WashU weekly Neuroscience publications

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, 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

Transfer learning in high-dimensional semiparametric graphical models with application to brain connectivity analysis
(2022) Statistics in Medicine, 41 (21), pp. 4112-4129. 

He, Y.^a , Li, Q.^a , Hu, Q.^b , Liu, L.^c

^a Institute for Financial Studies, Shandong University, Shandong, Jinan, China
^b School of Mathematics and Statistics, Shandong University at Weihai, Shandong, Weihai, China
^c Division of Biostatistics, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Transfer learning has drawn growing attention with the target of improving statistical efficiency of one study (dataset) by digging up information from similar and related auxiliary studies (datasets). In this article, we consider transfer learning problem in estimating undirected semiparametric graphical model. We propose an algorithm called Trans-Copula-CLIME for estimating an undirected graphical model while uncovering information from similar auxiliary studies, characterizing the similarity between the target graph and each auxiliary graph by the sparsity of a divergence matrix. The proposed method relaxes the restrictive Gaussian distribution assumption, which deviates from reality for the fMRI dataset related to attention deficit hyperactivity disorder (ADHD) considered here. Nonparametric rank-based correlation coefficient estimators are utilized in the Trans-Copula-CLIME procedure to achieve robustness against normality. We establish the convergence rate of the Trans-Copula-CLIME estimator under some mild conditions, which demonstrates that if the similarity between the auxiliary studies and the target study is sufficiently high and the number of informative auxiliary samples is sufficiently large, the Trans-Copula-CLIME estimator shows great advantage over the existing non-transfer-learning ones. Simulation studies also show that Trans-Copula-CLIME estimator has better performance especially when data are not from Gaussian distribution. Finally, the proposed method is applied to infer functional brain connectivity pattern for ADHD patients in the target Beijing site by leveraging the fMRI datasets from some other sites. © 2022 John Wiley & Sons Ltd.

Author Keywords
Gaussian copula;  graphical model;  nonparametric ranked-based statistic;  transfer learning

Funding details
National Institutes of HealthNIHUL1 TR002345
Shandong UniversitySDU
Fundamental Research Fund of Shandong University
National Natural Science Foundation of ChinaNSFC11801316, 12171282
China Postdoctoral Science Foundation2021M701997
Natural Science Foundation of Shandong ProvinceZR2019QA002

Document Type: Article
Publication Stage: Final
Source: Scopus

Schizophrenia Imaging Signatures and Their Associations With Cognition, Psychopathology, and Genetics in the General Population
(2022) The American Journal of Psychiatry, 179 (9), pp. 650-660. 

Chand, G.B., Singhal, P., Dwyer, D.B., Wen, J., Erus, G., Doshi, J., Srinivasan, D., Mamourian, E., Varol, E., Sotiras, A., Hwang, G., Dazzan, P., Kahn, R.S., Schnack, H.G., Zanetti, M.V., Meisenzahl, E., Busatto, G.F., Crespo-Facorro, B., Pantelis, C., Wood, S.J., Zhuo, C., Shinohara, R.T., Shou, H., Fan, Y., Koutsouleris, N., Kaczkurkin, A.N., Moore, T.M., Verma, A., Calkins, M.E., Gur, R.E., Gur, R.C., Ritchie, M.D., Satterthwaite, T.D., Wolf, D.H., Davatzikos, C.

Center for Biomedical Image Computing and Analytics (Chand, Wen, Erus, Doshi, Srinivasan, Mamourian, Varol, Sotiras, Hwang, Fan, Satterthwaite, Wolf, Davatzikos, Shinohara, Shou), Department of Radiology (Chand, Wen, Erus, Doshi, Srinivasan, Mamourian, Varol, Sotiras, Hwang, Fan, R.E. Gur, R.C. Gur, Davatzikos), Department of Genetics (Singhal, Verma, Ritchie), Department of Psychiatry (Kaczkurkin, Moore, Calkins, R.E. Gur, R.C. Gur, Satterthwaite, Wolf), and Penn Statistics in Imaging and Visualization Center, Department of Biostatistics, Epidemiology, and Informatics (Shinohara, Shou), Perelman School of Medicine, University of Pennsylvania, Philadelphia; Department of Radiology, School of Medicine (Chand, Sotiras), and Institute of Informatics (Sotiras), Washington University in St. Louis; Department of Psychiatry and Psychotherapy, Ludwig-Maximilian University, Munich (Dwyer, Koutsouleris); Department of Statistics, Zuckerman Institute, Columbia University, New York (Varol); Department of Psychological Medicine, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London (Dazzan); Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York (Kahn); Department of Psychiatry, University Medical Center Utrecht, Utrecht, the Netherlands (Schnack)

Abstract
OBJECTIVE: The prevalence and significance of schizophrenia-related phenotypes at the population level is debated in the literature. Here, the authors assessed whether two recently reported neuroanatomical signatures of schizophrenia-signature 1, with widespread reduction of gray matter volume, and signature 2, with increased striatal volume-could be replicated in an independent schizophrenia sample, and investigated whether expression of these signatures can be detected at the population level and how they relate to cognition, psychosis spectrum symptoms, and schizophrenia genetic risk. METHODS: This cross-sectional study used an independent schizophrenia-control sample (N=347; ages 16-57 years) for replication of imaging signatures, and then examined two independent population-level data sets: typically developing youths and youths with psychosis spectrum symptoms in the Philadelphia Neurodevelopmental Cohort (N=359; ages 16-23 years) and adults in the UK Biobank study (N=836; ages 44-50 years). The authors quantified signature expression using support-vector machine learning and compared cognition, psychopathology, and polygenic risk between signatures. RESULTS: Two neuroanatomical signatures of schizophrenia were replicated. Signature 1 but not signature 2 was significantly more common in youths with psychosis spectrum symptoms than in typically developing youths, whereas signature 2 frequency was similar in the two groups. In both youths and adults, signature 1 was associated with worse cognitive performance than signature 2. Compared with adults with neither signature, adults expressing signature 1 had elevated schizophrenia polygenic risk scores, but this was not seen for signature 2. CONCLUSIONS: The authors successfully replicated two neuroanatomical signatures of schizophrenia and describe their prevalence in population-based samples of youths and adults. They further demonstrated distinct relationships of these signatures with psychosis symptoms, cognition, and genetic risk, potentially reflecting underlying neurobiological vulnerability.

Author Keywords
Genetics/Genomics;  Machine Learning;  Neuroanatomy;  Neuroimaging;  Polygenic Risk Scores;  Schizophrenia Spectrum and Other Psychotic Disorders

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, 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

Subcortical-cortical dynamical states of the human brain and their breakdown in stroke
(2022) Nature Communications, 13 (1), p. 5069. 

Favaretto, C.^a b , Allegra, M.^a c d , Deco, G.^e f , Metcalf, N.V.^g , Griffis, J.C.^g , Shulman, G.L.^g h , Brovelli, A.^d , Corbetta, M.^{a b g h i}

^a Padova Neuroscience Center (PNC), University of Padova, via Orus 2/B, Padova, 35129, Italy
^b Department of Neuroscience (DNS), University of Padova, via Giustiniani 2, Padova, 35128, Italy
^c Department of Physics and Astronomy “Galileo Galilei”, University of Padova, via Marzolo 8, Padova, 35131, Italy
^d Institut de Neurosciences de la Timone UMR 7289, CNRS, Aix Marseille Université, Marseille, 13005, France
^e Center for Brain and Cognition (CBC), Department of Information Technologies and Communications (DTIC), Pompeu Fabra University, Barcelona, Catalonia 08005, Spain
^f Institució Catalana de Recerca I Estudis Avançats (ICREA), Passeig Lluis Companys 23, Barcelona, Catalonia 08010, Spain
^g Department of Neurology, Washington University School of Medicine, 660S. Euclid Ave, St. Louis, MO 63110, United States
^h Department of Radiology, Washington University School of Medicine, 660S. Euclid Ave, St. Louis, MO 63110, United States
ⁱ VIMM, Venetian Institute of Molecular Medicine (VIMM), Biomedical Foundation, via Orus 2, Padova, 35129, Italy

Abstract
The mechanisms controlling dynamical patterns in spontaneous brain activity are poorly understood. Here, we provide evidence that cortical dynamics in the ultra-slow frequency range (<0.01-0.1 Hz) requires intact cortical-subcortical communication. Using functional magnetic resonance imaging (fMRI) at rest, we identify Dynamic Functional States (DFSs), transient but recurrent clusters of cortical and subcortical regions synchronizing at ultra-slow frequencies. We observe that shifts in cortical clusters are temporally coincident with shifts in subcortical clusters, with cortical regions flexibly synchronizing with either limbic regions (hippocampus/amygdala), or subcortical nuclei (thalamus/basal ganglia). Focal lesions induced by stroke, especially those damaging white matter connections between basal ganglia/thalamus and cortex, provoke anomalies in the fraction times, dwell times, and transitions between DFSs, causing a bias toward abnormal network integration. Dynamical anomalies observed 2 weeks after stroke recover in time and contribute to explaining neurological impairment and long-term outcome. © 2022. The Author(s).

Document Type: Article
Publication Stage: Final
Source: Scopus

Diabetic retinopathy as a predictor of cardiovascular morbidity and mortality in subjects with type 2 diabetes
(2022) Frontiers in Medicine, 9, art. no. 945245, . 

Barrot, J.^a b c d , Real, J.^b c , Vlacho, B.^b e , Romero-Aroca, P.^f , Simó, R.^g h i , Mauricio, D.^b i j k , Mata-Cases, M.^b i l , Castelblanco, E.^b m , Mundet-Tuduri, X.^b d , Franch-Nadal, J.^b i n

^a Primary Health Care Center Dr. Jordi Nadal i Fàbregas (Salt), Gerència d’Atenció Primària, Institut Català de la Salut, Girona, Spain
^b Diabetis des de l’Atenció Primária (DAP)-Cat Group, Unitat de Suport a la Recerca Barcelona, Fundació Institut Universitari per a la Recerca a l’Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGOL), Barcelona, Spain
^c Fundació Institut Universitari per a la Recerca a l’Atenció Primària de Salut Jordi Gol i Gorina (IDIAPJGOL), Barcelona, Spain
^d Departament of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
^e Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
^f Ophthalmology Service, University Hospital Sant Joan, Institut de Investigacio Sanitaria Pere Virgili (IISPV), University of Rovira and Virgili, Reus, Spain
^g Diabetes and Metabolism Research Unit, Department of Endocrinology, Vall d’Hebron University Hospital, Vall d’Hebron Research Institute, Barcelona, Spain
^h Department of Medicine, Faculty of Medicine, Autonomous University of Barcelona, Barcelona, Spain
ⁱ Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain
^j Department of Endocrinology and Nutrition, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
^k Departament of Medicine, University of Vic—Central University of Catalonia, Vic, Spain
^l Centre d’Atenció Primària La Mina, Gerència d’Àmbit d’Atenció Primària de Barcelona, Institut Català de la Salut, Barcelona, Spain
^m Division of Endocrinology, Metabolism and Lipid Research, John T. Milliken Department of Medicine, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
ⁿ Primary Health Care Center Raval Sud, Gerència d’Àmbit d’Atenció Primaria, Institut Català de la Salut, Barcelona, Spain

Abstract
This study aimed to evaluate the predictive value of diabetic retinopathy (DR) and its stages with the incidence of major cardiovascular events and all-cause mortality in type 2 diabetes mellitus (T2DM) persons in our large primary healthcare database from Catalonia (Spain). A retrospective cohort study with pseudo-anonymized routinely collected health data from SIDIAP was conducted from 2008 to 2016. We calculated incidence rates of major cardiovascular events [coronary heart disease (CHD), stroke, or both—macrovascular events] and all-cause mortality for subjects with and without DR and for different stages of DR. The proportional hazards regression analysis was done to assess the probability of occurrence between DR and the study events. About 22,402 T2DM subjects with DR were identified in the database and 196,983 subjects without DR. During the follow-up period among the subjects with DR, we observed the highest incidence of all-cause mortally. In the second place were the macrovascular events among the subjects with DR. In the multivariable analysis, fully adjusted for DR, sex, age, body mass index (BMI), tobacco, duration of T2DM, an antiplatelet or antihypertensive drug, and HbA1c, we observed that subjects with any stage of DR had higher risks for all of the study events, except for stroke. We observed the highest probability of all-cause death events (adjusted hazard ratios, AHRs: 1.34, 95% CI: 1.28; 1.41). In conclusion, our results show that DR is related to CHD, macrovascular events, and all-cause mortality among persons with T2DM. Copyright © 2022 Barrot, Real, Vlacho, Romero-Aroca, Simó, Mauricio, Mata-Cases, Castelblanco, Mundet-Tuduri and Franch-Nadal.

Author Keywords
diabetic retinopathy;  macrovascular complication;  mortality;  primary healthcare;  real word data analyses

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, 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, . 

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, . 

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

Sex-related differences in violence exposure, neural reactivity to threat, and mental health
(2022) Neuropsychopharmacology, . 

Dark, H.E.^a e , Harnett, N.G.^a f g , Hurst, D.R.^a , Wheelock, M.D.^a h , Wood, K.H.^a i , Goodman, A.M.^a j , Mrug, S.^a , Elliott, M.N.^b , Emery, S.T.^c , Schuster, M.A.^d , Knight, D.C.^a

^a Department of Psychology, University of Alabama at Birmingham, Birmingham, AL, United States
^b RAND Corporation, Santa Monica, CA, United States
^c Texas Prevention Research Center, School of Public Health, University of Texas Health Science Center, Houston, TX, United States
^d Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, CA, United States
^e Laboratory of Behavioral Neuroscience, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States
^f Division of Depression and Anxiety, McLean Hospital, Belmont, MA, United States
^g Department of Psychiatry, Harvard Medical School, Boston, MA, United States
^h Department of Radiology, Washington University in St. Louis, St Louis, MO, United States
ⁱ Department of Psychology, Samford University, Homewood, AL, United States
^j Department of Neurology, University of Alabama at Birmingham School of Medicine, Birmingham, AL, United States

Abstract
The prefrontal cortex (PFC), hippocampus, and amygdala play an important role in emotional health. However, adverse life events (e.g., violence exposure) affect the function of these brain regions, which may lead to disorders such as depression and anxiety. Depression and anxiety disproportionately affect women compared to men, and this disparity may reflect sex differences in the neural processes that underlie emotion expression and regulation. The present study investigated sex differences in the relationship between violence exposure and the neural processes that underlie emotion regulation. In the present study, 200 participants completed a Pavlovian fear conditioning procedure in which cued and non-cued threats (i.e., unconditioned stimuli) were presented during functional magnetic resonance imaging. Violence exposure was previously assessed at four separate time points when participants were 11–19 years of age. Significant threat type (cued versus non-cued) × sex and sex × violence exposure interactions were observed. Specifically, women and men differed in amygdala and parahippocampal gyrus reactivity to cued versus non-cued threat. Further, dorsolateral PFC (dlPFC) and inferior parietal lobule (IPL) reactivity to threat varied positively with violence exposure among women, but not men. Similarly, threat-elicited skin conductance responses varied positively with violence exposure among women. Finally, women reported greater depression and anxiety symptoms than men. These findings suggest that sex differences in threat-related brain and psychophysiological activity may have implications for mental health. © 2022, The Author(s), under exclusive licence to American College of Neuropsychopharmacology.

Funding details
National Institutes of HealthNIHR01 MH098348

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

Precision Medicine Approach to Alzheimer’s Disease: Successful Pilot Project
(2022) Journal of Alzheimer’s Disease: JAD, 88 (4), pp. 1411-1421. 

Toups, K.^a , Hathaway, A.^b , Gordon, D.^c , Chung, H.^d , Raji, C.^e , Boyd, A.^f , Hill, B.D.^g , Hausman-Cohen, S.^h , Attarha, M.ⁱ , Chwa, W.J.^j , Jarrett, M.^d , Bredesen, D.E.^k

^a Bay Area WellnessCA, United States
^b Dr. Ann Hathaway, San Rafael, CA, United States
^c Northwest Memory Center, Ashland, OR, United States
^d Quesgen Systems, Burlingame, CA, United States
^e Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^f CNS Vital Signs, Morrisville, NC, United States
^g Department of Psychology, University of South Alabama, Mobile, AL, United States
^h Austin, TX, United States
ⁱ Posit Science, San Francisco, CA, United States
^j Department of Radiology, St. Louis University, St. Louis, MO, United States
^k Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, Los Angeles, CA, United States

Abstract
BACKGROUND: Effective therapeutics for Alzheimer’s disease are needed. However, previous clinical trials have pre-determined a single treatment modality, such as a drug candidate or therapeutic procedure, which may be unrelated to the primary drivers of the neurodegenerative process. Therefore, increasing data set size to include the potential contributors to cognitive decline for each patient, and addressing the identified potential contributors, may represent a more effective strategy. OBJECTIVE: To determine whether a precision medicine approach to Alzheimer’s disease and mild cognitive impairment is effective enough in a proof-of-concept trial to warrant a larger, randomized, controlled clinical trial. METHODS: Twenty-five patients with dementia or mild cognitive impairment, with Montreal Cognitive Assessment (MoCA) scores of 19 or higher, were evaluated for markers of inflammation, chronic infection, dysbiosis, insulin resistance, protein glycation, vascular disease, nocturnal hypoxemia, hormone insufficiency or dysregulation, nutrient deficiency, toxin or toxicant exposure, and other biochemical parameters associated with cognitive decline. Brain magnetic resonance imaging with volumetrics was performed at baseline and study conclusion. Patients were treated for nine months with a personalized, precision medicine protocol, and cognition was assessed at t = 0, 3, 6, and 9 months. RESULTS: All outcome measures revealed improvement: statistically significant improvement in MoCA scores, CNS Vital Signs Neurocognitive Index, and Alzheimer’s Questionnaire Change score were documented. No serious adverse events were recorded. MRI volumetrics also improved. CONCLUSION: Based on the cognitive improvements observed in this study, a larger, randomized, controlled trial of the precision medicine therapeutic approach described herein is warranted.

Author Keywords
Clinical trial;  mild cognitive impairment;  MRI volumetrics;  neurodegeneration;  systems medicine

Document Type: Article
Publication Stage: Final
Source: Scopus

Dorsal bed nucleus of stria terminalis in depressed and nondepressed temporal lobe epilepsy patients
(2022) Epilepsia, . 

Dhaher, R.^a , Bronen, R.A.^a b , Spencer, L.^c , Colic, L.^c d e f , Brown, F.^g , Mian, A.^h , Sandhu, M.ⁱ , Pittman, B.^c , Spencer, D.^a , Blumberg, H.P.^b c j , Altalib, H.^g

^a Department of Neurosurgery, Yale School of Medicine, New Haven, CT, United States
^b Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, CT, United States
^c Department of Psychiatry, Yale School of Medicine, New Haven, CT, United States
^d Department of Psychiatry and Psychotherapy, University Hospital Jena, Jena, Germany
^e Center for Intervention and Research on Adaptive and Maladaptive Brain Circuits Underlying Mental Health, Jena, Germany
^f Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany
^g Department of Neurology, Yale School of Medicine, New Haven, CT, United States
^h Department of Radiology, Washington University School of Medicine, St Louis, MO, United States
ⁱ Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT, United States
^j Child Study Center, Yale School of Medicine, New Haven, CT, United States

Abstract
Objective: Temporal lobe epilepsy (TLE) and depression are common comorbid disorders whose underlying shared neural network has yet to be determined. Although animal studies demonstrate a role for the dorsal bed nucleus of the stria terminalis (dBNST) in both seizures and depression, and human clinical studies demonstrate a therapeutic effect of stimulating this region on treatment-resistant depression, the role of the dBNST in depressed and nondepressed TLE patients is still unclear. Here, we tested the hypothesis that this structure is morphologically abnormal in these epilepsy patients, with an increased abnormality in TLE patients with comorbid depression. Methods: In this case-controlled study, 3-T structural magnetic resonance imaging scans were obtained from TLE patients with no depression (TLEonly), TLE patients with depression (TLEdep), and healthy control (HC) subjects. TLE subjects were recruited from the Yale University Comprehensive Epilepsy Center, diagnosed with the International League Against Epilepsy 2014 Diagnostic Guidelines, and confirmed by video-electroencephalography. Diagnosis of major depressive disorder was confirmed by a trained neuropsychologist through a Mini International Neuropsychiatric Interview based on the Diagnostic and Statistical Manual of Mental Disorders, 4th edition. The dBNST was delineated manually by reliable raters using Bioimage Suite software. Results: The number of patients and subjects included 35 TLEonly patients, 20 TLEdep patients, and 102 HC subjects. Both TLEonly and TLEdep patients had higher dBNST volumes compared to HC subjects, unilaterally in the left hemisphere in the TLEonly patients (p =.003) and bilaterally in the TLEdep patients (p <.0001). Furthermore, the TLEdep patients had a higher dBNST volume than the TLEonly patients in the right hemisphere (p =.02). Significance: Here, we demonstrate an abnormality of the dBNST in TLE patients, both without depression (left enlargement) and with depression (bilateral enlargement). Our results demonstrate this region to underlie TLE both with and without depression, implicating it as a target in treating the comorbidity between these two disorders. © 2022 International League Against Epilepsy.

Author Keywords
magnetic resonance imaging;  major depressive disorder;  neuromodulation;  volumetric analysis

Funding details
National Institute of Mental HealthNIMHR01MH070902
National Center for Advancing Translational SciencesNCATSUL1TR000142

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, . 

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 (&gt; 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

A metabolomic signature of the APOE2 allele
(2022) GeroScience, . 

Sebastiani, P.^a , Song, Z.^b , Ellis, D.^c , Tian, Q.^d , Schwaiger-Haber, M.^e , Stancliffe, E.^e , Lustgarten, M.S.^f , Funk, C.C.^c , Baloni, P.^c , Yao, C.-H.^g , Joshi, S.^g , Marron, M.M.^h , Gurinovich, A.^a , Li, M.ⁱ , Leshchyk, A.ⁱ , Xiang, Q.^b , Andersen, S.L.^j , Feitosa, M.F.^k , Ukraintseva, S.^q , Soerensen, M.^l , Fiehn, O.^m , Ordovas, J.M.ⁿ , Haigis, M.^g , Monti, S.^i o , Barzilai, N.^p , Milman, S.^p , Ferrucci, L.^d , Rappaport, N.^c , Patti, G.J.^e , Perls, T.T.^j

^a Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, 800 Washington Street, Boston, MA 02111, United States
^b Department of Biostatistics, Boston University, Boston, MA, United States
^c Institute for Systems Biology, Seattle, WA, United States
^d Longitudinal Studies Section, Translational Gerontology Branch, National Institute On Aging, Baltimore, MD, United States
^e Department of Chemistry, Department of Medicine, Center for Metabolomics and Isotope Tracing, Washington University in St. Louis, St. Louis, United States
^f Nutrition, Exercise Physiology, and Sarcopenia Laboratory, Jean Mayer USDA Human Nutrition Research Center On Aging at Tufts University, Boston, MA, United States
^g Department of Cell Biology at Harvard Medical School, Boston, MA, United States
^h Department of Epidemiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States
ⁱ Bioinformatics Program, Boston University, Boston, MA, United States
^j Department of Medicine, Boston University School of Medicine, Boston, MA, United States
^k Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St Louis, MI, United States
^l Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark, Odense, Denmark
^m West Coast Metabolomics Center, University of California, Davis, CA, United States
ⁿ Nutrition and Genomics Team, Jean Mayer USDA Human Nutrition Research Center On Aging and Gerald J. and Dorothy R. Friedman School of Nutrition Science and Policy, Tufts University, MB, Boston, United States
^o Section of Computational Biomedicine, Boston University School of Medicine, Boston, MA, United States
^p Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY, United States
^q Biodemography of Aging Research Unit, Social Science Research, Duke University, Durham, NC, United States

Abstract
With the goal of identifying metabolites that significantly correlate with the protective e2 allele of the apolipoprotein E (APOE) gene, we established a consortium of five studies of healthy aging and extreme human longevity with 3545 participants. This consortium includes the New England Centenarian Study, the Baltimore Longitudinal Study of Aging, the Arivale study, the Longevity Genes Project/LonGenity studies, and the Long Life Family Study. We analyzed the association between APOE genotype groups E2 (e2e2 and e2e3 genotypes, N = 544), E3 (e3e3 genotypes, N = 2299), and E4 (e3e4 and e4e4 genotypes, N = 702) with metabolite profiles in the five studies and used fixed effect meta-analysis to aggregate the results. Our meta-analysis identified a signature of 19 metabolites that are significantly associated with the E2 genotype group at FDR < 10%. The group includes 10 glycerolipids and 4 glycerophospholipids that were all higher in E2 carriers compared to E3, with fold change ranging from 1.08 to 1.25. The organic acid 6-hydroxyindole sulfate, previously linked to changes in gut microbiome that were reflective of healthy aging and longevity, was also higher in E2 carriers compared to E3 carriers. Three sterol lipids and one sphingolipid species were significantly lower in carriers of the E2 genotype group. For some of these metabolites, the effect of the E2 genotype opposed the age effect. No metabolites reached a statistically significant association with the E4 group. This work confirms and expands previous results connecting the APOE gene to lipid regulation and suggests new links between the e2 allele, lipid metabolism, aging, and the gut-brain axis. © 2022, The Author(s), under exclusive licence to American Aging Association.

Author Keywords
Apolipoprotein E;  Lipid metabolism;  Longevity;  Metabolomics

Funding details
National Institute on AgingNIA
U.S. Department of AgricultureUSDA58-8050-9-004

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, . 

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