WashU weekly Neuroscience publications

Depression and Buprenorphine Treatment in Patients with Non-cancer Pain and Prescription Opioid Dependence without Comorbid Substance Use Disorders
(2021) Journal of Affective Disorders, 278, pp. 563-569.

Scherrer, J.F.^a , Salas, J.^a , Grucza, R.^a , Sullivan, M.D.^b , Lustman, P.J.^c d , Copeland, L.A.^e f , Ballantyne, J.C.^g

^a Department of Family and Community Medicine, Saint Louis University School of Medicine, 1402 South Grand Blvd, St. Louis, MO 63104, United States
^b Department of Psychiatry and Behavioral Science, University of Washington School of Medicine, Seattle, WA 98195, United States
^c Department of Psychiatry, Washington University School of Medicine, St. Louis, 63110
^d The Bell Street Clinic Opioid Addiction Treatment Programs, VA St. Louis Healthcare System, St. Louis, MO 63106, United States
^e VA Central Western Massachusetts Healthcare System, Leeds, MA 01053, United States
^f Department of Quantitative Health Sciences, Univ. of Mass. Medical School, Worcester, MA 01605, United States
^g Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA 98195, United States

Abstract
Background: Depression occurs in 40% of patients with prescription opioid dependence (POD). Existing studies of the association between depression and buprenorphine (BUP) treatment for POD are inconsistent and often include patients with comorbid substance use disorders (SUD). We estimated the association between depression and BUP use in patients with pain and POD and free of comorbid SUD. Methods: Optum® de-identified Electronic Health Record dataset from 2010 to 2018 was used to identify 5,529 patients with chronic pain, with and without depression, receiving prescription opioids and free of substance use disorder diagnoses for one year before POD diagnoses. Unadjusted and adjusted Cox proportional hazard models and negative binomial regression models were computed to estimate the association between depression and time to BUP start, number of BUP prescriptions in the year after BUP start and time to >30 day BUP gap. Results: Patients’ mean age was 52.4 (SD±15.3) years, 62% were female and 84% were white and 4.9% (n=270) started BUP. Depression was not associated with BUP initiation. Among BUP starters, depression vs. no depression, was significantly associated with receiving 29% fewer BUP prescriptions (RR=0.71; 95%CI: 0.51-0.98) and an increased risk for > 30 day gap (HR=1.76; 95%CI:1.01-3.09). Limitations: Missing data prevented measuring BUP dose. Conclusions: Depression is likely associated with earlier BUP treatment dropout. Depression related medication non-adherence or possible worsening of depression following BUP taper could explain results. Research is needed to determine if depression severity is associated with BUP dose trajectories and multi-year BUP retention. © 2020

Author Keywords
Buprenorphine;  Dependence;  Depression;  Epidemiology;  Iatrogenic;  Prescription opioid

Document Type: Article
Publication Stage: Final
Source: Scopus

Spatiotemporal relationship between subthreshold amyloid accumulation and aerobic glycolysis in the human brain
(2020) Neurobiology of Aging, 96, pp. 165-175.

Goyal, M.S.^a b c d , Gordon, B.A.^a b d , Couture, L.E.^a b , Flores, S.^a b , Xiong, C.^d , Morris, J.C.^c d d , Raichle, M.E.^a b c d , L-S. Benzinger, T.^a b d , Vlassenko, A.G.^a b d

^a Neuroimaging Laboratories, Washington University School of Medicine, St. Louis, MO, United States
^b Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^d Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States

Abstract
In Alzheimer’s disease, brain amyloid deposition has a distinct topography that correlates with aerobic glycolysis (AG), that is, the use of glucose beyond that predicted by oxygen consumption. The causes for this relationship remain unclear but might provide crucialinsight into how amyloid deposition begins. Here we develop methods to study the earliest topography of amyloid deposition based on amyloid imaging and investigate its spatiotemporal evolution with respect to the topography of AG in adults. We find that the spatiotemporal dynamics of amyloid deposition are largely explained by 1 factor, defined here as the amyloid topography dissimilarity index (ATDI). ATDI is bimodal, more highly dynamic during early amyloid accumulation, and predicts which individuals will cross a conservative quantitative threshold at least 3–5 years in advance. Using ATDI, we demonstrate that subthreshold amyloid accumulates primarily in regions that have high AG during early adulthood. Our findings suggest that early on-target subthreshold amyloid deposition mirrors its later regional pattern, which best corresponds to the topography of young adult brain AG. © 2020 Elsevier Inc.

Author Keywords
Aerobic glycolysis;  Alzheimer’s disease;  Brain amyloid;  Positron emission tomography

Document Type: Article
Publication Stage: Final
Source: Scopus

Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders
(2020) Nature Communications, 11 (1), art. no. 4932, .

Wang, T.^a , Hoekzema, K.^a , Vecchio, D.^b c , Wu, H.^d , Sulovari, A.^a , Coe, B.P.^a , Gillentine, M.A.^a , Wilfert, A.B.^a , Perez-Jurado, L.A.^e f g , Kvarnung, M.^h i , Sleyp, Y.^j , Earl, R.K.^k , Rosenfeld, J.A.^l m , Geisheker, M.R.^a , Han, L.^d , Du, B.^d , Barnett, C.^e n , Thompson, E.^e , Shaw, M.ⁿ , Carroll, R.ⁿ , Friend, K.^o , Catford, R.^o , Palmer, E.E.^p q , Zou, X.^r , Ou, J.^s , Li, H.^t , Guo, H.^d , Gerdts, J.^k , Avola, E.^u , Calabrese, G.^u , Elia, M.^u , Greco, D.^u , Lindstrand, A.^h i , Nordgren, A.^h i , Anderlid, B.-M.^h i , Vandeweyer, G.^v , Van Dijck, A.^v , Van der Aa, N.^v , McKenna, B.^w , Hancarova, M.^x , Bendova, S.^x , Havlovicova, M.^x , Malerba, G.^y , Bernardina, B.D.^z , Muglia, P.^aa , van Haeringen, A.^ab , Hoffer, M.J.V.^ab , Franke, B.^ac ad , Cappuccio, G.^ae af , Delatycki, M.^ag , Lockhart, P.J.^ag ah , Manning, M.A.^ai aj , Liu, P.^l m , Scheffer, I.E.^{ag ak al am} , Brunetti-Pierri, N.^ae af , Rommelse, N.^ad an , Amaral, D.G.^ao , Santen, G.W.E.^ab , Trabetti, E.^y , Sedláček, Z.^x , Michaelson, J.J.^ap , Pierce, K.^aq , Courchesne, E.^aq , Kooy, R.F.^v , Acampado, J.^cc , Ace, A.J.^cc , Amatya, A.^cc , Astrovskaya, I.^cc , Bashar, A.^cc , Brooks, E.^cc , Butler, M.E.^cc , Cartner, L.A.^cc , Chin, W.^cc , Chung, W.K.^at cc cc , Daniels, A.M.^cc , Feliciano, P.^cc , Fleisch, C.^cc , Ganesan, S.^cc , Jensen, W.^cc , Lash, A.E.^cc , Marini, R.^cc , Myers, V.J.^cc , O’Connor, E.^cc , Rigby, C.^cc , Robertson, B.E.^cc , Shah, N.^cc , Shah, S.^cc , Singer, E.^cc , Snyder, L.A.G.^cc , Stephens, A.N.^cc , Tjernagel, J.^cc , Vernoia, B.M.^cc , Volfovsky, N.^cc , White, L.C.^cc , Hsieh, A.^at , Shen, Y.^at , Zhou, X.^at , Turner, T.N.^au , Bahl, E.^av , Thomas, T.R.^av , Brueggeman, L.^av , Koomar, T.^av , Michaelson, J.J.^av , O’Roak, B.J.^aw , Barnard, R.A.^aw , Gibbs, R.A.^ax , Muzny, D.^ax , Sabo, A.^ax , Ahmed, K.L.B.^ax , Eichler, E.E.^ay , Siegel, M.^az , Abbeduto, L.^ba , Amaral, D.G.^ba , Hilscher, B.A.^ba , Li, D.^ba , Smith, K.^ba , Thompson, S.^ba , Albright, C.^bb , Butter, E.M.^bb , Eldred, S.^bb , Hanna, N.^bb , Jones, M.^bb , Coury, D.L.^bb , Scherr, J.^bb , Pifher, T.^bb , Roby, E.^bb , Dennis, B.^bb , Higgins, L.^bb , Brown, M.^bb , Alessandri, M.^bc , Gutierrez, A.^bc , Hale, M.N.^bc , Herbert, L.M.^bc , Schneider, H.L.^bc , David, G.^bc , Annett, R.D.^bd , Sarver, D.E.^bd , Arriaga, I.^be , Camba, A.^be , Gulsrud, A.C.^be , Haley, M.^be , McCracken, J.T.^be , Sandhu, S.^be , Tafolla, M.^be , Yang, W.S.^be , Carpenter, L.A.^bf , Bradley, C.C.^bf , Gwynette, F.^bf , Manning, P.^bg , Shaffer, R.^bg , Thomas, C.^bg , Bernier, R.A.^bh , Fox, E.A.^bh , Gerdts, J.A.^bh , Pepper, M.^bh , Ho, T.^bh , Cho, D.^bh , Piven, J.^bi , Lechniak, H.^bj , Soorya, L.V.^bj , Gordon, R.^bj , Wainer, A.^bj , Yeh, L.^bj , Ochoa-Lubinoff, C.^bk , Russo, N.^bk , Berry-Kravis, E.^bl , Booker, S.^bm , Erickson, C.A.^bm , Prock, L.M.^bn , Pawlowski, K.G.^bn , Matthews, E.T.^bn , Brewster, S.J.^bn , Hojlo, M.A.^bn , Abada, E.^bn , Lamarche, E.^bo , Wang, T.^bp , Murali, S.C.^bp , Harvey, W.T.^bp , Kaplan, H.E.^bq , Pierce, K.L.^bq , DeMarco, L.^br , Horner, S.^br , Pandey, J.^br , Plate, S.^br , Sahin, M.^bs , Riley, K.D.^bs , Carmody, E.^bs , Constantini, J.^ay , Esler, A.^bt , Fatemi, A.^bu , Hutter, H.^bu , Landa, R.J.^bu , McKenzie, A.P.^bu , Neely, J.^bu , Singh, V.^bu , Van Metre, B.^bu , Wodka, E.L.^bu , Fombonne, E.J.^bv , Huang-Storms, L.Y.^bv , Pacheco, L.D.^bv , Mastel, S.A.^bv , Coppola, L.A.^bv , Francis, S.^bw , Jarrett, A.^bw , Jacob, S.^bw , Lillie, N.^bw , Gunderson, J.^bw , Istephanous, D.^bw , Simon, L.^bw , Wasserberg, O.^bw , Rachubinski, A.L.^bx , Rosenberg, C.R.^bx , Kanne, S.M.^by bz , Shocklee, A.D.^bz , Takahashi, N.^bz , Bridwell, S.L.^bz , Klimczac, R.L.^bz , Mahurin, M.A.^bz , Cotrell, H.E.^bz , Grant, C.A.^bz , Hunter, S.G.^bz , Martin, C.L.^ca , Taylor, C.M.^ca , Walsh, L.K.^ca , Dent, K.A.^ca , Mason, A.^cb , Sziklay, A.^cb , Smith, C.J.^cb , Nordenskjöld, M.^h i , Romano, C.^u , Peeters, H.^j , Bernier, R.A.^k , Gecz, J.^f n o , Xia, K.^d ar , Eichler, E.E.^a as , The SPARK Consortium^cc

^a Department of Genome Sciences, University of Washington, Seattle, WA, United States
^b Rare Disease and Medical Genetics, Academic Department of Pediatrics, Bambino Gesù Children’s Hospital, Rome, Italy
^c Genetics and Rare Diseases Research Division, Bambino Gesù Children’s Hospital, Rome, Italy
^d Center for Medical Genetics & Hunan Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
^e Paediatric and Reproductive Genetics unit, Women’s and Children’s Hospital, Adelaide, SA, Australia
^f South Australian Health and Medical Research Institute, Adelaide, SA, Australia
^g Genetics Unit, Universitat Pompeu Fabra, Hospital del Mar Research Institute (IMIM) and CIBERER, Barcelona, Spain
^h Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
ⁱ Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
^j Centre for Human Genetics, KU Leuven and Leuven Autism Research (LAuRes), Leuven, Belgium
^k Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, United States
^l Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX, United States
^m Baylor Genetics, Houston, TX, United States
ⁿ Adelaide Medical School and the Robinson Research Institute, the University of Adelaide, Adelaide, SA, Australia
^o Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia
^p Genetics of Learning Disability Service, Hunter New England Health Service, Waratah, NSW, Australia
^q School of Women’s and Children’s Health, University of New South Wales, Randwick, NSW, Australia
^r Children Development Behavior Center, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
^s Mental Health Institute of the Second Xiangya Hospital, Central South University, Changsha, China
^t Key Laboratory of Developmental Disorders in Children, Liuzhou Maternity and Child Healthcare Hospital, Liuzhou, China
^u Oasi Research Institute-IRCCS, Troina, Italy
^v Department of Medical Genetics, University of Antwerp, Antwerp, Belgium
^w Department of Psychology, Emory University, Atlanta, GA, United States
^x Department of Biology and Medical Genetics, Charles University 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic
^y Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy
^z Child Neuropsychiatry Unit, AOUI, Verona, Italy
^aa UCB Pharma, Bruxelles, Belgium
^ab Department of Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, Netherlands
^ac Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, Netherlands
^ad Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, Netherlands
^ae Department of Translational Medicine, Federico II University, Naples, Italy
^af Telethon Institute of Genetics and Medicine, Pozzuoli, Naples, Italy
^ag Murdoch Children’s Research Institute, Melbourne, Australia
^ah Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia
^ai Division of Medical Genetics, Department of Pediatrics, Stanford University, Stanford, CA, United States
^aj Department of Pathology, Stanford University, Stanford, CA, United States
^ak Department of Paediatrics, University of Melbourne, Royal Children’s Hospital, Melbourne, VIC, Australia
^al Department of Medicine, University of Melbourne, Austin Health, Melbourne, Australia
^am The Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia
^an Karakter Child and Adolescent Psychiatry Center, Nijmegen, Netherlands
^ao Department of Psychiatry and Behavioral Sciences and the MIND Institute, University of California, Davis, Sacramento, CA, United States
^ap Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, United States
^aq Department of Neurosciences, UC San Diego Autism Center, School of Medicine, University of California San Diego, La Jolla, CA, United States
^ar CAS Center for Excellence in Brain Science and Intelligences Technology (CEBSIT), Chinese Academy of Sciences, Shanghai, China
^as Howard Hughes Medical Institute, University of Washington, Seattle, WA, United States
^at Columbia University, New York, NY, United States
^au Washington University School of Medicine, St. Louis, MO, United States
^av University of Iowa Carver College of Medicine, Iowa City, IA, United States
^aw Oregon Health & Science University, Portland, OR, United States
^ax Baylor College of Medicine, Houston, TX, United States
^ay University of Washington School of Medicine & Howard Hughes Medical Institute, Seattle, WA, United States
^az Maine Medical Center Research Institute, Portland, OR, United States
^ba University of California, Davis, Sacramento, CA, United States
^bb Nationwide Children’s Hospital, Columbus, OH, United States
^bc University of Miami, Coral Gables, FL, United States
^bd University of Mississippi Medical Center, Jackson, MS, United States
^be University of California, Los Angeles, Los Angeles, CA, United States
^bf Medical University of Southern Carolina (MUSC), Portland, OR, United States
^bg Cincinnati Children’s Hospital Medical Center-Research Foundation, Cincinnati, OH, United States
^bh Seattle Children’s Autism Center/UW, Seattle, WA, United States
^bi University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
^bj Department of Child & Adolescent Psychiatry, Rush University Medical Center, Chicago, IL, United States
^bk Department of Developmental & Behavioral Pediatrics, Rush University Medical Center, Chicago, IL, United States
^bl Department of Neurological Sciences, Department of Pediatrics, Department of Biochemistry, Rush University Medical Center, Chicago, IL, United States
^bm Cincinnati Children’s Hospital Medical Center – Research Foundation, Cincinnati, OH, United States
^bn Boston Children’s Hospital (BCH), Boston, MA, United States
^bo University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
^bp University of Washington School of Medicine, Seattle, WA, United States
^bq University of California, San Diego, School of Medicine, La Jolla, CA, United States
^br Children’s Hospital of Philadelphia, Philadelphia, PA, United States
^bs Boston Children’s Hospital (BCH), Boston, MA, United States
^bt University of Minnesota, Minneapolis, MN, United States
^bu Kennedy Krieger Institute, Baltimore, MD, United States
^bv Oregon Health & Science University, Portland, OR, United States
^bw University of Minnesota, Minneapolis, MN, United States
^bx University of Colorado School of Medicine, Aurora, CO, United States
^by Department of Health Psychology, University of Missouri, Columbia, SC, United States
^bz Thompson Center for Autism and Neurodevelopmental Disorders, University of Missouri, Columbia, SC, United States
^ca Geisinger Autism & Developmental Medicine Institute, Lewisburg, PA, United States
^cb Southwest Autism Research and Resource Center, Phoenix, AZ, United States
^cc Simons Foundation, New York, NY, United States

Abstract
Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case–control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF < 0.01%) gene-disruptive mutations (FDR 5%), six of which reach family-wise error rate (FWER) significance (p < 1.25E−06). Among these 125 targeted genes, we also reevaluate DNM excess in 17,426 NDD trios with 6,499 new autism trios. We identify 90 genes enriched for DNMs (FDR 5%; e.g., GABRG2 and UIMC1); of which, 61 reach FWER significance (p < 3.64E−07; e.g., CASZ1). In addition to doubling the number of patients for many NDD risk genes, we present phenotype–genotype correlations for seven risk genes (CTCF, HNRNPU, KCNQ3, ZBTB18, TCF12, SPEN, and LEO1) based on this large-scale targeted sequencing effort. © 2020, The Author(s).

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Precision multidimensional neural population code recovered from single intracellular recordings
(2020) Scientific Reports, 10 (1), art. no. 15997, .

Johnson, J.K.^a , Geng, S.^a , Hoffman, M.W.^a , Adesnik, H.^b , Wessel, R.^a

^a Washington University in St. Louis, St. Louis, United States
^b University of California, Berkeley, Berkeley, United States

Abstract
Neurons in sensory cortices are more naturally and deeply integrated than any current neural population recording tools (e.g. electrode arrays, fluorescence imaging). Two concepts facilitate efforts to observe population neural code with single-cell recordings. First, even the highest quality single-cell recording studies find a fraction of the stimulus information in high-dimensional population recordings. Finding any of this missing information provides proof of principle. Second, neurons and neural populations are understood as coupled nonlinear differential equations. Therefore, fitted ordinary differential equations provide a basis for single-trial single-cell stimulus decoding. We obtained intracellular recordings of fluctuating transmembrane current and potential in mouse visual cortex during stimulation with drifting gratings. We use mean deflection from baseline when comparing to prior single-cell studies because action potentials are too sparse and the deflection response to drifting grating stimuli (e.g. tuning curves) are well studied. Equation-based decoders allowed more precise single-trial stimulus discrimination than tuning-curve-base decoders. Performance varied across recorded signal types in a manner consistent with population recording studies and both classification bases evinced distinct stimulus-evoked phases of population dynamics, providing further corroboration. Naturally and deeply integrated observations of population dynamics would be invaluable. We offer proof of principle and a versatile framework. © 2020, The Author(s).

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Satellite glial cells promote regenerative growth in sensory neurons
(2020) Nature Communications, 11 (1), art. no. 4891, .

Avraham, O.^a , Deng, P.-Y.^b , Jones, S.^a , Kuruvilla, R.^c , Semenkovich, C.F.^b d , Klyachko, V.A.^b , Cavalli, V.^a e f

^a Department of Neuroscience, Washington University School of Medicine, St Louis, MO 63110, United States
^b Department of Cell Biology and Physiology, Washington University School of Medicine, St Louis, MO 63110, United States
^c Department of Biology, Johns Hopkins University, Baltimore, MD 21218, United States
^d Division of Endocrinology, Metabolism & Lipid Research, Washington University School of Medicine, St Louis, MO 63110, United States
^e Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
^f Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Peripheral sensory neurons regenerate their axon after nerve injury to enable functional recovery. Intrinsic mechanisms operating in sensory neurons are known to regulate nerve repair, but whether satellite glial cells (SGC), which completely envelop the neuronal soma, contribute to nerve regeneration remains unexplored. Using a single cell RNAseq approach, we reveal that SGC are distinct from Schwann cells and share similarities with astrocytes. Nerve injury elicits changes in the expression of genes related to fatty acid synthesis and peroxisome proliferator-activated receptor (PPARα) signaling. Conditional deletion of fatty acid synthase (Fasn) in SGC impairs axon regeneration. The PPARα agonist fenofibrate rescues the impaired axon regeneration in mice lacking Fasn in SGC. These results indicate that PPARα activity downstream of FASN in SGC contributes to promote axon regeneration in adult peripheral nerves and highlight that the sensory neuron and its surrounding glial coat form a functional unit that orchestrates nerve repair. © 2020, The Author(s).

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Synthesis and in vitro evaluation of new TRPV4 ligands and biodistribution study of an 11C-labeled radiotracer in rodents
(2020) Bioorganic and Medicinal Chemistry Letters, 30 (22), art. no. 127573, .

Qiu, L.^a , Du, L.^b , Liang, Q.^a , Hu, H.^b , Tu, Z.^a

^a Department of Radiology, Washington University School of Medicine, 510 South Kingshighway Boulevard, St. Louis, MO 63110, United States
^b Department of Anesthesiology, Center for the Study of Itch and Sensory Disorders, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Nine new compounds targeting the transient receptor potential vanilloid-4 (TRPV4) were synthesized and their biological activities toward TRPV4 were determined using freshly isolated mouse skin macrophages through live cell Ca2+ imaging assay. Three compounds 4b, 4c, and 4i exhibited higher percentages of in vitro activation of TRPV4 as 48.1%, 59.3% and 33.5%, which are comparable to 56.4% activation response of the reported TRPV4 agonist GSK1016790A (3). The compound 4i was chosen for 11C-radiosynthesis using its phenol precursor 4g to reacted with [11C]methyl iodide. The radiosynthesis was achieved with good radiochemical yield (16 ± 5%), high chemical and radiochemical purity (&gt;95%), and high molar activity (16–21 GBq/μmol, decay corrected to the end of bombardment, EOB n ≥ 4). Furthermore, the initial ex vivo biodistribution study in rats showed that [11C]4i had higher uptake in kidney, liver and small intestine compared to other tissues with rapid washout. © 2020 Elsevier Ltd

Author Keywords
Analogues;  Biodistribution;  PET;  Radiosynthesis;  TRPV4

Document Type: Article
Publication Stage: Final
Source: Scopus

Brain responses to social feedback in internalizing disorders: A comprehensive review
(2020) Neuroscience and Biobehavioral Reviews, 118, pp. 784-808.

Rappaport, B.I.^a , Barch, D.M.^a b c

^a Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Radiology, Washington University School of Medicine in St Louis, St. Louis, MO, United States

Abstract
Problems with interpersonal relationships are often a chief complaint among those seeking psychiatric treatment; yet heterogeneity and homogeneity across disorders suggests both common and unique mechanisms of impaired interpersonal relationships. Basic science research has begun yielding insights into how the brain responds to social feedback. Understanding how these processes differ as a function of psychopathology can begin to inform the mechanisms that give rise to such interpersonal dysfunction, potentially helping to identify differential treatment targets. We reviewed 46 studies that measured the relationship between brain responses to social feedback and internalizing psychopathology. We found that socially relevant anxiety was associated with amygdala hyperactivity to the anticipation of social feedback. Depression was related to hyperreactivity of regions in the cingulo-opercular network to negative social feedback. Borderline personality disorder (BPD) was associated with hyperactivity of regions in the default mode network to negative social feedback. The review also identified key insights into methodological limitations and potential future directions for the field. © 2020 Elsevier Ltd

Author Keywords
fMRI;  internalizing;  neuroimaging;  psychopathology;  social feedback

Document Type: Review
Publication Stage: Final
Source: Scopus

Corrigendum to “Age disparities in six-month treatment retention for opioid use disorder” [Drug Alcohol Depend. 213 (2020) 108130] (Drug and Alcohol Dependence (2020) 213, (S0376871620302957), (10.1016/j.drugalcdep.2020.108130))
(2020) Drug and Alcohol Dependence, 216, art. no. 108312, .

Mintz, C.M.^a , Presnall, N.J.^a , Sahrmann, J.M.^b , Borodovsky, J.T.^a , Glaser, P.E.A.^a , Bierut, L.J.^a , Grucza, R.A.^a

^a Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
^b Department of Internal Medicine at Washington University School of Medicine, St Louis, MO, United States

Abstract
The authors regret that in the published article they incorrectly referenced their data source, and neglected to acknowledge a funding source for this work. The corrected sections can be found below: In the Methods section, it currently reads: Data source Data were from the MarketScan Commercial Claims and Encounters and Medicaid databases (Truven Health Analytics, Ann Arbor, Michigan). This should read: Data source The data source used for analyses was IBM® MarketScan® Commercial and Multi-State Medicaid Databases. This change does not material impact the findings. In addition, the Acknowledgements section should have read: Acknowledgements This work was supported by grants from the National Institutes of Health: T32DA007261-17 (Dr. Mintz), U10AA008401 (Dr. Bierut) R01DA036583 (Dr. Bierut), F32AA027941 (Dr. Borodovsky), R21AA02568901, R21 DA044744 (Dr. Grucza). In addition, the authors wish to acknowledge the Center for Administrative Data Research at Washington University for assistance with data acquisition and storage. The Center for Administrative Data Research is supported in part by the Washington University Institute of Clinical and Translational Sciences grant UL1 TR002345 from the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH) and Grant Number R24 HS19455 through the Agency for Healthcare Research and Quality (AHRQ). The authors would like to apologise for any inconvenience caused. © 2020 Elsevier B.V.

Document Type: Erratum
Publication Stage: Final
Source: Scopus

Pharmacokinetic Modeling of the Impact of P-glycoprotein on Ondansetron Disposition in the Central Nervous System
(2020) Pharmaceutical Research, 37 (10), art. no. 205, .

Chiang, M.^a b , Back, H.-M.^a b , Lee, J.B.^a , Oh, S.^a , Guo, T.^a , Girgis, S.^a , Park, C.^a , Haroutounian, S.^c , Kagan, L.^a b

^a Department of Pharmaceutics, Ernest Mario, School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, United States
^b Center of Excellence for Pharmaceutical Translational Research and Education, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, United States
^c Division of Clinical and Translational Research and Washington University Pain Center, Department of Anesthesiology, Washington University School of Medicine, St Louis, MO, United States

Abstract
Purpose: Modulation of 5-HT3 receptor in the central nervous system (CNS) is a promising approach for treatment of neuropathic pain. The goal was to evaluate the role of P-glycoprotein (Pgp) in limiting exposure of different parts of the CNS to ondansetron (5-HT3 receptor antagonist) using wild-type and genetic knockout rat model. Methods: Plasma pharmacokinetics and CNS (brain, spinal cord, and cerebrospinal fluid) disposition was studied after single 10 mg/kg intravenous dose. Results: Pgp knockout resulted in significantly higher concentrations of ondansetron in all tested regions of the CNS at most of the time points. The mean ratio of the concentrations between KO and WT animals was 2.39–5.48, depending on the region of the CNS. Male and female animals demonstrated some difference in ondansetron plasma pharmacokinetics and CNS disposition. Mechanistic pharmacokinetic model that included two systemic disposition and three CNS compartments (with intercompartmental exchange) was developed. Pgp transport was incorporated as an efflux from the brain and spinal cord to the central compartment. The model provided good simultaneous description of all data sets, and all parameters were estimated with sufficient precision. Conclusions: The study provides important quantitative information on the role of Pgp in limiting ondansetron exposure in various regions of the CNS using data from wild-type and Pgp knockout rats. CSF drug concentrations, as a surrogate to CNS exposure, are likely to underestimate the effect of Pgp on drug penetration to the brain and the spinal cord. © 2020, Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
5-HT3 receptor antagonist;  brain;  MDR1 knockout;  mechanistic modeling;  spinal cord

Document Type: Article
Publication Stage: Final
Source: Scopus

Five years of ocrelizumab in relapsing multiple sclerosis: OPERA studies open-label extension
(2020) Neurology, 95 (13), pp. e1854-e1867.

Hauser, S.L., Kappos, L., Arnold, D.L., Bar-Or, A., Brochet, B., Naismith, R.T., Traboulsee, A., Wolinsky, J.S., Belachew, S., Koendgen, H., Levesque, V., Manfrini, M., Model, F., Hubeaux, S., Mehta, L., Montalban, X.

From the Department of Neurology (S.L.H.), University of California, San Francisco; Neurologic Clinic and Policlinic (L.K.), Departments of Medicine, Clinical Research, Biomedicine and Biomedical Engineering, University Hospital Basel, University of Basel, Switzerland; NeuroRx Research (D.L.A.); Departments of Neurology and Neurosurgery (D.L.A.), McGill University, Montreal, Canada; Department of Neurology and Center for Neuroinflammation and Experimental Therapeutics (A.B.-O.), University of Pennsylvania, Philadelphia; Department of Neurology (B.B.), CHU de Bordeaux, France; Department of Neurology (R.T.N.), Washington University School of Medicine, St. Louis, MO; Division of Neurology (A.T.), Department of Medicine, University of British Columbia, Vancouver, Canada; Department of Neurology (J.S.W.), McGovern Medical School, University of Texas Health Science Center at Houston (UTHealth); F. Hoffmann-La Roche Ltd (S.B., H.K., M.M., F.M., S.H.), Basel, Switzerland; Genentech, Inc. (V.L., L.M.), South San Francisco, CA; Division of Neurology (X.M.), University of Toronto, Canada; and Department of Neurology-Neuroimmunology (X.M.), Vall d’Hebron University Hospital, Barcelona, Spain. During completion of the work related to this article, S.B. and L.M. were employees of F. Hoffmann-La Roche Ltd; current affiliations are Biogen (S.B.), Cambridge, MA; and Alder Biopharmaceuticals Inc. (L.M.), Bothell, WA

Abstract
OBJECTIVE: To assess over 3 years of follow-up the effects of maintaining or switching to ocrelizumab (OCR) therapy on clinical and MRI outcomes and safety measures in the open-label extension (OLE) phase of the pooled OPERA: I/II studies in relapsing multiple sclerosis. METHODS: After 2 years of double-blind, controlled treatment, patients continued OCR (600 mg infusions every 24 weeks) or switched from interferon (IFN)-β-1a (44 μg 3 times weekly) to OCR when entering the OLE phase (3 years). Adjusted annualized relapse rate, time to onset of 24-week confirmed disability progression (CDP)/improvement (CDP), brain MRI activity (gadolinium-enhanced and new/enlarging T2 lesions), and percentage brain volume change were analyzed. RESULTS: Of patients entering the OLE phase, 88.6% completed year 5. The cumulative proportion with 24-week CDP was lower in patients who initiated OCR earlier vs patients initially receiving IFN-β-1a (16.1% vs 21.3% at year 5; p = 0.014). Patients continuing OCR maintained and those switching from IFN-β-1a to OCR attained near complete and sustained suppression of new brain MRI lesion activity from years 3-5. Over the OLE phase, patients continuing OCR exhibited less whole brain volume loss from double-blind study baseline vs those switching from IFN-β-1a (-1.87% vs -2.15% at year 5; p < 0.01). Adverse events were consistent with past reports and no new safety signals emerged with prolonged treatment. CONCLUSION: Compared with patients switching from IFN-β-1a, earlier and continuous OCR treatment up to 5 years provided sustained benefit on clinical and MRI measures of disease progression. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that earlier and continuous treatment with OCR provided sustained benefit on clinical and MRI outcomes of disease activity and progression compared with patients switching from IFN-β-1a. The study is rated Class III because of the initial treatment randomization disclosure that occurred after inclusion in OLE. CLINICAL TRIAL IDENTIFIERS: NCT01247324/NCT01412333. Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Editorial: Performance and Participation Outcomes for Individuals With Neurological Conditions
(2020) Frontiers in Neurology, 11, art. no. 878, .

Josman, N.^a , Connor, L.T.^b , Lin, D.J.^c d

^a Department of Occupational Therapy, Faculty of Social Welfare Health Science, University of Haifa, Haifa, Israel
^b Program in Occupational Therapy, Departments of Neurology Social Work, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Neurology, Center for Neurotechnology and Neurorecovery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
^d Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Massachusetts General Hospital, Boston, MA, United States

Author Keywords
central nervous system deficits;  cognition;  neuroplasticity;  neurorecovery;  neurorehabiliation;  stroke recovery

Document Type: Editorial
Publication Stage: Final
Source: Scopus
Access Type: Open Access

BRAF Alteration in Central and Peripheral Nervous System Tumors
(2020) Frontiers in Oncology, 10, art. no. 574974, .

Srinivasa, K.^a , Cross, K.A.^b , Dahiya, S.^a

^a Department of Pathology Immunology, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States

Abstract
BRAF (alternately referred to as v-raf murine sarcoma viral oncogene homolog B1) is a proto-oncogene involved in the mitogen-activated protein kinase (MAPK) pathway. BRAF alterations are most commonly missense mutations or aberrant fusions. These mutations are observed in numerous primary central nervous system tumors as well as metastases. This review discusses the prevalence of BRAF alteration within select notable CNS tumors, and their prognostic associations. Included are some novel entities such as diffuse leptomeningeal glioneuronal tumor (DLGNT), polymorphous low grade neuroepithelial tumor of the young (PLNTY), and multinodular and vacuolating neuronal tumor (MVNT). Knowledge of this gene’s integrity in CNS and PNS tumors can have profound diagnostic and therapeutic implications. Also reviewed are the current state of targeted therapy against aberrant BRAF as it pertains mostly to the CNS and to a lesser extent in PNS, and certain diagnostic aspects. © Copyright © 2020 Srinivasa, Cross and Dahiya.

Author Keywords
BRAF;  CNS;  diagnosis;  PNS;  prognosis;  targeted-therapy;  tumor

Document Type: Review
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Central Vestibular Tuning Arises from Patterned Convergence of Otolith Afferents
(2020) Neuron, .

Liu, Z.^a , Kimura, Y.^c , Higashijima, S.-I.^c , Hildebrand, D.G.C.^d , Morgan, J.L.^b , Bagnall, M.W.^a

^a Department of Neuroscience, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Ophthalmology, Washington University in St. Louis, St. Louis, MO, United States
^c Department of Neurobiology, National Institute for Basic Biology, Okazaki, Japan
^d Laboratory of Neural Systems, The Rockefeller University, New York, NY, United States

Abstract
Though computational models predict how sensory inputs converge in central neurons, it is technically challenging to test these ideas experimentally. With whole-cell recordings in larval zebrafish in vivo, Liu et al. demonstrate that the convergence of similarly or differently tuned vestibular afferents produces more simple or complex postsynaptic tuning, respectively. © 2020 Elsevier Inc.

As sensory information moves through the brain, higher-order areas exhibit more complex tuning than lower areas. Though models predict that complexity arises via convergent inputs from neurons with diverse response properties, in most vertebrate systems, convergence has only been inferred rather than tested directly. Here, we measure sensory computations in zebrafish vestibular neurons across multiple axes in vivo. We establish that whole-cell physiological recordings reveal tuning of individual vestibular afferent inputs and their postsynaptic targets. Strong, sparse synaptic inputs can be distinguished by their amplitudes, permitting analysis of afferent convergence in vivo. An independent approach, serial-section electron microscopy, supports the inferred connectivity. We find that afferents with similar or differing preferred directions converge on central vestibular neurons, conferring more simple or complex tuning, respectively. Together, these results provide a direct, quantifiable demonstration of feedforward input convergence in vivo. © 2020 Elsevier Inc.

Author Keywords
body balance;  electrical synapse;  feedforward excitation;  high-pass tuning;  neural computation;  sensorimotor transformation;  sensory encoding;  vestibulospinal neuron

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

Pulse oral corticosteroids in pediatric chronic inflammatory demyelinating polyneuropathy
(2020) Muscle and Nerve, .

Rogers, A.B.^a , Zaidman, C.M.^a , Connolly, A.M.^b

^a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Pediatrics, Neurology Division, Nationwide Children’s Hospital, Ohio State University, Columbus, OH, United States

Abstract
Childhood onset chronic inflammatory demyelinating polyneuropathy (CIDP) often requires long-term immunomodulatory therapy. We report a comprehensive review of our treatment of pediatric CIDP with a focus on high-dose weekly corticosteroids (“pulse oral corticosteroids”), a treatment method that is not commonly reported. We retrospectively reviewed medical records of pediatric patients with CIDP treated at our center between 2000 and 2018 for whom we had at least 12 mo follow-up. Here, we describe the demographics, disease course, treatment regimens, and long-term outcomes of these patients. Twenty-five patients were identified for analysis. Pulse oral corticosteroid monotherapy was the predominant maintenance treatment in 56% of patients. Patients were followed for a median of 4 y. Side effects were seen in a minority of patients. The probability of a normal exam or being off treatment at last follow-up was similar regardless of predominant maintenance therapy. Pulse oral corticosteroid therapy is a safe and effective long-term treatment option in children with CIDP. © 2020 Wiley Periodicals LLC

Author Keywords
CIDP;  corticosteroids;  immunomodulatory therapy;  inflammatory neuropathy;  pediatric CIDP

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

Identifying and validating subtypes within major psychiatric disorders based on frontal–posterior functional imbalance via deep learning
(2020) Molecular Psychiatry, .

Chang, M.^a , Womer, F.Y.^b , Gong, X.^c , Chen, X.^d , Tang, L.^e , Feng, R.^a , Dong, S.^d , Duan, J.^e , Chen, Y.^e , Zhang, R.^e , Wang, Y.^e , Ren, S.^a , Wang, Y.^c , Kang, J.^f , Yin, Z.^e , Wei, Y.^e , Wei, S.^a , Jiang, X.^a , Xu, K.^a , Cao, B.^g , Zhang, Y.^h , Zhang, W.^i j , Tang, Y.^e , Zhang, X.^d k l , Wang, F.^a e

^a Department of Radiology, The First Affiliated Hospital of China Medical University, Shenyang, China
^b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^c State Key Laboratory of Genetic Engineering and Human Phenome Institute, School of Life Sciences, Fudan University, Shanghai, China
^d School of Computer Science and Engineering, Northeastern University, Shenyang, Liaoning, China
^e Department of Psychiatry, The First Affiliated Hospital of China Medical University, Shenyang, China
^f Shanghai Center for Mathematical Science, Fudan University, Shanghai, China
^g Department of Psychiatry, University of Alberta, Edmonton, AB, Canada
^h Department of Psychiatry, College of Medicine University of Saskatchewan Ellis Hall, Royal University Hospital, Saskatoon, SK, Canada
ⁱ Department of Computer Science and Engineering, Washington University, St. Louis, MO, United States
^j Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
^k School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing, Jiangsu, China
^l Nanjing Brain Hospital, Nanjing Medical University, Nanjing, Jiangsu, China

Abstract
Converging evidence increasingly implicates shared etiologic and pathophysiological characteristics among major psychiatric disorders (MPDs), such as schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD). Examining the neurobiology of the psychotic-affective spectrum may greatly advance biological determination of psychiatric diagnosis, which is critical for the development of more effective treatments. In this study, ensemble clustering was developed to identify subtypes within a trans-diagnostic sample of MPDs. Whole brain amplitude of low-frequency fluctuations (ALFF) was used to extract the low-dimensional features for clustering in a total of 944 participants: 581 psychiatric patients (193 with SZ, 171 with BD, and 217 with MDD) and 363 healthy controls (HC). We identified two subtypes with differentiating patterns of functional imbalance between frontal and posterior brain regions, as compared to HC: (1) Archetypal MPDs (60% of MPDs) had increased frontal and decreased posterior ALFF, and decreased cortical thickness and white matter integrity in multiple brain regions that were associated with increased polygenic risk scores and enriched risk gene expression in brain tissues; (2) Atypical MPDs (40% of MPDs) had decreased frontal and increased posterior ALFF with no associated alterations in validity measures. Medicated Archetypal MPDs had lower symptom severity than their unmedicated counterparts; whereas medicated and unmedicated Atypical MPDs had no differences in symptom scores. Our findings suggest that frontal versus posterior functional imbalance as measured by ALFF is a novel putative trans-diagnostic biomarker differentiating subtypes of MPDs that could have implications for precision medicine. © 2020, The Author(s), under exclusive licence to Springer Nature Limited.

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

Neurocognitive and functional heterogeneity in depressed youth
(2020) Neuropsychopharmacology, .

Baller, E.B.^a , Kaczkurkin, A.N.^a b , Sotiras, A.^c d e , Adebimpe, A.^a , Bassett, D.S.^{a f g h i j k} , Calkins, M.E.^a l , Chand, G.^c e , Cui, Z.^a , Gur, R.E.^a c i l , Gur, R.C.^a c l , Linn, K.A.^m , Moore, T.^a l , Roalf, D.R.^a l , Varol, E.^c e , Wolf, D.H.^a e l , Xia, C.H.ⁿ , Davatzikos, C.^c e , Satterthwaite, T.D.^a e l

^a Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
^b Department of Psychology, Vanderbilt University, Nashville, TN 37235, United States
^c Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
^d Department of Radiology, Washington University, St. Louis, MO 63130, United States
^e Center for Biomedical Image Computing and Analytics, University of Pennsylvania, Philadelphia, PA 19104, United States
^f Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, United States
^g Penn Center for Neuroimaging and Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, United States
^h Department of Electrical and Systems Engineering, University of Pennsylvania, Philadelphia, PA 19104, United States
ⁱ Department of Neurology, University of Pennsylvania, Philadelphia, PA 19104, United States
^j Department of Physics and Astronomy, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, PA 19104, United States
^k Santa Fe Institute, Santa Fe, NM 87501, United States
^l Lifespan Brain Institute, Penn Medicine and Children’s Hospital of Philadelphia, Philadelphia, PA 19104, United States
^m Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, PA 19104, United States

Abstract
Depression is a common psychiatric illness that often begins in youth, and is sometimes associated with cognitive deficits. However, there is significant variability in cognitive dysfunction, likely reflecting biological heterogeneity. We sought to identify neurocognitive subtypes and their neurofunctional signatures in a large cross-sectional sample of depressed youth. Participants were drawn from the Philadelphia Neurodevelopmental Cohort, including 712 youth with a lifetime history of a major depressive episode and 712 typically developing (TD) youth matched on age and sex. A subset (MDD n = 368, TD n = 200) also completed neuroimaging. Cognition was assessed with the Penn Computerized Neurocognitive Battery. A recently developed semi-supervised machine learning algorithm was used to delineate neurocognitive subtypes. Subtypes were evaluated for differences in both clinical psychopathology and brain activation during an n-back working memory fMRI task. We identified three neurocognitive subtypes in the depressed group. Subtype 1 was high-performing (high accuracy, moderate speed), Subtype 2 was cognitively impaired (low accuracy, slow speed), and Subtype 3 was impulsive (low accuracy, fast speed). While subtypes did not differ in clinical psychopathology, they diverged in their activation profiles in regions critical for executive function, which mirrored differences in cognition. Taken together, these data suggest disparate mechanisms of cognitive vulnerability and resilience in depressed youth, which may inform the identification of biomarkers for prognosis and treatment response. © 2020, The Author(s), under exclusive licence to American College of Neuropsychopharmacology.

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

Speed considerations for large field two-photon microscopy in the brain
(2020) Optics InfoBase Conference Papers, Part F176-BRAIN-2020, .

Banks, H.B., Bumstead, J.R., Brier, L.M., Bice, A., Culver, J.P.

Radiology Department, Washington University, St. Louis, MO 63111, United States

Abstract
Imaging large fields-of-view at high framerates with two-photon microscopy can limit signal. By taking advantage of the inherent signal nonlinearities, we show that a 5 mm field-of-view can be imaged at 15 Hz. © OSA 2020 © 2020 The Author(s)

Document Type: Conference Paper
Publication Stage: Final
Source: Scopus

Fast, high-density functional speckle contrast optical tomography of the adult brain
(2020) Optics InfoBase Conference Papers, Part F176-BRAIN-2020, .

Dragojević, T.^a , Hollmann, J.L.^a , Vidal Rosas, E.E.^a , Pasquinelli, K.^b , Cusini, I.^b , Culver, J.P.^c d , Villa, F.^b , Durduran, T.^a e

^a ICFO – Institute of Photonic Sciences, Barcelona Institute of Science and Technology, Spain
^b Politecnico di Milano, Dipartmento di Elettronica, Informatione e Bioingegneria, Italy
^c Department of Radiology, Washington University School of Medicine, United States
^d Department of Physics, Washington University, United States
^e Institucio Catalana de Reserca I Estudis Avancats (ICREA), Spain

Abstract
Fast high-density functional speckle contrast optical tomography (HD-SCOT) was developed to resolve transcranial three-dimensional changes in cerebral blood flow (CBF). It is demonstrated in a sensorimotor task showing good data fidelity, quantitative measure of CBF and the lateralization of the response. © OSA 2020 © 2020 The Author(s)

Document Type: Conference Paper
Publication Stage: Final
Source: Scopus

Overcoming presynaptic effects of VAMP2 mutations with 4-aminopyridine treatment
(2020) Human Mutation, .

Simmons, R.L.^a , Li, H.^b , Alten, B.^c , Santos, M.S.^b , Jiang, R.^a , Paul, B.^a , Lalani, S.J.^a , Cortesi, A.^a , Parks, K.^a , Khandelwal, N.^d , Smith-Packard, B.^e , Phoong, M.A.^f , Chez, M.^g , Fisher, H.^h , Scheuerle, A.E.ⁱ , Shinawi, M.^j , Hussain, S.A.^k , Kavalali, E.T.^c , Sherr, E.H.^a , Voglmaier, S.M.^b

^a Department of Neurology, Weill Institute for Neurosciences and Institute of Human Genetics, School of Medicine, University of California, San Francisco, San Francisco, CA, United States
^b Department of Psychiatry, Weill Institute for Neurosciences and Kavli Institute for Fundamental Neuroscience, School of Medicine, University of California, San Francisco, San Francisco, CA, United States
^c Department of Pharmacology and Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, United States
^d Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX, United States
^e Department of Pediatrics, Penn State Health Pediatric Specialties, Hershey, PA, United States
^f Division of Neuroscience, Department of Pediatric Neuropsychology, Sutter Medical Foundation, Sacramento, CA, United States
^g Neuroscience Medical Group, Sutter Medical Foundation, Sacramento, CA, United States
^h Department of Genetics, Children’s Medical Center of Texas, Dallas, TX, United States
ⁱ Division of Genetics and Metabolism, Department of Pediatrics, UT Southwestern Medical Center, Dallas, TX, United States
^j Division of Genetics and Genomic Medicine, St. Louis Children’s Hospital, Washington University School of Medicine, St. Louis, MO, United States
^k Department of Pediatrics, UCLA Mattel Children’s Hospital and Geffen School of Medicine, Los Angeles, CA, United States

Abstract
Clinical and genetic features of five unrelated patients with de novo pathogenic variants in the synaptic vesicle-associated membrane protein 2 (VAMP2) reveal common features of global developmental delay, autistic tendencies, behavioral disturbances, and a higher propensity to develop epilepsy. For one patient, a cognitively impaired adolescent with a de novo stop-gain VAMP2 mutation, we tested a potential treatment strategy, enhancing neurotransmission by prolonging action potentials with the aminopyridine family of potassium channel blockers, 4-aminopyridine and 3,4-diaminopyridine, in vitro and in vivo. Synaptic vesicle recycling and neurotransmission were assayed in neurons expressing three VAMP2 variants by live-cell imaging and electrophysiology. In cellular models, two variants decrease both the rate of exocytosis and the number of synaptic vesicles released from the recycling pool, compared with wild-type. Aminopyridine treatment increases the rate and extent of exocytosis and total synaptic charge transfer and desynchronizes GABA release. The clinical response of the patient to 2 years of off-label aminopyridine treatment includes improved emotional and behavioral regulation by parental report, and objective improvement in standardized cognitive measures. Aminopyridine treatment may extend to patients with pathogenic variants in VAMP2 and other genes influencing presynaptic function or GABAergic tone, and tested in vitro before treatment. © 2020 Wiley Periodicals LLC

Author Keywords
aminopyridine;  neurodevelopmental disorder;  synaptic transmission;  synaptic vesicle;  VAMP2

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

Wide-field optical imaging along the neurovascular coupling pathway
(2020) Optics InfoBase Conference Papers, Part F176-BRAIN-2020, .

Wang, X.^a b , Bice, A.R.^a , Bauer, A.Q.^a

^a Department of Radiology, Washington University School of Medicine, Saint Louis, MO 63110, United States
^b Department of Biomedical Engineering, Washington University School of Medicine, Saint Louis, MO 63110, United States

Abstract
We developed a dual fluorophore imaging system for simultaneous, high-speed mapping of neural, metabolic, and hemodynamic activity. Proof-of-concept measurements of spontaneous and stimulus-evoked dynamics are presented in awake and anesthetized mice. © OSA 2020 © 2020 The Author(s)

Document Type: Conference Paper
Publication Stage: Final
Source: Scopus

Deactivation of prospective memory intentions: Examining the role of the stimulus–response link
(2020) Memory and Cognition

Streeper, E., Bugg, J.M.

Department of Psychological and Brain Sciences, Washington University in St. Louis, Campus Box 1125, St. Louis, MO 63130, United States

Abstract
Successful prospective remembering involves formation of a stimulus (e.g., bottle of medication and/or place where the bottle is kept)–response (e.g., taking a medication) link. We investigated the role of this link in the deactivation of no-longer-relevant prospective memory intentions, as evidenced by commission error risk. Experiment 1a contrasted two hypotheses of intention deactivation (degree of fulfillment and response frequency) by holding constant the degree of intention fulfillment (e.g., participants responded to one of two target words) while manipulating the number of times the intention was performed. Findings supported the response frequency hypothesis. Experiment 1b employed novel lure trials to examine what “stimulus” participants link the prospective memory response to—target words and/or the salient contextual cue—and compared commission errors to Experiment 1a. Findings suggested the salient context alone does not always function as the stimulus. Collectively these findings, in conjunction with those of Experiment 2 (a within-experiment replication) and a combined analysis, suggest that (a) intention deactivation is facilitated by prior responding (formation/strengthening of stimulus–response links), but additional research is needed to establish the robustness of this effect, and (b) when responding frequently to targets, participants are more likely to bind the response to the context alone than to the target or target/context combination, possibly because they learn to rely on context to predict target occurrence. The latter finding was robust and indicates that deactivation of the appropriate stimulus (target and/or context)–response link may be a critical component of reducing commission errors. © 2020, The Psychonomic Society, Inc.

Author Keywords
Commission errors;  Episodic traces;  Intention deactivation;  Prospective memory;  Stimulus-response

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

Dopamine-induced interactions of female mouse hypothalamic proteins with progestin receptor-A in the absence of hormone
(2020) Journal of Neuroendocrinology, .

Acharya, K.D.^a , Nettles, S.A.^a , Lichti, C.F.^b , Warre-Cornish, K.^c d , Dutan Polit, L.^c d , Srivastava, D.P.^c d , Denner, L.^e , Tetel, M.J.^a

^a Neuroscience Department, Wellesley College, Wellesley, MA, United States
^b Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, United States
^c Department of Basic and Clinical Neuroscience, The Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry Psychology and Neuroscience, King’s College London, London, United Kingdom
^d MRC Centre for Neurodevelopmental Disorders, King’s College London, London, United Kingdom
^e Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, United States

Abstract
Neural progestin receptors (PR) function in reproduction, neural development, neuroprotection, learning, memory and the anxiety response. In the absence of progestins, PR can be activated by dopamine (DA) in the rodent hypothalamus to elicit female sexual behaviour. The present study investigated mechanisms of DA activation of PR by testing the hypothesis that proteins from DA-treated hypothalami interact with PR in the absence of progestins. Ovariectomised, oestradiol-primed mice were infused with a D1-receptor agonist, SKF38393 (SKF), into the third ventricle 30 minutes prior to death. Proteins from SKF-treated hypothalami were pulled-down with glutathione S-transferase-tagged mouse PR-A or PR-B and the interactomes were analysed by mass spectrometry. The largest functional group to interact with PR-A in a DA-dependent manner was synaptic proteins. To test the hypothesis that DA activation of PR regulates synaptic proteins, we developed oestradiol-induced PR-expressing hypothalamic-like neurones derived from human-induced pluripotent stem cells (hiPSCs). Similar to progesterone (P4), SKF treatment of hiPSCs increased synapsin1/2 expression. This SKF-dependent effect was blocked by the PR antagonist RU486, suggesting that PR are necessary for this DA-induced increase. The second largest DA-dependent PR-A protein interactome comprised metabolic regulators involved in glucose metabolism, lipid synthesis and mitochondrial energy production. Interestingly, hypothalamic proteins interacted with PR-A, but not PR-B, in an SKF-dependent manner, suggesting that DA promotes the interaction of multiple hypothalamic proteins with PR-A. These in vivo and in vitro results indicate novel mechanisms by which DA can differentially activate PR isoforms in the absence of P4 and provide a better understanding of ligand-independent PR activation in reproductive, metabolic and mental health disorders in women. © 2020 British Society for Neuroendocrinology

Author Keywords
energy homeostasis;  induced pluripotent stem cells;  metabolism;  progesterone;  synapse

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

Negative feedback control of neuronal activity by microglia
(2020) Nature, .

Badimon, A.^a b c , Strasburger, H.J.^a b c , Ayata, P.^a b c d , Chen, X.^e , Nair, A.^e , Ikegami, A.^f g , Hwang, P.^a b c , Chan, A.T.^a b c , Graves, S.M.^h , Uweru, J.O.ⁱ , Ledderose, C.^j , Kutlu, M.G.^k , Wheeler, M.A.^l , Kahan, A.^e , Ishikawa, M.^a , Wang, Y.-C.^m , Loh, Y.-H.E.^a , Jiang, J.X.ⁿ , Surmeier, D.J.^o , Robson, S.C.^p q , Junger, W.G.^j , Sebra, R.^m , Calipari, E.S.^{k r s t u} , Kenny, P.J.^a , Eyo, U.B.ⁱ , Colonna, M.^v , Quintana, F.J.^l w , Wake, H.^f g , Gradinaru, V.^e , Schaefer, A.^a b c d

^a Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^b Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^c Center for Glial Biology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^d Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^e Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, United States
^f Department of Anatomy and Molecular Cell Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan
^g Division of System Neuroscience, Kobe University Graduate School of Medicine, Kobe, Japan
^h Department of Pharmacology, University of Minnesota, Minneapolis, MN, United States
ⁱ Center for Brain Immunology and Glia, Department of Neuroscience, University of Virginia, Charlottesville, VA, United States
^j Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
^k Department of Pharmacology, Vanderbilt University, Nashville, TN, United States
^l Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
^m Department of Genetics and Genomic Sciences, Icahn Institute of Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
ⁿ Department of Biochemistry and Structural Biology, University of Texas Health Science Center, San Antonio, TX, United States
^o Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
^p Department of Anesthesia, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, United States
^q Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, United States
^r Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, United States
^s Vanderbilt Center for Addiction Research, Vanderbilt University, Nashville, TN, United States
^t Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, United States
^u Department of Psychiatry and Behavioral Sciences, Vanderbilt University, Nashville, TN, United States
^v Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
^w The Broad Institute of MIT and Harvard, Cambridge, MA, United States

Abstract
Microglia, the brain’s resident macrophages, help to regulate brain function by removing dying neurons, pruning non-functional synapses, and producing ligands that support neuronal survival1. Here we show that microglia are also critical modulators of neuronal activity and associated behavioural responses in mice. Microglia respond to neuronal activation by suppressing neuronal activity, and ablation of microglia amplifies and synchronizes the activity of neurons, leading to seizures. Suppression of neuronal activation by microglia occurs in a highly region-specific fashion and depends on the ability of microglia to sense and catabolize extracellular ATP, which is released upon neuronal activation by neurons and astrocytes. ATP triggers the recruitment of microglial protrusions and is converted by the microglial ATP/ADP hydrolysing ectoenzyme CD39 into AMP; AMP is then converted into adenosine by CD73, which is expressed on microglia as well as other brain cells. Microglial sensing of ATP, the ensuing microglia-dependent production of adenosine, and the adenosine-mediated suppression of neuronal responses via the adenosine receptor A1R are essential for the regulation of neuronal activity and animal behaviour. Our findings suggest that this microglia-driven negative feedback mechanism operates similarly to inhibitory neurons and is essential for protecting the brain from excessive activation in health and disease. © 2020, The Author(s), under exclusive licence to Springer Nature Limited.

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

Multiple Sclerosis Disease-Modifying Therapies in the COVID-19 Era
(2020) Annals of Neurology, . 

Ciotti, J.R.^a , Grebenciucova, E.^b , Moss, B.P.^c , Newsome, S.D.^d

^a Washington University School of Medicine, St. Louis, MO, United States
^b Northwestern University Feinberg School of Medicine, Chicago, IL, United States
^c Cleveland Clinic Mellen Center for MS, Cleveland, OH, United States
^d Johns Hopkins University School of Medicine, Baltimore, MD, United States

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