WashU weekly Neuroscience publications: February 18, 2024

A Cre-dependent reporter mouse for quantitative real-time imaging of protein kinase A activity dynamics
(2024) Scientific Reports, 14 (1), . 

Tilden, E.I.^a b , Maduskar, A.^a , Oldenborg, A.^a , Sabatini, B.L.^c , Chen, Y.^a

^a Department of Neuroscience, Washington University in St. Louis, St. Louis, MO, United States
^b Ph.D. Program in Neuroscience, Washington University in St. Louis, St. Louis, MO, United States
^c Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, United States

Abstract
Intracellular signaling dynamics play a crucial role in cell function. Protein kinase A (PKA) is a key signaling molecule that has diverse functions, from regulating metabolism and brain activity to guiding development and cancer progression. We previously developed an optical reporter, FLIM-AKAR, that allows for quantitative imaging of PKA activity via fluorescence lifetime imaging microscopy and photometry. However, using viral infection or electroporation for the delivery of FLIM-AKAR is invasive and results in variable expression. Here, we developed a reporter mouse, FL-AK, which expresses FLIM-AKAR in a Cre-dependent manner from the ROSA26 locus. FL-AK provides robust and consistent expression of FLIM-AKAR over time. Functionally, the mouse line reports an increase in PKA activity in response to activation of both Gαs and Gαq-coupled receptors in brain slices. In vivo, FL-AK reports PKA phosphorylation in response to neuromodulator receptor activation. Thus, FL-AK provides a quantitative, robust, and flexible method to reveal the dynamics of PKA activity in diverse cell types. © The Author(s) 2024.

Funding details
National Institute of Mental HealthNIMHMH126964
National Institute on AgingNIAF30 AG084271
National Institute of Neurological Disorders and StrokeNINDSR01 NS119821
Whitehall Foundation2019-08-64
Foundation for Barnes-Jewish HospitalFBJH3770, 4642
St. Louis Children’s HospitalSLCHCDI-CORE-2015-505, CDI-CORE-2019-813

Document Type: Article
Publication Stage: Final
Source: Scopus

Sensory Schwann cells set perceptual thresholds for touch and selectively regulate mechanical nociception
(2024) Nature Communications, 15 (1), . 

Ojeda-Alonso, J.^a , Calvo-Enrique, L.^b h , Paricio-Montesinos, R.^c d , Kumar, R.^b e , Zhang, M.-D.^b , Poulet, J.F.A.^c f , Ernfors, P.^b , Lewin, G.R.^a f g

^a Molecular Physiology of Somatic Sensation, Max Delbrück Center for Molecular Medicine, Berlin, 13125, Germany
^b Department of Medical Biochemistry and Biophysics, Division of Molecular Neurobiology, Karolinska Institutet, Stockholm, Sweden
^c Neural Circuits and Behavior, Max Delbrück Center for Molecular Medicine, Berlin, 13125, Germany
^d Deutsches Zentrum für Neurodegenerative Erkrankungen e. V. (DZNE), Venusberg-Campus 1/99, Bonn, 53127, Germany
^e Pain Center, Department of Anesthesiology Washington University School of Medicine, CB 8108, 660 S. Euclid Ave., St. Louis, MO 63110, United States
^f Charité-Universitätsmedizin Berlin, Charitéplatz 1, Berlin, 10117, Germany
^g German Center for Mental Health (DZPG), partner site Berlin, Berlin, Germany
^h Departamento de Biología Celular y Patología, Instituto de Neurociencias de Castilla y León, University of Salamanca, Salamanca, Spain

Abstract
Previous work identified nociceptive Schwann cells that can initiate pain. Consistent with the existence of inherently mechanosensitive sensory Schwann cells, we found that in mice, the mechanosensory function of almost all nociceptors, including those signaling fast pain, were dependent on sensory Schwann cells. In polymodal nociceptors, sensory Schwann cells signal mechanical, but not cold or heat pain. Terminal Schwann cells also surround mechanoreceptor nerve-endings within the Meissner’s corpuscle and in hair follicle lanceolate endings that both signal vibrotactile touch. Within Meissner´s corpuscles, two molecularly and functionally distinct sensory Schwann cells positive for Sox10 and Sox2 differentially modulate rapidly adapting mechanoreceptor function. Using optogenetics we show that Meissner’s corpuscle Schwann cells are necessary for the perception of low threshold vibrotactile stimuli. These results show that sensory Schwann cells within diverse glio-neural mechanosensory end-organs are sensors for mechanical pain as well as necessary for touch perception. © The Author(s) 2024.

Funding details
Wellcome TrustWT200183, RYC2021-034520-I
European Research CouncilERC101053091, 789128
Brain Foundation
Department of Biotechnology, Ministry of Science and Technology, IndiaDBTBT/HRD/35/02/2006
Deutsche ForschungsgemeinschaftDFGACoolTouch 682422, CRC 958
Svenska Sällskapet för Medicinsk ForskningSSMF
Medicinska ForskningsrådetMFR2019-00761

Document Type: Article
Publication Stage: Final
Source: Scopus

Potential causal association between gut microbiome and posttraumatic stress disorder
(2024) Translational Psychiatry, 14 (1), art. no. 67, . 

He, Q.^a , Wang, W.^b , Xu, D.^c , Xiong, Y.^d , Tao, C.^a , You, C.^a , Ma, L.^a , Ma, J.^a , Nievergelt, C.M.^e , Maihofer, A.X.^e , Klengel, T.^f , Atkinson, E.G.^g , Chen, C.-Y.^g , Choi, K.W.^g , Coleman, J.R.I.^h , Dalvie, S.ⁱ , Duncan, L.E.^j , Logue, M.W.^k , Provost, A.C.^l , Ratanatharathorn, A.^m , Stein, M.B.^e , Torres, K.^e , Aiello, A.E.ⁿ , Almli, L.M.^o , Amstadter, A.B.^p , Andersen, S.B.^q , Andreassen, O.A.^r , Arbisi, P.A.^s , Ashley-Koch, A.E.^t , Austin, S.B.^u , Avdibegovic, E.^v , Babić, D.^w , Bækvad-Hansen, M.^x , Baker, D.G.^e , Beckham, J.C.^y , Bierut, L.J.^z , Bisson, J.I.^aa , Boks, M.P.^ab , Bolger, E.A.^f , Børglum, A.D.^ac , Bradley, B.^ad , Brashear, M.^ae , Breen, G.^af , Bryant, R.A.^ag , Bustamante, A.C.^ah , Bybjerg-Grauholm, J.^x , Calabrese, J.R.^ai , Caldas-de-Almeida, J.M.^aj , Dale, A.M.^ak , Daly, M.J.^al , Daskalakis, N.P.^l , Deckert, J.^am , Delahanty, D.L.^an , Dennis, M.F.^ao , Disner, S.G.^ap , Domschke, K.^aq , Dzubur-Kulenovic, A.^ar , Erbes, C.R.^as , Evans, A.^aa , Farrer, L.A.^at , Feeny, N.C.^au , Flory, J.D.^av , Forbes, D.^aw , Franz, C.E.^e , Galea, S.^ax , Garrett, M.E.^y , Gelaye, B.^m , Gelernter, J.^ay , Geuze, E.^az , Gillespie, C.^ba , Uka, A.G.^bb , Gordon, S.D.^bc , Guffanti, G.^f , Hammamieh, R.^bd , Harnal, S.^be , Hauser, M.A.^y , Heath, A.C.^bf , Hemmings, S.M.J.^bg , Hougaard, D.M.^x , Jakovljevic, M.^bh , Jett, M.^bd , Johnson, E.O.^bi , Jones, I.^aa , Jovanovic, T.^ba , Qin, X.-J.^ao , Junglen, A.G.^an , Karstoft, K.-I.^q , Kaufman, M.L.^f , Kessler, R.C.^f , Khan, A.^bj , Kimbrel, N.A.^ao , King, A.P.^bk , Koen, N.^bl , Kranzler, H.R.^bm , Kremen, W.S.^bn , Lawford, B.R.^bo , Lebois, L.A.M.^f , Lewis, C.E.^aa , Linnstaedt, S.D.^bp , Lori, A.^bq , Lugonja, B.^aa , Luykx, J.J.^br , Lyons, M.J.^bs , Maples-Keller, J.^ba , Marmar, C.^bt , Martin, A.R.^g , Martin, N.G.^bc , Maurer, D.^bu , Mavissakalian, M.R.^ai , McFarlane, A.^bv , McGlinchey, R.E.^bw , McLaughlin, K.A.^bx , McLean, S.A.^bp , McLeay, S.^by , Mehta, D.^bz , Milberg, W.P.^bw , Miller, M.W.^k , Morey, R.A.^ao , Morris, C.P.^bz , Mors, O.^ca , Mortensen, P.B.^cb , Neale, B.M.^g , Nelson, E.C.^z , Nordentoft, M.^cc , Norman, S.B.^cd , O’Donnell, M.^aw , Orcutt, H.K.^ce , Panizzon, M.S.^e , Peters, E.S.^ae , Peterson, A.L.^cf , Peverill, M.^cg , Pietrzak, R.H.^ch , Polusny, M.A.^ci , Rice, J.P.^z , Ripke, S.^be , Risbrough, V.B.^e , Roberts, A.L.^cj , Rothbaum, A.O.^au , Rothbaum, B.O.^ba , Roy-Byrne, P.^cg , Ruggiero, K.^ck , Rung, A.^cl , Rutten, B.P.F.^cm , Saccone, N.L.^z , Sanchez, S.E.^cn , Schijven, D.^br , Seedat, S.^bg , Seligowski, A.V.^co , Seng, J.S.^cp , Sheerin, C.M.^p , Silove, D.^cq , Smith, A.K.^bq , Smoller, J.W.^g , Solovieff, N.^cr , Sponheim, S.R.^s , Stein, D.J.ⁱ , Sumner, J.A.^cs , Teicher, M.H.^f , Thompson, W.K.^ct , Trapido, E.^ae , Uddin, M.^cu , Ursano, R.J.^cv , van den Heuvel, L.L.^bg , van Hooff, M.^bv , Vermetten, E.^cw , Vinkers, C.H.^cx , Voisey, J.^bo , Wang, Y.^ct , Wang, Z.^cy , Werge, T.^ct , Williams, M.A.^m , Williamson, D.E.^y , Winternitz, S.^f , Wolf, C.^am , Wolf, E.J.^k , Wolff, J.D.^cz , Yehuda, R.^av , Young, K.A.^da , Young, R.M.D.^db , Zhao, H.^dc , Zoellner, L.A.^dd , Liberzon, I.^bk , Ressler, K.J.^ba , Haas, M.^l , Koenen, K.C.^de

^a Department of Neurosurgery, West China Hospital, Sichuan University, 37 Guoxue Lane, Wuhou District, Sichuan, Chengdu, 610041, China
^b Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital, Sichuan University, 37 Guoxue Lane, Wuhou District, Chengdu, China
^c Department of Neurosurgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
^d Department of Urology, West China Hospital, Sichuan University, Chengdu, China
^e Department of Psychiatry, University of California, San Diego, CA, United States
^f Department of Psychiatry, Harvard Medical School, Boston, MA, United States
^g Broad Institute, Stanley Center for Psychiatric Research, Cambridge, MA, United States
^h Institute of Psychiatry, Psychology and Neuroscience, Social, Genetic and Developmental Psychiatry Centre, King’s College London, London, United Kingdom
ⁱ South African Medical Research Council Unit on Risk and Resilience in Mental Disorders, Department of Psychiatry, University of Cape Town, Western Cape, Cape Town, South Africa
^j Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, United States
^k Veterans Affair Boston Healthcare System, National Center for PTSD, Boston, MA, United States
^l Cohen Veterans Bioscience, Cambridge, MA, United States
^m Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, United States
ⁿ Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
^o Carter Consulting, Atlanta, Georgia
^p Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Richmond, VA, United States
^q Research and Knowledge Centre, The Danish Veteran Centre, Ringsted, Denmark
^r Institute of Clinical Medicine, University of Oslo, Oslo, Norway
^s Mental Health Service Line, Minneapolis Veterans Affairs Health Care System, Minneapolis, MN, United States
^t Department of Psychiatry, Duke University, Durham, NC, United States
^u Division of Adolescent and Young Adult Medicine, Boston Children’s Hospital, Boston, MN, United States
^v Department of Psychiatry, University Clinical Center of Tuzla, Tuzla, Bosnia and Herzegovina
^w Department of Psychiatry, University Clinical Center of Mostar, Mostar, Bosnia and Herzegovina
^x Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark
^y Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, United States
^z Department of Psychiatry, Washington University in Saint Louis School of Medicine, St Louis, MO, United States
^aa Medical Research Council Centre for Psychiatric Genetics and Genomics, National Centre for Mental Health, Cardiff University, Cardiff, United Kingdom
^ab Utrecht Brain Center Rudolf Magnus, Department of Translational Neuroscience, University Medical Center, Utrecht, Netherlands
^ac Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark
^ad Mental Health Service Line, Atlanta Veterans Affairs Health Care System, Decatur, Georgia
^ae School of Public Health and Department of Epidemiology, Louisiana State University Health Sciences Center, New Orleans, LA, United States
^af National Institute for Health Research Biomedical Research Centre at the Maudsley, King’s College London, London, United Kingdom
^ag Department of Psychology, University of New South Wales, Sydney, NSW, Australia
^ah Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, United States
^ai Department of Psychiatry, University Hospitals, Cleveland, OH, United States
^aj Chronic Diseases Research Centre [CEDOC], Lisbon Institute of Global Mental Health, Lisbon, Portugal
^ak Department of Radiology, Department of Neurosciences, University of California, San Diego, CA, United States
^al Psychiatric and Neurodevelopmental Genetics Unit [PNGU], Massachusetts General Hospital, Boston, MA, United States
^am Center of Mental Health, Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Würzburg, Germany
^an Department of Psychological Sciences, Kent State University, Kent, OH, United States
^ao Duke Molecular Physiology Institute, Duke University, Durham, NC, United States
^ap Research Service Line, Minneapolis Veterans Affairs Health Care System, Minneapolis, MN, United States
^aq Department of Psychiatry and Psychotherapy, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany
^ar University Clinical Center of Sarajevo, Department of Psychiatry, Sarajevo, Bosnia and Herzegovina
^as Center for Care Delivery and Outcomes Research [CCDOR], Minneapolis Veterans Affairs Health Care System, Minneapolis, MN, United States
^at Department of Medicine, Boston University School of Medicine, Boston, MA, United States
^au Department of Psychological Sciences, Case Western Reserve University, Cleveland, OH, United States
^av Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^aw Department of Psychiatry, University of Melbourne, Melbourne, VIC, Australia
^ax Department of Psychological and Brain Sciences, Boston University, Boston, MA, United States
^ay Department of Psychiatry, US Department of Veterans Affairs, West Haven, CT, United States
^az Research Center Military Mental Healthcare, Netherlands Ministry of Defence, Utrecht, Netherlands
^ba Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Georgia
^bb Department of Psychiatry, University Clinical Centre of Kosovo, Prishtina
^bc Department of Genetics and Computational Biology, Queensland Institute of Medical Research (QIMR) Berghofer Medical Research Institute, Brisbane, QLD, Australia
^bd US Army Center for Environmental Health Research, Army Medical Research and Materiel Command, Fort Detrick, MD, United States
^be Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, United States
^bf Department of Genetics, Washington University in Saint Louis School of Medicine, St Louis, MO, United States
^bg Department of Psychiatry, Stellenbosch University Faculty of Medicine and Health Sciences, Cape Town, South Africa
^bh Department of Psychiatry, University Hospital Center of Zagreb, Zagreb, Croatia
^bi Behavioral Health and Criminal Justice Division, Research Triangle Institute International, Research Triangle Park, NC, United States
^bj Department of Health Care Policy, Harvard Medical School, Boston, MA, United States
^bk Department of Psychiatry, University of Michigan Medical School, Ann Arbor, MI, United States
^bl South Africa Medical Research Council Unit on Risk and Resilience in Mental Disorders, University of Cape Town, Cape Town, South Africa
^bm Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
^bn Department of Psychiatry and Department of Family Medicine and Public Health, University of California, San Diego, CA, United States
^bo Queensland University of Technology, Institute of Health and Behavioral Innovation, Brisbane, QLD, Australia
^bp Department of Anesthesiology, University of North Carolina Institute for Trauma Recovery, Chapel Hill, NC, United States
^bq Department of Gynecology and Obstetrics, Emory University, Atlanta, Georgia
^br Utrecht Brain Center Rudolf Magnus, Department of Psychiatry, University Medical Center, Las Vegas, NV, United States
^bs Dean’s Office, Boston University, Boston, MA, United States
^bt Department of Psychiatry, New York University, New York, NY, United States
^bu Command, US Army, Fort Sill, OK, United States
^bv Department of Psychiatry, University of Adelaide, Adelaide, SA, Australia
^bw GRECC/TRACTS, Veterans Affairs Boston Health Care System, Boston, MA, United States
^bx Department of Psychology, Harvard University, Cambridge, MA, United States
^by PTSD Initiative, Gallipoli Medical Research Institute, Greenslopes, QLD, Australia
^bz Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia
^ca Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark
^cb Centre for Integrated Register-Based Research, Aarhus University, Aarhus, Denmark
^cc The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark
^cd Executive Division, National Center for Posttraumatic Stress Disorder, White River Junction, Hartford, VT, United States
^ce Department of Psychology, Northern Illinois University, DeKalb, IL, United States
^cf Department of Psychology, University of Texas, San Antonio, TX, United States
^cg Department of Psychology, University of Washington, Seattle, WA, United States
^ch US Department of Veterans Affairs National Center for Posttraumatic Stress Disorder, West Haven, CT, United States
^ci Department of Mental Health, Minneapolis Veterans Affairs Health Care System, Minneapolis, MN, United States
^cj Department of Environmental Health, Harvard T.H. Chan School of Public Health, Harvard University, Cambridge, MA, United States
^ck Department of Nursing and Department of Psychiatry, Medical University of South Carolina, Charleston, SC, United States
^cl School of Medicine and Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA, United States
^cm School for Mental Health and Neuroscience, Department of Psychiatry and Neuropsychology, Maastricht Universitair Medisch Centrum, Maastricht, Netherlands
^cn Facultad de Ciencias de la Salud, Department of Medicine, Universidad Peruana de Ciencias Aplicadas, Lima, Peru
^co Department of Pediatrics, Harvard Medical School, Boston, MA, United States
^cp School of Nursing, University of Michigan, Ann Arbor, MI, United States
^cq Department of Psychiatry, University of New South Wales, Sydney, NSW, Australia
^cr Massachusetts General Hospital, Boston, MA, United States
^cs Department of Medicine, Columbia University Medical Center, New York, NY, United States
^ct Institute of Biological Psychiatry, Mental Health Centre, Sankt Hans, Roskilde, Denmark
^cu Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, United States
^cv Department of Psychiatry, Uniformed Services University, Bethesda, MD, United States
^cw Arq Psychotrauma Research Expert Group, Diemen, Netherlands
^cx Department of Anatomy and Neurosciences, Amsterdam Academic Medical Center, Amsterdam, Netherlands
^cy Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, United States
^cz McLean Hospital, Belmont, MA, United States
^da Department of Psychiatry, Baylor Scott and White Central Texas, Temple, TX, United States
^db School of Psychology and Counseling, Queensland University of Technology, Brisbane, QLD, Australia
^dc Department of Biostatistics, Yale University, New Haven, CT, United States
^dd Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, United States
^de Department of Epidemiology, Harvard School of Public Health, Boston, MA, United States

Abstract
Background: The causal effects of gut microbiome and the development of posttraumatic stress disorder (PTSD) are still unknown. This study aimed to clarify their potential causal association using mendelian randomization (MR). Methods: The summary-level statistics for gut microbiome were retrieved from a genome-wide association study (GWAS) of the MiBioGen consortium. As to PTSD, the Freeze 2 datasets were originated from the Psychiatric Genomics Consortium Posttraumatic Stress Disorder Working Group (PGC-PTSD), and the replicated datasets were obtained from FinnGen consortium. Single nucleotide polymorphisms meeting MR assumptions were selected as instrumental variables. The inverse variance weighting (IVW) method was employed as the main approach, supplemented by sensitivity analyses to evaluate potential pleiotropy and heterogeneity and ensure the robustness of the MR results. We also performed reverse MR analyses to explore PTSD’s causal effects on the relative abundances of specific features of the gut microbiome. Results: In Freeze 2 datasets from PGC-PTSD, eight bacterial traits revealed a potential causal association between gut microbiome and PTSD (IVW, all P < 0.05). In addition, Genus.Dorea and genus.Sellimonas were replicated in FinnGen datasets, in which eight bacterial traits revealed a potential causal association between gut microbiome and the occurrence of PTSD. The heterogeneity and pleiotropy analyses further supported the robustness of the IVW findings, providing additional evidence for their reliability. Conclusion: Our study provides the potential causal impact of gut microbiomes on the development of PTSD, shedding new light on the understanding of the dysfunctional gut-brain axis in this disorder. Our findings present novel evidence and call for investigations to confirm the association between their links, as well as to illuminate the underlying mechanisms. © 2024, The Author(s).

Document Type: Article
Publication Stage: Final
Source: Scopus

Brain injury drives optic glioma formation through neuron-glia signaling
(2024) Acta Neuropathologica Communications, 12 (1), . 

Chatterjee, J., Koleske, J.P., Chao, A., Sauerbeck, A.D., Chen, J.-K., Qi, X., Ouyang, M., Boggs, L.G., Idate, R., Marco Y Marquez, L.I., Kummer, T.T., Gutmann, D.H.

Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, United States

Abstract
Tissue injury and tumorigenesis share many cellular and molecular features, including immune cell (T cells, monocytes) infiltration and inflammatory factor (cytokines, chemokines) elaboration. Their common pathobiology raises the intriguing possibility that brain injury could create a tissue microenvironment permissive for tumor formation. Leveraging several murine models of the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome and two experimental methods of brain injury, we demonstrate that both optic nerve crush and diffuse traumatic brain injury induce optic glioma (OPG) formation in mice harboring Nf1-deficient preneoplastic progenitors. We further elucidate the underlying molecular and cellular mechanisms, whereby glutamate released from damaged neurons stimulates IL-1β release by oligodendrocytes to induce microglia expression of Ccl5, a growth factor critical for Nf1-OPG formation. Interruption of this cellular circuit using glutamate receptor, IL-1β or Ccl5 inhibitors abrogates injury-induced glioma progression, thus establishing a causative relationship between injury and tumorigenesis. © The Author(s) 2024.

Author Keywords
Brain tumor;  Cytokine;  Microglia;  Optic glioma;  Optic nerve crush;  Traumatic brain injury;  Tumor microenvironment;  Tumorigenesis

Funding details
National Institutes of HealthNIHR01-BX005204, R01-NS121612, R35-NS097211
National Eye InstituteNEIP30EY002687
National Cancer InstituteNCIP30-CA091842
National Center for Research ResourcesNCRR
Institute of Clinical and Translational SciencesICTS
Georgia Clinical and Translational Science AllianceGaCTSAUL1TR002345

Document Type: Article
Publication Stage: Final
Source: Scopus

Post-mortem changes of anisotropic mechanical properties in the porcine brain assessed by MR elastography
(2024) Brain Multiphysics, 6, art. no. 100091, . 

Wang, S.^a , Eckstein, K.N.^a , Guertler, C.A.^a , Johnson, C.L.^b , Okamoto, R.J.^a , McGarry, M.D.J.^c , Bayly, P.V.^a d

^a Washington University in St. Louis, Mechanical Engineering and Material Science, United States
^b University of Delaware, Biomedical Engineering, United States
^c Dartmouth College, Thayer School of Engineering, United States
^d Washington University in St. Louis, Biomedical Engineering, United States

Abstract
Knowledge of the mechanical properties of brain tissue in vivo is essential to understanding the mechanisms underlying traumatic brain injury (TBI) and to creating accurate computational models of TBI and neurosurgical simulation. Brain white matter, which is composed of aligned, myelinated, axonal fibers, is structurally anisotropic. White matter in vivo also exhibits mechanical anisotropy, as measured by magnetic resonance elastography (MRE), but measurements of anisotropy obtained by mechanical testing of white matter ex vivo have been inconsistent. The minipig has a gyrencephalic brain with similar white matter and gray matter proportions to humans and therefore provides a relevant model for human brain mechanics. In this study, we compare estimates of anisotropic mechanical properties of the minipig brain obtained by identical, non-invasive methods in the live (in vivo) and dead animals (in situ). To do so, we combine wave displacement fields from MRE and fiber directions derived from diffusion tensor imaging (DTI) with a finite element-based, transversely-isotropic nonlinear inversion (TI-NLI) algorithm. Maps of anisotropic mechanical properties in the minipig brain were generated for each animal alive and at specific times post-mortem. These maps show that white matter is stiffer, more dissipative, and more anisotropic than gray matter when the minipig is alive, but that these differences largely disappear post-mortem, with the exception of tensile anisotropy. Overall, brain tissue becomes stiffer, less dissipative, and less mechanically anisotropic post-mortem. These findings emphasize the importance of testing brain tissue properties in vivo. Statement of Significance: In this study, MRE and DTI in the minipig were combined to estimate, for the first time, anisotropic mechanical properties in the living brain and in the same brain after death. Significant differences were observed in the anisotropic behavior of brain tissue post-mortem. These results demonstrate the importance of measuring brain tissue properties in vivo as well as ex vivo, and provide new quantitative data for the development of computational models of brain biomechanics. © 2024 The Author(s)

Author Keywords
Anisotropy;  Brain tissue stiffness;  Diffusion tensor imaging;  Magnetic resonance elastography;  Post-mortem changes

Funding details
National Institutes of HealthNIHR01EB027577
Office of Naval ResearchONRN00014-22-1-2198

Document Type: Article
Publication Stage: Final
Source: Scopus

Genetic contribution to the comorbidity between attention-deficit/hyperactivity disorder and substance use disorders
(2024) Psychiatry Research, 333, art. no. 115758, . 

Koller, D.^a b c , Mitjans, M.^c d e f , Kouakou, M.^a , Friligkou, E.^a b , Cabrera-Mendoza, B.^a b , Deak, J.D.^a b , Llonga, N.^g , Pathak, G.A.^a b , Stiltner, B.^a b , Løkhammer, S.^a h i , Levey, D.F.^a b , Zhou, H.^a b , Hatoum, A.S.^j , Kember, R.L.^k l , Kranzler, H.R.^k l , Stein, M.B.^m n o , Corominas, R.^c e f p , Demontis, D.^q r s t , Artigas, M.S.^c d g u , Ramos-Quiroga, J.A.^c d g v , Gelernter, J.^a b w x , Ribasés, M.^c d g u , Cormand, B.^c e f p , Polimanti, R.^a b y

^a Department of Psychiatry, Yale School of Medicine, New Haven, CA, United States
^b Veterans Affairs Connecticut Healthcare Center, West Haven, CA, United States
^c Department of Genetics, Microbiology, and Statistics, Faculty of Biology, University of Barcelona, Catalonia, Spain
^d Biomedical Network Research Centre on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain
^e Institute of Biomedicine of the University of Barcelona (IBUB), Catalonia, Barcelona, Spain
^f Sant Joan de Déu Research Institute (IR-SJD), Esplugues de Llobregat, Catalonia, Spain
^g Psychiatric Genetics Unit, Group of Psychiatry Mental Health and Addiction, Vall d’Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
^h NORMENT, Department of Clinical Science, University of Bergen, Bergen, Norway
ⁱ Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
^j Department of Psychological and Brain Sciences, Washington University in Saint Louis, St. Louis, MO, United States
^k Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
^l Mental Illness Research, Education and Clinical Center, Veterans Integrated Service Network 4, Crescenz Veterans Affairs Medical Center, Philadelphia, Pennsylvania, United States
^m Department of Psychiatry, University of California, San Diego, La Jolla, United States
ⁿ Herbert Wertheim School of Public Health, University of California, San Diego, La Jolla, United States
^o VA San Diego Healthcare System, San Diego, CA, La Jolla, United States
^p Biomedical Network Research Centre on Rare Disorders (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
^q Department of Biomedicine – Human Genetics, Aarhus University, Aarhus, Denmark
^r The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark
^s Center for Genomics and Personalized Medicine, Aarhus, Denmark
^t The Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA 02142, United States
^u Department of Mental Health, Hospital Universitari Vall d’Hebron, Barcelona, Spain
^v Department of Psychiatry and Forensic Medicine, Universitat Autonoma de Barcelona, Barcelona, Spain
^w Department of Genetics, Yale School of Medicine, New Haven, CT, United States
^x Department of Neuroscience, Yale School of Medicine, New Haven, CT, United States
^y Wu Tsai Institute, Yale University, New Haven, CT, United States

Abstract
We characterized the genetic architecture of the attention-deficit hyperactivity disorder-substance use disorder (ADHD-SUD) relationship by investigating genetic correlation, causality, pleiotropy, and common polygenic risk. Summary statistics from genome-wide association studies (GWAS) were used to investigate ADHD (Neff = 51,568), cannabis use disorder (CanUD, Neff = 161,053), opioid use disorder (OUD, Neff = 57,120), problematic alcohol use (PAU, Neff = 502,272), and problematic tobacco use (PTU, Neff = 97,836). ADHD, CanUD, and OUD GWAS meta-analyses included cohorts with case definitions based on different diagnostic criteria. PAU GWAS combined information related to alcohol use disorder, alcohol dependence, and the items related to alcohol problematic consequences assessed by the alcohol use disorders identification test. PTU GWAS was generated a multi-trait analysis including information regarding Fagerström Test for Nicotine Dependence and cigarettes per day. Linkage disequilibrium score regression analyses indicated positive genetic correlation with CanUD, OUD, PAU, and PTU. Genomic structural equation modeling showed that these genetic correlations were related to two latent factors: one including ADHD, CanUD, and PTU and the other with OUD and PAU. The evidence of a causal effect of PAU and PTU on ADHD was stronger than the reverse in the two-sample Mendelian randomization analysis. Conversely, similar strength of evidence was found between ADHD and CanUD. CADM2 rs62250713 was a pleiotropic SNP between ADHD and all SUDs. We found seven, one, and twenty-eight pleiotropic variants between ADHD and CanUD, PAU, and PTU, respectively. Finally, OUD, CanUD, and PAU PRS were associated with increased odds of ADHD. Our findings demonstrated the contribution of multiple pleiotropic mechanisms to the comorbidity between ADHD and SUDs. © 2024 The Author(s)

Author Keywords
Attention-deficit hyperactivity disorder;  Mendelian randomization;  Pleiotropy;  Polygenic risk scoring;  Substance use disorders

Funding details
Fundació la Marató de TV3202218-31
Chiropractic and Osteopathic College of AustralasiaCOCA728018, 841899, Eat2beNICE
Ministerio de Ciencia, Innovación y UniversidadesMCIUPID2021-1277760B-I100
European CommissionEC667302, H2020/2014-2020
Generalitat de Catalunya
Agència de Gestió d’Ajuts Universitaris i de RecercaAGAUR2021-SGR-01093
Institució Catalana de Recerca i Estudis AvançatsICREA

Document Type: Article
Publication Stage: Final
Source: Scopus

H2A.Z histone variants facilitate HDACi-dependent removal of H3.3K27M mutant protein in pediatric high-grade glioma cells
(2024) Cell Reports, 43 (2), art. no. 113707, . 

Leszczynska, K.B.^a , Freitas-Huhtamäki, A.^a , Jayaprakash, C.^a , Dzwigonska, M.^a , Vitorino, F.N.L.^c , Horth, C.^d , Wojnicki, K.^a , Gielniewski, B.^a , Szadkowska, P.^a , Kaza, B.^a , Nazarian, J.^e f , Ciolkowski, M.K.^b , Trubicka, J.^b , Grajkowska, W.^b , Garcia, B.A.^c , Majewski, J.^d , Kaminska, B.^a , Mieczkowski, J.^a g

^a Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland
^b Children’s Memorial Health Institute, Warsaw, Poland
^c Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Human Genetics, McGill University, Montreal, QC, Canada
^e Center for Genetic Medicine Research, Children’s National Hospital, Washington, DC, United States
^f Department of Pediatrics, University Children’s Hospital Zürich, Zürich, Switzerland
^g 3P-Medicine Laboratory, Medical University of Gdansk, Gdansk, Poland

Abstract
Diffuse intrinsic pontine gliomas (DIPGs) are deadly pediatric brain tumors, non-resectable due to brainstem localization and diffusive growth. Over 80% of DIPGs harbor a mutation in histone 3 (H3.3 or H3.1) resulting in a lysine-to-methionine substitution (H3K27M). Patients with DIPG have a dismal prognosis with no effective therapy. We show that histone deacetylase (HDAC) inhibitors lead to a significant reduction in the H3.3K27M protein (up to 80%) in multiple glioma cell lines. We discover that the SB939-mediated H3.3K27M loss is partially blocked by a lysosomal inhibitor, chloroquine. The H3.3K27M loss is facilitated by co-occurrence of H2A.Z, as evidenced by the knockdown of H2A.Z isoforms. Chromatin immunoprecipitation sequencing (ChIP-seq) analysis confirms the occupancy of H3.3K27M and H2A.Z at the same SB939-inducible genes. We discover a mechanism showing that HDAC inhibition in DIPG leads to pharmacological modulation of the oncogenic H3.3K27M protein levels. These findings show the possibility of directly targeting the H3.3K27M oncohistone. © 2024 The Author(s)

Author Keywords
CP: Cancer;  DIPG;  H2A.Z;  H3.3;  H3.3K27M;  HDAC inhibitors;  histone variants;  multiomics;  pediatric high-grade gliomas;  SB939

Funding details
2019/33/B/NZ1/01556, MAB/2018/6
National Institutes of HealthNIHP01CA196539, R01HD106051
Canadian Institutes of Health ResearchIRSCPJT-183939
Fundacja na rzecz Nauki PolskiejFNP
Narodowym Centrum NaukiNCN2017/27/B/NZ2/02827

Document Type: Article
Publication Stage: Final
Source: Scopus

Oxytocin-induced birth causes sex-specific behavioral and brain connectivity changes in developing rat offspring
(2024) iScience, 27 (2), art. no. 108960, . 

Giri, T.^a , Maloney, S.E.^b , Giri, S.^c , Goo, Y.A.^d e , Song, J.H.^e , Son, M.^e , Tycksen, E.^f , Conyers, S.B.^b , Bice, A.^g , Ge, X.^g , Garbow, J.R.^g , Quirk, J.D.^g , Bauer, A.Q.^g , Palanisamy, A.^a h

^a Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Psychiatry, Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, St. Louis, MO, United States
^c Graduate Student, School of Public Health and Social Justice, St. Louis University, St. Louis, MO, United States
^d Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, United States
^e Mass Spectrometry Technology Access Center (MTAC), McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, United States
^f Genome Technology Access Center (GTAC), McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, United States
^g Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^h Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Despite six decades of the use of exogenous oxytocin for management of labor, little is known about its effects on the developing brain. Motivated by controversial reports suggesting a link between oxytocin use during labor and autism spectrum disorders (ASDs), we employed our recently validated rat model for labor induction with oxytocin to address this important concern. Using a combination of molecular biological, behavioral, and neuroimaging assays, we show that induced birth with oxytocin leads to sex-specific disruption of oxytocinergic signaling in the developing brain, decreased communicative ability of pups, reduced empathy-like behaviors especially in male offspring, and widespread sex-dependent changes in functional cortical connectivity. Contrary to our hypothesis, social behavior, typically impaired in ASDs, was largely preserved. Collectively, our foundational studies provide nuanced insights into the neurodevelopmental impact of birth induction with oxytocin and set the stage for mechanistic investigations in animal models and prospective longitudinal clinical studies. © 2024 The Author(s)

Author Keywords
Behavioral neuroscience;  Endocrinology;  Neuroscience

Funding details
National Institutes of HealthNIH1RF1AG079503, R01EB029752, R01NS102870, R01NS126326
Washington University in St. LouisWUSTL
Intellectual and Developmental Disabilities Research CenterIDDRC
Institute of Clinical and Translational SciencesICTS
Department of Anesthesiology, Medical College of Wisconsin
Washington University School of Medicine in St. LouisWUSM
Mallinckrodt Institute of RadiologyMIR
Genome Technology Access CenterGTAC

Document Type: Article
Publication Stage: Final
Source: Scopus

Recommended Resting-State fMRI Acquisition and Preprocessing Steps for Preoperative Mapping of Language and Motor and Visual Areas in Adult and Pediatric Patients with Brain Tumors and Epilepsy
(2024) American Journal of Neuroradiology, 45 (2), pp. 139-148. 

Kumar, V.A.^a , Lee, J.^a , Liu, H.-L.^a , Allen, J.W.^b , Filippi, C.G.^c , Holodny, A.I.^d , Hsu, K.^e , Jain, R.^e , McAndrews, M.P.^f , Peck, K.K.^d , Shah, G.^g , Shimony, J.S.^h , Singh, S.ⁱ , Zeineh, M.^j , Tanabe, J.^k , Vachha, B.^l , Vossough, A.^m , Welker, K.ⁿ , Whitlow, C.^o , Wintermark, M.^a , Zaharchuk, G.^j , Sair, H.I.^p

^a The University of Texas MD Anderson Cancer Center, Houston, TX, United States
^b Emory University, Atlanta, GA, United States
^c Tufts University, Boston, MA, United States
^d Memorial Sloan Kettering Cancer Center, New York, NY, United States
^e New York University, New York, NY, United States
^f University of Toronto, Toronto, ON, Canada
^g University of Michigan, Ann Arbor, MI, United States
^h Washington University School of Medicine, St. Louis, MO, United States
ⁱ University of Texas Southwestern Medical Center, Dallas, TX, United States
^j Stanford University, Palo Alto, CA, United States
^k University of Colorado, Aurora, CO, United States
^l University of Massachusetts, Worcester, MA, United States
^m Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, United States
ⁿ Mayo Clinic, Rochester, MN, United States
^o Wake Forest University, Winston-Salem, NC, United States
^p Johns Hopkins University, Baltimore, MD, United States

Abstract
Resting-state (rs) fMRI has been shown to be useful for preoperative mapping of functional areas in patients with brain tumors and epilepsy. However, its lack of standardization limits its widespread use and hinders multicenter collaboration. The American Society of Functional Neuroradiology, American Society of Pediatric Neuroradiology, and the American Society of Neuroradiology Functional and Diffusion MR Imaging Study Group recommend specific rs-fMRI acquisition approaches and preprocessing steps that will further support rs-fMRI for future clinical use. A task force with expertise in fMRI from multiple institutions provided recommendations on the rs-fMRI steps needed for mapping of language, motor, and visual areas in adult and pediatric patients with brain tumor and epilepsy. These were based on an extensive literature review and expert consensus. Following rs-fMRI acquisition parameters are recommended: minimum 6-minute acquisition time; scan with eyes open with fixation; obtain rs-fMRI before both task-based fMRI and contrast administration; temporal resolution of #2 seconds; scanner field strength of 3T or higher. The following rs-fMRI preprocessing steps and parameters are recommended: motion correction (seed-based correlation analysis [SBC], independent component analysis [ICA]); despiking (SBC); volume censoring (SBC, ICA); nuisance regression of CSF and white matter signals (SBC); head motion regression (SBC, ICA); bandpass filtering (SBC, ICA); and spatial smoothing with a kernel size that is twice the effective voxel size (SBC, ICA). The consensus recommendations put forth for rs-fMRI acquisition and preprocessing steps will aid in standardization of practice and guide rs-fMRI program development across institutions. Standardized rs-fMRI protocols and processing pipelines are essential for multicenter trials and to implement rs-fMRI as part of standard clinical practice. © 2024 American Society of Neuroradiology. All rights reserved.

Document Type: Article
Publication Stage: Final
Source: Scopus

Comprehensive workflow and its validation for simulating diffuse speckle statistics for optical blood flow measurements
(2024) Biomedical Optics Express, 15 (2), pp. 875-899. 

Frisk, L.K.^a , Verma, M.^a , Bešlija, F.^a , Lin, C.-H.P.^b c , Patil, N.^a , Chetia, S.^a , Trobaugh, J.W.^d , Culver, J.P.^b c , Durduran, T.^a e

^a ICFO-Institut de Ciències Fotòniques, The Barcelona Institute of Science and Technology, Castelldefels, Barcelona, Spain
^b Department of Physics, Washington University in St. Louis, St. Louis, MO 63110, United States
^c Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
^d Department of Electrical and Systems Engineering, Washington University School of Medicine, St. Louis, MO 63110, United States
^e Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain

Abstract
Diffuse optical methods including speckle contrast optical spectroscopy and tomography (SCOS and SCOT), use speckle contrast (κ) to measure deep blood flow. In order to design practical systems, parameters such as signal-to-noise ratio (SNR) and the effects of limited sampling of statistical quantities, should be considered. To that end, we have developed a method for simulating speckle contrast signals including effects of detector noise. The method was validated experimentally, and the simulations were used to study the effects of physical and experimental parameters on the accuracy and precision of κ. These results revealed that systematic detector effects resulted in decreased accuracy and precision of κ in the regime of low detected signals. The method can provide guidelines for the design and usage of SCOS and/or SCOT instruments. © 2024 Optica Publishing Group under the terms of the Optica Open Access Publishing Agreement.

Funding details
CEX2019-000910-S
National Institutes of HealthNIHR01NS090874
National Institute of Neurological Disorders and StrokeNINDS
Fundación Cellex
H2020 Marie Skłodowska-Curie ActionsMSCA847517, 860185, 871124
Generalitat de Catalunya
Agència de Gestió d’Ajuts Universitaris i de RecercaAGAUR2017SGR1380
Ministerio de Economía y CompetitividadMINECOPRE2018-085082
Agencia Estatal de InvestigaciónAEIID2019-106481RB-C31/10.13039/501100011033, PID2019-106481RB-C31/10.13039/501100011033

Document Type: Article
Publication Stage: Final
Source: Scopus

Investigating White Matter Neuroinflammation in Alzheimer Disease Using Diffusion-Based Neuroinflammation Imaging
(2024) Neurology, 102 (4), p. e208013. 

Wang, Q., Schindler, S.E., Chen, G., Mckay, N.S., McCullough, A., Flores, S., Liu, J., Sun, Z., Wang, S., Wang, W., Hassenstab, J., Cruchaga, C., Perrin, R.J., Fagan, A.M., Morris, J.C., Wang, Y., Benzinger, T.L.S.

From the Mallinckrodt Institute of Radiology (Q.W., G.C., N.S.M., A.M., S.F., Y.W., T.L.S.B.), Knight Alzheimer Disease Research Center (Q.W., S.E.S., G.C., N.S.M., A.M., J.H., R.J.P., A.M.F., J.C.M., T.L.S.B.), Department of Neurology (S.E.S., J.H., C.C., A.M.F., J.C.M.), Department of Surgery (J.L.), Department of Biomedical Engineering (Z.S.), Department of Electrical and System Engineering (S.W., W.W., Y.W.), Department of Psychiatry (C.C.), Department of Pathology & Immunology (R.J.P.), Department of Obstetrics & Gynecology (Y.W.), and Department of Neurosurgery (T.L.S.B.), Washington University School of Medicine, St. Louis, MO

Abstract
BACKGROUND AND OBJECTIVES: Alzheimer disease (AD) is primarily associated with accumulations of amyloid plaques and tau tangles in gray matter, however, it is now acknowledged that neuroinflammation, particularly in white matter (WM), significantly contributes to the development and progression of AD. This study aims to investigate WM neuroinflammation in the continuum of AD and its association with AD pathologies and cognition using diffusion-based neuroinflammation imaging (NII). METHODS: This is a cross-sectional, single-center, retrospective evaluation conducted on an observational study of 310 older research participants who were enrolled in the Knight Alzheimer’s Disease Research Center cohort. Hindered water ratio (HR), an index of WM neuroinflammation, was quantified by a noninvasive diffusion MRI method, NII. The alterations of NII-HR were investigated at different AD stages, classified based on CSF concentrations of β-amyloid (Aβ) 42/Aβ40 for amyloid and phosphorylated tau181 (p-tau181) for tau. On the voxel and regional levels, the relationship between NII-HR and CSF markers of amyloid, tau, and neuroinflammation were examined, as well as cognition. RESULTS: This cross-sectional study included 310 participants (mean age 67.1 [±9.1] years), with 52 percent being female. Subgroups included 120 individuals (38.7%) with CSF measures of soluble triggering receptor expressed on myeloid cells 2, 80 participants (25.8%) with CSF measures of chitinase-3-like protein 1, and 110 individuals (35.5%) with longitudinal cognitive measures. The study found that cognitively normal individuals with positive CSF Aβ42/Aβ40 and p-tau181 had higher HR than healthy controls and those with positive CSF Aβ42/Aβ40 but negative p-tau181. WM tracts with elevated NII-HR in individuals with positive CSF Aβ42/Aβ40 and p-tau181 were primarily located in the posterior brain regions while those with elevated NII-HR in individuals with positive CSF Aβ42/Aβ40 and p-tau181 connected the posterior and anterior brain regions. A significant negative correlation between NII-HR and CSF Aβ42/Aβ40 was found in individuals with positive CSF Aβ42/Aβ40. Baseline NII-HR correlated with baseline cognitive composite score and predicted longitudinal cognitive decline. DISCUSSION: Those findings suggest that WM neuroinflammation undergoes alterations before the onset of AD clinical symptoms and that it interacts with amyloidosis. This highlights the potential value of noninvasive monitoring of WM neuroinflammation in AD progression and treatment.

Document Type: Article
Publication Stage: Final
Source: Scopus

Everolimus for Children With Recurrent or Progressive Low-Grade Glioma: Results From the Phase II PNOC001 Trial
(2024) Journal of Clinical Oncology, 42 (4), pp. 441-451. 

Haas-Kogan, D.A.^a , Aboian, M.S.^b , Minturn, J.E.^c d , Leary, S.E.S.^e f g , Abdelbaki, M.S.^h , Goldman, S.^i j , Elster, J.D.^k , Kraya, A.^l , Lueder, M.R.^l m , Ramakrishnan, D.^b , von Reppert, M.^b n , Liu, K.X.^a , Rokita, J.L.^l , Resnick, A.C.^l , Solomon, D.A.^o , Phillips, J.J.^o p , Prados, M.^p q , Molinaro, A.M.^p , Waszak, S.M.^r s t , Mueller, S.^p q s u

^a Department of Radiation Oncology, Brigham and Women’s Hospital, Dana-Farber Cancer Institute, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States
^b Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, CT, United States
^c Division of Oncology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
^d Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
^e Cancer and Blood Disorders Center, Seattle Children’s Hospital, Seattle, WA, United States
^f Department of Pediatrics, University of Washington, Seattle, WA, United States
^g Ben Towne Center for Childhood Cancer Research, Seattle Children’s Research Institute, Seattle, WA, United States
^h Department of Pediatrics, Washington University School of Medicine, St Louis, MO, United States
ⁱ Phoenix Children’s Hospital, Phoenix, AZ, United States
^j University of Arizona College of Medicine, Phoenix, AZ, United States
^k Division of Hematology Oncology, Department of Pediatrics, Rady Children’s Hospital, University of California, San Diego, San Diego, CA, United States
^l Division of Neurosurgery, Center for Data-Driven Discovery in Biomedicine, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
^m Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
ⁿ University of Leipzig, Leipzig, Germany
^o Department of Pathology, University of California, San Francisco, San Francisco, CA, United States
^p Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, United States
^q Department of Pediatrics, University of California, San Francisco, San Francisco, CA, United States
^r Laboratory of Computational Neuro-Oncology, Swiss Institute for Experimental Cancer Research, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
^s Department of Neurology, University of California, San Francisco, San Francisco, CA, United States
^t Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo, Oslo University Hospital, Oslo, Norway
^u Department of Pediatrics, University of Zurich, Zurich, Switzerland

Abstract
PURPOSE The PNOC001 phase II single-arm trial sought to estimate progression-free survival (PFS) associated with everolimus therapy for progressive/recurrent pediatric low-grade glioma (pLGG) on the basis of phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway activation as measured by phosphorylated-ribosomal protein S6 and to identify prognostic and predictive biomarkers. PATIENTS AND Patients, age 3-21 years, with progressive/recurrent pLGG received everolimus METHODS orally, 5 mg/m2 once daily. Frequency of driver gene alterations was compared among independent pLGG cohorts of newly diagnosed and progressive/ recurrent patients. PFS at 6 months (primary end point) and median PFS (secondary end point) were estimated for association with everolimus therapy. RESULTS Between 2012 and 2019, 65 subjects with progressive/recurrent pLGG (median age, 9.6 years; range, 3.0-19.9; 46% female) were enrolled, with a median followup of 57.5 months. The 6-month PFS was 67.4% (95% CI, 60.0 to 80.0) and median PFS was 11.1 months (95% CI, 7.6 to 19.8). Hypertriglyceridemia was the most common grade ≥3 adverse event. PI3K/AKT/mTOR pathway activation did not correlate with clinical outcomes (6-month PFS, active 68.4% v nonactive 63.3%; median PFS, active 11.2 months v nonactive 11.1 months; P 5 .80). Rare/novel KIAA1549::BRAF fusion breakpoints were most frequent in supratentorial midline pilocytic astrocytomas, in patients with progressive/recurrent disease, and correlated with poor clinical outcomes (median PFS, rare/novel KIAA1549::BRAF fusion breakpoints 6.1 months v common KIAA1549::BRAF fusion breakpoints 16.7 months; P &lt; .05). Multivariate analysis confirmed their independent risk factor status for disease progression in PNOC001 and other, independent cohorts. Additionally, rare pathogenic germline variants in homologous recombination genes were identified in 6.8% of PNOC001 patients. CONCLUSION Everolimus is a well-tolerated therapy for progressive/recurrent pLGGs. Rare/novel KIAA1549::BRAF fusion breakpoints may define biomarkers for progressive disease and should be assessed in future clinical trials. © 2024 American Society of Clinical Oncology. All rights reserved.

Funding details
National Institutes of HealthNIHU01 CA168878
National Cancer InstituteNCI5P50CA165962-09
National Institute of Neurological Disorders and StrokeNINDS1R01NS091620
Pediatric Brain Tumor FoundationPBTF
Novartis
University of California, San FranciscoUCSFP50 CA097257
Morgan Adams Foundation
William M. Wood Foundation
École Polytechnique Fédérale de LausanneEPFL
Universitetet i OsloUiO
Norges Forskningsråd187615
Helse Sør-Øst RHFsorost

Document Type: Article
Publication Stage: Final
Source: Scopus

Caudate volume is prospectively associated with irritability in toddlerhood: A preliminary investigation
(2024) Developmental Psychobiology, 66 (2), art. no. e22465, . 

Dufford, A.J.^a b , MacNeill, L.^a b , Zhang, Y.^a b , Nielsen, A.^c , Smyser, C.^c d e , Luby, J.L.^f , Rogers, C.E.^e f , Norton, E.^a b g , Wakschlag, L.^a b

^a Department of Medical Social Sciences, Northwestern University, Chicago, IL, United States
^b Institute for Innovations in Developmental Sciences, Northwestern University, Chicago, IL, United States
^c Department of Neurology, Washington University, St. Louis, MO, United States
^d Department of Radiology, Washington University, St. Louis, MO, United States
^e Department of Pediatrics, Washington University, St. Louis, MO, United States
^f Department of Psychiatry, Washington University, St. Louis, MO, United States
^g Department of Communication Sciences and Disorders, Northwestern University, Evanston, IL, United States

Abstract
Irritability refers to the dispositional tendency to respond with anger and frustration to environmental challenges or limits, with both mood and behavioral elements. The dimensional spectrum of irritability is an RDoC-informed transdiagnostic marker of psychopathology risk, specifically for the common and modifiable internalizing and externalizing disorders. Despite substantial interest in this robust developmentally based transdiagnostic indicator of psychopathology risk, its early brain markers are understudied. Here, we leveraged high-quality, longitudinal behavioral phenotyping of irritability within an imaging substudy (n = 31) of toddlers, from the When to Worry (W2W) study. We examined prospective associations between volume in three subcortical regions implicated in irritability (the caudate, putamen, and amygdala) around the infants’ first birthday (Baseline) and the dimensional spectrum of observed irritability using the Disruptive Behavior Diagnostic Observation Schedule (DB-DOS) around toddlers’ second birthday (Follow-up). Both left (q =.04, FDR corrected) and right caudate volumes (q =.04, FDR corrected) at Baseline were negatively associated with observed irritability at Follow-up. We did not find support for associations between putamen and amygdala volumes at Baseline and observed irritability at Follow-up. These findings identify early prospective neuroanatomical correlates of toddler irritability and provide preliminary support for the caudate being one important brain region for further investigation regarding the early neural correlates of irritability. © 2024 The Authors. Developmental Psychobiology published by Wiley Periodicals LLC.

Author Keywords
infant neuroimaging;  irritability;  neurodevelopment;  toddlerhood

Document Type: Article
Publication Stage: Final
Source: Scopus

Multiformity of extracellular microelectrode recordings from Aδ neurons in the dorsal root ganglia: a computational modeling study
(2024) Journal of Neurophysiology, 131 (2), pp. 261-277. 

Madden, L.R.^a b , Graham, R.D.^c , Lempka, S.F.^a b d , Bruns, T.M.^a b

^a Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, United States
^b Biointerfaces Institute, University of Michigan, Ann Arbor, MI, United States
^c Department of Anesthesiology, Washington University, St. Louis, MO, United States
^d Department of Anesthesiology, University of Michigan, Ann Arbor, MI, United States

Abstract
Microelectrodes serve as a fundamental tool in electrophysiology research throughout the nervous system, providing a means of exploring neural function with a high resolution of neural firing information. We constructed a hybrid computational model using the finite element method and multicompartment cable models to explore factors that contribute to extracellular voltage waveforms that are produced by sensory pseudounipolar neurons, specifically smaller A-type neurons, and that are recorded by microelectrodes in dorsal root ganglia. The finite element method model included a dorsal root ganglion, surrounding tissues, and a planar microelectrode array. We built a multicompartment neuron model with multiple trajectories of the glomerular initial segment found in many A-type sensory neurons. Our model replicated both the somatic intracellular voltage profile of Aδ low-threshold mechanoreceptor neurons and the unique extracellular voltage waveform shapes that are observed in experimental settings. Results from this model indicated that tortuous glomerular initial segment geometries can introduce distinct multiphasic properties into a neuron’s recorded waveform. Our model also demonstrated how recording location relative to specific microanatomical components of these neurons, and recording distance from these components, can contribute to additional changes in the multiphasic characteristics and peak-to-peak voltage amplitude of the waveform. This knowledge may provide context for research employing microelectrode recordings of pseudounipolar neurons in sensory ganglia, including functional mapping and closed-loop neuromodulation. Furthermore, our simulations gave insight into the neurophysiology of pseudounipolar neurons by demonstrating how the glomerular initial segment aids in increasing the resistance of the stem axon and mitigating rebounding somatic action potentials.NEW & NOTEWORTHY We built a computational model of sensory neurons in the dorsal root ganglia to investigate factors that influence the extracellular waveforms recorded by microelectrodes. Our model demonstrates how the unique structure of these neurons can lead to diverse and often multiphasic waveform profiles depending on the location of the recording contact relative to microanatomical neural components. Our model also provides insight into the neurophysiological function of axon glomeruli that are often present in these neurons.

Author Keywords
computational model;  dorsal root ganglia;  electrophysiology;  extracellular recording;  microelectrode

Document Type: Article
Publication Stage: Final
Source: Scopus

Basis of executive functions in fine-grained architecture of cortical and subcortical human brain networks
(2024) Cerebral Cortex, 34 (2), art. no. bhad537, . 

Assem, M.^a , Shashidhara, S.^a b , Glasser, M.F.^c d , Duncan, J.^a e

^a MRC Cognition and Brain Sciences Unit, School of Clinical Medicine, University of Cambridge, Cambridge, CB2 7EF, United Kingdom
^b Psychology Department, Ashoka University, Sonipat, 131029, India
^c Department of Radiology, Washington University in St. Louis, Saint Louis, MO 63110, United States
^d Department of Neuroscience, Washington University in St. Louis, Saint Louis, MO 63110, United States
^e Department of Experimental Psychology, University of Oxford, Oxford, OX1 3UD, United Kingdom

Abstract
Theoretical models suggest that executive functions rely on both domain-general and domain-specific processes. Supporting this view, prior brain imaging studies have revealed that executive activations converge and diverge within broadly characterized brain networks. However, the lack of precise anatomical mappings has impeded our understanding of the interplay between domain-general and domain-specific processes. To address this challenge, we used the high-resolution multimodal magnetic resonance imaging approach of the Human Connectome Project to scan participants performing 3 canonical executive tasks: n-back, rule switching, and stop signal. The results reveal that, at the individual level, different executive activations converge within 9 domain-general territories distributed in frontal, parietal, and temporal cortices. Each task exhibits a unique topography characterized by finely detailed activation gradients within domain-general territory shifted toward adjacent resting-state networks; n-back activations shift toward the default mode, rule switching toward dorsal attention, and stop signal toward cingulo-opercular networks. Importantly, the strongest activations arise at multimodal neurobiological definitions of network borders. Matching results are seen in circumscribed regions of the caudate nucleus, thalamus, and cerebellum. The shifting peaks of local gradients at the intersection of task-specific networks provide a novel mechanistic insight into how partially-specialized networks interact with neighboring domain-general territories to generate distinct executive functions. © The Author(s) 2024.

Author Keywords
cognitive control;  executive functions;  fMRI;  multiple demand

Funding details
National Institutes of HealthNIHR01MH060974
Medical Research CouncilMRCMC_UU_00030/7
Cambridge Trust
Gates Cambridge Trust

Document Type: Article
Publication Stage: Final
Source: Scopus

Deep learning models to predict primary open-angle glaucoma
(2024) Stat, 13 (1), art. no. e649, . 

Zhou, R.^a , Philip Miller, J.^a , Gordon, M.^b , Kass, M.^b , Lin, M.^c , Peng, Y.^c , Li, F.^d e , Feng, J.^f , Liu, L.^a

^a Division of Biostatistics, Washington University in St. Louis, School of Medicine, St. Louis, MO, United States
^b Department of Ophthalmology and Visual Sciences, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
^c Department of Population Health Sciences, Weill Cornell Medicine, New York, NY, United States
^d Institute for Informatics (I2), Washington University in St. Louis School of Medicine, St. Louis, MO, United States
^e Department of Pediatrics, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
^f Department of Computer Science and Engineering, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Glaucoma is a major cause of blindness and vision impairment worldwide, and visual field (VF) tests are essential for monitoring the conversion of glaucoma. While previous studies have primarily focused on using VF data at a single time point for glaucoma prediction, there has been limited exploration of longitudinal trajectories. Additionally, many deep learning techniques treat the time-to-glaucoma prediction as a binary classification problem (glaucoma Yes/No), resulting in the misclassification of some censored subjects into the nonglaucoma category and decreased power. To tackle these challenges, we propose and implement several deep-learning approaches that naturally incorporate temporal and spatial information from longitudinal VF data to predict time-to-glaucoma. When evaluated on the Ocular Hypertension Treatment Study (OHTS) dataset, our proposed convolutional neural network (CNN)-long short-term memory (LSTM) emerged as the top-performing model among all those examined. The implementation code can be found online (https://github.com/rivenzhou/VF_prediction). © 2024 John Wiley & Sons Ltd.

Author Keywords
convolutional neural network;  dynamic prediction;  landmark analysis;  long short-term memory

Funding details
National Institutes of HealthNIHR21 AG068955, R21 EY031884, R21 EY033518, UL1 TR002345

Document Type: Article
Publication Stage: Final
Source: Scopus

Examining sense of purpose and conscientiousness as unique correlates of health: A bifactor examination
(2024) Journal of Health Psychology, . 

Hill, P.L.^a , Olaru, G.^b , Allemand, M.^c

^a Washington University in St. Louis, United States
^b Tilburg University, Netherlands
^c University of Zurich, Switzerland

Abstract
Conscientiousness and sense of purpose consistently predict health, wellbeing, and health behavior. However, it remains an open question whether they are unique or overlapping predictors of health and wellbeing. The current study considered this question using the MOSAiCH study, a nationally representative sample of 2305 Swiss adults (M: 52.33 years old; SD = 17.36). Participants reported on sense of purpose and conscientiousness, in addition to multiple health, wellbeing, and health behavior indicators (e.g. dietary practices, activity engagement, health conditions, psychological concerns, and doctor visits). Results found conscientiousness and sense of purpose were moderately associated with multiple health, wellbeing, and health behavior indicators. Bifactor modeling was employed to test the incremental validity of conscientiousness and sense of purpose, when accounting for their shared variance. The specific factor for purpose predicted outcomes even when accounting for conscientiousness. However, conscientiousness had little incremental validity over the general factor. © The Author(s) 2024.

Author Keywords
conscientiousness;  health behavior;  self-reported health;  sense of purpose;  well-being

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

Identification of direct connections between the dura and the brain
(2024) Nature, . 

Smyth, L.C.D.^a b , Xu, D.^a b , Okar, S.V.^c , Dykstra, T.^a b , Rustenhoven, J.^a b d e , Papadopoulos, Z.^a b f , Bhasiin, K.^a b , Kim, M.W.^a b g , Drieu, A.^a b , Mamuladze, T.^a b g , Blackburn, S.^a b , Gu, X.^a b , Gaitán, M.I.^c , Nair, G.^h , Storck, S.E.^a b , Du, S.^a b g , White, M.A.ⁱ , Bayguinov, P.^j k , Smirnov, I.^a b , Dikranian, K.^k , Reich, D.S.^c , Kipnis, J.^a b f g

^a Brain Immunology and Glia (BIG) Center, Washington University in St Louis, St Louis, MO, United States
^b Department of Pathology and Immunology, School of Medicine, Washington University in St Louis, St Louis, MO, United States
^c Translational Neuroradiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States
^d Department of Pharmacology and Clinical Pharmacology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
^e Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
^f Neuroscience Graduate Program, School of Medicine, Washington University in St Louis, St Louis, MO, United States
^g Immunology Graduate Program, School of Medicine, Washington University in St Louis, St Louis, MO, United States
^h Quantitative MRI Core Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States
ⁱ Department of Genetics, Washington University School of Medicine, Washington University in St Louis, St Louis, MO, United States
^j Washington University Center for Cellular Imaging, Washington University School of Medicine, Washington University in St Louis, St Louis, MO, United States
^k Department of Neuroscience, Washington University School of Medicine, Washington University in St Louis, St Louis, MO, United States

Abstract
The arachnoid barrier delineates the border between the central nervous system and dura mater. Although the arachnoid barrier creates a partition, communication between the central nervous system and the dura mater is crucial for waste clearance and immune surveillance1,2. How the arachnoid barrier balances separation and communication is poorly understood. Here, using transcriptomic data, we developed transgenic mice to examine specific anatomical structures that function as routes across the arachnoid barrier. Bridging veins create discontinuities where they cross the arachnoid barrier, forming structures that we termed arachnoid cuff exit (ACE) points. The openings that ACE points create allow the exchange of fluids and molecules between the subarachnoid space and the dura, enabling the drainage of cerebrospinal fluid and limited entry of molecules from the dura to the subarachnoid space. In healthy human volunteers, magnetic resonance imaging tracers transit along bridging veins in a similar manner to access the subarachnoid space. Notably, in neuroinflammatory conditions such as experimental autoimmune encephalomyelitis, ACE points also enable cellular trafficking, representing a route for immune cells to directly enter the subarachnoid space from the dura mater. Collectively, our results indicate that ACE points are a critical part of the anatomy of neuroimmune communication in both mice and humans that link the central nervous system with the dura and its immunological diversity and waste clearance systems. © The Author(s), under exclusive licence to Springer Nature Limited 2024.

Funding details
National Institutes of HealthNIH
National Institute on AgingNIAAG034113, AG078106
National Institute of Neurological Disorders and StrokeNINDSNS003119
National Multiple Sclerosis SocietyNMSSFG-2208-40289
Cure Alzheimer’s FundCAF

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

The impact of COVID-19 changes and disruptions on generalized anxiety disorder among young adults living with HIV (YLHIV) in Uganda
(2024) Journal of Health Psychology, . 

Girma, A.Z.^a , Brathwaite, R.^a , Karamagi, Y.^b , Nakabuye, F.^c , Nakasujja, N.^d , Byansi, W.^e , Nabunya, P.^a , Sensoy Bahar, O.^a , Ssewamala, F.M.^a

^a Washington University, St. Louis, United States
^b Mildmay Uganda, Uganda
^c International Center for Child Health and Development, Uganda
^d Makerere University, Uganda
^e Boston College School of Social Work, United States

Abstract
In the context of the COVID-19 pandemic, we investigated associations between specific COVID-19-related changes and its impact on generalized anxiety disorder (GAD) levels among vulnerable young adults living with HIV (YALHIV) in a low-resource setting in Southern Uganda. This research utilized data from 500 YALHIV aged 19 to 25 from the Suubi+Adherence-R2 COVID-19 Supplement study. Disruptions were assessed using an 8-item modified Coronavirus Impact Scale, while anxiety was measured with the GAD-7 questionnaire. Hierarchical logistic regression analysis and multivariate linear regression were employed, guided by the Social Determinants of Health framework. Key findings highlighted changes in routines, family income, stress from the pandemic, changes in family stress and discord, and reduced access to mental health services heightened levels of probable GAD for YALHIV during the pandemic. Additionally, female young adults showed greater levels than males. These results underscore the urgency to develop tailored support mechanisms for YALHIV, especially during challenging and unprecedented times. © The Author(s) 2024.

Author Keywords
adolescence;  anxiety;  HIV;  mental illness;  stress

Funding details
National Institutes of HealthNIH
Fogarty International CenterFIC
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHDD43TW011541, R01HD074949

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

Associations of Circadian Rest-Activity Rhythms With Affect and Cognition in Community-Dwelling Stroke Survivors: An Ambulatory Assessment Study
(2024) Neurorehabilitation and Neural Repair, . 

Lau, S.C.L.^a b c , Connor, L.T.^a b , Skidmore, E.R.^c

^a Program in Occupational Therapy, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Occupational Therapy, School of Health and Rehabilitation, University of Pittsburgh, Pittsburgh, PA, United States

Abstract
Background: Rest-activity rhythm (RAR) is a modifiable behavioral factor associated with affect and cognition. Identifying RAR characteristics associated with affect and cognition among stroke survivors provides insight into preventing poststroke affective and cognitive impairment. Objective: To examine the associations of RAR characteristics with affect and cognition among community-dwelling stroke survivors. Methods: Forty participants with mild stroke (mean age = 52.8; 42.5% female; 55% White) reported their affect and cognitive complaints using ecological momentary assessment and wore an accelerometer for 7 consecutive days and completed the National Institutes of Health Toolbox Cognition Battery. RAR characteristics were extracted using parametric and non-parametric approaches. Multivariable linear regressions were used to identify RAR characteristics associated with affect and cognition. Results: Later onset of rest (B = 0.45; P =.008) and activity (B = 0.36; P =.041) were positively associated with depressed affect. These associations were reversed for cheerful effect (rest onset: B = −0.42; P =.017; activity onset: B = −0.39; P =.033). Cheerful affect was also positively associated with relative amplitude (ie, distinctions in activity levels between rest and activity; B =.39; P =.030). Intra-daily variability (ie, RAR fragmentation; B = 0.35; P =.042) and later onset of activity (B =.36; P =.048) were positively associated with cognitive complaints. Less erratic RAR was positively associated with fluid cognition (B = 0.29; P =.036); RAR fragmentation was positively associated with crystallized cognition (B = 0.39; P =.015). Conclusions: We identified RAR correlates of affect and cognition among stroke survivors, highlighting the value of managing RAR and sleep in stroke rehabilitation. Future studies should test whether advancing the onset of rest and activity, promoting a regular active lifestyle, and improving rest and sleep in the nighttime protect stroke survivors from affective and cognitive impairment. © The Author(s) 2024.

Author Keywords
accelerometry;  affect;  circadian rhythm;  cognition;  ecological momentary assessment;  stroke

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

Examining associations between genetic and neural risk for externalizing behaviors in adolescence and early adulthood
(2024) Psychological Medicine, 54 (2), pp. 267-277. 

Brislin, S.J.^a , Salvatore, J.E.^a , Meyers, J.M.^b , Kamarajan, C.^b , Plawecki, M.H.^c , Edenberg, H.J.^d , Kuperman, S.^e , Tischfield, J.^a , Hesselbrock, V.^f , Anokhin, A.P.^g , Chorlian, D.B.^b , Schuckit, M.A.^h , Nurnberger, J.I., Jr^c , Bauer, L.^f , Pandey, G.^b , Pandey, A.K.^b , Kramer, J.R.^e , Chan, G.^e f , Porjesz, B.^b , Dick, D.M.^a , COGA Collaboratorsⁱ

^a Department of Psychiatry, Robert Wood Johnson Medical School, Rutgers UniversityNJ, United States
^b Department of Psychiatry and Behavioral Sciences, State University of New York Downstate Medical Center, New York, NY, USA
^c Department of Psychiatry, Indiana University, Bloomington, IN, United States
^d Department of Biochemistry and Molecular Biology, Indiana University, Bloomington, IN, United States
^e Department of Psychiatry, University of Iowa, Iowa City, IA, United States
^f Department of Psychiatry, University of Connecticut School of Medicine, Farmington, CT, United States
^g Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
^h Department of Psychiatry, University of California San Diego Medical School, San Diego, CA, United States

Abstract
BACKGROUND: Researchers have identified genetic and neural risk factors for externalizing behaviors. However, it has not yet been determined if genetic liability is conferred in part through associations with more proximal neurophysiological risk markers. METHODS: Participants from the Collaborative Study on the Genetics of Alcoholism, a large, family-based study of alcohol use disorders were genotyped and polygenic scores for externalizing (EXT PGS) were calculated. Associations with target P3 amplitude from a visual oddball task (P3) and broad endorsement of externalizing behaviors (indexed via self-report of alcohol and cannabis use, and antisocial behavior) were assessed in participants of European (EA; N = 2851) and African ancestry (AA; N = 1402). Analyses were also stratified by age (adolescents, age 12-17 and young adults, age 18-32). RESULTS: The EXT PGS was significantly associated with higher levels of externalizing behaviors among EA adolescents and young adults as well as AA young adults. P3 was inversely associated with externalizing behaviors among EA young adults. EXT PGS was not significantly associated with P3 amplitude and therefore, there was no evidence that P3 amplitude indirectly accounted for the association between EXT PGS and externalizing behaviors. CONCLUSIONS: Both the EXT PGS and P3 amplitude were significantly associated with externalizing behaviors among EA young adults. However, these associations with externalizing behaviors appear to be independent of each other, suggesting that they may index different facets of externalizing.

Author Keywords
Externalizing;  neurophysiology;  P3 amplitude;  polygenic score

Document Type: Article
Publication Stage: Final
Source: Scopus

People can reliably detect action changes and goal changes during naturalistic perception
(2024) Memory and Cognition, . 

Su, X.^a , Swallow, K.M.^b

^a Department of Psychological and Brain Sciences, Washington University in Saint Louis, Saint Louis, MO, United States
^b Department of Psychology and Cognitive Science Program, Cornell University, 211 Uris Hall, Ithaca, NY 14853, United States

Abstract
As a part of ongoing perception, the human cognitive system segments others’ activities into discrete episodes (event segmentation). Although prior research has shown that this process is likely related to changes in an actor’s actions and goals, it has not yet been determined whether untrained observers can reliably identify action and goal changes as naturalistic activities unfold, or whether the changes they identify are tied to visual features of the activity (e.g., the beginnings and ends of object interactions). This study addressed these questions by examining untrained participants’ identification of action changes, goal changes, and event boundaries while watching videos of everyday activities that were presented in both first-person and third-person perspectives. We found that untrained observers can identify goal changes and action changes consistently, and these changes are not explained by visual change and the onsets or offsets of contact with objects. Moreover, the action and goal changes identified by untrained observers were associated with event boundaries, even after accounting for objective visual features of the videos. These findings suggest that people can identify action and goal changes consistently and with high agreement, that they do so by using sensory information flexibly, and that the action and goal changes they identify may contribute to event segmentation. © 2024, The Psychonomic Society, Inc.

Author Keywords
Action perception;  Event cognition;  Event segmentation;  Goal processing;  Perspective

Funding details
College of Arts and Sciences, Cornell UniversityA&S

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

Prenatal substance exposure and child health: Understanding the role of environmental factors, genetics, and brain development
(2024) PNAS Nexus, 3 (1), art. no. pgae003, . 

Gu, Z.^a b , Barch, D.M.^c d e , Luo, Q.^b f

^a National Clinical Research Center for Aging and Medicine at Huashan Hospital, State Key Laboratory of Medical Neurobiology and Moe Frontiers Center for Brain Science, Institutes of Brain Science and Human Phenome Institute, Fudan University, Shanghai, 200032, China
^b Moe Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, 200433, China
^c Department of Psychological and Brain Sciences, Washington University in St Louis, St Louis, MO 63130, United States
^d Department of Psychiatry, Washington University in St Louis, St Louis, MO 63110, United States
^e Department of Radiology, Washington University in St Louis, St Louis, MO 63110, United States
^f Shanghai Research Center of Acupuncture and Meridian, Shanghai, 200433, China

Abstract
Prenatal substance exposure (PSE) has been linked to adverse health outcomes, but its interactions with environmental and genetic factors remain unclear. Using data from the adolescent brain cognitive development cohort (n = 9,838; baseline age: 9.92 ± 0.62 years), we tested for the robust associations of PSE-caffeine/alcohol/tobacco/marijuana with children’s health, cognition, and brain metrics after controlling for the environmental and genetic contexts. The environmental context involved birth, familial, and societal risk factors, while the genetic context included family histories and polygenic risk scores (PRSs) of mental disorders. In this sample, PSE-caffeine was observed in 59.8%, PSE-alcohol in 25.7%, PSE-tobacco in 13.2%, and PSE-marijuana in 5.6% of children. PSE-tobacco/marijuana was associated with higher environmental risks, PSE-alcohol was associated with lower familial risks, and all PSEs were associated with higher genetic risks. Controlling for these contexts reduced the number of significant health associations by 100, 91, 84, and 18% for PSE-tobacco/marijuana/caffeine/alcohol. Compared to the baseline, PSE-alcohol had the most health associations that were persistent over a 2-year period from preadolescence to adolescence, including associations with more sleep and mental health problems, improved cognitive functions, and larger brain volumes. These persistent associations with mental health problems and crystallized cognition were mediated by the surface areas of the frontal and the parietal cortices, respectively. Lower risk scores of the familial contexts attenuated associations between PSE-alcohol/marijuana and mental health problems. Higher PRS for substance use disorders enhanced late-onset associations of PSE-marijuana with externalizing problems. Results support the “health in context”concept, emphasizing modifiable factors mitigating adverse PSE effects. © 2024 The Author(s). Published by Oxford University Press on behalf of National Academy of Sciences.

Author Keywords
adolescence;  brain development;  health in context;  prenatal substance exposure

Funding details
National Institutes of HealthNIHU01DA041120
University of SydneyUSYD
National Natural Science Foundation of ChinaNSFC71834002, 82272079
Fudan UniversityU01DA041022, U01DA041028, U01DA041048, U01DA041089, U01DA041106, U01DA041117, U01DA041134, U01DA041148, U01DA041156, U01DA041174, U24DA041123, U24DA041147
Science and Technology Commission of Shanghai MunicipalitySTCSM2018SHZDZX01, 2021SHZDZX0103
National Key Research and Development Program of ChinaNKRDPC2023YFE0109700
Program of Shanghai Academic Research Leader23XD1423400

Document Type: Article
Publication Stage: Final
Source: Scopus

Elevating Voices, Addressing Depression, Toxic Stress, and Equity Through Group Prenatal Care: A Pilot Study
(2024) Health Equity, 8 (1), pp. 87-95. 

Lenze, S.N.^a , McKay-Gist, K.^c , Paul, R.^b , Tepe, M.^d , Mathews, K.^e , Kornfield, S.^f , Phillips, C.^c , Smith, R.^c , Stoermer, A.^c , Carter, E.B.^b

^a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO, United States
^c St. Louis Integrated Health Network, St. Louis, MO, United States
^d Affinia Healthcare, St. Louis, MO, United States
^e SSM Health St. Mary’s and Department of Obstetrics, Gynecology, and Women’s Health, St. Louis University, St. Louis, MO, United States
^f Center for Women’s Behavioral Wellness, Department of Psychiatry, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA, United States

Abstract
Introduction: Elevating Voices, Addressing Depression, Toxic Stress and Equity (EleVATE) is a group prenatal care (GC) model designed to improve pregnancy outcomes and promote health equity for Black birthing people. This article outlines the foundational community-engaged process to develop EleVATE GC and pilot study results. Methods: We used community-based participatory research principles and the Ferguson Commission Report to guide creation of EleVATE GC. The intervention, designed by and for Black birthing people, centers trauma-informed care, antiracism, and integrates behavioral health strategies into group prenatal care to address unmet mental health needs. Using a convenience sample of patients seeking care at one of three safety-net health care sites, we compared preterm birth, small for gestational age, depression scores, and other pregnancy outcomes between patients in individual care (IC), CenteringPregnancyTM (CP), and EleVATE GC. Results: Forty-eight patients enrolled in the study (n = 11 IC; n = 14 CP; n = 23 EleVATE GC) and 86% self-identified as Black. Patients participating in group prenatal care (EleVATE GC or CP) were significantly less likely to experience a preterm birth < 34 weeks. Rates of small for gestational age, preterm birth < 37 weeks, depression scores, and other pregnancy outcomes were similar across groups. Participants in CP and EleVATE GC were more likely to attend their postpartum visit and breastfeed at hospital discharge than those in IC. Discussion: Our findings model a systematic approach to design a feasible, patient-centered, community-based, trauma-informed, antiracist intervention. Further study is needed to determine whether EleVATE GC improves perinatal outcomes and promotes health equity. © Shannon N. Lenze et al., 2024.

Author Keywords
group prenatal care;  health equity;  mental health;  patient-centered outcomes research

Funding details
National Institutes of HealthNIH
Robert Wood Johnson FoundationRWJF74250
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHDHD095075-03

Document Type: Article
Publication Stage: Final
Source: Scopus

Regulation of headache response and transcriptomic network by the trigeminal ganglion clock
(2024) Headache, . 

Han, C.^a , Lim, J.Y.^a , Koike, N.^b , Kim, S.Y.^a , Ono, K.^a , Tran, C.K.^a , Mangutov, E.^c , Kim, E.^a , Zhang, Y.^c , Li, L.^d , Pradhan, A.A.^c , Yagita, K.^b , Chen, Z.^a , Yoo, S.-H.^a , Burish, M.J.^e

^a Department of Biochemistry and Molecular Biology, UTHealth Houston, Houston, TX, United States
^b Department of Physiology and Systems Bioscience, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
^c Center for Clinical Pharmacology, Department of Anesthesiology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^d Division of Molecular and Translational Biomedicine, Department of Anesthesiology and Perioperative Medicine, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
^e Department of Neurosurgery, UTHealth Houston, Houston, TX, United States

Abstract
Objective: To characterize the circadian features of the trigeminal ganglion in a mouse model of headache. Background: Several headache disorders, such as migraine and cluster headache, are known to exhibit distinct circadian rhythms of attacks. The circadian basis for these rhythmic pain responses, however, remains poorly understood. Methods: We examined trigeminal ganglion ex vivo and single-cell cultures from Per2::LucSV reporter mice and performed immunohistochemistry. Circadian behavior and transcriptomics were investigated using a novel combination of trigeminovascular and circadian models: a nitroglycerin mouse headache model with mechanical thresholds measured every 6 h, and trigeminal ganglion RNA sequencing measured every 4 h for 24 h. Finally, we performed pharmacogenomic analysis of gene targets for migraine, cluster headache, and trigeminal neuralgia treatments as well as trigeminal ganglion neuropeptides; this information was cross-referenced with our cycling genes from RNA sequencing data to identify potential targets for chronotherapy. Results: The trigeminal ganglion demonstrates strong circadian rhythms in both ex vivo and single-cell cultures, with core circadian proteins found in both neuronal and non-neuronal cells. Using our novel behavioral model, we showed that nitroglycerin-treated mice display circadian rhythms of pain sensitivity which were abolished in arrhythmic Per1/2 double knockout mice. Furthermore, RNA-sequencing analysis of the trigeminal ganglion revealed 466 genes that displayed circadian oscillations in the control group, including core clock genes and clock-regulated pain neurotransmitters. In the nitroglycerin group, we observed a profound circadian reprogramming of gene expression, as 331 of circadian genes in the control group lost rhythm and another 584 genes gained rhythm. Finally, pharmacogenetics analysis identified 10 genes in our trigeminal ganglion circadian transcriptome that encode target proteins of current medications used to treat migraine, cluster headache, or trigeminal neuralgia. Conclusion: Our study unveiled robust circadian rhythms in the trigeminal ganglion at the behavioral, transcriptomic, and pharmacogenetic levels. These results support a fundamental role of the clock in pain pathophysiology. Plain Language Summary: Several headache diseases, such as migraine and cluster headache, have headaches that occur at the same time each day. We learned that the trigeminal ganglion, an important pain structure in several headache diseases, has a 24-hour cycle that might be related to this daily cycle of headaches. Our genetic analysis suggests that some medications may be more effective in treating migraine and cluster headache when taken at specific times of the day. © 2024 American Headache Society.

Author Keywords
circadian transcriptome;  clock-controlled genes;  HTR2A;  OPRD1;  rhythmically expressed genes;  von Frey

Funding details
National Institutes of HealthNIH
National Institute on AgingNIAR01AG065984, RF1AG061901
National Institute of General Medical SciencesNIGMSR01GM114424, R35GM145232‐01
Welch FoundationAU‐2127‐20220331

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

Performance of the Lumipulse plasma Aβ42/40 and pTau181 immunoassays in the detection of amyloid pathology
(2024) Alzheimer’s and Dementia: Diagnosis, Assessment and Disease Monitoring, 16 (1), art. no. e12545, . 

Figdore, D.J.^a , Wiste, H.J.^b , Bornhorst, J.A.^a , Bateman, R.J.^c , Li, Y.^c , Graff-Radford, J.^d , Knopman, D.S.^d , Vemuri, P.^e , Lowe, V.J.^e , Jr, C.R.J.^e , Petersen, R.C.^d , Algeciras-Schimnich, A.^a

^a Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
^b Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, United States
^c Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Neurology, Mayo Clinic, Rochester, MN, United States
^e Department of Radiology, Mayo Clinic, Rochester, MN, United States

Abstract
INTRODUCTION: This study evaluated the performance of the Lumipulse plasma beta-amyloid (Aβ) 42/40 and pTau181 compared to other assays to detect an abnormal amyloid-positron emission tomography (PET). METHODS: Plasma samples from cognitively unimpaired (N = 179) and MCI/AD dementia (N = 36) individuals were retrospectively evaluated. Plasma Aβ42/40 and pTau181 were measured using the Lumipulse and Simoa immunoassays. An immunoprecipitation mass spectrometry (IP-MS) assay for plasma Aβ42/40 was also evaluated. Amyloid-PET status was the outcome measure. RESULTS: Lumipulse and IP-MS Aβ42/40 exhibited the highest diagnostic accuracy for detecting an abnormal amyloid-PET (areas under the curve [AUCs] of 0.81 and 0.84, respectively). The Lumipulse and Simoa pTau181 assays exhibited lower performance (AUCs of 0.74 and 0.72, respectively). The Simoa Aβ42/40 assay demonstrated the lowest diagnostic accuracy (AUC 0.57). Combining Aβ42/40 and pTau181 did not significantly improve performance over Aβ42/40 alone for Lumipulse (AUC 0.83) or over pTau181 alone for Simoa (AUC 0.71). DISCUSSION: The Lumipulse Aβ42/40 assay showed similar performance to the IP-MS Aβ42/40 assay for detection of an abnormal amyloid-PET; and both assays performed better than the two p-tau181 immunoassays. The Simoa Aβ42/Aβ40 assay was the least accurate at predicting an abnormal amyloid-PET status. Highlights: Lumipulse plasma Aβ42/Aβ40 AUC for abnormal amyloid-PET detection was 0.81. This performance was comparable to previously reported IP-MS and higher than Simoa. Performance of Alzheimer’s disease blood biomarkers varies between assays. © 2024 The Authors. Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.

Author Keywords
Alzheimer’s disease blood biomarkers;  amyloid beta;  amyloid-PET;  Aβ42/Aβ40;  plasma pTau;  pTau181

Funding details
National Institutes of HealthNIH
National Institute on AgingNIAR01 AG041851, R01 AG056366, R37 AG011378, RF1 AG061900, RF1 AG069052, U01 AG006786
National Cancer InstituteNCI
Mayo Clinic
Alzheimer’s Disease Research Center, Emory UniversityADRC
Novartis Pharmaceuticals CorporationNPC
GHR FoundationGHR
Bayer Schering

Document Type: Article
Publication Stage: Final
Source: Scopus

Feasibility of a telehealth-based contingency management intervention for alcohol use disorders using the phosphatidylethanol (PEth) 16:0/18:1 alcohol biomarker: a pilot randomized trial
(2024) American Journal of Drug and Alcohol Abuse, . 

Jett, J.D.^a , Beck, R.^a , Tyutyunnyk, D.^a , Sanchez, J.^b , Weeks, D.L.^a , Javors, M.A.^b , Hill-Kapturczak, N.^b , Lopez-Cruzan, M.^b , Kriegel, L.^a , Ginsburg, B.C.^b , Cabassa, L.^c , McDonell, M.G.^a

^a PRISM Collaborative, Department of Community and Behavioral Health, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA, United States
^b Department of Psychiatry and Behavioral Sciences, University of Texas Health San Antonio, San Antonio, TX, United States
^c Brown School, Washington University St. Louis, St Louis, MO, United States

Abstract
Background: Phosphatidylethanol (PEth) is a blood-based biomarker for alcohol consumption that can be self-collected and has high sensitivity, specificity, and a longer detection window compared to other alcohol biomarkers. Objectives: We evaluated the feasibility and acceptability of a telehealth-based contingency management (CM) intervention for alcohol use disorder (AUD) using the blood-based biomarker PEth to assess alcohol consumption. Methods: Sixteen adults (7 female, 9 male) with AUD were randomized to Control or CM conditions. Control participants received reinforcers regardless of their PEth levels. CM participants received reinforcers for week-to-week decreases in PEth (Phase 1) or maintenance of PEth consistent with abstinence (<20 ng/mL, Phase 2). Blood samples were self-collected using the TASSO-M20 device. Acceptability was assessed by retention in weeks. Satisfaction was assessed with the Client Satisfaction Questionnaire (CSQ-8) and qualitative interviews. The primary efficacy outcome was PEth-defined abstinence. Secondary outcomes included the proportion of visits with PEth-defined heavy alcohol consumption, negative urine ethyl glucuronide results, and self-reported alcohol use. Results: Retention averaged 18.6 ± 8.8 weeks for CM participants. CM participants reported high levels of satisfaction (CSQ-8, Mean = 30.3 ± 1.5). Interview themes included intervention positives, such as staff support, quality of life improvement, and accountability. 72% of PEth samples from CM participants were consistent with abstinence versus 34% for Control participants (OR = 5.0, p = 0.007). PEth-defined heavy alcohol consumption was detected in 28% of CM samples and 52% of Control samples (OR = 0.36, p = 0.159). CM participants averaged 1.9 ± 1.7 drinks/day versus 4.2 ± 6.3 for Control participants (p = 0.304). Conclusion: Results support the acceptability and satisfaction of a telehealth PEth-based CM intervention, though a larger study is needed to assess its efficacy [NCT04038021]. © 2024 Taylor & Francis Group, LLC.

Author Keywords
alcohol use disorder (AUD);  Contingency management (CM);  phosphatidylethanol (PEth);  TASSO-M20;  telehealth

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

Naturalistic assessment of reaction time variability in older adults at risk for Alzheimer’s disease
(2024) Journal of the International Neuropsychological Society, . 

Welhaf, M.S.^a , Wilks, H.^a , Aschenbrenner, A.J.^b , Balota, D.A.^a , Schindler, S.E.^b , Benzinger, T.L.S.^c , Gordon, B.A.^a c , Cruchaga, C.^d , Xiong, C.^e , Morris, J.C.^b , Hassenstab, J.^a b

^a Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Neurology, Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University, School of Medicine, St. Louis, MO, United States
^c Department of Radiology, Washington University, School of Medicine, St. Louis, MO, United States
^d Department of Psychiatry, Washington University, School of Medicine, St. Louis, MO, United States
^e Division of Biostatistics, Washington University, School of Medicine, St. Louis, MO, United States

Abstract
Objective: Maintaining attention underlies many aspects of cognition and becomes compromised early in neurodegenerative diseases like Alzheimer’s disease (AD). The consistency of maintaining attention can be measured with reaction time (RT) variability. Previous work has focused on measuring such fluctuations during in-clinic testing, but recent developments in remote, smartphone-based cognitive assessments can allow one to test if these fluctuations in attention are evident in naturalistic settings and if they are sensitive to traditional clinical and cognitive markers of AD. Method: Three hundred and seventy older adults (aged 75.8 +/- 5.8 years) completed a week of remote daily testing on the Ambulatory Research in Cognition (ARC) smartphone platform and also completed clinical, genetic, and conventional in-clinic cognitive assessments. RT variability was assessed in a brief (20-40 seconds) processing speed task using two different measures of variability, the Coefficient of Variation (CoV) and the Root Mean Squared Successive Difference (RMSSD) of RTs on correct trials. Results: Symptomatic participants showed greater variability compared to cognitively normal participants. When restricted to cognitively normal participants, APOE ϵ4 carriers exhibited greater variability than noncarriers. Both CoV and RMSSD showed significant, and similar, correlations with several in-clinic cognitive composites. Finally, both RT variability measures significantly mediated the relationship between APOE ϵ4 status and several in-clinic cognition composites. Conclusions: Attentional fluctuations over 20-40 seconds assessed in daily life, are sensitive to clinical status and genetic risk for AD. RT variability appears to be an important predictor of cognitive deficits during the preclinical disease stage. © The Author(s), 2024. Published by Cambridge University Press on behalf of International Neuropsychological Society.

Author Keywords
apolipoprotein e4;  attention consistency;  digital biomarkers;  mobile testing;  preclinical alzheimer disease

Funding details
National Institute on AgingNIAAG000030-47, K01AG071847, P01AG003991, P01AG026276, P30AG066444, R01AG057840

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