S.b , Egeland, M.T.b , Assis, A.B.b , Nelvagal, H.R.b , Cooper, J.D.b , Nestrasil, I.b , Mueller, B.A.b , Labounek, R.b , Paulson, A.b , Prill, H.b , Liu, X.Y.b , Zhou, H.b , Lawrence, R.b , Crawford, B.E.b , Grover, A.b , Cherala, G.b , Melton, A.C.b , Cherukuri, A.b , Vuillemenot, B.R.b , Wait, J.C.M.b , O’Neill, C.A.b , Pinkstaff, J.b , Kovalchin, J.b , Zanelli, E.b , McCullagh, E.a

a Departments of Animal Science (N.M.E., B.N.V., A.S.H., J.K.J., E.M.S., M.J.), Veterinary Clinical Science (N.M.E., N.D.J.), Veterinary Pathology (S.J.H., J.D.S.), Veterinary Diagnostics and Production Animal Medicine (S.T.M., R.L.P.), and Biomedical Science (S.T.M.), Iowa State University, Ames, Iowa; StageBio, Frederick, Maryland (M.T.B.); BioMarin Pharmaceutical Inc., Novato, California (S.C., H.P., X.Y.L., H.Z., R.L., B.E.C., A.G., G.C., A.C.M., A.C., B.R.V., J.C.M.W., C.A.O., J.P., E.M.); The Lundquist Institute (formerly Los Angeles Biomedical Research Institute) at Harbor-UCLA Medical Center, Torrance, California (M.T.E., A.B.A., H.R.N., J.D.C.); Department of Pediatrics, Washington University in St Louis, St Louis, Missouri (H.R.N., J.D.C.); Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota (I.N., B.A.M., R.L., A.P.); and Allievex Corporation, Marblehead, Massachusetts (J.K., E.Z.) matthew@mpssociety.org domainbiotechnologies@gmail.com
b Departments of Animal Science (N.M.E., B.N.V., A.S.H., J.K.J., E.M.S., M.J.), Veterinary Clinical Science (N.M.E., N.D.J.), Veterinary Pathology (S.J.H., J.D.S.), Veterinary Diagnostics and Production Animal Medicine (S.T.M., R.L.P.), and Biomedical Science (S.T.M.), Iowa State University, Ames, Iowa; StageBio, Frederick, Maryland (M.T.B.); BioMarin Pharmaceutical Inc., Novato, California (S.C., H.P., X.Y.L., H.Z., R.L., B.E.C., A.G., G.C., A.C.M., A.C., B.R.V., J.C.M.W., C.A.O., J.P., E.M.); The Lundquist Institute (formerly Los Angeles Biomedical Research Institute) at Harbor-UCLA Medical Center, Torrance, California (M.T.E., A.B.A., H.R.N., J.D.C.); Department of Pediatrics, Washington University in St Louis, St Louis, Missouri (H.R.N., J.D.C.); Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota (I.N., B.A.M., R.L., A.P.); and Allievex Corporation, Marblehead, Massachusetts (J.K., E.Z.)

Abstract
Mucopolysaccharidosis type IIIB (MPS IIIB; Sanfilippo syndrome B; OMIM #252920) is a lethal, pediatric, neuropathic, autosomal recessive, and lysosomal storage disease with no approved therapy. Patients are deficient in the activity of N-acetyl-alpha-glucosaminidase (NAGLU; EC 3.2.150), necessary for normal lysosomal degradation of the glycosaminoglycan heparan sulfate (HS). Tralesinidase alfa (TA), a fusion protein comprised of recombinant human NAGLU and a modified human insulin-like growth factor 2, is in development as an enzyme replacement therapy that is administered via intracerebroventricular (ICV) infusion, thus circumventing the blood brain barrier. Previous studies have confirmed ICV infusion results in widespread distribution of TA throughout the brains of mice and nonhuman primates. We assessed the long-term tolerability, pharmacology, and clinical efficacy of TA in a canine model of MPS IIIB over a 20-month study. Long-term administration of TA was well tolerated as compared with administration of vehicle. TA was widely distributed across brain regions, which was confirmed in a follow-up 8-week pharmacokinetic/pharmacodynamic study. MPS IIIB dogs treated for up to 20 months had near-normal levels of HS and nonreducing ends of HS in cerebrospinal fluid and central nervous system (CNS) tissues. TA-treated MPS IIIB dogs performed better on cognitive tests and had improved CNS pathology and decreased cerebellar volume loss relative to vehicle-treated MPS IIIB dogs. These findings demonstrate the ability of TA to prevent or limit the biochemical, pathologic, and cognitive manifestations of canine MPS IIIB disease, thus providing support of its potential long-term tolerability and efficacy in MPS IIIB subjects. SIGNIFICANCE STATEMENT: This work illustrates the efficacy and tolerability of tralesinidase alfa as a potential therapeutic for patients with mucopolysaccharidosis type IIIB (MPS IIIB) by documenting that administration to the central nervous system of MPS IIIB dogs prevents the accumulation of disease-associated glycosaminoglycans in lysosomes, hepatomegaly, cerebellar atrophy, and cognitive decline. Copyright © 2022 by The Author(s).

Document Type: Article
Publication Stage: Final
Source: Scopus



Age-associated suppression of exploratory activity during sickness is linked to meningeal lymphatic dysfunction and microglia activation” (2022) Nature Aging

Age-associated suppression of exploratory activity during sickness is linked to meningeal lymphatic dysfunction and microglia activation
(2022) Nature Aging, 2 (8), pp. 704-713. 

Goldman, D.H.a b c , Dykstra, T.a b , Smirnov, I.a b , Blackburn, S.M.a b , Da Mesquita, S.d , Kipnis, J.a b c , Herz, J.a b

a Center for Brain Immunology and Glia (BIG), Washington University in St. Louis, St. Louis, MO, United States
b Department of Pathology & Immunology, Washington University in St. Louis, St. Louis, MO, United States
c Neuroscience Graduate Program, University of Virginia, Charlottesville, VA, United States
d Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States

Abstract
Peripheral inflammation triggers a transient, well-defined set of behavioral changes known as sickness behavior1–3, but the mechanisms by which inflammatory signals originating in the periphery alter activity in the brain remain obscure. Emerging evidence has established meningeal lymphatic vasculature as an important interface between the central nervous system (CNS) and the immune system, responsible for facilitating brain solute clearance and perfusion by cerebrospinal fluid (CSF)4,5. Here, we demonstrate that meningeal lymphatics both assist microglial activation and support the behavioral response to peripheral inflammation. Ablation of meningeal lymphatics results in a heightened behavioral response to IL-1β-induced inflammation and a dampened transcriptional and morphological microglial phenotype. Moreover, our findings support a role for microglia in tempering the severity of sickness behavior with specific relevance to aging-related meningeal lymphatic dysfunction. Transcriptional profiling of brain myeloid cells shed light on the impact of meningeal lymphatic dysfunction on microglial activation. Furthermore, we demonstrate that experimental enhancement of meningeal lymphatic function in aged mice is sufficient to reduce the severity of exploratory abnormalities but not pleasurable consummatory behavior. Finally, we identify dysregulated genes and biological pathways, common to both experimental meningeal lymphatic ablation and aging, in microglia responding to peripheral inflammation that may result from age-related meningeal lymphatic dysfunction. © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.

Funding details
National Institutes of HealthNIHDP1AT010416, R37AG034113
University of VirginiaUV

Document Type: Article
Publication Stage: Final
Source: Scopus

Nitrous Oxide, a Rapid Antidepressant, Has Ketamine-like Effects on Excitatory Transmission in the Adult Hippocampus” (2022) Biological Psychiatry

Nitrous Oxide, a Rapid Antidepressant, Has Ketamine-like Effects on Excitatory Transmission in the Adult Hippocampus
(2022) Biological Psychiatry, . 

Izumi, Y.a b , Hsu, F.-F.c , Conway, C.R.a b , Nagele, P.d , Mennerick, S.J.a b , Zorumski, C.F.a b

a Department of Psychiatry and Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, Missouri, United States
b Center for Brain Research in Mood Disorders, Washington University School of Medicine, St. Louis, Missouri, United States
c Department of Medicine and Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, Missouri, United States
d Department of Anesthesia and Critical Care, University of Chicago, Chicago, Illinois, United States

Abstract
Background: Nitrous oxide (N2O) is a noncompetitive inhibitor of NMDA receptors that appears to have ketamine-like rapid antidepressant effects in patients with treatment-resistant major depression. In preclinical studies, ketamine enhances glutamate-mediated synaptic transmission in the hippocampus and prefrontal cortex. In this study, we examined the effects of N2O on glutamate transmission in the hippocampus and compared its effects to those of ketamine. Methods: Glutamate-mediated synaptic transmission was studied in the CA1 region of hippocampal slices from adult albino rats using standard extracellular recording methods. Effects of N2O and ketamine at subanesthetic concentrations were evaluated by acute administration. Results: Akin to 1 μM ketamine, 30% N2O administered for 15–20 minutes resulted in persistent enhancement of synaptic responses mediated by both AMPA receptors and NMDA receptors. Synaptic enhancement by both N2O and ketamine was blocked by co-administration of a competitive NMDA receptor antagonist at saturating concentration, but only ketamine was blocked by an AMPA receptor antagonist. Synaptic enhancement by both agents involved TrkB (tropomyosin receptor kinase B), mTOR (mechanistic target of rapamycin), and NOS (nitric oxide synthase) with some differences between N2O and ketamine. N2O potentiation occluded enhancement by ketamine, and in vivo N2O exposure occluded further potentiation by both N2O and ketamine. Conclusions: These results indicate that N2O has ketamine-like effects on hippocampal synaptic function at a subanesthetic, but therapeutically relevant concentration. These 2 rapid antidepressants have similar, but not identical mechanisms that result in persisting synaptic enhancement, possibly contributing to psychotropic actions. © 2022 Society of Biological Psychiatry

Author Keywords
Laughing gas;  mTOR;  Nitric oxide synthase;  NMDA receptors;  TrkB receptors

Funding details
National Institute of Mental HealthNIMHMH101874, MH114866, MH122379, MH123748
National Institute of General Medical SciencesNIGMSP30DK020579, P30DK056341, P41GM103422
National Institute of Diabetes and Digestive and Kidney DiseasesNIDDK
Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine in St. Louis
Sage Therapeutics

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Fiber photometry in striatum reflects primarily nonsomatic changes in calcium” (2022) Nature Neuroscience

Fiber photometry in striatum reflects primarily nonsomatic changes in calcium
(2022) Nature Neuroscience, . 

Legaria, A.A.a , Matikainen-Ankney, B.A.b , Yang, B.c , Ahanonu, B.d , Licholai, J.A.e , Parker, J.G.c , Kravitz, A.V.a b f

a Department of Neuroscience, Washington University School of Medicine, St Louis, MO, United States
b Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
c Department of Neuroscience, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
d Department of Anatomy, University of California, San Francisco, San Francisco, CA, United States
e Department of Neuroscience, Brown University, Providence, RI, United States
f Department of Anesthesiology, Washington University School of Medicine, St Louis, MO, United States

Abstract
Fiber photometry enables recording of population neuronal calcium dynamics in awake mice. While the popularity of fiber photometry has grown in recent years, it remains unclear whether photometry reflects changes in action potential firing (that is, ‘spiking’) or other changes in neuronal calcium. In microscope-based calcium imaging, optical and analytical approaches can help differentiate somatic from neuropil calcium. However, these approaches cannot be readily applied to fiber photometry. As such, it remains unclear whether the fiber photometry signal reflects changes in somatic calcium, changes in nonsomatic calcium or a combination of the two. Here, using simultaneous in vivo extracellular electrophysiology and fiber photometry, along with in vivo endoscopic one-photon and two-photon calcium imaging, we determined that the striatal fiber photometry does not reflect spiking-related changes in calcium and instead primarily reflects nonsomatic changes in calcium. © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.

Funding details
National Institute of Diabetes and Digestive and Kidney DiseasesNIDDKDK126355
American Heart AssociationAHA

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Radiosynthesis and Evaluation of a C-11 Radiotracer for Transient Receptor Potential Canonical 5 in the Brain” (2022) Molecular Imaging and Biology

Radiosynthesis and Evaluation of a C-11 Radiotracer for Transient Receptor Potential Canonical 5 in the Brain
(2022) Molecular Imaging and Biology, . 

Yu, Y.a , Jiang, H.a , Liang, Q.a , Qiu, L.a , Huang, T.a , Hu, H.b , Bolshakov, V.Y.c , Perlmutter, J.S.a d , Tu, Z.a

a Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
b Center for the Study of Itch and Sensory Disorders, Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Psychiatry, McLean Hospital, Harvard Medical School, Boston, MA 02115, United States
d Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Purpose: TRPC5 belongs to the mammalian superfamily of transient receptor potential (TRP) Ca2+-permeable cationic channels and it has been implicated in various CNS disorders. As part of our ongoing interest in the development of a PET radiotracer for imaging TRPC5, herein, we explored the radiosynthesis, and in vitro and in vivo evaluation of a new C-11 radiotracer [11C]HC070 in rodents and nonhuman primates. Procedures: [11C]HC070 was radiolabeled utilizing the corresponding precursor and [11C]CH3I via N-methylation protocol. Ex vivo biodistribution study of [11C]HC070 was performed in Sprague–Dawley rats. In vitro autoradiography study was conducted for the rat brain sections to characterize the radiotracer distribution in the brain regionals. MicroPET brain imaging studies of [11C]HC070 were done for 129S1/SvImJ wild-type mice and 129S1/SvImJ TRPC5 knockout mice for 0–60-min dynamic data acquisition after intravenous administration of the radiotracer. Dynamic PET scans (0–120 min) for the brain of cynomolgus male macaques were performed after the radiotracer injection. Results: [11C]HC070 was efficiently prepared with good radiochemical yield (45 ± 5%, n = 15), high chemical and radiochemical purity (> 99%), and high molar activity (320.6 ± 7.4 GBq/μmol, 8.6 ± 0.2 Ci/μmol) at the end of bombardment (EOB). Radiotracer [11C]HC070 has good solubility in the aqueous dose solution. The ex vivo biodistribution study showed that [11C]HC070 had a quick rat brain clearance. Autoradiography demonstrated that [11C]HC070 specifically binds to TRPC5-enriched regions in rat brain. MicroPET study showed the peak brain uptake (SUV value) was 0.63 in 129S1/SvImJ TRPC5 knockout mice compared to 1.13 in 129S1/SvImJ wild-type mice. PET study showed that [11C]HC070 has good brain uptake with maximum SUV of ~ 2.2 in the macaque brain, followed by rapid clearance. Conclusions: Our data showed that [11C]HC070 is a TRPC5-specific radiotracer with high brain uptake and good brain washout pharmacokinetics in both rodents and nonhuman primates. The radiotracer is worth further investigating of its suitability to be a PET radiotracer for imaging TRPC5 in animals and human subjects in vivo. © 2022, The Author(s), under exclusive licence to World Molecular Imaging Society.

Author Keywords
Carbon-11 Radiotracer;  Ionic Channel;  PET Imaging;  TRPC 5

Funding details
National Institutes of HealthNIH
National Institute on AgingNIANS075527, NS103957, NS103988
National Institute of Neurological Disorders and StrokeNINDS

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Deep Learning-Based Automatic Detection of Brain Metastases in Heterogenous Multi-Institutional Magnetic Resonance Imaging Sets: An Exploratory Analysis of NRG CC001” (2022) International Journal of Radiation Oncology Biology Physics

Deep Learning-Based Automatic Detection of Brain Metastases in Heterogenous Multi-Institutional Magnetic Resonance Imaging Sets: An Exploratory Analysis of NRG CC001
(2022) International Journal of Radiation Oncology Biology Physics, . 

Liang, Y.a , Lee, K.a , Bovi, J.A.a , Palmer, J.D.b , Brown, P.D.c , Gondi, V.d , Tomé, W.A.e , Benzinger, T.L.S.f , Mehta, M.P.g , Li, X.A.a

a Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI, United States
b Department of Radiation Oncology, The James Cancer Hospital and Solove Research Institute at the Ohio State University, Columbus, OH, United States
c Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, United States
d Department of Radiation Oncology, Northwestern Medicine Cancer Center and Proton Center, Warrenville, IL, United States
e Department of Radiation Oncology, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, NY, United States
f Department of Radiology, Washington University School of Medicine, St Louis, Missouri
g Miami Cancer Institute, Miami, Florida

Abstract
Purpose: Deep learning-based algorithms have been shown to be able to automatically detect and segment brain metastases (BMs) in magnetic resonance imaging, mostly based on single-institutional data sets. This work aimed to investigate the use of deep convolutional neural networks (DCNN) for BM detection and segmentation on a highly heterogeneous multi-institutional data set. Methods and Materials: A total of 407 patients from 98 institutions were randomly split into 326 patients from 78 institutions for training/validation and 81 patients from 20 institutions for unbiased testing. The data set contained T1-weighted gadolinium and T2-weighted fluid-attenuated inversion recovery magnetic resonance imaging acquired on diverse scanners using different pulse sequences and various acquisition parameters. Several variants of 3-dimensional U-Net based DCNN models were trained and tuned using 5-fold cross validation on the training set. Performances of different models were compared based on Dice similarity coefficient for segmentation and sensitivity and false positive rate (FPR) for detection. The best performing model was evaluated on the test set. Results: A DCNN with an input size of 64 × 64 × 64 and an equal number of 128 kernels for all convolutional layers using instance normalization was identified as the best performing model (Dice similarity coefficient 0.73, sensitivity 0.86, and FPR 1.9) in the 5-fold cross validation experiments. The best performing model demonstrated consistent behavior on the test set (Dice similarity coefficient 0.73, sensitivity 0.91, and FPR 1.7) and successfully detected 7 BMs (out of 327) that were missed during manual delineation. For large BMs with diameters greater than 12 mm, the sensitivity and FPR improved to 0.98 and 0.3, respectively. Conclusions: The DCNN model developed can automatically detect and segment brain metastases with reasonable accuracy, high sensitivity, and low FPR on a multi-institutional data set with nonprespecified and highly variable magnetic resonance imaging sequences. For large BMs, the model achieved clinically relevant results. The model is robust and may be potentially used in real-world situations. © 2022 Elsevier Inc.

Funding details
National Institutes of HealthNIHR702, U24CA180803, UG1CA189867
National Cancer InstituteNCI
Biogen

Document Type: Article
Publication Stage: Article in Press
Source: Scopus